Triazolone derivative salts as neutrophil elastase inhibitors.

Abstract

The present invention relates generally to novel triazolone derivative salts, particularly useful as neutrophil elastase inhibitors, and their use as pharmaceuticals. The present invention also relates to pharmaceutical compositions comprising the novel triazolone derivative salts and one or more pharma- ceutically acceptable carriers and / or excipients thereof, and their use as pharmaceuticals.

Description

[Technical field]

[0001] The present invention relates generally to novel triazolone derivative salts, which are particularly useful as neutrophil elastase inhibitors, and their use as pharmaceuticals. The present invention also relates to pharmaceutical compositions comprising the novel triazolone derivative salts and one or more pharma- ceutically acceptable carriers and / or excipients, and their use as pharmaceuticals. [Background technology]

[0002] Human neutrophil elastase (HNE) is a 32 kDa serine proteinase found in azurophilic granules of neutrophils. HNE 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 through the repair and disposal of damaged tissues via the degradation of tissue structural proteins. HNE is also involved in the defense against bacterial invasion by the degradation of bacterial bodies. In addition to its effects on matrix organization, HNE is also involved in the upregulation of IL-8 gene expression and induces IL-8 release from lung epithelial cells. In animal models of chronic obstructive pulmonary disease due to cigarette smoke exposure, both small molecule and protein inhibitors of HNE suppressed the inflammatory response and the development of emphysema (Wright, JL et al. Am. J. Respir. Crit. Care Med. 2002, 166, 954-960, and Churg, A. et al. Am. J. Respir. Crit. Care Med. 2003, 168, 199-207). Thus, HNE may play a role in both matrix destruction and amplification of the inflammatory response in chronic respiratory diseases characterized by neutrophil influx. Indeed, HNE is thought to play a role in several lung diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS), emphysema, pneumonia, and pulmonary fibrosis. It is also relevant in several cardiovascular diseases involving tissue remodeling, for example in heart failure and in the development of ischemic tissue injury following acute myocardial infarction.

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

[0004] Several human neutrophil inhibitors have been disclosed in the art so far.

[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 triazolone derivatives having human neutrophil elastase inhibitory properties and their use in therapy, in particular some 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 a potent neutrophil elastase inhibitor.

[0007] As mentioned above, several HNE inhibitors have been disclosed so far, but there remains a need for further HNE inhibitors.

[0008] It would be particularly advantageous to identify further effective HNE inhibitors with a safer profile for administration, also in terms of patient tolerability and local adverse effect profile.

[0009] The present invention addresses the above 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 hemi-pamoate 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 hemi-pamoate salt of formula (I). [ka] (I)

[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 hemi-pamoate 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 hemi-pamoate salt of formula (I) for use as a medicament.

[0013] In a still 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 hemi-pamoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use as a medicament.

[0014] 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 hemi-pamoate salt of formula (I) in the manufacture of a medicament for the prevention and / or treatment of an inflammatory or obstructive respiratory disease.

[0015] 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 hemi-pamoate 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.

[0016] In another aspect, the present invention provides a method for preventing and / or treating an inflammatory or obstructive respiratory disease 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 hemi-pamoate salt of formula (I).

[0017] In a further aspect, the present invention provides a method for preventing and / or treating 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 hemi-pamoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0018] In another aspect, the present invention provides a process for the preparation of a compound of formula (I) by reacting a triazolone derivative of formula (II) with a pamoate salt of formula (III), comprising: [ka] 1) Dissolve the 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)-trimethylammonium of formula (II) in water. [ka] (II) (where X - is an organic or inorganic anion), and 2) Add a solution of the pamoate salt of formula (III) [ka] (III) (where Y + is an alkali or alkaline earth metal cation) A method is provided, comprising the steps of: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] 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.

[0020] 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 hemi-pamoate salt of formula (I).

[0021] The term "hemi-pamoate salt" refers to a salt with a pamoate dianion having a 2:1 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]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium cation to pamoate dianion.

[0022] 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.

[0023] The compounds of the present invention have one stereoisomeric center (ie, represented below at carbon atom (1) marked with an *) and therefore may exist as optical stereoisomers. [ka]

[0024] In addition to the compounds of the present invention of formula (I) exhibiting the preferred (R) configuration on carbon atom (1), it is understood that the racemates and enantiomers (S) are also encompassed within the scope of the present invention.

[0025] The term "composition," as in pharmaceutical composition, is intended to encompass a product that includes active ingredients and any pharma- ceutically acceptable excipients or carriers, as well as any product that results directly or indirectly from the combination, complexation or aggregation of two or more ingredients, or from the dissociation of one or more ingredients, or from any other type of reaction or interaction of one or more ingredients.

[0026] Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and pharma- ceutically acceptable excipients and / or carriers.

[0027] The hemi-pamoate salt of formula (I) is characterised by physicochemical properties which make it particularly suitable for administration, also in terms of patient tolerance and local adverse effect profile.

[0028] In this respect, advantageously, the hemi-pamoate salt according to the compound of formula (I) of the present invention has the following properties: 1) when administered as a dry powder, it exhibited superior activity to the methanesulfonate salt in pharmacodynamic models, which was unexpected given its lower solubility in the methanesulfonate salt, as described in Biological Assay Example 2.1; and 2) As described and reviewed in this Example 2.2, when administered as a dry powder, it exhibits a very favorable irritation profile in HOP (head out plethysmography) tests in conscious rats compared to the methanesulfonate, bromide, and propionate salts, thus suggesting a possible safer profile in humans.

[0029] Considering 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 hemi-pamoate salt maintains good efficacy in HNE inhibition in vivo despite its lower solubility relative to the methanesulfonate salt and also when administered as a dry powder formulation.

[0030] Furthermore, in head-out plethysmography (HOP) assays, the hemi-pamoate salt of formula (I) showed improved pulmonary function parameters, in contrast to 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 methanesulfonate, bromide and propionate, suggesting that this salt is particularly suitable for administration, also in terms of patient tolerability and local adverse effects profile.

[0031] The present invention is also directed to pharmaceutical compositions comprising a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0032] Suitable excipients can be selected from those skilled in the art and can include carriers, diluents, wetting agents, emulsifiers, binders, coating agents, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffering substances, etc. Examples of excipients and their uses are described in Handbook of Pharmaceutical Excipients, 5th ed. (2006), Ed. Rowe et al., Pharmaceutical Press.

[0033] Optimal dosage can be determined by any known suitable method.However, it is understood that the specific dosage for any specific patient depends on various factors, including the activity of the compound of formula (I), the age, weight, eating habits, general health condition and sex of the patient, administration time, administration route, excretion rate, the use of any other drug, and the severity of the disease to be treated.

[0034] For delivery by inhalation, the active compounds of formula (I) are preferably in the form of microparticles. These may be prepared by a variety of techniques, including spray drying, freeze drying, and micronization.

[0035] In one embodiment, the compositions of the present invention are formulated as a suspension suitable for delivery from a nebulizer or, more preferably, an aerosol in a liquid propellant suitable for use in a pressurized metered dose inhaler (PMDI). Propellants suitable for use in pMDIs are known to those of skill in the art and include HFA-227, preferably HFA-134a, and more preferably HFA152a.

[0036] In certain preferred embodiments, the compositions of the present invention are in dry powder form for delivery using a dry powder inhaler (DPI).

[0037] For delivery by administration, microparticles can be formulated with excipients that aid delivery and release.For example, in dry powder formulations, microparticles can be formulated with large carrier particles that aid in the flow of DPI to the lungs.Suitable carrier particles are known in the art, and include, for example, lactose particles.

[0038] The agent of the present invention can be administered in an inhaled form.Aerosol generation can be achieved, for example, by using a pressure-driven jet nebulizer, or ultrasonic nebulizer, preferably propellant-driven metered-dose aerosol, or propellant-free administration of the micronized active compound of formula (I), for example, from an inhalation capsule or other "dry powder" delivery system.

[0039] As mentioned above, the present invention is also directed to the compounds of general formula (I) for use as pharmaceuticals.

[0040] According to one preferred embodiment, the present invention provides the use of the hemi-pamoate salt of formula (I) for the preparation of a medicament for the treatment of an inflammatory or obstructive pulmonary disease, preferably a 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.

[0041] The present invention is also directed to pharmaceutical compositions comprising a compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients, for use as a medicament.

[0042] In one preferred embodiment, the present invention is directed to a compound of formula (I) for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0043] In another preferred embodiment, the present invention is directed 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.

[0044] In a further preferred embodiment, the present invention provides a method for preventing and / or treating an inflammatory or obstructive respiratory disease 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 hemi-pamoate salt of formula (I).

[0045] In another preferred embodiment, the present invention provides a method for preventing and / or treating 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 hemi-pamoate salt of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0046] In an even more 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.

[0047] 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).

[0048] The magnitude of prophylactic or therapeutic dose of a compound of formula (I) will, of course, vary with the nature or severity of the condition to be treated and its route of administration, and will generally be determined by clinical trials, as required in the pharmaceutical arts.

[0049] It will also vary according to the age, weight, and response of the individual patient.

[0050] In therapeutic use, the compounds of formula (I) may be administered by any convenient, suitable or effective route.

[0051] Suitable routes of administration are well known and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal, pulmonary (inhalation), and the like.

[0052] The active compound of formula (I) can be administered as described according to the inhaler system used.In addition to the active compound, the dosage form can further comprise excipients such as propellants (for example, in the case of metered dose aerosol, Frigen), surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers (for example, in the case of powder inhalants, lactose), or if appropriate, other active compounds.

[0053] For inhalation purposes, numerous systems are available that allow the generation and administration of aerosols with optimal particle size using an inhalation technique suited to the patient. In the case of metered-dose aerosols, especially powder inhalers, numerous technical solutions are available (e.g. Diskhaler, Rotadisk, Turbohaler, or inhalers as described, for example, in EP-A-0505321) in addition to the use of adapters (spacers, expanders), pear-shaped containers (e.g. Nebulator®, Volumatic®) and automatic devices releasing puffer sprays (Autohaler®).

[0054] As mentioned above, the present invention also provides a process for the preparation of a compound of formula (I) by reacting a triazolone derivative of formula (II) with a pamoate salt of formula (III) as shown above, said process comprising: 1) The 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)-trimethylammonium of formula (II) is dissolved in water, where X - is an organic or inorganic anion), and 2) adding an aqueous solution of the pamoate salt of formula (III), where Y + is an alkali or alkaline earth metal cation) The process includes:

[0055] In another preferred embodiment, the present invention relates to a compound of formula (II) - is a bromide), providing a process for the preparation of compounds of formula (I).

[0056] In another preferred embodiment, the present invention relates to a compound of formula (II) - is methanesulfonic acid), provides a process for the preparation of compounds of formula (I).

[0057] In a further preferred embodiment, the present invention provides a method for the preparation of a cyclohexyl 1-methylcyclohexyl 1-(4-methylcyclohexyl)phenyl ester comprising reacting a pamoic acid salt of formula (III) + is sodium or potassium, more preferably sodium), provides a process for the preparation of compounds of formula (I).

[0058] In an even more preferred embodiment, the present invention also provides a process for the preparation of a compound of formula (I) by reacting a compound of formula (II) with a pamoic acid salt of formula (III), wherein the molar ratio of (II) to (III) is 2:1.

[0059] In a more preferred embodiment, a process is provided for the preparation of compounds of formula (I) 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]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-ethyl)-trimethyl-ammonium cation and pamoate dianion is 2:1, according to the general synthetic route reported in Scheme A below. [ka]

[0060] where X - is an organic or inorganic anion, preferably selected from the group consisting of methanesulfonate, propionate, and bromide; Y +is an alkali or alkaline earth metal cation, preferably selected from the group consisting of sodium and potassium.

[0061] The compounds of the invention of formula (I) can be prepared from (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 or methanesulfonate salts of formula (II), obtained, for example, according to the procedure described in WO 2014 / 095700, respectively, where X is bromide or methanesulfonic acid, as reported in Example 1,2, or by dissolving propionic acid in an aqueous or organic solvent, preferably water, and adding, under mechanical stirring, a solution of sodium or potassium salt of hemi-pamoic acid of formula (III) in a suitable aqueous or organic solvent, preferably water, as reported in Example 1.3.

[0062] Similarly, salts of the compounds of the invention of formula (I) 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.

[0063] The available methods described and reported in the examples should not be construed as limiting the scope of the synthetic methods used for the preparation of the compounds of the present invention.

[0064] The compounds used as starting materials or intermediates may be commercially available, their preparation may be specifically described in the literature, or may be prepared according to methods available in the literature and known to those skilled in the art.

[0065] The described methods are particularly advantageous because they are amenable to suitable adjustment by any suitable modification known to those skilled in the art to obtain the desired compounds of the invention, and such modifications are included within the scope of the invention.

[0066] The invention is further illustrated by the following non-limiting examples. EXAMPLES

[0067] Nuclear magnetic resonance spectroscopy (1H 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 5 mm 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.

[0068] Example 1 Example 1.1 (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 hemi-pamoate [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 bromide (500 mg; 0.8 mmol), prepared as described in WO 2014 / 095700, was dissolved in water (25 ml) and, under mechanical stirring, a solution of sodium pamoate (174 mg, 0.4 mmol) in water (8 ml) was added to give the hemi-pamoate salt as a solid. The 2:1 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 pamoate dianion is confirmed by NMR.

[0069] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.32 (s, 1 H) 8.19 (d, J=8.55 Hz, 1 H) 8.12 (s, 2 H) 7.87 - 7.97 (m, 2 H) 7.69 - 7.87 (m, 4 H) 7.59 (d, J=7.89 Hz, 1 H) 7.08 (t, J=7.12 Hz, 1 H) 6.97 (t, J=6.91 Hz, 1 H) 6.26 (s, 1 H) 4.65 (s, 1 H) 3.92 - 4.02 (m, 1 H) 3.64 - 3.79 (m, 2 H) 3.53 (s, 3 H) 3.33 - 3.46 (m, 1 H) 3.21 (s, 9 H) 2.16 (s, 3 H).

[0070] Example 1.2 (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 hemi-pamoate [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 (19.1 g, 30 mmol), prepared as described in WO 2014 / 095700, was dissolved in water (1000 ml) and a solution of sodium pamoate (6.5 g, 15 mmol) in water (250 ml) was added under mechanical stirring to obtain the hemi-pamoate salt as a solid. After filtering the solid and washing with water (50 ml), the wet solid was transferred to a flask and acetone (500 ml) was added. The slurry was stirred at 50° C. for 2 hours, then refrigerated and left at 5° C. overnight. The solid was filtered, washed with acetone and dried under vacuum at 45° C. 18 g of solid was obtained. The compound was identical to that obtained starting from the bromide salt of Example 1.

[0071] Similarly, any other 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 can be used in place of the bromide or methanesulfonate salt to give the hemi-pamoate salt.

[0072] A further 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 may be the propionate salt, which is obtained as described herein below.

[0073] Example 1.3 (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 propionic acid - method a To a solution 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 (1 g, 1.57 mmol) in water (25 mL) was added 5 mL of washed Amberlyst A26 OH resin and the mixture was rotated at room temperature for 1 h. The reaction mixture was filtered and the resin was washed with water (25 mL). The filtrate and washings were combined and lyophilized to give the betaine product as a solid (738 mg, 87%).

[0074] 1H NMR (400 MHz, d6-DMSO) δ 7.93 (1H, s), 7.89-7.82 (1H, m), 7.82-7.73 (3H, m), 7.68 (1H, dd, J = 8.3, 1.7 Hz), 7.53 (1H, d, J = 7.9 Hz), 5.98 (1H, s), 4.67 (1H, t, J = 11.1 Hz), 3.80 (1H, td, J = 12.4, 3.5 Hz), 3.59 (1H, td, J = 12.0, 6.1 Hz), 3.51 (3H, s), 3.32 (9H, br s), 3.27-3.22 (1H, m), 2.14 (3H, s).

[0075] To a solution of betaine (738 mg, 1.37 mmol) in water (5 mL), propionic acid (0.11 mL, 1.50 mmol) was added and the mixture was stirred at room temperature for 5 min. The reaction mixture was lyophilized to give the product as a solid (840 mg, 100%).

[0076] 1H NMR (400 MHz, d6-DMSO) δ 8.1 (1H, s), 7.95-7.87 (2H, m), 7.85-7.78 (2H, m), 7.75 (1H, dd, J = 8.0, 1.8 Hz), 7.68 (1H, d, J = 8.3 Hz), 6.22 (1H, s), 4.13-4.01 (1H, m), 3.78-3.65 (2H, m), 3.52 (3H, s), 3.42-3.31 (1H, m), 3.21 (9H, s), 2.16 (3H, s), 1.83 (2H, q, J = 7.6 Hz), 0.86 (3H, t, J = 7.6 Hz).

[0077] (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 propionic acid - method B 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 methanesulfonate (32.58 g, 51.2 mmol) in water (120 mL) was added 165 mL of washed Amberlyst A26 OH resin (ca. 150 mmol equiv. OH) and the mixture was rotated at room temperature for 1 h. The reaction mixture was filtered and the resin was washed with water (ca. 250 mL). The filtrate and washings were combined and propionic acid (4 mL, 53.7 mmol) was added and the mixture was stirred at room temperature for 5 min. The solution was lyophilized to give the product as a solid (26.1 g, 83%).

[0078] 1H NMR showed that this sample contained 1.15 equivalents of propionic acid. 1H NMR (400 MHz, d6-DMSO) δ 8.1 (1H, s), 7.98-7.86 (2H, m), 7.86-7.78 (2H, m), 7.75 (1H, dd, J = 8.0, 1.8 Hz), 7.68 (1H, d, J = 8.3 Hz), 6.22 (1H, s), 4.12-4.00 (1H, m), 3.79-3.65 (2H, m), 3.53 (3H, s), 3.42-3.30 (1H, m), 3.21 (9H, s), 2.16 (3H, s), 1.85 (2H, q, J = 7.6 Hz), 0.86 (3H, t, J = 7.6 Hz).

[0079] Example 2 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 lung injury model induced by human neutrophil elastase (HNE).

[0080] 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 to compare potential local adverse effects of each salt.

[0081] Example 2.1 / Comparative HNE-induced lung injury assay Male Sprague Dawley rats were treated with either vehicle (1% Tween 80 in saline), (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. Hemi-pamoate was administered intratracheally (it) to rats, followed 3 h later by phosphate-buffered saline (PBS) (control, PBS-only treated animals) or HNE (100 U / rat). Animals were then sacrificed 1 h after PBS or HNE administration 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 with known amounts of lysed blood cells was generated from the stem solution of lysed blood cells. 150 μL of standards and samples were transferred in duplicate to a 96-well plate and OD was measured at 412 nm. The efficacy rate (%) of a compound (assessed as 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 vehicle-treated rats exposed to PBS)] / [(mean hemoglobin concentration of vehicle-treated rats exposed to HNE)-(mean hemoglobin concentration of vehicle-treated rats exposed to PBS)]x100.

[0082] result In this model, HNE it administration caused a significant increase in hemoglobin content when compared to the control group (0 g / dL in the control group and 0.19 g / dL in the HNE group, p<0.001).

[0083] When (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 hemi-pamoate were administered it as wet formulations at three different doses (3, 30 and 300 μg / kg for methanesulfonate and hemi-pamoate), the hemoglobin content of the BAL fluid was inhibited in a dose-dependent manner. In particular, the methanesulfonate showed inhibition ranging from 19% at 3 μg / kg, 30% at 30 μg / kg and up to 73% at 300 μg / kg compared to the HNE-treated vehicle control group (p<0.001). Similarly, hemi-pamoate caused a reduction in BAL fluid hemoglobin content ranging from 30% at 3 μg / kg, 43% at 30 μg / kg (p<0.05), and 80% at 300 μg / kg (p<0.001) compared to HNE-treated vehicle controls.

[0084] These data indicate that (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 is able to inhibit HNE in vivo and, surprisingly, the hemi-pamoate salt shows slightly better efficacy than the methanesulfonate salt in this model, despite its lower solubility.

[0085] Furthermore, the efficacy of (2-{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-dddyl]-phenyl}-ethyl)-trimethylammonium hemi-pamoate in this model was maintained when the compound was administered as a dry powder formulation. Specifically, (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 hemi-pamoate administered it as a dry powder resulted in a dose-dependent inhibition of BAL fluid hemoglobin by 4% at 30 μg / kg, 54% at 300 μg / kg (p<0.05), and 60% at 600 μg / kg (p<0.01) compared to the HNE-treated vehicle (lactose) control group.

[0086] 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 in water 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 was placed in 1 mL of water at room temperature. Complete dissolution of the material was observed visually.

[0087] The visual observation of said immediate dissolution was an indication that the methanesulfonate salt of formula (I) had a solubility of >200 mg / ml.

[0088] 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 hemi-pamoate in water A saturated solution of hemi-pamoate salt in water was prepared at room temperature with a theoretical concentration of approximately 2 mg / ml. Excess solids were removed by filtration and the solution content was quantified by LC / UV at various checkpoints up to 24 hours.

[0089] The solubility of the hemi-pamoate salt is 0.17 mg / ml.

[0090] The results of the solubility tests are summarized in Table 1 below. [Table 1]

[0091] Table 1 above clearly shows that the solubility of the methanesulfonate salt is significantly higher versus the hemi-pamoate salt.

[0092] The results of the HNE-induced lung injury assay are summarized in Table 2 below. [Table 2]

[0093] Table 2 above clearly shows that both hemi-pamoate and methanesulfonate salts are capable of inhibiting HNE in vivo, however, hemi-pamoate salt exhibits superior activity in the above pharmacodynamic model relative to methanesulfonate salt, despite its lower solubility.

[0094] Example 2.2 / Comparative 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, (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 by nasal inhalation route. Hemi-pamoate 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 propionate (the synthesis of which is described in Example 1.3), (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 (the synthesis of which is described in WO 2014 / 095700), or lactose were administered as dry powder formulations. Aerosol exposure time was 60 min. On the day of dosing, animals were placed in plethysmograph tubes at least 30 min before dosing and their respiratory parameters (respiratory rate, tidal volume, 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, United Kingdom). The effects of test compounds on the different lung function parameters were measured as % change relative to the vehicle (lactose) control group and reported as peak effect (i.e. highest effect observed).

[0095] result (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 (0.6 and 6 mg / kg) produced statistically significant changes in all three respiratory parameters analyzed, with these effects observed primarily during exposure. Specifically, a significant increase in respiratory rate during inhalation was observed at both doses, with the 0.6 mg / kg dose producing a peak effect increase of 32% and the 6 mg / kg dose producing a maximum increase of 54%. (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 demonstrated a significant reduction in tidal volume of 35% and 39% (peak effects at 0.6 and 6 mg / kg, respectively) and a significant, dose-dependent increase in PenH of approximately 8-fold at the low dose and approximately 16-fold at the high dose compared to vehicle control.

[0096] 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 during inhalation, with a maximum decrease of 38% in the high dose group.

[0097] This reduction in tidal volume was also coincident with a statistically significant increase in PenH area of ​​approximately 8-fold at the low dose and 20-fold at the high dose compared to the vehicle control group, and respiratory rate was also significantly increased during inhalation, reaching a maximum effect of 59% at the low dose compared to the vehicle control group. Similarly, single nasal inhalation doses 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 propionate at 0.6 mg / kg (low dose) and 6 mg / kg (high dose) produced a statistically significant reduction in tidal volume (maximum reduction of 37% at the high dose) and a statistically significant increase in respiratory rate (maximum effect of 65% at the low dose) compared to the vehicle control group at both doses.

[0098] Peak effects 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 were observed 20-50 min after compound inhalation, returning to baseline values ​​immediately after administration.

[0099] 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 hemi-pamoate administered as a dry powder at 0.7 and 7 mg / kg as a single inhaled dose into the nose only did not alter any pulmonary function parameters either during or after administration.

[0100] The results of the head-out plethysmography (HOP) assay are summarized in Table 3 below. [Table 3]

[0101] These data show that, in contrast to the other salts, xinafoate does not affect any of the pulmonary function parameters and suggest that this salt is particularly suitable for administration in terms of patient tolerability and local adverse effects profile.

Claims

1. The compound of formula (I) (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 hemi-pamoate. 【Chemistry 1】 (I)

2. 10. A pharmaceutical composition comprising a compound of formula (I) of claim 1 and one or more pharmaceutically acceptable carriers and / or excipients.

3. 3. The pharmaceutical composition of claim 2, formulated in the form of a dry powder.

4. 4. A pharmaceutical composition according to claim 2 or 3 for use as a medicament.

5. 4. A pharmaceutical composition according to claim 2 or 3 for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

6. 6. The pharmaceutical composition according to claim 5, for use in the prevention and / or treatment of an inflammatory or obstructive respiratory disease, 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.

7. 10. A process for the preparation of a compound of formula (I) according to claim 1 by reacting a triazolone derivative of formula (II) with a pamoate salt of formula (III), 【Chemistry 2】 1) Dissolve the 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)-trimethylammonium of formula (II) in water. 【Transformation 3】 (II) (where X - is an organic or inorganic anion), and 2) Add a solution of the pamoate salt of formula (III) 【Chemistry 4】 (III) where Y+ is an alkali or alkaline earth metal cation. A method comprising the steps of:

8. 8. The process according to claim 7, wherein the molar ratio of the compound of formula (II) to the pamoate salt of formula (III) is 2:

1.

9. X - 8. The method of claim 7, wherein is bromide.

10. X - 8. The method of claim 7, wherein is methanesulfonic acid.

11. X - 8. The method of claim 7, wherein is propionic acid.

12. Y + 12. The method of any one of claims 7 to 11, wherein is sodium or potassium.

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