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WO2024240727A1 - Sels de dérivés d'amino quinazoline - Google Patents

Sels de dérivés d'amino quinazoline Download PDF

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Publication number
WO2024240727A1
WO2024240727A1 PCT/EP2024/063878 EP2024063878W WO2024240727A1 WO 2024240727 A1 WO2024240727 A1 WO 2024240727A1 EP 2024063878 W EP2024063878 W EP 2024063878W WO 2024240727 A1 WO2024240727 A1 WO 2024240727A1
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Prior art keywords
compound
salt
mesylate
crystalline
salt form
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English (en)
Inventor
Francesco AMADEI
Davide DE ANGELIS
Irene BASSANETTI
Susan Elizabeth OSBOURN
Andrew David Carr
Massimiliano MARI
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Priority to CN202480033796.2A priority Critical patent/CN121175304A/zh
Publication of WO2024240727A1 publication Critical patent/WO2024240727A1/fr
Priority to MX2025013807A priority patent/MX2025013807A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to salts of P2X purinoceptor 3 (hereinafter P2X3) inhibitors; particularly the invention relates to mesylate and esylate salts of (RJ-6-(5-fluoropyridin-2-yl)-8- methoxy-7V-(l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine, pharmaceutical compositions containing them and therapeutic use thereof.
  • P2X3 P2X purinoceptor 3
  • the mesylate and esylate salts of the invention may be useful in the treatment of many disorders associated with P2X3 receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
  • respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
  • IPF idiopathic pulmonary fibrosis
  • COPD chronic obstructive pulmonary disease
  • P2X receptors are cell surface ion channels activated by extracellular Adenosine 5- TriPhosphate (ATP).
  • P2X receptor family are trimeric assemblies composed of seven distinct subunit subtypes P2X1-?) that assemble as homomeric and heteromeric channels. Homomeric P2Xi, P2X2, P2X3, P2X4, P2X5, and P2X? channels and heteromeric P2X2/3 and P2X1/5 channels have been fully characterized following heterologous expression. All P2X receptors are non- selective cation channels permeable to Na+ and Ca+ ions and are activated by ATP; however, the pharmacology of the receptor subtypes varies with respect to sensitivity to ATP and to small molecules antagonists. (K Kaczmarek-Hajek et al: Molecular and functional properties of P2X receptors - recent progress and persisting challenges; Purinergic Signalling 8:375-417, 2012).
  • ATP enhances citric acid-evoked and histamine-evoked cough in preclinical models, wherein such effects can be attenuated by P2X3 selective antagonists (Kamei J and Takahashi Y: Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in guinea pigs, Eur J Pharmacol. 2006 Oct 10;547(l -3): 160-4).
  • P2X3 antagonists for the treatment of chronic cough was first recognized by Ford and Undem (Ford AP, Undem BJ: The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders, Front Cell Neurosci, Dec 19;7:267, 2013).
  • P2X3 are expressed by airway afferent nerves and mediate hypersensitivity of the cough reflex, which is dramatically reduced by the oral P2X3 antagonist, AF-219 (Abdulqawi et al: P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo- controlled phase 2 study, Lancet 385, 1198-205, 2015).
  • AF-219 Abdulqawi et al: P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo- controlled phase 2 study, Lancet 385, 1198-205, 2015.
  • WO2020239951 Al discloses amino quinazoline derivatives and the use of amino quinazoline derivatives as P2X3 inhibitors for the treatment of disorders associated with P2X3 receptor mechanisms, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
  • respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
  • fA -6-(5-fhioropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl) quinazolin-4-amine is disclosed as a potent and selective P2X3 inhibitor.
  • the present invention addresses the above mentioned needs by providing the compound of the invention, (7?J-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine mesylate and esylate salts.
  • the present invention relates to a salt of (AJ-6-(5-fluoropyridin-2-yl)-8-methoxy-A-(l-(5- methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine (compound A, shown below) selected from mesylate salt and esylate salt.
  • the present invention relates to a crystalline mesylate salt Form 2 of Compound A, wherein the crystalline Form 2 is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 6.6, 11.8 and 19.2 ⁇ 0.2 degrees 2-theta.
  • the invention in a second aspect, relates to a crystalline esylate salt Form 1 of Compound A, wherein the crystalline Form 1 is characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 5.8, 16.3 and 17.7 ⁇ 0.2 degrees 2-theta.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the mesylate salt or esylate salt of compound A, either alone or in combination with another one or more active ingredient, in admixture with one or more pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a pharmaceutical composition comprising the mesylate salt or esylate salt of compound A according to the above aspects for use as a medicament.
  • the present invention relates to the mesylate salt or esylate salt of compound A or a pharmaceutical composition according to the above aspects for use in the treatment of any disease wherein the P2X3 receptors are involved.
  • the present invention relates to the mesylate salt or esylate salt of compound A or a pharmaceutical composition as above described for use in the prevention and/or treatment of respiratory diseases including cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm, preferably in the treatment of chronic cough.
  • respiratory diseases including cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm, preferably in the treatment of chronic cough.
  • respiratory diseases including cough, sub-acute or chronic cough, treatment
  • the invention relates to a process for the preparation of a crystalline salt of (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin -4-amine (compound A) selected from mesylate and esylate salt, comprising the steps of:
  • Figure l is a characteristic XRPD pattern for free base Form A of Compound A.
  • Figure 2 is a DSC profile of free base Form A of Compound A.
  • Figure 3 is a TGA profile of free base Form A of Compound A.
  • Figure 4 is a DVS isotherm for free base Form A of Compound A.
  • Figure 5 is a characteristic XRPD pattern for mesylate salt Form 2 of Compound A.
  • Figure 6 is a DSC profile of mesylate salt Form 2 of Compound A.
  • Figure 7 is a TGA profile of mesylate salt Form 2 of Compound A.
  • Figure 8 is a DVS isotherm for mesylate salt Form 2 of Compound A.
  • Figure 9 is a characteristic XRPD pattern for mesylate salt Form 3 of Compound A.
  • Figure 10 is a characteristic XRPD pattern for mesylate salt Form 4 of Compound A.
  • Figure 11 is a characteristic XRPD pattern for mesylate salt Form 6 of Compound A.
  • Figure 12 is a characteristic XRPD pattern for esylate salt Form 1 of Compound A.
  • Figure 13 is a DSC profile of esylate salt Form 1 of Compound A.
  • Figure 14 is a TGA profile of esylate salt Form 1 of Compound A.
  • Figure 15 is a variable temperature XRPD pattern of the transition from mesylate salt Form 2 of Compound A to mesylate salt Form 3 of Compound A.
  • Figure 16 is an XRPD pattern of mesylate salt Form 2 of Compound A at zero weeks, two weeks, one month, two months, three months, six months and one year of storage in an open vial at 25°C and 60% RH.
  • Figure 17 is an XRPD pattern of mesylate salt Form 2 of Compound A at zero weeks, two weeks, one month, two months, three months, six months and one year of storage in a closed vial at 25°C and 60% RH.
  • Figure 18 is an XRPD pattern of mesylate salt Form 2 of Compound A at zero weeks, two weeks, one month, two months, three months, six months and one year of storage in an open vial at 40°C and 75% RH.
  • Figure 19 is an XRPD pattern of mesylate salt Form 2 of Compound A at zero weeks, two weeks, one month, two months, three months, six months and one year of storage in a closed vial at 40°C and 75% RH.
  • Figure 20 is an XRPD pattern of free base Form A of Compound A at 0, 28, 56 and 84 days of storage in an open vial at 40°C and 75% RH.
  • Figure 21 is an XRPD pattern of mesylate salt Form 2 of Compound A at 0, 28, 56 and 84 days of storage in an open vial at 40°C and 75% RH.
  • Figure 22 is an XRPD pattern of esylate salt Form 1 of Compound A at 0, 28, 56 and 84 days of storage in an open vial at 40°C and 75% RH.
  • Figure 23 is a dissolution profile of free base Form A of Compound A in FaSSIF, FeSSIF and FaSSGF.
  • Figure 24 is a dissolution profile of mesylate salt Form 2 of Compound A in FaSSIF, FeSSIF and FaSSGF.
  • Figure 25 is a two-sector dissolution profile of free base Form A of Compound A.
  • Figure 26 is a two-sector dissolution profile of mesylate salt Form 2 of Compound A.
  • Figure 27 is a pH-adjusted two-sector dissolution profile of free base Form A of Compound A and mesylate salt Form 2 of Compound A.
  • Figure 28 is a dissolution profile of mesylate salt Form 2, esylate salt Form 1 and free base Form A compared with other salts of Compound A in FaSSGF
  • Figure 29 is a pH-adjusted two-sector dissolution profile of esylate salt Form 1, free base Form A and mesylate salt Form 2 of Compound A.
  • compound A refers to (7?J-6-(5-fluoropyridin-2-yl)-8-methoxy-A-(l-(5-methyl- l,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine.
  • meylate refers to any salt of methanesulfonic acid, wherein the salt has a stoichiometry of 1 : 1 f7?J-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine: mesylate.
  • mesylate salt Form 2 refers to mesylate salt of Compound A Form 2.
  • mesylate salt Form 3 refers to mesylate salt of Compound A Form 3.
  • meylate salt Form 4 refers to mesylate salt of Compound A Form 4.
  • mesylate salt Form 6 refers to mesylate salt of Compound A Form 6.
  • esylate refers to any salt of ethanesulfonic acid, wherein the salt has a stoichiometry of 1 : 1 f7?J-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3- yl)ethyl)quinazolin-4-amine:esylate.
  • esylate salt Form 1 refers to esylate salt of Compound A Form 1.
  • polymorph means a compound having a particular molecular packing arrangement in a crystal lattice.
  • XRPD X-ray powder diffraction
  • NMR proton nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic vapor sorption
  • crystalline solid refers to any polymorph according to the invention prior to isolation.
  • XRPD means X-ray powder diffraction.
  • XRPD is a technique for providing an analytical characterisation of a sample. Polymorphous forms are characterized by having different XRPD patterns.
  • characteristic peaks means peaks observed in an XRPD pattern that are characteristic for a particular crystalline form differentiating it from other crystalline forms.
  • representative peaks means a selection of the characteristic peaks in an XRPD pattern for a particular form.
  • the representative peaks correspond to the characteristic peaks having the strongest signal in the XRPD pattern. These peaks distinguish the particular crystalline form from other crystalline forms.
  • characteristic and representative peaks values are reported as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A (copper radiation source, Cu Ka).
  • such peaks should be understood as comprising an error margin of ⁇ 0.2 degrees 2-theta.
  • the error margin should be understood as being ⁇ 0.1 degrees 2-theta.
  • NMR means proton nuclear magnetic resonance. NMR spectra provide structural information about organic compounds based on energy absorption by hydrogen atoms.
  • DSC differential scanning calorimetry.
  • DSC is a thermoanalytical technique measuring the difference in the amount of heat required to increase the temperature of a test compound and a reference as a function of temperature.
  • the output is a differential thermogram and can for instance be used to estimate melting temperatures of the test compound. It is used for characterising polymorphous forms of salts.
  • TGA thermogravimetric analysis. TGA is a technique where the mass of a substance is monitored as a function of temperature as a sample is subjected to a controlled temperature program in a controlled atmosphere. It is used for characterising polymorphous forms of salts.
  • DVS means dynamic vapour sorption.
  • DVS is a gravimetric sorption technique measuring a sample’s absorption and desorption of a solvent, such as water vapour. It is used for characterising polymorphous forms of salts.
  • LC/UV means liquid chromatography coupled with ultraviolet detection.
  • UPLC/UV/MS means UltraPerformance Liquid Chromatography coupled with ultraviolet detection and mass spectrometry.
  • amorphous refers to a solid form that is not crystalline. An amorphous form does not have a particular packing arrangement of molecules of a compound in a crystal lattice. In the present application the compound in question is compound A.
  • anhydrous refers to a crystalline form not containing any water molecules among molecules of a compound packed in its crystal lattice.
  • hemihydrate refers to a crystalline hydrate containing one water molecule for every two molecules of a compound in its crystal lattice.
  • polar solvent refers to both protic and aprotic polar solvents, including organic solvents and water.
  • solvent mixture refers to a mixture of at least two solvents, in variable proportions.
  • antisolvent refers to a liquid that, when combined with a solution of Compound A, and for example methanesulfonic or ethanesulfonic acid, reduces the solubility of the respective salt in the solution causing its crystallization or precipitation, in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
  • FaSSGF Fasted State Simulated Gastric Fluid. FaSSGF is a dissolution medium used for studying the behaviour of orally administered drugs in the stomach after consumption of a glass of water. The osmolarity and average pH of FaSSGF is similar to that of fasted gastric fluid. Tests using FaSSGF can generate stability, solubility and dissolution data.
  • FaSSIF Fasted State Simulated Intestinal Fluid.
  • FaSSIF is a dissolution medium used for studying the behaviour of orally administered drugs in the upper intestine after consumption of a glass of water.
  • the osmolarity and average pH of FaSSIF is similar to that of fasted intestinal fluid.
  • the data from FaSSIF testing can be used for evaluating drug dissolution and potential absorption in upper intestine fluid.
  • FeSSIF means Fed State Simulated Intestinal Fluid.
  • FeSSIF is a dissolution medium used for studying the behaviour of orally administered drugs in the upper intestine in a fed state.
  • the osmolarity and average pH of FeSSIF is similar to that of fed intestinal fluid.
  • the data from FeSSIF testing can be used for evaluating drug dissolution and potential absorption in upper intestine fluid after a meal.
  • RH relative humidity
  • room temperature means a temperature in the range of about 15°C to about 25°C, with an average of about 23°C.
  • treating includes: (i) inhibiting the disease state, i.e. arresting the development of the disease state or its clinical symptoms, or (ii) relieving the disease state, i.e. causing temporary or permanent regression of the disease state or its clinical symptoms.
  • preventing includes causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • treating or preventing a respiratory disease or disorder includes treating or preventing the symptoms the disorder such as cough and/or urge to cough associated with a respiratory disease.
  • terapéuticaally effective amount means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to affect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route, and form of administration.
  • the present invention relates to novel salts and crystalline forms of Compound A, an inhibitor of P2X3 receptor.
  • Compound A (7?J-6-(5-fluoropyridin-2-yl)-8-methoxy-A-(l-(5- methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine, having the chemical structure reported above, can be prepared by using procedures described in International Publication WO2020239951 Al.
  • novel salts of Compound A can be provided stably and constantly from the standpoint of the manufacturing process and are useful in the treatment of P2X3 mediated conditions.
  • mesylate and the esylate salts crystalline forms have many unexpected properties as described in more detail below.
  • the mesylate salt and the esylate salt of compound A show a higher degree of solubility in simulated gastric fluid (FaSSGF) in comparison with the free base Form A.
  • FaSSGF simulated gastric fluid
  • Example 8 of the Experimental part after 60 minutes the mesylate and esylate salts of compound A reach a concentration equal to or greater than about 25 mg/ml, higher than the free base Form A and surprisingly higher than other salts, such as the tosylate, the sulphate, the oxalate, saccharinate, fumarate and other salts of Compound A.
  • the mesylate salt of compound A in particular the crystalline Form 2, surprisingly shows a potentially improved bioavailability demonstrated by the supersaturation duration.
  • the mesylate salt Form 2 of compound A was tested in a two-sector model to evaluate the “spring -parachute effect”.
  • the term “spring-parachute effect” or, more simply, “parachute effect” refers to the high solubility observed in gastric fluid (spring) followed by supersaturation (parachute) in the intestinal fluid. The longer the duration of the supersaturation, the higher the potential bioavailability of the compound, as this phenomena predicts an higher dissolved amount available for absorption for a longer time.
  • the mesylate salt Form 2 of compound A shows a longer duration of the parachute effect than the free base Form A, with an estimated supersaturation duration of 14 minutes versus 8 minutes shown by the free base Form A.
  • the mesylate shows better formulability in solution than free base Form A which tends to give suspensions or gels, even if in presence of different excipients like solubilizing agents, surfactants and/or hydrophilic polymers which can promote supersaturation effect.
  • the longer supersaturation duration is confirmed even when the mesylate salt Form 2 of compound A is formulated in combination with excipients, such as HPMC, as shown in Example 12.
  • the formulation B comprising the mesylate salt Form 2 shows a supersaturation measured at 31 minutes against the 16 minutes of the formulation A comprising the free base Form A, clearly predicting an advantageous increased in vivo bioavailability, particularly useful for the formulation for oral administration.
  • the mesylate salt of compound A is stable for several months, during both regular and stressed storage conditions, as shown in Example 7.
  • the mesylate salt of compound A exists in one or more crystalline forms.
  • the identified crystalline polymorphs are designated mesylate salt Form 2, Form 3, Form 4 and Form 6.
  • the invention provides a mesylate salt of compound A in a crystalline Form 2.
  • the XRPD pattern of the mesylate salt Form 2 of compound A is substantially as shown in Figure 5.
  • the XRPD pattern of mesylate salt Form 2 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.6, 11.8 and 19.2 ⁇ 0.2 degrees. In a more preferred embodiment, the XRPD pattern of mesylate salt Form 2 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.6, 9.3, 11.8, 19.2 and 27.4 ⁇ 0.2 degrees. In an even more preferred embodiment, the XRPD pattern of mesylate salt Form 2 has characteristic diffraction peaks at diffraction angles 2-theta corresponding to 6.6, 9.3, 11.8, 18.1, 18.5, 19.2, 20.0, 22.4, 25.7 and 27.4 ⁇ 0.2 degrees.
  • the mesylate salt Form 2 was analysed by NMR, as reported in Example 2.
  • the mesylate salt Form 2 was analysed by DSC.
  • Mesylate salt Form 2 has a DSC profile substantially as shown in Figure 6.
  • the mesylate Form 2 has a differential scanning calorimetry (DSC) onset melting temperature in the range 220-240° C, more preferably about 232.13 °C.
  • the mesylate salt Form 2 was analysed by thermogravimetric analysis (TGA).
  • TGA thermogravimetric analysis
  • Mesylate salt Form 2 has a TGA profile substantially as shown in Figure 7.
  • mesylate salt Form 2 is characterized by a 1.487% weight loss by TGA in the range 30-120°C, indicating that mesylate salt Form 2 is hemihydrate.
  • hydrate mesylate salt exists in only one stable form (hemihydrate) differently to unstable hydrate forms of free base Compound A.
  • the present invention provides a crystalline salt of compound A which is the crystalline mesylate salt hemihydrate form.
  • the mesylate Form 2 was characterized by dynamic water sorption (DVS) analysis.
  • Mesylate salt Form 2 has a DVS profile substantially as shown in Figure 8.
  • Hygroscopicity was noted between 0% and 90% RH, with the sample gaining a total of about 1.049 wt% which does not correspond to a complete dehydration/hydration of the solid (slow kinetic process).
  • Approximately half of the weight gain occurred between 0% and 15% RH, confirming the ease of water uptake of instable anhydrous form.
  • the adsorption and desorption profiles are similar, although with some hysteresis between 40% and 80% RH.
  • Mesylate salt Form 2 of compound A may be prepared for instance as described in Example 2 methods A, B, C and D.
  • the invention provides a mesylate salt of compound A in a crystalline Form 3.
  • the XRPD pattern of the mesylate salt Form 3 of compound A is substantially as shown in Figure 9.
  • the XRPD pattern of mesylate salt Form 3 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.0, 17.6 and 26.4 ⁇ 0.2 degrees. In one embodiment, the XRPD pattern of Form 3 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.0, 9.0, 17.6, 21.2 and 26.4 ⁇ 0.2 degrees. In one embodiment, the XRPD pattern of Form 3 has characteristic diffraction peaks at diffraction angles 2-theta corresponding 6.0, 9.0, 13.2, 13.7, 16.6, 17.6, 19.1, 21.2, 26.4 and 27.6 ⁇ 0.2 degrees.
  • the mesylate salt Form 3 was analysed by DSC.
  • the mesylate Form 3 has a differential scanning calorimetry (DSC) onset melting temperature in the range 220-240° C, more preferably about 229.65°C.
  • the mesylate salt Form 3 was analysed by TGA. Negligible weight loss was observed until about 237.5°C, indicating that mesylate salt Form 3 is anhydrous.
  • the invention provides a mesylate salt of compound A in a crystalline Form 4.
  • the XRPD pattern of the mesylate salt Form 4 of compound A is substantially as shown in Figure 10.
  • the XRPD pattern of mesylate salt Form 4 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.0, 8.8 and 17.7 ⁇ 0.2 degrees.
  • the XRPD pattern of mesylate salt Form 4 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.0, 8.8, 17.7, 21.1 and 26.7 ⁇ 0.2 degrees.
  • the XRPD pattern of mesylate salt Form 4 has characteristic diffraction peaks at diffraction angles 2-theta corresponding 6.0, 8.8, 13.6, 16.5, 17.7, 18.9, 21.1, 22.0, 24.7 and 26.7 ⁇ 0.2 degrees.
  • the mesylate salt Form 4 was analysed by DSC.
  • the mesylate Form 4 has a DSC onset melting temperature in the range 220-240° C, more preferably about 236.74°C.
  • the mesylate salt Form 4 was analysed by TGA. Negligible weight loss was observed until about 240°C, indicating that mesylate salt Form 4 is anhydrous.
  • the invention provides a mesylate salt of compound A in a crystalline Form 6.
  • the XRPD pattern of the mesylate salt Form 6 of compound A is substantially as shown in Figure 11.
  • the XRPD pattern of Form 6 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.8, 8.5 and 19.2 ⁇ 0.2 degrees.
  • the XRPD pattern of Form 6 has representative diffraction peaks at diffraction angles 2-theta corresponding to 6.8, 8.5, 11.8, 14.1 and 19.2 ⁇ 0.2 degrees.
  • the XRPD pattern of Form 6 has characteristic diffraction peaks at diffraction angles 2-theta corresponding to 6.8, 8.5, 11.8, 14.1, 16.9, 17.2, 19.2, 21.0, 24.3 and 25.4 ⁇ 0.2 degrees.
  • the mesylate salt Form 6 was analysed by DSC.
  • the mesylate salt Form 6 has a DSC onset melting temperature in the range 220-240° C, more preferably about 235.43°C.
  • the mesylate salt Form 6 was analysed by TGA. Negligible weight loss was observed until about 237.5°C, indicating that the mesylate salt Form 6 is anhydrous.
  • the mesylate salt Form 6 was analysed by DVS. No hygroscopicity was noted as a total of 0.3% water uptake was registered between 20% and 80% RH.
  • the invention provides the esylate salt of compound A as described herein.
  • the XRPD pattern of the esylate salt Form 1 of compound A is substantially as shown in Figure 12.
  • the XRPD pattern of esylate salt Form 1 has representative diffraction peaks at diffraction angles 2-theta corresponding to 5.8, 16.3 and 17.7 ⁇ 0.2 degrees.
  • the XRPD pattern of esylate salt Form 1 has representative diffraction peaks at diffraction angles 2-theta corresponding to 5.8, 8.7, 16.3, 17.7 and 20.1 ⁇ 0.2 degrees.
  • the XRPD pattern of esylate salt Form 1 has characteristic diffraction peaks at diffraction angles 2-theta corresponding to 5.8, 8.7, 16.3, 17.7, 20.1, 21.5, 22.3, 23.5, 25.1 and 29.1 ⁇ 0.2 degrees.
  • Esylate salt Form 1 exhibits a DSC profile substantially as shown in Figure 13.
  • the esylate Form 1 has a differential scanning calorimetry (DSC) onset melting temperature in the range 220-240° C, more preferably about 235.73 °C.
  • Esylate salt Form 1 exhibits a TGA profile substantially as shown in Figure 14. Negligible weight loss was observed until about 237.5°C, indicating that esylate salt Form 1 is anhydrous.
  • Esylate salt Form 1 of compound A may be prepared for instance as described in Example 6.
  • the XRPD pattern of the free base Form A of compound A is substantially as shown in Figure 1.
  • the XRPD pattern of free base Form A has representative diffraction peaks at diffraction angles 2-theta corresponding to 8.4, 13.1 and 24.1 ⁇ 0.2 degrees.
  • the XRPD pattern of Form A has representative diffraction peaks at diffraction angles 2-theta corresponding to 8.4, 13.1, 16.8, 22.4, and 24.1 ⁇ 0.2 degrees.
  • the XRPD pattern of Form A has characteristic diffraction peaks at diffraction angles 2-theta corresponding to 8.4, 11.3, 12.2, 13.1, 16.8, 18.5, 22.4, 24.1, 25.3 and 27.9 ⁇ 0.2 degrees.
  • the free base Form A was analysed by proton NMR, as detailed in Example 1.
  • Free base form A has a DSC profile substantially as shown in Figure 2.
  • the free base Form A is characterized by a DSC profile having a peak at about 247.00°C.
  • the free base form A exhibits a TGA profile substantially as shown in Figure 4. Negligible weight loss was observed until about 250°C, indicating that free base Form A is anhydrous.
  • Form A has a DVS profile substantially as shown in Figure 4. No hygroscopicity was noted as a total of 0.249% water uptake was registered between 20% and 80% RH. The adsorption and desorption profiles are similar, although with some hysteresis between 40% and 90% RH.
  • the invention provides a process for the preparation of a salt of Compound A selected from mesylate salt and esylate salt, which comprises reacting the free base of Compound A with methanesulfonic or ethanesulfonic acid.
  • the process comprises suspending the free base of Compound A in a polar solvent or polar solvent mixture and adding methanesulfonic or ethanesulfonic acid, either alone or in solution, to cause formation of a crystalline precipitate of the mesylate or esylate salt.
  • the polar solvent or polar solvent mixture is preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • the method may further comprise a step of isolating the obtained crystalline precipitate of the mesylate or esylate salt.
  • it comprises a step of isolating the crystalline compound A mesylate or esylate salt by filtration.
  • the method may further comprise a step of washing the filtered crystalline mesylate or esylate salt with one or more polar solvents or solvent mixture, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • one or more polar solvents or solvent mixture preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • the method may further comprise a step of recrystallizing the crystalline mesylate or esylate salt with a polar solvent or solvent mixture, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • a polar solvent or solvent mixture preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • the invention provides a process for the preparation of a crystalline salt of (R)- 6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin-4- amine (compound A) selected from mesylate and esylate salt, comprising the steps of:
  • step 1) the compound A free base is suspended in a polar solvent or solvent mixture selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • a polar solvent or solvent mixture selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • step 2b) suspending the solid obtained in step 2a) in a polar solvent or solvent mixture and adding an antisolvent thus obtaining the precipitation of a crystalline salt;
  • the polar solvent or solvent mixture is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • the antisolvent is heptane.
  • the process further comprises a step of washing the filtered crystalline mesylate salt of compound A obtained according to steps 1) to 3) with one or more polar solvents or solvent mixture, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • one or more polar solvents or solvent mixture preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.
  • the process further comprises a step of drying the filtered mesylate salt.
  • the process further comprises a step of recrystallizing the crystalline mesylate salt of compound A from a mixture of isopropanol and water.
  • the process for the preparation of the esylate salt of Compound A comprises the steps of:
  • the process further comprises a step of washing the filtered crystalline esylate salt of compound A obtained according to steps 1) to 3) with tetrahydrofuran.
  • the invention provides a process for the preparation of a salt of (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(l-(5-methyl-l,2,4-oxadiazol-3-yl)ethyl)quinazolin -4-amine (compound A) selected from crystalline mesylate salt Form 2 and crystalline esylate salt Form 1.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mesylate or esylate salt of Compound A and their crystalline forms as described above in admixture with one or more pharmaceutically acceptable carrier or excipient, either alone or in combination with one or more further active ingredient.
  • the invention refers to a mesylate or esylate salt of Compound A and their crystalline forms as described above according to the invention for use as a medicament.
  • the invention refers to the use of a mesylate or esylate salt of Compound A and their crystalline forms, as described above according to the invention, in the manufacture of a medicament for the treatment of disorders associated with P2X3 receptors mechanism, preferably for the treatment of respiratory diseases.
  • the invention refers to a mesylate or esylate salt of Compound A and their crystalline forms as described above for use in the prevention and/or treatment of respiratory diseases, preferably cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.
  • respiratory diseases preferably cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.
  • the invention refers to a mesylate or esylate salt of Compound A and their crystalline forms as described above for use in the prevention and/or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.
  • the invention also provides a method for the prevention and/or treatment of disorders associated with P2X3 receptors mechanisms, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention.
  • the invention refers to a method for the prevention and/or treatment, wherein the disorder is cough, sub-acute or chronic cough, treatment-resistant cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cough associated with respiratory diseases such as COPD, asthma and bronchospasm, wherein said method comprises the administration of a proper amount of mesylate or esylate salt of Compound A and their crystalline forms as described above to a patient in the need thereof.
  • the disorder is chronic cough.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a mesylate or esylate salt of Compound A and their crystalline forms as described above to a patient in need thereof.
  • safe and effective amount in reference to a mesylate or esylate salt of Compound A and their crystalline forms as described above or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects, such amount being nevertheless routinely determined by the skilled artisan.
  • the mesylate or esylate salt of Compound A and their crystalline forms as described above may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the particular route of administration chosen.
  • the invention also provides pharmaceutical compositions of mesylate or esylate salt of Compound A and their crystalline forms as described above in a mixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • Administration of the mesylate or esylate salt of Compound A and their crystalline forms may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrastemally and by infusion) and by inhalation.
  • the mesylate or esylate salt of Compound A and their crystalline forms may be administered orally or by inhalation.
  • Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the mesylate or esylate salt of Compound A and their crystalline forms can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous in administering the compounds of the invention.
  • the mesylate or esylate salt of Compound A and their crystalline forms are administered orally. More preferably, the mesylate or esylate salt of Compound A and their crystalline forms are administered in the form of tablets.
  • the mesylate salt Form 2 of Compound A is administered in the form of tablets.
  • liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the mesylate or esylate salt of Compound A and their crystalline forms may be injected, for example, intravenously, in the form of an isotonic sterile solution.
  • the mesylate or esylate salt of Compound A and their crystalline forms may be administered by inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • inhalable powders for administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier chemically inert to the compounds of the invention e.g. lactose or any other additive suitable for improving the respirable fraction, may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the mesylate or esylate salt of Compound A and their crystalline forms either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as cosolvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising mesylate or esylate salt of Compound A and their crystalline forms may be in the form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.
  • the mesylate or esylate salt of Compound A and their crystalline forms can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.
  • mesylate or esylate salt of Compound A and their crystalline forms can be combined with therapeutic agents or active ingredients useful for the treatment of disease which are related to or mediated by P2X3 receptor.
  • mesylate or esylate salt of Compound A and their crystalline forms depend upon a variety of factors including, among others, the particular disease to be treated, the severity of the symptoms, the route of administration, and the like.
  • the invention is also directed to a device comprising a pharmaceutical composition comprising a mesylate or esylate salt of Compound A and their crystalline forms as described above according to the invention, in form of a single- or multi-dose dry powder inhaler or a metered dose inhaler.
  • the XRPD spectra were collected by X-ray powder diffraction (Empyrean V2.0, Panalytical) equipped with Cu radiation source (Cu Ka 1.5406 A). Samples were placed on Si zero background sample holders spinning with revolution time 4s. The measurements were performed in reflection mode, 2-theta scan from 1.5 to 45°, step size 0.02°, soller slit 0.02 rad, divergence slit 1/8°, antiscatter slit 1/4°.
  • variable temperature and humidity XRPD analysis were carried out with Anton Paar CHC+ camera equipped with CCU100 temperature control and MHG-32 humidity generator. The measurements were performed in reflection mode, 2-theta scan from 1.5 to 45°, step size 0.02°, soller slit 0.02 rad, divergence slit 1/8°, antiscatter slit 1/4°.
  • TGA analysis was performed using a TA Instruments thermogravimetric analyzer Discovery equipped with a computer analyzing system (TRIOS). Each sample (5-10 mg) was placed in an aluminium 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, up to a final temperature of 300 °C. Nickel was used as the calibration standard.
  • TRIOS computer analyzing system
  • DSC analysis was performed using a TA Instruments differential scanning calorimeter Discovery equipped with a computer analyzing system (TRIOS).
  • TRIOS computer analyzing system
  • Moisture sorption/desorption data were collected on a TA Instruments Vapor Sorption Analyzer Q5000SA.
  • Second Step desorption, sorption and desorption data were collected over a range of 0% to 90% RH at 10% RH intervals under a nitrogen purge. Samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.100% weight change in 20 minutes, with a maximum equilibration time of 1 hour if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples. NaBr was used as humidity verification.
  • Moisture sorption/desorption data were also collected on a ProUmid SnS 23 equipped with a 23 autosampler following Method 1.
  • sorption data was collected in the range 0% to 90% RH. Samples were not dried prior to analysis.
  • Crystallization systems Polar Bear Plus, Cambridge Reactor Design was used for slurry at 50 °C and temperature cycling experiments while for crystallization optimization Crystall6 (Technobis Crystallization systems) was used.
  • the free base Form A of compound A was characterized by XRPD, proton NMR, DSC, TGA and DVS.
  • the free base Form A is consistent with an anhydrous form of compound A.
  • a proton NMR spectrum for the material is consistent with the chemical structure of Compound A free base. The characteristic chemical shifts are reported herebelow:
  • the following characteristic diffraction peaks at diffraction angles 2-theta were identified for free base Form A of compound A: 8.4, 11.3, 12.2, 13.1, 16.8, 18.5, 22.4, 24.1, 25.3 and 27.9 ⁇ 0.2 degrees.
  • a selection of five representative diffraction peaks at diffraction angles 2-theta were identified from the characteristic diffraction peaks: 8.4, 13.1, 16.8, 22.4 and 24.1 ⁇ 0.2 degrees.
  • a further selection of three representative diffraction peaks at diffraction angles 2-theta were identified from the characteristic diffraction peaks: 8.4, 13.1 and 24.1 ⁇ 0.2 degrees.
  • a DSC profile of free base Form A is shown in Figure 2.
  • the DSC profile of free base Form A displays one enthalpy event having an onset at 245.82 °C and a peak at 247.00 °C.
  • the peak at 247.00 °C indicates the melting temperature of the free base Form A.
  • a TGA profile of free base Form A is shown in Figure 3. Negligible weight loss was observed until around 250 °C, corresponding to the melting temperature observed in the DSC profile. This weight loss continued until the end of measurements at 300 °C. The TGA profile is indicative of the anhydrous nature of free base Form A.
  • a DVS profile of free base Form A is shown in Figure 4. Hygroscopicity was noted between 2.5% and 90% RH, with the sample gaining a total of about 0.249 wt%. The adsorption and desorption profiles are similar, although with some hysteresis between 40% and 90% RH.
  • the mesylate salt Form 2 was analysed by proton NMR. The spectrum was consistent with a 1 : 1 mesylate salt Form 2 of compound A. The characteristic chemical shifts are reported herebelow:
  • a DSC profile of mesylate salt Form 2 is shown in Figure 6.
  • the first enthalpy event displayed an onset at 22.95 °C with a peak at 73.86 °C.
  • the second enthalpy event displayed an onset at 232.13 °C with a peak at 237.25 °C.
  • the peak at 237.25 °C indicates the melting temperature of the mesylate salt Form 2.
  • a TGA profile of mesylate salt Form 2 is shown in Figure 7.
  • An initial weight loss step of 1.487% occurred between about 37.5 °C and 75 °C. Little to no weight loss was observed between 75 °C and 237.5 °C, followed by a substantial weight loss corresponding to the melting temperature observed in the DSC profile. The weight loss continued until the end of measurements at 300°C.
  • a DVS profile of mesylate salt Form 2 is shown in Figure 8. Hygroscopicity was noted between 0% and 90% RH, with the sample gaining a total of about 1.049 wt%. Approximately half of the weight gain occurred between 0% and 15% RH. The adsorption and desorption profiles are similar, although with some hysteresis between 40% and 80% RH. Approximately half of the weight loss occurred between 0% and 15% RH.
  • Example 3 Preparation and characterisation of the mesylate salt Form 3 of Compound A
  • the anhydrous mesylate Form 3 was obtained from the hemihydrate mesylate Form 2 by dehydration. Dehydration began at 75°C and the Form 3 appeared.
  • the XRPD pattern of mesylate salt Form 3 of compound A is shown in Figure 9.
  • the DSC profile of mesylate salt Form 3 displayed one enthalpy event having an onset at 229.65 °C and a peak at 232.02 °C.
  • the peak at 232.03 °C indicates the melting temperature of the mesylate salt Form 3.
  • the TGA profile of mesylate salt Form 3 shows negligible weight loss until around 237.5 °C, corresponding to the melting temperature observed in the DSC profile. This weight loss continued until the end of measurements at 300 °C. The TGA profile is indicative of the anhydrous nature of Form 3.
  • An anhydrous mesylate salt Form 4 was scaled up by slurrying 10 mg/ml of mesylate salt Form 2 in acetone for at least 24 h, filtered, rinsed with diethyl ether and dried under nitrogen. Calorimetric analyses on Form 4 showed an endo peak at roughly 145 °C (data not shown).
  • the DSC profile of mesylate salt Form 4 displayed two enthalpy events.
  • the first enthalpy event is a minor event having an onset at 141.47 °C and a peak at 141.97 °C.
  • the second enthalpy event has an onset at 236.74 °C and a peak at 238.93 °C.
  • the peak at 238.93 °C indicates the melting temperature of the mesylate salt Form 4.
  • the TGA profile of mesylate salt Form 4 shows negligible weight loss until around 240 °C, corresponding to the melting temperature observed in the DSC profile. This weight loss continued until the end of measurements at 300 °C. The TGA profile is indicative of the anhydrous nature of mesylate salt Form 4.
  • the DSC profile of mesylate salt Form 6 displayed two enthalpy events.
  • the first enthalpy event has an onset at 221.51 °C and a peak at 226.50 °C.
  • the second enthalpy event has an onset at 235.43 °C and a peak at 237.96 °C.
  • the peak at 237.96 °C indicates the melting temperature of the mesylate salt Form 6.
  • the TGA profile of mesylate salt Form 6 has shown negligible weight loss of about 0.2% until around 237.5 °C, corresponding to the melting temperature observed in the DSC profile. This weight loss continued until the end of measurements at 300 °C. The TGA profile is indicative of the anhydrous nature of mesylate salt Form 6.
  • the DVS profile of mesylate salt Form 6 has shown substantially no hygroscopicity as a total of 0.3% water uptake was registered between 20% and 80% RH.
  • Example 6 Preparation and characterisation of the esylate salt Form 1 of compound A
  • a DSC profile of esylate salt Form 1 is shown in Figure 13.
  • the DSC profile of esylate salt Form 1 displayed one enthalpy event having an onset at 235.735 °C and a peak at 239.343 °C.
  • the peak at 239.343 °C indicates the melting temperature of the esylate salt Form 1.
  • a TGA profile of esylate salt Form 1 is shown in Figure 14. Negligible weight loss was observed until about 237.5 °C, corresponding to the melting temperature observed in the DSC profile. This weight loss continued until the end of measurements at 300 °C. The TGA profile is indicative of the anhydrous nature of the esylate salt Form 1 of compound A.
  • the stability of the mesylate salt Form 2 of Compound A was thereby tested in four distinct conditions: open condition at 25°C/60% RH, closed condition at 25 °C/60% RH, open condition at 40°C/75% RH, and closed condition at 40 °C/75% RH.
  • open condition at 25°C/60% RH closed condition at 25 °C/60% RH
  • open condition at 40°C/75% RH open condition at 40°C/75% RH
  • closed condition at 40 °C/75% RH closed condition at 40 °C/75% RH.
  • the mesylate salt Form 2 of compound A remains stable in dry form for at least one year at different conditions.
  • Example 8 Dissolution of mesylate salt Form 2 and esylate salt Form 1 of compound A in Fasted State Simulated Gastric Fluid (FaSSGF) in comparison with free base Form A and other salts
  • Fasted State Simulated Gastric Fluid (FaSSGF) of mesylate salt Form 2 of the compound A of Example 2 and esylate salt Form 1 of Example 6 in comparison with the free base Form A and with other salts was tested by means of manual experiment.
  • the medium for simulated oral fluids was FaSSGF obtained from Biorelevant.com Ltd. The experiments were conducted for 60 minutes at 37 °C.
  • the FaSSGF medium composition is listed in Table 9.
  • Table 8C Dissolution in FaSSGF
  • Table 8D Dissolution in FaSSGF
  • the mesylate salt Form 2 and the esylate salt Form 1 of compound A showed a consistently higher solubility than the free base Form A during the 60 minutes time.
  • Their solubility was surprisingly higher than that of the other tested salts, as reported in Table 8, 8 A, 8B, 8C and 8D.
  • the solubility of salts other than mesylate and esylate proved to be lower or, at best, comparable to the solubility of free base Form A.
  • Example 9 Dissolution of mesylate salt Form 2 of the compound A in all simulated oral fluids
  • FaSSGF Fested State Simulated Gastric Fluid
  • FaSSIF Fested State Simulated Intestinal Fluid
  • FeSSIF Fed State Simulated Intestinal Fluid
  • FaSSIF and FeSSIF were both tested in FaSSIF and FeSSIF than FaSSGF of 0.10 mg/ml and 0.07 mg/ml, respectively.
  • mesylate salt Form 2 of compound A unexpectedly demonstrates a sustained solubility for at least 24 hours compared to the drop in solubility for the free base Form A of compound A after approximately 3 hours.
  • the parachute effect is observable in two-sector dissolution studies.
  • a test compound is incubated with FaSSGF and its concentration is monitored over time. FaSSIF is then added to the solution whilst continuing the monitoring.
  • the period of time in which the test compound remains in solution without or before precipitating refers to the supersaturation time and represents the parachute effect.
  • the experiment was conducted using pDISS Profiler 6 Channel Pion.
  • the free base Form A and mesylate salt Form 2 of compound A were each incubated in 8 ml of FaSSGF (pH 1.6) for 20 minutes at the concentration of 350 mg/250 ml.
  • 16 ml of FaSSIF concentrated 1.5x (pH 6.5) was added with an incubation time of 180 minutes.
  • the resulting target pH should be approximately 5-6.
  • the experiment was conducted at 37°C. The entire dissolution profile was monitored until the end of the experiment to evaluate a possible parachute effect, its duration and to evaluate the maximum solubility reached after the addition of FaSSIF.
  • Free base Form A of compound A was tested in duplicate and the results are shown in Figure 25. Precipitation start was observed after about 10 minutes of FaSSIF addition. The pH after the addition of FaSSIF was 5.8.
  • a third experiment was conducted on esylate salt Form 1 of compound A, using the same protocol of the second experiment, with free base Form A and mesylate salt Form 2 of compound A as controls.
  • the experiment was aimed at evaluating comparatively a possible parachute effect of the esylate salt and its duration. Precipitation of the free base was observed after roughly 20 minutes, while precipitation of the esylate salt and mesylate salt were observed after 30 and 40 minutes respectively. The results are shown in figure 29. Esylate salt Form 1 and mesylate salt Form 2 of compound A showed a longer duration of the parachute effect compared to free base Form A, indicative of a potentially improved absorption profile.
  • the drug content and homogeneity of the mesylate salt Form 2 and the free base Form A of Compound A in 20% w/v SBE-PCD (Sulfobutyl-ether-P-Cyclodextrin, Captisol; CYDEX Pharmaceutical) were tested at different citrate buffer concentrations such as 0.05 M, 0.1 M, 0.5 M and 1 M, at pH 2.5.
  • SBE-PCD Sulfobutyl-ether-P-Cyclodextrin, Captisol; CYDEX Pharmaceutical
  • the free base Form A of compound A appeared as a suspension in the formulations with a citrate buffer concentration of 0.05 M, 0.1 M and 0.5 M.
  • Free base Form A of compound A appeared as a solution only in the formulation obtained with a citrate buffer concentration of 1 M, however gelification occurred within 24 hours.
  • the table 12 shows the results with the mesylate salt Form 2. Stable solutions were obtained with all concentrations of citrate buffer. No gelification was observed during the test period, differently from the formulations with free base Form A with 1 M citrate buffer that gelified at 24 hours.
  • mesylate salt Form 2 of compound A has a better formulability in solution than free base Form A of compound A.
  • the formulation having a 0.05 M citrate buffer concentration was chosen to be tested with the addition of polymers to investigate the effect due to a potential viscosity increase.
  • PVP polyvinylpyrrolidone
  • the formulations were studied with or without the use of the surfactant D-a-tocopherol polyethylene glycol succinate (Vit. E TPGS, Sigma Aldrich; CAS: 9002-96-4) in 0.05 M citrate buffer at pH 2.5 at the nominal concentration of 40 mg/ml.
  • D-a-tocopherol polyethylene glycol succinate Vit. E TPGS, Sigma Aldrich; CAS: 9002-96-4
  • citrate buffer pH 2.5 at the nominal concentration of 40 mg/ml.
  • To prepare the vehicle the proper amount of citric acid was dissolved in water in a volumetric flask, then the pH was increased up to 2.5 using 0.1 M NaOH. Then water was added and brought to the final volume.
  • the polymers PVP 40 (Sigma Aldrich; CAS: 9003-39-8) or HPMC (viscosity 46-60cP; Sigma Aldrich; CAS: 9004-65-3) were gently dissolved in citrate buffer and left under magnetic stirring for at least 1 hour to their complete hydration. When required, Vit. E TPGS was subsequently added to the media and gently left under magnetic stirring to avoid bubbles formation.
  • the required volume of vehicle was added to a known amount of Compound A free base Form A or Mesylate salt Form 2, then sonicated at RT for at least 10 min.
  • the formulation was kept under magnetic stirring for at least 10 min before analysis.
  • the supersaturation duration higher than 20 minutes can be considered sufficient to identify the formulations with a better chance to increase in vivo bioavailability, as this phenomena predicts an higher dissolved amount available for absorption for a longer time.
  • the formulation B comprising the mesylate salt Form 2 shows a supersaturation measured at 31 minutes against the 16 minutes of the formulation A, clearly demonstrating the advantageous likelihood of an increased in vivo bioavailability.

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Abstract

L'invention concerne des sels dérivés de (R)-6-(5-fluoropyridin-2-yl)-8-méthoxy-N-(1-(5-méthyl-1,2,4-oxadiazol-3-yl)éthyl)quinazolin-4-amine, en particulier l'invention concerne des sels de mésylate et d'ésylate de (R)-6-(5-fluoropyridin-2-yl)-8-méthoxy-N-(1-(5-méthyl-1,2,4-oxadiazol-3-yl)éthyl) quinazolin-4-amine, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique. Les sels selon l'invention peuvent être utiles dans le traitement de maladies ou d'états associés à des maladies respiratoires, en particulier la toux chronique.
PCT/EP2024/063878 2023-05-22 2024-05-21 Sels de dérivés d'amino quinazoline Pending WO2024240727A1 (fr)

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MX2025013807A MX2025013807A (es) 2023-05-22 2025-11-18 Sales de derivados de aminoquinazolina

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020239951A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés d'amino quinazoline servant d'inhibiteurs de p2x3

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