Treatment of cardiopulmonary disorders

Abstract

The present invention relates to the use of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl} fluorescein of formula (I) in the inhalation treatment of cardiopulmonary and pulmonary 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 due to idiopathic interstitial pneumonia (PH-IIP). (5S)-{[2-(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 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 in the form of 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 in the form of monohydrate I of formula (IM-II) Use 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 hydrate II, comprising 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}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid 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 one of its salts or solvates or hydrates, preferably in the form of monohydrate I of formula (IMI) or in the form of monohydrate II of formula (IM-II).The present invention relates to a use characterized in that an inhalation dosage form comprising 8-tetrahydroquinoline-2-carboxylic acid is administered to a patient in need thereof once or twice a day 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, the inhalation dosage form preferably comprising a combination of an active ingredient with a pharma- ceutical suitable excipient or carrier, preferably the active ingredient and the pharma-ceutical suitable excipient being filled into a hard capsule.

Description

[Technical field]

[0001] The present invention relates to the use of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl phosphate esters of formula (I) in the inhalation treatment of cardiopulmonary and pulmonary 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 due to idiopathic interstitial pneumonia (PH-IIP). (5S)-{[2-(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 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 in the form of 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 in the form of monohydrate I of formula (IM-II) Use 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 II, comprising 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}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid 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 one of its salts or solvates or hydrates, preferably in the form of monohydrate I of formula (IMI) or in the form of monohydrate II of formula (IM-II).The present invention relates to a use in which an inhalation dosage form comprising 8-tetrahydroquinoline-2-carboxylic acid is administered to a patient in need thereof once or twice daily 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, the inhalation dosage form preferably comprising a combination of the active ingredient with a pharma- ceutical suitable excipient or carrier, preferably the active ingredient and the pharma-ceutical suitable excipient being filled into a hard capsule.

[0002] The present invention further relates to a medicament for use in 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 due to idiopathic interstitial pneumonia (PH-IIP), comprising a medicament comprising (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-carboxyphenyl)ethyl]phenyl}-2-(4-carboxyphenyl)ethyl]phenyl ester 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 one of its salts or solvates or hydrates, preferably in the form of monohydrate I of formula (IMI) and (5S)-{[2-(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) 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 in the form of monohydrate II of formula (IM-II) and optionally a pharma- ceutical suitable excipient or carrier, preferably in the form of a dry powder formulation, optionally filled into a cavity, e.g. a hard capsule, wherein the medicament contains 240 to 4000 μg, preferably 480 to 2000 μg of the active ingredient, to a patient in need thereof, via inhalation, for a period of 2 or more consecutive 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 a day or twice a day from the start of the treatment and throughout the entire course of the disease.

[0003] The present invention further relates to a compound according to the present invention, comprising (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chlorophenyl)ethyl]phenyl ester of formula (I) for preparing an inhalation medicament in the form of an inhalation dosage form, preferably as a dry powder formulation, 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 due to idiopathic interstitial pneumonia (PH-IIP). (5S)-{[2-(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 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 of formula (IMI) Use of the monohydrate I 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 which an inhalation dosage form comprises the active ingredient and a pharma- ceutical suitable excipient or carrier, preferably the active ingredient and the pharma- ceutical suitable excipient are optionally filled in a hard capsule, and the medicament is administered continuously to a patient in need thereof. The medicament is administered once or twice daily for two or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular from the start of the treatment throughout the entire course of the disease, and the medicament comprises 240-4000 μg, preferably 480-4000 μg, preferably 480-2000 μg of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,The present invention relates to a use comprising 8-tetrahydroquinoline-2-carboxylic acid, 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 II of formula (IM-II).

[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). TIFF2025501309000001.tif83165

[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 notably the pseudopolymorphic form monohydrate I (IMI) or pseudopolymorphic form monohydrate II (IM-II) corresponding to the formulae (IMI), (IM-II). TIFF2025501309000002.tif83165

[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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), more particularly it relates to a method of treating 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 PH-COPD and PH-IIP. [Background technology]

[0007] 2. Background of the Invention Pulmonary hypertension (PH) is a progressive lung disorder that, if untreated, leads to death within a few years after diagnosis. Pulmonary hypertension is defined by an elevation in mean pulmonary artery pressure (mPAP) (normal value of less than 20 mmHg at rest). The pathophysiology of pulmonary hypertension is characterized by pulmonary vascular vasoconstriction and remodeling. In chronic PH, there is primarily neomuscularization of nonmuscularized pulmonary vessels, with an increase in vascular muscle in the surroundings of already muscularized vessels. This increasing obstruction of the pulmonary circulation leads to a progressive stress on the right heart, which results in reduced output from the right heart and ultimately right heart failure [M. Humbert et al., J. Am. Coll. Cardiol. 2004, 43, 13S-24S (Non-Patent Document 1)]. Idiopathic (primary) pulmonary arterial hypertension (IPAH) is a very rare disorder, whereas secondary pulmonary hypertension (non-PAH PH) is very common, and secondary pulmonary hypertension is currently considered to be the third most common group of cardiovascular disorders after coronary heart disease and systemic hypertension.Since 2008, pulmonary hypertension has been classified into various subgroups according to their etiology according to the Dana Point classification [M. Humbert and VV McLaughlin, J. Am. Coll. Cardiol. 2009, 54(1), S1-S2 (Non-Patent Document 2); D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3rd edition, Hodder Arnold Publ., 2011, pp. 197-206 (Non-Patent Document 3); the latest Nizza classification, Gerald Simonneau, David Montani, David S. Celermajer, Christopher P. Denton, Michael A. Gatzoulis, Michael Krowka, Paul G. Williams, Rogerio Souza: Haemodynamic definitions and updated clinical classification of pulmonary hypertension, in: European Respiratory Journal, 2018; DOI: 10.1183 / 13993003.01913-2018 (Non-patent Document 4)].

[0008] Despite all the progress in the therapy of PH, there is still no cure in sight for this serious disorder. The standard therapies available on the market (e.g. prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase inhibitors) can improve the quality of life, exercise tolerance and prognosis of patients. These are mainly systemically administered (in addition to inhaled treprostinil, and inhaled Iloprost or NO) and are therapeutic principles that act mainly hemodynamically by regulating vascular tone. The applicability of these medicines is limited due to side effects, some of which are severe, and / or complex administration forms. The time period during which the clinical situation of the patient can be improved or stabilized by a particular monotherapy is limited (e.g. due to the development of tolerance). Finally, the therapy is escalated and therefore combination therapy must be applied, in which several medicines are given simultaneously. Currently, these standard therapies are only approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In the case of secondary forms of PH (group 3 PH) associated with lung disease, such as PH-COPD or PH-IIP, these therapeutic principles (e.g. sildenafil, bosentan) have failed in clinical studies, because they lead to a reduction in arterial oxygen content (de-saturation) in patients as a result of non-selective vasodilatation.The reason for this is probably the adverse effect on ventilation-perfusion adaptation in the lungs in heterogeneous lung disorders, which is caused by the systemic administration of non-selective vasodilators [I.Blanco et al., Am.J.Respir.Crit.Care Med.2010,181,270-278 (Non-Patent Document 5); D.Stolz et al., Eur.Respir.J.2008,32,619-628 (Non-Patent Document 6)].

[0009] New combination therapy is one of the most promising future therapeutic options for the treatment of pulmonary hypertension. In this context, the discovery of new pharmacological mechanisms for the treatment of PH is of particular interest [Ghofrani et al., Herz 2005,30,296-302 (Non-Patent Document 7); EBRosenzweig, Expert Opin.Emerging Drugs 2006,11,609-619 (Non-Patent Document 8); T.Ito et al., Curr.Med.Chem.2007,14,719-733 (Non-Patent Document 9)]. In particular, new therapeutic approaches that can be combined with concepts of already commercially available therapies can form the basis of more efficient treatments and therefore be of great benefit to patients. In addition, the selective pulmonary applicability of such a novel principle of action may not only provide the option to use it for PAH, but also as a first therapeutic option for patients suffering from secondary forms of PH (group 3 PH), since the targeted application to the ventilated areas of the lung via inhalation application avoids non-selective systemic vasodilation.

[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 heme-free aposoluble guanylate cyclase. Specific targeting of this NO-insensitive form of sGC offers the potential to outline its unprecedented therapeutic opportunities for treating various cardiopulmonary diseases. sGC activators, via their unique mode of action by restoring critical cGMP signaling under oxidative stress conditions, in combination with novel local and lung-selective applications, can become 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, it was demonstrated that inhalation administration of the sGC activator BAY 58-2667 (cinacigaut) in the form of microparticles results in a dose-dependent selective reduction in pulmonary artery pressure. In this model, intravenous administration of 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes the heme prosthetic group of sGC, reduced the vasodilatory effect of inhaled NO (iNO), which was increased by BAY 58-2267. These results led to the hypothesis that inhalation administration of sGC activators may represent a new and effective method of treatment for patients suffering from pulmonary hypertension, especially when the response of these patients to iNO and / or PDE5 inhibitors is reduced as a result of the lack of NO or the oxidation of sGC [OVEvgenov et al., Am.J.Respir.Crit.Care Med.2007,176,1138-1145 (Non-Patent Document 10)]. However, in this model, cinaciguat by itself did not have sufficient duration of action, and in addition, higher dosages resulted in undesirable systemic side effects.

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

[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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), patients with PH due to underlying lung disease (group 3 PH) are primarily treated by administration of 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 are only used experimentally in the form of group 3 PH due to the observed desaturation effect 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 the local drug concentration and to avoid systemic side effects of the drug caused by systemic availability. Generally, less frequent dose regimens are desirable, for example, to improve patient adherence to therapy (patient compliance), but 24-hour coverage needs to be confirmed for sustained availability of hemodynamically active drugs during the dosing interval. Many lung-targeted inhaled drugs (e.g., Iloprost / Ventavis) require frequent application schemes, for example, due to their short half-life and / or lung residence time, which requires multiple daily applications for 24-hour coverage. In particular, once-daily application is preferred due to convenience for patients and compliance. However, this goal is often difficult to achieve depending on the specific behavior and properties of the drug substance, in particular its lung selectivity and lung residence time.

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

[0016] Pulmonary delivery by inhalation is one such alternative route of administration that can offer several advantages over oral and injection administration, including, among others, the potential for greater efficacy and reduced systemic drug side effects due to increased local concentrations, as well as the convenience of patient self-administration, ease of delivery by inhalation, and elimination of needles.

[0017] For pharmaceutical preparations for inhalation that do not require adjuvants, especially in the case of solid preparations for suspension inhalation, the preparation may consist of the active ingredient alone. However, for practical reasons, for example to facilitate drug delivery of very low doses of the active ingredient, the preparation is often a pharmaceutical that contains one or more pharmacologically inert physiologically acceptable excipients or carriers in addition to the active ingredient. A review of various suitable preparations and the corresponding inhalation drug delivery techniques can be found, for example, in the book by Paolo Colombo, Daniela Traini and Francesca Buttini “Inhalation Drug Delivery-Techniques and Products” (published by Wiley-Blackwell 2013) (Non-Patent Document 11). In 2019, Moon et al. published an updated review of delivery techniques for oral inhalation products (Moon et al., AAPS PharmSciTech 20:117 pp 1-17 (Non-Patent Document 12)).

[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 WO14 / 012934-A1.

[0019] However, some of these compounds, such as Examples 2, 37 and 39 (see Comparative Examples 3, 4 and 5 in the Experimental Section), show only limited or moderate duration of action in PAH animal models. Moreover, some of these compounds, such as Example 37 (see Comparative Example 3 in the Experimental Section), are not lung selective.

[0020] In addition, some examples disclosed in WO14 / 012934-A1 (Patent Document 1), such as Example 2 (Comparative Example 5, experimental part), 24 (Comparative Example 6, experimental part), 25 (Comparative Example 7, experimental part), 28 (Comparative Example 8, experimental part), 29 (Comparative Example 9, experimental part) and Example 31 (Comparative Example 10, experimental part) show only limited thermal stability (7 days at 90° C.).

[0021] Additionally, document WO14 / 012934-A1 does not disclose the suitability of the described compounds for use in once-daily or twice-daily inhalation treatment regimens and any specific dosages.

[0022] There was therefore a need to provide novel suitable once-daily or twice-daily inhalation dosing regimens for use in the treatment of cardiopulmonary diseases, based on active ingredients with advantageous properties, such as sufficient duration of action, lung-selective action (as opposed to systemic action), such as high lung selectivity, low to no VQ mismatch, its lung residence time. Furthermore, the drug substance should show improved ventilation, such as a bronchodilator effect, and / or an inhibitory effect on airway hyperresponsiveness and inflammation, and therefore be particularly suitable for use in the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0023] Further, there was a need to provide stable active ingredients that are suitable for use in the above-mentioned inhalation dosing regimens.

[0024] The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I (Comparative Example 11) was found to be stable in the thermal stability test.

[0025] Additionally, the acid of formula I (=Comparative Example 11) (Example 23 according to WO2014 / 012934-A1) surprisingly showed further advantageous properties, such as excellent long-lasting efficacy and intrapulmonary selectivity (C-2.1) in a predictive PAH animal model. Comparative Example 11 effectively reduced pulmonary artery pressure (PAP) in a unilateral bronchial obstruction model. In contrast to systemic administration, no adverse effects on the desaturation area could be detected after inhalation, and this administration route offers a better risk-benefit ratio. As a result, Comparative Example 11 showed strong pulmonary and intrapulmonary selectivity after inhalation application. Our data also show that Comparative Example 11 not only improved circulation, but also showed bronchodilatory properties (C-3.1; C-3.2) that may be beneficial in the treatment of PH patients with chronic lung disease or even have potential in the treatment of asthma patients (C-3.3). Therefore, Comparative Example 11 may be a suitable inhaled drug that targets ventilated regions of the lung and induces vasodilation only in the ventilated regions, thereby overcoming this limitation in current PAH treatment options that suffer from excessive V / Q mismatch.

[0026] In human airway smooth muscle cells (HASMCs), relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway. Notably, the majority of severe asthma donor HASMCs and lung samples expressed primarily dysfunctional oxidized sGC. Therefore, in particular, sGC activators may be a new target option for these patients (Arnab Ghosh, Cynthia J. Koziol-White, William F. Jester Jr., Serpil C. Erzurum, Kewal Asosingh, Reynold A. Panettieri Jr., Dennis J. Stuehr: An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling in Redox Biology 39(2021)101832(Non-Patent Document 13), Maggie Lam, Jane E. Bourke, Ph.D., A New Pathway to Airway Relaxation: Targeting the “Other” Cyclase in Asthma American Journal of Respiratory Cell and Molecular Biology Volume 62 Number 1|January 2020 (see non-patent document 14).sGC regulators have been reported to induce bronchodilation in human small airways (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 (Non-Patent Document 15)). Therefore, the inventors aimed to test the duration of action of the bronchodilation properties after topical application (recovery coefficient (C-3.1) as an index for duration) and compared the bronchodilation properties of Comparative Example 11 with those of the commercially available sGC stimulant riociguat (Comparative Example 2) and sGC activator cinaciguat (Comparative Example 1). Compared with vehicle, all sGC regulators cinaciguat (Comparative Example 1), riociguat (Comparative Example 2) and Comparative Example 11 induced relaxation. The relaxation mediated by cinaciguat (Comparative Example 1) and riociguat (Comparative Example 2) reached steady state within 1 hour. Surprisingly, the relaxation mediated by Comparative Example 11 further increased. The relaxation induced by riociguat (Comparative Example 2) was completely washed out within 1 hour (recovery coefficient of 0.34), and the relaxation induced by cinaciguat (Comparative Example 1) was stable and had a slight decreasing trend (recovery coefficient of 0.91) similar to vehicle (recovery coefficient of 0.99). In contrast, surprisingly, the relaxation induced by Comparative Example 11 was further enhanced, with a recovery coefficient of 1.41, which suggested a longer duration of action for the bronchodilator properties of Comparative Example 11.

[0027] Previous studies have shown that orally administered PAH drugs (e.g., bosentan, sildenafil, riociguat) dose-dependently reduced hypoxic PAP (i.e., positive therapeutic effect) but increased desaturation areas (i.e., undesirable desaturation effect) (Becker EM, Stasch JP, Bechem M, Keldenich J, Klipp A, Schaefer K, Ulbrich HF, Truebel H. Effects of different pulmonary vasodilators on arterial saturation in a model of pulmonary hypertension. PLoS One 2013;8:1-8 (Non-Patent Document 16)). sGC activation (intrapulmonary selectivity) concentrated in the ventilated area after inhalation application may selectively and potently reduce vasoconstriction in the lung without affecting V / Q mismatch. Inhalation Comparative Example 11 effectively reduced PAP in a unilateral bronchial obstruction model. In contrast to systemic administration, no adverse effects on desaturation areas can be detected after inhalation, and this route of administration provides a better risk-benefit ratio. In particular, Comparative Example 11 showed strong pulmonary and intrapulmonary selectivity after inhalation application (C-2.3). Therefore, Comparative Example 11 may be a suitable inhaled drug that targets the ventilated areas of the lung and induces vasodilation only in the ventilated areas, thereby overcoming this limitation in current PAH treatment options that suffer from excessive V / Q mismatch. Our data also show that Comparative Example 11 not only improved circulation, but also showed bronchodilator properties with a long duration of action (C-3.1; C-3.2; C-4.1), which may be beneficial in the treatment of PH patients with chronic lung disease, or even have potential in the treatment of asthma patients (C-3.3).

[0028] In order to provide a new suitable inhalation dosing regimen for use in the treatment of cardiopulmonary disease, an inhalation dosage form containing Comparative Example 11 (disclosed as Example 23 in WO2014 / 012934-A1) as an active ingredient is required. As a preferred option, dry powder inhalation dosage forms were selected due to their compatibility, convenience, and patient compliance and adherence. Dry powder inhalation dosage forms require 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 of formula (I) be provided in a single defined crystalline form.

[0029] However, as disclosed in Example 23 of WO14 / 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.

[0030] Furthermore, in document WO14 / 012934-A1 (Patent Document 1), there is no disclosure of a specific carrier-based inhaled medicament for use in the treatment of cardiopulmonary diseases, 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.

[0031] There was therefore a need to provide new suitable inhaled dosing regimens for use in the treatment of cardiopulmonary diseases based on (5S)-{[2-(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 a suitable crystalline form, having a sufficient duration of action in humans suitable for chronic treatment / use (e.g. improved hemodynamic effect, reduced pulmonary vascular resistance (PVR), intrapulmonary selectivity, bronchodilator effect, cGMP and bronchodilator effect specific airway resistance).

[0032] For inhalation therapy, generally, three drug product formulation options are 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 nebulized solution.The disadvantages of nebulized drugs are often poor delivery efficiency (producing 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).

[0033] The 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 of special manufacturing techniques, and, very importantly, the need to coordinate breathing technique with the actuation of the device. This often results in inadequate drug delivery (and therapy) and low patient compliance.

[0034] Dry powder inhalers (DPIs) have important advantages, such as a small portable design, the potential to deliver drugs over a wide range of doses, independence from drug solubility, and the absence of coordination between breathing technique and device actuation (passive devices). Thus, for many applications and therapeutic options, DPIs constitute the preferred technology of choice.

[0035] 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 airways. The key features that make inhalation an attractive drug delivery mode are optimized drug delivery by direct targeting of the drug to the site of action, reduced systemic side effects, rapid onset of action, 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.

[0036] The general goal when using pharmaceutical formulations for pulmonary delivery is that the amount of drug delivered relative to the nominal content of the dosage unit is as high as possible.In contrast, the deposition of inactive ingredients in the lung should be minimized to the lowest possible amount that is justified.There are different general formulation strategies for inhalable formulations, and all of these follow a strategy to optimize and increase the active ingredient fine particle deposition of drug particles less than 5 μm while minimizing exposure to inactive ingredients.

[0037] The simplest approach to 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.

[0038] Another strategy is to formulate micronized drug particles or dissolved drug into engineered particles, where the drug is formulated with inactive ingredients to result in shaped particles, which can be coated drug microparticles or porous particles or matrix particles with a somewhat homogeneous or narrow particle size distribution of 5 μm or less to increase the amount of drug delivered into the deep lung and airways. One disadvantage of these formulations is that the carrier and drug are bound together and delivered together to the site of action. A comprehensive overview of non-carrier-based dry powder inhalation formulations has been published by Healy et al. (Advance Drug Delivery reviews 75 (2014) pp 32-52).

[0039] Although there are some published studies that investigate the effect of variables in adhesive drug carrier mixtures, fundamental understanding remains limited.Overall, it remains difficult to predict the 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, and this is due in particular to the specific surface and physical properties of the active ingredient compound particles themselves.

[0040] 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].

[0041] However, currently there is no derivable clear guidance and guidelines on how to design new carrier-based mixtures for inhalation for new drug substances, since different factors and ingredients affect each other and are additionally highly dependent on drug substance properties. 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.

[0042] The overall most common strategy is to formulate the active ingredient with an inert carrier compound into a dry powder blend, in which the 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 the micronized drug particles onto the larger inert carrier material particles, and the subsequent deagglomeration or release of the micronized active drug particles from the carrier, which is influenced by the airflow energy generated in the dry powder inhaler used for the application of 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 crucial to control the adhesive forces of the drug on the carrier, so as to allow optimal release of a high portion of the dose that is available for drug delivery into the deep lung.

[0043] 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 some 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 therefore is less suitable for the next generation of inhalable products containing sensitive drugs.

[0044] Lactose can be obtained in either of two basic isomeric forms, namely alpha and beta lactose, or in an amorphous form. Alpha lactose exists in both monohydrate and anhydrous forms, with the monohydrate form being the most thermodynamically stable form. Alpha lactose monohydrate is prepared by crystallization from a supersaturated solution below 93.5°C. Its crystalline shape can be prismatic, pyramidal or camphor-shaped, depending on the precipitation and crystallization method. Anhydrous lactose (typically containing 70-80% anhydrous beta lactose and 20-30% anhydrous alpha lactose) is most frequently 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 alpha 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.

[11] 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 19)]

[0045] There are many different types of lactose with different physicochemical properties that can be used in DPI formulations. Lactose can be processed either by grinding, sieving, spray drying or granulation to give different properties. Thus, lactose excipients are commercially available in various grades with different physicochemical properties, especially related to coarseness, shape, particle size, particle size distribution, water content, compressibility or surface area. The aerosol performance of the powder is highly dependent on the lactose characteristics, e.g., particle size distribution and shape and surface properties.

[11] 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 19)]

[0046] Additional processes for lactose particle manipulation, e.g., seeding, crystallization, coating, molding, condensation and precipitation, have been reported and result in materials with different physicochemical properties, e.g., particle size, size distribution, fines content, shape, surface roughness, flow properties, electrostatic charge, solid-state changes related to the material. [

[12] X. Kou, L. Wah Chan, H. Steckel, PWS Sheng, Physico-chemical aspects of lactose for inhalation, Adv. Drug Del. Reviews 64 (2012) 220-232 (Non-Patent Document 20)]

[0047] In carrier-based mixtures for inhalation, a proper balance needs to be adjusted between the stability of the blend during storage and handling and the dispersibility during inhalation. It has been shown that the variables related to these processes can affect each other in different ways, and 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]

[0048] There is agreement that a series of subsequent processes, including selection or preparation of starting materials, mixing processes, dispersion and deagglomeration in an inhalation device, and finally, aerosol characterization, are necessary to identify suitable formulations that yield beneficial in vitro deposition results.

[0049] The required carrier properties depend on the type of drug being processed, the drug concentration (% w / w) in the mixture, as well as 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]

[0050] The interfacial forces between the drug and the 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 (Non-Patent Document 18)]

[0051] The main challenge is to find an 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 the aerosol particles in the respiratory tract [De Boer, 2012].

[0052] The design of the DPI controls the 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]

[0053] Additional factors may be the role of the rotating capsule and the influence of air flow rate in the device. De Boer et al. showed that additional variables that have an effect on the preparation and dispersion process of carrier-based formulations for inhalation and interact with each other, including drug properties, carrier surface properties, carrier bulk properties, carrier surface payload, mixing process, mixture properties, inhalation process, storage and regulation, 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 21)]

[0054] 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 development and adaptation and manipulation of certain parameters to obtain a customized formulation for each drug substance with sufficient stability and aerosol performance.

[0055] The latter important property is not predictable from the prior art references.

[0056] The manufacture 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.

[0057] Especially for low drug dose formulations containing micronized drug particles, optimal mixing is required to obtain 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 and ordered mixture in which the drug particles adhere to the 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 separation (or demixing, which is characterized by the separation of coarse particles from fine particles induced by differences in particle size, shape and density or by particle aggregation). In fact, fine excipients that improve aerosol performance by promoting the adhesion of drug particles to sites with lower energy than the active sites of the carrier reduce adhesion and thus affect drug uniformity. For optimal dry powder formulation, a balance is needed between adhesive forces that are 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, the rate of separation that occurs during mixing can be an interesting factor in predicting aerosol dispersion performance.

[0058] Optimal mixing depends on sufficient expansion of the powder bed, optimization of mixer and powder characteristics, and 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 place to another in the blend; 2) shear, which is a change in the configuration of the components through the formation of sliding surfaces or shear strains in the powder bed; and 3) diffusion, which is the random movement of individual particles relative to each other, resulting in their redistribution. Mixers can be classified as segregating and non-segregating mixers. The choice of mixer depends on the tendency of the powder blend to separate and form agglomerates. For mixtures containing powder blends that promote particle separation, non-segregating mixers must be used, and 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 the smaller components, additional stress (shear) is required to break up 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 homogenous 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 small amounts of excipients, can reduce the total mixing time. In contrast, achieving a multi-component mixture can increase the mixing time to reach homogeneity. [[x] 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 19)]. [Prior art documents] [Patent documents]

[0059] [Patent Document 1] WO14 / 012934-A1 [Non-patent literature]

[0060]

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Outdoor Tools 15

Outdoor Content 16

Outdoor Track 17

Outdoor Tools 18

[0061] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] Detailed Description of the Invention Solid forms of the acids of formula (I) The preparation of the compound of formula (I) can be carried out by It is disclosed in WO2014 / 012934 (see Example 23) and starts with 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) and is outlined in Scheme 1 below.

[0063] 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 TIFF2025501309000003.tif68165 However, this process results in the compound of formula I being obtained only in amorphous form (see Comparative Example 11).

[0064] 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 TIFF2025501309000004.tif73165 is disclosed in WO2021 / 233783. However, the synthetic approach to the compound of formula (I) itself is not disclosed in this reference.

[0065] The novel, undisclosed 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 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 made by starting from a solid NSA salt of formula (XII-NSA) (process steps [D], [A] and [B] = Route 3).

[0066] Scheme 2: Novel, undisclosed processes for making compounds of formula (I), including process routes 1, 2 and 3. TIFF2025501309000005.tif217165 The core process (pathway 1) comprising steps [A] and [B] is used in all three alternative routes. This process according to the invention has several advantages over the prior art process disclosed in WO2014 / 012934. Some by-products that were inevitably included in the product of formula I when made according to the prior art procedures may be avoided or at least easier to separate. The inventors have identified the formation of the target acid of formula (I) from the disodium salt of formula (I-diNa) in step [B] as the main problem. It is important to carry out this step in a reverse manner controlling the pH of the reaction mixture (carefully monitored to stay within a pH value window of 3.8-4.2). Thus, process step [B] requires the reverse addition of the disodium salt intermediate of formula (I-DiNa) to an equimolar amount of acid equivalent. This reverse addition significantly reduces the formation of poorly soluble monosodium salt of the compound of formula (I) compared to the prior art process (see Comparative Example 11).However, the small amount of monosodium salt formed mainly and other poorly soluble impurities can be separated by clarifying filtration of the disodium salt solution.In addition, further by-products, such as hydrochloride, are avoided by reverse addition.

[0067] Alternatively, compounds of formula (I) can be prepared starting from compounds (X) and (XI) by coupling without isolating intermediates, followed by cleavage of the diester and liberating the acid (see, for example, Scheme 2 (Route 2) as depicted in process steps [C], [A] and [B]).

[0068] In alternative route 3), the compound of formula (I) can be prepared via its NSA salt, characterized in that in a first step [D], the dibutyl ester needs to be liberated from the NSA salt of formula (XII-NSA), which is then further converted to the free acid via two steps: basic saponification of the dibutyl ester (step [A]) followed by back addition to an acid to liberate the free acid of formula (I) (step [B]).

[0069] For the development of pharmaceutical forms, in particular dry powder inhalation forms, comprising the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) in solid form, there is a high demand for the reproducible preparation and isolation of the compound of formula (I) in one defined crystalline form.

[0070] Many attempts were required to finally crystallize the compound of formula I into a defined solid form.

[0071] Surprisingly, the compound of formula I is obtained in several pseudopolymorphic forms and no anhydrous crystalline form has been found.

[0072] However, among several identified pseudopolymorphic forms, the most suitable stable form had to be identified during several stages.

[0073] The dihydrate was found to amorphize during the drying process (see FIG. 10a). The crystal lattice of the hemihydrate exhibits disorder (see FIG. 5), which may support phase transition and / or amorphization during mechanical processing, e.g., formulation processes. The crystallization of the sesquihydrate was not feasible for scale-up due to the very long stirring procedure.

[0074] Both monohydrates were found to overcome these undesirable properties of the different pseudopolymorphic forms.

[0075] 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). TIFF2025501309000006.tif73165

[0076] However, in the end, it was found that only one of these monohydrate forms is stable during micronization and is therefore the most suitable form for use, for example, in the manufacture of inhaled medicaments, in particular dry powder-based inhaled medicaments. Surprisingly, it was found that during micronization, monohydrate II either showed partial amorphization (see Example 8b, Figure 42) or additionally converted to monohydrate I (see Example 8a, Figure 43), depending on the micronization conditions. Moreover, it was observed that monohydrate II also showed conversion to monohydrate I during storage (see Example 7b, Figures 40 and 41). Thus, the pseudopolymorphic form monohydrate I is suitable for use in the pharmaceutical field and is preferred over other solid forms of the compound of formula I, in particular for pharmaceutical compositions, in particular for dry powder inhalation dosage forms.

[0077] 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).

[0078] 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 gives compound (IMI), while crystallization from acetone water selectively gives the monohydrate in form II (IM-II).

[0079] Moreover, it has been surprisingly found that the monohydrate (IMI) ensures that the undesired conversion of the compound of formula (I) to another form and the associated changes in the above-mentioned properties are prevented. Thus, the monohydrate I form is the most preferred crystalline form of the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I).

[0080] The monohydrate I of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid can be characterized by X-ray powder diffractometry on the basis of the respective diffractograms, which are recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The monohydrate I according to the invention exhibits at least 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.

[0081] The monohydrate I of formula (IMI), which is a pseudopolymorphic form of the compound of formula (I), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, 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 25.1, 17.7, and 23.7; or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7; or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7, and 11.5.

[0082] 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 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. 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.

[0083] In another embodiment, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), may be characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 12.8, 20.5 and 25.8, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2 and 25.1, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1 and 23.7, or at least 6.9, 7.2, 7.3, 12.8, 20.5, 25.8, 15.2, 25.1, 23.7, 9.9, 5.7 and 11.5.

[0084] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu-K alpha 1 as the radiation source) of the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.7, 6.9, 7.2, 7.3, 9.9, 10.4, 10.6, 11.1, 11.5, 12.0, 12.3, 12.4, 12.8, 13.7, 14.1, 14.3, 15. 2, 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.

[0085] 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 ±0.2°.

[0086] 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 ±0.2°.

[0087] 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 2θ values ​​±0.2°.

[0088] Additionally, monohydrate I of formula (IMI), which is a pseudopolymorphic form of compound of formula (I), may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0089] 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, 7.6, each expressed as a 2θ value ±0.2°.

[0090] 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, 14.8, each expressed as a 2θ value ±0.2°.

[0091] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, expressed respectively as 2θ values ​​±0.2°: 12.8 and 29.2, or at least 6.9, 7.2 and 7.3, or at least 6.9, 7.2, 7.3, 12.8 and 29.2, or at least 6.9, 7.2, 7.3, 12.8, 29.2, 23.0 and 15.2, or at least the following reflections: 6. 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7, or at least the following reflectances: 6.9, 7.2, 7.3, 12.8, 29.2, 23.0, 15.2, 25.8, 25.1, 17.7, and 23.7, while not exhibiting at least the following reflectances: 6.1 and 8.5.

[0092] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, 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.

[0093] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate I of formula (IMI), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, 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.

[0094] The compound of formula (I) in its polymorphic form, monohydrate I, can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG. 6.

[0095] The pseudopolymorphic form of the compound of formula (I), monohydrate I of formula (IMI), may be characterized by Raman spectroscopy exhibiting at least the following maxima: 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm-1.

[0096] The pseudopolymorphic form monohydrate I of compound of formula (I) may be characterized by IR spectroscopy exhibiting at least the following maxima: 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0097] Embodiment 7 (Monohydrate I of formula (IMI)) The present invention relates to a compound of formula (I) in the crystalline form monohydrate I of formula (IMI), TIFF2025501309000008.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.

[0098] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and with Cu-K alpha 1 as radiation source) of the compound exhibits at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3.

[0099] 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 with 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.

[0100] 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, There is further provided 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.

[0101] 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, There is further provided 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.

[0102] Alternatively, the present invention relates to a compound of formula (I) in crystalline form monohydrate I of formula (IMI), TIFF2025501309000009.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.

[0103] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 16.0, 25.8, 6.9, 7.2 and 7.3.

[0104] The present invention further provides a compound of formula (I) in the crystalline form of monohydrate I of formula (IMI) according to embodiment 7, characterized in that the x-ray diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) of the compound shows at least the following reflections, expressed as 2θ values ​​±0.2°: 6.9, 7.2 and 7.3, 12.8, 29.2, 23.0 and 15.2.

[0105] 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.

[0106] 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, There is further provided 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.

[0107] The present invention relates to a compound of formula (I) in the crystalline form monohydrate I of formula (IMI), Further provided is a compound, wherein the IR spectrum of the compound exhibits band maxima at 2933, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm-1cm-1.

[0108] The present invention relates to a compound of formula (I) in the crystalline form monohydrate I of formula (IMI), Further provided is a compound, wherein the Raman spectrum of the compound exhibits band maxima at 3073, 2950, ​​2937, 1685, 1616, 1527, 1293, 1278, 1259 cm-1.

[0109] 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.

[0110] In addition to monohydrate I, further pseudopolymorphic forms have been identified: monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate (see Example 6, Figures 2-29), which are further characterized below.

[0111] The pseudopolymorphic forms of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate, can be characterized by X-ray powder diffraction based on their respective diffractograms, which are recorded at 25°C and with Cu-K alpha 1 radiation (1.5406 Å). The pseudopolymorphic forms of monohydrate II, hemihydrate, 1,25-hydrate, sesquihydrate and dihydrate exhibit at least 3, often at least 5, in particular at least 7, more in particular at least 10, and in particular all of the reflections shown below as values.

[0112] 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 radiation source) which shows, respectively as 2θ values ​​±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 by exhibiting at least the following reflectances: 6.1, 8.5, 12.7, 23.9, 13.9, 23.0, 12.2, 10.8, 15.3, 17.3, 21.7, and 22; and most preferably by exhibiting at least the following reflectances: 6.1, 8.5, 12.7, 23.9, 13.9, 23.0, 12.2, 10.8, 15.3, 17.3, 21.7, and 22.

[0113] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate II of formula (IM-II), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, each expressed as 2θ values ​​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, 16.4, 17.2, 18.6, 19.8, 20.0, 21.0, 22.0, 23.0, 24.0, 25.0, 26.0, 27.0, 28.0, 29.0, 30.0, 31.0, 32.0, 33.0, 34.0, 35.0, 36.0, 37.0, 38.0, 39.0, 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, 60.0, 61.0, 62.0, 63.0, 64.0, 65.0, 66.0, 67.0, 68.0, 69.0, 70.0 , 15.7, 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.

[0114] Additionally, the pseudopolymorphic form of 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 2θ values ​​±0.2°.

[0115] Additionally, the pseudopolymorphic form of 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 2θ values ​​±0.2°.

[0116] 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, 29.2, each expressed as a 2θ value ±0.2°:

[0117] Additionally, the pseudopolymorphic form of 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°.

[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, 7.6, each expressed as a 2θ value ±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, 14.8, each expressed as a 2θ value ±0.2°.

[0120] Additionally, the pseudopolymorphic form of compound of formula (I), monohydrate II of formula (IM-II), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) of at least the following reflections, expressed as 2θ values ​​±0.2°, respectively: 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 by exhibiting at least the following reflectances: 6.1, 8.5, 12.8, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7 and 11.5, and also most preferably by exhibiting at least the following reflectances: 12.8, 23.0, 15.2, 25.8, 25.1, 17.7, 23.7, 9.9, 5.7, 6.1, 8.5 and 11.5, while not exhibiting at least the following reflectances: 6.9, 7.2 and 7.3.

[0121] The compound of formula (I) in the pseudopolymorphic form monohydrate II can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and with Cu—K alpha 1 as the radiation source) shown in FIG.

[0122] The pseudopolymorphic form monohydrate II of compound of formula (IM-II) may be characterized by Raman spectroscopy exhibiting at least the following maxima: 3073, 2950, ​​2936, 1685, 1615, 1526, 1294, 1279, 1259 cm −1 .

[0123] The pseudopolymorphic form monohydrate I of compound of formula (I) may be characterized by IR spectroscopy exhibiting at least the following band maxima: 2934, 1595, 1375, 1327, 1272, 1242, 1167, 1110 cm −1 .

[0124] 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), TIFF2025501309000012.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 ​​±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, and 13.9, 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, and 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.

[0125] The compound of formula (I) in the pseudopolymorphic form monohydrate II can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and with Cu—K alpha 1 as the radiation source) shown in FIG.

[0126] Additionally, the pseudopolymorphic form of 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 2θ values ​​±0.2°.

[0127] Additionally, the pseudopolymorphic form of 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 2θ values ​​±0.2°.

[0128] 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, 29.2, each expressed as a 2θ value ±0.2°:

[0129] Additionally, the pseudopolymorphic form of 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°.

[0130] 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°.

[0131] 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, 14.8, each expressed as a 2θ value ±0.2°.

[0132] Embodiment 9 (hemihydrate of compound of formula (I)) The pseudopolymorphic form of the compound of formula (I), hemihydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 3.1, 5.3, 6.7, 7.1, 9.3, 10.6, 12.4, 14.3, 16.1, 19.7, 20.8, 24.0, 31.1.

[0133] The pseudopolymorphic form of the compound of formula (I), hemihydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, 3.1, 5.3, 6.7, 7.1, 9.3 and 31.1, each expressed as 2θ values ​​±0.2°.

[0134] The compound of formula (I) in the pseudopolymorphic form hemihydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG.

[0135] 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 ±0.2°.

[0136] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0137] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, 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°.

[0138] 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°.

[0139] Additionally, the pseudopolymorphic form of the compound of formula (I), hemihydrate, 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°.

[0140] 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 ±0.2°: 14.8.

[0141] 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, 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°: 5.9, 6.1, 7.9, 10.5, 11.9, 12.2, 12.5, 13.2, 13.6, 13.7, 14.4, 15.2, 15.3, 15.4, 15.7, 15.9, 16.5, 16.9, 17.2 , 17.4, 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.

[0142] The pseudopolymorphic form of the compound of formula (I), the 1,25 hydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 7.9, 10.5, 12.2, 12.5, 13.6, 15.2, 16.9, 19.0, 24.0, 24.4, 24.6, 31.6.

[0143] The compound of formula (I) in the pseudopolymorphic form 1.25 hydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as radiation source) shown in FIG.

[0144] 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 ±0.2°.

[0145] Additionally, the pseudopolymorphic form of the compound of formula (I), 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°.

[0146] 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, 29.2, each expressed as a 2θ value ±0.2°:

[0147] Additionally, the pseudopolymorphic form of the compound of formula (I), 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°.

[0148] Additionally, the pseudopolymorphic form of the compound of formula (I), 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, 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0149] Additionally, the pseudopolymorphic form of the compound of formula (I), 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, 7.6, each expressed as a 2θ value ±0.2°.

[0150] Additionally, the pseudopolymorphic form of the compound of formula (I), 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, 14.8, each expressed as a 2θ value ±0.2°.

[0151] Embodiment 11 (Sesquihydrate of compound of formula (I)) The pseudopolymorphic form sesquihydrate of compound of formula (I) may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 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.

[0152] The sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may also be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 5.1, 7.6, 8.6, 12.2, 14.5, 18.3, 18.7, 21.5, 23.4, 24.7, 25.1, 26.4.

[0153] The pseudopolymorphic form of the compound of formula (I), the sesquihydrate, has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) that shows at least the following reflections, each expressed as 2θ values ​​of ±0.2°: 5.1, 6.3, 7.6, 8.6, 11.4, 12.2, 12.5, 12.9, 13.3, 14.3, 14.5, 15.2, 15.5, 15.6, 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, 17.8, 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, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 2 .8, 16.2, 16.4, 16.7, 17.3, 17.5, 17.7, 18.3, 18.7, 19.4, 20.5, 20.7, 20.8, 21.4, 21.5, 21.8, 22.4, 22.9, 23.4, 24.0, 24.7, 25.1, 26.1, 26.4, 27.0, 27.4, 28.5, 32.2, 36.5.

[0154] The compound of formula (I) in the pseudopolymorphic form sesquihydrate can also be clearly characterized by the X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) shown in FIG.

[0155] 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, 3.1 and 9.3, each expressed as a 2θ value ±0.2°.

[0156] 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°.

[0157] Additionally, the pseudopolymorphic form of the compound of formula (I), the sesquihydrate, may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0158] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, 8.5 and / or 30.0, each expressed as a 2θ value ±0.2°.

[0159] Additionally, the sesquihydrate, which is a pseudopolymorphic form of the compound of formula (I), may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, 7.9 and / or 31.6, each expressed as a 2θ value ±0.2°.

[0160] Additionally, the pseudopolymorphic form of the compound of formula (I), the sesquihydrate, may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 14.8.

[0161] Embodiment 12. Dihydrate of the compound of formula (I) The pseudopolymorphic form of the compound of formula (I), the dihydrate, may be unambiguously characterized by an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) showing at least the following reflections, each expressed as 2θ values ​​±0.2°: 10.1, 10.5, 11.2, 12.5, 13.6, 14.8, 15.5, 20.2, 20.5, 21.1, 22.2, 23.2, 25.1, 29.6.

[0162] The dihydrate, which is a pseudopolymorphic form of the compound of formula (I), has an X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) that shows at least the following reflections, each expressed as 2θ values ​​of ±0.2°: 6.1, 6.8, 10.1, 10.5, 11.2, 11.3, 12.3, 12.5, 13.1, 13.6, 14.6, 14.7, 14.9, 15.4, 15.5, 16.6, 16.8, 17.9, 17.9, 18.7, 18.9, 19.8, 20.7, 21.7, 22.7, 23.6, 24.4, 25.4, 26.2, 27.2, 28.2, 29.2, 30.7, 31.7, 32.2, 33.6, 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, .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.

[0163] 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 FIG.

[0164] 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 ±0.2°.

[0165] 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, 6.9, 7.2, and 7.3, each expressed as a 2θ value ±0.2°.

[0166] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, may be characterized in that its X-ray powder diffractogram (at 25° C. and using Cu—K alpha 1 as the radiation source) does not exhibit at least the following reflections, each expressed as a 2θ value ±0.2°: 29.2.

[0167] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, 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°.

[0168] 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°.

[0169] Additionally, the pseudopolymorphic form of the compound of formula (I), the dihydrate, 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°.

[0170] Treatment method The crystalline forms of the compound of formula (I) according to the invention, preferably monohydrate I (IMI) or monohydrate II (IM-II), more preferably monohydrate I (IMI), have useful pharmacological properties and can be used for the prevention and treatment of disorders in humans and animals. The forms of the compound of formula (I) according to the invention can open up further alternative treatments and thus enrich pharmacy.

[0171] In the context of the present invention, the term "treatment" or "treating" includes inhibiting, slowing, halting, ameliorating, attenuating, limiting, reducing, suppressing, reversing or curing a disease, condition, disorder, injury or health impairment, of the onset, course or progression of such a condition, and / or of the symptoms of such a condition, where the term "therapy" is understood to be synonymous with the term "treatment".

[0172] 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.

[0173] The treatment or prevention of a disease, condition, disorder, injury or health impairment may be effected partially or completely.

[0174] The term "therapeutic efficacy" within the context of the present invention is defined as reducing the mean pulmonary artery pressure in a patient by administering a therapeutically effective amount of a pharmaceutical dry powder formulation comprising a compound of formula (I), in particular that of Comparative Example 11, or a salt, solvate or polymorphic form or crystalline modification of a solvate or salt of the compound of formula (I), or a metabolite of the compound of formula (I), in particular its pseudopolymorphic forms, e.g., (IMI) and (IM-II), without a concomitant clinically relevant change in systemic blood pressure.

[0175] The term "pulmonary vascular resistance (PVR)" within the context of the present invention is defined as 1) a parameter for characterizing the severity of pulmonary hypertension as wall tension in the main pulmonary vessels analyzed by invasive methods measuring the blood pressure in the pulmonary artery, and 2) a parameter for evaluating the effect of new drugs by substantially reducing this parameter, which is directly related to the blood pressure in the pulmonary artery (see D. Singh, R. Tal-Singer, I. Faiferman, S. Lasenby, A. Henderson, D. Wessels, A. Goosen, N. Dallow, R. Vessey & M. Goldman, Plethysmography and impulse oscillometry assessment of tiotropium and ipratropium bromide; a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects, Br. Journal Clin Pharmacol, 2006, 61, 398-404).

[0176] Improved 6-minute walk test result within the context of the present invention is defined as an improvement in the distance a patient can walk within a 6 minute time frame, which corresponds to increased physical performance in patients with critical illness under treatment.

[0177] 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.

[0178] The physiological function of the lungs is evaluated under standardized conditions in pulmonary function tests, e.g. spirometry or body plethysmography, to obtain standardized and validated measurements of parameters, e.g. forced expiratory volume in 1 second (FEV1), which allow the direct assessment of drug effects, e.g. bronchodilation, an effect that is therapeutically used by different drugs to improve lung function in lung diseases with bronchoconstriction, e.g. COPD or asthma.

[0179] The term "improved hemodynamic effect" within the context of the present invention is defined as the vasodilatory effect of a drug to reduce pulmonary artery pressure, improve blood circulation in the ventilated areas of the lungs, improve pulmonary function without systemic side effects, thereby causing a clinically relevant improvement in physical performance and general condition for an individual patient.

[0180] The term "intrapulmonary selectivity" within the context of the present invention means the property of an inhaled active ingredient to develop its pharmacodynamic properties of vasodilatation only in the ventilated areas of the lungs and not in the non-ventilated areas. This is to prevent an exacerbation of the mismatch between ventilation and perfusion (due to increased perfusion in the non-ventilated areas) that could occur if the active ingredient also reached the non-ventilated areas. Intrapulmonary selectivity is ensured in particular by the inhalation application route, which is implemented by active inhalation of the patient.

[0181] The term "bronchodilatory effect" within the context of the present invention is defined as an improvement in a parameter, such as, for example, relaxation of carbachol precontracted guinea pig trachea (C-3.1), pulmonary resistance (RL) and dynamic compliance (Cdyn) (C-3.2 and C-3.3), specific airway resistance in humans (C-4.2), FEV1 in humans, or other parameter indicative of an improvement in ventilation.

[0182] The term "chronic treatment / use" within the context of the present invention is defined as once-daily or twice-daily inhalation treatment of a patient for at least 2 consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular from the start of treatment and throughout the entire course of the disease, and optionally in combination with standard of care (SoC, e.g. endothelin antagonists, e.g. bosentan, PDE5 inhibitors, e.g. sildenafil, IP agonists, e.g. Ilomedin or treprostinil, calcium channel blockers, sotatercept, and sGC stimulators, e.g. riociguat).

[0183] The term "once daily" is well known to those skilled in the art and refers to the administration of a drug once a day, and includes the administration of one dosage form, as well as the administration of two or more dosage forms simultaneously or sequentially within a short period of time.

[0184] The term "once-daily 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 throughout the day includes administration of one dosage form, as well as administration of two or more dosage forms simultaneously or sequentially within a short period of time.

[0185] 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.

[0186] The term "inhalation dosage form" refers to a combination of a drug substance, i.e. an active ingredient, preferably in one crystalline form, for example in the form of monohydrate I or monohydrate II or sesquihydrate, preferably in the form of monohydrate I or monohydrate II, more preferably in the form of monohydrate I of formula (IMI), and a pharma- ceutically suitable carrier for inhalation. The combination of the drug substance and the pharma-ceutically suitable carrier for inhalation is in the form of a dry powder. Preferably, the dry powder is filled in a cavity, more preferably in a capsule. Preferably, the pharma-ceutically suitable carrier is lactose for inhalation.

[0187] 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.

[0188] 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.

[0189] In the context of cardiopulmonary disorders, the term "local administration" or "local control" refers for the purposes of the present invention to administration by inhalation of active ingredients in inhalable dosage forms primarily to cover the lungs as a target organ, requiring lower doses and resulting in lower systemic drug exposure, as opposed to oral and intravenous administration of dosage forms intended for absorption via the gastrointestinal tract, which results in systemic drug distribution via the bloodstream. The preparations in powder form or in powder-containing suspensions used according to the present invention are inhaled preparations.

[0190] The term "inhalation" or "administration by inhalation" in this context refers to introduction into the respiratory tract, in particular introduction into and / or via the airways, preferably introduction into and / or via the nasal passages or oral cavity, particularly preferably introduction via the oral cavity, to achieve deposition of the active ingredient in the bronchi and lungs as sites of action.

[0191] The term "intracereal" or "intracereal administration" for purposes of this invention refers to the non-inhalational introduction of a compound into the trachea, particularly its introduction for the control of pulmonary disease in experimental animals as models of administration, such as rats or piglets and dogs (e.g., intratracheal application via a PennCentury device, which is applicable to dry powders, as well as drug solutions and suspensions).

[0192] The compounds according to the invention, for example (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, for example (IMI) and (IM-II), are potent activators of soluble guanylate cyclase. They result in vasorelaxation, inhibition of platelet aggregation, lowering of blood pressure, and increased coronary blood flow and microcirculation. In addition, they have a bronchodilatory effect. Their activity is mediated via a direct heme-independent activation of soluble guanylate cyclase and an increase in intracellular cGMP levels.

[0193] 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 lung residence time and / or their duration of action after intrapulmonary administration (C-2.1, C-2.2), as well as low to no VQ mismatch (intrapulmonary selectivity) (C-2.3). Furthermore, after inhalation application of the drug substance, improved ventilation, for example bronchodilator effect (C-3.1 and C-3.2), as well as inhibitory effect on airway hyperresponsiveness and inflammation (C-3.3), can be demonstrated preclinically.

[0194] Also, the good therapeutic efficacy and target association of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), can be clinically demonstrated. After inhalation application, reduced total specific airway resistance (C-4.1), an increase in plasma cGMP concentration as a surrogate for drug concentration in the lung (indicating target association) (C-4.1, C-4.2), and a selective decrease in pulmonary artery pressure and pulmonary vascular resistance (C-4.4) were observed.

[0195] Furthermore, favorable pharmacokinetic properties of the drug substance for inhalation application could be demonstrated: analysis of the plasma concentrations after oral, intravenous and inhalation administration of the drug substance showed the longest half-life of the active ingredient after inhalation application (C-4.3).

[0196] 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 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.

[0197] In conclusion, all the results show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms such as (IMI) and (IM-II), in particular the monohydrate I of formula (IMI), is particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), and is 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.

[0198] 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.

[0199] 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), may be used in medicine for the treatment and / or prevention of cardiovascular and cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), and pulmonary disorders, such as asthma, chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis.

[0200] In the context of the present invention, the term "sGC regulator" encompasses two different classes of compounds capable of regulating sGC: sGC stimulators and sGC activators (Sandner P, Becker-Pelster EM, Stasch JP. Discovery and development of sGC stimulators for the treatment of pulmonary hypertension and rare diseases. Nitric Oxide 2018; 77: 88-95. Hoenicka M, Becker EM, Apeler H, Sirichoke T, Schroder H, Gerzer R, Stasch JP. Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 system: stimulation by YC-1, nitric oxide, and carbon monoxide. J Mol Med (Berl) 1999; 77: 14-23, Evgenov OV, Kohane DS, Bloch KD, Stasch JP, Volpato GP, Bellas E, Evgenov NV, Buys ES, Gnoth MJ, Graveline AR, Liu R, Hess DR, Langer R, Zapol WM. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation.Am J Respir Crit Care Med 2007;176:1138-1145). Both classes of compounds bind directly to sGC as allosteric regulators. sGC stimulators have a dual mode of action, directly stimulating native sGC independent of NO and also sensitizing sGC to low levels of NO by stabilizing NO-sGC binding. In contrast, sGC activators bind to the unoccupied heme-binding domain, thereby mimicking NO-bound heme and activating pathologically altered NO-unresponsive apo-sGC. Recent evidence indicates that oxidative stress, associated with many cardiopulmonary diseases, shifts intracellular levels of native sGC to the apo-sGC form (Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 2006;5:755-768; Munzel T, Genth-Zotz S, Hink U. Targeting heme-oxidized soluble guanylate cyclase: solution for all cardiorenal problems in heart failure? Hypertension 2007;49:974-976), providing a rationale for sGC activators in various cardiovascular pathophysiological conditions, e.g., PH (Wood KC, Durgin BG, Schmidt HM, Hahn SA, Baust JJ, Bachman T, Vitturi DA, Ghosh S, Ofori-Acquah SF, Mora AL, Gladwin MT, Straub AC. Smooth muscle cytochrome b5 reductase 3 deficiency accelerates pulmonary hypertension development in sickle cell mice.Blood Adv 2019;3:4104-4116., Rahaman MM, Nguyen AT, Miller MP, Hahn SA, Sparacino-Watkins C, Jobbagy S, Carew NT, Cantu-Medellin N, Wood KC, Baty CJ, Schopfer FJ, Kelley EE, Gladwin MT, Martin E, Straub AC. Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling.Circ Res 2017;121:137-148., Durgin BG,Hahn SA,Schmidt HM,Miller MP,Hafeez N,Mathar I,Freitag D,Sandner P,Straub AC.Loss of smooth muscle CYB5R3 amplifies angiotensin II-induced hypertension by increasing sGC heme oxidation.JCI Insight 2019;4:e129183., Sandner P, Zimmer DP, Milne GT, Follmann M, Hobbs A, Stasch JP. Soluble guanylate cyclase stimulators and activators.Handb Exp Pharmacol 2019;doi:10.1007 / 164_2018_197). .

[0201] In the context of the present invention, the term "pulmonary hypertension" includes both its primary and secondary sub-forms, which are defined below according to their respective etiologies according to the Dana Point / Nizza classification [D. Montana and G. Simonneau, in: AJ Peacock et al. (Eds.), Pulmonary Circulation. Diseases and their treatment, 3 rdedition,Hodder Arnold Publ.,2011,pp.197-206, MMHoeper et al.,J.Am.Coll.Cardiol.2009,54(1),S85-S96] Latest Nizza classification, Gerald Simonneau,David Montani,David S.Celermajer,Christopher P.Denton,Michael A.Gatzoulis,Michael Krowka,Paul See G. Williams, Rogerio Souza: Haemodynamic definitions and updated clinical classification of pulmonary hypertension, in: European Respiratory Journal, 2018; DOI:10.1183 / 13993003.01913-2018]. These include, in particular, group 1 pulmonary arterial hypertension (PAH), which includes, inter alia, idiopathic and familial forms (IPAH and FPAH, respectively). In addition, PAH also includes persistent pulmonary hypertension of the newborn, as well as pulmonary arterial hypertension (APAH) associated with collagen disease, congenital systemic arteriopulmonary anastomosis lesions, portal hypertension, HIV infection, pulmonary arterial hypertension associated with certain drugs and medications (e.g., appetite suppressant intake), pulmonary arterial hypertension associated with disorders with significant venous / capillary components, such as pulmonary veno-occlusive disorders and pulmonary capillary hemangiomatosis, or pulmonary arterial hypertension associated with other disorders, such as thyroid disorders, glycogen storage disease, Gaucher's 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 anomalies).Group 4 includes, for example, PH patients with chronic thrombotic and / or embolic disorders, e.g., thromboembolic obstruction of the proximal and / or distal pulmonary arteries (CTEPH) or in cases of non-thrombotic embolism (e.g., as a result of oncological disorders, parasites, foreign bodies). Less common forms of pulmonary hypertension, e.g., in patients with sarcoidosis, histiocytosis X or lymphangiomatosis, are summarized in group 5.

[0202] 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.

[0203] In the context of the present invention, the term "asthma" encompasses heterogeneous chronic inflammatory diseases of the airways of the lungs. Asthma is characterized by variable and recurrent symptoms ranging from reversible airflow obstruction to bronchospasm, often caused by bronchial hyperresponsiveness. Symptoms include episodes of wheezing, coughing, chest tightness and shortness of breath. These may occur several times a day or several times a week. In some people, asthma symptoms may worsen at night or with exercise. Asthma is thought to be caused by a combination of genetic and environmental factors. Environmental factors include exposure to air pollution and allergens. Other potential triggers include medications, such as aspirin and beta-blockers. Diagnosis is usually based on the pattern of symptoms, response to therapy over time, and spirometry lung function tests. Asthma is classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEV1) and peak expiratory flow rate. Asthma may also be classified as atopic or non-atopic, with atopic referring to a predisposition to developing type 1 hypersensitivity reactions. There is no known cure for asthma, and asthma is treatable systematically. Symptoms may be prevented by avoiding triggers, such as allergens and respiratory irritants, and may be suppressed with the use of inhaled corticosteroids. If asthma symptoms remain uncontrolled, long-acting beta agonists (LABAs) and other substances, such as anti-leukotrienes, may be used in addition to inhaled corticosteroids. Treatment of acute exacerbation symptoms is usually performed with inhaled short-acting beta 2 agonists, such as salbutamol, and corticosteroids. In severe cases, systemic corticosteroids, magnesium sulfate, and hospitalization may be required. A subset of asthma patients develop severe forms of the disease, the pathogenesis of which involves airway inflammation with intrinsic drivers that remain undetermined. To address this, we studied human airway smooth muscle cells (HASMCs), whose relaxation drives airway bronchiectasis and whose dysfunction contributes to airway obstruction and hyperresponsiveness in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, HASMCs from severe asthma donors may have inherent defects in sGC or in oxidoreductases that support sGC function in severe asthma donors.The majority of severe asthma donor HASMCs (12 / 17) and lung samples predominantly expressed dysfunctional sGC, which was NO-unresponsive, had low heterodimer content, and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting oxidoreductases cytochrome b5 reductase, catalase, and thioredoxin 1, and higher expression of heme oxygenases 1 and 2, suggesting the hypothesis that severe asthma patients are predisposed to defective NO-sGC-cGMP signaling in their airway smooth muscle due to intrinsic sGC dysfunction, which in turn is associated with intrinsic changes in cellular oxidoreductases that affect sGC maturation and function.Therefore, sGC activators may be a new target option for these patients with regard to optimized bronchodilation under these pathophysiological conditions (see, for example, the following references: Arnab Ghosh, Cynthia J. Koziol-White, William F. Jester Jr., Serpil C. Erzurum, Kewal Asosingh, Reynold A. Panettieri Jr., Dennis J. Stuehr: An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling in Redox Biology 39(2021)101832, Maggie Lam, Jane E. Bourke, Ph.D., A New Pathway to Airway Relaxation: Targeting the “Other” Cyclase in Asthma American Journal of Respiratory Cell and Molecular Biology Volume 62 Number 1 | January 2020, Cynthia J.Koziol-White,Arnab Ghosh,Peter Sandner,Serpil E.Erzurum,Dennis J.Stuehr,and Reynold A.Panettieri,Jr.:Soluble Guanylate Cyclase Agonists Induce Bronchodilation in Human Small Airways,Am J Respir Cell Mol Biol Vol 62,Iss 1 pp 43-48,Jan Please refer to 2020. ).

[0204] 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.

[0205] The present invention further provides the use of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0206] The present invention further provides the use of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), for the 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 due to idiopathic interstitial pneumonia (PH-IIP).

[0207] 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 (class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0208] 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 (class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0209] The present invention relates to a method for the treatment and / or prevention of disorders, in particular cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to 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}-5, Further provided is a method comprising administering 6,7,8-tetrahydroquinoline-2-carboxylic acid, in particular Comparative Example 11, as well as its pseudopolymorphic forms, e.g., (IMI) and (IM-II), in an inhalable dosage form in the form of a dry powder formulation, e.g., a dry powder inhaler, for two or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular once or twice daily from the start of treatment throughout the entire course of the disease, wherein the sGC activator has sustained efficacy over a 24 hour period when administered by inhalation to a patient in need thereof.

[0210] The present invention relates to a method for the preparation 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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), comprising administering to the patient an sGC activator of formula I, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl ester of formula I, which is Comparative Example 11.

[0023] The present invention further relates to the use of an inhaled dosage form of sGC activator {5,6,7,8-tetrahydroquinoline-2-carboxylic acid} as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), which is administered once or twice daily for two or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular 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.

[0211] The present invention relates to a packaged pharmaceutical composition comprising a dry powder inhaler (=DPI) and a container containing 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 is provided with instructions for use of the dry powder, e.g., after one deep inhalation, the subject inhales the dry powder for about 2 seconds. The present invention further relates to a packaged pharmaceutical composition comprising: a) a patient receiving the package and holding their breath, whereby the dry powder drug will concentrate from the airstream onto the surface of the deeper lung regions and be deposited near its intended site of pharmacological action to treat cardiopulmonary disorders, preferably pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0212] In a preferred embodiment, the present invention provides a packaged pharmaceutical composition comprising a container containing a dry powder inhaler (=DPI) and a pharmaceutical formulation comprising (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, and pseudopolymorphic forms thereof, such as (IMI) and (IM-II), wherein the packaged pharmaceutical composition is (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, The present invention further relates to a packaged pharmaceutical composition comprising a container containing a dry powder comprising {phenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, the container further containing instructions for administering the dry powder once daily or twice daily to treat a cardiopulmonary disorder, preferably pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary hypertension (PH) associated with chronic lung disease (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), and further a pulmonary disorder.

[0213] The present invention further relates to medicaments containing at least one compound according to the invention, usually together with one or more inert, non-toxic, pharma- ceutically suitable excipients, and to their use for the abovementioned purposes.

[0214] The compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), may be used alone or, if necessary, in combination with other active compounds. The present invention further relates to medicaments containing at least one of the compounds according to the invention, in particular (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms, such as (IMI) and (IM-II), and one or more further active compounds, in particular for the treatment and / or prevention of the above-mentioned diseases. As suitable combined active compounds, the inventors consider, for example, preferably organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; Ca channel blockers for use 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 phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 3 inhibitors, for example ensifentrine, PDE 4 inhibitors, for example roflumilast, tanimilast or levamilast, and PDE 5 inhibitors, for example sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil, mirodenafil or lodenafil, NO-independent, heme-dependent stimulators of guanylate cyclase, in particular riociguat and the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301, WO03 / 095451, WO2011 / 147809, WO2012 / 004258, WO2012 / 028647, WO2012 / 059549 and WO2014 / 068099, prostacyclin analogues and IP receptor agonists, for example and preferably iloprost, beraprost, treprostinil, epoprostenol or NS-304, endothelin receptor antagonists, for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan, human neutrophil elastase (HNE) inhibitors, such as, preferably, sivelestat or DX-890 (Reltran), compounds that inhibit signal transduction cascades, in particular from the group of tyrosine kinase inhibitors, such as, preferably, dasatinib, nilotinib, bosutinib, regorafenib, sorafenib, sunitinib, cediranib, axitinib, telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib, erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib, semaxanib, masitinib or tanzutinib, Compounds that act as ligand traps with high selectivity for multiple proteins in the TGF-beta superfamily, including activins, GDFs, and others that 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 and potentially restore vascular homeostasis, such as sotatercept, Rho kinase inhibitors, for example and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049, anti-obstructive agents, such as those used for the therapy of chronic obstructive pulmonary disease (COPD) or bronchial asthma, for example preferably inhaled or systemically administered beta-receptor mimetics (e.g. salbutamol, salmeterol) or inhaled antimuscarinic agents (e.g. ipratropium, tiotropium), anti-inflammatory and / or immunosuppressive agents, such as those used for the therapy of chronic obstructive pulmonary disease (COPD), bronchial asthma or pulmonary fibrosis, such as, preferably, systemic or inhaled corticosteroids, flutiform, pirfenidone, acetylcysteine, azathioprine or BIBF-1120, nintedanib, or treprostinil, active compounds used for the systemic and / or inhaled treatment of lung disorders, e.g. for cystic fibrosis (alpha 1 antitrypsin, aztreonam, ivacaftor, lumacaftor, ataluren, amikacin, levofloxacin), for chronic obstructive pulmonary disease (COPD) (tiotropium, LABA / LAMA, LAS40464, PT003, SUN-101), for acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) (interferon beta-1a, traumakin, PEG-adrenomedullin, inhaled sGC modulators, e.g. BAY1211163), for obstructive sleep apnea (VI-0521, TASK channel blockers and ADRA2C antagonists), for bronchiectasis (mannitol, ciprofloxacin), for bronchiolitis obliterans (cyclosporine, aztreonam), Antithrombotic agents, for example preferably those from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances, may be mentioned.

[0215] Antithrombotic agents are preferably understood as compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

[0216] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, for example and preferably, coumarin.

[0222] 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.

[0223] 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.

[0224] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin receptor antagonist, such as, for example and preferably, bosentan, darusentan, asentan or sitaxsentan.

[0225] technical purpose Considering the background and the state of the art, it was a technical object of the present invention to provide suitable inhaled dosage forms / medications 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 due to idiopathic interstitial pneumonia (PH-IIP), and suitable inhaled dosing regimens for the treatment of cardiopulmonary disorders.

[0226] In order to develop suitable inhaled medicaments 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 due to idiopathic interstitial pneumonia (PH-IIP), and suitable inhaled dosing regimens for the treatment of cardiopulmonary disorders, certain technical and medical needs and requirements for drug substances and drug products need to be met.

[0227] First, the active ingredient (drug substance) should have suitable physicochemical, pharmacokinetic and pharmacodynamic properties. For example, the drug substance should be suitable for inhalation therapy and should have sufficient efficacy to treat cardiopulmonary disorders. Furthermore, the active ingredient should also have a clear efficacy in the contemplated PH form in addition to the standard of care (SoC, 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 should have further advantageous properties, in particular with regard to 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 intrapulmonary administration. The drug substance should be suitable for chronic treatment regimes / uses. 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) as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), e.g. pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0228] 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 formulas (IMI) and (IM-II), should have sustained vasodilatory and bronchodilatory efficacy over a period of more than 12 hours up to 24 hours, the sustained vasodilatory and bronchodilatory efficacy being characterized, for example, by improved pulmonary hemodynamics, which may be characterized, for example, by lower pulmonary vascular resistance (PVR), improved walking distance in the 6-minute walk test, improved pulmonary hemodynamics in the NYHA (New York Health The drug may result in a shift in (FEV1) (Forced Expiratory Volume) Association patient classification, or improved lung function, such as higher FEV1 (the forced expiratory volume a human 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 when administered by inhalation.

[0229] Furthermore, the active ingredient (drug substance) needs to be provided in a defined, stable, crystalline form so as to be suitable for dry powder pharmaceutical formulation and to be administered in a specific, optimized inhalation dosing regimen for the treatment of cardiopulmonary disorders.

[0230] Additionally, the final drug product (formulation) must have suitable properties, such as sufficient chemical stability and sufficient aerosol performance, for the drug substance to be delivered in sufficient quantities to the target organ, e.g., the lungs, with low to no adverse effects on the patient. Adequate physicochemical stability is required to keep the active ingredient in its chemical structure and avoid unacceptable degradation or stereochemical conversion. More importantly, the physical and geometrical form must be maintained so as not to alter the biopharmaceutical properties that affect the pharmacokinetic behavior of the active ingredient. Stable and adequate aerosol performance means reproducible drug delivery in the sense of average delivered dose and uniformity of delivered dose, as well as reproducible drug delivery of a desirable high fraction of the available nominal drug dose in the final dosage form to the site of action. In practical terms, the majority of the particles of the micronized active ingredient should be recovered as the fine particle dose (alternatively, the mass of fine particles) and fine particle fraction % relative to the delivered dose, when tested by an appropriate analytical method, such as aerodynamic particle size distribution by cascade impaction. Dose and / or nominal dose.

[0231] 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 in a more reliable manner through improved chemical processes.

[0232] Additionally, the 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).

[0233] 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 accessible 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.

[0234] Thus, 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, is made available for the first time in a format suitable for an inhaled dosage form, a medicament, and an inhaled dosage form, preferably a DPI.

[0235] Surprisingly, preclinical studies have demonstrated that the sGC activator of formula I, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, as well as its pseudopolymorphic forms, e.g., (IMI) and (IM-II) (see C-2.1), exhibits slower penetration of the saphenous artery in isolated vessels, isolated bronchiole, and pulmonary arteries in isolated vessels compared to cinaciguat. It has been shown to show a prolonged recovery index in bronchiole and increased washout scores in Langendorff heart experiments (see experimental parts C-1.1 (isolated vessels), C-3.1 (bronchioles) and C-1.2 (Langendorff)), as well as improved pulmonary selectivity and prolonged duration of action (prolonged selective pulmonary artery pressure (=PAP) reduction without systemic blood pressure (=BP) reducing effect after inhalation application) in PAH animal models (pig and dog) (see experimental parts C-2.1 (pig) and C-2.2 (dog)).

[0236] Furthermore, prediction of duration of action and prediction of human dose have been investigated. Considering 100 μg / kg as the effective dose in the minipig model, a lung-deposited dose of 300-1370 μg is deduced as the effective dose, depending on the consideration of different interspecies protein binding (see C-2.1).

[0237] Finally, the pharmacological effects of different pseudopolymorphic forms of active ingredient have been investigated.All dry powder formulations, including the crystal form of Comparative Example 11, e.g., Example 6e, which is sesquihydrate, selectively and dose-dependently reduce PAP after inhalation application in this model of acute PAH, with a long duration of action of at least 4 hours.A clear dose-response curve was observed for increasing applied doses (see C-2.1).

[0238] 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-4-yl]methoxy}phenyl]ethyl] 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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP). This application 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 form monohydrate I (Example 4) or monohydrate II (Example 2), for once-daily or twice-daily inhalation treatment regimens, including (IMI) and (IM-II).

[0239] (5S)-{[2-(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) and its pseudopolymorphic form monohydrate I of formula (IMI), as well as Comparative Examples 3, 4 and 5, were tested to evaluate the lung selectivity and duration of action in a miniature pig model (C-2.1). All three compounds show favorable lung selectivity, but only Comparative Example 11 and Comparative Example 4 show a sufficient duration of action. Comparative Example 11 shows a selective PAP effect with a maximum effect over the entire observation interval of 240 minutes, while Comparative Example 3 shows its maximum effect on PAP 30 minutes after inhalation application, which is completely eliminated again after 120 minutes. Comparative Example 11 and Comparative Example 4 were evaluated for duration of action in a conscious hypoxic exposure dog model (C-2.2). In this model, Comparative Example 11 showed a consistent long duration of effect (PAP reduction) of up to 17 hours, in contrast to Comparative Example 4. Thus, 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).

[0240] To evaluate intrapulmonary selectivity, Comparative Example 11 was evaluated against systemically applied vasodilators in a model of unilateral bronchial obstruction. In this model, after inhalation application, in contrast to systemically applied Comparative Example 11 or standard treatment, no negative effect on desaturation area was detectable. Thus, after inhalation application, Comparative Example 11 shows a better risk-benefit ratio compared to systemically applied vasodilators, and can be an effective and safe treatment for patients with PH who are at risk of ventilation-perfusion mismatch under the treatment of systemically applied vasodilators (C-2.3). Furthermore, after inhalation application of the drug substance, improved ventilation, such as bronchodilator effect (C-3.1 and C-3.2), and inhibitory effect on airway hyperresponsiveness and inflammation (C-3.3) can be shown preclinically.

[0241] Furthermore, the inventors found that 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 in the form of crystalline form monohydrate I of formula (IMI) (Example 4) in a first clinical study (see Experimental Section C-4.1), increased cGMP levels as a second messenger molecule for sGC activation as a surrogate for drug concentration in the lung (indicating target association) and beneficial bronchodilator properties (e.g. reduction in total specific airway resistance (sRaw), a parameter indicative of bronchodilator activity in the lung) in healthy volunteers over a period of more than 12 hours up to 24 hours after dry powder application, which clinically supports a long lung residence time and the suitability of Example 4 for successful use in the treatment of cardiopulmonary diseases. No clinically significant effects on systemic blood pressure were observed in healthy volunteers at doses up to 4000 μg.

[0242] The inventors also found a selective reduction in pulmonary artery pressure and pulmonary vascular resistance in patients with pulmonary hypertension at doses up to and including 4000 μg, without any clinically relevant effect on systemic blood pressure. This effect continued without a decrease in response until the end of the 3-hour measurement period (measurement periods longer than 3 hours were technically not feasible). The pulmonary residence time of Example 4 of more than 3 hours (presumably over a period of more than 12 hours up to 24 hours after dry powder application) can be concluded from the long plasma half-life measured in the study described in C4-3 (see Experimental Section C-4.3).

[0243] 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 (C-4.3). The emitted (pulmonary) dose was determined to be 720 μg after inhalation of 1000 μg in humans. The results from this study confirm that the pulmonary dose and half-life are appropriate for inhaled dry powder administration, allowing once-daily treatment for sufficient 24-hour drug coverage of Example 4 in the lungs.

[0244] In conclusion, all the results show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms such as (IMI) and (IM-II), in particular the monohydrate I of formula (IMI), are particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), and are suitable for inhaled dry powder administration allowing once-daily treatment for sufficient 24-hour drug coverage in the lungs of Example 4.

[0245] These findings also support the use of 240 to 4000 μg, preferably 480 to 2000 μg of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[ The results support the suitability of Example 4 for a once-daily or twice-daily inhalation treatment regimen comprising 3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid and its crystalline form monohydrate I of formula (IMI) for two or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular after the initiation of treatment and throughout the entire course of the disease.

[0246] Surprisingly, it has now been found that in healthy volunteers after 7 days of drug therapy (first dose followed by a 48-hour dose-free period, then 6 doses every 24 hours), the once-daily inhalation administration of the sGC activator of formula I, 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 in the form of monohydrate form I of formula (IMI) of Example 4, has a prolonged and sustained effect over a period of more than 12 hours up to 24 hours, which can lead to improved hemodynamic effects, such as lower pulmonary vascular resistance (PVR), improved 6-minute walk test, transition in NYHA patient classification, or improved lung function, such as higher FEV1 via bronchodilation, when administered once-daily or twice-daily by inhalation in patients.

[0247] Additionally, the 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 (Comparative Example 11) has beneficial physicochemical properties, such as protein binding and CACO flux (see Experimental Sections C-5.1 (Caco permeability) and C-5.2 (protein binding)), which makes Comparative Example 11 a suitable compound for the local treatment of cardiopulmonary diseases by dry powder inhalation into the lungs. Our data also show that Comparative Example 11, particularly the monohydrate form I, not only exhibited effective reduction of PAP via selective vasodilation in the lungs, but also longer lasting bronchodilator properties compared to cinaciguat, which may be beneficial in once-daily or twice-daily inhalation treatment of PH patients with chronic lung disease (group 3 PH) or may even have potential in the treatment of patients with limited lung function, e.g., asthma patients.

[0248] Thus, the drug substance according to the present invention, for example (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) as well as its pseudopolymorphic forms (IMI) and (IM-II) have the following excellent main pharmacological properties: ·(5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid is a potent selective sGC activator and offers a new approach in the treatment of PH after inhalation. ·(5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid selectively reduced elevated PAP after inhalation application in different disease-relevant animal models (thromboxane- and hypoxia-exposed rats, pigs, and dogs) and had a long duration of action, suggesting application once to twice daily. In a unilaterally ventilated minipig model as a surrogate for VQ mismatch, inhaled application of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid reduced PAP without having a negative effect on oxygenation, in contrast to systemically applied vasodilators. In addition to PAH standard of care (SoC) (e.g., bosentan, sildenafil, ilomedin, and riociguat), (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid selectively reduced elevated PAP after inhalation application in a PAH minipig model. The efficacy of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid was enhanced under experimental conditions of oxidative stress (treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ], a highly selective irreversible heme site inhibitor of soluble guanylyl cyclase, and L-Nω-nitroarginine methyl ester [L-NAME]). With regard to ventilation, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid showed bronchodilatory effects (acetylcholine [ACh] rat model) and inhibitory effects on airway hyperresponsiveness and inflammation (chronic ovalbumin asthma mouse model). The plasma concentrations of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, particularly in the form of its monohydrate I (Example 4), were measured after three types of administration (oral, intravenous, inhalation), revealing the longest elimination half-life after inhalation application. The emitted (pulmonary) dose has been determined to be 720 μg following inhalation of 1000 μg in humans. The first 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, as well as a selective reduction in pulmonary arterial pressure and pulmonary vascular resistance with good local and systemic tolerance up to the highest tested dose of 4000 μg (including 4000 μg).

[0249] Thus, the drug substances according to the invention, such as (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I), as well as its pseudopolymorphic forms (IMI) and (IM-II), have excellent key pharmacological and pharmacodynamic properties in patients, including reduction in pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), bronchodilation, e.g. as measured by FEV1, pulmonary selectivity with low to no systemic adverse effects (in particular clinically relevant changes in systemic hemodynamic effects, e.g. clinically relevant changes in blood pressure or heart rate) and low to no increase in VQ mismatch to avoid associated desaturations, furthermore sufficient lung residence time and / or sufficient duration of action following intrapulmonary administration.

[0250] Surprisingly, it has been found that the 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, especially in the form of monohydrate I, has the potential to successfully control cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP). The concentration of the active ingredient in the lungs can be maintained for a long period of time at a level that is desirable from a medical point of view for optimal treatment. In addition to higher and longer-lasting levels of the active ingredient at the site of the disease, it is possible to simultaneously achieve relatively low systemic concentrations of the active ingredient, which may avoid side effects of drug therapy, such as no clinically relevant systemic blood pressure reduction.

[0251] Surprisingly, the drug substance can be provided in a single, crystalline, chemically stable form, the monohydrate I of formula (IMI), which is also stable under micronization conditions.

[0252] 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. Moreover, the pharmaceutical dry powder formulations according to the present invention can be produced in a technically robust manner by novel processes (e.g., blend uniformity).

[0253] Surprisingly, the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I 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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0254] 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, e.g., Comparative Examples 3, 4 and 5, were not known.

[0255] Furthermore, these findings were not foreseeable as pseudopolymorphic forms, in particular stable crystalline hydrates, were not known.

[0256] 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.

[0257] Moreover, it was surprising that modification I (IMI) was available by selective crystallization from methanol, acetone / water.

[0258] Furthermore, inhaled 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 previously unknown.

[0259] The technical object of the present invention is therefore a novel and preferred inhalation dosing regimen for the treatment of cardiopulmonary disorders, which comprises administering to a patient in need thereof (5S)-{[2-(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 of formula (IMI) in the form of a dry powder application. The objective of the present invention was to provide an inhalation dosing regimen comprising administering to a patient an inhaled pulmonary vascular resistance (mPAP) and pulmonary vascular resistance (PVR) of 1,2,3,4-trimethylphenyl]-2,4,5-trimethylphenyl]-1,2,3,4,5-triphenylmethyl]-2,4,5,6,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I, wherein the active ingredient has excellent primary pharmacological and pharmacodynamic properties in a patient, including reduction in pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), bronchodilation, e.g. as measured by FEV1, pulmonary selectivity with low to no systemic adverse effects (in particular clinically relevant changes in systemic hemodynamic effects, e.g., in blood pressure or heart rate) and low to no increase in VQ mismatch to avoid associated desaturations, and furthermore sufficient lung residence time and / or sufficient duration of action following intrapulmonary administration.

[0260] The inventors have surprisingly discovered that a novel suitable inhalation dosing regimen for the treatment of cardiopulmonary disorders 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), 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 of formula (I), 240 to 4000 μg of -{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I 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) to a patient in need thereof; Preferably, in an inhalation formulation comprising 480-2000 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, preferably as a dry powder application, preferably with a dry powder inhaler and a dry powder formulation. and in combination with {aryl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid, administered once or twice daily for two or more 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 wherein the dry powder formulation comprises an active ingredient and a pharma- ceutical suitable excipient or carrier, preferably the active ingredient and the pharma-ceutical suitable excipient are filled into a hard capsule.

[0261] In order to provide a suitable 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 format at a particular dose, the nominal dosage being sufficient to treat the intended cardiopulmonary disease.

[0262] To determine a sufficient 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.

[0263] The active ingredient should therefore be administered to a patient in need thereof in an inhalable form containing 240-4000 μg, preferably 480-2000 μg, over a period of 2 or more days, preferably at least 2-7 consecutive days, preferably at least 14 consecutive days, in particular once or twice daily after the start of treatment and throughout the entire course of the disease.

[0264] As a result, the novel inhalation dosing regimen for the treatment of cardiopulmonary disorders according to the present invention is suitable for use in the treatment of cardiopulmonary disorders such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung disease (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0265] Human Dose Estimation The formulations according to the invention can be characterized in terms of delivered dose (DD) determined by the filter collection tube method and fine particle dose (FPD) determined by cascade impaction. Analytical methods for determining delivered dose and fine particle dose are generally described in the Pharmacopoeia as they are harmonised for inhalable dosage forms, e.g., dry powder inhalation formulations, and constitute regulations for the quality control of the release of DPI products for clinical use, e.g.

[0266] It has been found that different formulations with different nominal doses result in different delivered doses, and more importantly, result in a certain fine particle dose, which characterizes the effective dose as being delivered to the site of action in the deep lung.Theoretically, the delivered dose, as well as the fine particle dose and fraction, correlate with the loaded powder dose and have a linear relationship, but due to some interaction factors, this is not reliably predictable and may differ in practice, requiring related research.It is desirable that the delivered dose is as close as possible to the nominal dose.In practice, the delivered dose is not 100% consistent with the nominal dose, since residues always remain to some extent on the surface of the inhalation capsule and on the aerosol path of the dry powder inhaler used.Of course, this characteristic is highly dependent on the physicochemical properties of the active ingredient and its release behavior from the powder blend. Similarly, it is desirable for the fine particle dose and fine particle fraction to be as high as possible relative to the nominal active ingredient content packed in order to make the best possible use of the available drug amount and to reduce losses of active ingredient (e.g., by swallowing via oral impaction of larger drug particles) or to reduce the portion delivered to compartments other than the deep lung.

[0267] Due to the nature of inhalable formulations, not all of the nominal content is delivered into the lungs, in contrast to, for example, oral solid formulations.Several fractions can be defined and characterized by specific in vitro analytical methods, which 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 (fine particle dose).For an overview, see Table 1 below.

[0268] [Table 1] TIFF2025501309000014.tif35165

[0269] Assessment of pharmacokinetic / pharmacodynamic (PK / PD) relationships The anesthetized thromboxane A2-exposed PAH minipig model (see experimental section C-2.1) is considered to be the most relevant sensitivity model for prediction of human minimum effective and effective doses (MED, ED). To determine the effective LD, the experiment in minipigs was repeated with the difference that an absorption filter was attached at 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 about 0.15 μg / kg (ND of 3 μg / kg), 0.5 μg / kg (ND of 10 μg / kg), 1.5 μg / kg (ND of 30 μg / kg) and 5 μg / kg (ND of 100 μg / kg). Assuming a minimum effective ND of 3 μg / kg (5% reduction in PAP), the minimum effective deposited LD is considered as 0.15 μg / kg (see FIG. 1).

[0270] The resulting lung-deposited doses in minipigs of 0.15, 0.5, 1.5 and 5 μg / kg were multiplied by 60 kg to arrive at the lung dose in humans. The FPD reflecting the PAP reduction for a 60 kg human is therefore calculated to be 9, 30, 90 and 300 μg.

[0271] Thus, via direct scale-up from minipigs, the predicted MED for humans (5% PAP reduction) based on a body weight of 60 kg is calculated to be an LDD of 9 μg, without considering protein binding in the airways. As an alternative to the unbound concentration, which is the likely active concentration in the lung, we considered the respective differences in unbound fractions in plasma of minipigs and humans. This consideration results in a minimum effective lung dose (LD) for a 60 kg participant of an LDD of 41 μg for a 5% reduction in PAP. As a result, the predicted minimum human effective dose ranges from an LDD of 9 μg to an LDD of 41 μg, based on a body weight of 60 kg (see FIG. 2).

[0272] [Table 2]

[0273] 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 up to 4 hours) based on the relative lung-deposited doses in minipigs listed in Table 2.

[0274] 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.

[0275] Considering 100 μg / kg as the highest effective dose in the 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.

[0276] In order to address the need for a wide range of lung deposition doses and convert them into technical specifications for the fine particle dose (FPD target) of the dry powder inhalation capsules to be manufactured, several calculations and approximations were made. In general, inhalable products based on powder blend carrier formulations are considered to have excellent performance when a fine particle fraction of more than 20% of the nominal dose is achieved. Furthermore, a higher FPF(%) related to the delivered dose is desired for high-performance inhalation products. The FPF(%) was targeted to be 30% or higher. Taking into account technical and practical considerations (active concentration in the powder blend and capsule fill mass of the blend), the FPD target was then used to establish a defined nominal dose for the final dry powder inhalation capsule. The FPD and DD targets, as well as the corresponding nominal doses, are outlined in the following two Tables 3 and 4.

[0277] [Table 3]

[0278] There is no general binding (e.g., prescriptive) requirement for the relationship between delivered and nominal dose, since this is not definable due to the very different nature of different active ingredients with different properties and their manufactured pharmaceutical formulations. Rather, the uniformity of the delivered dose is defined by the Pharmacopoeia Act to ensure dose-to-dose consistency. The target delivered dose is an empirical parameter resulting from multiple determinations of a defined dosage form in a defined dry powder inhalation device under standardized conditions. The expected average delivered dose should be within 85-115% of the target DD. The minimum delivered dose requirement occupies the lower limit of 85% of the average delivered dose range. The target delivered dose percentage (50% or more to 65% or more of nominal) is defined for all nominal doses, which is not linear and must take into account, in particular, the relatively higher content of active ingredient adhesion on the capsule and device surfaces at lower nominal filled doses.

[0279] [Table 4]

[0280] The pharmaceutical dry powder formulation according to the invention is therefore a suitable medicament for the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0281] Taking into account 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)phenyl]phenyl)-1,3-dimethylphenyl]-2,4-dimethylphenyl] ... The objective of the present invention is 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, 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 combination with a lactose carrier.

[0282] In order to develop suitable inhaled medicaments 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 due to idiopathic interstitial pneumonia (PH-IIP), certain technical and medical needs and requirements for drug substances and drug products need to be met.

[0283] First, the active ingredient (drug substance) should have suitable physicochemical, pharmacokinetic and pharmacodynamic properties. For example, the drug substance should be suitable for inhalation therapy and should have sufficient efficacy to treat cardiopulmonary disorders. Furthermore, the active ingredient should also have a clear efficacy in the contemplated PH form in addition to the standard of care (SoC, 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). The active ingredient should also have further advantageous properties, in particular with regard to high pulmonary selectivity with pulmonary selective action (as opposed to systemic action), low to no VQ mismatch, its pulmonary residence time and / or its duration of action after intrapulmonary administration. Thus, the drug substance should be suitable for chronic treatment regimes / uses. Furthermore, the drug substance should cause improved ventilation, e.g. a bronchodilatory effect, as well as an inhibitory effect on airway hyperresponsiveness and inflammation and should therefore be particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH) as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), e.g. pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0284] 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 formulas (IMI) and (IM-II), should have sustained vasodilatory and bronchodilatory efficacy over a period of more than 12 hours up to 24 hours, the sustained vasodilatory and bronchodilatory efficacy being characterized, for example, by improved pulmonary hemodynamic effects, which may include lower pulmonary vascular resistance (PVR), improved walking distance in the 6-minute walk test, improved pulmonary hemodynamic effects as measured by the New York Health Association (NYHA) and the New York Medical Association (NYHA) guidelines. Therapeutic agents may result in a shift in the pulmonary function (PFoF) (FEV1) or improved lung function, such as a higher FEV1 (the forced expiratory volume a person can exhale in the first second of a forced breath) or lower specific airway resistance (sRaw), a parameter that indicates bronchodilator activity in healthy lungs when administered by inhalation.

[0285] Furthermore, the active ingredient (drug substance) needs to be provided in a defined, stable, crystalline form suitable for dry powder pharmaceutical formulations and corresponding inhalation dosing regimens for the treatment of cardiopulmonary disorders.

[0286] Additionally, the final drug product (formulation) must have suitable properties, such as sufficient chemical stability and sufficient aerosol performance, to deliver the drug substance in sufficient quantities to the target organ, e.g., the lungs, with low to no adverse effects on the patient. Adequate physicochemical stability is required to keep the active ingredient in its chemical structure and avoid unacceptable degradation or stereochemical conversion. More importantly, the physical and geometrical form must be maintained so as not to alter the biopharmaceutical properties that affect the pharmacokinetic behavior of the active ingredient. Stable and adequate aerosol performance means reproducible drug delivery in the sense of average delivered dose and uniformity of delivered dose, as well as reproducible drug delivery of a desirable high fraction of the available nominal drug dose in the final dosage form to the site of action. In practical terms, the majority of the particles of the micronized active ingredient should be recovered as the fine particle dose (alternatively, the mass of fine particles) and fine particle fraction % relative to the delivered dose, when tested by an appropriate analytical method, such as aerodynamic particle size distribution by cascade impaction. The dose and / or nominal dose are included.

[0287] 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 can be produced in larger quantities and in a more reliable manner through improved chemical processes.

[0288] Additionally, the 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).

[0289] 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 accessible by a novel selective crystallization process, preferably the monohydrate form I (IMI) can be selectively obtained by crystallization from methanol, acetone, water.

[0290] 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 format suitable for an inhaled dosage form, a medicament, and an inhaled dosage form, preferably a DPI.

[0291] Surprisingly, preclinical experiments have demonstrated that the sGC activator of formula I, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (=Comparative Example 11), exhibits slower penetration of the saphenous artery in isolated vessels, prolonged recovery coefficient in isolated bronchioles and Lange et al. It has been shown that the compound shows increased washout scores in Langendorff heart experiments (see experimental parts C-1.1 (isolated vessels), C-3.1 (bronchioles) and C-1.2 (Langendorff)) as well as improved pulmonary selectivity and extended duration of action (prolonged selective pulmonary artery pressure (=PAP) reduction without systemic blood pressure (=BP) lowering effect after inhalation application) in PAH animal models (pig and dog) (see experimental parts C-2.1 (pig) and C-2.2 (dog)). These findings support the suitability of Example 11 for a once-daily or twice-daily inhalation treatment regimen containing 240-4000 μg, preferably 480-2000 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 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 (Class 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0292] (5S)-{[2-(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 pulmonary selectivity and duration of action in a miniature pig model (C-2.1). All three compounds show favorable pulmonary selectivity, but only Comparative Example 11 and Comparative Example 4 show sufficient duration of action. Comparative Example 11 shows a selective PAP effect with a maximum effect over the entire observation interval of 240 minutes, while Comparative Example 3 shows its maximum effect on PAP 30 minutes after inhalation application, which is completely eliminated again after 120 minutes. Comparative Example 11 and Comparative Example 4 were evaluated for duration of action in a conscious hypoxic exposure dog model (C-2.2). In this model, Comparative Example 11 showed a consistent long duration of effect (PAP reduction) of up to 17 hours, in contrast to Comparative Example 4. Thus, 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).

[0293] Furthermore, the inventors have demonstrated that the sGC activator of formula I, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (=Comparative Example 11), in the form of monohydrate I of formula (IMI) (Example 4) in a first clinical study (see Experimental Section C-4), exhibits increased cGMP levels as a second messenger molecule for sGC activation and a decrease in the levels of cGMP over a period of more than 12 hours up to 24 hours after dry powder application. We found beneficial bronchodilator properties in healthy volunteers, such as a reduction in total specific airway resistance (sRaw), a parameter indicating bronchodilator activity in the lung, which clinically supports the long lung residence time and supports the suitability of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (=Comparative Example 11) of formula I in the form of monohydrate I of formula (IMI) for successful use in the treatment of cardiopulmonary disease. Up to 4000 μg, no clinically significant effect on systemic blood pressure was observed in healthy volunteers.

[0294] We also found a selective reduction in pulmonary arterial pressure and pulmonary vascular resistance in patients with pulmonary hypertension at doses up to and including 4000 μg, without any clinically relevant effect on systemic blood pressure (see Experimental Section C-4.4). This effect continued without a decrease in response until the end of the 3-hour measurement period (measurement periods longer than 3 hours were technically not feasible). The pulmonary residence time of Example 4 beyond the 3-hour measurement (presumably over a period of more than 12 hours and up to 24 hours after dry powder application) can be concluded from the long plasma half-life measured after inhalation application (see Experimental Section C-4.3).

[0295] Additionally, 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 (C-4.3). The emitted (pulmonary) dose was determined to be 720 μg after inhalation of 1000 μg in humans. The results from this study confirm that the pulmonary dose and half-life are appropriate for inhaled dry powder administration, allowing once-daily treatment for sufficient 24-hour drug coverage of Example 4 in the lungs.

[0296] In conclusion, all the results show that (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, as well as its pseudopolymorphic forms such as (IMI) and (IM-II), in particular the monohydrate I of formula (IMI), are particularly suitable for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP), and are suitable for inhaled dry powder administration allowing once-daily treatment for sufficient 24-hour drug coverage in the lungs of Example 4.

[0297] 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}-phenyl- of formula I in the form of monohydrate form I of formula (IMI) 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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to 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 (=Comparative Example 11) of formula I in the form of monohydrate form I of formula (IMI) for once-daily or twice-daily inhalation treatment regimens including 5,6,7,8-tetrahydroquinoline-2-carboxylic acid (=Comparative Example 11) for two or more consecutive days, preferably over a period of at least 2-7 consecutive days, preferably over a period of at least 14 consecutive days, in particular from the start of treatment over the entire course of the disease.

[0298] Additionally, the 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 (=Comparative Example 11) has beneficial physicochemical properties, such as protein binding and CACO flux (see Experimental Sections C-5.1 (Caco permeability) and C-5.2 (protein binding)), which makes Comparative Example 11 a suitable compound for the local treatment of cardiopulmonary diseases by dry powder inhalation into the lungs. Our data also show that Comparative Example 11, especially in monohydrate form I of formula (IMI), not only exhibited effective reduction of PAP via selective vasodilation in the lungs, but also exhibited longer lasting bronchodilatory properties compared to cinaciguat, which may be beneficial in once-daily or twice-daily inhalation treatment of PH patients with chronic lung disease (group 3 PH) or may even have potential in the treatment of patients with limited lung function, e.g., asthma patients.

[0299] Thus, the drug substance according to the present invention, for example (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (I) as well as its pseudopolymorphic forms (IMI) and (IM-II) have the following excellent main pharmacological properties: ·(5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid is a potent selective sGC activator and offers a new approach in the treatment of PH after inhalation. ·(5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid selectively reduced elevated PAP after inhalation application in different disease-relevant animal models (thromboxane- and hypoxia-exposed rats, pigs and dogs) and had a long duration of action, suggesting once-daily or twice-daily application, preferably once-daily. In a unilaterally ventilated minipig model as a surrogate for VQ mismatch, inhaled application of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid reduced PAP without having a negative effect on oxygenation, in contrast to systemically applied vasodilators. In addition to standard of care (SoC) in PAH (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 minipig model of PAH. The efficacy of (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid was enhanced under experimental conditions of oxidative stress (treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one [ODQ], a highly selective irreversible heme site inhibitor of soluble guanylyl cyclase, and L-Nω-nitroarginine methyl ester [L-NAME]). With regard to ventilation, (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid showed bronchodilatory effects (acetylcholine [ACh] rat model) and inhibitory effects on airway hyperresponsiveness and inflammation (chronic ovalbumin asthma mouse model). 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. The emitted (pulmonary) dose has been determined to be 720 μg following 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, as well as a selective reduction in pulmonary arterial pressure and pulmonary vascular resistance with good local and systemic tolerance up to the highest tested dose of 4000 μg (including 4000 μg).

[0300] Thus, the drug substance of formula (I) according to the present 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, as well as its pseudopolymorphic forms (IMI) and (IM-II), have excellent key pharmacological and pharmacodynamic properties in patients, including reduction in pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR), bronchodilation, e.g. as measured by FEV1, pulmonary selectivity with low to no systemic adverse effects (in particular clinically relevant changes in systemic hemodynamic effects, e.g. in blood pressure or heart rate) and low to no increase in VQ mismatch to avoid associated desaturations, as well as sufficient pulmonary residence time and / or sufficient duration of action following intrapulmonary administration.

[0301] Surprisingly, it has been found that the 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 of formula I, especially in the form of its monohydrate I of formula (IMI), has the potential to successfully control cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP). The concentration of the active ingredient in the lungs can be maintained for a long period of time at a level that is desirable from a medical point of view for optimal treatment. In addition to higher and longer-lasting levels of the active ingredient at the site of the disease, it is possible to simultaneously achieve relatively low systemic concentrations of the active ingredient, which may avoid side effects of drug therapy, such as no clinically relevant systemic blood pressure reduction.

[0302] Surprisingly, the drug substance can be provided in a single, crystalline, chemically stable form, the monohydrate I of formula (IMI), which is also stable under micronization conditions.

[0303] 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. Moreover, the pharmaceutical dry powder formulations according to the present invention can be produced in a technically robust manner by novel processes (e.g., blend uniformity).

[0304] Surprisingly, the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I 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 diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0305] 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, e.g., Comparative Examples 3, 4 and 5, were not known.

[0306] Furthermore, these findings were not foreseeable as pseudopolymorphic forms, in particular stable crystalline hydrates, were not known.

[0307] 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.

[0308] Moreover, it was surprising that modification I (IMI) was available by selective crystallization from methanol, acetone / water.

[0309] Furthermore, inhaled 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 previously unknown.

[0310] The technical object of the present invention is therefore 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 delivery). 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, these attributes being 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 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), with a particulate lactose carrier consisting of a coarse particle fraction and a fine particle fraction.

[0311] 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, the carrier being a lactose carrier, the lactose carrier comprising lactose monohydrate as a mixture of coarse lactose and fine lactose.

[0312] To obtain the pharmaceutical dry powder formulation according to the present invention, it is important a) to adjust a specific ratio between the drug substance and the lactose carrier, and b) to use engineered and customized lactose carriers including lactose monohydrate as a mixture of coarse and fine lactose, and c) to use drug substance and coarse and fine lactose with specific particle sizes, in particular the following specifications: A) 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 monohydrate I 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 X90 of at least 115 μm or at least 120 μm or at least 200 μm and / or X50 of at least 50 μm or at least 75 μm or at least 125 μm, X50 of at least 50 μm, C) fine lactose having a particle size of X90 less than 30 μm or less than 10 μm and / or fine lactose having a particle size of X50 less than 5 μm or less than 10 μm; and the crude lactose content of the formulation / dry powder blend is 94.25%-75% and 98.25%-75%.

[0313] 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 shows excellent aerosol performance (e.g. resulting in high fine particle dose, high fine particle fraction and high delivered dose relative to the nominal dose) and is sufficiently chemically stable over a certain period of time.

[0314] 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, so that they can reach the deep lung region. The strong binding of micronized drug particles onto lactose carrier particles can occur especially 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, surfaces of hard capsules and 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 portion 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, which can be overcome by the energy of the airflow in the dry powder inhalation device, allowing the drug particles to be separated and deagglomerated from the carrier.

[0315] As a result, the optimal temporary binding of micronized active ingredient particles depends on the following technical parameters: A specific ratio of lactose carrier components, i.e., coarse lactose and fine lactose; Selection of specific particle sizes for all components; and further a defined crude lactose content of the formulation / dry powder blend. This is achieved by optimizing and customizing the

[0316] These parameters are important in order to obtain a carrier-based dry powder formulation according to the present invention with excellent aerosol performance.

[0317] Thus, the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of one of its salts or solvates or hydrates, preferably the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula (IMI) The pharmaceutical dry powder formulations according to the invention comprising {-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid monohydrate I are suitable medicaments for the treatment of cardiopulmonary disorders, such as pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), as well as pulmonary hypertension (PH) associated with chronic lung diseases (group 3 PH), such as pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) and pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

[0318] 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 the monohydrate I of formula (IMI) or 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 matrix of a suitable inhalation grade carrier for the active compound. Usually, the amount of active ingredient is 0.5% to 20%, preferably 0.75% to 10%. The amount of active ingredient in the matrix is ​​usually at least 0.75% by weight, or at least 3% by weight, or at least 5% by weight, or at least 10% by weight, based on the ready-to-use preparation. Powder blends with an active ingredient content of 3%, 10% or 20% are highly preferred.

[0319] The solid preparations according to the invention for dry powder inhalation contain the active ingredient (i.e. (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I, preferably (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of the monohydrate I of formula (IMI) or the monohydrate I of formula (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 certain particle size suitable for inhalation application.

[0320] 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, 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 following table.

[0321] [Table 5]

[0322] For inhaled drug products, it is important to guarantee 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).

[0323] The appropriate specifications for particle size distribution of the active ingredient to achieve this requirement have been established as specified in Table 5.

[0324] Therefore, in order to ensure a suitable delivery of the active substance at the target sites, in particular in the deep airways and alveoli, the inventors have prepared a compound comprising 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 of formula I, preferably in the form of monohydrate I of formula (IMI) or monohydrate I of formula (IM-II) It has been found that it is important to provide the (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid in the form of compound II, preferably in the form of monohydrate I of formula (IMI), in a particle size of X90 at most 6 μm and / or X50 at most 1-3 μm and / or X10 at most 1 μm.

[0325] Lactose Carrier The solid preparation according to the invention for dry powder inhalation generally contains a suitable carrier in an amount of about 99.25% or less for the active compound. Usually, the amount of inhalation grade carrier is 99.25%-80%, preferably 99.25%-90%. The amount of carrier in the solid preparation is usually at least 99.25% by weight or at least 97% by weight or at least 95% by weight or at least 90% by weight, based on the dry powder blend.

[0326] A variety of inhalation grade carrier materials are available.

[0327] The inventors have found that superior aerosol performance of formulations for inhalation according to the invention is achieved by selecting lactose as the carrier material.

[0328] Lactose for inhalation is available in different particle size ranges and with different characteristics.

[0329] It is expected that coarse lactose carrier alone, with a particle size distribution centered on a higher particle size compared to the active ingredient, may result in poor aerosol performance due to the relatively strong binding of fine drug particles to the active sites of the coarse carrier particles (Paolo Colombo, Daniela Traini and Francesca Buttini “Inhalation Drug Delivery-Techniques and Products” (published by Wiley-Blackwell 2013). Advanced aerosol performance is characterized by an increased fine particle dose and fraction, as well as an increased delivered dose with respect to the nominal dose. This is expected by the equilibrium between the adhesion of the drug to the carrier and the subsequent separation of the drug from the carrier when the powder is aerosolized, which is often also described as powder or drug dispersion. It can also be expected that the aerosol performance behavior will improve with the addition of fine carrier particles or by the use of lactose materials that contain an inherent fine lactose fraction, although the degree is not predictable (de Boer et al 2012, Grasmejier et al 2013). 2015). As an indication of improved drug dispersion and release from the carrier, cascade impactor measurements are the established method of choice for fine particle dose (alternatively, fine particle mass) and fine particle fraction (the percentage fraction of drug mass having a defined particle size upper limit, e.g., 5 μm or 4.5 μm, relative to the delivered or nominal dose of a single dosage unit). These methods are also established as mandatory quality control methods for inhaled products in current pharmacopoeias (e.g., Pharm Eur. or USP).

[0330] However, the potential effect and its extent of the addition of fine lactose is not predictable since there may be other major effects within the dry powder adhesive mixture that overlap with the fine lactose effect. Very importantly, the properties of the micronized drug itself may have an effect on the adhesive and cohesive properties (e.g., cohesive:adhesive balance (CAB) or surface energy) of binary or ternary mixtures of particles of a particular drug molecule, making predictions even more difficult.

[0331] The inventors have found that the excellent aerosol performance of the formulation for inhalation according to the invention is achieved by selecting fine lactose and coarse lactose as carrier materials having specific particle sizes.

[0332] A coarse lactose material according to the present invention is sieved or milled crystalline a-lactose monohydrate having a low fines content (e.g. commercially available as Lactohale® 100 or Lactohale® 206).

[0333] Coarse lactose according to the invention with a similar particle size distribution may also be selected from other brands, such as Meggle Inhalac® 120 or DFE Respitose® SV010.

[0334] To select the main coarse carrier, a lactose quality with a particle size at least 10 times larger than that of the active ingredient X90 and a low inherent fines content was selected to allow for consistent quality of the majority of the carriers.

[0335] Fine lactose was selected to improve aerosol performance. We assumed that a particle size similar to that of the active ingredient may be suitable to control the temporary binding of the active ingredient particles to the coarse carrier particles, but also other fine lactose particle size specifications were potentially suitable. Therefore, the selection of fine lactose products with particle sizes of X90 less than 10 μm, or X90 less than 30 μm, or X50 less than 5 μm or 1.0-3.0 μm was considered appropriate to constitute the lactose carrier.

[0336] The fine lactose material according to the invention is milled or micronized crystalline a-lactose monohydrate ("fine lactose") having a low particle size of X90 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 characteristics and particle size may also be selected from, for example, Meggle Inhalac® 500. 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).

[0337] Particle size distributions for commercially available lactose for inhalation quality according to the present invention (eg, Lactohale® 100, Lactohale® 300) are summarized in Table 6 below.

[0338] [Table 6]

[0339] Solid formulations according to the invention for dry powder inhalation contain a mixture of coarse lactose (eg Lactohale® 100) and fine lactose (eg Lactohale® 300).

[0340] The inventors have found that the coarse lactose particle size can be varied over a certain range without compromising the aerosol performance or blend uniformity of the carrier-based formulation according to the invention.

[0341] According to the invention, the crude lactose has a X90 particle size of 200-250 μm or 120-160 μm or 115-170 μm or 115-250 μm. Furthermore, according to the invention, the crude lactose has a X90 particle size of 250 μm or less or 170 μm or less or 160 μm or less. Furthermore, according to the invention, the crude lactose has a X90 particle size of at least 115 μm or at least 120 μm or at least 200 μm.

[0342] According to the invention, the crude lactose has a particle size X50 of 125-145 μm or 50-100 μm or 75-95 μm or 50-145 μm. Furthermore, according to the invention, the crude lactose has a particle size X50 of 145 μm or less or 100 μm or less or 95 μm or less. Furthermore, according to the invention, the crude lactose has a particle size X50 of at least 50 μm or at least 75 μm or at least 125 μm and / or a particle size X10 of 45-65 μm or 5-15 μm or 20-50 μm.

[0343] According to the present invention, the fine lactose has a particle size of X90 of 10 μm or less or less than 30 μm, and X50 of 5 μm or less or 1.0-3.0 μm. By using Lactohale 200® with its inherent fine particle content, it is not necessary to add any additional fine lactose particles to the lactose carrier. Thus, the carrier-based formulation can be formulated with Lactohale 200® or similar lactose products with inherent fine lactose content.

[0344] According to the invention, Lactohale 100® and Lactohale 300® are preferred.

[0345] Furthermore, the inventors have found that excellent aerosol performance of the formulation for inhalation according to the invention is achieved by adjusting the specific content of fine lactose and the specific content of coarse lactose in the dry powder blend.

[0346] The inventors have identified the fine lactose content of the lactose carrier as an important critical parameter. In order to obtain a formulation for inhalation according to the invention characterized by good aerosol performance, the content of fine lactose should be selected within a certain range. For example, it has been found that a higher content of fine lactose in the powder blend / lactose carrier, for example a content of 20% or more, has a negative impact on blend uniformity (see, for example, Comparative Example 20). It has been shown that the powder blend and formulation according to the invention can have various contents of fine lactose in the range of 1% to 10%, also 5% to 10%, and the fine lactose content can also be the intrinsic portion of lactose for inhalation, i.e., the portion calculated as X10 of 5 to 15 μm in the case of Lactohale 2000® (see embodiment 34), without compromising aerosol performance.

[0347] According to the present invention, the content of fine lactose in the powder blend is 1%-10%, preferably 5%-10%, preferably 2.5%-7.5%, preferably 5%-7.5%, more preferably 5%.

[0348] 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.

[0349] According to the present invention, the content of crude lactose in the powder blend is 98.25% to 75%, preferably 94.25% to 75%, preferably 92.00% to 75%, more preferably 90.00% to 75%, particularly preferably 90% to 85%.

[0350] The dry powder blend according to the present invention is a ternary mixture, so all three components must be provided in a form with a defined maximum particle size and in a certain ratio.

[0351] The inventors have found that superior aerosol performance of formulations for inhalation according to the invention is achieved by selecting particular ratios of fine and coarse lactose and active ingredient.

[0352] 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.

[0353] 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.

[0354] According to the invention, the ratio of active ingredient of formula (I) or (IMI) to finely divided lactose in the powder blend is from 1:13 to 1:0.1, preferably from 1:13 to 1:0.25, preferably from 1:1.67 to 1:0.25.

[0355] Further excipients The preparations according to the invention can generally contain further pharmacologically acceptable excipients, which include, inter alia, carriers (e.g., inhalation grade lactose, lactose monohydrate, mannitol), dispersants, wetting agents, lubricants (e.g., magnesium stearate), surface active compounds (e.g., sodium lauryl sulfate, distearoylphosphatidylcholine), ionic compounds (e.g., calcium chloride, sodium chloride, potassium chloride), synthetic and natural polymers (e.g., carrageenan, hydroxypropylmethylcellulose, gelatin) or pH adjusters (e.g., sodium hydroxide, sodium chloride, citrate salts, trisodium citrate), colorants (e.g., inorganic pigments, e.g., iron or titanium oxide).

[0356] cavity According to the present invention, the dry powder blend comprising the active ingredient in the form of monohydrate form IMI or IM-II and lactose can be administered via a dry powder inhaler, such as a single unit dose inhaler, where each dose is loaded into the device before use, a multiple unit dose inhaler, where several single doses are individually sealed (pre-metered) and can be discharged into the dosing chamber before each actuation, or a reservoir multiple unit dose inhaler, where a bulk supply of drug is pre-loaded into the device and discharged (metered by the device) into the dosing chamber before each actuation. Preferably, the dry powder blend according to the present invention is administered via a single unit dose inhaler equipped / loaded with a cavity, such as a capsule or blister, that contains the dry powder blend. Preferably, the cavity is an individual capsule, preferably a hard capsule of gelatin or hydroxypropylmethylcellulose, most preferably a hydroxypropylmethylcellulose capsule.

[0357] The dry powder blends containing the active ingredient, for example the micronized monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) according to example 2 or 4, are filled into hard capsules (hydroxypropylmethylcellulose = hypromellose = HPMC, for example size 3) or alternative capsules made of hard gelatin or other suitable materials. The sizes of pharmaceutical hard capsules are standardized and characterized by defined measures, for example a size 3 capsule has a length of 157 mm and a diameter of 57 mm, a size 2 capsule has a length of 176 mm and a diameter of 62 mm, and a size 1 capsule has a length of 194 mm and a diameter of 68 mm.

[0358] 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.

[0359] [Table 7]

[0360] 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.

[0361] The hollow, 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.

[0362] According to the present invention, the following compositions are most preferred:

[0363] [Table 8]

[0364] According to the present invention, a powder blend having an active ingredient of formula (I) or (IMI) content of 3% in the powder blend, containing 480 μg of active ingredient of formula (I) or (IMI), 92% coarse lactose and 5% fine lactose, can be filled into a hard capsule, preferably a size 3 HMPC capsule, as a powder blend with a corresponding mass of 16 mg, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0365] According to the present invention, a powder blend having a content of 10% of the active ingredient of formula (I) or (IMI) in the powder blend, containing 1000 μg, 2000 μg, 3000 μg or 4000 μg of the active ingredient of formula (I) or (IMI), 85% coarse lactose and 5% fine lactose, can be filled (as a corresponding mass of powder blend of 10 mg, 20 mg, 30 mg or 40 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0366] According to the present invention, a powder blend having a content of 20% of the active ingredient of formula (I) or (IMI) in the powder blend, containing 2000 μg, 3000 μg or 4000 μg of the active ingredient of formula (I) or (IMI), 75% coarse lactose and 5% fine lactose, can be filled (as a corresponding mass of powder blend of 10 mg, 15 mg or 20 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, for example, preferably a Plastiape (Berry) RS01 low resistance device.

[0367] [Table 9]

[0368] According to the present invention, a powder blend having an active ingredient of formula (I) or (IMI) content of 30 mg / g in the powder blend, containing 480 μg of active ingredient of formula (I) or (IMI), 14.72 mg of coarse lactose, and 0.8 mg of fine lactose, can be filled into a hard capsule, preferably a size 3 HMPC capsule, as a powder blend with a corresponding mass of 16 mg, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0369] According to the invention, a powder blend having a content of 100 mg / g of active ingredient of formula (I) or (IMI) in the powder blend, containing 1000 μg, 2000 μg, 3000 μg or 4000 μg of active ingredient of formula (I) or (IMI), 8.9 mg, 8.75 mg, 8.5 mg, 17.0 mg, 25.5 mg or 34.0 mg of coarse lactose and 0.1 mg, 0.25 mg, 0.5 mg, 1.0 mg, 1.5 mg or 2.0 mg of fine lactose, can be filled (for a corresponding mass of powder blend of 10 mg, 20 mg, 30 mg or 40 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0370] According to the present invention, a powder blend having a content of 200 mg / g of active ingredient of formula (I) or (IMI) in the powder blend, containing 2000 μg, 3000 μg or 4000 μg of active ingredient of formula (I) or (IMI), 7.5 mg, 11.25 mg or 15.0 mg of coarse lactose and 0.5 mg, 0.75 mg or 1.0 mg of fine lactose, can be filled (for a corresponding mass of powder blend of 10 mg, 15 mg or 20 mg) into a hard capsule, preferably a size 3 HMPC capsule, which can then be administered via a "single unit dose" inhaler, such as, preferably, a Plastiape (Berry) RS01 low resistance device.

[0371] Manufacturing Process The preparations according to the invention may generally be produced by micronising the active ingredient and, optionally, blending the micronised active ingredient with an inert carrier compound, as is customary in the manufacture of inhalable free-flowing medicaments in powder form.

[0372] The compounds according to the invention can be converted into the described administration forms, which can be done in a manner known per se by mixing with inert, non-toxic, pharma- ceutically suitable excipients.

[0373] The dry powder formulation and final product (dry powder blend filled hard capsules) are manufactured according to the following flow chart and instructions.

[0374] [Table 10]

[0375] Step 1: The fine lactose portion was weighed and layered between the two layers of coarse lactose before mixing began.

[0376] Step 2: Mixing of the lactose preblend was carried out in a tumble mixer for 20 minutes at 72 rpm, 67 rpm or 34 rpm or 32 rpm or 30 rpm, preferably 32 rpm, for two cycles. The lactose preblend was sieved through a 500 μg sieve between cycles.

[0377] Step 3: The active ingredient, micronized monohydrate I or II, Example 2 or 4, was sieved through a 500 μm sieve and added to the pre-blended lactose. Prior to the start of the mixing cycle, the lactose pre-blend and active ingredient were layered alternately with six layers of lactose pre-blend and five layers of active ingredient (monohydrate I or II, Example 2 or 4) in between.

[0378] Step 4: The components were mixed in cycles, for example 3-5 cycles, preferably 3 cycles, in a tumble mixer, for example a glass or stainless steel tumble mixer, preferably a stainless steel tumble mixer. Each cycle was carried out at 72 rpm, 67 rpm, 34 rpm or 32 rpm, preferably 32 rpm for 20-30 minutes, preferably 30 minutes (total mixing time of 90 minutes), preferably 30 minutes at 32 rpm, with a rest time of 10 minutes between mixing cycles. If necessary (e.g. visual agglomerates), the blend can be sieved between each blending cycle.

[0379] Step 5: The blend was 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.

[0380] Step 6: Using a capsule filler (eg, MG2 Flexalab), the blend was filled into capsules at the desired fill weight.

[0381] Inhalation Devices In the context of the present invention, the sGC activator, for example Example 2 or 4, is applied as a dry powder or a dry powder formulation by means of a dry powder inhalation device.

[0382] A preferred dry powder inhalation device within the context of the present invention is defined as a capsule-based single unit dose inhaler that is a pre-metered inhalation device (see Figs. 3a and 3b). In the context of the present invention, the dose is applied using the Plastiape (Berry) RS01 low resistance device. This device (in higher resistance types) has been disclosed and described in publications on the treatment of other patient populations, for example cystic fibrosis (CF) or non-CF bronchiectasis (ELKINS et al. Inspiratory Flows and Volumes in Subjects with Cystic Fibrosis Using a New Dry Powder Inhaler Device, The Open Respiratory Medicine Journal, 2014, 8, 1-7 and ELKINS et al. Inspiratory Flows and Volumes in Subjects with Non-CF Bronchiectasis Using a New Dry Powder Inhaler Device, The Open Respiratory Medicine Journal, 2014, 8, 8-13).

[0383] The inhaler operates by inserting a single capsule filled with the dry powder formulation into the device. Two buttons are pressed to puncture the capsule and the user places their mouth around the mouthpiece and inhales deeply and forcefully. The energy from the inhalation draws the drug formulation from the capsule and disperses the powder as an aerosol, and the active ingredient particles are liberated from the lactose carrier particles and carried into the airways. The used capsule is removed and discarded. The device may be reused depending on the patient's therapy requirements and the corresponding markings on the clinical device. The number of capsules administered determines the dose of drug therapy.

[0384] 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).

[0385] Also disclosed in the context of the present invention are devices that can have a receptacle for containing the preparations containing Example 4 or for incorporating these preparations in capsules or blisters and that are suitable for administering the preparations by inhalation in solid form, i.e. aerosolizers, with which the preparations containing the active ingredient, for example Example 2 or 4, which are monohydrates I or II, can be administered by inhalation in solid form (powder inhaler).

[0386] In the case of multiple dose administration, the target plasma concentration (steady state approximation) can be reached after 3 to 5 half-lives (Donald J. Birkett, in "Pharmacokinetics Made Easy", McGraw-Hill Education: 2000; p 20). At steady state, the drug concentration, which rises and falls during each dosing interval, is repeated identically during each dosing interval (Goodman and Gillmans "The Pharmacological Basis of Therapeutics" 7th Edition, Macmillan Publishing Company, New York, 1985, p 28).

[0387] 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 daily, preferably twice daily, particularly preferably once daily.

[0388] However, in appropriate cases, it may be necessary to deviate from the amounts described, especially as a function of body weight, route of administration, individual response to active compound, type of preparation, and the time or interval at which administration is carried out.Thus, in some cases, it may be sufficient to use less than the above-mentioned minimum amount, and in other cases, it must exceed the upper limit described.When relatively large amounts are administered, it may be wise to distribute them over the course of a day in several single doses.

[0389] 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).

[0390] 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 for use in the inhalation treatment of cardiopulmonary disorders, below: 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 salts or solvates or hydrates is administered once daily or twice daily for a period of at least two consecutive days to a patient in need thereof.

[0391] 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 the inhalation treatment of cardiopulmonary disorders, below: 240-4000 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 the crystalline modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. Including, or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) contains peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; Inhalation Form is administered once a day or twice a day for a period of at least two consecutive days to a patient in need thereof.

[0392] 3. The following: 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 of the crystalline modification of said formula (IMI), Including, 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 12.8 and 29.2, preferably 6.9, 7.2, 7.3, 12.8 and 29.2, expressed as 2θ values ​​±0.2°; Inhalation Form 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 it is administered once a day or twice a day for a period of at least 2 consecutive days to a patient in need thereof.

[0393] 4. The following: 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 of the crystalline modification of said formula (IMI), Including, 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 12.8, 16.0 and 25.8, preferably 6.9, 7.2, 7.3, 12.8, 16.0 and 25.8, expressed as 2θ values ​​±0.2°; Inhalation Form (5S)-{[2-(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 the compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0394] 5. The following: 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 of the crystalline modification of said formula (IMI), Including, The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of the crystalline monohydrate I modification of formula (IMI) exhibits in an x-ray diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 20.5 and 25.8, preferably 6.9, 7.2, 7.3, 12.8, 20.5 and 25.8, Inhalation Form (5S)-{[2-(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 compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0395] 6. Below: 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 of the crystalline modification of said formula (IMI), Including, The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of the crystalline modification monohydrate I of formula (IMI) exhibits in an x-ray diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 5.7, 6.9, 7.2, 7.3 and 9.9, Inhalation Form (5S)-{[2-(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 compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0396] 7. Below: 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 of the crystalline modification of said formula (IMI), Including, The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of the crystalline modification monohydrate I of formula (IMI) exhibits in an x-ray diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 5.7 and 16.0, preferably 12.8, 5.7, 6.9, 7.2, 7.3 and 16.0, Inhalation Form 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 compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0397] 8. Below: 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 of the crystalline modification of said formula (IMI), Including, The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of the crystalline modification monohydrate I of formula (IMI) exhibits in an x-ray diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 5.7 and 20.5, preferably 12.8, 5.7, 6.9, 7.2, 7.3 and 20.5, Inhalation Form (5S)-{[2-(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 compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0398] 9. Below: 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 of the crystalline modification of said formula (IMI), Including, The (5S)-{[2-(4-carboxyphenyl)ethyl][2-(2-{[3-chloro-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)-ethyl]-amino}-5,6,7,8-tetrahydroquinoline-2-carboxylic acid of formula I in the form of the crystalline modification monohydrate I of formula (IMI) exhibits in an x-ray diffractogram (at 25°C and with Cu-K alpha 1 as radiation source) at least the following reflections, expressed as 2θ values ​​±0.2°: 12.8, 5.7 and 29.2, preferably 12.8, 5.7, 6.9, 7.2, 7.3 and 29.2, Inhalation Form (5S)-{[2-(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 compound is administered once daily or twice daily for a period of at least 2 consecutive days to a patient in need thereof.

[0399] 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.

[0400] 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 with Cu-Kalpha1 as the radiation source) shown in Figure 6.

[0401] 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-Kalpha1 as the radiation source) shown in Figure 7.

[0402] 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-Kalpha1 as the radiation source) shown in Figure 9.

[0403] 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 therapy of cardiopulmonary disorders according to any one of claims 1 to 13, characterized in that the compound in the crystalline modification monohydrate I of formula (IMI) is stable during micronization.

[0404] 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 at a diffraction angle 2θ value of ±0.2° and lacks peaks at 27.2 and 27.5.

[0405] 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 at least peaks at 12.8 and 5.7 at diffraction angles 2θ values ​​of ±0.2° and lacks peaks at 8.5 and 6.1.

[0406] 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.

[0407] 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.

[0408] 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.

[0409] 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 within a capsule.

[0410] 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.

[0411] 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 pharma- ceutically suitable carrier.

[0412] 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.

[0413] 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 X50 of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has a particle size X50 of less than 10 μm or 5 μm or less.

[0414] 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 an X50 particle size of 145 μm or less or 100 μm or less or 95 μm or less and the fine lactose has an X50 particle size of less than 10 μm or 5 μm or less.

[0415] 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 X90 of 115 μm or more or at least 120 μm or at least 200 μm and the fine lactose has a particle size X90 of less than 30 μm or less than 10 μm.

[0416] 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 an X90 particle size of less than 250 μm or less than 170 μm or less than 160 μm and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0417] 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.

[0418] 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.

[0419] 30. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. 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 therapy of cardiopulmonary disorders according to any one of claims 1 to 29, characterized in that it comprises

[0420] 31. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 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 it comprises

[0421] 32. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 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 it comprises

[0422] 33. The inhalation dosage form comprises: 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 said crystalline form monohydrate 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 for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 1 to 32, characterized in that it comprises

[0423] 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 disorders are 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 due to idiopathic interstitial pneumonia (PH-IIP).

[0424] 35. A method for treating a cardiopulmonary disorder, comprising: below: 240-4000 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 the crystalline modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. Including, or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) contains peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; Inhalation Form should be administered once or twice daily for at least 2 consecutive days. The method comprising:

[0425] 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 shown in Figure 6 (measured at 25°C and using Cu-Kalpha1 as the radiation source).

[0426] 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.

[0427] 38. A method for treating a cardiopulmonary disorder 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 least 12.8 and 5.7 at diffraction angles of 2θ values ​​±0.2°, and lacks peaks at 8.5 and 6.1.

[0428] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 7.

[0429] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 9.

[0430] 41. A method for treating cardiopulmonary disorders according to any one of claims 35 to 40, characterized in that the active ingredient is administered for a period of at least 2 to 7 consecutive days.

[0431] 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.

[0432] 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.

[0433] 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 within a capsule.

[0434] 45. A method for treating cardiopulmonary disorders according to any one of claims 35 to 44, characterized in that the inhalation dosage form contains the active ingredient in combination with a pharma- ceutically suitable carrier.

[0435] 46. ​​A method for treating cardiopulmonary disorders according to any one of claims 35 to 45, wherein the inhalation dosage form comprises lactose monohydrate as a carrier, preferably the carrier comprises a mixture of coarse and fine lactose.

[0436] 47. A method for treating cardiopulmonary disorders according to claim 46, characterized in that the coarse lactose has an X50 particle size of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has an X50 particle size of less than 10 μm or 5 μm or less.

[0437] 48. A method for treating cardiopulmonary disorders according to claim 46 or 47, characterized in that the coarse lactose has an X50 particle size of 145 μm or less or 100 μm or less or 95 μm or less, and the fine lactose has an X50 particle size of less than 10 μm or 5 μm or less.

[0438] 49. A method for treating a cardiopulmonary disorder according to any one of claims 46 to 48, characterized in that the coarse lactose has an X90 particle size of 115 μm or more, or at least 120 μm or at least 200 μm or more, and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0439] 50. A method for treating cardiopulmonary disorders according to any one of claims 46 to 49, characterized in that the coarse lactose has an X90 particle size of 250 μm or less or 170 μm or less or 160 μm or less, and the fine lactose has an X90 particle size of less than 30 μm or 10 μm or less.

[0440] 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.

[0441] 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.

[0442] 53. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. 53. The method for treating cardiopulmonary disorders according to any one of claims 35 to 52, comprising:

[0443] 54. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 54. The method for treating cardiopulmonary disorders according to any one of claims 35 to 53, comprising:

[0444] 55. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 55. The method for treating cardiopulmonary disorders according to any one of claims 35 to 54, comprising:

[0445] 56. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. 56. The method for treating cardiopulmonary disorders according to any one of claims 35 to 55, comprising:

[0446] 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 due to idiopathic interstitial pneumonia (PH-IIP).

[0447] 58. A medicament for use in the inhalation treatment of cardiopulmonary disorders, comprising: The pharmaceutical composition comprises: 240-4000 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 the crystalline modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. An inhalation formulation comprising The present invention is characterized in that it comprises or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 an X-ray powder diffractogram of the compound in the form of the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprises peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; The medicament is administered once daily or twice daily for at least two consecutive days to a patient in need thereof. The said medicine.

[0448] 59. A medicament for use in the 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-Kalpha1 as the radiation source) shown in Figure 6.

[0449] 60. A medicament for use in inhalation treatment of cardiopulmonary disorders as described in 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 of 2θ values ​​±0.2° and lacks peaks at 27.2 and 27.5.

[0450] 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 least 12.8 and 5.7 at diffraction angles of 2θ values ​​±0.2°, and lacks peaks at 8.5 and 6.1.

[0451] 62. A medicine 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 and using Cu-Kalpha1 as the radiation source).

[0452] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 9.

[0453] 64. A medicine for use in 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.

[0454] 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 over the entire course of the disease.

[0455] 66. A medicament for use in 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.

[0456] 67. A medicine 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 within a capsule.

[0457] 68. A medicament for use in 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 pharma- ceutically suitable carrier.

[0458] 69. A pharmaceutical 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.

[0459] 70. A medicament 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 X50 of 50 μm or more or 75 μm or more or 125 μm or more, and the fine lactose has a particle size X50 of less than 10 μm or 5 μm or less.

[0460] 71. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 70, characterized in that the coarse lactose has an X50 particle size of less than 145 μm or less than 100 μm or less than 95 μm, and the fine lactose has an X50 particle size of less than 10 μm or less than 5 μm.

[0461] 72. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 71, characterized in that the coarse lactose has an X90 particle size of 115 μm or more or at least 120 μm or at least 200 μm and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0462] 73. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 72, characterized in that the coarse lactose has an X90 particle size of less than 250 μm or less than 170 μm or less than 160 μm, and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0463] 74. A medicine 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 less than or equal to 6 μm.

[0464] 75. A medicine 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.

[0465] 76. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. 76. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 75, comprising:

[0466] 77. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 77. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 76, comprising:

[0467] 78. The inhalation dosage form comprises: 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 said crystalline form monohydrate I 78. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 77, comprising:

[0468] 79. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. 79. A medicament for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 58 to 78, comprising:

[0469] 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 due to idiopathic interstitial pneumonia (PH-IIP).

[0470] 81. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders, comprising: The packaged pharmaceutical composition comprises: A dry powder inhaler; below: 240-4000 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 the crystalline modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. A dry powder formulation comprising The present invention is characterized in that it contains or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 an X-ray powder diffractogram of the compound in the form of the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprises peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; the package containing instructions for administration of the dry powder formulation once daily or twice daily for a period of at least two consecutive days. The packaged pharmaceutical composition.

[0471] 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 due to idiopathic interstitial pneumonia (PH-IIP).

[0472] 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, the inhalation procedure being described as follows: placing a capsule into the dry powder inhaler, then after one deep inhalation the patient should hold their breath for about 2 seconds, which will concentrate the dry powder drug from the airstream onto the surface of the deeper lung regions and deposit it near its intended site of pharmacological action.

[0473] 84. A packaged pharmaceutical composition for use in 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).

[0474] 85. The packaged pharmaceutical composition comprises: 240-4000 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 the crystalline modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. A dry powder formulation comprising The present invention is characterized in that it contains or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 an X-ray powder diffractogram of the compound in the form of the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprises peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; the packaged pharmaceutical composition does not contain the dry powder inhaler; 85. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 84.

[0475] 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 in the form of monohydrate Form II of formula (IM-II), in combination with lactose monohydrate as a carrier, the carrier comprising a mixture of coarse and fine lactose.

[0476] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 6.

[0477] 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.

[0478] 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 least 12.8 and 5.7 at diffraction angles of 2θ values ​​±0.2° and lacks peaks at 8.5 and 6.1.

[0479] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 7.

[0480] 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 an X-ray powder diffraction pattern (measured at 25°C and using Cu-Kalpha1 as the radiation source) as shown in Figure 9.

[0481] 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.

[0482] 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 and throughout the entire course of the disease.

[0483] 94. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 93, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder.

[0484] 95. A packaged pharmaceutical composition for use in inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 94, characterized in that the inhalation dosage form contains the active ingredient in the form of a dry powder within a capsule.

[0485] 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 an X50 particle size of 50 μm or more, or 75 μm or more, or 125 μm or more, and the fine lactose has an X50 particle size of less than 10 μm or 5 μm or less.

[0486] 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 an X50 particle size of less than 145 μm or less than 100 μm or less than 95 μm, and the fine lactose has an X50 particle size of less than 10 μm or less than 5 μm.

[0487] 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 an X90 particle size of 115 μm or more, or at least 120 μm or at least 200 μm or more, and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0488] 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 an X90 particle size of less than 250 μm or less than 170 μm or less than 160 μm, and the fine lactose has an X90 particle size of less than 30 μm or less than 10 μm.

[0489] 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.

[0490] 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.

[0491] 102. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 101, characterized in that it comprises:

[0492] 103. The inhalation dosage form comprises: 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 said crystalline form monohydrate I A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 102, characterized in that it comprises:

[0493] 104. The inhalation dosage form comprises: 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 said crystalline form monohydrate I A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 103, characterized in that it comprises:

[0494] 105. The inhalation dosage form comprises: 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 said crystalline form monohydrate I. A packaged pharmaceutical composition for use in the inhalation treatment of cardiopulmonary disorders according to any one of claims 81 to 103, characterized in that it comprises:

[0495] Further specific embodiments of the present invention (formulations) 1. A formulation for inhalation comprising: The formulation comprises: 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 one of its salts or solvates or hydrates; b) Lactose carrier at a concentration by weight of 99.25% (w / w) to 80% (w / w) A dry powder blend consisting of The present invention is characterized in that it contains 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 said salts or solvates or hydrates 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 It is further characterized by the fact that e) The lactose has a particle size of X90 of 120 μm or more and / or X50 of 50 μm or more and / or X10 of 5 to 15 μm. The method according to claim 1, The formulation for inhalation. 2. The formulation, (5S)-{[2-(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 crystal modifications selected from the list consisting of monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) or sesquihydrate. The present invention is characterized in that it contains or the X-ray powder diffractogram of the compound of formula (IMI), measured at 25° C. and using Cu—K alpha 1 as the radiation source, comprises peaks at least 12.8 and 29.2, preferably 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. and using Cu—K alpha 1 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 the sesquihydrate (measured at 25° C. and using Cu—K alpha 1 as the radiation source) contains peaks at least 12.2 and 7.6, alternatively 12.2, 8.6 and 14.5, expressed as 2θ values ​​±0.2°; A formulation for inhalation as described in embodiment 1. 3. The formulation, a) monohydrate I of formula (IMI) or monohydrate II of formula (IM-II) in a concentration by weight of 0.75% (w / w) to 20% (w / w), 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 as the active ingredient in the form of monohydrate I of formula (IMI), 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 radiation source) shows at least the following reflections, expressed as 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); A dry powder blend consisting of a combination of The present invention is characterized in that it contains 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 consists of coarse and fine lactose. It is further characterized by the fact that e) the coarse lactose has an X50 particle size of 50 μm or more, or 75 μm or more, or 125 μm or more, f) the fine lactose has a particle size of X50 less than 10 μm or 5 μm or less; g) The crude lactose content of the dry powder blend is between 98.25% and 75%, preferably between 94.25% and 75%. The method according to claim 1, A formulation for inhalation according to embodiment 1 or 2. 4.e) the coarse lactose has an X50 particle size of 145 μm or less, or 100 μm or less, or 95 μm or less, f) The fine lactose has a particle size of X50 less than 10 μm or less than 5 μm 4. A formulation for inhalation according to any one of embodiments 1 to 3, characterized in that 5.e) the coarse lactose has an X90 particle size of at least 115 μm or at least 120 μm or at least 200 μm; f) The fine lactose has a particle size of X90 less than 30 μm or less than or equal to 10 μm. 5. A formulation for inhalation according to any one of embodiments 1 to 4, characterized in that 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) The fine lactose has a particle size of X90 less than 30 μm or less than or equal to 10 μm. 6. A formulation for inhalation according to any one of embodiments 1 to 5, characterized in that 7. A process for producing the formulation comprising: j) with or without sieving between mixing cycles, preferably without sieving and with a rest time of at least 10 minutes between mixing cycles 7. A formulation for inhalation according to any one of embodiments 1 to 6, characterized in that 8. During the process for producing the formulation, k) Glass containers are not used, stainless steel containers are used 8. A formulation for inhalation according to any one of embodiments 1 to 7, characterized in that 9. Formulation for inhalation according to any one of embodiments 1 to 8, characterized in that the content of fine lactose in the dry powder blend is from 1% to a maximum of 15%, from 1% to 10% or from 5% to 10%. 10. A formulation for inhalation according to any one of embodiments 1 to 9, characterized in that the ratio of active ingredient to crude lactose is between 1:126 and 1:3.8. 11. A formulation for inhalation according to any one of embodiments 1 to 10, characterized in that the ratio of active ingredient to crude lactose is between 1:31 and 1:3.8. 12. A formulation for inhalation according to any one of embodiments 1 to 11, characterized in that the ratio of active ingredient to crude lactose is 1:31. 13. A formulation for inhalation according to any one of embodiments 1 to 12, characterized in that the ratio of active ingredient to crude lactose is 1:8.5. 14. A formulation for inhalation according to any one of embodiments 1 to 13, characterized in that the ratio of active ingredient to crude lactose is 1:3.8. 15. A preparation for inhalation according to any one of embodiments 1 to 14, characterized in that the ratio of active ingredient to finely divided lactose is between 1:13 and 1:0.1. 16. A preparation for inhalation according to any one of embodiments 1 to 15, characterized in that the ratio of active ingredient to finely divided lactose is between 1:1.67 and 1:0.25. 17. A formulation for inhalation according to any one of embodiments 1 to 16, characterized in that the ratio of active ingredient to finely divided lactose is 1:1.67. 18. A formulation for inhalation according to any one of embodiments 1 to 17, characterized in that the ratio of active ingredient to finely divided lactose is 1:0.5. 19. A formulation for inhalation according to any one of embodiments 1 to 18, characterized in that the ratio of active ingredient to finely divided lactose is 1:0.25 or 1:0.1. 20. A formulation for inhalation according to any one of embodiments 1 to 19, characterized in that the ratio of the coarse lactose to the fine lactose is from 445:5 to 65:5 or from 94.25:5 to 65:5. 21. A formulation for inhalation according to any one of embodiments 1 to 20, characterized in that the ratio of the coarse lactose to the fine lactose is 92:5. 22. A formulation for inhalation according to any one of embodiments 1 to 21, characterized in that the ratio of the coarse lactose to the fine lactose is 85:5. 23. A formulation for inhalation according to any one of embodiments 1 to 22, characterized in that the ratio of the coarse lactose to the fine lactose is 75:5. 24. A formulation for inhalation according to any one of embodiments 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). 25. Formulation for inhalation according to any one of embodiments 1 to 24, 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 monohydrate I of formula (IMI) has a particle size X50 of 1 to 3 μm. 26. A formulation for inhalation according to any one of embodiments 1 to 25, characterized in that the active i...

Claims

1. A compound of the formula:

1. A pharmaceutical comprising a crystalline form of the monohydrate of the method comprises administering to a subject about 240 μg to about 4000 μg of the monohydrate crystalline form; an X-ray powder diffractogram of the monohydrate crystalline form (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprising at least one reflection at 6.9 ± 0.2° 2θ, 7.2 ± 0.2° 2θ, 7.3 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 15.2 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 23.0 ± 0.2° 2θ, 25.8 ± 0.2° 2θ, or 29.2 ± 0.2° 2θ; The medicine.

2. The pharmaceutical described in claim 1, wherein in the method, the monohydrate crystalline form is administered in an inhaled dosage form.

3. The pharmaceutical described in claim 2, wherein the inhalation dosage form comprises the crystalline form of the monohydrate as a dry powder.

4. The pharmaceutical described in claim 3, wherein the dry powder is contained in a capsule.

5. A pharmaceutical described in any one of claims 2 to 4, wherein the inhalation dosage form further contains lactose monohydrate.

6. The pharmaceutical described in claim 5, wherein the lactose monohydrate comprises coarse lactose and fine lactose.

7. The pharmaceutical described in claim 1, wherein in the method, the monohydrate crystalline form is administered via a dry powder inhaler.

8. A method for treating or preventing cardiopulmonary disorders in a subject, comprising administering to a subject a compound of formula (I) comprising:

1. A pharmaceutical comprising a dry powder formulation comprising a crystalline form of the monohydrate of the method comprising administering the dry powder formulation to a subject via a dry powder inhaler; an X-ray powder diffractogram of the monohydrate crystalline form (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprising at least one reflection at 6.9 ± 0.2° 2θ, 7.2 ± 0.2° 2θ, 7.3 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 15.2 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 23.0 ± 0.2° 2θ, 25.8 ± 0.2° 2θ, or 29.2 ± 0.2° 2θ; The medicine.

9. A method for treating or preventing cardiopulmonary disorders in a subject, comprising administering to a subject a compound of formula (I) comprising:

1. A pharmaceutical comprising a dry powder formulation comprising a crystalline form of the monohydrate of the method comprising administering the dry powder formulation, which is located within a capsule, to a subject via a dry powder inhaler; an X-ray powder diffractogram of the monohydrate crystalline form (measured at 25° C. and using Cu—K alpha 1 as the radiation source) comprising at least one reflection at 6.9 ± 0.2° 2θ, 7.2 ± 0.2° 2θ, 7.3 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 15.2 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 23.0 ± 0.2° 2θ, 25.8 ± 0.2° 2θ, or 29.2 ± 0.2° 2θ; The medicine.

10. A pharmaceutical described in any one of claims 1, 8 and 9, wherein the monohydrate crystalline form has reflections in an X-ray powder diffractogram at 12.8 ± 0.2°2θ and 29.2 ± 0.2°2θ.

11. The pharmaceutical composition of claim 10, wherein the monohydrate crystalline form has at least one additional reflection at 6.9 ± 0.2°2θ, 7.2 ± 0.2°2θ, 7.3 ± 0.2°2θ, 15.2 ± 0.2°2θ, or 23.0 ± 0.2°2θ.

12. A pharmaceutical described in any one of claims 1, 8 and 9, wherein the monohydrate crystalline form has X-ray powder diffractogram reflections at 12.8 ± 0.2°2θ, 16.0 ± 0.2°2θ, and 25.8 ± 0.2°2θ.

13. The pharmaceutical described in claim 12, wherein the monohydrate crystalline form has at least one additional reflection at 6.9 ± 0.2°2θ, 7.2 ± 0.2°2θ, 7.3 ± 0.2°2θ, or 15.2 ± 0.2°2θ.

14. A pharmaceutical described in any one of claims 1, 8 and 9, wherein the monohydrate crystalline form has X-ray powder diffractogram reflections at 12.8 ± 0.2°2θ, 20.5 ± 0.2°2θ, and 25.8 ± 0.2°2θ.

15. The pharmaceutical composition of claim 14, wherein the monohydrate crystalline form has at least one additional reflection at 6.9 ± 0.2°2θ, 7.2 ± 0.2°2θ, 7.3 ± 0.2°2θ, 15.2 ± 0.2°2θ, or 25.1 ± 0.2°2θ.

16. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered at a dose of about 480 μg to about 4000 μg.

17. The pharmaceutical described in claim 8 or 9, wherein the method involves administering the dry powder formulation containing about 480 μg to about 4000 μg of the monohydrate crystalline form.

18. The pharmaceutical described in claim 16, wherein in the method, the monohydrate crystalline form is administered at a dose of about 480 μg to about 2000 μg.

19. The pharmaceutical described in claim 17, wherein the method involves administering the dry powder formulation containing about 480 μg to about 2000 μg of the monohydrate crystalline form.

20. The pharmaceutical described in claim 16, wherein in the method, the monohydrate crystalline form is administered at a dose of approximately 1000 μg.

21. The pharmaceutical described in claim 17, wherein the dry powder formulation containing approximately 1000 μg of the monohydrate crystalline form is administered in the method.

22. The pharmaceutical described in claim 16, wherein in the method, the monohydrate crystalline form is administered at a dose of approximately 2000 μg.

23. The pharmaceutical described in claim 17, wherein the method involves administering the dry powder formulation containing approximately 2000 μg of the monohydrate crystalline form.

24. The pharmaceutical described in claim 16, wherein in the method, the monohydrate crystalline form is administered at a dose of approximately 4000 μg.

25. The pharmaceutical described in claim 17, wherein the dry powder formulation containing approximately 4000 μg of the monohydrate crystalline form is administered in the method.

26. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation further contains lactose monohydrate.

27. The pharmaceutical composition of claim 26, wherein the lactose monohydrate comprises coarse lactose and fine lactose.

28. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered once a day or twice a day.

29. The pharmaceutical described in claim 8 or 9, wherein in the method, the dry powder formulation is administered once a day or twice a day.

30. The pharmaceutical described in Claim 28, wherein in the method, the monohydrate crystalline form is administered once a day.

31. The pharmaceutical described in Claim 29, wherein in the method, the dry powder formulation is administered once a day.

32. The pharmaceutical described in claim 28, wherein the monohydrate crystalline form is administered twice daily.

33. The pharmaceutical described in Claim 29, wherein in the method, the dry powder formulation is administered twice a day.

34. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered over a period of at least two consecutive days.

35. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation is administered over a period of at least two consecutive days.

36. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered over a period of about 2 to about 5 consecutive days.

37. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation is administered over a period of about 2 to about 5 consecutive days.

38. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered for a period of about 2 to about 7 consecutive days.

39. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation is administered for a period of about 2 to about 7 consecutive days.

40. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered for a period of at least 5 consecutive days.

41. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation is administered for a period of at least 5 consecutive days.

42. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered for a period of at least 7 consecutive days.

43. A pharmaceutical described in claim 8 or 9, wherein in the method, the dry powder formulation is administered for a period of at least 7 consecutive days.

44. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered for a period of at least 14 consecutive days.

45. The pharmaceutical described in claim 8 or 9, wherein the dry powder formulation is administered for a period of at least 14 consecutive days.

46. A pharmaceutical described in any one of claims 1 to 4, wherein in the method, the monohydrate crystalline form is administered after the onset of cardiopulmonary disorder.

47. The pharmaceutical described in claim 8 or 9, wherein in the method, the dry powder formulation is administered after the onset of cardiopulmonary disorder.

48. A pharmaceutical described in any one of claims 1, 8 and 9, wherein the cardiopulmonary disorder is selected from pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH) associated with chronic lung disease (group 3 PH).

49. The pharmaceutical composition of claim 48, wherein the pulmonary hypertension (PH) associated with a chronic lung disease (group 3 PH) is pulmonary hypertension in chronic obstructive pulmonary disease (PH-COPD) or pulmonary hypertension due to idiopathic interstitial pneumonia (PH-IIP).

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