Novel salt of imidazo[1,2-a]pyridine compound, crystalline form thereof, and preparation method

Abstract

In a novel salt of imidazo[1,2-a]pyridine compound of the present invention, a Crystalline Form thereof, and a method for preparing the same, the novel salt of imidazo[1,2-a]pyridine compound is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

Description

Novel salt of imidazo[1,2-A]pyridine compound, crystal form thereof and preparation method thereof

[0001] The present invention relates to a novel salt of an imidazo[1,2-a]pyridine compound, its crystal form, and a method for preparing the same.

[0002] Gastrointestinal inflammatory diseases or acid-related diseases, such as peptic ulcer, gastric / duodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), and non-erosive reflux disease (NERD), are the most common digestive diseases that affect most people in Korea and around the world.

[0003] To solve the problems of conventional proton pump inhibitors (PPIs), H + / K + -K of ATPase + There is growing interest in and need for potassium-competitive acid blockers (P-CABs, acid pump antagonists), drugs that reversibly bind to the binding site and inhibit acid secretion through potassium-competitive inhibition. In particular, unlike irreversible proton pump inhibitors (PPIs), reversible proton pump inhibitors (P-CABs) exhibit rapid onset of action due to their mechanism of action, are easy to take regardless of mealtime, and are expected to be highly effective in alleviating nocturnal symptoms, a problem with irreversible PPIs.

[0004] Meanwhile, to be considered as a candidate for development as a pharmaceutical, a compound must possess not only desirable biological properties but also physical properties that facilitate its use in the preparation of pharmaceutical compositions. Furthermore, such compounds should preferably possess a solid phase, allowing for easy preparation and stable formulation.

[0005] Accordingly, the inventors of the present invention have conducted extensive research efforts to discover a form of the imidazo[1,2-a]pyridine compound that is stable in various aspects and can be applied industrially for pharmaceutical purposes, and as a result, they have confirmed a novel salt that exhibits remarkable effects that could not be predicted, thereby completing the present invention.

[0006] Prior art literature

[0007] Patent documents

[0008] Republic of Korea Patent Publication No. 10-1777971

[0009] One object of the present invention is to provide a novel salt of an imidazo[1,2-a]pyridine compound.

[0010] Another object of the present invention is to provide a crystalline form of a novel salt of an imidazo[1,2-a]pyridine compound.

[0011] Another object of the present invention is to provide a method for preparing a novel salt of an imidazo[1,2-a]pyridine compound.

[0012] Novel salts of imidazo[1,2-a]pyridine compounds

[0013] (1) The novel salt of the imidazo[1,2-a]pyridine compound according to the present invention is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

[0014] Hereinafter, in this specification, the terms “Chemical Formula I citrate salt” or “citrate salt” all mean “azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.”

[0015] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is represented by the following chemical formula I.

[0016] [Chemical Formula I]

[0017]

[0018] (2) In the above (1), in the citric acid salt of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone, the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be 1:0.3 to 1:1.3. For example, the molar ratio may be 1:0.5 to 1:1.

[0019] (3) In the above (1) or (2), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt of the present invention can be represented by the following chemical formula II.

[0020] [Chemical Formula II]

[0021]

[0022] In the above chemical formula II, n represents 0.3 to 1.3.

[0023] In one embodiment, n in the above formula II may be 0.5 to 1.

[0024] (4) In any one of the above (1) to (3), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be an anhydride.

[0025] (5) In any one of the above (1) to (4), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be crystalline or amorphous.

[0026] (6) In any one of the above (1) to (5), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be in an anhydrous crystalline form.

[0027] (7) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be crystalline Form A exhibiting a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 5.46°, 7.14°, 10.61°, 11.82°, 18.27°, and 25.77°.

[0028] (8) In the above (7), the powder X-ray diffraction pattern of crystalline form A may further include at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79°, and 24.21°.

[0029] (9) In the above (7) or (8), crystalline form A may have differential scanning calorimetry (DSC) endothermic peaks at 88.69°C, 135.61°C, and 154.84°C (±0.5°C) when the heating rate is 10°C / min.

[0030] (10) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be crystalline Form B exhibiting a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13° in 2θ (±0.2°) values ​​of the powder X-ray diffraction pattern.

[0031] (11) In the above (10), crystalline form B may have a differential scanning calorimetry (DSC) endothermic peak at 144.57°C (±0.5°C) when the heating rate is 10°C / min.

[0032] (12) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be crystalline form C1 exhibiting a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 7.35°, 15.31°, 17.42°, and 22.26°.

[0033] (13) In the above (12), the powder X-ray diffraction pattern of crystalline form C1 may further include at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22°, and 26.00°.

[0034] (14) In the above (12) or (13), the crystalline form C1 may have a differential scanning calorimetry (DSC) endothermic peak at 168.93°C (±0.5°C) when the heating rate is 10°C / min.

[0035] (15) In any one of the above (1) to (6), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may be crystalline form C2 exhibiting a powder X-ray diffraction pattern including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 5.63°, 8.90°, 9.51°, and 13.01°.

[0036] (16) In the above (15), the powder X-ray diffraction pattern of crystalline form C2 may further include at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 12.31°, 14.34°, 14.80°, 18.38°, 18.75°, and 19.62°.

[0037] (17) In the above (15) or (16), the crystalline form C2 may have a differential scanning calorimetry (DSC) endothermic peak at 161.48°C (±0.5°C) when the heating rate is 10°C / min.

[0038] (18) In any one of the above (1) to (5), the amorphous form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt may have a differential scanning calorimetry (DSC) endothermic peak at 161.42°C (±0.5°C) when the heating rate is 10°C / min.

[0039] (19) In any one of the above (1) to (11), the crystalline form A and the crystalline form B of the citric acid salt according to the present invention may each have a molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid of 1:0.5.

[0040] (20) In any one of the above (1) to (6) and (12) to (17), the crystalline forms C1 and C2 of the citric acid salt according to the present invention may have a molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid of 1:1.

[0041] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention exhibits unexpectedly excellent bioavailability, and thus can be used as an active ingredient of a pharmaceutical composition to exhibit excellent effects in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0042] In addition, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention has the advantage of being easily manufactured by a simple process and being obtained with a high purity and a high yield of 90% or more.

[0043] Furthermore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention produces various crystal forms due to slight differences in reaction temperature, reaction speed, etc. even under similar solvent conditions, and these crystal forms have excellent photostability, heat / moisture stability, long-term storage stability, etc., and can be usefully utilized in the formulation of pharmaceuticals.

[0044] The pharmaceutical composition of the present invention comprises azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt in a therapeutically effective amount.

[0045] The pharmaceutical composition of the present invention can treat or prevent a disease selected from the group consisting of peptic ulcer, gastric / duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcer, Helicobacter pylori infection, functional dyspepsia, Zollinger-Ellison syndrome, gastritis, and gastroesophageal reflux disease (GERD) and non-erosive reflux disease (NERD).

[0046] Method for preparing a novel salt of imidazo[1,2-a]pyridine compound

[0047] (21) The method for producing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention includes a step of reacting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone with citric acid to produce a citric acid salt.

[0048] (22) In the step of preparing the citric acid salt according to the above (21), azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid can be reacted in at least one solvent selected from among alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and purified water.

[0049] (23) In the above (21) or (22), azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be synthesized according to the following reaction scheme 1.

[0050] [Reaction Formula 1]

[0051]

[0052] (24) In the reaction scheme 1 according to the above (23), 8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid can be obtained as described in Korean Patent Publication No. 10-1777971, and the specific process of the reaction scheme 1 can also be performed according to the contents disclosed therein.

[0053] (25) In any one of the above (21) to (24), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be a non-solvate, a solvate, or a mixture thereof.

[0054] (26) In any one of the above (23) to (25), the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to the above reaction scheme 1 can be crystallized in an alcohol solvent having 1 to 3 carbon atoms, vacuum-dried, and the obtained solvate, non-solvate, or mixture thereof can be reacted with citric acid. The solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be obtained by vacuum-drying at about 20°C or higher to about 35°C or lower. The unsolvated product of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone can be obtained by vacuum drying at a temperature of about 45°C or higher and about 60°C or lower. The mixture of the solvated product and the unsolvated product can be obtained by vacuum drying at a temperature of about 35°C or higher and about 45°C or lower.

[0055] (27) In any one of the above (21) to (26), in the step of preparing the citric acid salt, a citric acid salt containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:0.3 to about 1:1.3 can be prepared. For example, in the step of preparing the citric acid salt, a citric acid salt containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:1 or about 1:0.5 can be prepared.

[0056] (28) In any one of the above (21) to (27), the step of preparing the citric acid salt may be performed by mixing a solvate, a non-solvate or a mixture thereof of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a weight ratio of about 1:1.3 to about 1:0.3.

[0057] (29) In any one of the above (21) to (28), the step of preparing the citric acid salt may include a step of mixing a first solution containing a solvate, a non-solvate or a mixture thereof of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent, and a second solution containing citric acid and a second solvent.

[0058] (30) In the above (29), the first solution may be first stirred in the reactor and then the second solution may be added, or the second solution may be first stirred in the reactor and then the first solution may be added.

[0059] (31) In the above (29) or (30), the first solvent and the second solvent may each independently include at least one solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, NMP, and purified water.

[0060] (32) In any one of the above (29) to (31), the first solvent may be a single solvent of purified water, or a mixed solvent comprising at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, and NMP, together with purified water. At this time, the second solvent may be a single solvent of purified water, or a mixed solvent comprising at least one organic solvent selected from alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, THF, dichloromethane, DMF, and NMP, together with purified water. In the first and second solvent conditions, the citric acid salt according to the present invention may be in crystalline form A.

[0061] (33) In any one of the above (29) to (31), the first solvent may be an organic solvent, and the second solvent may be a single solvent of purified water, or a mixed solvent containing one or more organic solvents together with purified water. Under the first and second solvent conditions, the citric acid salt according to the present invention may be in crystalline form A.

[0062] (34) In any one of the above (29) to (31), the first solvent is an organic solvent, the second solvent is an organic solvent, and the first and second solvents may be the same. Under the condition that the first and second solvents are alcohols having 1 to 3 carbon atoms as organic solvents, the citric acid salt according to the present invention may be in crystalline form B.

[0063] (35) In any one of the above (29) to (31), the first solvent may be acetone or a mixed solvent in which acetone is mixed with at least one other organic solvent other than acetone, and the second solvent may be acetone. Under the first and second solvent conditions, the citric acid salt of the present invention may be in crystalline form C1 or crystalline form C2.

[0064] (36) In any one of the above (21) to (33), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid can be reacted at about 10°C to about 30°C, preferably at about 20°C to about 25°C, and the subsequent stirring process can also be continuously performed at the same temperature. Under the above temperature conditions, the citric acid salt according to the present invention can be in crystalline form A.

[0065] (37) In any one of the above (21) to (31) and (34), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be reacted at about 10°C to about 30°C, preferably about 20°C to about 25°C, and then cooled and stirred at about 0°C to about 10°C, preferably about 0°C to about 5°C. Under the above process conditions, the citric acid salt according to the present invention may be in crystalline form B.

[0066] (38) In any one of the above (21) to (31) and (35), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid may be reacted at about 45°C to about 60°C, preferably about 50°C to about 55°C, and then cooled and stirred at about 10°C to about 30°C, preferably about 20°C to about 25°C. Under the above process conditions, the citric acid salt according to the present invention may be in crystalline form C1.

[0067] (39) In any one of the above (21) to (31) and (35), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid can be reacted at about 10°C to about 30°C, preferably about 20°C to about 25°C, and then cooled and stirred at about 0°C to about 10°C, preferably about 0°C to about 5°C. Here, the time for adding citric acid to azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone at about 10°C to about 30°C can be performed within a short period of time, such as within 15 minutes, preferably within 10 minutes. Under the above process conditions, the citric acid salt can be obtained in the form of crystalline C1.

[0068] (40) In any one of the above (21) to (31) and (35), in the step of preparing the citric acid salt, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid are reacted at about 10°C to about 30°C, preferably about 20°C to about 25°C, and then heated and stirred at about 45°C to about 60°C, preferably about 50°C to about 55°C, and then cooled and stirred at about 10°C to about 30°C, preferably about 20°C to about 25°C. Here, the time for adding citric acid to azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone may be at least 30 minutes, preferably at least 60 minutes. Under the above process conditions, the citric acid salt according to the present invention may be in crystalline form C2.

[0069] (41) In any one of the above (21) to (40), the step of preparing the citric acid salt may include the steps of filtering the solid produced by the reaction of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid, i.e., the citric acid salt; washing; and drying. The filtering step and the washing step may each be performed by a method performed in a typical salt preparation. The drying step may be performed at about 35°C to about 50°C, preferably about 35°C to about 45°C, and may be performed by vacuum drying or nitrogen drying.

[0070] In the novel salt of the imidazo[1,2-a]pyridine compound of the present invention, its crystal form and preparation method, the citrate salt of the imidazo[1,2-a]pyridine compound of the present invention exhibits unexpectedly excellent bioavailability, and thus can be used as an active ingredient of a pharmaceutical composition to exhibit excellent effects in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0071] In addition, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention has the advantage of being easily manufactured by a simple process and being obtained with a high purity and a high yield of 90% or more.

[0072] Furthermore, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention produces various crystal forms due to slight differences in reaction temperature, reaction speed, etc. even under similar solvent conditions, and these crystal forms have excellent photostability, heat / moisture stability, long-term storage stability, etc., and can be usefully utilized in the formulation of pharmaceuticals.

[0073] FIG. 1, FIG. 2 and FIG. 3 are drawings showing the XRD, DSC and TGA analysis results of crystalline form A of citric acid salt according to the present invention, respectively.

[0074] FIG. 4, FIG. 5 and FIG. 6 are drawings showing the XRD, DSC and TGA analysis results of the crystalline form B of the citric acid salt according to the present invention, respectively.

[0075] FIG. 7, FIG. 8 and FIG. 9 are drawings showing the XRD, DSC and TGA analysis results of the crystalline form C1 of the citric acid salt according to the present invention, respectively.

[0076] Figures 10, 11 and 12 are drawings showing the XRD, DSC and TGA analysis results of the crystalline form C2 of the citric acid salt according to the present invention, respectively.

[0077] FIG. 13, FIG. 14 and FIG. 15 are drawings showing the results of XRD, DSC and TGA analysis of the amorphous citric acid salt according to the present invention, respectively.

[0078] Figure 16 is a drawing showing the results of XRD analysis of the citric acid salt according to the present invention after 36 months of storage.

[0079] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning within the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0080] <Measurement method>

[0081] The following measurement method is commonly applied to each of the embodiments according to the present invention.

[0082] 1. X-ray powder diffraction (XPRD)

[0083] X-ray powder diffraction patterns were obtained using a solid-state detector with a D8 Focus (Bruker ASX) over the range of diffraction angles (2θ) from 2° to 40° with a step size of 0.02°.

[0084] 2. Thermal analysis (DSC)

[0085] Differential scanning calorimetry (DSC) was performed using a DSC 8000 (PerkinElmer). Samples were evaluated using a linear heating ramp at 10°C / min over the range of 30°C to 300°C.

[0086] 3. Thermogravimetric analysis (TGA)

[0087] Thermogravimetric analysis was performed using a TGA 8000 (PerkinElmer) at 30°C to 900°C, with 0.5 mg to 2 mg of sample weighed in a ceramic crucible and measured at 5°C / min.

[0088] 4. NMR analysis

[0089] Nuclear magnetic resonance (NMR) analysis was performed using a Varian Mercury 400.

[0090] 5. Moisture content measurement / analysis

[0091] The moisture content of the obtained sample was measured using an 870KF Titrino Plus (Metrohm) Karl-Fischer moisture meter.

[0092] Manufacturing Example 1: Synthesis of Compound I

[0093] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was synthesized in the same manner as the preparation method of compound Example 6 of Korean Patent Publication No. 10-1777971.

[0094] 1 H NMR (400 MHz, CDCl3); δ7.63(d,J=1.2 Hz, 1H), 7.13(dd,J=8.4, 6.8 Hz, 1H), 7.06-7.04(m, 2H), 6.42(d,J=1.2 Hz, 1H), 4.86-4.84(m, 1H), 4.41-4.28(m, 4H), 4.37(d,J=4.4 Hz, 2H), 3.75-3.69(m, 1H), 2.43-2.34(m, 13H)

[0095] Manufacturing Example 2: Preparation of a solvate of compound I

[0096] The azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained in Manufacturing Example 1 was crystallized in an alcohol solvent (isopropyl alcohol, IPA) and vacuum-dried at about 30°C to 35°C to obtain a solvate of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone.

[0097] Example 1(1): Preparation of Compound I Citrate Salt - Crystalline Form A

[0098] 10 g of the solvate of compound I obtained in the above Preparation Example 2 and 211 g of purified water or a mixed solvent (dichloromethane, DMF, NMP, or acetone) of purified water were added to a reactor, and stirred at 20 to 25°C for 10 minutes. Next, a solution of 42.3 g of purified water in 4.9 g of citric acid was added at about 20 to 25°C, and the formation of a solid was confirmed. The mixture was stirred at the same temperature for 2 hours, and the formed solid was filtered, washed with 25.4 g of purified water, and dried under vacuum or nitrogen at about 40°C to prepare 9.70 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0099] Example 1(2): Preparation of Compound I Citrate Salt - Crystalline Form A

[0100] A solution of 9.8 g of citric acid dissolved in 16.9 g of purified water or a mixed solvent of purified water (acetone, DMF, or NMP) was added to the reactor, and the mixture was stirred at 20 to 25°C for 10 minutes. Thereafter, a solution of 90 g of dichloromethane dissolved in 20 g of the solvate of compound I obtained in Preparation Example 2 was added at the same temperature, and the formation of a solid was confirmed. The mixture was stirred continuously at the same temperature for 2 hours, and the formed solid was filtered, washed with 50.0 g of purified water, and then dried under vacuum or nitrogen at about 40°C to prepare 19.4 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0101] Analysis 1 - XRD, DSC, and TGA measurements of crystalline form A

[0102] Referring to FIG. 1 and Table 1 below, the 2θ values ​​(unit: °) of the XRD pattern of crystalline Form A according to the present invention can be confirmed. Specifically, the XRD pattern of crystalline Form A according to the present invention includes diffraction peaks having 2θ values ​​of 5.46°, 7.14°, 10.61°, 10.93°, 11.82°, 13.11°, 14.15°, 15.84°, 16.35°, 18.27°, 19.79°, 24.21°, and 25.77°.

[0103] Referring to Figure 2, crystalline form A shows endothermic peaks in DSC at 88.69°C, 135.61°C, and 154.84°C.

[0104] Referring to Fig. 3, the results measured by TGA confirm that crystalline form A decomposes in three stages. Specifically, decomposition occurred at approximately 56.98°C to 72.37°C in the first stage, approximately 161.59°C to 196.61°C in the second stage, and approximately 301.27°C to 350.19°C in the third stage, and the maximum decomposition inflection points were confirmed at approximately 67.85°C, 179.58°C, and 330.88°C, respectively.

[0105] Meanwhile, through the moisture content, it can be confirmed that crystalline form A is anhydrous.

[0106] In addition, it was confirmed that the crystalline form A according to the present invention is a combination of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:0.5.

[0107] [Table 1]

[0108]

[0109] Example 2: Preparation of Compound I Citrate Salt - Crystalline Form B

[0110] 166.2 g of IPA and 10 g of the solvate of compound I obtained in Preparation Example 2 were added to the reactor, and stirred for 10 minutes. Subsequently, a solution of 33.2 g of IPA dissolved in 4.9 g of citric acid was added at 20 to 25°C, and the formation of a solid was confirmed. The mixture was stirred continuously at the same temperature for 1 hour, cooled to 0 to 5°C, and stirred for an additional 1 hour. The formed solid was filtered and washed with 19.9 g of IPA, and 9.63 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate was obtained.

[0111] Analysis 2 - XRD, DSC, and TGA measurements of crystalline form B

[0112] Referring to FIG. 4 and Table 2 below, the 2θ values ​​(unit: °) of the XRD pattern of crystalline Form B according to the present invention can be confirmed. Specifically, the XRD pattern of crystalline Form B according to the present invention includes diffraction peaks having 2θ values ​​of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13°.

[0113] Referring to Figure 5, the endothermic peak of crystalline form B appears at 144.57°C in DSC.

[0114] Referring to Fig. 6, the TGA analysis results confirm that crystalline form B decomposes in two stages. Specifically, crystalline form B decomposes at about 163.24°C to 196.32°C in the first stage and about 305.85°C to 342.24°C in the second stage, and the maximum inflection points of decomposition are confirmed at about 180.52°C and 331.48°C, respectively.

[0115] Meanwhile, through the moisture content, it can be confirmed that crystalline form B is anhydrous.

[0116] In addition, it was confirmed that the crystalline form B according to the present invention is azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid combined in a molar ratio of about 1:0.5.

[0117] [Table 2]

[0118]

[0119] Example 3(1): Preparation of Compound I Citrate Salt - Crystalline Form C1

[0120] 167.2 g of acetone and 10 g of the solvate of compound I obtained in Preparation Example 2 were added to a reactor, heated to 50°C to 55°C, and stirred for 10 minutes. Thereafter, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was added, stirred at the same temperature for 1 hour, cooled to 20°C to 25°C, and stirred for an additional hour. The resulting solid was filtered, washed with 20.1 g of acetone, and dried under vacuum at about 40°C to obtain 11.75 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0121] Examples 3(2) to 3(4): Preparation of compound I citrate salt - crystalline form C1

[0122] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salts according to Examples 3(2) to 3(4) of the present invention were obtained by a process substantially the same as that for producing compound I citrate salt described in Example 3(1), except that the solvents shown in Table 3 below were used as a mixed solvent together with acetone as a solvent added to the reactor together with the solvate.

[0123] [Table 3]

[0124]

[0125] Example 3(5): Preparation of Compound I citrate salt - Crystalline form C1

[0126] Acetone (167.2 g) or dichloromethane (32.1 g) and the solvate of compound I obtained in Preparation Example 2 (10 g) were added to a reactor, and stirred at 10°C to 30°C for 10 minutes. Thereafter, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was added within 10 minutes, and stirred at the same temperature for 1 hour. Subsequently, the mixture was cooled to 0°C to 5°C and stirred for an additional hour. The resulting solid was filtered, washed with 20.1 g of acetone, and dried under vacuum at about 40°C to obtain 11.74 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0127] Analysis 3 - XRD, DSC, and TGA measurements of crystalline C1

[0128] Referring to FIG. 7 and Table 4 below, the 2θ values ​​(unit: °) of the XRD pattern of the crystalline form C1 of the present invention can be confirmed. Specifically, the XRD pattern of the crystalline form C1 according to the present invention includes diffraction peaks having 2θ values ​​of 7.35°, 10.23°, 12.90°, 14.68°, 15.31°, 15.97°, 17.42°, 18.21°, 21.22°, 22.26°, and 26.00°.

[0129] Referring to Figure 8, the crystalline form C1 exhibits an endothermic peak in DSC at 168.93°C.

[0130] Referring to Figure 9, the TGA analysis results confirm that crystalline C1 decomposes in two stages. Specifically, crystalline C1 decomposes at approximately 172.76°C to 192.20°C in the first stage and approximately 297.93°C to 337.46°C in the second stage, and the maximum decomposition inflection points are confirmed at 178.36°C and 324.77°C, respectively.

[0131] Meanwhile, through the moisture content, it can be confirmed that the crystalline C1 is anhydrous.

[0132] In addition, it was confirmed that the crystalline form C1 according to the present invention is a combination of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:1.

[0133] [Table 4]

[0134]

[0135] Example 4(1): Preparation of Compound I Citrate Salt - Crystalline Form C2

[0136] 167.2 g of acetone and 10 g of the solvate of compound I obtained in Preparation Example 2 were added to a reactor, and the mixture was stirred at 20°C to 25°C for 10 minutes. Thereafter, a solution of 33.4 g of acetone dissolved in 4.9 g of citric acid was slowly added dropwise over 60 minutes, and the mixture was stirred at the same temperature for 1 hour. Subsequently, the mixture was heated to 50°C to 55°C and stirred for an additional hour. The mixture was cooled to 20°C to 25°C and stirred for an additional hour. The resulting solid was filtered, washed with 20.1 g of acetone, and dried under vacuum at 40°C to obtain 11.76 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0137] Examples 4(2) to 4(4): Preparation of compound I citrate salt - crystalline form C2

[0138] Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salts according to Examples 4(2) to 4(4) of the present invention were obtained by a process substantially the same as that for producing citric acid salts described in Example 4(1), except that the solvents shown in Table 5 below were used as a mixed solvent together with acetone as a solvent added to the reactor together with the solvate.

[0139] [Table 5]

[0140]

[0141] Analysis 4 - XRD, DSC, and TGA measurements of crystalline C2

[0142] Referring to FIG. 10 and Table 6 below, the 2θ values ​​(unit: °) of the XRD pattern of the crystalline form C2 of the present invention can be confirmed. Specifically, the XRD pattern of the crystalline form C2 according to the present invention includes diffraction peaks having 2θ values ​​of 5.63°, 8.90°, 9.51°, 12.31°, 13.01°, 14.34°, 14.80°, 18.38°, 18.75°, and 19.62°.

[0143] Referring to Figure 11, the endothermic peak of DSC of crystalline form C2 appears at 161.48 ℃.

[0144] Referring to Figure 12, the TGA analysis results confirm that crystalline C2 decomposes in two stages. Specifically, crystalline C2 decomposes at approximately 166.37°C to 191.88°C in the first stage and approximately 282.15°C to 311.08°C in the second stage, and the maximum inflection points of decomposition are confirmed at 173.44°C and 304.81°C, respectively.

[0145] In addition, it was confirmed that the crystalline form C2 according to the present invention is a combination of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in a molar ratio of about 1:1.

[0146] [Table 6]

[0147]

[0148] Example 5(1): Preparation of Compound I Citrate Salt - Amorphous

[0149] 237.6 g of methanol was added to 10 g of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt prepared according to Example 3(1) in a reactor, and the mixture was stirred at 20°C to 25°C for 20 minutes to dissolve. Thereafter, the resulting solid was concentrated and vacuum-dried at about 40°C to obtain 9.8 g of amorphous azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

[0150] Examples 5(2) and 5(3): Preparation of compound I citrate salt - amorphous

[0151] An amorphous form of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Examples 5(2) and 5(3) of the present invention was obtained by a process substantially the same as that for preparing compound I citrate salt described in Example 5(1), except that an alcohol solvent shown in Table 7 below was used instead of methanol.

[0152] [Table 7]

[0153]

[0154] Analysis 5 - DSC and TGA measurements of amorphous

[0155] Referring to FIG. 13, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Examples 5(1) to 5(3) of the present invention is amorphous.

[0156] Referring to Figure 14, the amorphous compound I of the present invention exhibits an endothermic peak in DSC at 161.42°C.

[0157] Referring to Fig. 15, the TGA analysis results confirm that the amorphous form of the present invention decomposes in three stages. Specifically, the amorphous form decomposes in the first stage at about 79.55°C to 118.51°C, in the second stage at about 165.24°C to 190.12°C, and finally in the third stage at about 289.01°C to 333.88°C, and the maximum decomposition inflection points are confirmed at 105.71°C, 175.22°C, and 315.61°C, respectively.

[0158] Meanwhile, through the moisture content, it can be confirmed that the amorphous is also anhydrous.

[0159] Experimental Example 1: Bioavailability Evaluation

[0160] The bioavailability of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate according to Example 4(1) of the present invention and azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained according to Preparation Example 1 as a comparative example was evaluated. The specific pharmacodynamic experiment and evaluation method are as follows.

[0161] <Medication and Blood Collection>

[0162] Fasted male beagle dogs were orally administered 10 mg / kg using capsules, and blood samples were collected at 0.08, 0.25, 0.5, 1, 3, 5, 8, and 24 hours after administration. 3 ml of blood was collected from the jugular vein, centrifuged to separate plasma, and stored frozen in an ultra-low temperature freezer until analysis.

[0163] <Plasma pretreatment>

[0164] Plasma pretreatment was performed using protein precipitation. 100 μl of plasma sample was mixed with 300 μl of acetonitrile containing an internal standard (200 ng / ml carbamazepine). After thorough mixing, the sample was centrifuged at 12,000 rpm for 10 min. The supernatant was transferred to an analytical vial and injected into LC-MS / MS to analyze the blood concentration of compounds.

[0165] <LC-MS / MS 분석 조건>

[0166]

[0167] Pharmacodynamic evaluation

[0168] Time to peak blood concentration (T max ), peak blood concentration (C max ), area under the curve (AUC) 0-t , AUC 0-inf ) parameters were obtained using PK Solution. The results are shown in Table 8 below.

[0169] [Table 8]

[0170]

[0171] Referring to Table 8 above, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention reached the maximum blood concentration in a significantly faster time than the comparative example, Compound I (free base), and it can be confirmed that the Cmax was significantly increased by more than 11 times compared to the comparative example, and the AUC was also significantly improved by more than 5 times compared to the comparative example. That is, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention exhibits a significantly superior bioavailability that significantly exceeds the level that can be typically predicted.

[0172] Through this, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention exhibits very excellent bioavailability that the inventors could not have predicted, and is expected to exhibit very excellent effects in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases when used as an active ingredient of a pharmaceutical composition.

[0173] Experimental Example 2: Photostability Evaluation

[0174] For the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Example 4(1) of the present invention, the sample was spread thinly on a petri dish and then irradiated using a photostability chamber (CARON 6542-2) at 25°C and 60% humidity with a visible light intensity of 35k lux so that the total irradiation dose was 1200k lux. After spreading the sample thinly on a petri dish, the sample was irradiated using a photostability chamber (CARON 6542-2) at 25°C and 60% humidity with a visible light intensity of 35W so that the total irradiation dose was 200 watt, and then discoloration was observed with the naked eye. The results are shown in Table 9 below. It is judged to be suitable if it maintains a white to slightly yellowish white powder form as a solid.

[0175] [Table 9]

[0176]

[0177] Referring to Table 9, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention maintains a color suitable for the physical standard of off-white or off-white even when irradiated with ultraviolet and visible light. In this way, it can be seen that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention has excellent photostability.

[0178] Experimental Example 3: Short-term storage stability (heat / moisture) evaluation

[0179] The purity of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Example 4(1) of the present invention was measured, and then the salt was left at 60°C for 4 days before being measured for purity. The purity measurement was performed using HPLC. In addition, the purity of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Example 4(1) of the present invention was measured after being left at 75 to 90% humidity (RH) for 2 days. The results are shown in Table 10 below.

[0180] [Table 10]

[0181]

[0182] Referring to Table 10, it can be confirmed that the purity of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention does not substantially change even when left under high temperature conditions or high humidity conditions. Therefore, it can be seen that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention is stable against heat and moisture, respectively.

[0183] Experimental Example 4: Long-term Storage Stability Evaluation

[0184] Immediately after the preparation of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Example 4(1) of the present invention, the appearance was visually confirmed, and the moisture content, purity, and XRD were each measured, and then the bag was sealed in a polyethylene bag for the first time and then in an aluminum bag for the second time, and stored at 25±2℃ and 60±5% RH. After 12 months, 24 months, and 36 months, the appearance was visually confirmed, and the moisture content, purity, and XRD were also measured. The results are shown in Table 11 and Fig. 16 below.

[0185] [Table 11]

[0186]

[0187] Referring to Table 11, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention remains stable even after 36 months from the date of manufacture.

[0188] In addition, referring to Fig. 16, which is the XRD analysis result after 36 months, it can be confirmed that the XRD pattern immediately after the production of the citric acid salt of the present invention shown in Fig. 10 was maintained without any substantial change, specifically, without any shift in each diffraction peak. In other words, it can be confirmed that the citric acid salt according to the present invention has excellent long-term storage stability.

[0189] Experimental Example 5: Evaluation of thermal and moisture stability (accelerated conditions)

[0190] Immediately after the preparation of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to Example 4(1) of the present invention, the appearance was visually confirmed, and the moisture content, purity, and XRD were each measured, and then the bag was sealed in a polyethylene bag for the first time and then in an aluminum bag for the second time, and stored under accelerated conditions of 40±2℃ and 75±5% RH. After 1 month and 6 months, the appearance was visually confirmed, and the moisture content, purity, and XRD were also measured. The results are shown in Table 12 below.

[0191] [Table 12]

[0192]

[0193] Referring to Table 12, it can be confirmed that the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt according to the present invention remains stable even after 6 months from the time of manufacture under accelerated conditions.

[0194] Although the present invention has been described above with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various modifications and changes may be made to the present invention without departing from the spirit and scope of the present invention as set forth in the claims below.

Claims

1. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

2. In paragraph 1, The molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid is 1:0.3 to 1:1.3, Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

3. In the first paragraph, the citric acid salt is anhydrous. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

4. In the first paragraph, the citric acid salt is in crystalline form. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

5. In the first paragraph, the citric acid salt is anhydrous crystalline. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

6. In the first paragraph, the crystalline form A includes three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 5.46°, 7.14°, 10.61°, 11.82°, 18.27°, and 25.77° of the powder X-ray diffraction pattern. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

7. In the 6th paragraph, the crystalline form A further includes at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 10.93°, 13.11°, 14.15°, 15.84°, 16.35°, 19.79°, and 24.21°. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

8. In the 6th paragraph, when the heating rate is 10℃ / min, it has differential scanning calorimetry (DSC) endothermic peaks at 88.69℃, 135.61℃, and 154.84℃ (±0.5℃). Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

9. In the first paragraph, the crystalline form B including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 7.03°, 7.69°, 9.47°, 13.21°, 14.86°, and 21.13° of the powder X-ray diffraction pattern. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

10. In the 9th paragraph, when the heating rate is 10℃ / min, it has a differential scanning calorimetry (DSC) endothermic peak at 144.57℃ (±0.5℃). Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

11. In the first paragraph, the crystalline form C1 including three or more diffraction peaks selected from the group consisting of 2θ (±0.2°) values ​​of 7.35°, 15.31°, 17.42°, and 22.26° in the powder X-ray diffraction pattern, Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

12. In the 11th paragraph, the crystalline form C1 further includes at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 10.23°, 12.90°, 14.68°, 15.97°, 18.21°, 21.22°, and 26.00° of the powder X-ray diffraction pattern. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amina]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

13. In the 11th paragraph, when the heating rate is 10℃ / min, it has a differential scanning calorimetry (DSC) endothermic peak at 168.93℃ (±0.5℃). Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

14. In paragraph 1, A crystalline form C2 having a powder X-ray diffraction pattern having at least three diffraction peaks selected from the group consisting of 5.63°, 8.90°, 9.51° and 13.01° in 2θ (±0.2°) values, Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

15. In the 14th paragraph, the crystalline form C2 further includes at least one diffraction peak selected from the group consisting of 2θ (±0.2°) values ​​of 12.31°, 14.34°, 14.80°, 18.38°, 18.75°, and 19.62° of the powder X-ray diffraction pattern. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amina]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

16. In the 14th paragraph, when the heating rate is 10℃ / min, it has a differential scanning calorimetry (DSC) endothermic peak at 161.48℃ (±0.5℃). Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

17. In the first paragraph, the citric acid salt is amorphous. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt.

18. A method comprising the step of reacting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid in the presence of at least one solvent selected from among alcohols having 1 to 3 carbon atoms, acetone, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and purified water. A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

19. In paragraph 18, In the above step, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone for reaction with citric acid is a solvate, A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

20. In paragraph 18, In the above step, a citric acid salt is prepared in which the molar ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and citric acid is 1:0.3 to 1:1.

3. A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

21. In paragraph 18, The above step comprises mixing a first solution containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone and a first solvent, and a second solution containing citric acid and a second solvent, The first solvent is a single solvent of acetone or a mixed solvent containing at least one selected from among acetone and an alcohol having 1 to 3 carbon atoms, acetonitrile, tetrahydrofuran (THF), dichloromethane, dimethylformamide (DMF), and N-methylpyrrolidone (NMP). The second solvent is acetone, A method for preparing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.