Novel crystalline forms of 1-(8-bromopyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrazin-4-yl)-n-methylazetidine-3-amine

Abstract

Provided are novel crystalline forms of 1-(8-bromopyrido [2, 3-e] [1, 2, 4] triazolo [4, 3-a] pyrazin-4-yl)-N-methylazetidine-3-amine and pharmaceutical compositions comprising the same. Also disclosed is the use of the novel polymorphs for the treatment of diseases, such as atopic dermatitis (AD), pruritus, pruritus and various forms of urticaria, such as the chronic idiopathic urticaria subtype.

Description

SUMMARY OF THE INVENTION

[0002] The present invention relates to a new crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, a pharmaceutical composition comprising the new crystalline form of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, and the use of the new crystalline form for treating diseases such as atopic dermatitis (AD), pruritus, prurigo and various forms of urticaria, such as the chronic idiopathic urticaria subtype, such as cholinergic urticaria. The present invention also provides a method for preparing the crystalline form of the present invention. BACKGROUND OF THE INVENTION

[0004] U.S. Patent No. 9,586,959 particularly relates to 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 and pharmaceutical compositions comprising the same. The patent 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.

[0005] 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine exhibits strong histamine 4 receptor inhibitory effects and shows inhibitory effects on histamine-induced infiltration of inflammatory cells such as mast cells and eosinophils. Therefore, the compound has strong anti-inflammatory and anti-itch effects and can thus be used to treat a series of diseases, such as the diseases disclosed in U.S. Patent No. 9,586,959, including AD.

[0006] Different crystalline solid forms of a compound can have different physical properties, such as, for example, chemical stability, physical stability, hygroscopicity, melting point, solubility, dissolution rate, morphology and bioavailability, which make them more or less suitable as the active ingredient selected in a pharmaceutical product.

[0007] In addition, a chemical entity can exist in several different crystalline solid forms, and these forms include different polymorphs (e.g., anhydrates) having the same total formula and different solvates (e.g., hemihydrates, monohydrates and dihydrates) of the same chemical entity that do not have the same total formula. Such crystalline solid forms have different crystal structures and different physical properties as described above. Different crystalline solid forms can be characterized by, for example, melting point, XRPD pattern, spectral features (e.g., FT-IR, Raman and 13distinguished from each other by, for example, solid state nuclear magnetic resonance (CP / MAS-NMR) and other physical and chemical properties. Chemical entities can also exist in amorphous form.

[0008] Thus, the actual crystal form selected plays an important role in the development and preparation of the active pharmaceutical ingredient. If a single crystal form is required, it is important that the crystallization process is robust and reliably produces the desired crystal form in polymorphically pure form, and that the crystal form does not change (e.g., convert to a different crystal form) during the relevant preparation process and / or during storage.

[0009] A variety of different salts of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidine have been identified. Some salts occur as anhydrates, others as monohydrates and dihydrates, and each salt exists in multiple polymorphs that interconvert when dried or lose water at relatively low temperatures, and thus they are not suitable for development as drugs.

[0010] The new crystal form according to the present invention is a crystal form 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. This new crystal form is hereinafter referred to as Form A.

[0011] Form A has thermodynamic stability up to 273 °C and is highly crystalline. Form A is also stable during a stress test at high temperature (60 °C) and high humidity (75%) for 4 weeks. SUMMARY OF THE INVENTION

[0013] The present invention relates to Crystal Form A of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine, characterized by one or more XRPD reflections at about 2θ = 7.0, 22.6, and / or 26.3 (±0.2 degrees).

[0014] The present invention also relates to a pharmaceutical composition comprising the above crystal form and a pharmaceutically acceptable carrier.

[0015] In one embodiment, the present invention relates to the above-described compound or pharmaceutical composition for the treatment of diseases selected from atopic dermatitis, pruritus, prurigo, and various forms of urticaria, including the chronic idiopathic urticaria subtype. DETAILED DESCRIPTION OF THE INVENTION

[0017] The technical problem underlying the present invention is to overcome 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 the ability to form crystals, filtration properties, solubility, thermodynamic properties, stability problems (e.g., due to water uptake), density, and transitions at different humidities and during the crystallization process (e.g., conversion to other polymorphs or hydrates / anhydrates).

[0018] Hundreds of crystallization experiments yielded multiple polymorphs of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine.

[0019] The pure forms A, E, and F were obtained, but only form A was stable during mild drying, and attempts to prepare larger amounts of pure forms E and F were unsuccessful.

[0020] Definitions

[0021] As used herein, the terms "rt" or "room temperature" indicate that the temperature applied is not critical and the exact temperature value need not be maintained. Generally, "rt" or "room temperature" is understood to mean a temperature of about 15 °C to about 25 °C [see, for example, European Pharmacopoeia 7.5, 1.2 (2012)].

[0022] As used herein, the term "solvate" describes a crystalline compound in which solvent molecules are incorporated into the lattice of the compound in a stoichiometric or non-stoichiometric manner. If the solvent molecule is water, the term "hydrate" is used herein.

[0023] 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 molecules.

[0024] 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.

[0025] An anhydrate is a crystalline form that does not contain any water in the lattice.

[0026] As used herein, the term "non-hygroscopic" indicates that the mass increase of the drug substance is less than 0.2 wt% between about 0% and 80% relative humidity.

[0027] In the context of the present invention, the term "XRPD reflection peak" refers to a specific 2Θ position in the XRPD pattern, where the signal-to-noise ratio (calculated according to Article 2.2.46 of the European Pharmacopoeia) is greater than 3 / 1. "Absence of peak" is defined herein as a peak having at most 1% (such as 0.5% or 0.2%) of the intensity of the highest peak in the XRPD of a sample of the compound of the present invention, i.e., there is no detectable XRPD peak above the background signal.

[0028] In the XRPD pattern, the main characteristics of the diffraction line curve are the 2Θ position, peak height, peak area, and shape (which are characterized by, for example, peak width or asymmetry, analytical function, empirical representation). The 2Θ position is the most important factor because, for example, the intensity will be affected by sample preparation, and the peak width will be affected by particle size. In addition to the diffraction peaks, the X-ray diffraction experiment also produces a more or less uniform background in the XRPD pattern, on which the peaks are superimposed. In addition to sample preparation, other factors also affect the background, such as the sample holder, diffuse scattering from air and equipment, and other instrument parameters (such as detector noise, general radiation from the X-ray tube, etc.). The peak-to-background ratio can be increased by minimizing the background and / or by selecting an extended exposure time.

[0029] Abbreviations

[0030] DSC: Differential Scanning Calorimetry

[0031] TGA: Thermogravimetric Analysis

[0032] XRPD: X-ray Powder Diffraction

[0033] 13 C CP / MAS NMR: 13 C Cross-Polarization Magic Angle Spinning Nuclear Magnetic Resonance

[0034] SXRD: Single Crystal X-ray Diffraction Brief Description of the Drawings

[0036] Figure 1A : XRPD pattern (3 - 45° 2θ) of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine form A

[0037] Figure 1B : XRPD pattern (3 - 30° 2θ) of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine form A

[0038] Figure 2:DSC and TGA curves of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A.

[0039] Figure 3 :ORTREP drawing of the absolute crystal structure of crystalline form A of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A.

[0040] Figure 4 :1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A 13 C CP / MAS NMR (14.1T) spectrum.

[0041] The results from single crystal structure determination are shown in Table 1.

[0042]

[0043]

[0044] Table 1. Crystal parameters from single crystal structure determination.

[0045] 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 Form A.

[0046] 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 Form A, characterized by one or more XRPD reflections at approximately (°2θ) 7.0, 22.6, and / or 26.3 (±0.2 degrees).

[0047] 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 Form A, characterized by one or more XRPD reflections at approximately (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4, and / or 26.3 (±0.2 degrees).

[0048] 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 Form A, characterized by one or more XRPD reflections at approximately (°2θ) 7.0, 22.6 and 26.3 (±0.2 degrees).

[0049] 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 Form A, characterized by one or more XRPD reflections at approximately (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4 and 26.3 (±0.2 degrees).

[0050] 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 Form A, wherein the crystalline compound has an XRPD pattern substantially similar to Figure 1A and / or the XRPD pattern in 1B.

[0051] 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 Form A, wherein the crystalline compound has an XRPD pattern according to Figure 1A and / or the XRPD pattern in 1B.

[0052] In one embodiment, crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A has a DSC and TGA curve substantially similar to that shown in Figure 2 which consists of unresolved endothermic-exothermic events and has an onset at 273.6 ± 2 °C and a corresponding weight loss in the TGA curve.

[0053] 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 Form A, wherein the crystalline compound is characterized by having one or more peaks at 149.1, 148.1, 139.9, 128.0, 119.9, 112.7, 64.6, 63.1, 61.1, 53.6, 51.7, 37.7 and / or 35.4 ppm ± 0.2 ppm in the solid state 13C CP / MAS NMR spectrum.

[0054] 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 Form A, characterized by having a Figure 4 C CP / MAS NMR spectrum substantially similar to that of 13 C CP / MAS NMR spectrum. 13 C CP / MAS NMR spectrum.

[0055] 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 Form A, characterized by having a Figure 4 C CP / MAS NMR spectrum according to that of 13 C CP / MAS NMR spectrum. 13 C CP / MAS NMR spectrum.

[0056] 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 Form A, characterized by having the above 13 C CP / MAS NMR spectrum and further characterized by one or more XRPD reflections at approximately (°2θ) 7.0, 22.6 and 26.3 and (±0.2 degrees).

[0057] 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 Form A, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters as shown in Table 1.

[0058] In a further embodiment of the present invention, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A is characterized by having single crystal parameters substantially the same as those provided in Table 1.

[0059] In a further embodiment of the present invention, 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A has a structure obtained by single crystal X-ray diffraction (SXRD) as shown in Figure 3 .

[0060] In additional embodiments, the present invention relates to pharmaceutical compositions comprising a crystalline compound as described above and a pharmaceutically acceptable carrier.

[0061] In additional embodiments, the present invention relates to a pharmaceutical composition as above for the treatment of diseases selected from atopic dermatitis, pruritus, prurigo and various forms of urticaria.

[0062] In specific embodiments, the present invention relates to a pharmaceutical composition as above, wherein the form of urticaria includes chronic idiopathic urticaria subtypes such as cholinergic urticaria.

[0063] The free base of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine can be prepared as described in U.S. Patent No. 9,586,959.

[0064] Another aspect of the present invention relates to pharmaceutical compositions comprising a crystalline compound of the present invention and at least one pharmaceutically acceptable excipient. The pharmaceutical composition may be an oral dosage form, preferably tablets and / or capsules.

[0065] Furthermore, the present invention relates to the use of the crystalline compound of the present invention for the preparation of solid medicaments.

[0066] In another embodiment, the present invention relates to solid pharmaceutical compositions comprising an effective amount of a crystalline compound of the present invention and a pharmaceutically acceptable carrier, and to a method for their preparation. Furthermore, the present invention relates to the pharmaceutical compositions and / or the crystalline compounds of the present invention for the treatment of any disease or disorder mentioned in U.S. Patent No. 9,586,959, including diseases and disorders such as atopic dermatitis (AD), pruritus, prurigo and any various types of urticaria.

[0067] The pharmaceutical compositions of the present invention comprising a crystalline compound of the present invention may also comprise one or more pharmaceutically acceptable excipients. Such excipients are preferably selected from the group consisting of diluents, sweeteners, buffers, glidants, flow agents, flavoring agents, lubricants, preservatives, surfactants, wetting agents, binders, disintegrants and thickening agents. Other excipients known in the art of pharmaceutical compositions may also be used. Furthermore, the pharmaceutical composition may comprise a combination of two or more excipients, each of which is also a member of the above group.

[0068] Suitable binders for the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention also include, for example, alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose, carboxyalkyl celluloses such as carboxymethyl cellulose, alkali metal salts of carboxyalkyl celluloses such as sodium carboxymethyl cellulose, carboxyalkyl alkyl celluloses such as carboxymethyl ethyl cellulose, carboxyalkyl cellulose esters, starches such as starch 1551, modified starches such as sodium carboxymethyl starch, pectin, chitosan derivatives such as chitosan, heparin and heparinoids, polysaccharides such as alginic acid, its alkali metal salts and ammonium salts, carrageenan, galactomannans, tragacanth, agar, gum arabic, guar gum and xanthan gum, polyacrylic acid and its salts, polymethacrylic acid and its salts, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate, polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, for example poloxamer and poloxamine, copovidone.

[0069] Suitable diluents for the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention also include, for example, calcium carbonate, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, calcium phosphate, calcium sulfate, microcrystalline cellulose (including silicified microcrystalline cellulose), powdered cellulose, glucose binders, dextrin, glucose excipients, 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) (available commercially as a co-processed spray-dried mixture of microcrystalline cellulose and colloidal silicon dioxide (98:2) (available commercially as a commercial product).

[0070] Suitable glidants for the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention also include, for example, talc, colloidal silicon dioxide, starch and magnesium stearate.

[0071] Suitable disintegrants for the pharmaceutical compositions of the present invention containing the crystalline compounds of the present invention also include, for example, starch, ion exchange resins (such as Amberlite), crosslinked polyvinylpyrrolidone, modified cellulose gums (such as crosslinked sodium carboxymethyl cellulose), sodium starch glycolate, sodium carboxymethyl cellulose, sodium dodecyl sulfate, modified corn starch, microcrystalline cellulose, magnesium aluminum silicate, alginic acid, alginates and powdered cellulose.

[0072] Suitable lubricants for the pharmaceutical compositions of the invention which also contain the crystalline compounds of the invention include, for example, magnesium stearate, calcium stearate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate and magnesium lauryl sulfate.

[0073] Some formulations, such as tablets, may contain components that have XRPD reflection peaks or broad peaks in the same position or region as the crystalline compounds of the invention. When performing XRPD experiments on formulations containing the crystalline compounds of the invention rather than on the pure crystalline salts alone, these components may hide some of the XRPD patterns or peaks of the crystalline compounds of the invention. This means that when performing XRPD experiments on formulations of crystalline compounds, not all of the XRPD reflection peaks of the crystalline compounds of the invention can always be seen.

[0074] Accordingly, in one embodiment, the invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein the pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more components that exhibit XRPD reflection peaks that include one or more XRPD reflection peaks that overlap and hide one or more XRPD reflection peaks of the crystalline compound of the invention.

[0075] 13 The same problem can occur with C CP / MAS NMR, where, for example, strong signals from the cellulose component are expected in the spectral region of 60 - 110 ppm, and peaks from the stearate will be seen in the spectral region of 15 - 40 ppm - as well as a carbonyl peak at around 172 ppm.

[0076] Accordingly, in one embodiment, the invention relates to a pharmaceutical composition comprising a crystalline compound as defined herein and a pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s), wherein the pharmaceutically acceptable vehicle, excipient or pharmaceutically acceptable carrier(s) comprises one or more components characterized by such 13 C CP / MAS NMR spectra, the 13 C CP / MAS NMR spectra may include one or more 13 C CP / MAS NMR peaks that overlap and hide one or more 13 C CP / MAS NMR peaks of the crystalline compound of the invention.

[0077] The XRPD pattern collected from 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 its salt can be compared with, for example, the XRPD pattern of Form F obtained from Example 1 and as shown in Figure 1A or as shown in Form F in 1B to test whether other crystalline forms of 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine are present. For such a comparison, Figure 1A and 1B the XRPD patterns shown in can be regarded as the XRPD patterns of 100% pure crystalline compounds of Form A or B of the present invention.

[0078] Description of the test methods for characterizing the polymorphs disclosed herein

[0079] X-ray powder diffraction (XRPD)

[0080] XRPD patterns were collected using a PANalytical X’pert PRO MPD diffractometer, with incident Cu Kα radiation and operating at 45 kV and 40 mA. The XRPD patterns were collected in the 2θ range from 3 to 45 degrees, with a step size of 0.0066°, a counting time of 148.93 s, and in transmission geometry. In the incident beam path, an elliptically graded multilayer mirror, a 4 mm fixed mask, a 1° fixed anti-scatter slit, and 1 / 2 ° fixed divergence slits were placed to focus the Cu Kα X-ray beam through the sample and onto the detector. In the diffracted beam path, a long anti-scatter extension and a 2 mm anti-scatter slit were placed to minimize the background generated by air. In addition, 0.02 rad Soller slits were placed in both the incident and diffracted beam paths to minimize broadening caused by axial divergence.

[0081] The sample was placed on a 3 μm thick foil on a 96-well high-throughput plate stage and oscillated in the X direction for better particle statistics. The diffraction pattern was collected using a PIXel RTMS detector with an effective length of 3.347° and located 240 mm from the sample.

[0082] Thermogravimetric analysis (TGA):

[0083] The TGA experiment was carried out using a TGA550 instrument from TA Instruments. Approximately 1 - 10 mg of the sample was loaded into a ceramic pan for measurement. The sample temperature was increased from 25 to 500 °C at a rate of 10 °C / min. Nitrogen with a flow rate of 50 mL / min was used as the purge gas.

[0084] Differential Scanning Calorimetry (DSC)

[0085] DSC: The heating rate was 10 °C / min under a nitrogen atmosphere. Approximately 1 - 2 mg of the sample was loaded into an open aluminum pan for measurement. Instrument Q20 from TA Instruments.

[0086] Single - crystal X - ray diffraction

[0087] Data were collected using a SuperNova Dual diffractometer with an Atlas CCD area detector (temperature: 120(2) K; Cu Kα radiation Data collection method: ω - scan). Further details can be found in Table 1. Programs used for structure solution: CrysAlisPro, Agilent Technologies, version 1.171.37.34 (CrysAlis171.NET release on May 22, 2014), ShelXL (Sheldrick, 2008) for structure refinement, and Olex2 (Dolomanov et al., 2009) for ORTEP drawings.

[0088] Solid - state NMR spectroscopy

[0089] During a 45.9 - ms acquisition time, using a 6 - ms contact time, a 64 - s recycle delay, a 14.1 - kHz rotation rate, 256 scans, and high - power 1 H decoupling, recorded at 298 K on a Bruker AvanceIII HD 600 NMR spectrometer (14.1 T) equipped with a 4 - mm dual - tuned ( 1 H - 13 C)CMP probe. The 13C CP / MAS NMR spectra were recorded. Before Fourier transformation, the time - domain data (free induction decay) were apodized with a 5 - Hz Lorentzian linebroadening. All spectra were referenced to the chemical shift of the carbonyl group in α - glycine at 176.5 ppm (external sample). 13

[0090] ​The given error ranges for the spectral characteristics in the present application, including those in the claims, can more or less depend on factors well-known to the person skilled in the art of spectroscopy and can depend, for example, on sample preparation such as particle size distribution, or if the crystal form is part of the formulation, on the composition of the formulation, as well as on instrument fluctuations and other factors. Examples

[0091] Example 1

[0092] 11 mg 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 to a test tube or a 4 ml glass vial, and 2 mL of a CHCl 3 :THF (1:3) mixture was added. The solution was heated with a heat gun until all the solid material was visually dissolved. The solution was then filtered through a 0.45 μm syringe filter. The filtered solution was placed in a fume cup with a loose lid on the table to allow crystallization during the slow evaporation of the solvent system. The crystals obtained had a rhombic shape. The XRPD pattern of Form A is shown in Figure 1A and 1B below.

Claims

1. Crystalline 1-(8-bromopyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-4-yl)-N-methylazetidin-3-amine Form A, characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6, and / or 26.3 (±0.2 degrees).

2. The crystalline compound according to claim 1, characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4, and / or 26.3 (±0.2 degrees).

3. The crystalline compound according to any one of claims 1-2, characterized by one or more XRPD reflections at about 7.0, 22.6, and 26.3 (±0.2 degrees).

4. The crystalline compound according to any one of claims 1-3, characterized by one or more XRPD reflections at about (°2θ) 7.0, 14.3, 15.8, 22.6, 23.4, and 26.3 (±0.2 degrees).

5. The crystalline compound according to any one of claims 1-4, wherein the crystalline compound has an XRPD pattern substantially similar to the XRPD pattern in Figure 1A or 1B.

6. The crystalline compound according to any one of claims 1-4, wherein the crystalline compound has an XRPD pattern according to the XRPD pattern in Figure 1A or 1B.

7. The crystalline compound according to any one of claims 1-6, wherein the crystalline compound is characterized by having a solid state 13 C CP / MAS NMR spectrum with peaks at one or more of 149.1, 148.1, 139.9, 128.0, 119.9, 112.7, 64.6, 63.1, 61.1, 53.6, 51.7, 37.7 and / or 35.4 ppm ± 0.2 ppm. 13 C CP / MAS NMR spectrum.

8. The crystalline compound according to claim 7, characterized by having a substantially similar to that in Figure 4 13 C CP / MAS NMR spectrum 13 C CP / MAS NMR spectrum.

9. The crystalline compound according to claim 7, characterized by Having a 13 C CP / MAS NMR spectrum according to FIG. 4 13 C CP / MAS NMR spectrum.

10. The crystalline compound according to any one of claims 7-9, further characterized by one or more XRPD reflections at about (°2θ) 7.0, 22.6, and 26.3 (±0.2 degrees).

11. The crystalline compound according to any one of claims 1-10, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters as shown in Table 1.

12. The crystalline compound according to any one of claims 1-10, wherein the crystalline compound is characterized by having single crystal X-ray crystallography (SXRC) parameters substantially the same as the parameters provided in Table 1.

13. The crystalline compound according to any one of claims 1-12, wherein the crystalline compound has DSC and TGA curves substantially similar to those shown in Figure 2, which consist of unresolved endothermic-exothermic events, having an onset at 273.6 ± 2 °C and a corresponding weight loss in the TGA curve.

14. A pharmaceutical composition comprising the crystalline salt according to any one of the preceding claims and a pharmaceutically acceptable carrier.

15. The compound or pharmaceutical composition according to any one of the preceding claims for use in the treatment of a disease selected from atopic dermatitis, pruritus, prurigo, and various forms of urticaria.

16. The compound or pharmaceutical composition for use according to claim 15, wherein the disease is atopic dermatitis.

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