Salts of aminoquinazoline derivatives

Abstract

The present invention relates to salt derivatives of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, and more particularly to mesylates and esylates of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, pharmaceutical compositions containing them, and their therapeutic uses. The salts of the present invention may be useful in the treatment of respiratory diseases, particularly diseases or conditions associated with chronic cough.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to salts of P2X purine receptor 3 (hereinafter referred to as P2X3) inhibitors; in particular, the present invention relates to mesylates and esylates of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, pharmaceutical compositions containing them, and their therapeutic use.

[0002] The mesylates and esylates of the present invention may be useful in treating many disorders related to the P2X3 receptor mechanism, such as respiratory diseases including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). [Background technology]

[0003] P2X receptors are cell surface ion channels activated by extracellular adenosine 5-triphosphate (ATP). The P2X receptor family consists of seven different subunit subtypes that assemble as homomeric and heteromeric channels (P2X 1~7 It is a trimer aggregate composed of homomeric P2X1, P2X2, P2X3, P2X4, P2X5 and P2X7 channels and heteromeric P2X 2 / 3 and P2X 1 / 5 The channels are fully characterized after heterologous expression. All P2X receptors are Na + and Ca +These are non-selective cation channels that are permeable to ions and activated by ATP; however, the pharmacology of receptor subtypes varies depending on their sensitivity to ATP and small molecule antagonists (K Kaczmarek-Hajek et al: Molecular and functional properties of P2X receptors - recent progress and persisting challenges; Purinergic Signalling 8:375-417, 2012).

[0004] ATP enhances citrate-induced and histamine-induced cough in preclinical models, and these effects can be reduced 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(1-3):160-4). In humans, local delivery of ATP induces cough and bronchospasm (Basoglu OK et al: Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy non-smokers and patients with asthma, Chest. Oct;128(4):1905-9, 2005).

[0005] The therapeutic prospects of P2X3 antagonists for the treatment of chronic cough were 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 is expressed by afferent airway nerves and mediates hypersensitivity to 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).

[0006] Several compounds have been described in the literature as P2X3 inhibitors.

[0007] International Publication No. 2020 / 239951 (WO2020239951 A1) (Chiesi Farmaceutici SPA) discloses aminoquinazoline derivatives and their use as P2X3 inhibitors for the treatment of respiratory diseases, including cough, asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), which are disorders related to the P2X3 receptor mechanism. In particular, (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine is disclosed as a potent and selective P2X3 inhibitor.

[0008] As mentioned above, although several P2X3 inhibitors have been disclosed to date, there is still a need for further P2X3 inhibitors.

[0009] Identifying further P2X3 inhibitors with improved solubility and stability, and suitable for formulation for oral administration, could be particularly advantageous.

[0010] The present invention addresses the above needs by providing mesylates and esylates of the compound of the present invention, (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine. [Overview of the Initiative]

[0011] Summary of the Invention The present invention relates to a salt of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine (compound A shown below), selected from mesylates and esylates. [ka] Compound A

[0012] In a first embodiment, the present invention relates to a crystalline mesylate form 2 of compound A, where the crystalline form 2 is characterized by an X-ray powder diffraction pattern that includes characteristic peaks at 6.6, 11.8 and 19.2 ± 0.2 degrees 2-theta.

[0013] In a second embodiment, the present invention relates to a crystalline esylate form 1 of compound A, wherein the crystalline form 1 is characterized by an X-ray powder diffraction pattern that includes characteristic peaks at 5.8, 16.3 and 17.7 ± 0.2 degrees 2-theta.

[0014] In a third embodiment, the present invention relates to a pharmaceutical composition comprising a mesylate or esylate of compound A, alone or in combination with one or more other active ingredients, mixed with one or more pharmaceutically acceptable carriers or additives.

[0015] In a further aspect, the present invention relates to a pharmaceutical composition for use as a medicament, comprising a mesylate or esylate of compound A according to the above aspect.

[0016] In a further aspect, the present invention relates to a mesylate or esylate of compound A according to the above aspect or a pharmaceutical composition for use in the treatment of any disease involving the P2X3 receptor.

[0017] In a further aspect, the present invention relates to the use of a mesylate or esylate of the above compound A or a pharmaceutical composition for the prevention and / or treatment of respiratory diseases, including cough, subacute 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 for the treatment of chronic cough.

[0018] In a further aspect, the present invention provides a method for producing a crystalline salt of (R)-6-(5-fluoropyridin-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)ethyl)quinazolin-4-amine (Compound A) selected from mesylate and esylate, comprising: 1) suspending the free base of Compound A in a polar solvent or a solvent mixture; 2) adding methanesulfonic acid or ethanesulfonic acid; and 3) isolating the resulting crystalline salt by filtration The method is related to this. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [Figure 1] Figure 1 is an XRPD pattern characteristic of the free base form A of Compound A. [Figure 2] Figure 2 is a DSC profile of the free base form A of Compound A. [Figure 3]Figure 3 is the TGA profile of the free base form A of Compound A. [Figure 4] Figure 4 is the DVS isotherm for the free base form A of Compound A. [Figure 5] Figure 5 is the XRPD pattern characteristic of the mesylate form 2 of Compound A. [Figure 6] Figure 6 is the DSC profile of the mesylate form 2 of Compound A. [Figure 7] Figure 7 is the TGA profile of the mesylate form 2 of Compound A. [Figure 8] Figure 8 is the DVS isotherm for the mesylate form 2 of Compound A. [Figure 9] Figure 9 is the XRPD pattern characteristic of the mesylate form 3 of Compound A. [Figure 10] Figure 10 is the XRPD pattern characteristic of the mesylate form 4 of Compound A. [Figure 11] Figure 11 is the XRPD pattern characteristic of the mesylate form 6 of Compound A. [Figure 12] Figure 12 is the XRPD pattern characteristic of the esylate form 1 of Compound A. [Figure 13] Figure 13 is the DSC profile of the esylate form 1 of Compound A. [Figure 14] Figure 14 is the TGA profile of the esylate form 1 of Compound A. [Figure 15] Figure 15 is the variable temperature XRPD pattern of the transition from the mesylate form 2 of Compound A to the mesylate form 3 of Compound A. [Figure 16] Figure 16 is the XRPD pattern of the mesylate form 2 of Compound A at 0 week, 2 weeks, 1 month, 2 months, 3 months, 6 months and 1 year of storage in an open vial at 25 °C and 60% RH. [Figure 17] Figure 17 is the XRPD pattern of the mesylate form 2 of Compound A at 0 week, 2 weeks, 1 month, 2 months, 3 months, 6 months and 1 year of storage in a closed vial at 25 °C and 60% RH. [Figure 18] Figure 18 shows the XRPD patterns of compound A in mesylate form 2 at 0 weeks, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 1 year of storage in an open vial at 40°C and 75% RH. [Figure 19] Figure 19 shows the XRPD patterns of compound A in mesylate form 2 at 0 weeks, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 1 year of storage in a closed vial at 40°C and 75% RH. [Figure 20] Figure 20 shows the XRPD patterns 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] Figure 21 shows the XRPD patterns of compound A in mesylate form 2 at 0, 28, 56, and 84 days of storage in an open vial at 40°C and 75% RH. [Figure 22] Figure 22 shows the XRPD patterns of compound A in ethylate form 1 at 0, 28, 56, and 84 days of storage in an open vial at 40°C and 75% RH. [Figure 23] Figure 23 shows the solubility profile of compound A in free base form A in FaSSIF, FeSSIF, and FaSSGF. [Figure 24] Figure 24 shows the solubility profile of compound A in mesylate form 2 in FaSSIF, FeSSIF, and FaSSGF. [Figure 25] Figure 25 shows the two-sector solubility profile of free base form A of compound A. [Figure 26] Figure 26 shows the two-step dissolution profile of compound A in mesylate form 2. [Figure 27] Figure 27 shows the pH-adjusted two-step dissolution profiles of compound A in free base form A and compound A in mesylate form 2. [Figure 28] Figure 28 shows the solubility profiles of mesylate form 2, esylate form 1, and free base form A in FaSSGF, compared to other salts of compound A. [Figure 29]Figure 29 shows the pH-adjusted two-step dissolution profiles of esylate form 1, free base form A, and mesylate form 2 of compound A. [Modes for carrying out the invention]

[0020] Detailed description of the invention definition Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art.

[0021] The term "compound A" refers to (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine.

[0022] In addition to compound A exhibiting the preferred (R) configuration, it is understood that racemic mixtures and other proportions of mixtures with the enantiomer (S) are also included within the scope of the present invention.

[0023] The term "mesylate" refers to any salt of methanesulfonic acid, wherein the salt has a stoichiometric ratio of 1:1 (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine:mesylate.

[0024] The term "mesylate form 2" refers to form 2 of the mesylate salt of compound A.

[0025] The term "mesylate form 3" refers to form 3 of the mesylate salt of compound A.

[0026] The term "mesylate form 4" refers to form 4 of the mesylate salt of compound A.

[0027] The term "mesylate form 6" refers to form 6 of the mesylate salt of compound A.

[0028] The term "esylate" refers to any salt of ethanesulfonic acid, wherein the salt has a stoichiometric ratio of 1:1 (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine:esylate.

[0029] The term "Esilate Form 1" refers to Form 1 of the esilate salt of compound A.

[0030] The terms "polymorph," "polymorphic form," "crystal," "crystalline form," and "form" refer to compounds having a specific molecular packing arrangement in their crystal lattice. X-ray powder diffraction (XRPD), proton nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic water vapor adsorption (DVS) are techniques that can be used to identify and characterize the properties of polymorphic forms, such as the polymorphic forms of mesylates, esylates, and free base compound A described herein.

[0031] The term "crystalline solid" refers to any polymorph according to the present invention before isolation.

[0032] The term "XRPD" stands for X-ray powder diffraction. XRPD is a technique for providing analytical characterization of samples. Polymorphisms are characterized by having different XRPD patterns.

[0033] The term "characteristic peak" refers to a peak observed in an XRPD pattern that is characteristic of a particular crystal morphology and distinguishes that morphology from others.

[0034] The term “representative peak” refers to the selection of characteristic peaks in the XRPD pattern for a particular morphology. Representative peaks correspond to the characteristic peaks with the strongest signals in the XRPD pattern. These peaks distinguish a particular crystal morphology from others. In this disclosure, the values ​​of characteristic and representative peaks are described as values ​​measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å (copper source, Cu Kα). In one embodiment, these peaks are understood to have an error range of ±0.2 degrees 2 theta. In a further embodiment, the error range is understood to be ±0.1 degrees 2 theta.

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

[0036] The term "DSC" stands for 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 substance as a function of temperature. The output is a differential thermogram, which can be used, for example, to estimate the melting point of a test compound. It is also used to characterize the polymorphisms of salts.

[0037] The term "TGA" stands for thermogravimetric analysis. TGA is a technique that monitors the mass of a substance as a function of temperature when a sample is subjected to a controlled temperature program under a controlled atmosphere. It is used to characterize the polymorphisms of salts.

[0038] The term "DVS" stands for Dynamic Water Vapor Adsorption. DVS is a gravimetric adsorption technique that measures the absorption and desorption of a sample by a solvent such as water vapor. It is used to characterize the polymorphisms of salts.

[0039] The term "LC / UV" refers to liquid chromatography combined with ultraviolet detection.

[0040] The term "UPLC / UV / MS" refers to Ultra-Performance Liquid Chromatography, which combines ultraviolet detection and mass spectrometry.

[0041] The term "amorphous" refers to a solid form that is not crystalline. An amorphous form does not have a specific packing arrangement of compound molecules in its crystalline lattice. In this application, the compound in question is compound A.

[0042] The term "anhydrous" refers to a crystalline form in which no water molecules are present between the compound molecules filling the crystal lattice.

[0043] The term "hemihydrate" refers to a crystalline hydrate that contains one water molecule for every two molecules of a compound in its crystal lattice.

[0044] The term "polar solvent" refers to both protic and aprotic polar solvents, including organic solvents and water.

[0045] The term "solvent mixture" refers to a mixture of at least two solvents in variable proportions.

[0046] The term "antisolvent" refers to a liquid that, when combined with a solution of compound A, such as methanesulfonic acid or ethanesulfonic acid, reduces the solubility of each salt in the solution, thereby causing crystallization or precipitation, sometimes spontaneously, and sometimes involving further steps such as seeding, cooling, scratching, and / or concentration.

[0047] The term "FaSSGF" stands for Fasted State Simulated Intestinal Fluid. FaSSGF is a solvent used to test the behavior of orally administered drugs in the stomach after a glass of water has been consumed. The osmotic pressure and mean pH of FaSSGF are similar to those of fasted gastric fluid. Tests using FaSSGF can generate data on stability, solubility, and dissolution.

[0048] The term "FaSSIF" stands for Fasted State Simulated Intestinal Fluid. FaSSIF is a dissolving medium used to test the behavior of orally administered drugs in the upper intestinal tract after ingesting a glass of water. The osmotic pressure and mean pH of FaSSIF are similar to those of fasted intestinal fluid. Data obtained from FaSSIF tests can be used to evaluate drug dissolution and potential absorption in upper intestinal fluid.

[0049] The term "FeSSIF" refers to Fed-State Simulated Intestinal Fluid. FeSSIF is a dissolving medium used to test the behavior of orally administered drugs in the upper intestinal tract during feeding. The osmotic pressure and mean pH of FeSSIF are similar to those of intestinal fluid during feeding. Data obtained from FeSSIF tests can be used to evaluate drug dissolution and potential absorption in postprandial upper intestinal fluid.

[0050] The term "relative humidity," abbreviated as RH, refers to the percentage of water vapor present in the air relative to the amount of water vapor at saturation.

[0051] The term "room temperature" is abbreviated as RT and refers to a temperature range of approximately 15°C to 25°C, with an average temperature of approximately 23°C.

[0052] The terms “to treat” or “to treat” a disease state include: (i) preventing a disease state, i.e., stopping the progression of a disease state or its clinical symptoms; or (ii) alleviating a disease state, i.e., causing a temporary or permanent regression of a disease state or its clinical symptoms.

[0053] The terms “prevent” or “prevent” a disease state include preventing the progression of the clinical symptoms of the disease state in subjects who may be exposed to or predisposed to the disease state but have not yet experienced or shown symptoms of the disease state. For example, treatment or prevention of a respiratory disease or disorder includes treatment or prevention of symptoms of the disorder, such as cough and / or coughing urges associated with the respiratory disease.

[0054] The term "therapeutic dose" refers to the amount of a compound administered to a subject to treat a disease condition that is sufficient to have an effect on treating that disease condition. The therapeutic dose may vary depending on the compound, the disease condition being treated, the severity of the disease being treated, the subject's age and relative health status, as well as the route and form of administration.

[0055] The present invention relates to novel salts and crystalline forms of compound A, which is an inhibitor of the P2X3 receptor. Compound A having the above chemical structure, namely (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, can be prepared using the procedure described in International Publication No. 2020 / 239951 (WO2020239951 A1).

[0056] Novel salts of compound A, particularly the mesylate and esylate salts of compound A described herein, can be supplied stably and continuously from the standpoint of manufacturing methods and are useful in the treatment of P2X3-mediated conditions.

[0057] In particular, the crystalline forms of mesylates and esylates are described in more detail below. It possesses many unexpected properties.

[0058] Advantageously, the mesylate and esylates of compound A exhibit higher solubility in artificial gastric juice (FaSSGF) compared to the free base form A. As shown in Table 8 of the experimental section and Example 8, after 60 minutes, the mesylate and esylates of compound A reach concentrations of approximately 25 mg / ml or higher, which is higher than that of the free base form A and, surprisingly, higher than that of other salts, such as the tosylate, sulfate, oxalate, saccharate, fumarate, and other salts of compound A.

[0059] Even more advantageously, the mesylate of compound A, particularly crystalline form 2, surprisingly exhibits potentially improved bioavailability, as indicated by its supersaturation duration. As may be shown in Example 10, mesylate form 2 of compound A was tested in a two-stage 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 juice (spring) followed by supersaturation in intestinal juice (parachute). A longer duration of supersaturation indicates higher potential bioavailability of the compound, as this phenomenon predicts a higher amount of solubility available for absorption over a longer period.

[0060] Surprisingly, the mesylate form 2 of compound A exhibits a longer parachute effect duration than the free base form A, with an estimated supersaturation duration of 14 minutes compared to 8 minutes for the free base form A.

[0061] As shown in Example 11, even in the presence of various additives such as solubilizers, surfactants, and / or hydrophilic polymers that can promote the supersaturation effect, mesylates exhibit better formulation suitability in solution compared to free base form A, which is prone to forming suspensions or gels.

[0062] As shown in Example 12, a longer supersaturation duration is observed even when compound A in mesylate form 2 is formulated in combination with additives such as HPMC.

[0063] As can be shown in Table 15, Formulation B, containing mesylate form 2, exhibits supersaturation measured at 31 minutes compared to 16 minutes for Formulation A, containing free base form A, which clearly predicts a favorable increase in in vivo bioavailability, particularly useful for oral formulations.

[0064] As a further advantage, as shown in Example 7, the mesylate of compound A is stable for several months under both normal and stress storage conditions.

[0065] The mesylate of compound A exists in one or more crystalline forms. The identified crystalline polymorphs are named mesylate form 2, form 3, form 4, and form 6. In one embodiment, the present invention provides the mesylate of compound A in crystalline form 2. The XRPD pattern of mesylate form 2 of compound A is substantially as shown in Figure 5.

[0066] In one preferred embodiment, the XRPD pattern of mesylate form 2 has characteristic diffraction peaks at diffraction angle 2 thetas corresponding to 6.6, 11.8, and 19.2 ± 0.2 degrees. In a more preferred embodiment, the XRPD pattern of mesylate form 2 has characteristic diffraction peaks at diffraction angle 2 thetas 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 form 2 has characteristic diffraction peaks at diffraction angle 2 thetas 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.

[0067] In one embodiment, mesylate form 2 was analyzed by NMR as described in Example 2.

[0068] In one embodiment, mesylate form 2 was analyzed by DSC. Mesylate form 2 has a DSC profile substantially as shown in Figure 6. Preferably, mesylate form 2 has a differential scanning calorimetry (DSC) melting onset temperature in the range of 220 to 240°C, and more preferably, a differential scanning calorimetry (DSC) melting onset temperature of about 232.13°C.

[0069] In one embodiment, mesylate form 2 was analyzed by thermogravimetric analysis (TGA). Mesylate form 2 has a TGA profile substantially as shown in Figure 7. In one embodiment, mesylate form 2 is characterized by a weight loss of 1.487% by TGA in the range of 30 to 120°C, which indicates that mesylate form 2 is a hemihydrate. As a hydrate, the mesylate exists only in a stable form (hemihydrate), unlike the unstable hydrate form of free base compound A. Therefore, in a preferred embodiment, the present invention provides a crystalline salt of compound A, which is in the crystalline mesylate hemihydrate form.

[0070] In one embodiment, mesylate form 2 was characterized by dynamic water vapor adsorption (DVS) analysis. Mesylate form 2 has a DVS profile substantially as shown in Figure 8. Hygroscopicity was observed from 0% to 90% RH, and the sample increased by approximately 1.049 wt% in total, although this does not correspond to complete dehydration / hydration of the solid (a slow kinetic process). Approximately half of the weight increase occurred from 0% to 15% RH, indicating that the unstable anhydrous form readily absorbs water. The adsorption and desorption profiles are similar, but some hysteresis is observed from 40% to 80% RH.

[0071] Form 2 of the mesylate of compound A can be prepared, for example, as described in methods A, B, C, and D of Example 2.

[0072] In a further embodiment, the present invention provides a mesylate of compound A in crystalline form 3. The XRPD pattern of mesylate form 3 of compound A is substantially as shown in Figure 9.

[0073] In one embodiment, the XRPD pattern of mesylate form 3 has characteristic diffraction peaks at two theta diffraction angles corresponding to 6.0, 17.6, and 26.4 ± 0.2 degrees. In another embodiment, the XRPD pattern of form 3 has characteristic diffraction peaks at two theta diffraction angles corresponding to 6.0, 9.0, 17.6, 21.2, and 26.4 ± 0.2 degrees. In yet another embodiment, the XRPD pattern of form 3 has characteristic diffraction peaks at two theta diffraction angles corresponding to 6.0, 9.0, 13.2, 13.7, 16.6, 17.6, 19.1, 21.2, 26.4, and 27.6 ± 0.2 degrees.

[0074] Mesylate form 3 was analyzed by DSC. Preferably, mesylate form 3 has a differential scanning calorimetry (DSC) melting onset temperature in the range of 220–240°C, and more preferably, a differential scanning calorimetry (DSC) melting onset temperature of about 229.65°C.

[0075] Mesylate form 3 was analyzed by TGA. A very slight weight loss was observed up to approximately 237.5°C, indicating that mesylate form 3 is anhydrous.

[0076] In a further embodiment, the present invention provides a mesilate of compound A in crystalline form 4. The XRPD pattern of mesilate form 4 of compound A is substantially as shown in Figure 10. In one embodiment, the XRPD pattern of mesilate form 4 has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 6.0, 8.8 and 17.7 ± 0.2 degrees. In one embodiment, the XRPD pattern of mesilate form 4 has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 6.0, 8.8, 17.7, 21.1 and 26.7 ± 0.2 degrees. In one embodiment, the XRPD pattern of mesilate form 4 has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 6.0, 8.8, 13.6, 16.5, 17.7, 18.9, 21.1, 22.0, 24.7 and 26.7 ± 0.2 degrees.

[0077] Mesylate form 4 was analyzed by DSC. Preferably, mesylate form 4 has a DSC melting onset temperature in the range of 220-240°C, and more preferably, a DSC melting onset temperature of about 236.74°C.

[0078] Mesylate form 4 was analyzed by TGA. A very slight weight loss was observed up to approximately 240°C, indicating that mesylate form 4 is anhydrous.

[0079] In a further embodiment, the present invention provides a mesylate of compound A in crystalline form 6. The XRPD pattern of mesylate form 6 of compound A is substantially as shown in Figure 11. In one embodiment, the XRPD pattern of form 6 has characteristic diffraction peaks at diffraction angles 2 theta corresponding to 6.8, 8.5 and 19.2 ± 0.2 degrees. In one embodiment, 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 and 19.2 ± 0.2 degrees. In one embodiment, 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.

[0080] Mesylate form 6 was analyzed by DSC. Preferably, mesylate form 6 has a DSC melting onset temperature in the range of 220-240°C, and more preferably, a DSC melting onset temperature of about 235.43°C.

[0081] Mesylate form 6 was analyzed by TGA. A very slight weight loss was observed up to approximately 237.5°C, indicating that mesylate form 6 is an anhydrous form.

[0082] Mesylate form 6 was analyzed by DVS. A total of 0.3% water uptake was recorded at 20%–80% RH, and no hygroscopicity was observed.

[0083] In another embodiment, the present invention provides an esylate of compound A described herein. The XRPD pattern of esylate form 1 of compound A is substantially as shown in Figure 12. In one embodiment, the XRPD pattern of esylate form 1 has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 5.8, 16.3 and 17.7 ± 0.2 degrees. In one embodiment, the XRPD pattern of esylate form 1 has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 5.8, 8.7, 16.3, 17.7 and 20.1 ± 0.2 degrees. In one embodiment, the XRPD pattern of esylate form 1 has characteristic diffraction peaks at diffraction angle 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.

[0084] Esilate form 1 exhibits a DSC profile substantially as shown in Figure 13. Preferably, ethylate form 1 has a differential scanning calorimetry (DSC) melting onset temperature in the range of 220 to 240°C, and more preferably, a differential scanning calorimetry (DSC) melting onset temperature of about 235.73°C.

[0085] Esilate form 1 exhibits a TGA profile substantially as shown in Figure 14. A very slight weight loss is observed up to approximately 237.5°C, indicating that ethylate form 1 is anhydrous.

[0086] Form 1 of the esylate salt of compound A can be prepared, for example, as described in Example 6.

[0087] Free base form A of compound A was used as a starting material for producing other forms, as will be described in more detail in the experimental section.

[0088] The XRPD pattern of free base form A of compound A is substantially as shown in Figure 1. The XRPD pattern of free base form A has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 8.4, 13.1, and 24.1 ± 0.2 degrees. In another embodiment, the XRPD pattern of form A has characteristic diffraction peaks at diffraction angle 2 theta corresponding to 8.4, 13.1, 16.8, 22.4, and 24.1 ± 0.2 degrees. In a further embodiment, the XRPD pattern of form A has characteristic diffraction peaks at diffraction angle 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.

[0089] Free base form A was analyzed by proton NMR, as described in detail in Example 1. Free base form A has a DSC profile substantially as shown in Figure 2. Free base form A is characterized by a DSC profile with a peak at approximately 247.00°C.

[0090] Free base form A exhibits a TGA profile substantially as shown in Figure 4. A very slight weight loss is observed up to approximately 250°C, indicating that free base form A is anhydrous.

[0091] Morphology A has a DVS profile essentially as shown in Figure 4. A total of 0.249% water uptake was recorded between 20% and 80% RH, and no hygroscopicity was observed. The adsorption and desorption profiles are similar, but some hysteresis is observed between 40% and 90% RH.

[0092] In a further embodiment, the present invention provides a method for producing a salt of compound A selected from mesylates and esylates, the method comprising reacting a free base of compound A with methanesulfonic acid or ethanesulfonic acid.

[0093] In one embodiment, the method comprises suspending the free base of compound A in a polar solvent or a mixture of polar solvents, and adding methanesulfonic acid or ethanesulfonic acid alone or in solution to form a crystalline precipitate of mesylate or esylate.

[0094] The polar solvent or mixture of polar solvents is preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

[0095] The method may further include a step of isolating the resulting mesylate or esylate crystal precipitate. Preferably, this includes a step of isolating the crystalline compound A mesylate or esylate by filtration.

[0096] The method may further include washing the filtered crystalline mesylate or esylate with one or more polar solvents or solvent mixtures, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

[0097] The method may further include the step of recrystallizing a crystalline mesylate or esylate in a polar solvent or solvent mixture, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

[0098] Therefore, the present invention relates to a method for producing a crystalline salt of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine (compound A), selected from mesylates and esylates, 1) A step of suspending the free base of compound A in a polar solvent or solvent mixture; 2) The step of adding methanesulfonic acid or ethanesulfonic acid; and 3) The process of isolating the obtained crystalline salt by filtration. The present invention provides a method that includes the present invention.

[0099] More preferably, in step 1), the free base of compound A is suspended in a polar solvent or solvent mixture selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

[0100] In a preferred embodiment, a method for producing the mesylate of compound A is: 1) A step of suspending the free base of compound A in a polar solvent or solvent mixture; 2) The step of adding methanesulfonic acid; 2a) A step of drying the solution obtained in step 2); 2b) A step of suspending the solid obtained in step 2a) in a polar solvent or solvent mixture and adding a poor solvent to obtain a precipitate of the crystalline salt; and 3) The process of isolating the obtained crystalline compound A mesylate by filtration. Includes.

[0101] Preferably, in steps 1) and 2b), the polar solvent or solvent mixture is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof. Also preferably, in step 2b), the poor solvent is heptane.

[0102] In another embodiment, the method further comprises washing the filtered crystalline mesylate of compound A obtained according to steps 1) to 3) with one or more polar solvents or solvent mixtures, preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

[0103] In yet another embodiment, the method further includes the step of drying the filtered mesylate.

[0104] In another preferred embodiment, the method further comprises the step of recrystallizing a crystalline mesylate of compound A from a mixture of isopropanol and water.

[0105] In another preferred embodiment, a method for producing the esylate of compound A is: 1) A step of suspending the free base of compound A in tetrahydrofuran; 2) The step of adding ethanesulfonic acid; and 3) The process of isolating the obtained crystalline compound A esylate by filtration. Includes.

[0106] In yet another preferred embodiment, the method further comprises washing the filtered crystalline ethylate of compound A obtained according to steps 1) to 3) with tetrahydrofuran.

[0107] In one preferred embodiment, the present invention provides a method for producing a salt of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine (compound A), selected from crystalline mesylate form 2 and crystalline esylate form 1.

[0108] The present invention also provides pharmaceutical compositions comprising the mesylate or esylate of compound A and their crystalline forms, either alone or in combination with one or more further active ingredients, mixed with one or more pharmaceutically acceptable carriers or additives.

[0109] In one embodiment, the present invention refers to mesylate or esylate salts of compound A described above in accordance with the present invention and their crystalline forms for use as pharmaceuticals.

[0110] In a further embodiment, the present invention refers to the use of mesylates or esylates of compound A described above and their crystalline forms in accordance with the present invention in the manufacture of pharmaceuticals for the treatment of disorders related to the P2X3 receptor mechanism, preferably for the treatment of respiratory diseases.

[0111] Preferably, the present invention refers to mesylates or esylates of compound A and their crystalline forms for use in the prevention and / or treatment of cough associated with respiratory diseases, preferably cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, cough after viral infection, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with COPD, asthma, and bronchospasm.

[0112] More preferably, the present invention refers to mesylate or esylate salts of compound A and their crystalline forms for use in the prevention and / or treatment of chronic cough and cough associated with respiratory diseases such as COPD, asthma and bronchospasm.

[0113] The present invention also provides a method for the prevention and / or treatment of disorders related to the P2X3 receptor mechanism, the method comprising administering a therapeutically effective amount of the compound of the present invention to a patient in need of such treatment.

[0114] In particular, the present invention relates to a method for prevention and / or treatment, wherein the disorder is cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, postviral 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, and the method comprises administering an appropriate amount of the mesylate or esylate of compound A and their crystalline forms to a patient in need. In a more preferred embodiment, the disorder is chronic cough.

[0115] The treatment method of the present invention involves administering a safe and effective amount of the mesylate or esylate of compound A and its crystalline form to a patient in need. In this specification, “safe and effective amount” means, with respect to the mesylate or esylate of compound A and its crystalline form, or other pharmaceutically active agents, an amount of compound sufficient to treat the patient’s condition but low enough to avoid serious side effects, such an amount is also typically determined by those skilled in the art. The mesylate or esylate of compound A and its crystalline form may be administered as a single dose or according to a dosing regimen in which multiple doses are administered at different time intervals over a predetermined period. A typical daily dose may vary depending on the specific route of administration selected.

[0116] The present invention also provides pharmaceutical compositions of mesylate or esylates of compound A and their crystalline forms, mixed with one or more pharmaceutically acceptable carriers or additives, for example, those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA.

[0117] The administration of compound A's mesylate or esylate and their crystalline forms may be achieved, depending on the patient's needs, for example, by oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and infusion) and inhalation.

[0118] Preferably, the mesylate or esylate salt of compound A and their crystalline forms can be administered orally or by inhalation.

[0119] Various solid oral administration forms may be used to administer the compounds of the present invention, including solid forms such as tablets, gel capsules, capsules, caplets, granules, lozenges, and bulk powders. The mesylate or esylate of compound A and their crystalline forms may be administered alone or in combination with various pharmaceutically acceptable carriers, diluents (e.g., sucrose, mannitol, lactose, starch), and known additives including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavoring agents, lubricants, etc. Time-release capsules, tablets, and gels are also advantageous for administering the compounds of the present invention.

[0120] Preferably, the mesylate or esylate of compound A and their crystalline forms are administered orally. More preferably, the mesylate or esylate of compound A and their crystalline forms are administered in tablet form.

[0121] More preferably, compound A in mesylate form 2 is administered in tablet form.

[0122] Various liquid oral administration forms, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs, may also be used to administer the compounds of the present invention. Such administration forms may also contain suitable known inert diluents such as water, and suitable known additives such as preservatives, humectants, sweeteners, flavorings, and additives for emulsifying and / or suspending the compounds of the present invention. Mesylates or esylates of compound A and their crystalline forms may be injected intravenously, for example, in the form of an isotonic sterile solution.

[0123] For the treatment of respiratory diseases, the mesylate or esylate salts of compound A and their crystalline forms may be administered by inhalation.

[0124] Inhalable formulations include inhalable powders, quantified aerosols containing propellants, or inhalable formulations without propellants.

[0125] For administration as a dry powder, single-dose or multi-dose inhalers known from the prior art may be used. In this case, the powder may be filled into gelatin, plastic or other capsules, cartridges, blister packs, or reservoirs.

[0126] A chemically inert diluent or carrier for the compound of the present invention, such as lactose, or any other additive suitable for improving the inhalable fraction, may be added to the powdered compound of the present invention.

[0127] Inhalation aerosols containing propellant gases such as hydrofluoroalkanes may contain mesylate or esylate salts of compound A and their crystalline forms, either in solution or dispersion form. Propellant-driven formulations may also contain other components, such as cosolvents, stabilizers, and optionally other additives.

[0128] Inhalable formulations without propellants, comprising mesylate or esylate of compound A and their crystalline forms, may be in the form of solutions or suspensions in aqueous, alcoholic, or hydroalcoholic media, or they may be delivered by jet or ultrasonic nebulizers known from the prior art, or by soft mist nebulizers.

[0129] Compound A's mesylate or esylate salts and their crystalline forms may be administered as a standalone active agent or in combination with other pharmaceutically active ingredients.

[0130] Preferably, the mesylate or esylate salts of compound A and their crystalline forms may be combined with therapeutic agents or active ingredients useful for treating diseases related to or mediated by P2X3 receptors.

[0131] The dosage of compound A's mesylate or esylate salts and their crystalline forms depends on various factors, including the specific disease being treated, the severity of the symptoms, and the route of administration.

[0132] The present invention also relates to a device comprising a pharmaceutical composition in the form of a single-dose or multi-dose dry powder inhaler or metered-dose inhaler, comprising a mesylate or esylate of compound A described above in accordance with the present invention and their crystalline forms.

[0133] The following examples illustrate the present invention without limiting its scope. [Examples]

[0134] Experiment Section Apparatus and method X-ray powder diffraction (XRPD) XRPD spectra were collected by X-ray powder diffraction (Empyrean V2.0, Panalytical) with a Cu radiation source (Cu Kα 1.5406 Å). The sample was placed in a Si-zero background sample holder rotating at a rotation time of 4 s. Measurements were performed in reflection mode, with a 2-theta scan of 1.5–45°, a step size of 0.02°, a solar slit of 0.02 radians, a divergent slit of 1 / 8°, and a scattering prevention slit of 1 / 4°.

[0135] Variable temperature and humidity XRPD analysis was performed using an Anton Paar CHC+ camera equipped with a CCU100 temperature control and an MHG-32 humidity generator. Measurements were performed in reflection mode, with a 2-theta scan of 1.5–45°, a step size of 0.02°, a solar slit of 0.02 radians, a divergence slit of 1 / 8°, and a scattering prevention slit of 1 / 4°.

[0136] Thermogravimetric analysis (TGA) TGA analysis was performed using a TA Instruments Discovery thermogravimetric analyzer equipped with a computer analysis system (TRIOS). Each sample (5-10 mg) was placed in an aluminum sample pan, inserted into the TGA heating furnace, and accurately weighed. The furnace was first equilibrated at 25°C, and then heated under nitrogen (flow rate 30 mL / min) at a rate of 10°C / min to a final temperature of 300°C. Nickel was used as the calibration standard.

[0137] Differential Scanning Calorimetry (DSC) DSC analysis was performed using a TA Instruments Discovery differential scanning calorimeter equipped with a computer analysis system (TRIOS).

[0138] Approximately 1–5 mg of each sample was placed in a Perkin Elmer Aluminum DSC pan. The pan was covered with a lid, but not sealed. The sample cell was equilibrated at 0°C and heated under nitrogen purging (50 mL / min). All samples were subjected to a similar thermal history by linearly heating to 300°C at a heating rate of 10°C / min. Indium metal was used as a calibration standard.

[0139] Dynamic water vapor adsorption (DVS) Moisture absorption / dehumidification data was collected using the TA Instruments Vapor Sorption Analyzer Q5000SA.

[0140] Step 1: Adsorption data was collected in the range of 40% to 90% relative humidity (RH).

[0141] Step 2: Desorption, adsorption, and desorption data were collected under nitrogen purge, in the range of 0% to 90% RH, at 10% RH intervals. Samples were not dried before analysis. The equilibrium criterion used for analysis was a weight change of less than 0.100% in 20 minutes; if the weight criterion was not met, the maximum equilibrium time was 1 hour. Data were not corrected for the initial moisture content of the samples. NaBr was used to verify humidity.

[0142] Furthermore, moisture absorption / dehumidification data was collected using a ProUmid SnS 23 equipped with an autosampler, according to Method 1.

[0143] Method 1 In the first step, adsorption data was collected in the range of 0% to 90% RH. The samples were not dried before analysis.

[0144] In the second step, desorption, adsorption, and desorption data were collected at intervals of 10% RH over the range of 0% to 90% (RH) under nitrogen purge. The equilibrium criteria and cycle parameters are listed in Tables 1 and 2. The data were not corrected for the initial moisture content of the samples.

Table 1

Table 2

[0145] Nuclear magnetic resonance spectroscopy ( 1 H NMR) All 1 H NMR spectra were measured 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 H-C / N-D-0.5-Z ATMA. The probe had an actively shielded uniaxial Z-gradient and 13 C and 15 enabled simultaneous decoupling for multiple X nuclei such as N, as well as automatic tuning and matching. Characteristic chemical shifts are reported in ppm (parts per million) as δ values. Coupling constants (J values) are reported in Hertz (Hz), and multiplicities are reported using the following common abbreviations to indicate the major peaks: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad, nd = not determined.

[0146] Ultra-high performance liquid chromatography combined with UV detection and mass spectrometry (UPLC / UV / MS) Samples were dissolved in a solvent (water / ACN 40 / 60) at approximately 1 mg / mL and diluted to approximately 0.07 mg / mL.

Table 3

[0147] Crystallization system Polar Bear Plus and Cambridge Reactor Design were used for slurry and temperature cycling tests at 50°C, while Crystal16 (Technobis Crystallization systems) was used for crystallization optimization.

[0148] Example 1: Characterization of free base form A of compound A The method for synthesizing the free base form A of compound A is described in International Publication No. 2020 / 239951 (WO2020239951 A1) (Example 315, pp. 231-232).

[0149] The free base form A of compound A was characterized by XRPD, proton NMR, DSC, TGA, and DVS.

[0150] Free base form A is consistent with the anhydrous form of compound A. The proton NMR spectrum of the substance is consistent with the chemical structure of free base of compound A. Characteristic chemical shifts are as follows: 1 H NMR (600MHz, DMSO-d6) δppm 1.68(d, J=6.92Hz, 3H) 2.56(s, 3H) 4.00(s, 3H) 5.76(quin, J=7.24Hz, 1H) 7.94-8.00(m, 2H) 8.29(dd, J=8.98, 4.36Hz, 1H) 8.46(s, 1H) 8.57(d, J=1.80Hz, 1H) 8.70-8.72(m, 1H) 8.70-8.75(m, 1H)

[0151] Figure 1 shows the XRPD pattern of free base form A of compound A, and the complete peak list is shown below. [Table 6]

[0152] The following characteristic diffraction peaks at a diffraction angle of 2 theta are 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. From the characteristic diffraction peaks, five representative diffraction peaks at a diffraction angle of 2 theta were identified: 8.4, 13.1, 16.8, 22.4, and 24.1 ± 0.2 degrees. From the characteristic diffraction peaks, three further representative diffraction peaks at a diffraction angle of 2 theta were identified: 8.4, 13.1, and 24.1 ± 0.2 degrees.

[0153] The DSC profile of free base form A is shown in Figure 2. The DSC profile of free base form A shows a single enthalpy event with an onset point at 245.82°C and a peak at 247.00°C. The peak at 247.00°C indicates the melting point of free base form A.

[0154] The TGA profile of free base form A is shown in Figure 3. A very slight weight loss was observed up to approximately 250°C, which corresponds to the melting point observed in the DSC profile. This weight loss continued until 300°C, the end of the measurement. The TGA profile shows the anhydrous properties of free base form A.

[0155] The DVS profile of free base form A is shown in Figure 4. Hygroscopicity was observed between 2.5% and 90% RH, and the total sample volume increased by approximately 0.249 wt%. The adsorption and desorption profiles were similar, but some hysteresis was observed between 40% and 90% RH.

[0156] Example 2: Preparation and Characterization of Mesylate Form 2 of Compound A Preparation of compound A's mesylate form 2 - Method A In a round-bottom flask, 150 mg of compound A (free base form A, 0.39 mmol) described in Example 1 was suspended in acetone (15 mL) and stirred at ambient temperature. Then, methanesulfonic acid (25 μL, 0.39 mmol) was added and the mixture was stirred in a closed vial. After 2 hours, the crystalline solid was isolated by filtration, washed with acetone (2 x 5 ml), and dried at room temperature for 2 hours (yield 95%). The acetone used in this preparation was commercially available and used without further distillation or purification (moisture content >0.1%).

[0157] Preparation of compound A's mesylate form 2 - Method B In a round-bottom flask, 150 mg of compound A (free base form A, 0.39 mmol) described in Example 1 was suspended in tetrahydrofuran (THF) (15 mL) and stirred under RT at ambient temperature. Then, methanesulfonic acid (25 μL, 0.39 mmol) was added while stirring, and the solution was dried under nitrogen under RT. The resulting solid was suspended in acetone, and heptane was added as a poor solvent. The crystalline solid was isolated by filtration and dried at room temperature (yield 90%).

[0158] The solvent used in this manufacturing process was commercially available and was used without further distillation or purification (water content > 0.1%).

[0159] Preparation of compound A's mesylate form 2 - Method C In a round-bottom flask, 5 g of compound A (free base form A) described in Example 1 was suspended in isopropanol (47.5 mL). The mixture was stirred and heated until reflux was achieved, after which a mixture of methanesulfonic acid (1.5 mL) and water (2.5 mL) was added dropwise. The solution was cooled to 0°C over 3 hours and left to stand with stirring at this temperature for 6 hours. The solid was filtered through a Gooch filter and washed with isopropanol (15 mL). Yield: 78%.

[0160] Preparation of compound A's mesylate form 2 - Method D In a round-bottom flask, 7.5 g of the mesylate of compound A, prepared according to method A, B, or C, was suspended in a solvent mixture of isopropanol (71.25 mL) and water (3.75 mL). The mixture was stirred and heated until refluxed, then cooled to 55°C. The slurry was aged at this temperature for 30 minutes, cooled to 10°C for 3 hours, and left to stand with stirring at this temperature for 6 hours. The solid was filtered through a Gooch filter and washed with isopropanol (15 mL). Yield: 80%.

[0161] Characterization of compound A in mesylate form 2 The XRPD pattern of the mesylate form 2 of compound A obtained according to Method A or Method B is shown in Figure 5, and the complete peak list is shown below: [Table 7]

[0162] The mesylate form 2 was analyzed by proton NMR. Its spectrum matched that of compound A in a 1:1 ratio. Characteristic chemical shifts are shown below: 1 H NMR (600MHz, DMSO-d6) δppm 1.76(d, J=7.16Hz, 3H), 2.30(s, 3H), 2.60(s, 3H), 4.17(s, 3H), 5.96(quin, J=7.16Hz, 1H), 8.04(dt, J=8.72, 3.11Hz, 1H), 8 .25(d, J=1.25Hz, 1H), 8.32(dd, J=9.03, 4.36Hz, 1H), 8.78(d, J=2.80Hz, 1H), 8.81(d, J=1.25Hz, 1H), 8.83(s, 1H), 10.52(br s, 1H), 13.75-15.33(br s, 1H).

[0163] The DSC profile of mesylate form 2 is shown in Figure 6. The first enthalpy event began at 22.95°C and peaked at 73.86°C. The second enthalpy event began at 232.13°C and peaked at 237.25°C. The peak at 237.25°C indicates the melting point of mesylate form 2.

[0164] The TGA profile of mesylate form 2 is shown in Figure 7. An initial weight loss of 1.487% occurred between approximately 37.5°C and 75°C. Between 75°C and 237.5°C, little to no weight loss was observed, followed by a significant weight loss corresponding to the melting point observed in the DSC profile. The weight loss continued until 300°C, the end of the measurement.

[0165] Figure 8 shows the DVS profile of mesylate form 2. Hygroscopicity was observed between 0% and 90% RH, and the sample increased in total weight by approximately 1.049 wt%. About half of the weight increase occurred between 0% and 15% RH. The adsorption and desorption profiles were similar, but some hysteresis was observed between 40% and 80% RH. About half of the weight increase occurred between 0% and 15% RH.

[0166] Example 3: Preparation and Characterization of Mesylate Form 3 of Compound A Anhydrous mesylate form 3 was obtained by dehydrating hemihydrate mesylate form 2. Dehydration was initiated at 75°C, and form 3 appeared.

[0167] As shown in Figure 15, the variable-temperature XRPD (VT-XRPD) pattern, which shows the transformation of mesylate form 2 to mesylate form 3 of compound A at 5°C intervals from 50°C to 160°C, appears to have been achieved at 160°C, indicating that complete dehydration was achieved at that temperature.

[0168] Figure 9 shows the XRPD pattern of mesylate form 3 of compound A. The DSC profile of mesylate form 3 showed a single enthalpy event with an onset at 229.65°C and a peak at 232.02°C. The peak at 232.03°C indicates the melting point of mesylate form 3.

[0169] The TGA profile of mesylate form 3 shows a very slight weight loss up to approximately 237.5°C, corresponding to the melting point observed in the DSC profile. This weight loss continued up to 300°C, the end of the measurement. The TGA profile exhibits the anhydrous properties of form 3.

[0170] Example 4: Preparation and Characterization of Mesylate Form 4 of Compound A Anhydrous mesylate form 4 was scaled up by slurring mesylate form 2 in acetone at 10 mg / ml for at least 24 hours, filtered, rinsed with diethyl ether, and dried under nitrogen. Calorimetry of form 4 showed an end peak at approximately 145°C (data not shown).

[0171] The XRPD pattern of compound A in mesylate form 4 is shown in Figure 10, and the complete peak list is shown below: [Table 8]

[0172] The DSC profile of mesylate form 4 shows two enthalpy events. The first enthalpy event is a small event with 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 point of mesylate form 4.

[0173] The TGA profile of mesylate form 4 shows a very slight weight loss up to approximately 240°C, corresponding to the melting point observed in the DSC profile. This weight loss continued until 300°C, the end of the measurement. The TGA profile exhibits the anhydrous properties of mesylate form 4.

[0174] Example 5: Preparation and Characterization of Mesylate Form 6 of Compound A Preparation of compound A's mesylate form 6 - Method E The mesylate form 2 was stirred overnight in methyl ethyl ketone (MEK) at 40°C (10 mg / ml), filtered, rinsed with diethyl ether, and dried under nitrogen flux.

[0175] Characterization of compound A in mesylate form 6 The XRPD pattern of the mesylate form 6 of compound A obtained according to Method E is shown in Figure 11, and the complete peak list is shown below: [Table 9]

[0176] The DSC profile of mesylate form 6 showed two enthalpy events. The first enthalpy event had an onset at 221.51°C and a peak at 226.50°C. The second enthalpy event had an onset at 235.43°C and a peak at 237.96°C. The peak at 237.96°C indicates the melting point of mesylate form 6.

[0177] The TGA profile of mesylate form 6 showed a very slight weight loss of approximately 0.2% up to approximately 237.5°C, which corresponds to the melting point observed in the DSC profile. This weight loss continued up to 300°C, the end of the measurement. The TGA profile exhibits the anhydrous properties of mesylate form 6.

[0178] The DVS profile of mesylate form 6 recorded a total water uptake of 0.3% at 20%–80% RH, indicating virtually no hygroscopicity.

[0179] Example 6: Preparation and Characterization of Esilate Form 1 of Compound A In a round-bottom flask, 150 mg (0.39 mmol) of free base of compound A described in Example 1 was suspended in THF (5 mL) and stirred under RT. Then, while stirring, excess ethanesulfonic acid (32 μL, 0.395 mmol) was added and the mixture was concentrated in an open vial. After 1 hour, the crystalline solid was isolated by filtration, washed with THF (2 x 1 ml), and dried under nitrogen for 2 hours (yield 80%).

[0180] The XRPD pattern of compound A's esylate form 1 is shown in Figure 12, and the complete peak list is shown below: [Table 10]

[0181] Esilate form 1 was analyzed by proton NMR. The spectrum is consistent with 1:1 ethylate form 1 of compound A. The characteristic chemical shifts are as follows: 1 H NMR (400MHz, DMSO-d6) δppm 1.05 (3H, t, J=7.50Hz), 1.75 (3H, d, J=7.06Hz), 2.36 (2H, q, J=7.35Hz), 2.60 (3H, s), 4.17 (3H, s), 5.96 (1H, t, J =7.28Hz), 8.04(1H, td, J=8.71, 3.09Hz), 8.24(1H, s), 8.32(1H, dd, J=8.82, 4.41Hz), 8.80(3H, m), 10.48(1H, br s).

[0182] The DSC profile of ethylate form 1 is shown in Figure 13. The DSC profile of ethylate form 1 showed a single enthalpy event with an onset point at 235.735°C and a peak at 239.343°C. The peak at 239.343°C indicates the melting point of ethylate form 1.

[0183] The TGA profile of ethylate form 1 is shown in Figure 14. A very slight weight loss was observed up to approximately 237.5°C, which corresponds to the melting point observed in the DSC profile. This weight loss continued up to 300°C, the end of the measurement. The TGA profile shows the anhydride properties of ethylate form 1 of compound A.

[0184] Example 7: Stability of compound A in mesylate form 2 Approximately 120 mg of compound A mesylate form 2, as described in Example 2, was stored in a properly labeled open amber glass vial covered with filter paper to simulate open conditions, and in a screw-cap glass vial to simulate closed conditions. The sample was prepared so that the powder layer spread uniformly at the bottom of the vial. Approximately 70 mg of the powder was weighed and filled into hydroxypropyl methylcellulose (HPMC) capsule size 3 (Capsugel), and two capsules were stored for each condition. The sample was placed in a desiccator RT with NaBr to reach approximately 60% RH, and in a stability chamber to reach 75% RH at 40°C. Thus, the stability of compound A mesylate form 2 was tested under four different conditions: open conditions at 25°C / 60% RH, closed conditions at 25°C / 60% RH, open conditions at 40°C / 75% RH, and closed conditions at 40°C / 75% RH. Samples were removed from the corresponding sample stability chambers at time points 0, 14, 28, 56, 84, 168, and 365. After being placed in RT, the samples were analyzed by UPLC / UV / MS and XRPD. One or two extra samples were saved for each condition.

[0185] The results under open and closed conditions at 25°C / 60%RH are shown in Table 6, Figure 16, and Figure 17. The XRPD patterns shown in Figures 16 and 17 show no significant changes, indicating that the mesylate form 2 of compound A was stable throughout the entire test period under both open conditions (Figure 16) and closed conditions (Figure 17). This demonstrates that the mesylate form 2 showed excellent stability at RT for at least one year. [Table 11]

[0186] The results under open and closed conditions at 40°C / 75%RH are shown in Table 7, Figure 18, and Figure 19. The XRPD patterns shown in Figures 18 and 19 show no significant changes, indicating that the mesylate form 2 of compound A was stable throughout the entire test period under both open conditions (Figure 18) and closed conditions (Figure 19). [Table 12]

[0187] The results above demonstrate that compound A's mesylate form 2 exhibits remarkably good stability under normal and stress storage conditions. Compound A's mesylate form 2 is stable in dry form for at least one year under various conditions.

[0188] In the second test, approximately 100 mg of compound A in mesylate form 2 as described in Example 2, free base form A as described in Example 1, and ethylate form 1 as described in Example 6 were stored in three open amber glass vials covered with filter paper to simulate open conditions. To compare their stability, the samples were stored in a stability chamber at 75% RH and 40°C. At days 0, 28, 56, and 84, the corresponding samples were removed from the stability chamber. After being placed in RT, the samples were analyzed by ULC / UV and XRPD.

[0189] The results are shown in Table 7A. The XRPD patterns are shown in Figures 20, 21, and 22. Both the mesylate form 2 and esylate form 1 of compound A exhibit surprisingly good stability during storage under stress. [Table 13]

[0190] Example 8: Dissolution of compound A in mesylate form 2 and esylate form 1 in fasting artificial gastric juice (FaSSGF) compared with free base form A and other salts. The solubility of compound A in mesylate form 2 of Example 2 and compound A in ethylate form 1 of Example 6 in fasting artificial gastric fluid (FaSSGF), compared to free base form A and other salts, was tested by manual testing. The artificial oral fluid medium was FaSSGF obtained from Biorelevant.com Ltd. The tests were conducted at 37°C for 60 minutes. The composition of the FaSSGF medium is shown in Table 9.

[0191] General preparation of salts: In a round-bottom flask, 200 mg (0.52 mmol) of the free base form A of compound A described in Example 1 was suspended in 5 ml of solvent and stirred at RT. Acetone was used for bromide salts, ethane disulfonates, malons, sulfates, saccharinates, tosylates, orotates, besilates, hemisulfates, phosphates, and tartrates; water was used for chloride salts; ethyl formate was used for maleates, oxalates, gentisicate salts, fumarates, and mandelates; tetrahydrofuran was used for camphor sulfonates and pamoates; isopropyl acetate was used for 4-hydroxybenzoic acid, and methanol was used for camphorates. The corresponding acids were added in equimolar amounts under stirring (except for hemisulfates, which were added in 0.5 molar amounts). After 1 hour, the crystalline solid was isolated by filtration, washed with the corresponding solvent (2 x 1 ml), and dried under nitrogen for 2 hours.

[0192] The amount of dissolved compounds was determined using an LC / UV system at various checkpoints for up to 60 minutes. The saturated solution concentration was approximately 25-30 mg / ml. Compound A in mesylate form 2 and ethylate form 1 were completely dissolved. The dissolution results are shown in Table 8. In the second test, the quantification was repeated for mesylate form 2 at a saturated solution concentration of 170 mg / ml and for ethylate form 1 at a saturated solution concentration of 100 mg / ml. The results are shown in Tables 8A, 8B, 8C, 8D and Figure 28.

[0193] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0194] As can be understood, the mesylate form 2 and esylate form 1 of compound A consistently showed higher solubility than the free base form A over a 60-minute period. Their solubility was surprisingly higher than that of the other salts tested, as shown in Tables 8, 8A, 8B, 8C, and 8D. The solubility of salts other than the mesylate and esylate forms was shown to be lower than, or at best similar to, the solubility of the free base form A.

[0195] Example 9: Dissolution of compound A in mesylate form 2 in all artificial oral solutions The solubility of compound A in its mesylate form 2, compared to its free base form A, was tested in all artificial oral solutions. The tests were performed using a μDISS Profiler 6 Channel Pion. The tests were conducted at 37°C for up to 24 hours.

[0196] The media used, namely FaSSGF (Fasted State Simulated Gastric Fluid), FaSSIF (Fasted State Simulated Intestinal Fluid), and FeSSIF (Fed State Simulated Intestinal Fluid), were obtained from Biorelevant.com Ltd. The composition of the media is shown in Table 9. The saturated solution concentrations were approximately 14–15 mg / ml (as free base) in FaSSGF and approximately 3–4 mg / ml (as free base) in FaSSIF and FeSSIF. [Table 19]

[0197] The results for free base form A are shown in Figure 23. In FaSSGF, free base form A of compound A showed a steady increase in solubility, but complete dissolution was not achieved. The solubility in FaSSGF was approximately 11 mg / ml. A continued decrease was observed after about 3 hours.

[0198] Lower solubility of 0.02 mg / ml and 0.1 mg / ml was observed in FaSSIF and FeSSIF, respectively.

[0199] Table 10 shows the maximum solubility and final pH obtained during the test for free base form A of compound A. [Table 20]

[0200] The results for compound A in mesylate form 2 are shown in Figure 24. As can be understood, complete dissolution was achieved in FaSSGF with a maximum solubility of 14.00 mg / ml for compound A in mesylate form 2. No decrease in solubility was observed over 24 hours.

[0201] Lower solubility was observed in FaSSIF and FeSSIF, at concentrations of 0.10 mg / ml and 0.07 mg / ml, respectively, compared to FaSSGF.

[0202] Table 11 shows the maximum solubility value obtained during the test and the pH observed at the end of the test for compound A in mesylate form 2.

[0203] The lower maximum solubility in FaSSIF and FeSSIF was also confirmed by ULC / UV / MS at the end of the test, yielding similar results of 0.03 mg / ml and 0.17 mg / ml, respectively. [Table 21]

[0204] The above results indicate that the mesylate form 2 of compound A results in an unexpected increase in maximum solubility in FaSSGF compared to the free base form A of compound A.

[0205] Furthermore, unexpectedly, the mesylate form 2 of compound A exhibits sustained solubility for at least 24 hours, compared to the free base form A of compound A, which shows a decrease in solubility after approximately 3 hours.

[0206] The solubility of compound A in mesylate form 2 in FaSSGF is therefore particularly advantageous in gastric juice, and subsequent absorption may also be potentially enhanced.

[0207] Example 10: Two-stage dissolution test To evaluate the possibility of the "spring parachute effect," the solubility behavior of compound A in mesylate form 2 was tested in a two-step model compared to that of the free base form A.

[0208] The parachute effect can be observed in a two-step dissolution test. The test compound is incubated with FaSSGF, and its concentration is monitored over time. Then, while continuing the monitoring, FaSSGF is added to the solution. The period during which the test compound remains in the solution without precipitation or before precipitation refers to the supersaturation time and represents the parachute effect.

[0209] The tests were performed using a μDISS Profiler 6 Channel Pion. Compound A's free base form A and mesylate form 2 were incubated at a concentration of 350 mg / 250 ml in 8 ml of FaSSGF (pH 1.6) for 20 minutes. 16 ml of 1.5-fold concentrated FaSSGF (pH 6.5) was added, and the incubation time was 180 minutes. The target pH was approximately 5–6. The tests were conducted at 37°C. The entire solubility profile was monitored until the end of the test to assess the potential and duration of the parachute effect, and to evaluate the maximum solubility achieved after the addition of FaSSGF.

[0210] The free base form A of compound A was tested by duplicate assay, and the results are shown in Figure 25. Precipitation began approximately 10 minutes after the addition of FaSSIF. The pH after the addition of FaSSIF was 5.8.

[0211] The mesylate form 2 of compound A was tested by dual assay, and the results are shown in Figure 26. No precipitate was observed after the addition of FaSSIF. The pH measured at the end of the test was 4.5.

[0212] A second test was conducted, involving a further step of adjusting the pH to 6.5 after the addition of FaSSIF. Both free base form A and mesylate form 2 of compound A were tested.

[0213] The results are shown in Figure 27. Surprisingly, mesylate form 2 of compound A showed a longer duration of parachute effect than free base form A of compound A, with an estimated supersaturation duration of 14 minutes compared to 8 minutes for free base form A. This suggests that mesylate form 2 of compound A is likely to increase in vivo bioavailability more than free base form A of compound A. This potential improvement in the absorption profile suggests that mesylate form 2 of compound A is particularly suitable for oral administration.

[0214] A third test was conducted using compound A's esylate form 1, with the same protocol as the second test, using compound A's free base form A and mesylate form 2 as controls. This test aimed to compare and evaluate the potential and duration of the parachute effect of the esylate. Precipitation of the free base was observed after approximately 20 minutes, and precipitation of the esylate and mesylate was observed after 30 and 40 minutes, respectively. The results are shown in Figure 29. Esilate form 1 and compound A's mesylate form 2 showed a longer duration of the parachute effect than free base form A, which indicates a potentially improved absorption profile.

[0215] Example 11: Formulation The formulation suitability of compound A in mesylate form 2 was tested in comparison with that of the free base form A.

[0216] The drug content and homogeneity of compound A in mesylate form 2 and free base form A in 20% w / v SBE-βCD (sulfobutyl ether-β-cyclodextrin, Captisol; CYDEX Pharmaceutical) were tested at various citrate buffer concentrations, e.g., 0.05 M, 0.1 M, 0.5 M, and 1 M, at pH 2.5. To prepare the medium, an appropriate amount of citrate (Sigma Aldrich; CAS: 77-92-9) was dissolved in water in a volumetric flask, and the pH was increased to 2.5 using 1 M NaOH. Water was then added to reach the final volume. SBE-βCD was weighed and added to a beaker containing citrate buffer, and then stirred until dissolved. The required amount of medium was added to a known amount of compound A in free base form A or mesylate form 2, and then sonicated at RT for at least 10 minutes. Before analysis, the formulations were placed under magnetic stirring for at least 10 minutes. Stability in terms of content uniformity and pH was evaluated over a maximum of 8 days. The samples were placed in RT, and the nominal concentration was 40 mg / ml. The results are shown in Tables 12 and 13. [Table 22] [Table 23]

[0217] As shown in Table 13, the free base form A of Compound A was observed as a suspension in formulations with citrate buffer concentrations of 0.05 M, 0.1 M, and 0.5 M. The free base form A of Compound A was observed as a solution only in the formulation obtained from 1 M citrate buffer, but gelation occurred within 24 hours.

[0218] Table 12 shows the results using mesylate form 2. Stable solutions were obtained with citrate buffer at all concentrations. Gelation was not observed during the test period, unlike the formulation of free base form A using 1 M citrate buffer which gelled within 24 hours.

[0219] It can be understood that the mesylate form 2 of Compound A has better formulation suitability in solution than the free base form A of Compound A.

[0220] To examine the effect of potential viscosity increase, a formulation with a citrate buffer concentration of 0.05 M was selected for testing with the addition of polymers.

[0221] Polymers at various ratios were used, such as 5% w / v polyvinylpyrrolidone (PVP) 40 or 1% w / v HPMC.

[0222] The formulations were tested with or without the surfactant D-α-tocopherol polyethylene glycol succinate (Vit. E TPGS, Sigma Aldrich; CAS: 9002-96-4) in a 0.05 M citrate buffer solution with a nominal concentration of 40 mg / ml and a pH of 2.5. To prepare the medium, an appropriate amount of citric acid was dissolved in water in a volumetric flask, and then the pH was increased to 2.5 using 0.1 M NaOH. Water was then added to the final volume. Polymer PVP 40 (Sigma Aldrich; CAS: 9003-39-8) or HPMC (viscosity 46-60 cP; Sigma Aldrich; CAS: 9004-65-3) was gently dissolved in the citrate buffer solution and left under magnetic stirring for at least 1 hour until completely hydrated. If necessary, Vit. E TPGS was then added to the medium, and it was left under gentle magnetic stirring to avoid foam formation.

[0223] The required amount of medium was added to either the free base form A or the mesylate form 2 of compound A in a known amount, and then sonicated at RT for at least 10 minutes. Before analysis, the formulations were placed under magnetic agitation for at least 10 minutes.

[0224] The results are shown in Table 14. [Table 24]

[0225] As shown in Table 14, all formulations using free base form A were recognized as suspensions.

[0226] Even when viscosity was increased by adding polymers, all additives examined showed superior formulation suitability in solution in mesylate form 2.

[0227] Example 12: Two-step dissolution test - Formulation A formulation containing the mesylate form 2 of compound A described in Example 11 (Formulation B) was tested in a two-step dissolution test according to Example 10, compared with a formulation containing the free base form A (Formulation A).

[0228] The test was conducted using a 40 mg / ml formulation.

[0229] The tested formulations, along with their composition and properties, are shown in Table 15 below. [Table 25]

[0230] According to the present invention, a supersaturation duration exceeding 20 minutes is considered sufficient to identify formulations that are likely to have increased bioavailability in vivo, and this phenomenon predicts a greater amount of solubility available for absorption over a longer period of time.

[0231] As shown in Table 15, Formulation B, containing mesylate form 2, showed supersaturation measured at 31 minutes compared to 16 minutes for Formulation A, which clearly indicates the advantageous potential for increased bioavailability in vivo.

Claims

1. A salt of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine, selected from mesylate and esylate salts.

2. The salt according to claim 1, which is in the form of a crystalline mesylate hemihydrate.

3. The salt according to claim 1 or 2, which is a crystalline mesylate form 2 characterized by an X-ray powder diffraction pattern having characteristic peaks at 6.6, 11.8, and 19.2 ± 0.2 degrees 2-theta.

4. The salt according to any one of claims 1 to 3, which is a crystalline mesylate form 2 characterized by an X-ray powder diffraction pattern including characteristic peaks at 6.6, 9.3, 11.8, 19.2 and 27.4 ± 0.2 degrees 2-theta.

5. The salt according to any one of claims 1 to 4, which is a crystalline mesylate form 2 characterized by an X-ray powder diffraction pattern including characteristic peaks at 6.6, 9.3, 11.8, 18.1, 18.5, 19.2, 20.0, 22.4, 25.7, and 27.4 ± 0.2 degrees 2-theta.

6. The salt according to claim 1, which is a crystalline esylate form characterized by an X-ray powder diffraction pattern that includes characteristic peaks at 5.8, 16.3, and 17.7 ± 0.2 degrees 2-theta.

7. The salt according to claim 1 or 6, which is a crystalline esylate form 1 characterized by an X-ray powder diffraction pattern including characteristic peaks at 5.8, 8.7, 16.3, 17.7 and 20.1 ± 0.2 degrees 2-theta.

8. The salt according to any one of claims 1, 6, or 7, which is a crystalline esylate form 1 characterized by an X-ray powder diffraction pattern including characteristic peaks at 5.8, 8.7, 16.3, 17.7, 20.1, 21.5, 22.3, 23.5, 25.1, and 29.1 ± 0.2 degrees 2-theta.

9. The salt according to claim 1, selected from crystalline mesylate form 2 and crystalline esylate form 1 as defined in claims 3, 4 or 5 and 6, 7 or 8, respectively.

10. A pharmaceutical composition comprising a salt defined in any one of claims 1 to 9, either alone or in combination with one or more other active ingredients, mixed with one or more pharmaceutically acceptable carriers or additives.

11. A pharmaceutical composition according to claim 10, for oral administration.

12. A salt according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11, for use as a pharmaceutical.

13. P2X ３ A salt according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use in the treatment of any disease involving receptors.

14. A salt according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11 for use in the prevention and / or treatment of respiratory diseases, including cough, subacute or chronic cough, treatment-resistant cough, idiopathic chronic cough, cough after viral infection, 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 for use in the treatment of chronic cough.

15. A method for producing a crystalline salt of (R)-6-(5-fluoropyridine-2-yl)-8-methoxy-N-(1-(5-methyl-1,2,4-oxadiazole-3-yl)ethyl)quinazoline-4-amine (compound A), selected from mesylates and esylates, 1) A step of suspending the free base of compound A in a polar solvent or solvent mixture; 2) The step of adding methanesulfonic acid or ethanesulfonic acid; and 3) The process of isolating the obtained crystalline salt by filtration. The method, including the method described above.

16. The method according to claim 15, wherein the polar solvent or solvent mixture is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

17. The method according to claim 16, 1) A step of suspending the free base of compound A in a polar solvent or solvent mixture; 2) The step of adding methanesulfonic acid; 2a) A step of drying the solution obtained in step 2); 2b) A step of suspending the solid obtained in step 2a) in a polar solvent or solvent mixture and adding a poor solvent to obtain a precipitate of the crystalline salt; and 3) The process of isolating the obtained crystalline compound A mesylate by filtration. The method, including the method described above.

18. The method according to claim 17, wherein in step 1) and step 2b), the polar solvent or solvent mixture is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof, and in step 2b), the poor solvent is heptane.

19. The method according to any one of claims 15 to 18, further comprising the step of washing the filtered crystalline mesylate or esylate with one or more polar solvents or solvent mixtures preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water and mixtures thereof.

20. The method according to any one of claims 15 to 19, further comprising the step of recrystallizing a crystalline mesylate or esylate in a polar solvent or solvent mixture preferably selected from the group consisting of acetone, tetrahydrofuran, isopropanol, water, and mixtures thereof.

21. The method according to any one of claims 15 to 20, further comprising the step of recrystallizing a crystalline mesylate of compound A from a mixture of isopropanol and water.

22. The method according to any one of claims 15 to 21, wherein the salt is in the form of crystalline mesylate 2.

23. The method according to any one of claims 15, 16, 19, or 20, wherein the salt is crystalline esylate form 1.

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