Crystalline forms of PDE4 inhibitors

Abstract

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

Description

Field of the Invention

[0001] The present invention relates to a crystalline form 2 of a compound of formula (I), to a method for isolating the crystalline form 2 and to a pharmaceutical composition thereof. The present invention also relates to a crystalline form 2 of a compound of formula (I), which is used as a medicament and for preparing a medicament for preventing and / or treating inflammatory respiratory system or obstructive respiratory system diseases. Background of the Invention

[0003] Compound of formula (I)

[0004]

[0005] Also known as tanimilast or CHF6001 or CHF-6001, with INN (3,5-dichloro-4-[(2S)-2-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-{[3-(cyclopropylmethoxy)-4-(methylsulfonylamino)benzoyl]oxy}ethyl]pyridine 1-oxide), is a highly potent and selective PDE4 inhibitor with strong anti-inflammatory activity and is currently in clinical development.

[0006] The compound of formula (I) has been disclosed in the prior art documents under the name of Chiesi: WO2009 / 018909 relates to its general formula, preparation method, composition and therapeutic use; WO2010 / 089107 relates in particular to sulfonylamino derivatives as (-) enantiomers, including compounds of formula (I), preparation methods, compositions and therapeutic uses; WO2012 / 016889 relates to dry powder formulations comprising compounds of formula (I); WO2015 / 059050 relates to a crystalline form of the compound of formula (I), referred to as Form A, characterized by specific XRPD peaks, and to a method for obtaining it.

[0007] Despite the above cited prior art, there is a need to develop forms of compounds of formula (I) having improved solubility and bioavailability.

[0008] In this direction, the inventors have unexpectedly found that crystalline form 2 of the compound of formula (I) according to the invention has advantageous properties selected from the group consisting of solubility, dissolution rate, low risk of lung accumulation after repeated administration, bioavailability and efficacy. SUMMARY OF THE INVENTION

[0010] In a first aspect, the present invention relates to a crystalline form of a compound of formula (I)

[0011]

[0012] It is referred to as Form 2 and is characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ].

[0013] In a second aspect, the present invention provides a method for preparing a crystalline form 2 of a compound of formula (I) characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ]), which is carried out by dissolving the crystalline form A of the compound of formula (I) in acetone.

[0014] In another aspect, the present invention relates to crystalline Form 2 of the compound of formula (I), which is obtained (or obtainable) by dissolving crystalline Form A of the compound of formula (I) in acetone.

[0015] In another aspect, the present invention provides crystalline Form 2 of the compound of formula (I) for use as a medicament.

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form 2 of the compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients, for use as a medicament.

[0017] In yet another aspect, the present invention provides the use of crystalline form 2 of the compound of formula (I) as defined above for the preparation of a medicament for the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0018] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form 2 of a compound of formula (I) as defined above and one or more pharmaceutically acceptable carriers and / or excipients, for use in preventing and / or treating inflammatory or obstructive respiratory diseases.

[0019] In another aspect, the present invention provides the use of a pharmaceutical composition for the preparation of a medicament for preventing and / or treating inflammatory or obstructive respiratory diseases, wherein the pharmaceutical composition comprises the crystalline form 2 of the compound of formula (I) as defined above and one or more pharmaceutically acceptable carriers and / or excipients.

[0020] In another aspect, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases in humans, said method comprising administering an effective amount of crystalline Form 2 of the compound of formula (I) as defined above.

[0021] In another aspect, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases in humans, the method comprising administering an effective amount of a pharmaceutical composition comprising Form 2 of a compound of formula (I) as defined above and one or more pharmaceutically acceptable carriers and / or excipients.

[0022] In another aspect, the invention relates to a device comprising a pharmaceutical composition comprising crystalline Form 2 of the compound of formula (I). BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 : XRPD of the crystalline form 2 of the compound of formula (I)

[0025] Figure 2 : XRPD of the crystalline form A of the compound of formula (I)

[0026] Figure 3 : DSC of the crystalline form 2 of the compound of formula (I)

[0027] Figure 4 : DSC of the crystalline form A of the compound of formula (I)

[0028] Figure 5 : TGA of the crystalline form 2 of the compound of formula (I)

[0029] Figure 6 : TGA of the crystalline form A of the compound of formula (I) DETAILED DESCRIPTION OF THE INVENTION

[0031] definition

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0033] The term "compound of the present invention" refers to the crystalline form 2 of the compound of formula (I).

[0034] Unless otherwise specified, the compounds of formula (I) of the present invention are intended to also include stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof.

[0035] The term "pharmaceutically acceptable salts", as used herein, refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or base groups (if present) into the corresponding addition salts with any base or acid conventionally considered to be pharmaceutically acceptable.

[0036] Suitable examples of such salts may thus include inorganic or organic acid addition salts of basic residues such as amino groups, and inorganic or organic base addition salts of acidic residues such as carboxyl groups.

[0037] Cations of inorganic bases which may be suitable for preparing salts include ions of alkali or alkaline earth metals, for example potassium, sodium, calcium or magnesium.

[0038] Those obtained by reacting the main compound (acting as a base) with an inorganic or organic acid to form a salt 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.

[0039] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In certain instances, the solvate will be capable of separation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0040] The term "stereoisomer" refers to isomers of identical composition which differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

[0041] The term "racemate" or "racemic mixture" refers to a composition consisting of equimolar amounts of two enantiomeric species, wherein the composition is optically inactive.

[0042] The term "tautomer" refers to each of two or more isomers of a compound which exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule.

[0043] The term "composition" as in pharmaceutical composition is intended to encompass a product comprising the active ingredients and any pharmaceutically acceptable excipients or carriers, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other type of reaction or interaction of one or more of the ingredients.

[0044] Thus, the pharmaceutical compositions of the present invention encompass any type of composition prepared by mixing a compound of the present invention and a pharmaceutically acceptable excipient and / or carrier.

[0045] The term "high level of chemical purity" refers to a crystalline form wherein the total amount of readily detectable impurities as determined by standard analytical methods such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) is less than 5%, advantageously less than 2.5%, even less than 1.0, or more preferably even less than 0.5% w / w.

[0046] The term "high level of crystallinity" refers to a crystalline form wherein the percentage of crystallinity as determined by standard analytical methods such as X-ray powder diffraction or microcalorimetry is equal to or higher than 90%, preferably higher than 95% w / w.

[0047] The terms "polymorph", "polymorphic form", "crystal", "crystalline form", "crystalline", "crystalline form" and "form" refer to a compound having a particular packing arrangement of molecules 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 properties of polymorphic forms, such as Form 2 of the compound of Formula (I) described herein.

[0048] The term "XRPD" refers to X-ray powder diffraction. XRPD is a technique used to provide analytical characterization of a sample. Polymorphic forms are characterized by having different XRPD patterns.

[0049] The term "NMR" refers to proton nuclear magnetic resonance. NMR spectroscopy provides structural information about organic compounds based on the energy absorption by hydrogen atoms.

[0050] The term "DSC" refers to differential scanning calorimetry. DSC is a thermal analysis technique that measures the difference in the amount of heat required to raise the temperature of a test compound and a reference as a function of temperature. The output is a differential thermogram and can be used, for example, to estimate the melting temperature of the test compound. It is used to characterize the polymorphic form of a salt.

[0051] The term "TGA" refers to Thermogravimetric Analysis. TGA is a technique that monitors the change in mass of a substance with temperature when a sample is subjected to a controlled temperature program in a controlled atmosphere. It is used to characterize the polymorphic forms of salts.

[0052] The term "room temperature", abbreviated RT, refers to a temperature in the range of about 15°C to about 25°C, with an average of about 23°C.

[0053] The terms "treating" or "treatment" of a disease state include: (i) inhibiting the disease state, i.e., arresting the development 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.

[0054] The terms "preventing" or "prevention" of a disease state include causing clinical symptoms of a disease state to not develop in a subject who may be exposed to or susceptible to the disease state but does not yet experience or display 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 cough and / or the urge to cough associated with a respiratory disease.

[0055] The present invention relates to a crystalline form of the compound of formula (I), which is referred to as Form 2.

[0056] Unexpectedly, the crystalline form 2 of the compound of formula (I) according to the present invention shows increased solubility in simulated lung fluid (SLF) relative to the crystalline form A of the compound of formula (I) as known in the art. As can be understood in Table 2 of Example 4 in this experimental part, after 0.5, 1 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 simulating physiological lung fluid is known to be a useful parameter to provide a good understanding of the dissolution mechanism and possible in vivo behavior of the product, enhancing the predictive power of the dissolution test in terms of bioavailability and therapeutic effectiveness.

[0057] More advantageously, the crystalline form 2 of the compound of formula (I) according to the present invention unexpectedly shows a low risk of lung accumulation after repeated administration. As can be understood from Table 3 of Example 5 in this experimental part, the crystalline form 2 of the compound of formula (I) according to the present invention shows a lung t of 7.7 hours. 1 / 2 , indicating a low risk of accumulation in the lungs after repeated administration.

[0058] More advantageously, the lung t reported in Table 3 of Example 5 in this experimental part 1 / 2 and lung MRT last The value of 400 μg / mL predicted that the crystalline form 2 of the compound of formula (I) has the potential for good in vivo bioavailability.

[0059] In addition, the crystalline form 2 of the compound of formula (I) of the present invention can also be used to treat diseases in which the activity of the PDE4 receptor is involved and inhibition of the PDE4 receptor activity is desired, or even disease states mediated by PDE4 activity.

[0060] In a preferred embodiment, the present invention provides a crystalline form of a compound of formula (I)

[0061]

[0062] It is referred to as Form 2 and is characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ].

[0063] In another preferred embodiment, the present invention provides a crystalline form of the compound of formula (I), which is referred to as Form 2, wherein the crystalline form is characterized by the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ].

[0064] In another preferred embodiment, the present invention provides a crystalline form of the compound of formula (I), which is referred to as Form 2, wherein the crystalline form is characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [Cu Kα radiation ].

[0065] In a more preferred embodiment, the present invention provides a crystalline form of the compound of formula (I), which is referred to as Form 2, wherein the crystalline form is 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 / 2θ [Cu Kα radiation ].

[0066] In another embodiment, the present invention also relates to Form 2 of the compound of formula (I), characterized by a DSC melting range of 120°-135°C (heating rate 10°C / min, N2 flow rate 50 ml / min).

[0067] In one embodiment, the present invention also relates to a process for preparing Form 2 of the compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ], the method comprising the step of dissolving the crystalline form A of the compound of formula (I) in acetone.

[0068] Therefore, the present invention also relates to the thus obtained crystalline form 2 of the compound of formula (I) according to the following embodiments herein.

[0069] In another embodiment, the present invention is directed to a process for preparing Form 2 of the compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ], the method comprising the steps of dissolving the crystalline form A of the compound of formula (I) in acetone, stirring and isolating the crystalline solid thus formed.

[0070] In another preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C.

[0071] In another preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ], whereupon the crystalline solid was isolated by microfiltration.

[0072] In another preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the compound of formula (I), characterized by at least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C and the crystalline solid is isolated by microfiltration.

[0073] In another embodiment, the present invention also relates to a process for preparing Form 2 of the compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [Cu Kα radiation ], the method comprising the step of dissolving the crystalline form A of the compound of formula (I) in acetone.

[0074] In another embodiment, the present invention is directed to a process for preparing Form 2 of the compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [Cu Kα radiation ], the method comprising the steps of dissolving the crystalline form A of the compound of formula (I) in acetone, stirring and isolating the crystalline solid thus formed.

[0075] In another preferred embodiment, the present invention relates to a process for preparing Form 2 of the compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [Cu Kα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C.

[0076] In a further preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [CuKα radiation ], whereupon the crystalline solid was isolated by microfiltration.

[0077] In a further preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the compound of formula (I), characterized by the following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [CuKα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C and the crystalline solid is isolated by microfiltration.

[0078] In another embodiment, the present invention also relates to a process for preparing Form 2 of the 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 / 2θ [Cu Kα radiation ], the method comprising the step of dissolving the crystalline form A of the compound of formula (I) in acetone.

[0079] In another embodiment, the present invention is directed to a process for preparing Form 2 of the 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 / 2θ [Cu Kα radiation ], the method comprising the steps of dissolving the crystalline form A of the compound of formula (I) in acetone, stirring and isolating the crystalline solid thus formed.

[0080] In another preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the 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 / 2θ [Cu Kα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C.

[0081] In a further preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the 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 / 2θ [Cu Kα radiation ] and the crystalline solid was isolated by microfiltration.

[0082] In a further preferred embodiment, the present invention relates to a process as defined above for the preparation of crystalline form 2 of the 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 / 2θ [Cu Kα radiation ], wherein stirring is carried out at a temperature of 15°C to 30°C and the crystalline solid is isolated by microfiltration.

[0083] In another aspect, the present invention provides a pharmaceutical composition for inhalation comprising crystalline Form 2 of the compound of formula (I) in combination with a suitable carrier and / or excipient.

[0084] In another aspect, the present invention provides crystalline form 2 of the compound of formula (I) for use in preventing and / or treating inflammatory or obstructive respiratory diseases.

[0085] In a preferred embodiment, the present invention provides 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 the group consisting of: 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.

[0086] The present invention also relates to a pharmaceutical composition comprising the crystalline form 2 of the compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0087] Suitable excipients can be selected among those in the art, and they may include carriers, diluents, wetting agents, emulsifiers, binders, coatings, fillers, glidants, lubricants, disintegrants, preservatives, surfactants, pH buffer substances, etc. Examples of excipients and their uses are provided in Handbook of Pharmaceutical Excipients, 5th edition, (2006), Rowe et al., eds., Pharmaceutical Press.

[0088] The most suitable dosage level can be determined by any known suitable method. However, it should be understood that the specific amount used for any particular patient will depend on a variety of factors, including, for example, the activity of the crystalline form 2 of the compound of formula (I), the age, weight, diet, overall 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 to be treated.

[0089] In one embodiment, the crystalline form 2 of the compound of formula (I) is preferably in the form of microparticles, more preferably for administration by inhalation. The microparticles can be prepared by various techniques known in the art, including spray drying, freeze drying and micronization.

[0090] In one embodiment, the composition of the present invention is prepared in the form of a suspension suitable for delivery by a nebulizer or as an aerosol in a liquid propellant, even more preferably for use in a pressurized metered dose inhaler (pMDI). Suitable propellants for use in pMDIs are known to the skilled person and include HFA-227, preferably HFA-134a and more preferably HFA152a.

[0091] In a preferred embodiment, the composition of the invention is in the form of a dry powder, more preferably for use in a dry powder inhaler (DPI).

[0092] Microparticles for delivery by administration can be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles can be formulated with large carrier particles that aid flow from the DPI into the lungs. Suitable carrier particles are known in the art and include, for example, lactose particles.

[0093] The medicament of the present invention can be administered in the form of inhalation. The generation of the aerosol can be carried out using, for example, a pressure-driven jet nebulizer or an ultrasonic nebulizer, preferably a propellant-driven metered dose aerosol or a propellant-free administration of the crystalline form 2 of the compound of formula (I) from, for example, an inhalation capsule or other "dry powder" delivery system.

[0094] In a preferred embodiment, the present invention relates to crystalline Form 2 of the compound of formula (I) in the form of a capsule.

[0095] As mentioned above, the present invention relates to crystalline form 2 of the compound of formula (I) for use as a medicament.

[0096] According to a preferred embodiment, the present invention relates to the use of crystalline form 2 of the compound of formula (I) for the preparation of a medicament for the treatment of inflammatory or obstructive lung diseases, 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.

[0097] The present invention also relates to a pharmaceutical composition comprising the crystalline form 2 of the compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients, wherein the pharmaceutical composition is used as a medicament.

[0098] In a preferred embodiment, the present invention relates to crystalline form 2 of the compound of formula (I) for use in the prevention and / or treatment of inflammatory or obstructive respiratory diseases.

[0099] In another preferred embodiment, the present invention relates to a pharmaceutical composition comprising the crystalline form 2 of the compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients, wherein the pharmaceutical composition is used for preventing and / or treating inflammatory or obstructive respiratory diseases.

[0100] In another preferred embodiment, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases, which comprises administering an effective amount of crystalline form 2 of the compound of formula (I).

[0101] In another preferred embodiment, the present invention provides a method for preventing and / or treating inflammatory or obstructive respiratory diseases, which comprises administering an effective amount of a pharmaceutical composition comprising Form 2 of a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0102] In another preferred embodiment, the above-mentioned inflammatory or obstructive respiratory diseases are 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.

[0103] Any suitable route of administration may be used for providing an effective dose of the crystalline Form 2 of the compound of formula (I) to a mammal, particularly a human.

[0104] Of course, the size of the preventive or therapeutic dose of Form 2 of the compound of formula (I) will vary with the nature of the severity of the condition to be treated and with its route of administration, and will generally be determined by clinical trials as required in the pharmaceutical art.

[0105] It will also vary according to the age, weight, and response of the individual patient.

[0106] In therapeutic use, the crystalline form 2 of the compound of formula (I) may be administered by any convenient, suitable or effective route.

[0107] Suitable routes of administration are known and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal, and pulmonary (by inhalation).

[0108] The crystalline form 2 of the compound of formula (I) can be taken as described according to the inhaler system used. In addition to the active compound, the application form may also contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered-dose aerosols), surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or additional active compounds (if appropriate).

[0109] The present invention also relates to a device comprising a pharmaceutical composition comprising crystalline form 2 of the compound of formula (I) as described above according to the present invention, the device being in the form of a single-dose or multi-dose dry powder inhaler, capsule or metered dose inhaler (pMDI).

[0110] For inhalation purposes, a large number of systems are available with which an aerosol of optimal particle size can be generated and administered using an inhalation technique that is appropriate for the patient. In addition to the use of adapters (spacers, expanders) and pear-shaped containers (e.g. ) and automatic device for spraying with a jet sprayer (puffer) Outside of metered dose aerosols, particularly in the case of powder inhalers, many technical solutions are available (e.g. or inhalers, for example as described in EP-A-0505321).

[0111] In a more preferred embodiment, the present invention provides a process for preparing Form 2 of the compound of formula (I), said process starting from Form A of the compound of formula (I) obtained according to the general synthetic route described in WO2015 / 059050.

[0112] The following non-limiting examples are illustrative of the present disclosure and should not be construed as limiting the scope of the invention in any way.

[0113] Experimental Section

[0114] instrument

[0115] X-ray powder diffraction (XRPD)

[0116] By equipped with a Cu radiation source The crystalline state of the form 2 sample of the compound of formula (I) was studied by X-ray powder diffraction (Empyrean V2.0, Panalytical). The sample was placed on a Si zero background sample holder and rotated with a rotation time of 4 s. The measurement was carried out in reflection mode, with 2θ scanning from 1.5 to 45°, a step length of 0.02°, a soller slit of 0.02 rad, a divergence slit of 1 / 8°, and an anti-scattering slit of 1 / 4°. The variable temperature and humidity XRPD analysis was carried out with an Anton Paar CHC+ camera equipped with a CCU100 temperature control and a MHG-32 humidity generator. The measurement was carried out in reflection mode, with 2θ scanning from 1.5 to 45°, a step length of 0.02°, a soller slit of 0.02 rad, a divergence slit of 1 / 8°, and an anti-scattering slit of 1 / 4°.

[0117] Thermogravimetric analysis (TGA)

[0118] TGA analysis was performed using a TA Instruments Thermogravimetric Analyzer Discovery equipped with a computer analysis system (TRIOS). Each sample (5-10 mg) was placed in an aluminum sample pan, inserted into a TGA furnace and accurately weighed. The furnace was first equilibrated at 25°C and then heated at a rate of 10°C / min under nitrogen (flow rate 30 mL / min) until a final temperature of 230°C. Nickel was used as a calibration standard.

[0119] Differential Scanning Calorimetry (DSC)

[0120] DSC analyses were performed using a TA Instruments Differential Scanning Calorimeter Discovery equipped with a computer analysis system (TRIOS).

[0121] Approximately 1-5 mg of each sample was placed in a Perkin Elmer aluminum DSC pan. The pan was covered with a lid without crimping it. The sample wells were equilibrated at 0°C and heated under a nitrogen purge (50 mL / min). All samples were provided with similar thermal histories by linear heating to 300°C at a heating rate of 10°C / min. Indium metal was used as a calibration standard. Modulated DSC (mDSC) analysis was performed using the same TA Instruments Discovery DSC. All samples were analyzed with a period of 60 s and an amplitude of 1°C.

[0122] Nuclear Magnetic Resonance Spectroscopy (1H NMR)

[0123] 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 was equipped with an actively shielded uniaxial Z gradient and allowed simultaneous decoupling on multiple X nuclei (such as 13C and 15N), as well as automatic tuning and matching.

[0124] Ultra-performance liquid chromatography-mass spectrometry (UPLC / MS)

[0125] LC conditions

[0126] UPLC instrument: Waters Acquity

[0127] Column: Acquity UPLC CSH C18 1.7um 50x2.10 (Waters)

[0128] Column temperature (℃): 55

[0129] Mobile phase: HCOONH4 0.025M pH3 (A); MeCN + 0.1% HCOOH (B)

[0130] Flow rate (mL / min): 0.5 (MS1:10 split)

[0131] Stop time (min): 10

[0132] gradient:

[0133] Time (min) ％A ％B 0.00 90.0 10.0 0.50 90.0 10.0 3.00 75.0 25.0 7.50 50.0 50.0 8.00 20.0 80.0 8.10 90.0 10.0 10.00 90.0 10.0

[0134] Injection volume (μL): 2

[0135] Sample solvent: acetonitrile / water 60 / 40

[0136] MS conditions

[0137] MS instrument: Waters XEVO-TQS

[0138] Acquisition mode: Multiple reaction monitoring (MRM) of 2 mass pairs

[0139] Parent ion (m / z): 687.15; daughter ions (m / z): 402.08, 456, 12

[0140] Ionization mode: ES+

[0141] Capillary voltage (kV): 1.60

[0142] Cone voltage (V): 20.0

[0143] Ion source default voltage (V): 60.0

[0144] Source temperature (℃): 150

[0145] Desolvation temperature (℃): 250

[0146] Cone gas flow rate (L / Hr): 250

[0147] Desolventizing gas flow rate (L / Hr): 500

[0148] Total running time (min): 5

[0149] Crystallization system

[0150] For slurry and temperature cycling experiments at 50°C, a Polar Bear Plus, Cambridge Reactor Design was used, while for crystallization optimization, a Crystal 16 (Technobis Crystallization System) was used. Example

[0151] Example 1: Preparation of Crystalline Form 2 of the Compound of Formula (I)

[0152] According to the following preparation method, the crystalline form 2 of the compound of formula (I) is prepared starting from the crystalline form A of the compound of formula (I) prepared according to the procedure disclosed in Example 10 of WO2015 / 059050A1.

[0153] 2 g of the crystalline form A of the compound of formula (I) were dissolved in 200 ml of acetone. The resulting organic phase was stirred at RT for 2 h, microfiltered and dried in an open vial at room temperature overnight to give a white solid (99 mg, quantitative yield).

[0154] Example 2: Characterization of Form 2 of the Compound of Formula (I)

[0155] The XRPD pattern of the crystalline form 2 of the compound of formula (I) obtained according to the preparation method of Example 1 is shown in Figure 1 For the crystalline form 2 of the compound of formula (I), the following characteristic diffraction peaks at diffraction angles 2-θ were identified: 4.0, 7.9, 8.6, 9.1, 12.2, 13.2, 15.0, 19.8, 20.9 and 23.6 ± 0.2 degrees / 2θ [Cu Kα radiation

[0156] The DSC curve of the crystalline form 2 of the compound of formula (I) is shown in Figure 3 No thermal events are shown until the first endothermic peak with an onset temperature of about 123.84°C and a peak temperature of about 130.44°C, which is due to the melting of the sample.

[0157] Form 2 of the compound of formula (I) is characterized by a DSC melting range of 120°C-135°C (heating rate 10°C / min, N2 flow rate 50 ml / min).

[0158] The TGA curve of the crystalline form 2 of the compound of formula (I) is shown in Figure 5 Negligible weight loss was observed until about 250° C. The TGA curve indicated the anhydrous nature of Form 2 of the compound of formula (I).

[0159] The proton NMR (1H-NMR, δppm, DMSO-d6) of the crystalline form 2 of the compound of formula (I) 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).

[0160] Example 3: Characterization of Form A of the Compound of Formula (I)

[0161] According to Example 10 of WO2015 / 059050A1 and Figure 4 The XRPD pattern of the crystalline form A of the compound of formula (I) is shown in Figure 2 middle.

[0162] According to Example 10 of WO2015 / 059050A1 and Figure 6 The DSC curve of the crystalline form A of the compound of formula (I) is shown in Figure 4 Form A of the compound of formula (I) is characterized by a melting range of 144°C-147°C as determined by DSC at a scan rate of 10°C / min.

[0163] The TGA curve of the crystalline form A of the compound of formula (I) is shown in Figure 6 middle.

[0164] The proton NMR (1H-NMR, δppm, DMSO-d6) of the crystalline form A of the compound of formula (I) 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).

[0165] Example 4: Solubility of Form A and Form 2 of the Compound of Formula (I) in Simulated Lung Fluid (SLF)

[0166] Preparation of simulated lung fluid

[0167] Studies were performed to characterize the solubility of Form 2 and Form A of the compound of formula (I) in SLF. The use of SLF, which simulates physiological lung fluid, can provide a good understanding of the dissolution mechanism and possible in vivo behavior of the product, enhancing the predictive power of dissolution testing in terms of bioavailability and therapeutic effectiveness.

[0168] The experimental method used is based on the saturated shake flask method. The samples were prepared by adding an excess of the crystalline form 2 of the compound of formula (I) and an excess of the crystalline form A of the compound of formula (I) in the solubility medium SLF, respectively. The solubility concentration value is the thermodynamic equilibrium concentration, which is determined by measuring the solute concentration of the filtrate from the saturated solution using an analytical method by UPLC-MS (MRM quantification; calibration: 0.01 to 10 μg / ml; each batch was tested in duplicate, and the duplicate samples were filtered and diluted 1 / 10).

[0169] The SLF used for the experiment 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). In order to better simulate lung fluid, surfactants, especially Tween 80, were added (0.02% v / v).

[0170] Table 1: SLF compositions used for solubility testing of Form A and Form 2 of the compound of formula (I)

[0171] Components <![CDATA[Amount (g) in 1 L of H2O]]> <![CDATA[MgCl2.6H2O]]> 0.2033 NaCl 6.019 KCl 0.2982 <![CDATA[Na2HPO4.7H2O]]> 0.268 <![CDATA[Na2SO4]]> 0.071 <![CDATA[CaCl2.2H2O]]> 0.3676 <![CDATA[NaH3C2O2.3H2O]]> 0.9526 <![CDATA[NaHCO3]]> 2.6043 <![CDATA[Na3H5C6O7.2H2O]]> 0.097

[0172] The solubility profiles of Form 2 and Form A of the compound of formula (I) were determined in SLF adjusted to a pH of 6.5 with acetic acid (1 M) to simulate inflammatory conditions in the lung. The experiments were performed at 37°C.

[0173] The following experimental conditions were used for the SLF dissolution curve study of the crystalline form 2 and the crystalline form A of the compound of formula (I), respectively. About 2.5 mg of the crystalline form 2 or the crystalline form A of the compound of formula (I) was dispersed in 2.5 ml of SLF using a stirring system. The concentration of the material in the solution was determined after 0.5, 1 and 3 hours. At each time interval, the container stirring was stopped, and 180-250 μl of each sample was collected and filtered through a RC membrane syringe filter 0.45 μm and injected into the UPLC device.

[0174] The results of the solubility tests of Form A and Form 2 of the compound of formula (I) are summarized in Table 2 below.

[0175] Table 2: Solubility of Form A and Form 2 of the compound of formula (I)

[0176] Time (h) Crystalline form A (μg / ml) Crystal form 2 (μg / ml) 0.5 0.16 0.74 1 0.18 0.89 3 0.20 0.88

[0177] Table 2 clearly shows that Form 2 of the compound of formula (I) has a solubility in SLF that is at least about 4.5 times higher than Form A of the compound of formula (I) at 0.5, 1 and 3 hours.

[0178] Example 5: Crystalline Form 2 of the Compound of Formula (I) 1 / 2 and lung MRT last

[0179] Crystalline Form 2 of the compound of formula (I) was administered intratracheally to Sprague-Dawley rats at a dose of 10 μg / lung deposition dose using the PreciseInhale system. A powder aerosol was generated using a generation pressure of 40 bar. A total of 24 Sprague-Dawley male rats were used for the PK study; for each study, 8 time points, n=3 rats / time point. Prior to administration, the rats were anesthetized with sevoflurane and intubated intratracheally using a suitable steel catheter. The catheter was connected to a PreciseInhale system previously set to deliver a 10 μg / lung deposition dose to each animal for aerosol administration.

[0180] Table 3: Crystalline Form 2 of the compound of formula (I) 1 / 2 and lung MRT last

[0181] <![CDATA[Lung t 1 / 2 (h)]]> <![CDATA[Lung MRT last (h)]]> 7.7 9.4

[0182] Table 3 shows the lung t of Form 2 of the compound of formula (I) after intratracheal administration to Sprague Dawley rats at a dose of 10 μg / lung (deposited dose). 1 / 2 and lung MRT last .

[0183] Lung 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; that is, the time required for the concentration of drug in the lung to decrease to 50%.

[0184] Lung MRI last It is the mean residence time from the time of drug administration to the time of last measurable concentration; that is, the average time a molecule stays in the lungs.

[0185] Crystalline Form 2 of the compound of formula (I) 1 / 2 The values ​​correspond to short lung retention, indicating a potentially low risk of lung accumulation after repeated administration.

[0186] Lung 1 / 2 and lung MRT last The values ​​indicate that the crystalline form 2 of the compound of formula (I) has the potential for good in vivo bioavailability.

Claims

1. Crystalline forms of the compound of formula (I) It is called Form 2 and is characterized by At least the following XRPD peaks: 4.0, 7.9, 13.2 ± 0.2 degrees / 2θ [Cu Kα radiation ].

2. The crystalline form 2 according to claim 1, characterized in that The following XRPD peaks: 4.0, 7.9, 8.6, 13.2, 15.0 ± 0.2 degrees / 2θ [Cu Kα radiation ].

3. The crystalline form 2 according to claim 1 and 2, characterized in that 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 / 2θ [Cu Kα radiation ].

4. The crystalline form 2 according to claims 1 to 3, characterized in that DSC melting range of 120°-135°C (heating rate 10°C / min, N2 flow rate 50 ml / min).

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

6. The method according to claim 5, further comprising the steps of stirring and separating the crystal form 2 thus formed.

7. The method according to claim 6, wherein the stirring is performed at a temperature of 15°C to 30°C.

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

9. A pharmaceutical composition comprising the crystalline form 2 of the compound of formula (I) as defined in any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers and / or excipients.

10. The pharmaceutical composition according to claim 9, which is formulated in the form of dry powder.

11. The crystalline form 2 according to claims 1 to 4 for use as a medicament.

12. The crystalline form 2 according to claims 1 to 4, for use in preventing and / or treating inflammatory or obstructive respiratory diseases.

13. The crystalline form 2 according to 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. The pharmaceutical composition according to any one of claims 9 or 10, for use in preventing and / or treating inflammatory or obstructive respiratory diseases.

15. A pharmaceutical composition for use according to claim 14, wherein the inflammatory or obstructive respiratory disease is selected from the group consisting of 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 a compound of formula (I) as defined in any one of claims 1 to 4.

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

18. A device according to claim 16 in the form of a pressurised metered dose inhaler (pMDI).

19. Crystalline Form 2 of the compound of formula (I) as defined in any one of claims 1 to 4, obtained by dissolving Crystalline Form A of the compound of formula (I) in acetone.

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