Crystal of imidazopyridone compound or its salt

Abstract

The present invention provides a crystal with excellent physical properties preferably as an active pharmaceutical ingredient. However, the optimal crystal form of the active pharmaceutical ingredient varies from compound to compound. In general, it is difficult to predict the crystal form with excellent physical properties of an active pharmaceutical ingredient, and therefore various studies of each compound are required. Therefore, an object of the present invention is to provide a crystal with excellent physical properties of a novel compound or a salt thereof as an active pharmaceutical ingredient. The present invention relates to a crystal of a compound or a salt thereof shown in formula (I) that can be used to treat inflammatory bowel disease.

Description

Technical Field

[0001] The present invention relates to a crystal of an imidazopyridone compound or a salt thereof which is useful as a medicine.

[0002] More specifically, the present invention relates to a crystal of an imidazopyridone compound or a salt thereof which has a prolyl hydroxylase inhibitory effect and is useful as a therapeutic agent for inflammatory bowel diseases such as ulcerative colitis. Background Art

[0003] Inflammatory bowel disease (IBD) is a chronic disease in which an excessive immune response leads to inflammation and ulceration of the intestinal mucosa. IBD includes, for example, ulcerative colitis and Crohn's disease.

[0004] Ulcerative colitis is a colorectal disease that causes diffuse nonspecific inflammation of unknown cause. The colorectal mucosa ulcerates, and erosions or ulcers may form in the mucosa. Ulcerative colitis can be divided into an "active phase" in which bloody stools, erosions, ulcers, etc. are observed, and a "remission phase" in which the findings of the active phase disappear. Because relapses and remissions often occur repeatedly during the course of the disease, long-term treatment is required.

[0005] For the treatment of ulcerative colitis, 5-aminosalicylic acid preparations (5-ASA) were first used as standard drugs. However, it is reported that the effectiveness of 5-ASA is about 46% to 64%, and the number of patients who are relieved by the administration of 5-ASA does not exceed 29% to 45%. When the effect of 5-ASA is not observed, steroids are used. In addition to these agents, immunosuppressants, TNF-α antibodies, etc. are sometimes used to treat ulcerative colitis. However, all of these agents have problems such as side effects and the need for cautious administration. Therefore, a therapeutic agent with a new mode of action for ulcerative colitis is needed.

[0006] It is known that in the pathological state of IBD, hypoxia-inducible factor 1α (HIF-1α) induces the expression of genes related to the barrier function of the gastrointestinal epithelium. HIF-1α is one of the subtypes of hypoxia-inducible factor α (HIF-α). HIF-α is stabilized in a low-oxygen environment (hypoxia), and then it activates the transcription of various genes in response to hypoxia. On the other hand, the proline residues of HIF-α are hydrolyzed by prolyl hydroxylases (PHDs) in an oxygen-rich environment (normoxia), and then HIF-α is degraded through the proteasome pathway.

[0007] It is known that PHD has three subtypes, namely PHD1, PHD2 and PHD3. AKB-4924 is known to be a PHD inhibitor. It is reported that AKB-4924 has a PHD2 inhibitory effect and stabilizes HIF-1α in large intestine tissue (Non-patent Document 1). In addition, AKB-4924 has an improvement effect on the TNBS-induced colitis model.

[0008] On the other hand, PHD inhibitors such as Roxadustat and Daprodustat have hematopoietic effects and have been developed as anemia therapeutic agents (Non-Patent Document 2). Therefore, when PHD inhibitors are used as IBD therapeutic agents, it is important to avoid systemic effects such as hematopoietic effects.

[0009] For example, spiro compounds as PHD inhibitors are described in Patent Documents 1 and 5 and Non-Patent Documents 3 and 4. Compounds containing imidazopyridone are described or exemplified in Patent Documents 2 to 4. However, the crystals of the imidazopyridone compound or a salt thereof of the present invention are neither described nor suggested in the above documents.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: US Patent Application No. 2011 / 0152304

[0013] Patent Document 2: International Publication No. 2009 / 029609

[0014] Patent Document 3: International Publication No. 2003 / 037890

[0015] Patent Document 4: International Publication No. 2017 / 066014

[0016] Patent Document 5: US Patent Application No. 2010 / 0137297

[0017] Non-patent literature

[0018] Non-patent document 1: Ellen Marks et al., "Inflamm. Bowel. Dis." 2015, Vol. 21, No. 2, pp. 267-275

[0019] Non-patent document 2: Mun Chiang Chan et al., "Molecular Aspects of Medicine", 2016, Vol. 47-48, pp. 54-75

[0020] Non-patent document 3: Guanghui Deng et al., "Bioorganic & Medicinal Chemistry", 2013, Vol. 21, pp. 6349-6358

[0021] Non-patent document 4: Petr Vachal et al., "Journal of Medicinal Chemistry", 2012, Vol. 55, pp. 2945-2959 Summary of the invention

[0022] Problem that the invention aims to solve

[0023] The applicant has developed a compound represented by the following formula (I) (hereinafter referred to as "Compound 1") as a novel compound having a PHD2 inhibitory effect, and submitted an invention patent application (PCT / JP2019 / 035792).

[0024] [Chemical formula 1]

[0025]

[0026] (Chemical name: 2-{[(3S)-3-{1-[6-(4-carboxyphenyl)pyridin-3-yl]-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-3-yl}pyrrolidin-1-yl]methyl}-1-methyl-1H-imidazole-5-carboxylic acid).

[0027] As a bulk drug, a crystal with good physical properties is preferred. However, the most excellent crystal form as a bulk drug may vary from compound to compound. Generally speaking, it is difficult to predict the crystal form of a bulk drug with good physical properties, and various tests need to be performed on each compound. Therefore, an object of the present invention is to provide a crystal with good physical properties as a bulk drug of a novel compound (Compound 1) or a salt thereof.

[0028] Means of solving the problem

[0029] The present invention relates to a crystal of Compound 1 or a salt thereof which has a PHD2 inhibitory effect and is useful for treating inflammatory bowel disease. That is, the present invention relates to the following [1] to

[12] and the like.

[0030] [1] A crystal of a compound represented by the following formula (I):

[0031] [Chemical formula 2]

[0032]

[0033] Or a crystal of a salt of the compound represented by formula (I), the salt being a salt with an acid or a base selected from methanesulfonic acid, hydrochloric acid, p-toluenesulfonic acid, sodium, potassium and calcium.

[0034] [2] The crystal of the above-mentioned [1], which is a crystal of the mesylate salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction:

[0035] (i) peaks at 10.6±0.2 and 14.1±0.2 (crystalline form I);

[0036] (ii) peaks at 21.8±0.2 and 25.5±0.2 (form II);

[0037] (iii) peaks at 12.8±0.2 and 22.6±0.2 (Form III); and

[0038] (iv) Peaks at 6.0±0.2 and 15.4±0.2 (Form IV).

[0039] [3] The crystal of the above-mentioned [1], which is a crystal of the mesylate salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction:

[0040] (i) peaks at 7.0±0.2 and 10.6±0.2 (crystalline form I);

[0041] (ii) peaks at 18.4±0.2 and 25.5±0.2 (form II);

[0042] (iii) peaks at 17.8±0.2 and 22.6±0.2 (Form III); and

[0043] (iv) Peaks at 6.0±0.2 and 11.0±0.2 (Form IV).

[0044] [4] The crystal described in [1] above, which is the hydrochloride crystal having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction:

[0045] (i) peaks at 13.1±0.2 and 17.4±0.2 (crystalline form I);

[0046] (ii) peaks at 6.2±0.2 and 8.1±0.2 (form II);

[0047] (iii) peaks at 12.9±0.2 and 21.4±0.2 (Form III); and

[0048] (iv) Peaks at 10.5±0.2 and 11.0±0.2 (Form IV).

[0049] [5] The crystal of the above-mentioned [1], which is a crystal of a salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction:

[0050] (i) p-toluenesulfonate with peaks at 6.1±0.2 and 24.7±0.2;

[0051] (ii) sodium salt with peaks at 5.8 ± 0.2 and 22.7 ± 0.2;

[0052] (iii) potassium salt having peaks at 5.7±0.2 and 22.8±0.2; and

[0053] (iv) Calcium salt with peaks at 7.3±0.2 and 16.1±0.2.

[0054] [6] The crystal of the above-mentioned [1], which is a crystal of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iii) in powder X-ray diffraction:

[0055] (i) peaks at 10.1±0.2 and 18.0±0.2 (crystalline form I);

[0056] (ii) peaks at 12.5±0.2 and 17.0±0.2 (Form II); and

[0057] (iii) Peaks at 11.1±0.2 and 14.1±0.2 (Form III).

[0058] [7] The crystal of [1] above, which is a crystal of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iii) in powder X-ray diffraction:

[0059] (i) peaks at 7.6±0.2 and 18.0±0.2 (crystalline form I);

[0060] (ii) peaks at 11.4±0.2 and 17.0±0.2 (Form II); and

[0061] (iii) Peaks at 10.5±0.2 and 11.1±0.2 (Form III).

[0062] [8] The crystal described in [1] above, which is a crystal of the compound having peaks at diffraction angles (2θ (°)) of 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2, 17.1±0.2, 18.0±0.2, 19.1±0.2, 21.1±0.2, 21.7±0.2, 23.4±0.2, 26.2±0.2 and 27.5±0.2 in powder X-ray diffraction (crystalline form I).

[0063] [9] A pharmaceutical composition comprising the crystal according to any one of [1] to [8] above and a pharmaceutical additive.

[0064]

[10] The pharmaceutical composition described in [9] above, which is a pharmaceutical composition for treating inflammatory bowel disease.

[0065]

[11] The pharmaceutical composition of the above-mentioned

[10] , wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

[0066]

[12] A crystal of a compound represented by the following formula (I) or a salt thereof:

[0067] [Chemical formula 3]

[0068]

[0069] In one embodiment, the present invention relates to a method for treating inflammatory bowel disease, comprising administering a necessary amount of the pharmaceutical composition described in [9] above to a patient.

[0070] In one embodiment, the present invention relates to use of the crystal described in any one of [1] to [8] above in the manufacture of a pharmaceutical composition for treating inflammatory bowel disease.

[0071] In one embodiment, the present invention relates to the crystal described in [1] above, which is a crystal of the mesylate salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction:

[0072] (i) peaks of 7.0±0.2, 10.6±0.2, 14.1±0.2 and 16.2±0.2 (crystalline form I);

[0073] (ii) peaks of 18.4±0.2, 18.7±0.2, 21.8±0.2, and 25.5±0.2 (Form II);

[0074] (iii) peaks at 12.8±0.2, 17.8±0.2, 18.3±0.2 and 22.6±0.2 (Form III); and

[0075] (iv) Peaks at 6.0±0.2, 11.0±0.2, 15.4±0.2 and 16.3±0.2 (Form IV).

[0076] In one embodiment, the present invention is the crystal described in [1] above, which is a crystal of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iii) in powder X-ray diffraction:

[0077] (i) peaks of 7.6±0.2, 10.1±0.2, 13.0±0.2 and 18.0±0.2 (crystalline form I);

[0078] (ii) peaks at 11.4±0.2, 12.2±0.2, 12.5±0.2 and 17.0±0.2 (Form II); and

[0079] (iii) Peaks at 10.5±0.2, 11.1±0.2, 14.1±0.2 and 24.7±0.2 (Form III).

[0080] In one embodiment, the present invention relates to the crystal described in [1] above, which is a crystal of a mesylate salt having a subset of peaks at a diffraction angle (2θ (°)) and an endothermic reaction in powder X-ray diffraction, wherein the subset of peaks and the endothermic reaction are selected from the following (i) to (iv):

[0081] (i) peaks at 7.0±0.2, 10.6±0.2, 14.1±0.2 and 16.2±0.2 and an endothermic peak top at around 253°C (crystalline form I);

[0082] (ii) peaks at 18.4±0.2, 18.7±0.2, 21.8±0.2, and 25.5±0.2, and an endothermic peak top at around 248°C (crystalline form II);

[0083] (iii) peaks at 12.8±0.2, 17.8±0.2, 18.3±0.2 and 22.6±0.2 and an endothermic peak top at around 252°C (crystalline form III); and

[0084] (iv) Peaks at 6.0±0.2, 11.0±0.2, 15.4±0.2 and 16.3±0.2 and a broad endotherm from 22°C to 100°C (Crystal Form IV).

[0085] In one embodiment, the present invention is the crystal described in [1] above, which is a crystal of a mesylate salt having the subset of peaks at diffraction angles (2θ (°)) and an endothermic reaction in powder X-ray diffraction, wherein the subset of peaks and the endothermic reaction are selected from the following (i) to (iii):

[0086] (i) peaks at 7.6±0.2, 10.1±0.2, 13.0±0.2 and 18.0±0.2 and an endothermic peak top at around 266°C (crystalline form I);

[0087] (ii) peaks at 11.4±0.2, 12.2±0.2, 12.5±0.2 and 17.0±0.2 and an endothermic peak top at around 233°C (crystalline form II); and

[0088] (iii) Peaks at 10.5±0.2, 11.1±0.2, 14.1±0.2 and 24.7±0.2 and a broad endotherm from 30°C to 120°C (crystal form III).

[0089] In one embodiment, the present invention relates to the crystal described in [1] above, which is a crystal of a methanesulfonate having peaks at diffraction angles (2θ (°)) of 7.0±0.2, 10.6±0.2, 13.7±0.2, 14.1±0.2, 16.2±0.2, 17.6±0.21, 8.6±0.2, 20.5±0.2, 21.6±0.2 and 24.5±0.2 in powder X-ray diffraction.

[0090] In one embodiment, the present invention relates to the crystal described in [1] above, which is a crystal of the compound having peaks at diffraction angles (2θ (°)) of 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2, 17.1±0.2, 18.0±0.2, 19.1±0.2, 21.1±0.2, 21.7±0.2, 23.4±0.2, 26.2±0.2 and 27.5±0.2 in powder X-ray diffraction.

[0091] In one embodiment, the present invention relates to the crystal described in [1] above, which is a crystal of the compound having peaks at diffraction angles (2θ (°)) of 11.4±0.2, 12.2±0.2, 12.5±0.2, 13.8±0.2, 15.0±0.2, 15.3±0.2, 17.0±0.2, 17.6±0.2, 23.1±0.2, 23.4±0.2, 24.4±0.2, and 27.1±0.2 in powder X-ray diffraction.

[0092] Effects of the Invention

[0093] The crystals of the compound of the present invention or its salt have good physical properties as a raw material drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figures 1 to 15 This is a powder X-ray diffraction pattern of a crystal. The vertical axis represents the diffraction intensity (counts). The horizontal axis represents the diffraction angle (2θ (°)).

[0095] Figures 16 to 30 This is a thermogravimetric differential thermal analysis graph (TG-DTA measurement graph) of a crystal. The vertical axis (left) represents the mass change (%) in the thermogravimetric (TG) curve. The vertical axis (right) represents the heat flow (μV) in the differential thermal analysis (DTA) curve. The horizontal axis represents the temperature (°C).

[0096] [ Figure 1 ] Powder X-ray diffraction pattern of Form I of Compound 1

[0097] [ Figure 2 ] Powder X-ray diffraction pattern of Form II of Compound 1

[0098] [ Figure 3 ] Powder X-ray diffraction pattern of Form III of Compound 1

[0099] [ Figure 4 ] Powder X-ray diffraction pattern of the crystalline form I of the mesylate salt of compound 1

[0100] [ Figure 5 ] Powder X-ray diffraction pattern of the crystalline form II of the mesylate salt of compound 1

[0101] [ Figure 6 ] Powder X-ray diffraction pattern of the crystalline form III of the mesylate salt of compound 1

[0102] [ Figure 7 ] Powder X-ray diffraction pattern of Form IV of the mesylate salt of Compound 1

[0103] [ Figure 8 ] Powder X-ray diffraction pattern of the crystalline form I of the hydrochloride salt of compound 1

[0104] [ Fig. 9 ] Powder X-ray diffraction pattern of the crystalline form II of the hydrochloride salt of compound 1

[0105] [ Fig.10 ] Powder X-ray diffraction pattern of the crystalline form III of the hydrochloride salt of compound 1

[0106] [ Fig.11 ] Powder X-ray diffraction pattern of the crystalline form IV of the hydrochloride salt of compound 1

[0107] [ Fig.12 ] Powder X-ray diffraction pattern of the crystalline form I of the p-toluenesulfonate salt of compound 1

[0108] [ Fig.13 ] Powder X-ray diffraction pattern of the crystalline form I of the sodium salt of compound 1

[0109] [ Fig.14 ] Powder X-ray diffraction pattern of the crystalline form I of the potassium salt of compound 1

[0110] [ Fig.15 ] Powder X-ray diffraction pattern of the crystalline form I of the calcium salt of compound 1

[0111] [ Fig.16 TG-DTA measurement diagram of the crystalline form I of compound 1

[0112] [ Fig.17 TG-DTA measurement diagram of the crystalline form II of compound 1

[0113] [ Fig.18 TG-DTA measurement diagram of the crystalline form III of compound 1

[0114] [ Fig.19 TG-DTA measurement diagram of the crystalline form I of the mesylate salt of compound 1

[0115] [ Fig. 20 TG-DTA measurement diagram of the crystal form II of the mesylate salt of compound 1

[0116] [ Fig.21 TG-DTA measurement diagram of the crystalline form III of the mesylate salt of compound 1

[0117] [ Fig. 22 TG-DTA measurement diagram of the crystal form IV of the mesylate salt of compound 1

[0118] [ Fig.23 TG-DTA measurement diagram of the crystalline form I of the hydrochloride salt of compound 1

[0119] [ Fig.24 TG-DTA measurement diagram of the crystalline form II of the hydrochloride salt of compound 1

[0120] [ Fig.25 TG-DTA measurement diagram of the crystalline form III of the hydrochloride salt of compound 1

[0121] [ Fig.26 TG-DTA measurement diagram of the crystalline form IV of the hydrochloride salt of compound 1

[0122] [ Fig. 27 TG-DTA measurement diagram of the crystalline form I of the p-toluenesulfonate salt of compound 1

[0123] [ Fig.28 TG-DTA measurement diagram of the crystalline form I of the sodium salt of compound 1

[0124] [ Fig.29 TG-DTA measurement diagram of the crystalline form I of the potassium salt of compound 1

[0125] [ Fig.30 TG-DTA measurement diagram of the crystal form I of the calcium salt of compound 1 DETAILED DESCRIPTION

[0126] Embodiments of the present invention are described in more detail below.

[0127] In the present invention, unless otherwise specified, each term has the following meaning.

[0128] The following abbreviations in the specification, drawings and tables have the following meanings, respectively.

[0129] CDI: Carbonyldiimidazole

[0130] DMF: N,N-dimethylformamide

[0131] DMSO: dimethyl sulfoxide

[0132] MTBE: Methyl tert-butyl ether

[0133] NaBH(OAc)3: Sodium triacetoxyborohydride

[0134] NMP: 1-Methyl-2-pyrrolidone

[0135] Pd(amphos)Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)

[0136] THF: Tetrahydrofuran

[0137] TNBS: Trinitrobenzenesulfonic acid

[0138] Amino Silicone: Aminopropyl Silicone

[0139] ODS column chromatography: octadecyl silylation silica gel column chromatography

[0140] Ex.No.: Example number

[0141] Structure: Structural formula

[0142] Physical Data: Physical Data

[0143] IC 50 : Concentration required for 50% inhibition

[0144] FITC: fluorescein isothiocyanate

[0145] 1 H-NMR: Hydrogen Nuclear Magnetic Resonance Spectroscopy

[0146] DMSO-d6: dimethyl sulfoxide-d6

[0147] D2O: Heavy Water

[0148] MS: Mass spectrometry

[0149] ESI_APCI: Multiple ionization using electrospray ionization-atmospheric pressure chemical ionization

[0150] In the present invention, “having good physical properties as a drug substance” means, for example, that the crystal is physicochemically stable or chemically stable in the solid stability test shown in Test Example 4.

[0151] Compound 1 of the present invention may also be referred to as "(S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid".

[0152] The crystals of compound 1 of the present invention also include solvates thereof with pharmaceutically acceptable solvents such as water or ethanol. In addition, the crystals of the salt of compound 1 of the present invention also include salts, solvates thereof with pharmaceutically acceptable solvents such as water or ethanol, co-crystals of compound 1 with suitable co-crystal formers, and salt co-crystals (ionic co-crystals) of salts with suitable co-crystal formers.

[0153] For example, the crystalline form I of the mesylate of compound 1 also includes a hydrate of the mesylate. The number of water molecules incorporated into the crystal lattice can vary from 0 to 1 depending on humidity, and the crystalline form I of the mesylate of compound 1 also includes any hydrate.

[0154] In the compound 1 of the present invention, a part of the atoms may be replaced by corresponding isotopes. The present invention includes compounds in which the atoms are replaced by these isotopes. Examples of isotopes include 2 H. 3 H. 11 C. 13 C. 14 C. 36 Cl, 18 F. 123 I. 125 I. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P and 35 S represents an isotope of a hydrogen atom, a carbon atom, a chlorine atom, a fluorine atom, an iodine atom, a nitrogen atom, an oxygen atom, a phosphorus atom, and a sulfur atom. In one embodiment, some of the hydrogen atoms of compound 1 are replaced by 2 H (D: deuterium atom) substituted compounds.

[0155] The compound 1 of the present invention in which a part of atoms are replaced with isotopes can be produced by a method similar to the following production method using a commercially available structural unit into which an isotope is introduced.

[0156] Compound 1 of the present invention has excellent PHD2 inhibitory effect, and thus can be used as a therapeutic agent for IBD (see Nature Reviews Drug Discovery, 2014, 13, pp. 852-869). In the present invention, the term "IBD" includes, for example, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, radiation enteritis, drug-induced enteritis, ischemic enteritis, mesenteric venous sclerosis (venous sclerosing colitis), obstructive colitis, and enteritis caused by collagen disease. Preferably, compound 1 of the present invention can be used as a therapeutic agent for ulcerative colitis or Crohn's disease (see Inflamm. Bowel. Dis., 2015, 21 (2), pp. 267-275).

[0157] In the present invention, the word "treatment" includes the meaning of "prevention." The treatment of ulcerative colitis includes the meanings of, for example, "preventing relapse" and "maintaining remission."

[0158] The therapeutic effect of compound 1 of the present invention on colitis can be determined according to the method described in Test Example 2 or a method known in the art. For example, the effect can also be determined according to the method described in Biol. Pharm. Bull., 2004, 27(10), pp. 1599-1603 or a method similar thereto.

[0159] In one embodiment, compound 1 of the present invention is a PHD2 inhibitor that specifically acts on large intestinal tissue to limit the off-target effects of HIF-α stabilization. The term "specifically acts on large intestinal tissue" means, for example, that the concentration of the compound in large intestinal tissue is higher than that in blood, and the compound exerts a therapeutic effect on the large intestine but has no systemic effect (e.g., hematopoietic effect) (see Test Examples 2 and 3).

[0160] Depending on the usage, the pharmaceutical composition of the present invention is used in various dosage forms. As such dosage forms, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches and enemas can be cited. Preferably, the pharmaceutical composition of the present invention is administered orally.

[0161] The pharmaceutical composition of the present invention contains a crystal of Compound 1 or a salt thereof as an active ingredient.

[0162] The pharmaceutical composition of the present invention is prepared using crystals of Compound 1 or a salt thereof and at least one pharmaceutical additive. Depending on their dosage forms, these pharmaceutical compositions can be formulated by appropriately mixing, diluting or dissolving with appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc. according to known preparation procedures.

[0163] When the pharmaceutical composition of the present invention is used for treatment, the dosage of Compound 1 or its salt is appropriately determined depending on the age, sex, weight, and degree of disease and treatment of each patient. The daily dose can be divided into once, twice, three times, or four times a day for administration.

[0164] In the case of oral administration, the dosage for adults can be determined, for example, within the range of 0.1 to 1000 mg per day. In one embodiment, the dosage for oral administration can be determined within the range of 1 to 500 mg per day, preferably within the range of 10 to 200 mg per day.

[0165] In the case of parenteral administration, the dosage for adults can be determined, for example, at 0.1 to 1000 mg per day. In one embodiment, the dosage for parenteral administration can be determined within the range of 0.5 to 200 mg per day, preferably within the range of 1 to 20 mg per day.

[0166] In one embodiment, the pharmaceutical composition of the present invention can also be used in combination with any other drug except the PHD inhibitor. As other drugs that can be used in combination for the treatment of inflammatory bowel disease, for example, 5-ASA, steroids, immunosuppressants, TNF-α antibodies, Janus kinase inhibitors and α4β7 integrin antibodies can be mentioned.

[0167] When the crystals of compound 1 or its salt of the present invention are used in combination with other medicaments, they can be administered as an integrated preparation containing these active ingredients or as preparations prepared separately from each active ingredient. When prepared separately, these preparations can be administered separately or simultaneously. In addition, the dosage of compound 1 or its salt of the present invention can be appropriately reduced depending on the dosage of other medicaments used in combination.

[0168] Powder X-ray diffraction measurements

[0169] For powder X-ray diffraction, the crystals were ground with a mortar and then measured with a powder X-ray diffraction apparatus SmartLab (Rigaku) ​​by a reflection method according to the following conditions.

[0170] X-ray source, wavelength: CuKα rays (CuKα1 and CuKα2),

[0171] Tube voltage, tube current, scanning speed: 40kV, 50mA, 13°2(θ) / min

[0172] Data analysis software: SmartLab Studio II (Rigaku)

[0173] Data analysis method (peak definition): peak position (peak top position, diffraction angle when irradiated with CuKα1 and CuKα2), peak height (excluding background)

[0174] It is well known that the relative intensity (relative peak height) of the peaks in the powder X-ray diffraction pattern can vary due to sample conditions and measurement conditions. The relative intensity will vary slightly due to crystal growth direction, particle size, measurement conditions, etc., and should not be interpreted strictly.

[0175] It is also well known that the 2θ value of each peak in powder X-ray diffraction may vary slightly due to sample conditions and measurement conditions. Generally speaking, the 2θ value may vary within a range of about ±0.2 (°). Therefore, the present invention includes not only crystals in which the diffraction angles (2θ (°)) of the peaks in powder X-ray diffraction completely overlap, but also crystals in which the diffraction angles (2θ (°)) of all or part of the peaks overlap within a range of ±0.2 (°).

[0176] Thermal analysis measurement (thermogravimetric differential thermal analysis (TG-DTA))

[0177] Thermal analysis was performed under a nitrogen atmosphere using a differential thermal balance (TG8120 model or Thermo plus EVO2 model, Rigaku) ​​according to the following measurement conditions.

[0178] Heating rate: 10℃ / min

[0179] Reference material: Alumina

[0180] The temperature at which the mass reduction starts and the temperature at which it converges at one point are measured, and the mass change (%) is calculated from the mass difference at the temperatures.

[0181] In the TG-DTA measurement graph, the "absorption" in the DTA curve is represented by the temperature at the peak apex (peak top) or the "extrapolated starting temperature". The "extrapolated starting temperature" refers to the intersection between the starting point or offset point in the DTA curve and the baseline extrapolation, also known as the "extrapolated starting temperature". The "extrapolated starting temperature" is the temperature of the starting point of the peak, which refers to the exothermic or endothermic starting temperature calculated by extrapolation. The peak top and the extrapolated starting temperature in the TG-DTA measurement graph may fluctuate slightly due to the measurement conditions. For example, in general, the temperature may fluctuate within the range of ±5°C. Therefore, the crystals specified by the above peaks include crystals that overlap within the range of ±5°C.

[0182] In the present invention, "around" used in the thermal analysis refers to a range of ±5°C.

[0183] The crystal form of the crystal of Compound 1 or a salt thereof of the present invention can be specified by a subset of diffraction peaks in powder X-ray diffraction described in each example. In the present invention, "having a subset of peaks" means that the crystal contains at least the peaks of the subset as characteristic peaks.

[0184] Alternatively, the crystal form can be specified by a combination of a subset of diffraction peaks in powder X-ray diffraction and physical properties such as endotherms in TG-DTA measurements of individual crystals.

[0185] Example

[0186] The present invention is further described in more detail by the following examples. However, the present invention is not limited thereto.

[0187] Reference Example 1

[0188] (S)-tert-Butyl 3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

[0189] 2-Fluoro-3-nitropyridine (10.00 g), (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (13.10 g) and potassium carbonate (11.67 g) were added to NMP (100 mL) under ice cooling. The reaction mixture was stirred at 150 ° C for 1 hour. The reaction mixture was cooled to room temperature. Ethyl acetate and water were added to the reaction mixture, and the resultant was mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate added thereto, and concentrated under reduced pressure to give the title compound (21.70 g).

[0190] Reference Example 2

[0191] (S)-tert-Butyl 3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate

[0192] To a mixture of Reference Example 1 (21.70 g) and ethanol (300 mL) was added 10% palladium on carbon (2.17 g, wet) under an argon atmosphere. The mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (19.74 g).

[0193] Reference Example 3

[0194] (S)-tert-Butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

[0195] CDI (22.82 g) was added to a mixture of Reference Example 2 (19.59 g) and THF (200 mL) with stirring under ice cooling. The reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (5 mol / L, 30 mL) was added to the reaction mixture, and the resulting mixture was stirred for 10 minutes. Hydrochloric acid (2 mol / L, 75 mL) was added to the reaction mixture. After stirring, the mixture was concentrated under reduced pressure. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50-0 / 100) to give the title compound (17.61 g). MS (ESI_APCI, m / z): 303 (MH) - .

[0196] Reference Example 4

[0197] (S)-tert-Butyl 3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

[0198] A mixture of Reference Example 3 (100 mg), 2-chloro-5-iodopyridine (94 mg), N,N'-dimethylethylenediamine (0.042 mL), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) was stirred at 100 ° C for 1 hour under microwave radiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (117 mg).

[0199] Reference Example 5

[0200] (S)-tert-Butyl 3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

[0201] A mixture of Reference Example 4 (117 mg), (4-(methoxycarbonyl)phenyl)boric acid (61 mg), Pd(amphos)Cl2 (20 mg), sodium carbonate (72 mg), DMF (3 mL) and water (0.3 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-30 / 70) to give the title compound (95 mg).

[0202] Reference Example 6

[0203] (S)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride

[0204] Reference Example 5 (95 mg), 1,4-dihydrochloride A mixture of an oxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (126 mg).

[0205] Reference Example 7

[0206] (S)-methyl 4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoate

[0207] To a mixture of Reference Example 6 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (167 mg) and dichloromethane (2 mL) was added NaBH(OAc)3 (375 mg). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-0 / 100) to give the title compound (214 mg). MS (ESI_APCI, m / z): 588 (M+H) + .

[0208] Reference Example 8

[0209] (S)-methyl 4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoate

[0210] A mixture of Reference Example 7 (214 mg), tetrakis(triphenylphosphine)palladium(0) (42 mg), zinc cyanide (86 mg) and NMP (3 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate=80 / 20-0 / 100) to give the title compound (244 mg). MS (ESI_APCI, m / z): 535 (M+H) + .

[0211] Compound 1

[0212] 2-{[(3S)-3-{1-[6-(4-carboxyphenyl)pyridin-3-yl]-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-3-yl}pyrrolidin-1-yl]methyl}-1-methyl-1H-imidazole-5-carboxylic acid

[0213] A mixture of Reference Example 8 (195 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110 ° C for 1 hour under microwave irradiation. Aqueous sodium hydroxide solution (5 mol / L) was added to neutralize the reaction mixture. DMSO was added thereto to dilute the mixture. Then, insoluble matter was removed by diatomaceous earth. The filtrate was purified by ODS column chromatography (eluent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (60 mg).

[0214] [Table 1]

[0215]

[0216] Test Example 1: PHD2 inhibition test

[0217] (1) Human PHD2 184-418 Expression and preparation

[0218] Human PHD2 containing amino acid residues 184 to 418 of the protein represented by CAC42509 (GenBank Accession ID) was expressed and prepared by the following method: 184-418 .

[0219] Human PHD2 containing an N-terminal histidine tag 184-418The expression construct was introduced into the pET-30a(+) vector and the sequence was confirmed. The vector was introduced into the BL21(DE3) strain and cultured in LB medium containing antibiotics at 37°C. After culture, cell lysis solution was added to the cells, and then the cells were broken and suspended by ultrasound. The broken suspension was centrifuged and the supernatant was purified by Ni column to obtain human PHD2 184-418 .

[0220] (2) Test methods

[0221] Human HIF-1α 556-574 (FITC-labeled HIF-1α 556-574 ) contains amino acid residues 556 to 574 of human HIF-1α (partial peptide) and in the HIF-1α 556-574 The N-terminus of the FITC-Ahx was used as a substrate. 556-574 , based on FITC-labeled HIF-1α 556-574 The competitive inhibition between 2-ketoglutarate and the test compound (PHD inhibitor) was evaluated by the following method.

[0222] The enzyme (human PHD2 184-418 ) and the substrate were diluted with an assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, 10 μM MnCl2-4H2O, 2 μM 2-ketoglutaric acid and 0.05% Tween-20. The test compound was diluted with DMSO. 184-418 Pre-filled into 384-well plates (Corning, black, opaque bottom). 556-574 The reaction was started. After incubation at 37°C for 60 minutes, fluorescence polarization (excitation wavelength: 470 nm, fluorescence wavelength: 530 nm) was measured by PHERAstar FSX (BMG Labtech). The fluorescence polarization of each well was measured, and the human PHD2 binding inhibitory activity of the test compound was calculated based on the value of the group without the test substance.

[0223] (3) Results

[0224] As shown in Table 1, the compound 1 of the present invention inhibited the binding between PHD2 and HIF-1α. Therefore, it was demonstrated that the compound 1 of the present invention is useful as a PHD2 inhibitor.

[0225] Experimental Example 2: Therapeutic effect in colitis model

[0226] (1) TNBS-induced colitis model rats

[0227] It is known that when TNBS is administered to the large intestine of rats, inflammation is induced locally in the large intestine, and then intestinal permeability increases due to the destruction of the barrier function in the intestine. Therefore, the inhibitory effect of the test compound on intestinal permeability after oral administration was evaluated as an indicator of drug efficacy.

[0228] (2) Test methods

[0229] SD male rats were used: 8-week-old SLC (Japan SLC). Under pentobarbital anesthesia, 300 μL of 28 mg / mL TNBS adjusted with 50% ethanol was applied to the large intestine at a position 8 cm from the anus to cause inflammation. 300 μL of 50% ethanol was applied to the solvent-treated group. The animals were fasted for 48 hours before the administration of TNBS. From the next day, the test compound (3 mg / kg) prepared with 0.05% methylcellulose solution was orally administered once a day for a total of 3 days. After 3 days of administration, 50 mg / kg FITC was orally administered 4 hours after the administration of the test compound. Blood samples were collected from the jugular vein under isoflurane anesthesia 4 hours later. The serum was separated by centrifugation, and the fluorescence intensity was detected by PHERAstar FSX (BMG Labtech) to measure the concentration of FITC that penetrated the circulating blood through the mesentery. The inhibition rate of the test compound on intestinal permeability was calculated as 0 for the group without the test substance and 100 for the group without TNBS treatment.

[0230] (3) Results

[0231] The inhibition rates (% average) of the test compounds on intestinal permeability (inhibition) are shown below.

[0232] [Table 2]

[0233] inhibition(%) Compound 1 101

[0234] Administration of the compound 1 of the present invention inhibited the intestinal permeability of FITC increased by administration of TNBS. Therefore, it was demonstrated that the compound 1 of the present invention is useful as a therapeutic agent for inflammatory bowel disease.

[0235] Test Example 3: Compound Concentration in Large Intestine Tissue

[0236] (1) Rat PK test

[0237] The test compound (3mg / kg / 5mL) prepared with 0.05% methylcellulose was orally administered to unfasted rats (SD, 8 weeks old, male, Japan SLC). Blood samples were collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration. Under isoflurane anesthesia, laparotomy was performed to separate the large intestine. The collected distal large intestine (about 5cm) was cut open, and the extracted large intestine was then washed with saline on a plate. After washing, the large intestine was cut into pieces with small scissors. About 150mg of it was moved to a test tube. 100μL of saline was added to the test tube, and the mixture was homogenized using a shaker (1000rpm×30 minutes). The sample was prepared by adding four times the volume of saline as the final volume. The concentration of the test compound in large intestinal tissue and plasma was measured by quantitative analysis using liquid chromatography-mass spectrometry (LC / MS).

[0238] (2) Compound concentrations in large intestinal tissue and plasma

[0239] As shown in the following table, it is proved that the concentration of the compound 1 of the present invention in the large intestine tissue is higher than that in the plasma. Therefore, the compound 1 of the present invention is a PHD2 inhibitor that specifically acts on the large intestine tissue.

[0240] [Table 3]

[0241] Cmax AUC Plasma Colon C / P Compound 1 1 117 ＜1 164 ＞164

[0242] The symbols in the table have the following meanings.

[0243] Cmax: Maximum plasma concentration of the test compound in the case of oral administration (ng / mL)

[0244] AUC: Area under the plasma test compound concentration-time curve (ng*min / mL)

[0245] Plasma: Test compound concentration in plasma after 8 hours (ng / mL)

[0246] Colon: concentration of test compound in colon tissue after 8 hours (ng / g)

[0247] C / P: The ratio of the above Colon to Plasma

[0248] Example 1-1: Crystalline Form I of Compound 1

[0249] Compound 1 (100 mg) was added to DMSO (1 mL), dissolved at 60 ° C, and the mixture was passed through a glass filter. DMSO was removed from the filtrate using a centrifugal evaporator. Ethanol (2 mL) was added to the residue in the container. The mixture was stirred at room temperature for 1 hour, and the slurry was filtered. The obtained solid was washed with water (1 mL) once and ethanol (2 mL) twice. The obtained solid was dried under reduced pressure at 50 ° C for 1 day to obtain crystalline form I (66 mg) of compound 1.

[0250] Powder X-ray diffraction of the crystalline form I of compound 1 was measured. Table 4 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0251] [Table 4]

[0252] 2θ(°) Relative strength.(%) 2θ(°) Relative strength (%) 7.6 32 19.1 29 9.0 29 21.1 24 10.1 56 21.7 42 13.0 81 23.4 23 17.1 24 26.2 30 18.0 100 27.5 19

[0253] For the identification of the crystalline form I of Compound 1, for example, a diffraction peak subset selected from the following [1-1-1] to [1-1-7] can be used:

[0254] [1-1-1] Peaks at 10.1±0.2 and 18.0±0.2;

[0255] [1-1-2] Peaks at 7.6 ± 0.2 and 18.0 ± 0.2;

[0256] [1-1-3] Peaks at 10.1±0.2, 13.0±0.2, and 18.0±0.2;

[0257] [1-1-4] Peaks at 7.6 ± 0.2, 13.0 ± 0.2, and 18.0 ± 0.2;

[0258] [1-1-5] Peaks at 7.6 ± 0.2, 10.1 ± 0.2, 13.0 ± 0.2, and 18.0 ± 0.2;

[0259] [1-1-6] peaks at 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2, and 18.0±0.2; and

[0260] [1-1-7] Peaks of 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2, 17.1±0.2, 18.0±0.2, 19.1±0.2, 21.1±0.2, 21.7±0.2, 23.4±0.2, 26.2±0.2 and 27.5±0.2.

[0261] Thermal analysis of Form I of Compound 1 was performed.

[0262] Endothermic: around 266°C (peak, extrapolated starting temperature around 264°C)

[0263] Mass reduction: 28℃ to 200℃ (0.4%)

[0264] Example 1-2: Crystalline Form II of Compound 1

[0265] At room temperature, 2mol / L sodium hydroxide aqueous solution (1.85mL) was added to a mixture of compound 1 (1.00g), ethanol (3.8mL) and water (12mL). After dissolution, the solution was passed through a glass filter. The filtrate was stirred at 64°C for 40 minutes. 2mol / L hydrochloric acid (0.925mL) was added to the solution at the same temperature. After stirring for 20 minutes at the same temperature, 2mol / L hydrochloric acid (0.463mL) was added to the mixture. After further stirring for 1 hour, 2mol / L hydrochloric acid (0.463mL) was added to the mixture. After the mixture was stirred at room temperature for 1 day, the slurry was filtered. The obtained solid was washed twice with water (10mL) and washed with ethanol (2mL) in sequence. The obtained solid was dried under reduced pressure at 50°C for 4 days to obtain the crystalline form II (940mg) of compound 1.

[0266] Powder X-ray diffraction was measured for the crystalline form II of compound 1. Table 5 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0267] [Table 5]

[0268] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 11.4 25 17.0 43 12.2 38 17.6 28 12.5 100 23.1 17 13.8 22 23.4 19 15.0 25 24.4 19 15.3 15 27.1 15

[0269] For the identification of the crystalline form II of compound 1, for example, a diffraction peak subset selected from the following [1-2-1] to [1-2-7] can be used:

[0270] [1-2-1] Peaks at 12.5 ± 0.2 and 17.0 ± 0.2;

[0271] [1-2-2] Peaks at 11.4 ± 0.2 and 17.0 ± 0.2;

[0272] [1-2-3] Peaks at 11.4 ± 0.2, 12.5 ± 0.2, and 17.0 ± 0.2;

[0273] [1-2-4] Peaks at 12.2 ± 0.2, 12.5 ± 0.2, and 17.0 ± 0.2;

[0274] [1-2-5] peaks at 11.4 ± 0.2, 12.2 ± 0.2, 12.5 ± 0.2, and 17.0 ± 0.2;

[0275] [1-2-6] peaks of 11.4±0.2, 12.2±0.2, 12.5±0.2, 17.0±0.2, and 17.6±0.2; and

[0276] [1-2-7] Peaks of 11.4±0.2, 12.2±0.2, 12.5±0.2, 13.8±0.2, 15.0±0.2, 15.3±0.2, 17.0±0.2, 17.6±0.2, 23.1±0.2, 23.4±0.2, 24.4±0.2 and 27.1±0.2.

[0277] Thermal analysis of Form II of Compound 1 was performed.

[0278] Endothermic: around 96°C (wide endothermic range from 50 to 120°C), around 233°C (peak, extrapolated onset temperature around 226°C)

[0279] Mass reduction: 30℃ to 150℃ (1.8%)

[0280] Example 1-3: Crystalline Form III of Compound 1

[0281] At room temperature, 2 mol / L sodium hydroxide aqueous solution (0.280 mL) was added to a mixture of compound 1 (150 mg), 2-propanol (3 mL) and water (1.5 mL). After dissolution, a mixed solution of 2 mol / L hydrochloric acid (0.280 mL), 2-propanol (0.200 mL) and water (0.200 mL) was slowly added dropwise to the solution at 50 ° C. The mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours. The slurry was filtered. The resulting solid was dried under reduced pressure at room temperature for 15 hours to obtain crystalline form III (135 mg) of compound 1.

[0282] Powder X-ray diffraction was measured for the crystalline form III of compound 1. Table 6 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0283] [Table 6]

[0284]

[0285] For the identification of the crystalline form III of compound 1, for example, a diffraction peak subset selected from the following [1-3-1] to [1-3-7] can be used:

[0286] [1-3-1] Peaks at 11.1±0.2 and 14.1±0.2;

[0287] [1-3-2] Peaks at 10.5 ± 0.2 and 11.1 ± 0.2;

[0288] [1-3-3] Peaks at 10.5 ± 0.2, 11.1 ± 0.2, and 14.1 ± 0.2;

[0289] [1-3-4] Peaks at 11.1±0.2, 14.1±0.2, and 24.7±0.2;

[0290] [1-3-5] peaks of 10.5 ± 0.2, 11.1 ± 0.2, 14.1 ± 0.2, and 24.7 ± 0.2;

[0291] [1-3-6] peaks of 10.5±0.2, 11.1±0.2, 13.5±0.2, 14.1±0.2, and 24.7±0.2; and

[0292] [1-3-7] Peaks of 10.5±0.2, 11.1±0.2, 11.6±0.2, 13.5±0.2, 13.9±0.2, 14.1±0.2, 15.4±0.2, 20.9±0.2, 21.1±0.2, 23.8±0.2 and 24.7±0.2.

[0293] Thermal analysis of Form III of Compound 1 was performed.

[0294] Endothermic: around 57°C and 78°C (peak, wide endothermic range from 30 to 120°C), around 191°C (peak, extrapolated onset temperature around 183°C), around 206°C (extrapolated onset temperature)

[0295] Mass reduction: 30℃ to 120℃ (9.7%)

[0296] Example 2-1: Crystalline Form I of the Methanesulfonate Salt of Compound 1

[0297] Compound 1 (2.063 g) was suspended in acetone / water (1 / 1) (6.2 mL). Methanesulfonic acid (0.370 g) was dissolved in acetone / water (1 / 1) (4.1 mL) alone, and the solution was added to the suspension of compound 1. The mixture was stirred at 61 ° C for 15 minutes. After dissolution, the solution was cooled to room temperature, then filtered using a filter, and the container and filter were washed twice with acetone / water (1 / 1) (1 mL). At 64 ° C, acetone (10.31 mL) was added to the resulting filtrate under stirring, and the solution was stirred for 5 minutes. Acetone (10.31 mL) was further added to the solution, and the mixture was stirred for 5 minutes. The heating of the water bath was stopped. Acetone (10.31 mL) was added to the solution at 40 ° C, and the mixture was stirred for 80 minutes. At 40 ° C, acetone (20.62 mL) was added to the mixture under stirring, and the mixture was stirred at 60 ° C for 45 minutes. The mixture was stirred at room temperature for 16 hours. The mixture was filtered and washed twice with 5% acetone aqueous solution (4 mL). The obtained solid was dried under reduced pressure at 40°C for 2 hours to obtain Form I of the methanesulfonate of Compound 1 (2.183 g) as a white powder.

[0298] The powder X-ray diffraction of the crystalline form I of the mesylate salt of Compound 1 was measured. Table 7 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0299] [Table 7]

[0300] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 7.0 34 17.6 31 10.6 57 18.6 17 13.7 19 20.5 20 14.1 100 21.6 15 16.2 42 24.5 26

[0301] For the identification of the crystalline form I of the mesylate salt of Compound 1, for example, a diffraction peak subset selected from the following [2-1-1] to [2-1-7] can be used:

[0302] [2-1-1] Peaks at 10.6 ± 0.2 and 14.1 ± 0.2;

[0303] [2-1-2] Peaks at 7.0 ± 0.2 and 10.6 ± 0.2;

[0304] [2-1-3] Peaks at 7.0 ± 0.2, 10.6 ± 0.2, and 14.1 ± 0.2;

[0305] [2-1-4] Peaks at 10.6±0.2, 14.1±0.2, and 16.2±0.2;

[0306] [2-1-5] peaks of 7.0 ± 0.2, 10.6 ± 0.2, 14.1 ± 0.2, and 16.2 ± 0.2;

[0307] [2-1-6] peaks of 7.0±0.2, 10.6±0.2, 14.1±0.2, 16.2±0.2, and 17.6±0.2; and

[0308] [2-1-7] Peaks of 7.0±0.2, 10.6±0.2, 13.7±0.2, 14.1±0.2, 16.2±0.2, 17.6±0.2, 18.6±0.2, 20.5±0.2, 21.6±0.2 and 24.5±0.2.

[0309] Thermal analysis of Form I of the mesylate salt of Compound 1 was performed.

[0310] Endothermic: around 253°C (peak, extrapolated starting temperature around 250°C)

[0311] Mass reduction: 27℃ to 100℃ (2.8%)

[0312] Example 2-2: Crystalline Form II of the Methanesulfonate Salt of Compound 1

[0313] The methanesulfonate of compound 1 (200 mg) was suspended in 1,4-dihydrochloric acid. The product was prepared by purifying the mixture of 1,2-dimethylformamide (2,4-dihydro-1 ...

[0314] Powder X-ray diffraction was measured for the crystal form II of the mesylate salt of Compound 1. Table 8 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0315] [Table 8]

[0316]

[0317] For the identification of the crystalline form II of the mesylate salt of Compound 1, for example, a diffraction peak subset selected from the following [2-2-1] to [2-2-6] can be used:

[0318] [2-2-1] Peaks at 21.8 ± 0.2 and 25.5 ± 0.2;

[0319] [2-2-2] Peaks at 18.4 ± 0.2 and 25.5 ± 0.2;

[0320] [2-2-2] peaks at 18.4 ± 0.2, 21.8 ± 0.2, and 25.5 ± 0.2;

[0321] [2-2-3] peaks of 18.4±0.2, 18.7±0.2, 21.8±0.2, and 25.5±0.2;

[0322] [2-2-4] peaks of 6.3±0.2, 12.7±0.2, 18.4±0.2, 18.7±0.2, 21.8±0.2, 24.9±0.2, and 25.5±0.2;

[0323] [2-2-5] peaks at 6.3±0.2, 10.6±0.2, 12.7±0.2, 18.4±0.2, 18.7±0.2, 21.8±0.2, 24.9±0.2, and 25.5±0.2; and

[0324] [2-2-6] Peaks of 6.3±0.2, 10.6±0.2, 12.7±0.2, 17.7±0.2, 18.4±0.2, 18.7±0.2, 21.8±0.2, 24.9±0.2 and 25.5±0.2.

[0325] Thermal analysis of Form II of the mesylate salt of Compound 1 was performed.

[0326] Exothermic: around 172°C (peak)

[0327] Endothermic: around 248°C (peak, extrapolated starting temperature around 243°C)

[0328] Mass reduction: 27℃ to 100℃ (2.1%)

[0329] Example 2-3: Crystalline Form III of the Methanesulfonate of Compound 1

[0330] The methanesulfonate of compound 1 (300 mg) was suspended in 1,4-dihydrochloric acid. The suspension was dissolved in decanane / water (1 / 1) (6.0 mL) at 60° C. The solution was frozen in a dry ice-acetone bath and the solid was lyophilized overnight.

[0331] To the solid obtained by lyophilization (10 mg) was added propyl acetate (0.2 mL), and the mixture was stirred at 60° C. for 5 days. The slurry was filtered to obtain Form III of mesylate of Compound 1. Using this crystal as a seed crystal, the following scale-up was performed using this lyophilized solid.

[0332] To the solid (100 mg) obtained by freeze drying, propyl acetate (5 mL) and seed crystals (1 mg) were added, and the mixture was stirred at 60° C. for 5 days. The slurry was filtered by suction. The obtained solid was washed with propyl acetate (1 mL) and dried under reduced pressure at 40° C. for 5 hours to obtain Form III (98 mg) of the mesylate of Compound 1.

[0333] The powder X-ray diffraction of the crystal form III of the mesylate salt of Compound 1 was measured. The diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak are shown in Table 9.

[0334] [Table 9]

[0335] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 6.4 24 18.3 64 12.8 59 19.3 38 16.8 25 22.6 73 17.8 100 24.3 47

[0336] For the identification of the crystalline form III of the mesylate salt of Compound 1, for example, a diffraction peak subset selected from the following [2-3-1] to [2-3-7] can be used:

[0337] [2-3-1] Peaks at 12.8 ± 0.2 and 22.6 ± 0.2;

[0338] [2-3-2] peaks at 17.8 ± 0.2 and 22.6 ± 0.2;

[0339] [2-3-3] peaks at 12.8 ± 0.2, 17.8 ± 0.2, and 22.6 ± 0.2;

[0340] [2-3-4] peaks of 17.8 ± 0.2, 18.3 ± 0.2, and 22.6 ± 0.2;

[0341] [2-3-5] peaks at 12.8 ± 0.2, 17.8 ± 0.2, 18.3 ± 0.2, and 22.6 ± 0.2;

[0342] [2-3-6] peaks at 6.4±0.2, 12.8±0.2, 17.8±0.2, 18.3±0.2, 19.3±0.2, 22.6±0.2, and 24.3±0.2; and

[0343] [2-3-7] Peaks of 6.4±0.2, 12.8±0.2, 16.8±0.2, 17.8±0.2, 18.3±0.2, 19.3±0.2, 22.6±0.2 and 24.3±0.2.

[0344] Thermal analysis of Form III of the mesylate salt of Compound 1 was performed.

[0345] Endothermic: around 252°C (peak, extrapolated starting temperature around 248°C)

[0346] Mass reduction: 30℃ to 230℃ (0.9%)

[0347] Example 2-4: Crystalline Form IV of the Methanesulfonate Salt of Compound 1

[0348] The methanesulfonate of compound 1 (161 mg) was dissolved in 1,4-dihydrochloric acid at 60°C. The product was added to 1% 4-nitropropene / 1 ...

[0349] Powder X-ray diffraction was measured for the crystal form IV of the mesylate salt of Compound 1. The diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak are shown in Table 10.

[0350] [Table 10]

[0351] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 6.0 70 15.4 100 9.9 21 16.3 21 11.0 41 18.2 20 12.0 15 19.9 16 13.5 17 24.9 21

[0352] For the identification of the crystalline form IV of the mesylate salt of Compound 1, for example, a diffraction peak subset selected from the following [2-4-1] to [2-4-6] can be used:

[0353] [2-4-1] Peaks at 6.0 ± 0.2 and 15.4 ± 0.2;

[0354] [2-4-2] Peaks at 6.0 ± 0.2 and 11.0 ± 0.2;

[0355] [2-4-3] peaks at 6.0 ± 0.2, 11.0 ± 0.2, and 15.4 ± 0.2;

[0356] [2-4-4] peaks at 6.0 ± 0.2, 9.9 ± 0.2, 11.0 ± 0.2, and 15.4 ± 0.2;

[0357] [2-4-5] peaks at 6.0 ± 0.2, 11.0 ± 0.2, 15.4 ± 0.2, and 16.3 ± 0.2;

[0358] [2-4-6] peaks at 6.0±0.2, 9.9±0.2, 11.0±0.2, 15.4±0.2, 16.3±0.2, 18.2±0.2, and 24.9±0.2; and

[0359] [2-4-7] Peaks of 6.0±0.2, 9.9±0.2, 11.0±0.2, 12.0±0.2, 13.5±0.2, 15.4±0.2, 16.3±0.2, 18.2±0.2, 19.9±0.2 and 24.9±0.2.

[0360] Thermal analysis of Form IV of the mesylate salt of Compound 1 was performed.

[0361] Endothermic: around 64°C (peak, wide endothermic range from 22 to 100°C), around 155°C (extrapolated onset temperature)

[0362] Mass reduction: 22℃ to 100℃ (8.1%)

[0363] Example 3-1: Crystalline Form I of the Hydrochloride Salt of Compound 1

[0364] Compound 1 (300 mg) was suspended in 1,4-dihydrochloric acid. 1mol / L hydrochloric acid (0.56mL) was added to the suspension in alkane / water (1 / 1) (7.5mL). After dissolution, the solution was freeze-dried. 2-propanol (6.0mL) was added to the obtained solid, and the mixture was stirred at room temperature for 30 minutes. Then, the mixture was stirred at 53°C for 2 hours and at room temperature for 4 days. The slurry was filtered. The obtained solid was dried under reduced pressure at 43°C for 2 hours to obtain the crystalline form I (310mg) of the hydrochloride of compound 1.

[0365] The powder X-ray diffraction of the crystalline form I of the hydrochloride salt of compound 1 was measured. The diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak are shown in Table 11.

[0366] [Table 11]

[0367] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 13.1 100 19.2 11 13.4 24 23.2 14 13.7 14 23.9 28 14.0 12 24.6 12 17.4 16 26.9 13

[0368] For the identification of the crystalline form I of the hydrochloride salt of Compound 1, for example, a diffraction peak subset selected from the following [3-1-1] to [3-1-5] can be used:

[0369] [3-1-1] Peaks at 13.1 ± 0.2 and 17.4 ± 0.2;

[0370] [3-1-2] peaks of 13.1 ± 0.2, 17.4 ± 0.2, and 23.9 ± 0.2;

[0371] [3-1-3] Peaks at 13.1±0.2, 13.4±0.2, 17.4±0.2, and 23.9±0.2;

[0372] [3-1-4] peaks of 13.1±0.2, 13.4±0.2, 17.4±0.2, 23.9±0.2, and 26.9±0.2; and

[0373] [3-1-5] Peaks of 13.1±0.2, 13.4±0.2, 13.7±0.2, 14.0±0.2, 17.4±0.2, 19.2±0.2, 23.2±0.2, 23.9±0.2, 24.6±0.2 and 26.9±0.2.

[0374] Thermal analysis of Form I of the hydrochloride salt of Compound 1 was performed.

[0375] Endothermic: around 235°C (peak, extrapolated starting temperature around 217°C)

[0376] Mass reduction: 24℃ to 200℃ (3.0%)

[0377] Example 3-2: Crystalline Form II of the Hydrochloride Salt of Compound 1

[0378] 1 mol / L hydrochloric acid (0.20 mL) was added to compound 1 (103 mg) at room temperature, and water (0.20 mL) and acetone (0.40 mL) were added to the mixture. The mixture was stirred at 61 ° C for 20 minutes. After dissolution, the solution was stirred at room temperature for 1 hour. Acetone (1.24 mL) was added to the solution, and the mixture was stirred for 1 hour. Acetone / water (20 / 1) (0.62 mL) was added to the mixture, and the mixture was stirred for 30 minutes. The solid in the slurry was filtered and the solid was dried under reduced pressure at 43 ° C for 1 hour to obtain a crystalline form II (97 mg) of the hydrochloride of compound 1.

[0379] Powder X-ray diffraction of the crystal form II of the hydrochloride salt of Compound 1 was measured. The diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak are shown in Table 12.

[0380] [Table 12]

[0381] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 6.2 78 13.0 30 8.1 100 16.4 25 8.4 31 25.2 23 10.2 64 26.4 38 12.1 55 27.1 18

[0382] For the identification of the crystalline form II of the hydrochloride salt of Compound 1, for example, a diffraction peak subset selected from the following [3-2-1] to [3-2-6] can be used:

[0383] [3-2-1] Peaks at 6.2±0.2 and 8.1±0.2;

[0384] [3-2-2] Peaks at 6.2 ± 0.2, 8.1 ± 0.2, and 10.2 ± 0.2;

[0385] [3-2-3] peaks at 6.2 ± 0.2, 8.1 ± 0.2, 10.2 ± 0.2, and 12.1 ± 0.2;

[0386] [3-2-4] peaks at 6.2 ± 0.2, 8.1 ± 0.2, 10.2 ± 0.2, 12.1 ± 0.2, and 13.0 ± 0.2;

[0387] [3-2-5] peaks at 6.2±0.2, 8.1±0.2, 10.2±0.2, 12.1±0.2, 13.0±0.2, and 26.4±0.2; and

[0388] [3-2-6] Peaks of 6.2±0.2, 8.1±0.2, 8.4±0.2, 10.2±0.2, 12.1±0.2, 13.0±0.2, 16.4±0.2, 25.2±0.2, 26.4±0.2 and 27.1±0.2.

[0389] Thermal analysis of Form II of the hydrochloride salt of Compound 1 was performed.

[0390] Endothermic: around 63°C (peak, wide endothermic range from 28 to 100°C), around 189°C (peak, extrapolated onset temperature around 180°C)

[0391] Mass reduction: 28℃ to 100℃ (9.7%)

[0392] Example 3-3: Crystalline Form III of the Hydrochloride Salt of Compound 1

[0393] Acetone (1.8 mL), water (0.8 mL) and 1 mol / L hydrochloric acid (0.58 mL) were added to the hydrochloride crystal II (334 mg) of compound 1 obtained by the method of Example 3-2, and the suspension was stirred at 45 ° C for 3 hours. After the suspension was cooled to room temperature, acetone (3.3 mL) was added to the suspension, and the mixture was stirred at room temperature overnight. The slurry was filtered. The obtained solid was dried under reduced pressure at 40 ° C for 2 hours to obtain the hydrochloride crystal III (242 mg) of compound 1.

[0394] Powder X-ray diffraction of the crystal form III of the hydrochloride salt of Compound 1 was measured. The diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak are shown in Table 13.

[0395] [Table 13]

[0396]

[0397] For the identification of the crystalline form III of the hydrochloride salt of Compound 1, for example, a diffraction peak subset selected from the following [3-3-1] to [3-3-3] can be used:

[0398] [3-3-1] Peaks at 12.9 ± 0.2 and 21.4 ± 0.2;

[0399] [3-3-2] Peaks at 12.9±0.2, 13.6±0.2, and 21.4±0.2; and

[0400] [3-3-3] Peaks of 12.9±0.2, 13.6±0.2, 20.5±0.2, 21.4±0.2, 22.8±0.2, 24.0±0.2, 26.3±0.2, 27.3±0.2 and 30.6±0.2.

[0401] Thermal analysis of Form III of the hydrochloride salt of Compound 1 was performed.

[0402] Endothermic: around 68°C (peak, wide endothermic range from 24°C to 90°C), around 191°C (peak, wide endothermic range from 150°C to 208°C), around 226°C (peak, extrapolated onset temperature around 208°C)

[0403] Mass reduction: 28℃ to 100℃ (2.6%), 100℃ to 208℃ (6.5%)

[0404] Example 3-4: Crystalline Form IV of the Hydrochloride Salt of Compound 1

[0405] The crystalline form I (352 mg) of the mesylate of compound 1 obtained by the method of Example 2-1 was suspended in the first solution (25 mL) of the dissolution test in the Japanese Pharmacopoeia, and the suspension was shaken at 37° C. for 24 hours. The suspension was left at room temperature for 2 hours and filtered. The obtained solid was dried under reduced pressure at room temperature for 3 hours to obtain the crystalline form IV (300 mg) of the hydrochloride of compound 1 as a white powder.

[0406] Powder X-ray diffraction was measured for the crystal form IV of the hydrochloride salt of Compound 1. Table 14 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0407] [Table 14]

[0408] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 5.2 17 12.5 11 10.5 100 16.2 52 11.0 98 24.1 11

[0409] For the identification of the crystalline form IV of the hydrochloride salt of Compound 1, for example, a diffraction peak subset selected from the following [3-4-1] to [3-4-4] can be used:

[0410] [3-4-1] Peaks at 10.5 ± 0.2 and 11.0 ± 0.2;

[0411] [3-4-2] peaks at 10.5 ± 0.2, 11.0 ± 0.2, and 16.2 ± 0.2;

[0412] [3-4-3] peaks at 5.2 ± 0.2, 10.5 ± 0.2, 11.0 ± 0.2, and 16.2 ± 0.2;

[0413] [3-4-4] peaks at 5.2±0.2, 10.5±0.2, 11.0±0.2, 12.5±0.2, and 16.2±0.2; and

[0414] [3-4-5] Peaks of 5.2±0.2, 10.5±0.2, 11.0±0.2, 12.5±0.2, 16.2±0.2 and 24.1±0.2.

[0415] Thermal analysis of Form IV of the hydrochloride salt of Compound 1 was performed.

[0416] Endothermic: around 67°C (peak, extrapolated starting temperature around 49°C), around 179°C (peak, extrapolated starting temperature around 174°C), around 216°C (peak, extrapolated starting temperature around 197°C)

[0417] Mass reduction: 25℃ to 100℃ (12.9%)

[0418] Example 4: Crystalline Form I of p-toluenesulfonate of Compound 1

[0419] Compound 1 (260 mg) was suspended in 1,4-dihydrochloric acid. The mixture was stirred for 3 hours at 45 ° C and stirred for 3 days at room temperature. The slurry was filtered. The obtained solid was dried under reduced pressure at 40 ° C for 2 hours to obtain the crystalline form I (340 mg) of the p-toluenesulfonic acid salt of compound 1, which was a white powder.

[0420] The powder X-ray diffraction of the crystalline form I of the p-toluenesulfonate salt of Compound 1 was measured. Table 15 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0421] [Table 15]

[0422] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 6.1 95 16.4 32 12.2 73 16.7 71 12.9 32 20.6 29 13.8 48 21.2 30 14.0 64 24.7 100 15.3 44 25.4 62

[0423] For the identification of the crystalline form I of the p-toluenesulfonate salt of Compound 1, for example, a diffraction peak subset selected from the following [4-1] to [4-6] can be used:

[0424] [4-1] peaks at 6.1 ± 0.2 and 24.7 ± 0.2;

[0425] [4-2] Peaks at 6.1 ± 0.2 and 12.2 ± 0.2;

[0426] [4-3] peaks of 6.1 ± 0.2, 12.2 ± 0.2, and 24.7 ± 0.2;

[0427] [4-4] peaks of 6.1±0.2, 12.2±0.2, 14.0±0.2, 16.7±0.2, and 24.7±0.2;

[0428] [4-5] peaks at 6.1±0.2, 12.2±0.2, 14.0±0.2, 16.7±0.2, 24.7±0.2, and 25.4±0.2; and

[0429] [4-6] Peaks of 6.1±0.2, 12.2±0.2, 12.9±0.2, 13.8±0.2, 14.0±0.2, 15.3±0.2, 16.4±0.2, 16.7±0.2, 20.6±0.2, 21.2±0.2, 24.7±0.2 and 25.4±0.2.

[0430] Thermal analysis of Form I of the p-toluenesulfonate salt of Compound 1 was performed.

[0431] Endothermic: around 100°C (peak, extrapolated starting temperature around 87°C), around 236°C (peak, extrapolated starting temperature around 225°C)

[0432] Mass reduction: 29℃ to 120℃ (1.9%)

[0433] Example 5: Crystalline Form I of the Sodium Salt of Compound 1

[0434] Compound 1 (50 mg) was suspended in 2-propanol / water (1 / 1) (0.5 mL), and 1 mol / L sodium hydroxide aqueous solution (0.185 mL) was added to the suspension. After dissolution, 1 mol / L hydrochloric acid (0.093 mL) was added to the solution, and the mixture was stirred at room temperature for 3 days. The mixture was stirred at 40 ° C for 5 hours and further stirred overnight at room temperature. The slurry was filtered. The obtained solid was dried under reduced pressure at 40 ° C for 3 hours to obtain the crystalline form I (34 mg) of the sodium salt of compound 1, which was a white powder.

[0435] Powder X-ray diffraction of the crystalline form I of the sodium salt of Compound 1 was measured. Table 16 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0436] [Table 16]

[0437] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 5.8 28 17.4 41 12.1 33 22.7 100 13.0 27 23.8 45 15.9 63 25.1 36 16.2 28 26.2 24

[0438] For the identification of the crystalline form I of the sodium salt of Compound 1, for example, a diffraction peak subset selected from the following [5-1] to [5-7] can be used:

[0439] [5-1] Peaks at 5.8 ± 0.2 and 22.7 ± 0.2;

[0440] [5-2] peaks of 15.9 ± 0.2 and 22.7 ± 0.2;

[0441] [5-3] peaks of 5.8 ± 0.2, 15.9 ± 0.2, and 22.7 ± 0.2;

[0442] [5-4] peaks of 5.8 ± 0.2, 12.1 ± 0.2, 15.9 ± 0.2, and 22.7 ± 0.2;

[0443] [5-5] peaks of 5.8±0.2, 12.1±0.2, 15.9±0.2, 17.4±0.2, and 22.7±0.2;

[0444] [5-6] peaks at 5.8±0.2, 12.1±0.2, 15.9±0.2, 17.4±0.2, 22.7±0.2, and 23.8±0.2; and

[0445] [5-7] Peaks of 5.8±0.2, 12.1±0.2, 13.0±0.2, 15.9±0.2, 16.2±0.2, 17.4±0.2, 22.7±0.2, 23.8±0.2, 25.1±0.2 and 26.2±0.2.

[0446] Thermal analysis of Form I of the sodium salt of Compound 1 was performed.

[0447] Endothermic: around 75°C (peak, wide endothermic range from 50 to 120°C), around 197°C (peak, extrapolated onset temperature around 194°C)

[0448] Mass reduction: 29℃ to around 150℃ (13.9%)

[0449] Example 6: Crystalline Form I of Potassium Salt of Compound 1

[0450] Compound 1 (100mg) is suspended in 2-propanol / water (1 / 1) (1.0mL), and 1mol / L potassium hydroxide aqueous solution (0.370mL) is added to the suspension. After dissolution, 1mol / L hydrochloric acid (0.185mL) is added to the solution at room temperature, and the mixture is stirred for 10 minutes. 2-propanol (1.25mL) is added to the mixture at room temperature, and the mixture is stirred for 2 hours. 2-propanol (0.25mL) is added to the mixture at room temperature, and the mixture is stirred for 1 hour. 2-propanol (0.5mL) is added to the mixture again at room temperature, and the mixture is stirred for 6 hours. The slurry is filtered and washed twice with 2-propanol / water (4 / 1) (1.0mL). The resulting solid is dried under reduced pressure at room temperature for 1 hour, and dried at 40°C for 1 hour to obtain the crystalline form I (70mg) of the potassium salt of compound 1, which is a white powder.

[0451] Powder X-ray diffraction of the crystalline form I of the potassium salt of Compound 1 was measured. Table 17 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0452] [Table 17]

[0453] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 5.7 41 17.4 21 11.6 23 22.5 30 12.0 26 22.8 100 15.8 25 29.4 16

[0454] For the identification of the crystalline form I of the potassium salt of Compound 1, for example, a diffraction peak subset selected from the following [6-1] to [6-6] can be used:

[0455] [6-1] peaks of 5.7 ± 0.2 and 22.8 ± 0.2;

[0456] [6-2] peaks of 5.7 ± 0.2, 12.0 ± 0.2, and 22.8 ± 0.2;

[0457] [6-3] peaks of 5.7 ± 0.2, 11.6 ± 0.2, 12.0 ± 0.2, and 22.8 ± 0.2;

[0458] [6-4] peaks of 5.7±0.2, 11.6±0.2, 12.0±0.2, 15.8±0.2, 17.4±0.2, and 22.8±0.2;

[0459] [6-5] peaks of 5.7±0.2, 11.6±0.2, 12.0±0.2, 15.8±0.2, 17.4±0.2, 22.5±0.2, and 22.8±0.2; and

[0460] [6-6] Peaks of 5.7±0.2, 11.6±0.2, 12.0±0.2, 15.8±0.2, 17.4±0.2, 22.5±0.2, 22.8±0.2 and 29.4±0.2.

[0461] Thermal analysis of Form I of the potassium salt of Compound 1 was performed.

[0462] Endothermic: around 70°C (peak, wide endothermic range from 23 to 100°C), around 187°C (peak, extrapolated onset temperature around 182°C)

[0463] Mass reduction: 23℃ to 100℃ (12.9%)

[0464] Example 7: Crystalline Form I of the Calcium Salt of Compound 1

[0465] Compound 1 (300 mg) was suspended in methanol / water (1 / 1) (3.0 mL), 1 mol / L sodium hydroxide aqueous solution (1.12 mL) was added to the suspension, and the mixture was stirred at room temperature. After dissolution, calcium chloride (62 mg) was added to the solution at room temperature, and the mixture was stirred for 1 hour. The mixture was stirred at 45 ° C for 3 hours and further stirred overnight at room temperature. The slurry was filtered. The resulting solid was dried under reduced pressure at 43 ° C (3 hours) to obtain the crystalline form I (310 mg) of the calcium salt of compound 1, which was a white powder.

[0466] Powder X-ray diffraction of the crystal form I of the calcium salt of Compound 1 was measured. Table 18 shows the diffraction angle (2θ (°)) of the main diffraction peak and the relative intensity (Rel. Den. (%)) of the diffraction peak.

[0467] [Table 18]

[0468] 2θ(°) Relative strength (%) 2θ(°) Relative strength (%) 7.3 100 17.3 24 16.1 45 17.7 35 16.5 20 20.1 35 17.0 31 25.4 23

[0469] For the identification of the crystalline form I of the calcium salt of Compound 1, for example, a diffraction peak subset selected from the following [7-1] to [7-5] can be used:

[0470] [7-1] Peaks at 7.3 ± 0.2 and 16.1 ± 0.2;

[0471] [7-2] Peaks at 7.3 ± 0.2, 16.1 ± 0.2, and 20.1 ± 0.2;

[0472] [7-3] peaks of 7.3 ± 0.2, 16.1 ± 0.2, 17.7 ± 0.2, and 20.1 ± 0.2;

[0473] [7-4] peaks at 7.3±0.2, 16.1±0.2, 17.0±0.2, 17.7±0.2, and 20.1±0.2; and

[0474] [7-5] Peaks at 7.3±0.2, 16.1±0.2, 16.5±0.2, 17.0±0.2, 17.3±0.2, 17.7±0.2, 20.1±0.2 and 25.4.

[0475] Thermal analysis of Form I of the salt of Compound 1 was performed.

[0476] Endothermic: around 79°C (peak, wide endothermic range from 25 to 150°C)

[0477] Mass reduction: 25℃ to around 200℃ (13.4%)

[0478] The salts of Examples 2-1 to 7 1 The chemical shift values ​​of the H-NMR spectrum are shown in the following table.

[0479] [Table 19]

[0480]

[0481] [Table 20]

[0482]

[0483] [Table 21]

[0484]

[0485] Test Example 4: Solid Stability Test

[0486] The physicochemical and chemical stabilities of the crystals of Compound 1 (Forms I to III), the crystals of the methanesulfonate salt of Compound 1 (Forms I, II and IV), the crystals of the hydrochloride salt (Forms I and III), the Form I of the p-toluenesulfonate salt, the Form I of the sodium salt and the Form I of the calcium salt were investigated.

[0487] (1) Methods

[0488] Physicochemical stability: Each crystal was stored in an open environment at 40°C. Powder X-ray diffraction of the sample was measured at the beginning and after 1 month, and the change of crystal form was confirmed. The change of properties was also observed.

[0489] Chemical stability: Each crystal was stored in an open condition at 40° C. The mass of Compound 1 in the sample was measured under the following HPLC measurement conditions at the beginning and after 1 month.

[0490] [HPLC conditions]

[0491] Detector: UV-visible absorbance spectrophotometer / wavelength: 225nm

[0492] Column: L-column2 ODS, 3μm, 4.6×150mm (Chemical Evaluation Research Institute)

[0493] Column temperature: Constant temperature around 40°C

[0494] Flow rate: 1.0mL / min

[0495] Mobile phase A: Aqueous solution of potassium dihydrogen phosphate and dipotassium hydrogen phosphate, adjusted to 10 mmol / L with water

[0496] Mobile phase B: acetonitrile

[0497] Mobile phase ratio:

[0498] 0 to 30 minutes: Mobile phase A / Mobile phase B = 88 / 12

[0499] 30 to 50 minutes: Mobile phase A / Mobile phase B = 88 / 12 to 25 / 75

[0500] 50 to 55 minutes: Mobile phase A / Mobile phase B = 25 / 75

[0501] 55 to 55.01 minutes: Mobile phase A / Mobile phase B = 25 / 75 to 88 / 12

[0502] 55.01 to 75 minutes: Mobile phase A / mobile phase B = 88 / 12

[0503] Injection volume: 5 μL

[0504] Sample cooler: 4°C

[0505] Dissolving solvent: mixed solution (mobile phase / acetonitrile = 75 / 25)

[0506] Sample solution: The sample is dissolved in a dissolving solvent and adjusted to approximately 1 mg / mL.

[0507] The peaks from the blank were excluded, the peak areas of compound 1 and similar substances were measured by automatic integration, and the mass of compound 1 was calculated by area normalization. In addition, the mass change of compound 1 before and after storage was calculated.

[0508] (2) Results

[0509] When stored in an open environment at 40°C, the crystals of Compound 1 and the crystals of the salt of Compound 1 were physically and chemically stable, and the crystal shape and properties were almost unchanged. In addition, the crystals of Compound 1 and the crystals of the salt of Compound 1 were chemically stable, and the amount of Compound 1 was almost unchanged (Table 22).

[0510] Therefore, it was demonstrated that the crystal of Compound 1 or a salt thereof of the present invention had good physical properties as a raw material drug.

[0511] [Table 22]

[0512]

[0513] Industrial Availability

[0514] The crystal of Compound 1 or a salt thereof of the present invention has good physical properties as a raw material drug and can be used as a therapeutic agent for inflammatory bowel disease.

Claims

1. A crystal of a methanesulfonate salt of a compound represented by the following formula (I): It is a crystal of a mesylate salt of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction: (i) peaks at 7.0 ± 0.2, 10.6 ± 0.2, 14.1 ± 0.2, 16.2 ± 0.2, and 17.6 ± 0.2; (ii) peaks at 6.3 ± 0.2, 12.7 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 24.9 ± 0.2, and 25.5 ± 0.2; (iii) peaks at 6.4±0.2, 12.8±0.2, 17.8±0.2, 18.3±0.2, 19.3±0.2, 22.6±0.2, and 24.3±0.2; and (iv) Peaks at 6.0±0.2, 9.9±0.2, 11.0±0.2, 15.4±0.2, 16.3±0.2, 18.2±0.2, and 24.9±0.

2.

2. The crystal according to claim 1, which is a crystal of a mesylate salt of the compound selected from the following (i) to (iv): (i) having a subset of peaks at diffraction angles (2θ (°)) of 7.0±0.2, 10.6±0.2, 14.1±0.2, 16.2±0.2 and 17.6±0.2 in powder X-ray diffraction, and an endothermic peak of 253°C±5°C in TG-DTA; (ii) a subset of peaks at diffraction angles (2θ (°)) of 6.3±0.2, 12.7±0.2, 18.4±0.2, 18.7±0.2, 21.8±0.2, 24.9±0.2 and 25.5±0.2 in powder X-ray diffraction, and an endothermic peak at 248°C±5°C in TG-DTA; (iii) having a subset of peaks at diffraction angles (2θ (°)) of 6.4±0.2, 12.8±0.2, 17.8±0.2, 18.3±0.2, 19.3±0.2, 22.6±0.2 and 24.3±0.2 in powder X-ray diffraction, and an endothermic peak at 252°C±5°C in TG-DTA; and (iv) having a subset of peaks at diffraction angles (2θ (°)) of 6.0±0.2, 9.9±0.2, 11.0±0.2, 15.4±0.2, 16.3±0.2, 18.2±0.2 and 24.9±0.2 in powder X-ray diffraction, and an endothermic peak at 64°C±5°C in TG-DTA.

3. The crystal according to claim 1, which is a crystal of the mesylate salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction: (i) peaks at 7.0 ± 0.2, 10.6 ± 0.2, 13.7 ± 0.2, 14.1 ± 0.2, 16.2 ± 0.2, 17.6 ± 0.21, 18.6 ± 0.2, 20.5 ± 0.2, 21.6 ± 0.2, and 24.5 ± 0.2; (ii) peaks at 6.3 ± 0.2, 10.6 ± 0.2, 12.7 ± 0.2, 17.7 ± 0.2, 18.4 ± 0.2, 18.7 ± 0.2, 21.8 ± 0.2, 24.9 ± 0.2, and 25.5 ± 0.2; (iii) peaks at 6.4±0.2, 12.8±0.2, 17.8±0.2, 18.3±0.2, 19.3±0.2, 22.6±0.2, and 24.3±0.2; and (iv) peaks at 6.0±0.2, 9.9±0.2, 11.0±0.2, 12.0±0.2, 13.5±0.2, 15.4±0.2, 16.3±0.2, 18.2±0.2, 19.9±0.2, and 24.9±0.

2.

4. A crystal of a hydrochloride salt of a compound represented by the following formula (I), It is a crystal of the hydrochloride salt of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction: (i) peaks at 13.1 ± 0.2, 13.4 ± 0.2, 17.4 ± 0.2, 23.9 ± 0.2, and 26.9 ± 0.2; (ii) peaks at 6.2 ± 0.2, 8.1 ± 0.2, 10.2 ± 0.2, 12.1 ± 0.2, and 13.0 ± 0.2; (iii) peaks at 12.9±0.2, 13.6±0.2, 20.5±0.2, 21.4±0.2, 22.8±0.2, 24.0±0.2, 26.3±0.2, 27.3±0.2, and 30.6±0.2; and (iv) Peaks at 5.2±0.2, 10.5±0.2, 11.0±0.2, 12.5±0.2 and 16.2±0.

2.

5. The crystal according to claim 4, which is a crystal of a hydrochloride salt of the compound selected from the following (i) to (iv): (i) having a subset of peaks at diffraction angles (2θ (°)) of 13.1±0.2, 13.4±0.2, 17.4±0.2, 23.9±0.2 and 26.9±0.2 in powder X-ray diffraction, and an endothermic peak at 235°C±5°C in TG-DTA; (ii) a subset of peaks at diffraction angles (2θ (°)) of 6.2±0.2, 8.1±0.2, 10.2±0.2, 12.1±0.2 and 13.0±0.2 in powder X-ray diffraction, and endothermic peaks at 63°C±5°C and 189°C±5°C in TG-DTA; (iii) having a subset of peaks at diffraction angles (2θ (°)) of 12.9±0.2, 13.6±0.2, 20.5±0.2, 21.4±0.2, 22.8±0.2, 24.0±0.2, 26.3±0.2, 27.3±0.2 and 30.6±0.2 in powder X-ray diffraction, and endothermic peaks at 68°C±5°C, 191°C±5°C and 226°C±5°C in TG-DTA; and (iv) having a subset of peaks at diffraction angles (2θ (°)) of 5.2±0.2, 10.5±0.2, 11.0±0.2, 12.5±0.2 and 16.2±0.2 in powder X-ray diffraction, and endothermic peaks at 67°C±5°C, 179°C±5°C and 216°C±5°C in TG-DTA.

6. A crystal of a salt of a compound represented by the following formula (I): It is a crystal of a salt having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iv) in powder X-ray diffraction: (i) p-toluenesulfonate with peaks at 6.1±0.2, 12.2±0.2, 14.0±0.2, 16.7±0.2, and 24.7±0.2; (ii) sodium salt with peaks at 5.8±0.2, 12.1±0.2, 15.9±0.2, 17.4±0.2, and 22.7±0.2; (iii) potassium salt having peaks at 5.7±0.2, 11.6±0.2, 12.0±0.2, 15.8±0.2, 17.4±0.2, and 22.8±0.2; and (iv) Calcium salt with peaks at 7.3±0.2, 16.1±0.2, 17.0±0.2, 17.7±0.2 and 20.1±0.

2.

7. The crystal according to claim 6, which is a crystal of a salt of the compound selected from the following (i) to (iv): (i) a p-toluenesulfonate salt having a subset of peaks at diffraction angles (2θ (°)) of 6.1±0.2, 12.2±0.2, 14.0±0.2, 16.7±0.2 and 24.7±0.2 in powder X-ray diffraction, and endothermic peaks at 100°C±5°C and 236°C±5°C in TG-DTA; (ii) a sodium salt having a subset of peaks at diffraction angles (2θ (°)) of 5.8±0.2, 12.1±0.2, 15.9±0.2, 17.4±0.2 and 22.7±0.2 in powder X-ray diffraction, and endothermic peaks at 75°C±5°C and 197°C±5°C in TG-DTA; (iii) a potassium salt having a subset of peaks at diffraction angles (2θ (°)) of 5.7±0.2, 11.6±0.2, 12.0±0.2, 15.8±0.2, 17.4±0.2 and 22.8±0.2 in powder X-ray diffraction, and endothermic peaks at 70°C±5°C and 187°C±5°C in TG-DTA; and (iv) a calcium salt having a subset of peaks at diffraction angles (2θ (°)) of 7.3±0.2, 16.1±0.2, 17.0±0.2, 17.7±0.2 and 20.1±0.2 in powder X-ray diffraction, and an endothermic peak of 79°C±5°C in TG-DTA.

8. A crystal of a compound represented by the following formula (I): It is a crystal of the compound having a subset of peaks at diffraction angles (2θ (°)) selected from the following (i) to (iii) in powder X-ray diffraction: (i) peaks at 7.6 ± 0.2, 9.0 ± 0.2, 10.1 ± 0.2, 13.0 ± 0.2, and 18.0 ± 0.2; (ii) peaks at 11.4±0.2, 12.2±0.2, 12.5±0.2, 17.0±0.2, and 17.6±0.2; and (iii) Peaks at 10.5±0.2, 11.1±0.2, 13.5±0.2, 14.1±0.2, and 24.7±0.

2.

9. The crystal according to claim 8, which is a crystal of the compound selected from the following (i) to (iv): (i) having a subset of peaks at diffraction angles (2θ (°)) of 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2 and 18.0±0.2 in powder X-ray diffraction, and an endothermic peak of 266°C±5°C in TG-DTA; (ii) having a subset of peaks at diffraction angles (2θ (°)) of 11.4±0.2, 12.2±0.2, 12.5±0.2, 17.0±0.2 and 17.6±0.2 in powder X-ray diffraction, and an endothermic peak at 233°C±5°C in TG-DTA; and (iii) having a subset of peaks at diffraction angles (2θ (°)) of 10.5±0.2, 11.1±0.2, 13.5±0.2, 14.1±0.2 and 24.7±0.2 in powder X-ray diffraction, and endothermic peaks of 57°C±5°C and 78°C±5°C in TG-DTA.

10. The crystal according to claim 8, which is a crystal of the compound having peaks at diffraction angles (2θ (°)) of 7.6±0.2, 9.0±0.2, 10.1±0.2, 13.0±0.2, 17.1±0.2, 18.0±0.2, 19.1±0.2, 21.1±0.2, 21.7±0.2, 23.4±0.2, 26.2±0.2 and 27.5±0.2 in powder X-ray diffraction.

11. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 10 and a pharmaceutical additive.

12. Use of the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating inflammatory bowel disease.

13. The use according to claim 12, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

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