Salts of triazolone derivatives as neutrophil elastase inhibitors.

Abstract

The present invention generally relates to novel triazolone derivative salts, particularly useful as neutrophil elastase inhibitors, and their use as pharmaceuticals; the present invention also relates to methods for their synthesis and pharmaceutical compositions. The present invention also relates to methods for the isolation by crystallization of compound (I). The present invention also relates to crystalline forms of the compound of formula (I).

Description

[Technical field]

[0001] The present invention generally relates to novel triazolone derivative salts, particularly useful as neutrophil elastase inhibitors, and their use as pharmaceuticals; the present invention also relates to methods for their synthesis and pharmaceutical compositions. The present invention also relates to methods for the isolation by crystallization of compound (I). The present invention also relates to crystalline forms of the compound of formula (I). [Background technology]

[0002] Human neutrophil elastase (HNE) is a 32 kDa serine proteinase found in azurophilic granules of neutrophils. It plays a role in the degradation of a wide range of extracellular matrix proteins, including fibronectin, laminin, proteoglycans, collagens III and IV, and elastin (Bieth, G. In Regulation of Matrix accumulation, Mecham, RP (Eds), Academic Press, NY, USA 1986, 217-306). HNE has long been thought to play an important role in homeostasis by repairing and disposing of damaged tissues via the degradation of tissue structural proteins. HNE has also been implicated in the defense against bacterial invasion by the degradation of bacterial bodies. In addition to its effects on matrix organization, HNE has been implicated in the upregulation of IL-8 gene expression and also induces IL-8 release from lung epithelial cells. In animal models of chronic obstructive pulmonary disease induced by cigarette smoke exposure, both small molecule and protein inhibitors of HNE suppress the inflammatory response and the development of emphysema (Wright, JL et al. Am. J. Respir. Crit. Care Med. 2002, 166, 954-960; Churg, A. et al. Am. J. Respir. Crit. Care Med. 2003, 168, 199-207). Thus, HNE is a key mediator of lung tissue degradation and inflammation (KM Heutinck, IJ ten Berge, CE Hack, J. Hamann, AT Rowshani, Mol. Immunol., 47 (11-12) (2010), 1943-55) and may play a role in both matrix breakdown and amplification of the inflammatory response in chronic respiratory diseases characterized by neutrophil influx. Indeed, HNE is thought to play a role in several pulmonary diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), emphysema, pneumonia, and pulmonary fibrosis. It is also involved in several cardiovascular diseases involving tissue remodeling, such as the development of ischemic tissue injury after acute myocardial infarction.

[0003] Excessive HNE activity has been implicated in the pathology of inflammatory lung diseases, including bronchiectasis (BE), and therefore this protein has been identified as a target for drug development (B. Schaaf, A. Wieghorst, S.-P. Aries, K. Dalhoff, J. Braun, Respiration, 67 (1) (2000), 52-59).

[0004] To date, several human neutrophil inhibitors have been disclosed in the art.

[0005] In particular, International Patent Applications WO 2011 / 110858 and WO 2011 / 110859 describe certain pyrimidine derivatives having human neutrophil elastase inhibitory properties and their use in therapy.

[0006] WO 2014 / 095700 describes several triazolone derivatives having human neutrophil elastase inhibitory properties and their use in therapy, in particular several salts of the compound (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium as neutrophil elastase inhibitors.

[0007] As noted above, although several HNE inhibitors have been disclosed to date, there remains a need for further HNE inhibitors.

[0008] Of particular advantage would be the identification of further HNE inhibitors that have a safer profile, also in terms of patient tolerance and local adverse effect profile, particularly suitable for administration as an inhaled treatment.

[0009] The present invention fulfills the above-mentioned needs by providing the compound of the present invention, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I). Summary of the Invention

[0010] In a first aspect, the present invention provides (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I). [ka]

[0011] In a second aspect, the present invention provides a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0012] In a further aspect, the present invention provides (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) for use as a medicament.

[0013] In a further aspect, the present invention provides a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0014] In another aspect, the present invention provides the use of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) for the manufacture of a medicament.

[0015] In another aspect, the present invention provides (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) for use in the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0016] In another aspect, the present invention provides (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) for the manufacture of a medicament for the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0017] In a further aspect, the present invention provides a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use in the prophylaxis and / or treatment of an inflammatory or obstructive respiratory disease.

[0018] In a further aspect, the present invention provides the use of a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients in the manufacture of a medicament for the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0019] In another embodiment, the present invention provides a method for the prevention and / or treatment of inflammatory or obstructive respiratory diseases comprising administering an effective amount of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I).

[0020] In a further aspect, the present invention provides a method for the prevention and / or treatment of an inflammatory or obstructive respiratory disease comprising administering an effective amount of a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0021] In another aspect, the present invention provides a process for preparing a compound of formula (I) by reacting a triazolone derivative of formula (II) with a xinafoate salt of formula (III), comprising the steps of: [ka] Next step: 1) (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium salt (II) [ka] [In the formula, X - is any organic or inorganic anion. Dissolve in water; 2) Formula (III): [ka] [In the formula, Y + is an alkali or alkaline earth metal cation. Add a solution of xinafoate The present invention provides a method comprising:

[0022] In a further embodiment, the present invention also refers to a method for preparing a compound of formula (I), further comprising step 3) of washing the compound of formula (I) obtained in steps 1) and 2) with one or more aqueous or organic solvents.

[0023] In another embodiment, the present invention refers to a crystalline form of the compound of formula (I), said crystals being characterized by at least one of the following XRPD peaks: 8.6, 9.9, 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

[0024] In another embodiment, the present invention also refers to a crystalline form of the compound of formula (I), said crystalline form being obtained by the above steps 1) to 3).

[0025] In a further aspect, the present invention provides a crystalline form of a compound of formula (I) for use as a medicament.

[0026] In a further aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use as a medicament.

[0027] In another aspect, the present invention provides the use of a crystalline form of compound of formula (I) as defined above for the manufacture of a medicament for the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0028] In a further aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of compound of formula (I) as defined above and one or more pharma- ceutically acceptable carriers and / or excipients for use in the prophylaxis and / or treatment of an inflammatory or obstructive respiratory disease.

[0029] In a further aspect, the present invention provides the use of a pharmaceutical composition comprising a crystalline form of compound of formula (I) as defined above and one or more pharma- ceutically acceptable carriers and / or excipients for the manufacture of a medicament for the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0030] In another aspect, the present invention provides a method for the prevention and / or treatment of inflammatory or obstructive respiratory diseases comprising administering an effective amount of a crystalline form of compound of formula (I) as defined above.

[0031] In a further aspect, the present invention provides a method for the prevention and / or treatment of an inflammatory or obstructive respiratory disease comprising administering an effective amount of a pharmaceutical composition comprising a crystalline form of a compound of formula (I) as defined above and one or more pharma- ceutically acceptable carriers and / or excipients. [Brief description of the drawings]

[0032] [Figure 1] 1 shows the XRPD of compound (I). 2θ (°) corresponds to 2θ (degrees). [Diagram 2] The 1H NMR of compound (I) is shown.

[0033] Detailed Description of the Invention definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0034] The term "compound of the invention" refers to (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I).

[0035] The term "xinafoate", also referred to as hydroxynaphthoate or salt of 1-hydroxy-2-naphthalene, refers to a salt from the hydroxynaphthoic acid anion, in which the stoichiometric ratio of 2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium cation to the hydroxynaphthoate anion is 1:1.

[0036] The term "alkali or alkaline earth metal cation" is intended to denote a cation of a metallic element selected from sodium, potassium, magnesium and calcium.

[0037] The compounds of the present invention have one stereocenter, namely the one represented below by the carbon atom (1) bearing an *, and therefore may exist as multiple optical stereoisomers. [ka]

[0038] It is to be understood that in addition to compounds of formula (I) of the present invention exhibiting the preferred (R) configuration on carbon atom (1), the racemates and enantiomers (S) are encompassed within the scope of the present invention.

[0039] The term "composition," as in pharmaceutical composition, is intended to encompass a product comprising active ingredients and any pharma- ceutically acceptable excipients or carriers, as well as products that result directly or indirectly from the combination, complexation or aggregation of any two or more components, or dissociation of one or more components, or other type of reaction or interaction of one or more components.

[0040] Accordingly, the pharmaceutical compositions of the present invention encompass any type of composition made by admixing a compound of the present invention and pharma- ceutically acceptable excipients and / or carriers.

[0041] The xinafoate salt of formula (I) is characterised by having physicochemical characteristics which make it particularly suitable for administration, also in terms of physicochemical characteristics, patient tolerance and local adverse effects profile.

[0042] In this respect, advantageously, the xinafoate salt according to the compound of formula (I) of the invention exhibits the following: 1) As described in Biological Assay Example 2.1, it shows unexpectedly superior activity in pharmacodynamic models versus the methanesulfonate salt when administered as a dry powder, which is particularly unexpected given the poor solubility of the xinafoate salt versus the methanesulfonate salt. and 2) When administered as a dry powder, it showed a very favorable irritation profile in HOP (head out plethysmography) tests in conscious rats compared to the methanesulfonate, bromide and acetate salts, suggesting a possible safer profile in humans as well, as described and commented in this Example 2.1.

[0043] In view of the above, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt maintains good efficacy in HNE inhibition in vivo despite its low solubility relative to the methanesulfonate salt and also when administered as a dry powder formulation.

[0044] Furthermore, in the head-out plethysmography (HOP) assay, the xinafoate salt of formula (I) leads to an improvement in pulmonary function parameters, in contrast to the other salts of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium, the methanesulfonate, bromide and acetate, suggesting that this salt is particularly suitable for administration, also in terms of patient tolerability and local adverse effects profile.

[0045] In view of the above, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt maintains good efficacy in inhibiting HNE in vivo and also when administered as a dry powder formulation.

[0046] As mentioned above, the present invention provides (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I). [ka]

[0047] The present invention also relates to a process for the preparation of a compound of formula (I) by reacting a salt of formula (II) as specified above with a xinafoate salt of formula (III), comprising the following steps: 1) X -is an organic or inorganic anion, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium salt (II) is dissolved in water; 2) Y + is an alkali or alkaline earth metal cation. The present invention relates to a method for

[0048] The present invention also relates to X - is an organic or inorganic anion, preferably an anion selected from the group consisting of methanesulfonate, acetate, iodide and bromide.

[0049] In another preferred embodiment, the present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of: - The present invention provides a process for the preparation of a compound of formula (I) by reacting a compound of formula (II) in which

[0050] In another preferred embodiment, the present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of: - The present invention provides a process for the preparation of a compound of formula (I) by reacting a compound of formula (II) in which

[0051] In another preferred embodiment, the present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of: - The present invention provides a process for the preparation of a compound of formula (I) by reacting a compound of formula (II) in which

[0052] In a further preferred embodiment, the present invention provides a method for the preparation of a medicament comprising the steps of: + is sodium or potassium, with sodium being more preferred.

[0053] In yet another preferred embodiment, the present invention also provides a process for preparing a compound of formula (I) by reacting a compound of formula (II) with a xinafoate salt of formula (III), wherein the molar ratio of formulas (II) and (III) is 1:1.

[0054] In another preferred embodiment, the present invention provides a method for preparing a compound of formula (I), further comprising step 3) of washing the compound of formula (I) obtained according to steps 1) and 2) with one or more aqueous or organic solvents, the solvent being preferably water, acetone or a mixture thereof.

[0055] In a further preferred embodiment, the present invention provides a method for preparing a compound of formula (I), wherein the solvent used for washing the compound of formula (I) obtained according to steps 1) and 2) is an aqueous or organic solvent.Preferably, the solvent is water, acetone or a mixture thereof.

[0056] In another preferred embodiment, the present invention provides a crystalline form of compound of formula (I), wherein said crystalline form is characterized by at least one of the following XRPD peaks: 8.6, 9.9 and 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

[0057] In another embodiment, the present invention provides a crystalline form of compound of formula (I), wherein said crystalline form is characterized by the following XRPD peaks: 8.6, 9.9 and 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

[0058] In another preferred embodiment, the present invention provides a crystalline form of compound of formula (I), wherein said crystalline form is characterized by the following XRPD peaks: 8.6, 9.9, 10.7, 11.0 and 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

[0059] In another preferred embodiment, the present invention provides a crystalline form of compound of formula (I), said crystalline form being characterized by the following XRPD peaks: 8.6, 9.9, 10.7, 11.0, 13.0, 15.3, 19.3, 19.7, 23.2 and 27.6±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

[0060] In another preferred embodiment, the present invention provides a crystalline form of the compound of formula (I), preferably, said crystals are obtained according to steps 1) to 3) as defined above.

[0061] In another preferred embodiment, the present invention provides a crystalline form for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0062] In a further preferred embodiment, the present invention provides a crystalline form as defined above for use in the prevention and / or treatment of an inflammatory or obstructive respiratory disease selected from asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking induced emphysema and cystic fibrosis.

[0063] In a further preferred embodiment, the present invention provides a pharmaceutical composition for inhalation comprising a crystalline form of the compound of formula (I) in combination with suitable carriers and / or excipients.

[0064] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0065] Suitable excipients may be selected from those in the art and may include carriers, diluents, wetting agents, emulsifiers, binders, coating agents, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffer substances, etc. Examples of excipients and their uses are provided in Handbook of Pharmaceutical Excipients, 5th ed. (2006), Ed. Rowe et al., Pharmaceutical Press.

[0066] The most suitable dosage level can be determined by any known suitable method.However, it is understood that the specific amount for any particular patient depends on various factors, including the activity of the compound of formula (I), the patient's age, weight, diet, general health and sex, administration time, administration route, excretion rate, the use of any other drugs and the severity of the disease being treated.

[0067] For inhalation delivery, the active compounds of formula (I) are preferably in the form of microparticles, which may be prepared by a variety of techniques, including spray drying, freeze drying and micronization.

[0068] In some embodiments, the compositions of the present invention are prepared as a suspension suitable for delivery from a nebulizer or as an aerosol in a liquid propellant, more preferably for use in a pressurized metered dose inhaler (pMDI). Propellants suitable for use in pMDIs are known to those skilled in the art and include HFA-227, preferably HFA-134a and, more preferably, HFA152a.

[0069] In a preferred embodiment, the compositions of the invention are in dry powder form for delivery using a dry powder inhaler (DPI).

[0070] For delivery by administration, microparticles can be formulated with excipients that aid delivery and release.For example, in dry powder formulation, microparticles can be formulated with large carrier particles that aid in the flow from DPI to lungs.Suitable carrier particles are known in the art, and include, for example, lactose particles.

[0071] The agent of the present invention can be administered in inhalation form.Aerosol generation can be carried out, for example, by using pressure-driven jet nebulizer or ultrasonic nebulizer, preferably by using propellant-driven metered-dose aerosol, or for example, by inhalation capsule, or for example, by propellant-free administration of fine particles of the compound of formula (I) from inhalation capsule or other "dry powder" delivery system.

[0072] As mentioned above, the present invention relates to compounds of general formula (I) for use as medicaments.

[0073] According to a preferred embodiment, the present invention refers to the use of a xinafoate salt of formula (I) for the manufacture of a medicament for the treatment of an inflammatory or obstructive pulmonary disease. Preferably, the disease is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema and cystic fibrosis.

[0074] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients, for use as a medicament.

[0075] In a preferred embodiment, the invention relates to compounds of formula (I) for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0076] In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0077] In a further preferred embodiment, the present invention provides a method for the prevention and / or treatment of inflammatory or obstructive respiratory diseases comprising administering an effective amount of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate of formula (I).

[0078] In another preferred embodiment, the present invention provides a method for the prevention and / or treatment of an inflammatory or obstructive respiratory disease comprising administering an effective amount of a pharmaceutical composition comprising (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0079] In yet another preferred embodiment, said inflammatory or obstructive respiratory disease is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema and cystic fibrosis.

[0080] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of formula (I).

[0081] The magnitude of prophylactic or therapeutic dose of a compound of formula (I) will, of course, depend on the nature of the severity of the condition to be treated and its route of administration, and will generally be determined by clinical trials required in the medical arts.

[0082] It will also vary according to the age, weight and response of the individual patient.

[0083] In therapeutic use, the compounds of formula (I) may be administered by any convenient, suitable or effective route.

[0084] Suitable routes of administration are known and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (by inhalation).

[0085] The active compound of formula (I) can be administered as described according to the inhalation system used.In addition to the active compound, the dosage form further comprises excipients such as propellant (e.g. Frigen for metered dose aerosol), surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose for powder inhalers), or if appropriate, further active compound.

[0086] For inhalation purposes, numerous systems are available that generate an aerosol of optimal particle size and can be administered to the patient using an appropriate inhalation technique. In the case of metered dose aerosols, especially powder inhalers, numerous technical solutions are available (e.g. Diskhaler, Rotadisk, Turbohaler, or inhalers, e.g. as described in EP-A-0505321) in addition to the use of adapters (spacers, expanders) and pear-shaped containers (e.g. Nebulator, Volumatic) and automatic devices that release puffer sprays (Autohaler).

[0087] In a more preferred embodiment, the present invention provides a process for the preparation of compounds of formula (I) of the present invention by the general synthetic route depicted in Scheme A below. [ka] Scheme A:X - is an organic or inorganic anion, preferably selected from the group consisting of methanesulfonate, acetate and bromide; Y +is an alkali or alkaline earth metal cation, preferably selected from the group consisting of sodium and potassium.

[0088] As shown in Example 1, the compound of formula (I) of the present invention can be obtained, for example, according to the method described in WO 2014 / 095700, by preparing (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-methanesulfonate salt of formula (II), dissolving in an aqueous or organic solvent such as water, and adding sodium or potassium xinafoate salt of formula (III) in a suitable aqueous or organic solvent, preferably in water, under mechanical stirring to obtain a precipitate of xinafoate salt, which is filtered, washed with an aqueous or organic solvent such as water or acetone, and then adding an aqueous or organic solvent, preferably acetone, preferably in the range of 2 to 10 ml, sonicating for a suitable time, preferably at intervals of 5 to 20 minutes, drying under reduced pressure to obtain a crystalline form.

[0089] Similarly, the salts of the compound of formula (I) of the present invention can be obtained using any water-soluble salt of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium.

[0090] The methods that may be used and are described and illustrated in the examples should not be construed as limiting the scope of synthetic methods available for preparing the compounds of the present invention.

[0091] The compounds used as starting materials or intermediates may be commercially available, their preparation may be specifically described in the literature, or they may be prepared according to methods available in the literature or known to those skilled in the art.

[0092] The described method is particularly advantageous since it can be appropriately adjusted to reach the desired synthetic purity of the product by any suitable modification known to those skilled in the art to obtain the desired compound of the present invention. Such modifications are included within the scope of the present invention.

[0093] The following examples illustrate the invention without limiting its scope. EXAMPLES

[0094] [Table 1]

[0095] X-ray powder diffraction (XRPD) The crystalline state of the samples was investigated by X-ray powder diffraction (Empyrean V2.0, Panalytical) equipped with a Cu irradiation source (CuKαλ=1.5406 Å). Samples were placed on a Si zero-background sample holder rotating with a rotation time of 4 s. Measurements were performed in reflection mode, 2θ scan from 1.5 to 45°, step width 0.02°, Soller slits 0.02 rad, divergence slits 1 / 8°, and anti-scatter slits 1 / 4°.

[0096] Nuclear magnetic resonance spectroscopy ( 1 H NMR) All 1H NMR spectra were performed on a Bruker AVANCE III HD 600 spectrometer operating at 600 MHz (proton frequency). The spectrometer was equipped with a TCI INVERSE TRIPLE RESONANCE CRYOPROBE HC / ND-0.5-Z ATMA. The probe had an actively shielded single-axis Z-gradient, allowing simultaneous decoupling of multiple X nuclei such as 13C and 15N, as well as automatic tuning and matching.

[0097] Example 1 (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate [ka] (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate (IV) (50 mg; 0.08 mmol), prepared as described in WO 2014 / 095700, was dissolved in water (2 ml) and a solution of sodium xinafoate (V) (15 mg, 0.08 mmol) in water (1 ml) was added with mechanical stirring, resulting in the precipitation of the xinafoate salt as an amorphous solid. The amorphous solid was washed twice with 3 ml of water, followed by the addition of 5 ml of acetone and sonication for 10 min. A white solid precipitated. The solid was filtered and dried under reduced pressure at 25° C. to give 55 mg of solid (95% yield). The stoichiometry of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium cation to xinafoate anion is 1:1, as confirmed by NMR and XRPD. 1H NMR (400MHz, DMSO-d6) δ ppm 2.16(s, 3H), 3.21(s, 9H), 3.35-3.44(m, 1H), 3.51(s, 3H), 3.64-3.79(m, 2H), 3.9 3-4.03(m, 1H), 6.22(s, 1H), 6.91(d, J=8.38Hz, 1H), 7.28(ddd, 1H), 7.37(ddd, 1H) , 7.64-7.78(m, 4H), 7.79-7.86(m, 2H), 7.88-7.98(m, 2H), 8.09(s, 1H), 8.14(d, 1H), 11.26(s, 1H) XRPD:8.6, 9.9, 10.7, 11.0, 13.0, 15.3, 19.3, 19.7, 23.2, 27.6±0.2° / 2θ

[0098] Aqueous solubility of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate(IV). At room temperature, 200 mg of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate (IV) was placed in 1 ml of water. Complete dissolution of the material was observed visually. Visual observation of instantaneous dissolution was taken as an indication that the methanesulfonate salt of formula (IV) had a solubility >200 mg / ml.

[0099] Aqueous solubility of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate (I) 2 mg of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate (I) was placed in 1 ml of water and diluted with more water until dissolved. Complete dissolution of the material was observed visually. From this experiment, the xinafoate salt has a solubility of less than 0.05 mg / ml.

[0100] The results of the solubility tests are summarized in Table 1 below. [Table 2]

[0101] Table 1 above clearly shows the significantly higher solubility of the methanesulfonate salt relative to the xinafoate salt.

[0102] Biological assays The efficacy of various salts of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium was evaluated in an in vivo model of human neutrophil elastase (HNE)-induced lung injury.

[0103] Furthermore, the effects of various (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium salts on pulmonary function parameters were also evaluated in rats by head-out plethysmography in order to compare potential local adverse effects of each salt.

[0104] Example 2.1 / Comparative Example HNE-induced lung injury assay Male Sprague Dawley rats were administered either vehicle (lactose), (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate or (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate as a dry powder. Xinafoate was administered by nasal inhalation and 3 hours later phosphate-buffered saline (PBS) (control, animals treated with PBS only) or HNE was administered intratracheally (it) (100 U / rat). One hour after PBS or HNE administration, animals were sacrificed and bronchoalveolar lavage (BAL) was performed to assess HNE-induced lung injury, measured as hemoglobin concentration. BAL fluid samples were centrifuged at 800 g for 15 min at 4°C. The supernatant was collected and the pellet was resuspended in 3 mL of distilled water. A standard curve was generated from the stem solution of lysed hemocytes using known amounts of lysed hemocytes. 150 μL of standards and samples were transferred in duplicate to a 96-well plate and the OD at 412 nm was measured.

[0105] The efficacy rate of the compound (assessed as the inhibition of HNE-induced hemoglobin content in BALF) was calculated according to the following formula: 100-[(mean hemoglobin concentration of test compound treated rats exposed to HNE)-(mean hemoglobin concentration of PBS-exposed vehicle-treated rats)] / [(mean hemoglobin concentration of HNE-exposed vehicle-treated rats)-(mean hemoglobin concentration of PBS-exposed vehicle-treated rats)]×100.

[0106] result In this model, it exposure to HNE induces a significant increase in BAL fluid hemoglobin content when compared to the control group (0 g / dL for the control group and 0.19 g / dL for the HNE group, p<0.001).(2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate and xinafoate administered by inhalation as a dry powder formulation at three doses (0.03, 0.3 and 0.6 mg / kg for methanesulfonate and xinafoate) showed a dose-dependent inhibition of BAL fluid hemoglobin content. Specifically, methanesulfonate demonstrated inhibition ranging from 20% at 0.3 mg / kg to 25% at 0.6 mg / kg when compared to HNE-treated vehicle controls. Similarly, xinafoate reduced BAL fluid hemoglobin content ranging from 35% at 0.3 mg / kg (p<0.05) to 80% at 0.6 mg / kg (p<0.001) when compared to HNE-treated vehicle controls.

[0107] These data show that two salts of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium are capable of inhibiting HNE in vivo and surprisingly the xinafoate salt shows superior efficacy to the methanesulfonate salt in this model.

[0108] The results of the HNE-induced lung injury assay are summarized in Table 2 below. [Table 3]

[0109] Table 2 above shows that both xinafoate and methanesulfonate salts can inhibit HNE in vivo. Moreover, despite its lower solubility, xinafoate salt exhibits superior activity to methanesulfonate salt in the pharmacodynamic model.

[0110] Example 2.2 / Comparative Example Head-out plethysmography (HOP) assay Male Wistar rats were administered (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate (described in WO 2014 / 095700), (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium in the form of a dry powder. Xinafoate (I) and (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium acetate (described in WO 2014 / 095700), (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium Bromide salts (synthesis described in WO 2014 / 095700) or lactose (vehicle) were administered by nasal inhalation route. Aerosol exposure time was 60 min. On the dosing day, animals were placed in plethysmograph tubes at least 30 min before dosing and respiratory parameters: respiratory rate, tidal volume and PenH were recorded continuously for at least 30 min before dosing, 60 min during dosing (exposure) and 90 min after exposure. Respiratory parameters were recorded every minute for a total of 3 h using an EMMS eDacq system (PLY231, EMMS, Bordon, UK). The effect of test compounds on lung function parameters was measured as % change relative to vehicle (lactose) dose and the peak effect (i.e. the greatest effect observed) was reported.

[0111] result A single inhalation administration of two doses (0.6 and 6 mg / kg) of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate as a dry powder showed statistically significant changes in all three respiratory parameters analyzed, with these effects observed primarily during exposure. Specifically, a significant increase in respiratory rate was observed compared to vehicle (lactose)-treated rats, with a peak effect of 32% increase observed at the 0.6 mg / kg dose and a maximum increase of 54% induced by the 6 mg / kg dose. The increase in respiration rate observed during inhalation of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium methanesulfonate was associated with a significant decrease in tidal volume of 35% and 39% (peak effect at doses of 0.6 and 6 mg / kg, respectively), and was increased significantly and dose-dependently by approximately 8-fold at the low dose and 16-fold at the high dose compared to the vehicle group.

[0112] A similar effect was observed with (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium bromide salt (0.55 and 5.5 mg / kg), which produced a statistically significant decrease in tidal volume when compared to vehicle, with a maximum decrease of 38% in the high dose group. This decrease in tidal volume was also coincident with a statistically significant increase in PenH area of ​​approximately 8-fold at the low dose compared to vehicle and 20-fold at the high dose, as well as a significant increase in respiratory rate during inhalation, reaching a maximum effect of 59% at the low dose compared to vehicle.

[0113] Similarly, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium acetate administered at 7 mg / kg in a single nasal inhalation showed a significant reduction in tidal volume of up to 50% compared to vehicle control when compared to vehicle. This salt also induced a statistically significant increase in respiratory rate, reaching a maximum effect of 51%. These changes correlated with a significant increase in PenH area of ​​approximately 9-fold.

[0114] For all three (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium salts, peak effects were observed 20-50 min after compound inhalation and returned to baseline values ​​immediately after administration.

[0115] In contrast, (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate administered as a dry powder at 8 and 25 mg / kg by nasal inhalation only did not alter any pulmonary function parameters during or after administration.

[0116] The results of the head-out plethysmography (HOP) assay are summarized in Table 3 below. [Table 4]

[0117] These data show that, in contrast to the other salts, xinafoate does not affect any of the pulmonary function parameters, suggesting that this salt is particularly suitable for administration in terms of patient tolerability and also the local adverse effect profile.

Claims

1. Formula (I): 【Chemistry 1】 (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium xinafoate compound.

2. 10. A process for preparing a compound of formula (I) according to claim 1 by reacting a triazolone derivative of formula (II) with a xinafoate salt of formula (III): 【Chemistry 2】 Next step: 1) (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium salt (II) 【Transformation 3】 [In the formula, X － is an organic or inorganic anion. Dissolve in water; 2) Formula (III): 【Chemistry 4】 [In the formula, Y ＋ is an alkali or alkaline earth metal cation. Add a solution of xinafoate A method comprising:

3. 3) washing the compound of formula (I) obtained in steps 1) and 2) with one or more aqueous or organic solvents.

4. X － 2. The method of claim 1, wherein is bromide, methanesulfonic acid, or acetic acid.

5. Y ＋ 2. The method of claim 1, wherein is sodium or potassium.

6. A crystalline form of the compound of formula (I), characterized by at least one of the following XRPD peaks: 8.6, 9.9 and 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

7. 7. The crystal of claim 6, characterized by the following XRPD peaks: 8.6, 9.9, 10.7, 11.0 and 23.2±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

8. 7. The crystal of claim 6, characterized by the following XRPD peaks: 8.6, 9.9, 10.7, 11.0, 13.0, 15.3, 19.3, 19.7, 23.2 and 27.6±0.2° / 2θ [CuKα radiation (λ=1.5406 Å)].

9. A pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

10. A pharmaceutical composition comprising a crystal of a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

11. 10. The pharmaceutical composition of claim 9, formulated in the form of a dry powder.

12. A pharmaceutical composition according to any one of claims 9 to 11 for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

13. 13. The pharmaceutical composition of claim 12, wherein the inflammatory or obstructive respiratory disease is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, chronic bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking-induced emphysema, and cystic fibrosis.

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