Novel crystalline forms of PDE4 inhibitors

Abstract

The present invention relates to crystalline form 2 of the compound of formula (I), its isolation process and pharmaceutical compositions thereof. The present invention also relates to crystalline form 2 of the compound of formula (I) for use as a medicament and for the manufacture of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to crystalline form 2 of the compound of formula (I), to a process for its isolation and to pharmaceutical compositions thereof. The present invention also relates to crystalline form 2 of the compound of formula (I) for use as a medicament and for the manufacture of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases. [Background technology]

[0002] 2. Background of the Invention Formula (I), also referred to as Tanimilast or CHF6001 or CHF-6001, which is INN (3,5-dichloro-4-[(2S)-2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-{[3-(cyclopropylmethoxy)-4-(methanesulfonamido)benzoyl]oxy}ethyl]pyridine 1-oxide) [ka] The compound is a highly potent and selective PDE4 inhibitor with robust anti-inflammatory activity and is currently in clinical development.

[0003] The compound of formula (I) has been disclosed in prior documents in the name of Chiesi: WO2009 / 018909 relating to the general formula, methods of preparation, compositions and therapeutic uses; WO2010 / 089107 relating to sulfonamide derivatives, in particular comprising the compound of formula (I) as the (-) enantiomer, methods of preparation, compositions and therapeutic uses; WO2012 / 016889 relating to dry powder formulations comprising the compound of formula (I); WO2015 / 059050 relating to a crystalline form of the compound of formula (I), named Form A, characterized by specific XRPD peaks, and methods of obtaining same. Summary of the Invention [Problem to be solved by the invention]

[0004] Notwithstanding the prior art cited above, there remains a need to develop forms of the compound of formula (I) that have improved solubility and bioavailability.

[0005] In this way, the inventors have surprisingly discovered that crystalline Form 2 of compound of formula (I) according to the invention has advantageous properties selected from solubility, dissolution rate, low risk of pulmonary accumulation after repeated administration, bioavailability and efficacy. [Means for solving the problem]

[0006] Summary of the Invention In a first aspect, the present invention provides a crystalline form of formula (I), denominated Form 2, characterized by at least the following XRPD peaks: [ka] for the crystalline form of the compound: 4.0, 7.9, 13.2 ± 0.2 degrees / 2theta [Cu Kα radiation (λ = 1.5406 Å)].

[0007] In a second aspect, the present invention provides a process for preparing crystalline Form 2 of compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], by dissolving crystalline Form A of compound of formula (I) in acetone.

[0008] In a further embodiment, the present invention relates to crystalline form 2 of compound of formula (I) which was obtained (or is obtainable) by dissolving crystalline form A of compound of formula (I) in acetone.

[0009] In another aspect, the present invention provides crystalline Form 2 of the compound of formula (I) for use as a medicament.

[0010] In a further aspect, the present invention provides a pharmaceutical composition comprising crystalline Form 2 of compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use as a medicament.

[0011] In a still further embodiment, the present invention defines the use of crystalline form 2 of compound of formula (I) as defined above, for the manufacture of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0012] In a further aspect, the present invention provides a pharmaceutical composition comprising crystalline Form 2 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 inflammatory or obstructive respiratory diseases.

[0013] In a further aspect, the present invention provides the use of a pharmaceutical composition comprising crystalline Form 2 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.

[0014] In another aspect, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases in a human, comprising the administration of an effective amount of crystalline Form 2 of compound of formula (I) as defined above.

[0015] In a further aspect, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases in humans, comprising the administration of a pharmaceutical composition comprising an effective amount of crystalline Form 2 of the compound of formula (I) as defined above and one or more pharma- ceutically acceptable carriers and / or excipients.

[0016] In a further aspect, the present invention relates to a device comprising a pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I). [Brief description of the drawings]

[0017] [Figure 1] XRPD of crystalline form 2 of compound of formula (I) [Diagram 2] XRPD of crystalline form A of compound of formula (I) [Diagram 3]DSC of crystalline form 2 of compound of formula (I) [Figure 4] DSC of crystalline form A of compound of formula (I) [Diagram 5] TGA of crystalline form 2 of compound of formula (I) [Figure 6] TGA of crystalline form A of compound of formula (I) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] 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.

[0019] The term "compound of the invention" refers to crystalline Form 2 of the compound of formula (I).

[0020] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include their stereoisomers, tautomers, or pharma- ceutically acceptable salts or solvates.

[0021] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of formula (I) where the parent compound, if any free acid or basic group is present, is suitably modified by converting it into the corresponding addition salt with any base or acid that is conventionally intended to be pharmaceutically acceptable.

[0022] Thus, suitable examples of such salts may include inorganic or organic acid addition salts of basic residues such as amino groups as well as inorganic or organic base addition salts of acidic residues such as carboxylic acid groups.

[0023] Cations of inorganic bases which may be suitably used in the preparation of salts include those of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.

[0024] Salts obtained by reacting the main compound functioning as a base with an inorganic or organic acid include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.

[0025] The term "solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonds. In some cases, the solvate may be isolated, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. Solvates contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0026] The term "stereoisomers" refers to isomers that are identical in constitution but differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0027] The terms "racemate" or "racemic mixture" refer to a composition consisting of equimolar amounts of two enantiomers, wherein the composition is devoid of optical activity.

[0028] The term "tautomer" refers to each of two or more isomers of a compound that exist in equilibrium with one another and are readily interconverted by shifting of atoms or groups within the molecules.

[0029] The term "composition," in pharmaceutical composition, is intended to encompass a product comprising an active ingredient(s) and any pharma- ceutically acceptable excipients or carriers, as well as any product resulting, directly or indirectly, from the combination of any two or more of the components, from complex formation or aggregation or from dissociation of one or more of the components, or from any other type of reaction or interaction of one or more of the components.

[0030] 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.

[0031] The term "high level of chemical purity" refers to a crystalline form having a total amount of readily detectable impurities of less than 5%, advantageously less than 2.5%, and even less than 1.0 or more preferably less than 0.5% w / w, as determined by standard analytical methods such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).

[0032] The term "high level of crystallinity" refers to a crystalline form having a percentage of crystallinity of 90% or more, preferably greater than 95% w / w, as determined by standard analytical methods such as X-ray powder diffraction or microcalorimetry.

[0033] The terms "polymorph", "polymorphic form", "crystal", "crystalline form", "crystalline", "crystalline form" and "form" refer to a compound having a particular molecular packing arrangement in a crystal lattice. X-ray powder diffraction (XRPD), proton nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are techniques that can be used to identify and characterize the nature of polymorphic forms, such as crystalline Form 2 of the compound of Formula (I) described herein.

[0034] The term "XRPD" means X-ray powder diffraction. XRPD is a technique for providing analytical characterization of a sample. Polymorphic forms are characterized by different XRPD patterns.

[0035] The term "NMR" means proton nuclear magnetic resonance. NMR spectra provide structural information about organic compounds based on the absorption of energy by hydrogen atoms.

[0036] The term "DSC" means differential scanning calorimetry. DSC is a thermoanalytical technique that measures the difference in the amount of heat required to raise the temperature of a test compound and a control as a function of temperature. The output is a differential thermogram, which can be used, for example, to estimate the melting point of the test compound. It is used to characterize polymorphic forms of salts.

[0037] The term "TGA" means thermogravimetric analysis. TGA is a technique that monitors the mass of a substance as a function of temperature when a sample is subjected to a controlled temperature program under controlled atmospheric conditions. It is used to characterize polymorphic forms of salts.

[0038] The term "room temperature", abbreviated as RT, refers to a temperature ranging from about 15°C to about 25°C, with an average of about 23°C.

[0039] The term "treating" or "treatment" of a disease state includes: (i) preventing the disease state, i.e., arresting the progression of the disease state or its clinical symptoms, or (ii) alleviating the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0040] The term "preventing" or "prevention" of a disease state includes preventing the development of clinical symptoms of a disease state in a subject who may be exposed to or predisposed to the disease state, but who has not yet experienced or exhibited symptoms of the disease state. For example, treating or preventing a respiratory disease or disorder includes treating or preventing symptoms of the disorder, such as coughing and / or the urge to cough, associated with a respiratory disease.

[0041] The present invention relates to a crystalline form of the compound of formula (I), designated as crystalline form 2.

[0042] Surprisingly, the crystalline form 2 of the compound of formula (I) according to the present invention, as known in the art, shows increased solubility in simulated lung fluid (SLF) with respect to the crystalline form A of the compound of formula (I). As can be seen from Table 2 of Example 4 of the present experimental part, after 0.5 hours, 1 hour and 3 hours, the crystalline form 2 of the compound of formula (I) shows at least about 4.5 times higher solubility in SLF than the crystalline form A of the compound of formula (I). The use of SLF, which mimics physiological lung fluid, is known as a useful parameter to better understand the dissolution mechanism and possible in vivo behavior of the product, enhancing the predictive power of dissolution tests in terms of bioavailability and therapeutic efficacy.

[0043] More advantageously, the crystalline form 2 of the compound of formula (I) according to the present invention unexpectedly exhibits a low risk of lung accumulation after repeated administration. As can be seen from Table 3 of Example 5 of the present experimental part, the crystalline form 2 of the compound of formula (I) according to the present invention exhibits a lung t of 7.7 hours. 1 / 2 This indicates a low risk of accumulation in the lungs after repeated administration.

[0044] Even more advantageously, the lung t 1 / 2 and pulmonary MRT last The value predicts that crystalline Form 2 of compound of formula (I) is likely to have good in vivo bioavailability.

[0045] Furthermore, crystalline Form 2 of the compound of formula (I) of the present invention may also be useful in the treatment of diseases in which activity of the PDE4 receptor is involved and in which inhibition of PDE4 receptor activity is desired, or disease states mediated by PDE4 activity.

[0046] In certain preferred embodiments, the present invention provides a crystalline form of formula (I), denominated Form 2, characterized by at least the following XRPD peaks: [ka] The crystal forms of the compound are given as follows: 4.0, 7.9, 13.2 ± 0.2 degrees / 2 theta [Cu Kα radiation (λ = 1.5406 Å)].

[0047] In another preferred embodiment, the present invention provides a crystalline form of compound of formula (I) denominated crystalline form 2, characterized by the following XRPD peaks: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

[0048] In a further preferred embodiment, the present invention provides a crystalline form of compound of formula (I) denominated crystalline form 2, characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

[0049] In a more preferred embodiment, the present invention provides a crystalline form of compound of formula (I) denominated crystalline form 2, characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

[0050] In another embodiment, the present invention also relates to crystalline Form 2 of compound of formula (I), characterized by a DSC melting range of 120°-135° C. (heating rate 10° C. / min, N2 flow 50 ml / min).

[0051] In certain embodiments, the present invention also relates to a process for preparing crystalline Form 2 of compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the step of dissolving crystalline Form A of compound of formula (I) in acetone.

[0052] The present invention therefore also relates to the crystalline form 2 of the compound of formula (I) thus obtained according to the following embodiment.

[0053] In another embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the steps of dissolving crystalline form A of compound of formula (I) in acetone, stirring, and isolating the crystalline solid thus formed.

[0054] In another preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by at least the following XRPD peaks as defined above: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], wherein stirring is carried out at a temperature between 15° C. and 30° C.

[0055] In another preferred embodiment, the present invention relates to a process for preparing crystalline Form 2 of compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)] as defined above, wherein the crystalline solid is isolated by microfiltration.

[0056] In another preferred embodiment, the present invention relates to a process for preparing crystalline Form 2 of compound of formula (I), characterized by at least the following XRPD peaks as defined above: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], wherein stirring is carried out at a temperature between 15° C. and 30° C. and the crystalline solid is isolated by microfiltration.

[0057] In a further embodiment, the present invention also relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the step of dissolving crystalline form A of compound of formula (I) in acetone.

[0058] In another embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the steps of dissolving crystalline form A of compound of formula (I) in acetone, stirring, and isolating the crystalline solid thus formed.

[0059] In another preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I) characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], wherein stirring is carried out at a temperature between 15° C. and 30° C.

[0060] In a further preferred embodiment, the present invention relates to a process for preparing crystalline Form 2 of compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)] as defined above, wherein the crystalline solid is isolated by microfiltration.

[0061] In a further preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I) characterized by the following XRPD peaks as defined above: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], wherein stirring is carried out at a temperature between 15° C. and 30° C. and the crystalline solid is isolated by microfiltration.

[0062] In a further preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the step of dissolving crystalline form A of compound of formula (I) in acetone.

[0063] In another embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)], comprising the steps of dissolving crystalline form A of compound of formula (I) in acetone, stirring, and isolating the crystalline solid thus formed.

[0064] In another preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I) characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)] as defined above, wherein stirring is carried out at a temperature between 15° C. and 30° C.

[0065] In a further preferred embodiment, the present invention relates to a process for preparing crystalline Form 2 of compound of formula (I) characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)] as defined above, wherein the crystalline solid is isolated by microfiltration.

[0066] In an even more preferred embodiment, the present invention relates to a process for preparing crystalline form 2 of compound of formula (I) characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)] as defined above, wherein stirring is carried out at a temperature between 15° C. and 30° C. and the crystalline solid is isolated by microfiltration.

[0067] In a further aspect, the present invention provides a pharmaceutical composition for inhalation comprising crystalline Form 2 of the compound of formula (I) in combination with suitable carriers and / or excipients.

[0068] In another embodiment, the present invention provides crystalline Form 2 of compound of formula (I) for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0069] In a preferred embodiment, the present invention provides crystalline Form 2 as defined above 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, cystic fibrosis, pneumonia, acute respiratory distress syndrome (ARDS), emphysema, smoking induced emphysema and cystic fibrosis.

[0070] The present invention also relates to a pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0071] Suitable excipients may be selected from those in the art and may include carriers, diluents, wetting agents, emulsifiers, binders, coatings, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffering substances, etc. Examples of excipients and their uses are provided in Handbook of Pharmaceutical Excipients, 5th ed. (2006), Ed. Rowe et al., Pharmaceutical Press.

[0072] The most suitable dosage level can be determined by any known suitable method. However, it is understood that the specific amount for a particular patient will vary depending on a variety of factors, including, for example, the activity of the crystalline form 2 of the compound of formula (I), the age, weight, dietary habits, general health and sex of the patient, the time of administration, the route of administration, the rate of excretion, the use of any other drugs and the severity of the disease being treated.

[0073] In some embodiments, the crystalline form 2 of the compound of formula (I) is preferably in the form of microparticles, and even more preferably for administration by inhalation. The microparticles can be prepared by a variety of techniques known in the art, including spray drying, freeze drying and micronization.

[0074] In some embodiments, the compositions of the present invention are prepared in the form of a suspension suitable for delivery by nebulizer or as an aerosol in liquid propellant, even more preferably for use in pressurized metered dose inhalers (pMDIs).Suitable propellants for use in pMDIs are known to those skilled in the art and include HFA-227, preferably HFA-134a and more preferably HFA152a.

[0075] In a preferred embodiment, the compositions of the present invention are in the form of a dry powder, more preferably for use in a dry powder inhaler (DPI).

[0076] Microparticles for delivery by administration can be formulated with additives that aid delivery and release.For example, in dry powder formulations, microparticles can be formulated with large carrier particles that aid flow from DPI to lungs.Suitable carrier particles are known in the art and include, for example, lactose particles.

[0077] The agent of the present invention can be administered in inhalation form.Aerosol production can be carried out, for example, by using a pressure-driven jet atomizer or ultrasonic atomizer, preferably by using a propellant-driven metered-dose aerosol or propellant-free administration of micronized crystalline Form 2 of compound of formula (I) from, for example, an inhalation capsule or other "dry powder" delivery system.

[0078] In a preferred embodiment, the present invention relates to crystalline Form 2 of compound of formula (I) in the form of a capsule.

[0079] As mentioned above, the present invention relates to crystalline Form 2 of the compound of formula (I) for use as a medicament.

[0080] According to a preferred embodiment, the present invention relates to the use of crystalline Form 2 of compound of formula (I) for the preparation 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.

[0081] The present invention also relates to a pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients for use as a medicament.

[0082] In a preferred embodiment, the invention relates to crystalline Form 2 of compound of formula (I) for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0083] In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising crystalline Form 2 of 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.

[0084] In a further preferred embodiment, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases comprising the administration of an effective amount of crystalline Form 2 of the compound of formula (I).

[0085] In another preferred embodiment, the present invention provides a method for preventing and / or treating an inflammatory or obstructive respiratory disease comprising administration of a pharmaceutical composition comprising an effective amount of crystalline Form 2 of the compound of formula (I) and one or more pharma- ceutically acceptable carriers and / or excipients.

[0086] In an even further 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.

[0087] Any suitable route of administration may be used for providing a mammal, especially a human, with an effective dosage of crystalline Form 2 of the compound of formula (I).

[0088] The strength of a prophylactic or therapeutic dose of crystalline Form 2 of the 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 is generally determined by clinical trials as required in the medical art.

[0089] It will also vary according to the age, weight and response of the individual patient.

[0090] For therapeutic use, crystalline Form 2 of the compound of formula (I) may be administered by any conventional, suitable or effective route.

[0091] Suitable routes of administration are known and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary (by inhalation).

[0092] The crystalline form 2 of the compound of formula (I) can be administered as described, depending on the inhalation system used. In addition to the active compound, the dosage form can further contain additives such as, for example, propellants (e.g., Frigen for metered dose aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g., lactose for powder inhalers) or, if appropriate, further active compounds.

[0093] The present invention also relates to a device comprising a pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I) above, in a metered dose, in the form of a single or multi-dose dry powder inhaler, capsule or metered dose inhaler (pMDI).

[0094] For inhalation purposes, numerous systems are available with which an aerosol of optimal particle size can be produced and administered using an inhalation technique suitable for the patient. In addition to the use of adapters (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®) and automatic devices releasing puffer sprays (Autohaler®), several technical solutions are available for metered-dose aerosols, especially in the case of powder inhalers (e.g. Diskhaler®, Rotadisk®, Turbohaler® or inhalers as described, for example, in EP-A-0505321.

[0095] In a more preferred embodiment, the present invention describes a low-K process for the preparation of crystalline form 2 of compound of formula (I) starting from crystalline form A of compound of formula (I) obtained according to the general synthetic route described in WO2015 / 059050.

[0096] The following non-limiting examples are illustrative of the present invention and should not be construed in any way as limiting the scope of the invention.

[0097] Experimental part Device X-ray powder diffraction (XRPD) The crystalline state of a sample of Form 2 of compound of formula (I) was examined by X-ray powder diffraction (Empyrean V2.0, Panalytical) equipped with a Cu radiation source (Cu Kα λ=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 reflectance mode, 2 theta scan 1.5-45°, step width 0.02°, Soller slits 0.02 rad, divergence slits 1 / 8°, anti-scatter slits 1 / 4°. Variable temperature and humidity XRPD analysis was performed on an Anton Paar CHC+ camera equipped with a CCU100 temperature control and an MHG-32 humidity generator. Measurements were performed in reflectance mode, 2 theta scan 1.5-45°, step width 0.02°, Soller slits 0.02 rad, divergence slits 1 / 8°, anti-scatter slits 1 / 4°.

[0098] Thermogravimetric analysis (TGA) TGA analysis was performed using a TA Instruments Thermogravimetric Analyzer Discover equipped with a computerized analysis system (TRIOS). Each sample (5-10 mg) was placed in an aluminum sample pan, inserted into the TGA furnace, and accurately weighed. The furnace was first equilibrated at 25°C and then heated under nitrogen (flow rate 30 mL / min) at a rate of 10°C / min to a final temperature of 230°C. Nickel was used as the calibration standard.

[0099] Differential Scanning Calorimetry (DSC) DSC analyses were carried out using a TA Instruments Differential Scanning Calorimeter Discovery equipped with a computerized analysis system (TRIOS).

[0100] Approximately 1-5 mg of each sample was placed into a Perkin Elmer Aluminum DSC pan. The pan was covered with a lid. , which was not crimped. The sample cells were equilibrated at 0°C and heated under nitrogen purge (50 mL / min). All samples were linearly heated to 300°C at a heating rate of 10°C / min to give similar thermal histories. Indium metal was used as a calibration standard. Temperature modulated DSC (mDSC) analysis was performed on the same TA Instruments Discovery DSC. All samples were analyzed for a duration of 60 s and an amplitude of 1°C.

[0101] Nuclear magnetic resonance spectroscopy ( 1 H NMR) 1 H 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 inversion triple resonance cryoprobe HC / ND-0.5-Z ATMA. The probe was equipped with an active shielded single axis Z gradient. 13 C and 15 Simultaneous decoupling on multiple X nuclei such as N, as well as automatic tuning and matching, are now possible.

[0102] Coupled Ultra Performance Liquid Chromatography and Mass Spectrometry (UPLC / MS) LC conditions UPLC equipment: Waters Acquity Column: Acquity UPLC CSH C18 1.7um 50x2.10 (Waters) Column temperature (℃): 55 Mobile phase: HCOONH40.025M pH3(A);MeCN+0.1%HCOOH(B) Flow rate (mL / min): 0.5 (split 1:10 in MS) Stop time (min): 10 [Table 1] Injection volume (μL): 2 Sample solvent: Acetonitrile / water 60 / 40

[0103] MS conditions MS instrument: Waters XEVO-TQS Acquisition mode: Multiple reaction monitoring (MRM) of two mass pairs Parent (m / z): 687.15; Daughter (m / z): 402.08, 456,12 Ionization mode: ES+ Capillary (kV): 1.60 Cone (V): 20.0 Source offset (V): 60.0 Source temperature (℃): 150 Desolvation temperature (℃): 250 Cone gas flow (L / hr): 250 Desolvation gas flow (L / h): 500 Total runtime (min): 5

[0104] Crystallization system A Polar Bear Plus, Cambridge Reactor Design was used for slurry at 50° C. and temperature cycling experiments, while a Crystal 16 (Technobis Crystallization systems) was used for crystallization optimization. EXAMPLES

[0105] Example 1: Preparation of Crystalline Form 2 of Compound of Formula (I) Crystalline Form 2 of compound of formula (I) was prepared according to the following preparation, starting from crystalline Form A of compound of formula (I) prepared according to the method disclosed in Example 10 of WO2015 / 059050A1.

[0106] 2 g of crystalline form A of compound of formula (I) was dissolved in 200 ml of acetone. The resulting organic phase was stirred at RT for 2 hours, microfiltered, and dried overnight in an open vial at room temperature to obtain a white solid (99 mg, quantitative yield).

[0107] Example 2: Characterization of Crystalline Form 2 of Compound of Formula (I) The XRPD pattern of crystalline form 2 of compound of formula (I) obtained by preparation in Example 1 is shown in Figure 1. The following characteristic diffraction peaks at diffraction angles 2 theta were identified for crystalline form 2 of compound of formula (I): 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9 and 23.6±0.2 degrees / 2 theta [Cu Kα radiation (λ=1.5406 Å)].

[0108] The DSC profile of crystalline Form 2 of compound of formula (I) is shown in Figure 3. No thermal event is observed until the first endothermic peak with an onset temperature of about 123.84°C and a peak temperature of 130.44°C, which is due to the melting of the sample.

[0109] Crystalline Form 2 of the compound of formula (I) is characterized by a DSC melting range of 120°-135° C. (heating rate 10° C. / min, N 2 flow 50 ml / min).

[0110] The TGA profile of crystalline Form 2 of compound of formula (I) is shown in Figure 5. Insignificant mass loss was observed up to about 250°C. The TGA profile indicates the anhydrous nature of crystalline Form 2 of compound of formula (I).

[0111] Proton NMR of crystalline form 2 of compound of formula (I) ( 1 H-NMR, δ ppm, DMSO-d6) shows the following signals: 0.38 (dq, 4H, CH2), 0.58 (dq, 4H, CH2), 1.21 (m, 1H, CH), 1.30 (m, 1H, CH), 3.12 (s, 3H, CH3), 3.35 (m, 2H, CH2), 3.61 (dd, 1H, CH), 3.94 (m, 4H, CH2), 6.18 (dd, 1H, CH), 7.07 (m, 1H, CH arom ), 7.20 (m, 2H, CH arom ), 7.41 (d, 1H, CH arom ), 7.50 (d, 1H, CH arom ), 7.60 (dd, 1H, CH arom ), 8.57 (s, 2H, CH arom), 9.19 (s br , 1H, NH).

[0112] Example 3: Characterization of Crystalline Form A of Compound of Formula (I) The XRPD pattern of crystalline form A of the compound of formula (I) according to Example 10 and FIG. 4 of WO2015 / 059050A1 is shown in FIG.

[0113] The DSC profile of crystalline form A of compound of formula (I) is shown in Figure 4, in accordance with Example 10 and Figure 6 of WO2015 / 059050A1. Crystalline form A of compound of formula (I) is characterized by a melting range of 144°-147°C, as determined by DSC at a scan rate of 10°C / min.

[0114] The TGA profile of crystalline form A of compound of formula (I) is shown in FIG.

[0115] Proton NMR of crystalline form A of compound of formula (I) ( 1 H-NMR, δ ppm, DMSO-d6) shows the following signals: 0.30 (dq, 4H, CH2), 0.55 (dq, 4H, CH2), 1.12 (m, 1H, CH), 1.31 (m, 1H, CH), 3.30 (s, 3H, CH3), 3.34 (m, 2H, CH2), 3.59 (dd, 1H, CH), 3.90 (m, 4H, CH2), 6.14 (dd, 1H, CH), 7.03 (m, 1H, CH arom ), 7.20 (m, 2H, CH arom ), 7.38 (d, 1H, CH arom ), 7.48 (d, 1H, CH arom ), 7.59 (dd, 1H, CH arom ), 8.56 (s, 2H, CH arom ), 9.18 (s br , 1H, NH).

[0116] Example 4: Solubility of Crystalline Form A and Crystalline Form 2 of Compound of Formula (I) in Simulated Lung Fluid (SLF) Preparation of simulated lung fluid Solubility studies in SLF were performed for the characterization of crystalline Form 2 and Form A of compound of formula (I). The use of SLF, which mimics physiological lung fluid, is known to be a useful parameter to better understand the dissolution mechanism and potential in vivo behavior of a product, enhancing the predictive power of dissolution studies in terms of bioavailability and therapeutic efficacy.

[0117] The experimental method used is based on the saturated shake flask method. Samples were prepared by adding an excess of crystalline form 2 of compound of formula (I) and an excess of crystalline form A of compound of formula (I) to the solubility medium SLF. The solubility concentration values ​​are the thermodynamic equilibrium concentrations determined by assaying the solute concentration of the filtrate from the saturated solution using an analytical method by UPLC-MS (MRM quantification; calibration: 0.01-10 μg / ml; all batches were tested in duplicate, samples were filtered and diluted 1 / 10 in duplicate).

[0118] The SLF used in the study was prepared similarly to the literature (Simulated Biological Fluids with Possible Application in Dissolution Testing, Dissolution Technologies, 2011, dx.doi.org / 10.14227 / DT180311P15, table 11, page 2215). To better mimic lung fluids, surfactants were added, specifically Tween 80 (0.02% v / v).

[0119] [Table 2]

[0120] The solubility profiles of crystalline Form 2 and Form A of the compound of formula (I) were determined in an SLF adjusted to pH 6.5 with acetic acid (1M) to mimic inflammatory conditions in the lung. The experiments were carried out at 37°C.

[0121] The following experimental conditions were applied for the SLF dissolution profile study of crystalline form 2 and crystalline form A of compound of formula (I), respectively. Approximately 2.5 mg of crystalline form 2 or crystalline form A of compound of formula (I) was dispersed in 2.5 ml of SLF under stirring. The concentration of the substance in the solution was determined after 0.5, 1 and 3 hours. At each time interval, the stirring of the vessel was stopped and 180-250 μl of each sample was collected, filtered through a RC membrane syringe filter 0.45 μm and injected into the UPLC instrument.

[0122] The solubility test results for crystalline form A and crystalline form 2 of compound of formula (I) are summarized in Table 2 below.

[0123] [Table 3]

[0124] Table 2 clearly shows that crystalline Form 2 of compound of formula (I) exhibits at least about 4.5-fold higher solubility relative to crystalline Form A of compound of formula (I) in SLF at 0.5, 1 and 3 hours.

[0125] Example 5: The crystalline form 2 of the compound of formula (I) 1 / 2 and pulmonary MRT last Crystalline Form 2 of the compound of formula (I) was administered intratracheally to Sprague-Dawley rats using a PreciseInhale system at a dose of 10 μg / lung-deposited dose. Powder aerosols were produced using 40 bar generating pressure. A total of 24 Sprague-Dawley male rats were used in the PK study; 8 time points per study, n=3 rats / time point. Prior to administration, rats were anesthetized with sevoflurane and intubated intratracheally using an appropriate steel catheter. Aerosol administration was performed by connecting the catheter to a PreciseInhale system that was pre-set to deliver 10 μg / lung-deposited dose to each animal.

[0126] [Table 4]

[0127] Table 3 shows the lung t value of crystalline Form 2 of compound of formula (I) following intratracheal administration to Sprague-Dawley rats at a dose (deposited dose) of 10 μg / lung. 1 / 2 and pulmonary MRT last Shows.

[0128] lung t 1 / 2 is the terminal half-life, calculated by the formula ln(2) / λz, where λz is the first-order rate constant associated with the terminal (log-linear) portion of the curve. It is estimated by linear regression of time versus log concentration; i.e., the time it takes for the drug concentration in the lungs to decrease by 50%.

[0129] lung MRT last means the residence time from the time of administration to the last measurable concentration; i.e., the average time a molecule resides in the lung.

[0130] The crystalline form 2 of the compound of formula (I) 1 / 2 The values ​​correspond to short lung retention, indicating a low risk of lung accumulation following repeated dosing.

[0131] lung t 1 / 2 and pulmonary MRT last The values ​​indicate the likelihood of crystalline Form 2 of compound of formula (I) having good in vivo bioavailability.

Claims

1. Crystalline Form 2 of formula (I), characterized by at least the following XRPD peaks: 【Chemistry 1】 Compound: 4.0, 7.9, 13.2±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

2. 2. The crystalline form 2 of claim 1, characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

3. 3. The crystalline form 2 of claims 1 and 2, characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9, 23.6±0.2 degrees / 2theta [Cu Kα radiation (λ=1.5406 Å)].

4. 120° to 135°C (heating rate 10°C / min, N ２ The crystalline form 2 of any of claims 1 to 3, characterized by a DSC melting range at a flow rate of 50 ml / min.

5. A process for preparing crystalline form 2 of compound of formula (I) of any of claims 1 to 4, comprising the step of dissolving crystalline form A of compound of formula (I) in acetone.

6. 6. The process of claim 5, further comprising the steps of stirring and isolating the crystalline form 2 thus formed.

7. 7. The process of claim 6, wherein the stirring is carried out at a temperature between 15°C and 30°C.

8. 8. The process of claim 6 or 7, wherein the crystalline form 2 is isolated by microfiltration.

9. A pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I) according to any one of claims 1 to 4 and one or more pharma- ceutically acceptable carriers and / or excipients.

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

11. The crystalline form 2 of any one of claims 1 to 4 for use as a medicament.

12. Crystalline form 2 of any of claims 1 to 4 for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

13. Crystalline form 2 of any of claims 1 to 4, for use according to 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.

14. 11. The pharmaceutical composition of claim 9 or 10 for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

15. 15. The pharmaceutical composition for use according to claim 14, 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.

16. A device comprising a pharmaceutical composition comprising crystalline form 2 of compound of formula (I) as defined in any one of claims 1 to 4.

17. 17. The device of claim 16 in the form of a single or multi-dose dry powder inhaler or capsule.

18. 17. The device of claim 16 in the form of a pressurized metered dose inhaler (pMDI).

19. 5. Crystalline form 2 of the compound of formula (I) according to any of claims 1 to 4, obtained by dissolving crystalline form A of the compound of formula (I) in acetone.

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