Method for preparing salts and crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, and novel crystalline forms

Abstract

Novel methods for preparing crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine salts, novel crystalline forms, and pharmaceutical compositions containing the same are provided. Also disclosed are uses of the novel polymorphic forms for the treatment of diseases such as atopic dermatitis (AD), pruritus, and various forms of urticaria, including subtypes of chronic idiopathic urticaria.

Description

[Technical Field]

[0001] The present invention relates to a new process for preparing pharmaceutically acceptable salts of the compound of formula (I) using a particular salt or crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine. [ka]

[0002] The present invention also relates to novel crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate and ethylsulfate, pharmaceutical compositions containing the novel crystalline forms, and uses of the novel crystalline forms for the treatment of diseases such as atopic dermatitis (AD), pruritus, pruritus, and various forms of urticaria, e.g., subtypes of chronic idiopathic urticaria such as cholinergic urticaria. Also provided herein are methods for preparing the crystalline forms of the present invention. [Background technology]

[0003] U.S. Patent No. 9,586,959 relates to, among other compounds, the compound 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine and its pharmaceutically acceptable salts, methods for preparing said compounds, as well as pharmaceutical compositions containing them. U.S. Patent No. 9,586,959 discloses the preparation of various salts of the compound 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0004] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine exhibits potent histamine 4 receptor inhibitory activity and exhibits inhibitory effects on histamine-induced infiltration of inflammatory cells, such as mast cells and eosinophils. Therefore, this compound has potent anti-inflammatory and antipruritic effects and may be useful in treating various diseases, including AD, as disclosed in U.S. Pat. No. 9,586,959.

[0005] Different crystalline solid forms of a chemical compound may have different physical properties, such as, for example, chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology, and bioavailability, that affect their suitability as the selected active ingredient of a pharmaceutical product.

[0006] Chemical substances may also exist in multiple different crystalline solid forms, including different polymorphic forms (e.g., anhydrates) that share the same total formula, and different solvates of the same chemical substance (e.g., hemihydrate, monohydrate, and dihydrate) that do not share the same total formula. Such crystalline solid forms have distinct crystal structures and differ in the physical properties described above. Different crystalline solid forms can be distinguished from each other by melting point, XRPD pattern, spectral characteristics (e.g., FT-IR, Raman, and SS-NMR), and other physical and chemical properties. Chemical substances may also exist in amorphous forms.

[0007] Therefore, the actual crystalline form selected plays an important role in the development and manufacture of an active pharmaceutical ingredient. When a single crystalline form is desired, it is important that the crystallization process is robust, reliably produces the desired crystalline form in polymorphically pure form, and does not change crystalline form (e.g., interconvert to different crystalline forms) during the associated manufacturing steps and / or storage.

[0008] Various salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine have been identified and disclosed in US Pat. No. 9,586,959.

[0009] Some salts occur as anhydrous salts, while others occur as monohydrates and dihydrates, each of which has several polymorphic forms that interconvert when dried or lose water at relatively low temperatures, making them unsuitable for pharmaceutical development.

[0010] The present invention also relates to novel crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine salts having beneficial properties that make them suitable as APIs in the manufacture of pharmaceuticals and other suitable salts and crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0011] It has been found that the methyl and ethyl sulfate salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, including Forms A and B, have very high solubility in solvents suitable for the manufacture of pharmaceuticals, making the salts particularly useful for purification by recrystallization and for the preparation of other crystalline salts of the compound of formula (I).

[0012] Other crystalline forms, such as 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate and 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate, have similarly useful properties in connection with purification by recrystallization and the preparation of other crystalline salts of the compound of formula (I). Summary of the Invention

[0013] Accordingly, the present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, which comprises the steps of: [ka] Ai) obtaining crystalline forms of the methylhydrogen sulfate, ethyl sulfate and / or methanesulfonate of the compound of formula (I); ii) optionally recrystallizing the methyl sulfate, ethyl sulfate and / or methanesulfonate salt crystalline forms of the compound of formula (I) in a suitable solvent or solvent mixture. preparing a crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) by: B. dissolving the crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) in a suitable solvent or solvent mixture, followed by adding an acid capable of forming a pharmaceutically acceptable acid addition salt of the compound of formula (I), or dissolving the crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) in a suitable solvent or solvent mixture containing an acid capable of forming a pharmaceutically acceptable acid addition salt of the compound of formula (I); C. crystallizing the acid addition salt of the compound of formula (I) or the free base of the compound of formula (I) by cooling the reaction mixture or adding an antisolvent; and D. Optionally, recrystallizing and isolating the acid addition salt of the compound of formula (I) or the free base of said compound of formula (I) from a suitable solvent.

[0014] The present invention also relates to crystalline form A of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, and / or 15.7 (±0.2 degrees).

[0015] The present invention also relates to crystalline form B of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.9, and / or 26.5 (±0.2 degrees).

[0016] The present invention also relates to a crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate Form A characterized by one or more XRPD reflections at (°2θ) 8.1, 14.6, and / or 23.4 (±0.2 degrees).

[0017] The present invention also relates to a pharmaceutical composition comprising said novel crystalline form and a pharmaceutically acceptable carrier.

[0018] In one embodiment, the present invention relates to the novel crystalline form or a pharmaceutical composition comprising the novel crystalline form for treating a disease selected from atopic dermatitis, itching, pruritus, and various forms of urticaria, including chronic idiopathic urticaria subtypes.

[0019] The present invention also relates to a pharmaceutical composition comprising said crystalline form and a pharmaceutically acceptable carrier.

[0020] In one embodiment, the invention relates to said compound or pharmaceutical composition for treating a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria, including chronic idiopathic urticaria subtypes. DETAILED DESCRIPTION OF THE INVENTION

[0021] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate salt, and 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate salt have been found to be particularly useful for crystallization, recrystallization and purification, or crystallization of other salt forms of the same compound, due to their high solubility in solvents useful for crystallization and recrystallization purposes in the manufacture of APIs for pharmaceutical use.

[0022] Compared to the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hydrogen sulfate salt disclosed in U.S. Pat. No. 9,586,959, the methyl sulfate, ethyl sulfate, and methanesulfonate salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine have a more neutral pH in aqueous environments and are therefore much more stable to hydrolysis of the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine molecule during aqueous processing, even at elevated temperatures of at least 50° C. This means that the use of methyl sulfate, ethyl sulfate, and / or methanesulfonate salts can reduce losses of API during manufacturing.

[0023] The process of the present invention can be used to prepare any pharmaceutically acceptable acid addition salt of a compound of formula (I). Suitable pharmaceutically acceptable acid addition salts are formed by reaction with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, stilsan, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid, fumaric acid, or any other suitable acid suitable for pharmaceutical use.

[0024] In some embodiments, the acid addition salt of the compound of Formula (I) is a "hemisalt," e.g., a hemisuccinate. The hemisalt form is typically prepared by crystallization from a suitable solvent or solvent mixture containing about 1 / 2 equivalent of acid per equivalent of the compound of Formula (I), resulting in a free base to acid ratio significantly different from 1:1. For hemi forms containing a diacid (e.g., succinic acid), the free base to acid ratio is about 1:0.5.

[0025] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate is obtained by a method comprising the steps of: i) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents including methanol followed by the addition of sulfuric acid; or dissolving a compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents comprising methanol and methylhydrogen sulfate; ii) crystallizing the methyl sulfate salt of the compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; iii) optionally recrystallizing and isolating the crystalline form of the methylhydrogen sulfate salt of the compound of formula (I) in a suitable solvent or mixture of solvents.

[0026] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate is obtained by a process comprising the steps of: i) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents including ethanol followed by the addition of sulfuric acid; or dissolving a compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents comprising ethanol and ethyl hydrogen sulfate; ii) crystallizing the ethyl sulfate salt of the compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; iii) optionally recrystallizing and isolating the crystalline form of the ethyl sulfate salt of the compound of formula (I) in a suitable solvent or mixture of solvents.

[0027] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate is obtained by a process comprising the steps of: i) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents followed by the addition of methanesulfonic acid; or dissolving a compound of formula (I) or a salt thereof in a suitable solvent or mixture of solvents and methanesulfonic acid; ii) crystallizing the methanesulfonate of compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; iii) optionally recrystallizing and isolating the crystalline form of the methanesulfonate of compound of formula (I) in a suitable solvent or solvent mixture.

[0028] According to one embodiment, the present invention relates to a process as described above, wherein the solvent used in steps i) and iii) is selected from methanol or a mixture of methanol and water, and the optional anti-solvent is isopropanol or acetone.

[0029] According to one embodiment, the present invention relates to a process as described above, wherein the acid used in steps i) and iii) is selected from ethanol or a mixture of ethanol and water, and the optional anti-solvent is isopropanol or acetone.

[0030] According to one embodiment, the present invention relates to a process as described above, wherein the solvent used in steps i) and iii) is selected from methanol or a mixture of methanol and water, and the optional anti-solvent is isopropanol or acetone.

[0031] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate is obtained by a process comprising the step of deprotecting the compound of formula (II) in a suitable solvent or solvent mixture comprising methylhydrogen sulfate, followed by crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate by cooling the reaction mixture and / or adding an anti-solvent. [ka] The hydrate of the monohydrate 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate Form A can be formed by adding water to the reaction mixture.

[0032] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate is obtained by a process comprising the step of deprotecting the compound of formula (II) in a suitable solvent or solvent mixture comprising methanesulfonic acid, followed by crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate by cooling the reaction mixture and / or adding an anti-solvent. [ka]

[0033] According to one embodiment, the present invention relates to a process as described above, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate is obtained by a process comprising the step of: cyclizing a compound of formula (III) to obtain a compound of formula (II), followed by crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate by cooling the reaction mixture and / or adding an anti-solvent. [ka]

[0034] According to one embodiment, the present invention relates to such a process, wherein the pharmaceutically acceptable acid addition salt of the compound of formula (I) obtained in step D. is crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate, preferably in the form of a monohydrate.

[0035] According to one embodiment, the present invention relates to a process as described above, wherein in step B., the solvent used to dissolve the methylhydrogen sulfate salt, methanesulfonate and / or ethylhydrogen sulfate salt of the compound of formula (I) is water or a solvent mixture containing water.

[0036] According to one embodiment, the present invention relates to such a method, wherein the anti-solvent in step C. is acetone and / or isopropyl alcohol.

[0037] Two crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate have been identified: one form (Form A) is a monohydrate and the other form (Form B) is anhydrous.

[0038] One crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate has been identified. Form A is anhydrous.

[0039] The technical problem underlying the present invention is to avoid the disadvantages of other crystalline and / or amorphous forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, such as crystal forming ability, filtration properties, solubility, thermodynamic properties, stability issues (e.g., due to water absorption), density, and transformations (e.g., interconversion to other polymorphic forms or hydrates / anhydrates) at different humidities and during the crystallization process.

[0040] A total of 98 crystallization experiments covering a wide range of organic solvents resulted in eight different polymorphic forms (AH) of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate.

[0041] Of these, pure forms A, B, E, G and H were obtained, but only forms A and B were stable during mild drying, and attempts to produce pure forms E and G in large quantities were unsuccessful.

[0042] The novel crystalline form according to the present invention is a methyl sulfate salt, i.e., a salt form in which one 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine molecule is present per methyl sulfate molecule in the crystal lattice.

[0043] Two crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate have been identified: one form (Form A) is a monohydrate and the other form (Form B) is anhydrous.

[0044] Form A is a channel hydrate and in general channel hydrates / solvates are not very stable as the solvent molecules have a tendency to enter and exit the channels, causing disruption of the crystal lattice.

[0045] Analysis of the crystal packing based on single-crystal X-ray analysis revealed that the water molecules in Form A are located within channels. Such hydrates are known as nonstoichiometric hydrates, and the presence of water within channels often poses stability problems. However, in Form A, the channels in which the water molecules reside are small (shortest and longest diameters of 3.2 Å and 5.4 Å, respectively), making it difficult to remove water from the crystal lattice, improving stability during processing.

[0046] Therefore, in the case of Form A, the water molecules are arranged in narrow channels, making it difficult for water to escape, resulting in a stable hydrate, making Form A particularly useful for use in solid pharmaceutical products such as tablets. Form A can also be dried under drying conditions such as a freeze dryer or vacuum oven at 60°C without collapsing the crystal lattice. Form A has also been found to be suitable for large-scale drying.

[0047] Crystal packing analysis of Form B based on single crystal X-ray analysis revealed that Form B packs as a low-symmetry triclinic packing stabilized by counterions located between the planes of the free base and TT stacking of the heteroaromatic moieties along all three triaxial axes (a, b, c). Despite having fewer molecules in the unit cell and a smaller unit cell volume than Form A, both crystal forms have the same density. Form B is stable in an environment containing 60% water.

[0048] Furthermore, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt was found to have relatively high solubility in many solvents, and therefore, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt is It is particularly useful as a starting material for purification by recrystallization and for forming any other salt of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, such as, for example, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate monohydrate. Other salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine generally have relatively low solubility.

[0049] The solubility of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt is shown in Table 1. [Table 1]

[0050] As can be seen from Table 1, the solubility is very low in THF, EtOAC, toluene, MTBE and methyl ethyl ketone, low in isoamyl alcohol and 2-propanol, moderate in 1-propanol acetonitrile and ethanol, high in methanol and DMF, and very high in 1-propanol:H2O (1:5) and DMSO.

[0051] The solubility of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate salt Form A is shown in Table 2. [Table 2]

[0052] definition As used herein, the term "rt" or "room temperature" indicates that the temperature applied is not critical and that a precise temperature value need not be maintained. Typically, "rt" or "room temperature" is understood to mean a temperature of about 15°C to about 25°C [see, e.g., EU Pharmacopoeia 7.5, 1.2 (2012)].

[0053] The term "solvate," as used herein, refers to a crystalline compound wherein a solvent molecule is incorporated into the crystal lattice of the compound in a stoichiometric or non-stoichiometric manner. When the solvent molecule is water, the term "hydrate" is used herein.

[0054] The type of hydrate depends on the molar ratio of water molecules to 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate molecules.

[0055] The term "monohydrate" means 0.8 to 1.2 moles of water per mole of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate.

[0056] An anhydrate is a crystalline form that does not contain any water in the crystal lattice.

[0057] As used herein, the term "non-hygroscopic" refers to a drug substance that exhibits a mass gain of less than 0.2% by weight between about 0% and 80% relative humidity.

[0058] In the context of the present invention, the term "XRPD reflection peak" refers to a specific 2θ position in an XRPD pattern, with a signal-to-noise ratio (calculated according to European Pharmacopoeia article 2.2.46) greater than 3 / 1. "Absence of peaks" is defined as a peak having an intensity of at most 1%, e.g., 0.5% or 0.2%, of the highest peak in the XRPD of a sample of a compound of the invention, i.e., no detectable XRPD peak above the background signal.

[0059] In an XRPD pattern, the main features of the diffraction line profile are the 2θ position, peak height, peak area, and shape (e.g., peak width or asymmetry, characterized by analytical functions, empirical expressions). The 2θ position is the most important factor, since, for example, intensity is affected by sample formulation, and peak width is affected by particle size. In addition to the diffraction peaks, X-ray diffraction experiments also produce a nearly uniform background in the XRPD pattern, onto which the peaks are superimposed. Besides specimen formulation, other factors also affect the background, such as diffuse scattering from the sample holder, air, and instrument, detector noise, and other instrument parameters, such as general radiation from the X-ray tube. The peak-to-background ratio can be increased by minimizing the background and / or selecting a long exposure time.

[0060] Abbreviation DSC: Differential injection calorimeter DVS: Dynamic Vapor Sorption TGA: Thermogravimetric analysis XRPD: X-ray powder diffraction 13 C CP / MAS NMR: 13C cross-polarization magic-angle spinning nuclear magnetic resonance SXRD: Single crystal X-ray diffraction [Brief explanation of the drawings]

[0061] [Figure 1A] Figure 1 is the XRPD pattern (3-45° 2θ) for methyl sulfate Form A. [Figure 1B] Figure 1 is the XRPD pattern (3-30° 2θ) for methyl sulfate Form A. [Figure 2A] XRPD pattern (3-45° 2θ) for methyl sulfate Form B. [Figure 2B] XRPD pattern (3-30° 2θ) for methyl sulfate Form B. [Figure 3] 1 is a DSC and TGA curve of methyl sulfate Form A. [Figure 4] 1 is a DSC and TGA curve of methyl sulfate Form B. [Figure 5A] ORTREP diagram for the absolute crystal structure of Form A. The asymmetric unit cell consists of one 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine molecule, one water, and one methyl sulfate ion. [Figure 5B] ORTREP diagram for the absolute crystal structure of Form B. The asymmetric unit cell consists of one 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine molecule and one methyl sulfate ion. [Figure 6] 13C CP / MAS NMR (14.1 T) spectrum of methyl sulfate Form A. [Figure 7] 13C CP / MAS NMR (14.1 T) spectrum of methyl sulfate Form B. [Figure 8] 1 is the XRPD pattern for ethyl sulfate Form A. [Figure 9]13C CP / MAS NMR spectrum for ethyl sulfate Form A.

[0062] The crystal parameters obtained from the single crystal structure determination of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate forms A and B are shown in Table 3. [Table 3]

[0063] From the data in Table 3, it can be concluded that Form A is a monoclinic monohydrate and Form B is a triclinic anhydrate.

[0064] Thus, in one embodiment, the present invention relates to 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt.

[0065] In another embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, and / or 15.7 (±0.2 degrees).

[0066] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and / or 29.8 (±0.2 degrees).

[0067] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by one or more XRPD reflections at about 8.9, 12.3, and 15.7 (±0.2 degrees).

[0068] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and 29.8 (±0.2 degrees).

[0069] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern of FIG. 1.

[0070] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern of FIG.

[0071] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, wherein the crystalline compound is a solid having peaks at one or more of 149.0, 147.3, 127.8, 119.0, 59.0, 48.9, and / or 33.7 ppm ± 0.2 ppm. 13It is characterized by C CP / MAS NMR spectrum.

[0072] In a further embodiment, the present invention relates to the 13 C CP / MAS NMR spectrum essentially similar 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, characterized by having a C CP / MAS NMR spectrum.

[0073] In a further embodiment, the present invention relates to the 13 According to C CP / MAS NMR spectrum 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, characterized by having a C CP / MAS NMR spectrum.

[0074] In a further embodiment, the present invention provides 13 crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by having a C CP / MAS NMR spectrum additionally characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and 29.8 (±0.2 degrees).

[0075] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters as shown in Table 2 for Form A.

[0076] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate having a DSC curve containing an endothermic-exothermic event with an onset at 242.2±2° C. and a corresponding weight loss in the TGA curve.

[0077] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate, wherein the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine to methylsulfate is in the range of 1:0.8 to 1:1.2, preferably about 1:1.

[0078] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.9, and / or 26.5 (±0.2 degrees).

[0079] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and / or 26.5 (±0.2 degrees).

[0080] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.9, and 26.5 (±0.2 degrees).

[0081] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and 26.5 (±0.2 degrees).

[0082] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern of FIG. 2.

[0083] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern of FIG.

[0084] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, wherein the crystalline compound is a solid having peaks at one or more of 148.1, 146.4, 128.6, 119.9, 60.3, 48.0, and / or 32.2 ppm ± 0.2 ppm. 13 It is characterized by C CP / MAS NMR spectrum.

[0085] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, wherein the crystalline compound is a solid having peaks at one or more of 148.1, 146.4, 128.6, 119.9, 60.3, 48.0, and 32.2 ppm ± 0.2 ppm. 13 It is characterized by C CP / MAS NMR spectrum.

[0086] In a further embodiment, the present invention relates to the 13 C CP / MAS NMR spectrum essentially similar 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydride, characterized by having a C CP / MAS NMR spectrum.

[0087] In a further embodiment, the present invention relates to the 13 According to C CP / MAS NMR spectrum 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydride, characterized by having a C CP / MAS NMR spectrum.

[0088] In a further embodiment, the present invention provides 13 The present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, characterized by having a C CP / MAS NMR spectrum, further characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and / or 26.0 (±0.2 degrees).

[0089] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters set forth in Table 1 for Form B.

[0090] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate having a DSC curve containing an endothermic event with an onset value consisting of an unresolved endothermic-exothermic event beginning at about 247.6±2°C and a corresponding weight loss in the TGA curve.

[0091] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate, characterized in that the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine to methylsulfate is in the range of 1:0.8 to 1:1.2, preferably about 1:1.

[0092] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate characterized by one or more XRPD reflections at about 8.1, 14.6, and / or 23.4 (±0.2 degrees).

[0093] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, 16.3, 17.2, 18.8, 19.0, 20.1, 21.7, 23.4, and / or 26.8 (±0.2 degrees).

[0094] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate characterized by one or more XRPD reflections at about 8.1, 14.6, and 23.4 (±0.2 degrees).

[0095] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, 16.3, 17.2, 18.8, 19.0, 20.1, 21.7, 23.4, and 26.8 (±0.2 degrees).

[0096] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, wherein the crystalline compound has an XRPD pattern essentially similar to the XRPD pattern of FIG. 8.

[0097] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern of FIG.

[0098] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, wherein the crystalline compound is a solid having peaks at one or more of 147.7, 145.8, 139.6, 138.7, 128.9, 119.5, 109.8, 63.2, 59.3, 56.6, 48.2, 31.8, and / or 17.0 ppm ± 0.2 ppm. 13 It is characterized by C CP / MAS NMR spectrum.

[0099] In a further embodiment, the present invention relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, wherein the crystalline compound is a solid having peaks at one or more of 147.7, 145.8, 139.6, 138.7, 128.9, 119.5, 109.8, 63.2, 59.3, 56.6, 48.2, 31.8, and 17.0 ppm ± 0.2 ppm. 13 It is characterized by C CP / MAS NMR spectrum.

[0100] In a further embodiment, the present invention relates to the 13 C CP / MAS NMR spectrum essentially similar 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, characterized by having a C CP / MAS NMR spectrum.

[0101] In a further embodiment, the present invention relates to the 13 According to C CP / MAS NMR spectrum 13 This relates to crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate, characterized by having a C CP / MAS NMR spectrum.

[0102] In a further embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as described above and a pharmaceutically acceptable carrier.

[0103] In a further embodiment, the present invention relates to a pharmaceutical composition as described above for use in the treatment of a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria.

[0104] In certain embodiments, the present invention relates to the aforementioned pharmaceutical composition, wherein the form of urticaria comprises a subtype of chronic idiopathic urticaria, such as cholinergic urticaria.

[0105] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate can be prepared by crystallization from methanol in the presence of sulfuric acid.

[0106] The crystalline forms of the present invention can be prepared by recrystallization of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine in the form of its methyl sulfate salt from a suitable solvent such as lower alcohols (e.g., methanol, ethanol, propanol, and mixtures thereof), acetone, acetonitrile, lower alkyl acetates (e.g., ethyl acetate and propyl acetate), tetrahydrofuran, and mixtures of these solvents with various amounts of water and / or liquid hydrocarbons (e.g., hexane and heptane) at room temperature, or by cooling to a temperature below room temperature, for example, below 0°C, preferably at a temperature of -18°C.

[0107] For the formation of Form B, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate hydrate was suspended in methanol, and then the reaction was heated and the solution was cooled to room temperature once most of the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate had dissolved.

[0108] To form Form A, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate is suspended in a solvent (e.g., 2-propanol), the reaction is heated, and once most of the 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate has dissolved, a small amount of water is added, and the solution is cooled to room temperature. The amount of water relative to the amount of solvent is preferably in the range of 1:2 to 1:6, and preferably 1:4.

[0109] It can be conveniently obtained by deprotecting the Boc group using methylhydrogen sulfate in methanol. Solvents for this crystallization include methanol and water, with isopropyl alcohol as an antisolvent. It can also be conveniently obtained directly from the reaction mixture (solvent is methanol) by cooling the reaction mixture to room temperature and filtering.

[0110] The free base of the compound of formula (I), including crystalline forms, can be conveniently obtained from the methyl sulfate salt by stirring the salt in acetone in the presence of triethylamine.

[0111] The hemisuccinate of the compound of formula (I), including crystalline forms, can be obtained from the free base by stirring a mixture of the free base with succinic acid in a suitable solvent, such as 1-propanol, optionally with water.

[0112] The hemisuccinate of the compound of formula (I), including the crystalline salt, can be prepared from the methylsulfate salt by dissolving the methylsulfate salt in water, optionally in the presence of another solvent such as acetone, followed by the addition of disodium succinate (0.55 eq). The hemisuccinate is then precipitated by cooling or the addition of an anti-solvent, or both.

[0113] The ethyl sulfate salt of the compound of formula (I), including crystalline forms, can be conveniently prepared from the free base by stirring a solution of the ethyl hydrogen sulfate salt in ethanol with the addition of water and isopropanol.

[0114] The ethyl sulfate salt of the compound of formula (I), including crystalline forms, can be conveniently converted to the hemisuccinate of the compound of formula (I) by dissolving the ethyl sulfate salt in water, followed by the addition of sodium succinate, optionally followed by the addition of an anti-solvent (e.g., acetone), and optionally cooling.

[0115] The methanesulfonate salt of the compound of formula (I), including crystalline forms, can be conveniently converted to the free base of the compound of formula (I) by treating the methanol sulfate salt with acetonitrile and triethylamine. The product is isolated by filtration and then washed with a suitable solvent, such as isopropanol and water.

[0116] The methanesulfonate salt of the compound of formula (I), including crystalline forms, can be conveniently prepared in a variety of ways, one of which is by treating the free base with methanesulfonic acid in a suitable solvent such as acetonitrile.

[0117] The methanesulfonate salt of the compound of formula (I) can also be obtained from precursor (II) (the Boc-protected analog of the free base). [ka]

[0118] In this step, the compound of formula (II) is stirred with methanesulfonic acid in methanol. The solution is concentrated, and water and isopropanol are added. The suspension is cooled and filtered to obtain the product.

[0119] The methanesulfonate salt can also be obtained in a one-pot process from the previous intermediate compound of formula (III). [ka]

[0120] In this step, intermediate (III) is first treated with trimethyl orthoformate in methanol to give intermediate (II), which is then treated with methanesulfonic acid in the same manner as in the previous example.

[0121] The methanesulfonate salt of the compound of formula (I), including its crystalline form, can also be conveniently converted to the hemisuccinate salt by slurrying the methanesulfonate salt with water, or optionally with water and acetone. A solution of disodium succinate in water is added, followed by seeding. After the conversion is complete, the mixture is cooled and filtered to obtain the hemisuccinate salt.

[0122] A further aspect of the present invention relates to a pharmaceutical composition comprising a crystalline compound of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may be in oral dosage form, preferably a tablet and / or a capsule.

[0123] The present invention also relates to the use of the crystalline compounds of the present invention for the preparation of a solid medicament.

[0124] In another embodiment, the present invention relates to a solid pharmaceutical composition comprising an effective amount of a crystalline compound of the present invention and a pharmaceutically acceptable carrier, and a method for preparing the same. The present invention also relates to a pharmaceutical composition of the present invention and / or a crystalline compound of the present invention for use in treating any of the diseases or disorders described in U.S. Patent No. 9,586,959, including diseases and disorders such as atopic dermatitis (AD), itch, pruritus, and various types of urticaria.

[0125] The pharmaceutical composition of the present invention containing the crystalline compound of the present invention can further contain one or more pharmaceutically acceptable additives. Such additives are preferably selected from the group consisting of diluents, sweeteners, buffers, glidants, fluidizers, flavoring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants, and thickeners. Other additives known in the field of pharmaceutical compositions can also be used. The pharmaceutical composition can also contain a combination of two or more additives from one of the above groups.

[0126] Suitable binders that can be used in the pharmaceutical compositions of the present invention comprising the crystalline compounds of the present invention further include, for example, alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, carboxyalkylcelluloses such as carboxymethylcellulose, alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose, carboxyalkylalkylcelluloses such as carboxymethylethylcellulose, carboxyalkylcelluloses such as carboxyalkylcellulose esters, and the like. Examples of suitable cellulose derivatives include esters, starches, modified starches such as sodium carboxymethyl starch, pectins, chitosan, chitin derivatives such as heparin and heparinoids, polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylic acid copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of vinyl acetate and polyvinylpyrrolidone, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, e.g., poloxamer and poloxamine, and copovidone.

[0127] Suitable diluents that can be used in pharmaceutical compositions of the invention comprising crystalline compounds of the invention further include, for example, calcium carbonate, dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose including silicified microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrose additives, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, starch, modified starch, sodium chloride, sucrose, compressible sugar, confectioner's sugar, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25) (commercially available under the trademark Microcelac®), and a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2) (commercially available under the trademark Prosolv®).

[0128] Suitable glidants that can be used in pharmaceutical compositions of the present invention, including crystalline compounds of the present invention, further include, for example, talc, colloidal silicon dioxide, starch, and magnesium stearate.

[0129] Suitable disintegrants that can be used in the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention further include, for example, starch, ion exchange resins such as Amberlite, cross-linked polyvinylpyrrolidone, modified cellulose gums such as croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates, and powdered cellulose.

[0130] Suitable lubricants that can be used in pharmaceutical compositions of the present invention, including crystalline compounds of the present invention, further include, for example, magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, and magnesium lauryl sulfate.

[0131] Some formulations, e.g., tablets, may contain components that have XRPD reflection peaks in the same location or region as the crystalline compound of the present invention, or components that have broad peaks. These may mask some of the XRPD pattern or peaks of the crystalline compound of the present invention when XRPD experiments are performed on formulations that contain the crystalline compound of the present invention rather than just the pure crystalline salt. This means that not all of the XRPD reflection peaks of the crystalline compound of the present invention will always be visible when XRPD experiments are performed on dosage forms of the crystalline compound.

[0132] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more components that exhibit XRPD reflection peaks, including one or more XRPD reflection peaks that overlap with and mask one or more XRPD reflection peaks of the crystalline compound of the invention.

[0133] For example, strong signals from cellulose components are expected in the 60–110 ppm spectral region, and peaks from stearates are observed in the 15–40 ppm spectral region, along with a carbonyl peak around 172 ppm. 13 The same problem can occur in C CP / MAS NMR.

[0134] Thus, according to one embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein together with a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein said pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) is / are one or more of the crystalline compounds of the present invention. 13 May contain one or more peaks that overlap and mask the C CP / MAS NMR peaks 13 It contains one or more components characterized by a C CP / MAS NMR spectrum.

[0135] The absence of other crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate, ethyl sulfate and methanesulfonate can be tested by comparing the XRPD pattern of any crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine or a salt thereof with the XRPD pattern of the crystalline forms of the present invention disclosed in the figures herein.

[0136] Description of Test Methods Used to Characterize the Polymorphic Forms Disclosed herein X-ray powder diffraction (XRPD): XRPD patterns were collected using a PANalytical X'pert PRO MPD diffractometer operating at 45 kV and 40 mA using incident CuKα radiation. XRPD patterns were collected over a 2θ range of 3–45° with a step size of 0.0066°, a count time of 148.93 s, and in transmission geometry. The incident beam path contained a 4 mm fixed mask, a 1° fixed anti-scatter slit, and a 1 / 2° fixed divergence slit, along with an elliptically tilted multilayer mirror, to focus the CuKα X-rays from the sample to the detector. The diffraction beam path contained a long anti-scatter extension and a 2 mm anti-scatter slit to minimize background caused by air. Additionally, 0.02 rad Soller slits were placed in both the incident and diffraction beam paths to minimize broadening due to axial divergence.

[0137] For better particle statistics, the sample was placed on a 3 μm thick foil on a 96-well high-throughput plate stage and oscillated in the X direction. Diffraction patterns were collected with a PIXel RTMS detector with an active length of 3.347°, located 240 mm from the sample.

[0138] Thermogravimetric analysis (TGA): TGA experiments were performed using a TA Instruments TGA550 instrument. Approximately 1–10 mg of sample was placed in a ceramic pan for measurement. The sample temperature was increased from 25°C to 500°C at a rate of 10°C / min. Nitrogen was used as the purge gas at a flow rate of 50 mL / min.

[0139] Differential Scanning Calorimetry (DSC): DSC: heating rate 10°C / min under nitrogen atmosphere. For the measurement, approximately 1-2 mg of sample was placed in an open aluminum pan for measurement. Instrument Q20 manufactured by TA Instruments.

[0140] Single crystal X-ray diffraction: Data were collected using a SuperNova dual diffractometer equipped with an Atlas CCD area detector (temperature: 120(2) K; CuKα radiation λ = 1.5418 Å; data collection method: ω scan). Details can be found in Table 1. Programs used for structure interpretation: CrysAlisPro, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlisl71 .NET), ShelXL (Sheldrick, 2008) for structure refinement, and Olex2 (Dolomanov et al., 2009) for ORTEP drawing.

[0141] Solid-state NMR spectroscopy: 13 C CP / MAS NMR spectra were obtained using a 4 mm double alignment ( 1 H- 13 C), recorded at 298 K using a Bruker Avance III HD600 NMR spectrometer (14.1 T) equipped with a CMP probe: contact time 6 ms, recycle delay 64 s, spin speed 14.1 kHz, 256 scans, and high power during an acquisition time of 45.9 ms. 1H decoupling was used. Prior to the Fourier transformation, time-domain data (free induction decay) were apodized through 5 Hz Lorentzian line broadening. All spectra were referenced to the chemical shift of the carbonyl group of α-glycine at 176.5 ppm (external sample).

[0142] The error ranges provided in this application for spectroscopic properties, including those set forth in the claims, depend on factors well known to those skilled in the art of spectroscopy and may vary due to, for example, sample preparation, such as particle size distribution, or the composition of the formulation if the crystalline form is part of a formulation, as well as instrumental variations, and other factors. [Example]

[0143] Example 1 Form A 11 mg of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ammonium methyl sulfate was added to a test tube or 4 mL glass vial, followed by 4 mL of 2-propanol, followed by 0.2 mL of water. The solution was heated with a heat gun until all solids were visibly dissolved. The solution was then filtered through a 0.45 μm syringe filter. The filtered solution was placed in a loose-lidded fume cup and placed on a table to allow crystallization while the solvent system slowly evaporated. The resulting crystals were isolated by filtration. The XRPD of the crystalline material is shown in Figure 1.

[0144] Example 2 Form B 11 mg of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ammonium methyl sulfate was added to a test tube or 4 mL glass vial, and 4 mL of EtOH, followed by 0.2 mL of water, was added. The solution was heated with a heat gun until all solids were visibly dissolved. The solution was then filtered through a 0.45 μm syringe filter. The filtered solution was placed in a loose-lidded fume cup and placed on a table to allow crystallization while the solvent system slowly evaporated. The resulting crystals were isolated by filtration. The XRPD of the crystalline material is shown in Figure 2.

[0145] Example 3 Preparation of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ammonium methylsulfate (Form B) Concentrated sulfuric acid (6.5 g) was added in portions to methanol (33 mL) over 10 minutes. The initial temperature was 15°C, and despite the exothermic reaction, the temperature never exceeded 37°C. After the addition, the mixture was brought to a gentle reflux (internal temperature 64°C). After 1 hour at reflux, the solution was cooled to 20°C and stirred at that temperature until use.

[0146] Methanol (150 mL) was added to compound (III) (15 g) and the mixture was stirred. The mixture was heated to 50°C over 15 minutes. The previously prepared solution of methyl hydrogen sulfate in methanol (0.24 mL) was added, and after 10 minutes, trimethyl orthoformate (8.9 mL) was added dropwise over 30 minutes. After approximately 2.3 mL had been added, the mixture turned orange. After the addition was complete, the reaction mixture was stirred at 50°C for approximately 18 hours. The orange suspension became a very thick red suspension and then slowly turned to a yellow suspension overnight. After 18 hours, the remaining solution of methyl hydrogen sulfate in methanol was added dropwise over 30 minutes. By the end of the addition, most of the solid had dissolved. The mixture was stirred at 50°C for 8 hours, then the temperature was lowered to 2°C over 2 hours, and the suspension was stirred overnight. The suspension was filtered, and the residue was washed with methanol (45 mL). The residue was dried on the filter and vacuum dried at 35° C. over the weekend to give the desired methyl sulfate salt as a yellow solid (13.4 g, approximately 92% yield, >99% purity).

[0147] Example 4 Preparation of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ammonium ethyl sulfate A solution of sulfuric acid (12 mL) and ethanol (250 mL) was heated overnight at 50° C. The solution was then concentrated to approximately 75 mL and cooled to room temperature.

[0148] In a separate flask, 25 g of the free base of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine was added, followed by the previously prepared ethanol solution. 375 mL of water was added, followed by 500 mL of isopropanol, and the mixture was stirred. Once crystallization was complete, the product was isolated by filtration, and the filter cake was washed with isopropanol. Yield: approx. 82%, Purity: approx. 95%.

[0149] Example 5 Preparation of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-ammonium methanesulfonate After stirring a mixture of tert-butyl N-[1-(12-bromo-2,4,5,8,10-pentaazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaen-7-yl)azetidin-3-yl]-N-methyl-carbamate (50 g) in methanol (750 mL), methanesulfonic acid (22.4 mL) was added dropwise over approximately 7 minutes. The mixture was stirred at 50° C. overnight. After cooling, the mixture was concentrated under reduced pressure (approximately 500 mL of solvent was removed). The mixture was filtered, and the residue was transferred to a suitable flask. Water (500 mL) was added, followed by activated carbon (10 g). The mixture was allowed to stand at 50° C. for approximately 30 minutes. The carbon was removed by filtration. The filtrate was transferred to a suitable flask, and isopropanol (1500 mL) was added. The slurry was stirred at room temperature overnight. The mixture was filtered and the filter cake was washed with isopropanol. The filter cake was sucked dry on the filter and then dried under vacuum overnight. Yield: about 76%, Purity: about 99%.

[0150] Example 6 Preparation of the free base from the methyl sulfate salt 1-(8-Bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt (1200 g) was suspended in acetone (17.5 L) with stirring. Triethylamine (750 mL) was added and the mixture was stirred at room temperature overnight. The solid product was isolated by filtration, washed with acetone, and then dried under vacuum. Yield: approx. 95%, Purity: >90%.

[0151] Example 7 Preparation of Hemisuccinate Form F from the Methyl Sulfate Salt To a suitable flask was added 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate salt (20 g), followed by water (180 mL) and acetone (40 mL). The reaction mixture was filtered, and the filtrate was transferred to a suitable reactor. A solution of disodium succinate (4 g) in water was slowly added over 60 minutes. The solution was then seeded, and acetone (160 mL) was added over approximately 60 minutes. Precipitation was observed after approximately 20 mL of acetone had been added. Once the acetone addition was complete, the mixture / slurry was stirred overnight at 40°C. The reaction mixture was then cooled to 5°C over 2 hours and filtered. The filter cake was washed with acetone and then dried under vacuum at 50°C overnight. Yield: approximately 85%, Purity: approximately 99%.

[0152] Example 8 Preparation of Hemisuccinate Form F from the Ethyl Sulfate Salt To 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate salt (5 g) was added water (50 mL) with stirring, and the suspension was heated to 40 °C. Complete dissolution was not observed, so additional water (50 mL) was added, and the suspension was heated to 50 °C until the solid dissolved. Disodium succinate (480 mg) was added as a solid, and the mixture was seeded. Acetone (100 mL) was added, and the reaction mixture was stirred at 40 °C overnight. The next day, the reaction mixture was cooled to 5 °C for 2 hours. The slurry was then filtered. The filter cake was washed with acetone and then dried under vacuum at 50 °C overnight. Yield: approx. 72%, Purity: >90%.

[0153] Example 9 Conversion of the methanesulfonate salt to the free base A mixture of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate salt (4.5 g) and acetonitrile (90 mL) was stirred and cooled to approximately 7°C. Triethylamine (2.2 mL) was added, and the mixture was stirred for approximately 90 minutes. The mixture was filtered, and the filter cake was washed with acetonitrile. The filter cake was transferred to a suitable container and slurried in a mixture of isopropanol (38.3 mL) and water (6.75 mL). The slurry was then filtered, and the filter cake was dried under vacuum overnight. Yield: approximately 92%, Purity: approximately 94%.

[0154] Example 10 Conversion of intermediate (II) to methanesulfonate Methanol (750 mL) was added to intermediate (II) (50 g) and the slurry was stirred using a mechanical stirrer. Methanesulfonic acid (22.4 mL) was added slowly over approximately 7 minutes, after which the temperature of the reactor was raised to 50°C and stirred at that temperature overnight. The solution was then cooled and the solvent was reduced under vacuum (approximately 500 mL removed). Water (500 mL) was added, followed by activated carbon (10 g), and the mixture was heated to 50°C. After approximately 30 minutes, the suspension was filtered and the filtrate was returned to a suitable reaction vessel. Isopropanol (1500 mL) was added dropwise, and the resulting slurry was stirred at room temperature overnight. The slurry was cooled in an ice-water bath and filtered after approximately 30 minutes. The filter cake was washed with isopropanol and first sucked dry on the filter, then dried under vacuum for approximately 3 days. Yield: approximately 76%, Purity: >90%.

Claims

1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, which comprises the steps of: 【Chemical 1】 E. iii) Obtaining crystalline forms of the methylhydrogen sulfate, ethyl sulfate and / or methanesulfonate of the compound of formula (I); iv) optionally recrystallizing the methyl sulfate, ethyl sulfate and / or methanesulfonate salt crystalline forms of the compound of formula (I) in a suitable solvent or solvent mixture. preparing a crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) by F. dissolving the crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) in a suitable solvent or solvent mixture, followed by adding an acid capable of forming a pharmaceutically acceptable acid addition salt of the compound of formula (I), or dissolving the crystalline form of the methyl sulfate, ethyl sulfate and / or methanesulfonate salt of the compound of formula (I) in a suitable solvent or solvent mixture containing an acid capable of forming a pharmaceutically acceptable acid addition salt of the compound of formula (I); G. Crystallizing the acid addition salt of the compound of formula (I) or the free base of the compound of formula (I) by cooling the reaction mixture or adding an antisolvent; and H. Optionally, recrystallizing and isolating the acid addition salt of the compound of formula (I) or the free base of formula (I) from a suitable solvent.

2. 2. The method of claim 1, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate is obtained by a process comprising the steps of: iv) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture comprising methanol followed by adding sulfuric acid, or dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture comprising methanol and methylhydrogen sulfate; v) crystallizing the methyl sulfate salt of the compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; vi) optionally recrystallizing and isolating the crystalline form of the methylhydrogen sulfate salt of the compound of formula (I) in a suitable solvent or solvent mixture.

3. 2. The method of claim 1, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate is obtained by a process comprising the steps of: iv) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture comprising ethanol followed by adding sulfuric acid, or dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture comprising ethanol and ethyl hydrogen sulfate; v) crystallizing the ethyl sulfate salt of the compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; vi) optionally recrystallizing and isolating the crystalline form of the ethyl sulfate salt of the compound of formula (I) in a suitable solvent or mixture of solvents.

4. 2. The method of claim 1, wherein the crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate is obtained by a process comprising the steps of: iv) dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture and then adding methanesulfonic acid, or dissolving the compound of formula (I) or a salt thereof in a suitable solvent or solvent mixture and methanesulfonic acid; v) crystallizing the methanesulfonate of compound of formula (I) by cooling the reaction mixture and / or adding an anti-solvent; vi) optionally recrystallizing and isolating the crystalline form of the methanesulfonate of compound of formula (I) in a suitable solvent or solvent mixture.

5. 3. The process according to claim 2, wherein the solvent used in steps i) and iii) is selected from methanol or a mixture of methanol with water, and the optional anti-solvent is isopropanol or acetone.

6. 4. The process according to claim 3, wherein the acid used in steps i) and iii) is selected from ethanol or a mixture of ethanol and water, and the optional anti-solvent is isopropanol or acetone.

7. 5. The process according to claim 4, wherein the solvent used in steps i) and iii) is selected from methanol or a mixture of methanol and water, and the optional anti-solvent is isopropanol or acetone.

8. The crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate can be obtained by deprotecting the compound of formula (II) in a suitable solvent or solvent mixture containing methylhydrogen sulfate, The method according to claim 1, wherein the methyl 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate is obtained by a method comprising the step of crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate by cooling the reaction mixture and / or adding an anti-solvent. 【Chemistry 2】

9. The crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate can be obtained by deprotecting the compound of formula (II) in a suitable solvent or solvent mixture containing methanesulfonic acid, The method according to claim 1, wherein the methyl 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate is obtained by a method comprising the step of crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate by cooling the reaction mixture and / or adding an anti-solvent. 【Chemistry 3】

10. The crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methanesulfonate is obtained by ring closure of the compound of formula (III) to obtain the compound of formula (II), The method according to claim 1, wherein the methyl 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate is obtained by a method comprising the step of crystallizing 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methyl sulfate by cooling the reaction mixture and / or adding an anti-solvent. 【Chemistry 4】

11. The method according to any one of claims 1 to 10, wherein the pharmaceutically acceptable acid addition salt of the compound of formula (I) obtained in step D is crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine hemisuccinate, preferably in the form of a monohydrate.

12. The method according to any one of claims 1 to 10, wherein in step B, the solvent used to dissolve the methylhydrogen sulfate salt, methanesulfonate and / or ethylhydrogen sulfate salt of the compound of formula (I) is water or a solvent mixture containing water.

13. The method according to any one of claims 1 to 12, wherein the anti-solvent in step C is acetone and / or isopropyl alcohol.

14. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate monohydrate characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, and 15.7 (±0.2 degrees).

15. 15. The crystalline compound of claim 14, characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and / or 29.8 (±0.2 degrees).

16. 16. The crystalline compound of claim 14 or 15, characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, and 15.7 (±0.2 degrees).

17. 17. The crystalline compound of any one of claims 14 to 16, characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and 29.8 (±0.2 degrees).

18. 17. The crystalline compound of any one of claims 14 to 16, having an XRPD pattern essentially similar to the XRPD pattern of Figure 1.

19. 17. The crystalline compound of any one of claims 14 to 16, having an XRPD pattern according to the XRPD pattern of Figure 1.

20. A solid state having peaks at one or more of 149.0, 147.3, 127.8, 119.0, 59.0, 48.9, and / or 33.7 ppm ± 0.2 ppm. 13 The crystalline compound of any one of claims 14 to 19 characterized by a C CP / MAS NMR spectrum.

21. Solids having peaks at one or more of 149.0, 147.3, 127.8, 119.0, 59.0, 48.9, and 33.7 ppm ± 0.2 ppm 13 The crystalline compound according to any one of claims 14 to 20, characterized by a C CP / MAS NMR spectrum.

22. In FIG. 13 C CP / MAS NMR spectrum essentially similar 13 22. The crystalline compound according to claim 20 or 21, having a C CP / MAS NMR spectrum.

23. In FIG. 13 According to C CP / MAS NMR spectrum 13 22. The crystalline compound according to claim 20 or 21, having a C CP / MAS NMR spectrum.

24. 24. The crystalline compound of any one of claims 20 to 23, further characterized by one or more XRPD reflections at about (°2θ) 8.9, 12.3, 15.7, 16.5, 21.1, 22.4, 23.7, 25.8, 26.0, and 29.8 (±0.2 degrees).

25. 25. The crystalline compound of any one of claims 14 to 24, having single crystal X-ray crystallography (SXRC) parameters as shown in Table 1 for Form A.

26. 26. The crystalline compound of any one of claims 14 to 25, having a DSC curve containing an endothermic-exothermic event with an onset at 242.2±2°C and a corresponding weight loss in the TGA curve.

27. 27. The crystalline compound according to any one of claims 14 to 26, wherein the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine to methyl sulfate is in the range of 1:0.8 to 1:1.2, preferably about 1:

1.

28. 28. The crystalline compound according to any one of claims 14 to 27, characterized in that the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate to water is in the range of 1:0.8 to 1:1.2, preferably about 1:

1.

29. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine methylsulfate anhydrate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.9, and / or 26.5 (±0.2 degrees).

30. 30. The crystalline compound of claim 29, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and / or 26.5 (±0.2 degrees).

31. 31. The crystalline compound of claim 29 or 30, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.9, and 26.5 (±0.2 degrees).

32. 31. The crystalline compound of claim 29 or 30, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and 26.5 (±0.2 degrees).

33. 33. The crystalline compound of any one of claims 29 to 32, having an XRPD pattern essentially similar to the XRPD reflections of Figure 2.

34. 33. The crystalline compound of any one of claims 29 to 32, having an XRPD pattern according to the XRPD pattern of Figure 2.

35. Solids having peaks at one or more of 148.1, 146.4, 128.6, 119.9, 60.3, 48.0, and / or 32.2 ppm ± 0.2 ppm 13 The crystalline compound of any one of claims 29 to 34, characterized by a C CP / MAS NMR spectrum.

36. Solids having peaks at one or more of 148.1, 146.4, 128.6, 119.9, 60.3, 48.0, and 32.2 ppm ± 0.2 ppm 13 The crystalline compound of any one of claims 19 to 34, characterized by a C CP / MAS NMR spectrum.

37. In FIG. 13 C CP / MAS NMR spectrum essentially similar 13 37. The crystalline compound of claim 35 or 36, having a C CP / MAS NMR spectrum.

38. In FIG. 13 According to C CP / MAS NMR spectrum 13 37. The crystalline compound of claim 35 or 36, having a C CP / MAS NMR spectrum.

39. 39. The crystalline compound of any one of claims 35 to 38, further characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.3, 14.9, 17.6, 20.1, 21.5, 22.1, and 26.5 (±0.2 degrees).

40. 40. The crystalline compound of any one of claims 29 to 39, having single crystal X-ray crystallography (SXRC) parameters as shown in Table 1 for Form B.

41. 41. The crystalline compound of any one of claims 29 to 40, having a DSC curve containing an endothermic event with an onset value consisting of an unresolved endothermic-exothermic event beginning at about 247.6±2°C and a corresponding weight loss in the TGA curve.

42. 42. The crystalline compound according to any one of claims 29 to 41, wherein the molar ratio of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine to methyl sulfate is in the range of 1:1.2 to 1:0.8, preferably about 1:

1.

43. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine ethyl sulfate characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, and / or 23.4 (±0.2 degrees).

44. 44. The crystalline compound of claim 43, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, 16.3, 17.2, 18.8, 19.0, 20.1, 21.7, 23.4, and / or 26.8 (±0.2 degrees).

45. No content

46. 45. The crystalline compound of claim 43 or 44, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, and 23.4 (±0.2 degrees).

47. 47. The crystalline compound of any one of claims 43 to 46, characterized by one or more XRPD reflections at about (°2θ) 8.1, 14.6, 16.3, 17.2, 18.8, 19.0, 20.1, 21.7, 23.4, and 26.8 (±0.2 degrees).

48. 48. The crystalline compound of any one of claims 43 to 47, having an XRPD pattern essentially similar to the XRPD pattern of Figure 8.

49. 33. The crystalline compound of any one of claims 29 to 32, having an XRPD pattern according to the XRPD pattern of Figure 8.

50. 50. The crystalline compound of any one of claims 43-49, characterized by a solid state C CP / MAS NMR spectrum having peaks at one or more of 147.7, 145.8, 139.6, 138.7, 128.9, 119.5, 109.8, 63.2, 59.3, 56.6, 48.2, 31.8, and / or 17.0 ppm±0.2 ppm.

51. Solids having peaks at one or more of 147.7, 145.8, 139.6, 138.7, 128.9, 119.5, 109.8, 63.2, 59.3, 56.6, 48.2, 31.8, and 17.0 ppm ± 0.2 ppm 13 51. The crystalline compound of any one of claims 43 to 50, characterized by a C CP / MAS NMR spectrum.

52. In FIG. 13 C CP / MAS NMR spectrum essentially similar 13 The crystalline compound according to any one of claims 43 to 51, characterized in that it has a C CP / MAS NMR spectrum.

53. In FIG. 13 According to C CP / MAS NMR spectrum 13 The crystalline compound according to any one of claims 43 to 52, characterized in that it has a C CP / MAS NMR spectrum.

54. A pharmaceutical composition comprising the crystalline salt of any one of claims 12 to 53 and a pharmaceutically acceptable carrier.

55. A compound or pharmaceutical composition according to any one of claims 12 to 53 for use in the treatment of a disease selected from atopic dermatitis, itching, pruritus and various forms of urticaria.

56. 56. The compound or pharmaceutical composition of claim 55, wherein the disease is atopic dermatitis.

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