Salts of triazine compounds, their crystalline form, and method of production

Abstract

The present invention provides a triazine compound salt that has an aldosterone synthase inhibitory effect and is useful as a medicine, in particular, an agent for preventing or treating primary aldosteronism and the like, a crystal, and a production method therefor. Specifically, the present invention provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoyl methyl]piperazine-1-yl]-5-(p-tolyl)-1,2,4-triazine, the salt being a hydrobromide, a sulfate, a succinate, or a tosilate.

Description

[Technical Field]

[0001] The present invention relates to a salt of a triazine compound that has an inhibitory effect on aldosterone synthase and is useful as a pharmaceutical, particularly as a preventive or therapeutic agent for primary aldosteronism, as well as its crystalline form and method of production. More specifically, the present invention relates to 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine (hereinafter sometimes referred to as "triazine compound A") which has excellent properties as a pharmaceutical active ingredient, or a pharmaceutically acceptable salt thereof, its crystalline form, a method of production thereof, and a pharmaceutical composition containing it as an active ingredient. [Background technology]

[0002] Patent Document 1 discloses several triazine compounds having aldosterone synthase inhibitory activity or pharmaceutically acceptable salts thereof, and Triazine Compound A is described in Example 48. However, Patent Document 1 does not describe or suggest any specific salt or crystalline form of Triazine Compound A. Furthermore, Patent Document 1 discloses the following method for producing triazine compound A. [ka] [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2015 / 163427 brochure [Overview of the project] [Problems that the invention aims to solve]

[0004] The present invention provides a novel salt of triazine compound A used for the prevention or treatment of primary aldosteronism, its crystalline form, and an industrially advantageous method for producing the compound. [Means for solving the problem]

[0005] To solve the above problems, the inventors diligently studied and attempted to obtain a salt in order to obtain an active pharmaceutical ingredient with a certain level of quality suitable for use as a pharmaceutical. As a result, hydrobromide, sulfate, succinate, or tosylate of triazine compound A was found to be a salt that yields crystals with excellent purity, thermal stability, hygroscopicity, deliquescence, chemical stability, safety, and ease of handling. Next, the inventors conducted intensive studies on the salt of the above-mentioned triazine compound A and found that the hydrobromide salt of triazine compound A exhibits stable pharmacokinetics under both conditions of increased and suppressed gastric acid secretion. Although the hydrobromide salt of triazine compound A possessed unexpectedly excellent properties as a pharmaceutical active pharmaceutical ingredient, it was found that various crystalline forms existed. The inventors found that the A-form crystal of triazine compound A hydrobromide was the most preferable crystalline form in terms of stability and other factors. However, depending on the amount of hydrogen bromide added in the crystallization process, the crystallization temperature, and the composition of the crystallization solvent, problems such as polymorph contamination, increased impurities, and increased residual solvent were observed, making it difficult to obtain the desired crystals reproducibly and stably. Therefore, the inventors diligently investigated the types, amounts, and ratios of reagents and solvents used in crystallization, as well as the crystallization procedure. As a result, they found a method for efficiently obtaining A-form crystals of triazine compound A hydrobromide, which are crystals of a quality suitable for pharmaceutical active pharmaceutical ingredients, and completed the present invention. Furthermore, similar to the A-form crystal of triazine compound A hydrobromide, methods for obtaining stable crystalline forms of high quality for the sulfate, succinate, and tosylate salts of triazine compound A were also found.

[0006] Furthermore, as a result of differential scanning calorimetry, it was confirmed that the compounds (B), (C), and (E), which are production intermediates described in Patent Document 1, are compounds having an explosion risk. Furthermore, as a result of genotoxicity risk assessment by DEREK; MultiCASE, it was confirmed that the compounds (B), (C), and (D) are compounds potentially having a genotoxic risk. Thus, the production method described in Patent Document 1 was a production method disadvantageous for implementation on an industrial scale because it used compounds having an explosion risk or a genotoxic risk as production intermediates. In addition, since the triazine compound A is a poorly soluble compound and has physical properties similar to those of insoluble impurities generated in intermediate steps, purification such as isolation in the final step is not easy, and it has become clear that it is difficult to supply triazine compound A of a quality suitable as a pharmaceutical raw material. Therefore, as a result of various studies, the inventors of the present invention have found that by using a compound having a low explosion risk and a low genotoxic risk as a production intermediate, and further by using a compound having a high solubility as a production intermediate, insoluble impurities can be easily removed, and an industrially advantageous production method of triazine compound A having a quality suitable as a pharmaceutical raw material has been found.

[0007] That is, the present invention is as follows. [1] A pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is a hydrobromide, a sulfate, a succinate, or a tosylate. [2] The salt according to [1], wherein the salt is a hydrobromide. [3] A crystal of the salt according to [1]. [4] The crystal according to [3], wherein the salt is a hydrobromide. [4-1] The crystal according to [3], wherein the salt is a dihydrobromide. [4-2] A crystal described in any one of [3] to [4-1], wherein the salt is a hydrate. [5] A crystal according to any one of [4] to [4-2], having peaks at 8.8°±0.2°, 18.1°±0.2°, 20.9°±0.2°, and 25.6°±0.2° as diffraction angles represented by 2θ in its powder X-ray diffraction spectrum. [6] A crystal according to any one of [4] to [5], having an endothermic peak at 265-275°C as determined by differential scanning calorimetry analysis. [7] An aldosterone synthase inhibitor containing the crystal described in any one of [3] to [6] as an active ingredient. [8] A pharmaceutical composition containing the crystal described in any one of [3] to [6] and a pharmaceutically acceptable additive. [9] The pharmaceutical composition according to [8] for preventing or treating a disease in which improvement of the pathological condition is expected by inhibiting aldosterone synthase.

[10] The pharmaceutical composition according to [9], wherein the disease is one or more diseases selected from the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrotic lesions, post-myocardial ischemia injury, coronary artery disease, myocardial or vascular fibrosis or remodeling, vascular restenosis, vascular wall thickening, arteriosclerosis, acute kidney injury, chronic kidney disease, renal fibrosis, nephropathy, hypokalemia, metabolic syndrome, obesity, sleep apnea syndrome, retinopathy, liver disease, idiopathic and / or periodic edema, and sympathetic hyperactivity.

[11] A method for preventing or treating a disease in which improvement of the condition is expected by inhibiting aldosterone synthase, comprising administering an effective amount of the crystal described in any one of [3] to [6] to a patient.

[12] Use of any one of the crystals described in [3] to [6] in the manufacture of a pharmaceutical product for preventing or treating a disease in which improvement of the pathological condition is expected by inhibition of aldosterone synthase.

[13] A crystal according to any one of [3] to [6] for preventing or treating a disease in which improvement of the pathological condition is expected by inhibition of aldosterone synthase.

[14] The following reaction equation: [ka] (In the formula, R 1 and R 2 (Each of these independently represents an amino protecting group.) A method for producing 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, which is compound (10) represented by the following steps: (Step 1) A step of reacting compound (2) and compound (3) to obtain compound (4) or a salt thereof; (Step 2) A step of subjecting compound (4) or its salt to a deprotection reaction to obtain compound (5) or its salt; (Step 3) A step of reacting compound (5) or a salt thereof with compound (7) to obtain compound (8) or a salt thereof; (Step 4) A step of subjecting compound (8) or its salt to a deprotection reaction to obtain compound (9) or its salt; and (Step 5) A step of reacting compound (9) or a salt thereof with an acetylating agent to obtain compound (10). A manufacturing method that includes this.

[15] A method for producing crystals of hydrobromide salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, characterized by crystallizing 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine by adding 0.9 to 1.1 equivalents of hydrogen bromide to a mixed solvent of water and acetone with a water content of 2.0 to 3.0 volume%.

[16] Formula (4) [ka] (In the formula, R 1 and R 2 (Each of these independently represents an amino protecting group.) A compound represented by or a salt thereof.

[17] Formula (5) [ka] (In the formula, R 2 (This indicates an amino protecting group.) A compound represented by or a salt thereof.

[18] Formula (8) [ka] (In the formula, R 2 (This indicates an amino protecting group.) A compound represented by or a salt thereof. [Effects of the Invention]

[0008] The hydrobromide, sulfate, succinate, and tosylate salts of triazine compound A of the present invention are all excellent salts for use as pharmaceutical raw materials. In particular, its crystals do not leave any solvent residue, have excellent thermal stability, are stable with minimal weight change to humidity, do not deliquesce, and have excellent chemical stability. Thus, salts or crystals of triazine compound A are useful as pharmaceutical raw materials. In particular, the hydrobromide salt of triazine compound A of the present invention exhibits stable pharmacokinetics under both gastric acid secretion promotion and gastric acid secretion suppression conditions. Furthermore, its crystals exhibit excellent stability and purity, and a method has been established to stably obtain crystals that do not contain compounds that may adversely affect the body from a safety standpoint. Thus, the hydrobromide salt or crystals of triazine compound A are particularly useful as pharmaceutical active pharmaceutical ingredients. Furthermore, the method for producing triazine compound A of the present invention is useful as an industrial method for producing pharmaceutical active pharmaceutical ingredients of good quality, since it allows for the reproducible and industrially suitable acquisition of triazine compound A. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 shows the results of powder X-ray diffraction measurements of the sulfate form B crystal of triazine compound A. [Figure 2] Figure 2 shows the results of differential scanning calorimetry performed on the sulfate form B crystal of triazine compound A. [Figure 3] Figure 3 shows the results of powder X-ray diffraction measurements of the tosylate C-type crystal of triazine compound A. [Figure 4] Figure 4 shows the results of differential scanning calorimetry performed on the tosylate C-type crystal of triazine compound A. [Figure 5] Figure 5 shows the results of powder X-ray diffraction measurements of succinate type A crystals of triazine compound A. [Figure 6] Figure 6 shows the results of differential scanning calorimetry performed on succinate type A crystals of triazine compound A. [Figure 7] Figure 7 shows the results of powder X-ray diffraction measurements of the hydrobromide F-type crystal of triazine compound A. [Figure 8] Figure 8 shows the results of differential scanning calorimetry performed on the hydrobromide F-type crystal of triazine compound A. [Figure 9] Figure 9 shows the results of powder X-ray diffraction measurements of the hydrobromide N-type crystal of triazine compound A. [Figure 10] Figure 10 shows the results of differential scanning calorimetry performed on N-type crystals of the hydrobromide salt of triazine compound A. [Figure 11] Figure 11 shows the results of powder X-ray diffraction measurements of the hydrobromide A-type crystal of triazine compound A. [Figure 12] Figure 12 shows the results of differential scanning calorimetry performed on the hydrobromide A-type crystal of triazine compound A. [Figure 13] Figure 13 shows the results of infrared absorption spectroscopy measurements of the hydrobromide A-type crystal of triazine compound A. [Figure 14]Figure 14 is a diagram showing the pharmacokinetics of free triazine compound A and the hydrobromide salt of triazine compound A under combination with pentagastrin, which is a gastric acid secretion promoter, or omeprazole, which is a gastric acid secretion inhibitor.

Embodiments for Carrying Out the Invention

[0010] In this specification, the substituents represented by each symbol have the following meanings respectively. Examples of the “amino protecting group” include protecting groups commonly used in the field of organic synthetic chemistry, such as t-butoxycarbonyl group, benzyloxycarbonyl group, and p-methoxybenzyl group, etc. Among them, t-butoxycarbonyl group and benzyloxycarbonyl group are preferred.

[0011] Triazine compound A can be produced as follows.

Chemical formula

[0012] Step 1: Step 1 is a step of reacting compound (2) and compound (3) to obtain compound (4) or its salt. Compound (2) and compound (3) are known or can be produced according to known methods. Examples of the salt of compound (4) include acid addition salts, etc., such as inorganic acid salts like hydrochloride, sulfate, phosphate or hydrobromide, and organic acid salts like acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate, etc. Preferably, hydrochloride is mentioned. The reaction between compound (2) and compound (3) can be carried out in accordance with the method described in International Publication No. 2015 / 163427, for example, by reacting compound (2), compound (3), and a coupling agent in a solvent in the presence of a base. Examples of condensing agents include carbodiimides, acid azides, phosphonium-based condensing agents, triazoles, and acid anhydrides, with acid anhydrides being preferred, and propanephosphonic anhydride being particularly preferred. Any solvent that does not affect this reaction can be used, and examples include aromatic hydrocarbons (benzene, toluene, and xylene, etc.), aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), and ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.). These can also be used in appropriate combinations. Of these, nitriles are preferred, and acetonitrile is particularly preferred. Examples of bases include triethylamine, diisopropylethylamine, and 1,8-diazabi. C Examples include chloro[5.4.0]undeca-7-ene (DBU), of which diisopropylethylamine is preferred. The amount of compound (3) used is 1.0 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents, relative to compound (2). The amount of condensing agent used is 0.9 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, relative to compound (2). The amount of base used is 1.0 to 1.5 equivalents, preferably 1.0 to 1.3 equivalents, relative to compound (2). This reaction can be carried out at 0 to 30°C.

[0013] Step 2: Step 2 is a step in which compound (4) or a salt thereof is subjected to a deprotection reaction to obtain compound (5) or a salt thereof. Examples of salts of compound (5) include acid addition salts, inorganic salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, or maleate. Hydrochloride salts are preferred. The deprotection reaction of compound (4) can be carried out in accordance with the method described in Theodora W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4th Ed. / John Wiley & Sons, Inc., 2007, for example, in a solvent, in the presence of palladium carbon, and under a hydrogen atmosphere. Any solvent that does not affect this reaction is acceptable, and examples include aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). These can also be used in appropriate combinations. Of these, alcohols are preferred, and methanol is more preferred. The amount of palladium carbon used is 0.1 to 10% by weight, preferably 0.5 to 10% by weight, relative to compound (4) or its salt. This reaction can be carried out at 0 to 30°C.

[0014] Step 3: Step 3 is the step of chlorinating compound (6) to obtain compound (7). Compound (6) is known or can be produced according to known methods. The chlorination reaction of compound (6) can be carried out in a solvent in the presence of a chlorinating agent. If necessary, it can also be carried out in the presence of a catalyst. Any solvent that does not affect this reaction can be used, and examples include aromatic hydrocarbons (benzene, toluene, and xylene, etc.), aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), and ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.). These can also be used in appropriate combinations. Of these, ethers are preferred, and dimethoxyethane is more preferred. Examples of chlorinating agents include thionyl chloride, phosphorus oxychloride, and oxalyl chloride, of which thionyl chloride is preferred. The amount of chloroforming agent used is 1.0 to 3.0 equivalents, preferably 1.8 to 2.2 equivalents, relative to compound (6). N,N-dimethylformamide is preferred as the catalyst. The amount of catalyst used is 0.01 to 0.5 equivalents, preferably 0.05 to 0.1 equivalents, relative to compound (6). This reaction can be carried out at 50-100°C, preferably 70-80°C.

[0015] Step 4: Step 4 is a step in which compound (5) or a salt thereof is reacted with compound (7) to obtain compound (8) or a salt thereof. Examples of salts of compound (8) include acid addition salts, inorganic salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, or maleate. Hydrochloride salts are preferred. This reaction can be carried out in a solvent in the presence of a base. Any solvent that does not affect this reaction is acceptable, and examples include aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). These can also be used in appropriate combinations. Of these, aprotic solvents and alcohols are preferred, N-methyl-2-pyrrolidone and methanol are more preferred, and a mixed solvent of N-methyl-2-pyrrolidone and methanol is even more preferred. Examples of bases include triethylamine, diisopropylethylamine, and 1,8-diazabi. C Examples include chloro[5.4.0]undeca-7-ene (DBU), of which triethylamine is preferred. The amount of base used is 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to compound (7). This reaction can be carried out at 50 to 100°C, preferably 50 to 70°C.

[0016] Step 5: Step 5 is a step in which compound (8) or a salt thereof is subjected to a deprotection reaction to obtain compound (9) or a salt thereof. Examples of salts of compound (9) include acid addition salts, inorganic salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, or maleate. Hydrochloride salts are preferred. The deprotection reaction of compound (8) can be carried out according to the method described in Theodora W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4th Ed. / John Wiley & Sons, Inc., 2007, etc. This reaction can be carried out, for example, in a solvent in the presence of an acid. Any solvent that does not affect this reaction can be used, and examples include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). These can also be used in appropriate combinations. Of these, water is preferred. Examples of acids include trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, and methanesulfonic acid, of which hydrochloric acid is preferred. The amount of acid used is 3 to 10 equivalents, preferably 3 to 5 equivalents, relative to compound (8). This reaction can be carried out at 30 to 50°C. The mixture containing the compound (9) or its salt obtained after the reaction can be used directly in the next step, but it is preferable to remove insoluble matter before using it in the next step. When removing insoluble matter, it is even more preferable to filter the mixture. When filtering the mixture, it is preferable to use the same solvent as used in the reaction. The temperature during filtration is preferably 5 to 95°C, and more preferably 30 to 50°C. It is even more preferable to crystallize the filtrate to obtain compound (9) as a solid and then use it in the next step.

[0017] Step 6: Step 6 is a step in which compound (9) or a salt thereof is reacted with an acetylating agent to obtain compound (10). The reaction between compound (9) or a salt thereof and the acetylating agent can be carried out in a solvent. Any solvent that does not affect this reaction can be used, and examples include aromatic hydrocarbons (benzene, toluene, and xylene, etc.), aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). These can also be used in appropriate combinations. Of these, aromatic hydrocarbons and alcohols are preferred, toluene and methanol are more preferred, and a mixed solvent of toluene and methanol is even more preferred. Examples of acetylating agents include acetyl chloride and acetic anhydride, of which acetic anhydride is preferred. The amount of acetylating agent used is 1 to 1.5 equivalents, preferably 1.05 to 1.2 equivalents, relative to compound (9) or its salt. This reaction can be carried out at 40 to 60°C.

[0018] Compounds (4), (5), and (8) are novel manufacturing intermediates for producing compound (10).

[0019] The present invention relates to a salt, crystals, and method for producing the same of triazine compound A.

[0020] The salt of the present invention is a salt of triazine compound A, preferably a hydrobromide, sulfate, tosylate, or succinate of triazine compound A, and more preferably a hydrobromide of triazine compound A. The molar ratio of acid to triazine compound A is not particularly limited; for example, the molar ratio of acid to triazine compound A may be 1 to 3 equivalents. For example, the hydrobromide salt of triazine compound A includes the mono-hydrobromide salt and the di-hydrobromide salt of triazine compound A, etc. Furthermore, the salt of triazine compound A may be a hydrate.

[0021] The crystals of the present invention are crystals of a salt of triazine compound A, preferably crystals of hydrobromide of triazine compound A, crystals of sulfate of triazine compound A, crystals of tosylate of triazine compound A, and crystals of succinate of triazine compound A, more preferably crystals of hydrobromide of triazine compound A, and even more preferably A-type crystals of hydrobromide of triazine compound A.

[0022] The crystalline form of the sulfate of triazine compound A is preferably the B-form crystal of the sulfate of triazine compound A.

[0023] The tosylate crystal of triazine compound A is preferably a C-type crystal of the tosylate of triazine compound A.

[0024] The succinate crystal of triazine compound A is preferably an A-type crystal.

[0025] The following describes a method for producing crystals of the hydrobromide salt of triazine compound A. While multiple crystal forms exist for the hydrobromide salt of triazine compound A, the most preferred crystal forms are A-form, F-form, and N-form. In particular, A-form crystals are preferred, but simply adding hydrogen bromide to triazine compound A in a solvent will result in the inclusion of F-form and N-form crystals as well. However, by appropriately controlling the amount of hydrogen bromide added, the amount of water present in the system, and the crystallization temperature, the crystal form can be concentrated on A-form crystals, allowing for the stable and efficient acquisition of only A-form crystals.

[0026] The A-type crystals of the hydrobromide salt of triazine compound A can be produced as follows. Compound (10) is reacted with 0.9 to 1.1 equivalents of hydrogen bromide, preferably 0.95 to 1.05 equivalents of hydrogen bromide, and crystallization yields form A crystals of the hydrobromide salt of triazine compound A. This reaction can be carried out in a solvent. Examples of solvents include water, ketones (such as acetone and methyl ethyl ketone), and alcohols (such as methanol, ethanol, and isopropanol), and two or more solvents can be used in appropriate combinations. Preferably, a mixed solvent of water and a solvent that is easily miscible with water is used. More preferably, a mixed solvent in which the water content is 1.0 to 5.0% of the total solvent volume is used. In particular, a mixed solvent of water and acetone in which the water content present in the system is 1.0 to 5.0% of the total solvent volume is used, and more preferably a mixed solvent of water and acetone in which the water content is 2.0 to 3.0% of the total solvent volume is used. This reaction can be carried out at 5 to 55°C, preferably at 20 to 55°C, and more preferably at 40 to 55°C.

[0027] The hydrobromide F-form crystals of triazine compound A can be prepared as follows. By reacting compound (10) with 2.0 to 2.2 equivalents of hydrogen bromide and crystallizing the reaction, F-form crystals of the hydrobromide salt of triazine compound A can be obtained. This reaction can be carried out in a solvent. Examples of solvents include water, ketones (such as acetone and methyl ethyl ketone), and alcohols (such as methanol, ethanol, and isopropanol). Two or more solvents can be used in appropriate combinations, and a mixed solvent of water and acetone is preferred. This reaction can be carried out at 10-50°C, preferably at 40-50°C.

[0028] The hydrobromide N-form crystals of triazine compound A can be prepared as follows. By reacting compound (10) with 1.2 to 1.5 equivalents of hydrogen bromide and crystallizing the reaction, N-form crystals of the hydrobromide salt of triazine compound A can be obtained. This reaction can be carried out in a solvent. Examples of solvents include water, ketones (such as acetone and methyl ethyl ketone), and alcohols (such as methanol, ethanol, and isopropanol), and two or more solvents can be used in appropriate combinations. Water is preferred. This reaction can be carried out at 10-50°C, preferably at 40-50°C.

[0029] The sulfate crystalline form of triazine compound A can be prepared as follows.

[0030] By reacting compound (10) with sulfuric acid and crystallizing the reaction, crystals of the sulfate salt of compound (10) can be obtained. This reaction can be carried out in a solvent. Any solvent that does not affect this reaction is acceptable, and examples include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), alcohols (methanol, ethanol, and isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, and xylene, etc.), which can be used in appropriate combinations. The amount of sulfuric acid used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (10). This reaction can be carried out at 10 to 60°C.

[0031] The tosylate crystals of triazine compound A can be produced as follows.

[0032] The tosylate salt of compound (10) is obtained by reacting compound (10) with tosylic acid and crystallizing the reaction. This reaction can be carried out in a solvent. Any solvent that does not affect this reaction is acceptable, and examples include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), alcohols (methanol, ethanol, and isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, and xylene, etc.), which can be used in appropriate combinations. The amount of tosylic acid used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (10). This reaction can be carried out at 10 to 60°C.

[0033] The succinate crystal of triazine compound A can be prepared as follows.

[0034] By reacting compound (10) with succinic acid and crystallizing the reaction, crystals of the succinate salt of compound (10) can be obtained. This reaction can be carried out in a solvent. Any solvent that does not affect this reaction is acceptable, and examples include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone and methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, and dimethoxyethane, etc.), alcohols (methanol, ethanol, and isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, and xylene, etc.), which can be used in appropriate combinations. The amount of succinic acid used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (10). This reaction can be carried out at 10 to 60°C.

[0035] In the crystal of the present invention, triazine compound A and / or hydrogen bromide, sulfuric acid, tosylic acid, and succinic acid are isotopes (for example,3 H, 13 C, 14 C, 15 N, 18 F, 32 This includes compounds labeled with P, etc., and deuterium converters.

[0036] In the crystals of the present invention, the A-type crystals of the hydrobromide salt of triazine compound A are free of other molecules used in obtaining the crystals, and contain triazine compound A and hydrobromide in a 1:1 molar ratio.

[0037] The A-type crystals of the hydrobromide salt of triazine compound A are characterized by one or more of the following: (1) Preferably, the powder X-ray diffraction pattern shown in Figure 11 and / or the differential scanning calorimetry (DSC) curve shown in Figure 12. (2) Characteristic peaks in the powder X-ray diffraction pattern of type A crystals include diffraction angles of 8.8°±0.2° and 25.6°±0.2°, expressed as 2θ. In one embodiment, the type A crystal has further peaks in the powder X-ray diffraction pattern at diffraction angles of 18.1°±0.2° and 20.9°±0.2°, expressed as 2θ. Other characteristic peaks include 15.1°±0.2°, 17.5°±0.2°, 21.5°±0.2°, and 25.0°±0.2°. Furthermore, other characteristic peaks include 13.0°±0.2°, 13.1°±0.2°, 13.8°±0.2°, 15.4°±0.2°, 19.6°±0.2°, 22.9°±0.2°, 26.2°±0.2°, 26.3°±0.2°, and 28.2°±0.2°. The A-type crystal of the hydrobromide salt of triazine compound A has a powder X-ray diffraction pattern substantially equivalent to that shown in Figure 11. (3) The melting point (extranexation start temperature) determined by DSC is 265-275°C, with a particularly notable value being around 268°C.

[0038] The crystals of the present invention have the advantage of having residual solvent levels below the standards set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (hereinafter referred to as ICH). Other advantages include the fact that the crystals have solvent impurities, inorganic impurities, residual metals, residual solvents, genotoxic impurities, etc., below the standards set by the ICH guidelines.

[0039] Since the salt and crystals of the present invention have an inhibitory effect on aldosterone synthase, they can be used as active ingredients in aldosterone synthase inhibitors. Furthermore, the crystals of the present invention and pharmaceutical compositions containing them as active ingredients are useful for the treatment or prevention of various diseases in which improvement of the pathological condition is expected by inhibiting aldosterone synthase. Examples of such diseases include primary aldosteronism (unilateral or bilateral adrenal adenoma, unilateral or bilateral adrenal hyperplasia, aldosterone-producing adrenal carcinoma, unilateral adrenal multiple nodular aldosteronism, glucocorticoid-responsive aldosteronism, familial aldosteronism, or ectopic aldosterone-producing tumors, etc.), secondary aldosteronism (hypertension caused by estrogen preparations, renovascular hypertension, gestational hypertension, malignant hypertension, pheochromocytoma, congestive heart failure, pseudohypoaldosteronism, chronic liver disease accompanied by ascites (cirrhosis, etc.), inappropriate use of drugs such as laxatives and diuretics, or hyperaldosteronism associated with nephrotic syndrome, Bartter syndrome, or Gittellmann syndrome, etc.), and hypertension (essential hypertension, secondary hypertension (renovascular hypertension, renal parenchymal hypertension, primary aldosteronism, pheochromocytoma, sleep apnea syndrome) Examples of conditions that may be present include: Cushing's syndrome, drug-induced hypertension, aortic stenosis or hyperparathyroidism, treatment-resistant hypertension, mineralocorticoid-related hypertension, heart failure (congestive heart failure, left ventricular failure, right ventricular failure, systolic dysfunction, diastolic dysfunction, etc.), cardiomyopathy, cardiac hypertrophy (left ventricular hypertrophy, etc.), myocardial infarction, myocardial necrotic lesions, post-myocardial ischemia injury, coronary artery disease, myocardial or vascular fibrosis or remodeling (cardiovascular fibrosis and remodeling associated with hypertension and / or vascular endothelial dysfunction, etc.), vascular restenosis, vascular wall thickening, arteriosclerosis, renal failure (chronic renal failure, etc.), acute kidney injury, chronic kidney disease, renal fibrosis, nephropathy (diabetic nephropathy, etc.), hypokalemia, obesity, metabolic syndrome, sleep apnea syndrome, retinopathy (diabetic retinopathy, etc.), liver disease, lipid metabolism disorders, sympathetic hyperactivity, idiopathic and / or periodic edema, headache, anxiety disorders, and depressive disorders.In particular, hydrobromide crystals of triazine compound A are useful for the treatment or prevention of one or more diseases selected from the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrotic lesions, post-myocardial ischemia, coronary artery disease, myocardial or vascular fibrosis or remodeling, vascular restenosis, vascular wall thickening, arteriosclerosis, acute kidney injury, chronic kidney disease, renal fibrosis, nephropathy, hypokalemia, metabolic syndrome, obesity, sleep apnea syndrome, retinopathy, liver disease, idiopathic and / or periodic edema, and sympathetic hyperactivity.

[0040] A pharmaceutical composition containing the salt or crystal of the present invention as an active ingredient can be obtained by mixing the salt or crystal of the present invention with pharmaceutically acceptable additives, such as diluents, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone, etc.), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbitol, and glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, and silica, etc.), disintegrants (potato starch, etc.), and wetting agents (sodium lauryl sulfate, etc.).

[0041] The salts, crystals, and pharmaceutical compositions containing them as active ingredients of the present invention can be prepared in an appropriate dosage form, such as a powder, injection, tablet, capsule, or topical preparation, and then administered to a patient by an appropriate administration method according to the dosage form, such as intravenous administration, oral administration, or transdermal administration. In the present invention, the term "patient" refers to an individual that is the target of prevention or treatment by the crystals of the present invention, preferably a mammal, more preferably a human.

[0042] The dosage is determined based on the patient's age, weight, general health, sex, diet, administration time, method of administration, excretion rate, drug combination, and the severity of the patient's symptoms at the time of administration, taking into consideration these and other factors. The salts, crystals, and pharmaceutical compositions containing them as active ingredients of the present invention are low in toxicity and safe to use. The daily dose (i.e., effective dose) varies depending on the patient's condition, weight, and route of administration, but for example, it is desirable to administer approximately 0.0001 to 1000 mg / person / day, preferably approximately 0.01 to 1000 mg / person / day, and particularly preferably approximately 0.01 to 500 mg / person / day parenterally, and approximately 0.01 to 1000 mg / person / day orally, preferably approximately 0.01 to 500 mg / person / day.

[0043] In this invention, "prevention" means administering the salt, crystal, or pharmaceutical composition containing the salt to the present invention to an individual who has not yet developed a disease, disorder, or symptoms. "Treatment" means administering the salt, crystal, or pharmaceutical composition containing the salt to the present invention to an individual who has already developed a disease, disorder, or symptoms. Therefore, administering the salt to an individual who has already developed a disease, disorder, or symptoms to prevent the worsening of symptoms, prevent seizures, or prevent recurrence is a form of "treatment." [Examples]

[0044] The present invention will be described in detail below with reference to examples and experimental examples, but the present invention is not limited thereto. In this specification, "equivalent" means "molar equivalent".

[0045] Example 1 Synthesis of form A crystals of hydrobromide salt of triazine compound A [ka] Under an inert gas atmosphere, acetonitrile (112.30 kg), compound 2 (48.00 kg), diisopropylethylamine (78.80 kg), and compound 3 (39.20 kg) were mixed, and a 50% T3P acetonitrile solution was added dropwise over 2 hours and 30 minutes at 16-24°C. After 5 hours, a 10% potassium carbonate aqueous solution (potassium carbonate: 38.40 kg, water: 345.6 kg) was added dropwise over 23 minutes at 19-22°C, then cooled to 15°C and stirred at 9-15°C for 16 hours and 30 minutes. The resulting mixture was filtered, and the crystals were washed with water (240 kg). The mixture was dried under reduced pressure at 50°C to obtain 67.1 kg of compound 4 (yield: 93%). 1 H NMR (DMSO-d6, 500 MHz): δ1.15-1.30 (m, 4H), 1.37 (s, 9H), 1.70-1.76 (m, 4H), 2.39 (t, J = 4.6, 4H), 2.90 (s, 2H), 3.16 (br, 1H), 3.42 (br, 4H), 3.45-3.51 (m, 1H), 5.07 (s, 2H), 6.70 (d, J = 7.8 Hz, 1H), 7.30-7.39 (m, 5H), 7.52 (d, J = 8.2 Hz, 1H). MS Calc for C 25 H 38 N4O5474.3, found m / z 475 [M+H] + .

[0046] Under an inert gas atmosphere, methanol (471.6 kg), compound 4 (59.7 kg), and 10% palladium carbon (6.0 kg) were mixed at 15-17°C. Hydrogen was supplied at 0.2 MPa, and the mixture was stirred at 17-23°C for 3 hours and 40 minutes. After replacing with an inert gas, the mixture was pressure filtered. Further methanol (235.8 kg) was added, and the mixture was pressure filtered again. The filtrate was concentrated to a volume of 180 L over 9 hours and 20 minutes. Methanol (71.7 kg) was added, and 228.1 kg of methanol solution of compound 5 was obtained. 1H NMR (CDCl3, 500 MHz): δ1.19-1.30 (m, 4H), 1.44 (s, 9H), 1.97-2.04 (m, 4H), 2.46 (br, 4H), 2.89 (t, J = 4.9 Hz, 4H), 2.94 (s, 2H), 3.43 (br, 1H), 3.70-3.77 (m, 1H), 4.39 (br, 1H), 6.99 (d, J = 8.4 Hz, 1H). MS Calc for C 17 H 32 N4O3340.2, found m / z 341 [M+H] + .

[0047] Under an inert gas atmosphere, 1,2-dimethoxyethane (237.5 kg), compound 6 (42.0 kg), and dimethylformamide (1.64 kg) were mixed at 15-16°C and heated to 74°C over 1 hour. Thionyl chloride (53.4 kg) was added dropwise at 73-79°C over 1 hour, and the mixture was stirred at 71-77°C for 5 hours. After cooling to 20°C, water (210.0 L) was added dropwise at 20-22°C over 2 hours and 30 minutes, and the mixture was stirred at 21-22°C for 13 hours and 30 minutes. The resulting mixture was filtered, and the crystals were washed with water (630.0 L). Under an inert gas atmosphere, ethanol (99.5 kg) and the crystals were mixed at 19°C and stirred at 19-21°C for 2 hours. The resulting mixture was filtered, and the crystals were washed with ethanol (99.5 kg). Compound 7 was dried under reduced pressure at 30°C to obtain 23.7 kg (yield: 51%). 1 H NMR (DMSO-d6, 500 MHz): δ2.43 (s, 3H), 7.46 (d, J = 7.9 Hz, 2H), 8.25 (d, J = 8.3 Hz, 2H), 10.12 (s, 1H). MS Calc for C 10 H8ClN3205.0, found m / z 206 [M+H] + .

[0048] Under an inert gas atmosphere, triethylamine (23.1 kg) was added to a methanol solution of compound 5 at 18-20°C and the temperature was raised to 57°C. A solution of compound 7 (23.5 kg) in N-methyl-2-pyrrolidone (96.8 kg) was added dropwise at 57-62°C, followed by the addition of N-methyl-2-pyrrolidone (24.2 kg), and the mixture was stirred at 59-61°C for 2 hours. Water (470.0 L) was added at 54-58°C, and the mixture was stirred at 54-55°C for 35 minutes, then cooled to 30°C, and stirred at 24-30°C for 13 hours and 45 minutes. The resulting mixture was filtered, and the crystals were washed with water (235.0 kg). The mixture was dried under reduced pressure at 50°C to obtain 56.6 kg of compound 8 (yield: 97%). 1 H NMR (CDCl3, 500 MHz): δ1.22-1.34 (m, 4H), 1.44 (s, 9H), 2.01-2.06 (m, 4H), 2.44 (s, 3H), 2.64 (t, J = 5.2 Hz, 4H), 3.06 (s, 2H), 3.44 (br, 1H), 3.75-3.82 (m, 1H), 4.04 (br, 1H), 4.40 (br, 1H), 6.99 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H), 9.00 (s, 1H). MS Calc for C 27 H 39 N7O3509.3, found m / z 510 [M+H] + .

[0049] Under an inert gas atmosphere, water (564.0 L) and 35% hydrochloric acid (133.1 kg) were mixed at 19-24°C and the temperature was raised to 37°C. Compound 8 (56.4 kg) was added in portions over 1 hour at 37-41°C. Dilute hydrochloric acid was prepared from water (141.0 L) and 35% hydrochloric acid (33.3 kg) and added at 39-41°C 1 hour after the addition of compound 8. After stirring for 17 hours and 40 minutes from the addition of compound 8, the mixture was pressure filtered at 40°C. Further, water (112.8 L) was added and the mixture was pressure filtered again. The mixture was cooled to 18°C, and a 13.4 wt% sodium hydroxide aqueous solution (480.95 kg; prepared from 48% sodium hydroxide (156.2 kg) and water (402.1 L)) was added at 18-23°C to adjust the pH of the solution to 11.51. After stirring at 20-21°C for 45 minutes, seed crystals of compound 9 (0.11 kg) were added at 20°C. After stirring at 19-20°C for 16 hours and 50 minutes, the resulting mixture was filtered and the crystals were washed with water (564.0 kg). The mixture was dried under reduced pressure at 50°C, and the resulting solid was crushed. Compound 9 was dried under reduced pressure at 50°C to obtain 42.2 kg (yield: 93%). 1H NMR (CD3OD, 500 MHz): δ1.22-1.41 (m, 4H), 1.92 (d, J = 6.3 Hz, 4H), 2.43 (s, 3H), 2.60-2.65 (m, 5H), 3.07 (s, 2H), 3.66-3.72 (m, 1H), 4.02 (t, J = 5.0 Hz, 4H), 7.36 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 9.06 (s, 1H). MS Calc for C 22 H 31 N7O 409.3, found m / z 410 [M+H] + .

[0050] Under an inert gas atmosphere, methanol (55.4 kg), toluene (60.2 kg), and compound 9 (14.4 kg, after moisture correction: 14.0 kg) were mixed to dissolve compound 9. Activated carbon (0.28 kg) was added, and the mixture was stirred at 20°C for 1 hour and 50 minutes, followed by pressure filtration. A mixture of methanol (22.1 kg) and toluene (25.1 kg) was then added, and the temperature was raised to 47°C. Acetic anhydride (4.19 kg) was added at 47-50°C, and the mixture was stirred at 50-51°C for 2 hours. Purified water (56.0 L) and 24% sodium hydroxide (6.8 kg) were mixed and added over 40 minutes at 50°C. After stirring at 50°C for 1 hour, the mixture was cooled to 15°C, and stirred at 15-11°C for 13 hours and 20 minutes. The resulting mixture was filtered, and the crystals were washed with methanol (33.2 kg) and then further washed with purified water (70.0 L). The mixture was dried under reduced pressure at 50°C to obtain 15.0 kg of compound 10. Under a nitrogen atmosphere, purified water (119.9 L), maleic acid (5.3 kg), compound 10 (14.8 kg), and methanol (10.5 kg) were mixed at 24°C to dissolve compound 10, and then pressurized. Further, purified water (13.3 L) and methanol (1.2 kg) were added, the temperature was raised to 60°C, and an aqueous solution of 24% sodium hydroxide (8.7 kg) and purified water (45.9 L) was added dropwise over 50 minutes at 59-60°C. After stirring at 59-60°C for 40 minutes, the mixture was cooled to 25°C and stirred at 20-25°C for 14 hours and 30 minutes. The resulting mixture was filtered, and the crystals were washed with purified water (74.0 L). The mixture was dried under reduced pressure at 50°C to obtain 14.5 kg of compound 10 (yield: 98%). 1H NMR (CDCl3, 500 MHz): δ1.24-1.38 (m, 4H), 1.97 (s, 3H), 2.02-2.06 (m, 4H), 2.44 (s, 3H), 2.65 (t, J = 5.1 Hz, 4H), 3.06 (s, 2H), 3.76-3.83 (m, 2H), 4.04 (br, 4H), 5.32 (d, J = 8.1, 1H), 7.01 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 9.00 (s, 1H). MS Calc for C 24H 33 N7O2451.3, found m / z 452 [M+H] + .

[0051] Under a nitrogen atmosphere, acetone (478.0 kg) and compound 10 (37.8 kg) were mixed and heated to 50°C. 48% hydrobromic acid (13.9 kg), purified water (12.1 kg), and acetone (119.2 kg) were added, and the mixture was stirred at 46-50°C for 2 hours. Further, acetone (150.7 kg) was added, and the mixture was stirred at 47-50°C for a further 3 hours. The mixture was cooled to 15°C and stirred at 15°C for 12 hours and 30 minutes. The resulting mixture was filtered, and the crystals were washed with acetone (596.4 kg). By drying under reduced pressure at 50°C for 7 hours, 42.1 kg of compound 1 (hydrobromide salt of triazine compound A) was obtained (yield: 94%). At this time, the obtained hydrobromide salt crystals of triazine compound A were hydrobromide A-type crystals. 1H NMR (CDCl3, 500 MHz): δ1.24-1.38 (m, 4H), 1.97 (s, 3H), 2.02-2.06 (m, 4H), 2.44 (s, 3H), 2.66 (t, J = 5.1 Hz, 4H), 3.07 (s, 2H), 3.75-3.84 (m, 2H), 4.05 (br, 4H), 5.40 (d, J = 8.0, 1H), 7.02 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 9.01 (s, 1H). MS Calc for C 24 H 33 N7O2451.3, found m / z 452 [M+H] + .

[0052] The elemental analysis results are shown in Table 1 below.

[0053] [Table 1]

[0054] <Powder X-ray diffraction (hereinafter sometimes referred to as XRPD) measurement> The measurements were performed using a powder X-ray diffractometer X'PertPro (manufactured by PANalyical B.V.) under the following conditions. X-ray generator: X-ray tube (anti-cathode: copper, tube Voltage: 45kV, Current: 40mA) Entrance optical system: Focusing condensing mirror Photodetector optics: High-speed semiconductor array detector (X-Celerator), extended photodetector arm Sample stage: HTS sample stage (vibrates in the X-axis direction with a width of 4 mm) Number of cumulative trials: 5 (with incident angles changed to -2, -1, 0, 1, and 2° respectively) Measurement range: 2θ = 3~40° Scan speed: 0.668451° / sec Step: 0.0167°

[0055] Figure 11 shows the XRPD results for the hydrobromide A-type crystals of triazine compound A. Table 2 shows the peaks with a relative peak intensity of 15 or greater (each ±0.2°) when the peak intensity at a diffraction angle of 25.6°, represented by 2θ, is set to 100.

[0056] [Table 2]

[0057] <Differential Scanning Calorimetry (DSC) Measurement> Measurements were taken using a differential scanning calorimetry system X-DSC7000 (SII Nanotechnology Co., Ltd.) under the following conditions. Heating rate: 10°C / min (30°C to 300°C) Atmosphere: Nitrogen 100 mL / min The results for the hydrobromide A-type crystals of triazine compound A are shown in Figure 12. An endothermic peak was observed at approximately 265–275°C.

[0058] <Infrared absorption spectrum measurement> The tests were conducted using the potassium bromide tablet method of infrared absorption spectroscopy, and the obtained infrared absorption spectra were compared. The results for the hydrobromide A-type crystals of triazine compound A are shown in Figure 13. The assignment of the infrared absorption spectra is shown in Table 3 below.

[0059] [Table 3]

[0060] <Single-crystal X-ray diffraction measurement> Using a single-crystal X-ray diffractometer R-AXIS RAPID / R (Rigaku Corporation) (CuKα rays), the lattice constant was determined and the diffraction peak intensity was measured at -40°C. Subsequently, the phase was determined by the direct method, and the structure was refined using the full-matrix least squares method. The obtained crystallographic data and crystal structure analysis results are shown in Table 4. The reliability factor (R value) was 12.35%, and other parameters also indicated that this crystal structure analysis yielded sufficiently reliable results.

[0061] [Table 4]

[0062] Example 2: Investigation of salt crystallization of triazine compound A <Experimental Method> Approximately 600 mg of triazine compound A was dissolved in 40 mL of chloroform, and 200 μL was dispensed into each vial of a 96-well plate (approximately 3 mg / vial). In addition, 1 equivalent (70 μL) or 2 equivalents (140 μL) of a 0.1 mol / L solution of an acid compound was dispensed. 140 μL of a 0.05 mol / L solution of fumaric acid was dispensed. After evaporating the solvent by nitrogen blowing, 300 μL of eight selected screening solvents was dispensed into each vial, the vials were sealed, and stirred at room temperature for 4 days. For vials with precipitates, the precipitate was filtered and measured by XRPD. For vials without precipitates, the lids were left open and stored at room temperature overnight. If a solid was observed, it was filtered and measured by XRPD.

[0063] <Result> Crystallization studies were conducted using triazine compound A with mixed solvents prepared using 18 acids and 8 solvents. As a result, novel crystals were obtained for 14 acids (hydrobromide, hydrochloric acid, sulfuric acid, tosylic acid, mesylic acid, benzenesulfonic acid, maleic acid, citric acid, fumaric acid, tartaric acid, malic acid, succinic acid, 2-oxoglutaric acid, and glycolic acid). The crystal forms were distinguished by XRPD patterns, and each salt was assigned an alphabetical order in the order in which new XRPD patterns were confirmed. The XRPD results show that the hydrobromide A-form crystals of triazine compound A are the same crystals as the hydrobromide A-form crystals of triazine compound A obtained in Example 1.

[0064] For some of the crystals described above, we evaluated their thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0065] <Thermal Stability Evaluation> The following conditions were used for measurement and evaluation using the TG / DTA7200 thermogravimetric / differential thermal simultaneous measurement device (SII Nanotechnology Co., Ltd.). Heating rate: 10°C / min Temperature range: 25~300℃ Atmosphere: Nitrogen 200 mL / min

[0066] <Evaluation of hygroscopicity and deliquescence> The moisture adsorption was evaluated using the DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited) as follows: Approximately 5 mg of the sample was placed in an aluminum pan pre-corrected for tare weight, suspended from the instrument's precision balance, and the initial weight was precisely measured. The weight change over time was recorded as the humidity was gradually changed in a 25°C chamber, and the equilibrium weight at each humidity level was determined. The weight at dry conditions (0% RH) was used as the baseline, and the rate of weight change and hydration number at each humidity level were determined.

[0067] <Chemical Stability Evaluation> Approximately 1 mg was weighed from samples stored at 60°C (sealed) and 60°C / 75%RH (open) for one week, as well as from unstored samples (at the start of the test). These were dissolved in 5 mL of acetonitrile / water (1:1) mixture to prepare the sample solution. The test was performed by liquid chromatography under the following conditions, and the individual peak area percentage was determined. Measurements were taken using Waters ACQUITY UPLC under the following conditions. Detector: Photodiode array (measurement wavelength 239 nm) Column: Waters ACQUITY BEH C18 (2.1mm x 100mm, 1.7μm) Column temperature: Constant temperature around 40°C Mobile phase: Solution A; Water / TFA (2000:1), Solution B; Acetonitrile / TFA (2000:1) Concentration gradient control: B% 2 → 100% (15 minutes) Flow rate: 0.5mL / min Injection volume: 2μL

[0068] The results are shown in Table 5. [Table 5]

[0069] As shown in the thermal stability results in Table 5, no significant weight changes were observed in hydrobromide type A crystals, hydrochloride type A crystals, sulfate type B crystals, tosylate type B crystals, tosylate type C crystals, mesylate type A crystals, maleate type A crystals, maleate type B crystals, and citrate type A crystals, confirming that these are crystalline forms with good thermal stability. Furthermore, succinate type A crystals showed no significant weight change between 25 and 148°C (melting point), confirming that this is a crystalline form with good thermal stability.

[0070] Furthermore, as shown in the hygroscopic and deliquescent evaluation results in Table 5, no significant increase in related substances was observed in hydrobromide type A crystals, sulfate type B crystals, tosylate type B crystals, tosylate type C crystals, succinate type A crystals, and glycolate type A crystals, confirming that these are good crystal forms with low hygroscopic and deliquescent properties. In addition, sulfate type B crystals were found to have a hydration stage and were confirmed to be hydrated at room temperature and relative humidity of 10-95%.

[0071] Furthermore, as shown in the chemical stability test results in Table 5, no significant increase in related substances was observed in hydrobromide A-type crystals, hydrochloride A-type crystals, sulfate B-type crystals, tosylate B-type crystals, tosylate C-type crystals, maleate A-type crystals, citrate A-type crystals, succinate A-type crystals, and glycolate A-type crystals, confirming that these are crystalline forms with good chemical stability.

[0072] The hydrobromide A-type crystals, sulfate B-type crystals, tosylate C-type crystals, and succinate A-type crystals exhibited good physical properties including thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0073] Experimental Example 1: Synthesis of Sulfate Type B Crystals Triazine compound A (50 mg) was dissolved in 2 mL of chloroform at room temperature. 30 mg (2.7 equivalents) of sulfuric acid was diluted in 2 mL of methanol and added at room temperature. After stirring at room temperature for 0.5 hours, the solvent was evaporated with nitrogen. To the dry solution, 3 mL of acetonitrile and 100 μL of water were added to obtain a candy-like substance. Seed crystals were added to this candy-like substance to form a suspension, which was then stirred overnight at room temperature. The precipitate was filtered, the filtrate was washed twice with 0.5 mL of acetonitrile, and the suspension was dried under reduced pressure at 40°C for 2.5 hours to obtain 75 mg of sulfate type B crystals (yield 92%, calculated as 2.5 sulfate dihydrate).

[0074] Experimental Example 2: Synthesis of Tosylate C-type Crystals Triazine compound A (50 mg) was dissolved in 2 mL of chloroform at room temperature. Tosylic acid (45 mg, 2 equivalents) was dissolved in 2 mL of chloroform and 0.5 mL of methanol and added at room temperature. The solvent was evaporated with nitrogen, 2.5 mL of 1,2-dimethoxyethane was added, and the mixture was stirred overnight at room temperature. The precipitate was filtered and dried under reduced pressure at 40°C for 3 hours to obtain 70 mg of tosylate C-type crystals (79% yield, calculated as 2-tosylate).

[0075] Experimental Example 3: Synthesis of succinate type A crystals 40 mg of triazine compound A was dissolved in 2 mL of chloroform at room temperature. 12 mg (1 equivalent) of succinic acid was dissolved in 1 mL of tetrahydrofuran and added at room temperature. After stirring for 0.5 hours, 1 mL of methanol was added to the reaction mixture to make a solution, and the solvent was evaporated by nitrogen blowing. 2.5 mL of toluene was added, and the mixture was stirred overnight at room temperature. The precipitate was filtered, washed with toluene, and dried under reduced pressure at 40°C for 2 hours to obtain 43 mg of succinate type A crystals (yield 85%, calculated as 1 succinate).

[0076] Experimental Example 4: Synthesis of hydrobromide type A crystals (alternative method) 50 mg of triazine compound A was dissolved in 2 mL of chloroform at room temperature. 39 mg of 25% hydrobromide / acetic acid was diluted in 1 mL of methanol and added at room temperature. After stirring at room temperature for 1 hour, the solvent was evaporated with nitrogen. 2.5 mL of acetonitrile was added to the dry mixture and stirred overnight at room temperature. The precipitate was filtered, the filtrate was washed twice with 0.5 mL of acetonitrile, and the mixture was dried under reduced pressure at 40°C for 3 hours to obtain 50 mg of hydrobromide type A crystals (yield 85%).

[0077] Example 3: Polymorphic search of hydrobromide salt of triazine compound A <Experimental Method> Approximately 500 mg of form A hydrobromide crystals of triazine compound A were dissolved in 5.0 mL of chloroform to obtain a suspension. 50 μL of this suspension was dispensed into each vial of a 96-well plate. After drying the solvent under a nitrogen stream, the solvents listed in Table 6 were added in the order of poor solvents (6 types) followed by good solvents (4 types) to a total of 200 μL. Acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene were selected as poor solvents. Methanol, benzyl alcohol, N-methylpyrrolidone, and dimethyl sulfoxide were selected as good solvents. The vials were sealed and stirred at room temperature for 5 days. The presence or absence of suspension was visually confirmed. Vials containing suspension were filtered using a 96-well filtration filter plate (MultiScreen® HTS+Hi-Flow, FC, Merck Millipore), and the XRPD of the residue on the filter was measured.

[0078] <Result> Polymorphism searches were performed using form A hydrobromide crystals of triazine compound A with mixed solvents prepared using six poor solvents (acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene) and four good solvents (methanol, benzyl alcohol, N-methylpyrrolidone, and dimethyl sulfoxide). Powder X-ray diffraction measurements of the obtained crystals yielded the crystals listed in Table 6. The crystal forms were distinguished by XRPD patterns, and each salt was assigned an alphabetical order in the order in which new XRPD patterns were identified. The XRPD results indicate that the form A hydrobromide crystals of triazine compound A are the same crystals as the form A hydrobromide crystals of triazine compound A obtained in Example 1.

[0079] [Table 6]

[0080] In the 96 conditions shown in Table 6, there was no change in crystal form from the hydrobromide A-type crystal in 55 conditions, the crystal form changed from the hydrobromide A-type crystal to the triazine compound A hydrobromide C-type crystal (dimethyl sulfoxide monohydrate) in 11 conditions, and the crystal form changed to the triazine compound A hydrobromide D-type crystal (N-methylpyrrolidone monohydrate) in 1 condition. Here, "not applicable" indicates that the crystal changed to a form such as a solution that cannot be measured by powder X-ray diffraction, and "amorphous" indicates that the hydrobromide A-type crystal changed to an amorphous form. Thus, it was found that the A-type crystal is the most stable among the crystals of the hydrobromide of triazine compound A.

[0081] Example 4 Polymorph Search of Hydrobromide Crystals of Triazine Compound A - 2 Using triazine compound A, polymorphisms of the hydrobromide salt crystals of triazine compound A were investigated by varying the equivalent amount of hydrogen bromide or the crystallization temperature in acetone, water, or a mixed solvent of acetone and water. As a result, 11 different crystal forms were obtained. Among the many crystalline forms obtained, the A-form crystals of triazine compound A hydrobromide, the F-form crystals of triazine compound A hydrobromide, and the N-form crystals of triazine compound A hydrobromide exhibited good physical properties including thermal stability, hygroscopicity, deliquescence, and chemical stability. Table 7 shows the crystallization conditions for the A-type hydrobromide crystals, F-type hydrobromide crystals, and N-type hydrobromide crystals of triazine compound A that had physical properties suitable for pharmaceutical manufacturing. The XRPD measuring device and measurement conditions were the same as in Example 1. The XRPD results show that the A-type hydrobromide crystals of triazine compound A are the same crystals as the A-type hydrobromide crystals of triazine compound A obtained in Example 1.

[0082] [Table 7]

[0083] (a) Method yielded form A crystals of the hydrobromide salt of triazine compound A. These crystals were found to contain 1.0 equivalent of hydrobromic acid.

[0084] (b) Method yielded F-form crystals of the hydrobromide salt of triazine compound A. These crystals were found to contain 2.0 equivalents of hydrobromic acid.

[0085] In method (c), N-form crystals of the hydrobromide salt of triazine compound A were obtained. These crystals were found to contain 1.0 equivalent of hydrobromic acid.

[0086] Experimental Example 5 (a) Experimental example of the method Crystals were obtained using the crystallization method described in Example 1.

[0087] Experimental Example 6 (b) Experimental example of the method Triazine compound A (10.0 g) was suspended in acetone (300 mL) at 50°C, then 48% hydrobromic acid aqueous solution (7.84 g, 2.1 equivalents) was added, and the mixture was stirred for about 20 hours. The mixture was cooled to 10°C and filtered. The wet mixture was washed with acetone (50 mL), and hydrobromic acid salt F-type crystals (13.45 g) were obtained by drying under reduced pressure at 40°C for 24 hours.

[0088] Experimental Example 7 (c) Experimental example of the method Triazine compound A (50.0 g) was suspended in water (450 mL) at 50°C, then 48% hydrobromic acid aqueous solution (26.19 g, 1.4 equivalents) was added and the mixture was stirred for about 5 hours. The mixture was cooled to 14°C and filtered. The wet material was washed with acetone (200 mL) and air-dried for 21 hours to obtain hydrobromic acid N-type crystals (57.43 g).

[0089] Example 5 Comparison of hydrobromide A-form crystals of triazine compound A, hydrobromide F-form crystals of triazine compound A, and hydrobromide N-form crystals of triazine compound A. In the comparative test results shown below, the hydrobromide A-type crystals of triazine compound A refer to the crystals obtained by the method described in Example 1.

[0090] In the comparative test results shown below, the hydrobromide F-form crystals of triazine compound A refer to the crystals obtained by the method described in Experimental Example 6.

[0091] In the comparative test results shown below, the N-form crystals of the hydrobromide salt of triazine compound A refer to the crystals obtained by the method described in Experimental Example 7.

[0092] The results of powder X-ray diffraction measurements for the hydrobromide F-form and hydrobromide N-form crystals of the aforementioned triazine compound A are shown below.

[0093] <Powder X-ray diffraction measurement> The measurements were performed using a powder X-ray diffractometer X'PertPro (manufactured by PANalyical B.V.) under the following conditions. X-ray generator: X-ray tube (anti-cathode: copper, tube Voltage: 45kV, Current: 40mA) Entrance optical system: Focusing condensing mirror Photodetector optics: High-speed semiconductor array detector (X-Celerator), extended photodetector arm Sample stage: HTS sample stage (vibrates in the X-axis direction with a width of 4 mm) Number of cumulative trials: 5 (with incident angles changed to -2, -1, 0, 1, and 2° respectively) Measurement range: 2θ = 3~40° Scan speed: 0.668451° / sec Step: 0.0167°

[0094] The XRPD results for the hydrobromide F-form crystals of triazine compound A are shown in Figure 7. The peaks (each ±0.2°) are shown in Table 8 below.

[0095] [Table 8]

[0096] Characteristic peaks in the powder X-ray diffraction pattern of F-type crystals include diffraction angles of 10.0°±0.2° and 27.5°±0.2°, expressed as 2θ. In one embodiment, the F-type crystal has further peaks in the powder X-ray diffraction pattern at diffraction angles of 3.3°±0.2° and 14.4°±0.2°, expressed as 2θ. Other characteristic peaks include 17.4°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.6°±0.2°. Furthermore, other characteristic peaks include 14.1°±0.2°, 14.9°±0.2°, 16.5°±0.2°, 18.5°±0.2°, 21.2°±0.2°, 24.3°±0.2°, 24.7°±0.2°, 28.5°±0.2°, and 29.6°±0.2°. The F-form crystal of the hydrobromide salt of triazine compound A has a powder X-ray diffraction pattern substantially equivalent to that shown in Figure 7.

[0097] Figure 9 shows the XRPD results for the N-form hydrobromide crystals of triazine compound A. The peaks (each ±0.2°) are shown in Table 9 below.

[0098] [Table 9]

[0099] Characteristic peaks in the powder X-ray diffraction pattern of N-type crystals include diffraction angles of 11.3°±0.2° and 24.3°±0.2°, expressed as 2θ. In one embodiment, the N-type crystal has further peaks in the powder X-ray diffraction pattern at diffraction angles of 6.2°±0.2° and 31.9°±0.2°, expressed as 2θ. Other characteristic peaks include 11.9°±0.2°, 22.4°±0.2°, 23.8°±0.2°, and 26.8°±0.2°. Furthermore, other characteristic peaks include 9.8°±0.2°, 14.0°±0.2°, 15.6°±0.2°, 16.2°±0.2°, 18.8°±0.2°, 19.1°±0.2°, 20.4°±0.2°, 20.9°±0.2°, and 22.1°±0.2°. The N-form crystal of the hydrobromide salt of triazine compound A has a powder X-ray diffraction pattern substantially equivalent to that shown in Figure 9.

[0100] For each of the crystals described above, we evaluated their thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0101] <Thermal Stability Evaluation> The following conditions were used for measurement and evaluation using the TG / DTA7200 thermogravimetric / differential thermal simultaneous measurement device (SII Nanotechnology Co., Ltd.). Heating rate: 10°C / min Temperature range: 30~300℃ Atmosphere: Nitrogen 200 mL / min Or, TGA / DSC1 Thermogravimetric Analyzer (Mettler-Toledo, STARe system) The following conditions were used for measurement and evaluation. Heating rate: 10°C / min Temperature range: 25~300℃ Atmosphere: Nitrogen 50 mL / min

[0102] <Evaluation of hygroscopicity and deliquescence> The moisture adsorption was evaluated using the DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited) as follows: The sample was placed in a cell pre-corrected for tare weight, and the weight at the start of measurement was precisely measured by suspending the device on a precision balance. The weight change over time was recorded as the humidity was changed in stages, and the equilibrium weight at each humidity was determined. The rate of change in weight at each humidity was determined, using the dry state (0% RH) or the anhydrous state calculated from the initial moisture content confirmed by another method as the reference.

[0103] <Chemical Stability Evaluation> The samples were stored at 60°C in a sealed state and at 60°C and 75% RH for one week. The increase or decrease in related substances before and after storage was calculated by high-performance liquid chromatography using the area percentage of each peak, and the state after storage was also observed.

[0104] The results are shown in Table 10. [Table 10]

[0105] Of the many crystalline forms obtained, hydrobromide A-form, hydrobromide F-form, and hydrobromide N-form crystals exhibited good physical properties including thermal stability, hygroscopicity, deliquescentity, and chemical stability. However, hydrobromide F-form and hydrobromide N-form crystals had a hydration stage, and it was confirmed that they were hydrated at room temperature and relative humidity of 10-95%.

[0106] Example 6: Effect of water during crystallization of hydrobromide type A crystals [Table 11]

[0107] <Experimental Method> Triazine compound A was added to acetone and water-mixed solvents with different water content, and 1 equivalent of hydrobromic acid aqueous solution was added. The mixture was stirred at 50°C, and a portion of the reaction solution was filtered after 1 hour, 19 hours, and 45 hours from the start of stirring. The filtered material was then measured by powder X-ray diffraction. The transition rate to type A crystals was confirmed in acetone and water-mixed solvents with different water content.

[0108] <Result> The results are shown in Table 11. In a mixed solvent with a water content of 0.64% (Entry 1), after 19 hours of stirring, the mixture consisted of hydrobromide type A crystals, hydrobromide type F crystals, and triazine compound A. However, after 45 hours of stirring, the mixture converged to hydrobromide type A crystals. In mixed solvents with a water content of 2-5% (Entry 2-5), the mixture converged to hydrobromide type A crystals after 1 hour of stirring. Furthermore, while the incorporation rate of triazine compound A into the mother liquor was good at 0.6-1.1% at a water content of 2-3%, it was confirmed that the incorporation rate of triazine compound A into the mother liquor increased to 5.5% at a water content of 5%.

[0109] We confirmed that hydrobromide type A crystals can be obtained with a short stirring time and high recovery rate by adding triazine compound A to a mixed solvent of acetone and water with a water content of 2.0-3.0%, adding 1 equivalent of hydrobromic acid aqueous solution, and stirring at 50°C. This method is an industrially advantageous crystallization method for pharmaceuticals.

[0110] Example 7 Comparison of pharmacokinetics of triazine compound A and hydrobromide of triazine compound A when used in combination with a gastric acid secretion promoter or gastric acid secretion inhibitor. <Experimental Method> The hydrobromide salt of triazine compound A and the pharmacokinetics of triazine compound A were evaluated in a 2-group, 4-period crossover study using dogs treated with gastric acid secretion promoters or gastric acid secretion inhibitors, under gastric acid secretion and gastric pH adjustment conditions. For treatment with a gastric acid secretion stimulant, pentagastrin was used. Pentagastrin (2.8 mg) was dissolved in dimethyl sulfoxide (7.0 mL) and sterile water for injection (7.0 mL) to prepare the administration solution, which was administered intramuscularly into the thigh at a dose of 10 μg / 0.05 mL / kg. Pentagastrin was administered 0.5 hours before and 0.5 hours after administration of the test substance (hydrobromide of triazine compound A (compound 1 produced in Example 1), or triazine compound A (compound 10 produced in Example 1)). For treatment with a gastric acid secretion inhibitor, omeprazole was used. Omeprazole 90 mg was dissolved in 22.5 mL of a 1:1 mixed solution of 0.1% sodium bicarbonate aqueous solution (w / v) and polyethylene glycol 400 to prepare the administration solution, which was administered intravenously into the saphenous vein of the hind limb at a dose of 1 mg / 0.25 mL / kg. Omeprazole was administered 1 hour before administration of the test substance. Triazine compound A hydrobromide and triazine compound A were administered orally at a dose of 10 mg / capsule (the hydrobromide of triazine compound A was equivalent to the free salt form (10 mg as triazine compound A)) using a syringe fitted with an oral catheter, after the subjects had been given 25 mL of sterile water for injection. Another 25 mL of sterile water for injection was then administered via the syringe fitted with the oral catheter. The test substance was administered to fasted subjects, and they were fed 6 hours after administration. The subjects were deprived of water from 1 hour before administration to 2 hours after administration. Six four-year-old male beagle dogs were divided into two groups of three dogs each. Dogs in Group 1 were administered in the following order: (Phase 1) Omeprazole followed by triazine compound A, (Phase 2) Omeprazole followed by triazine compound A hydrobromide, (Phase 3) Pentagastrin followed by triazine compound A, and (Phase 4) Pentagastrin followed by triazine compound A hydrobromide. Dogs in Group 2 were administered in the following order: (Phase 1) Omeprazole followed by triazine compound A hydrobromide, (Phase 2) Omeprazole followed by triazine compound A, (Phase 3) Pentagastrin followed by triazine compound A hydrobromide, and (Phase 4) Pentagastrin followed by triazine compound A. The drug-free period between each phase was 6 or 7 days. Heparin sodium was administered via the cephalic vein 15 minutes, 30 minutes, 1, 2, 4, 6, 8 and 24 hours after administration of triazine compound A or triazine compound A. Note A 0.6 mL whole blood sample was collected using a nebulizer while the subject was awake. The whole blood sample was treated with plasma, and the drug concentration of triazine compound A was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS / MS). Area under the plasma concentration-time curve (AUC; area from time 0 to the time when the final concentration could be measured) was calculated based on plasma-versus-time data. 0-t and the area AUC from time 0 to infinite time calculated by extrapolating the final disappearing phase. 0-∞ ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max ), and the elimination half-life (T) from plasma. 1 / 2 The calculation was performed using Phoenix WinNonlin Software Ver.6.3 (Certara LP).

[0111] <Result> The results are shown in Table 12 and Figure 14. [Table 12]

[0112] Triazine compound A's absorption is inhibited under gastric acid suppression conditions, and compared to conditions that promote gastric acid secretion, C max A decrease of approximately 50% was observed in both the CV% and AUC. Furthermore, it was suggested that individual differences were more likely to occur under gastric acid suppression conditions, as the CV% was large. With the hydrobromide salt of triazine compound A, there was no change in plasma concentration under gastric acid conditions, confirming that it is not affected by gastric pH. The hydrobromide salt of triazine compound A used in Example 7 is hydrobromide type A crystal.

[0113] Experimental Example 8: Measurement of Aldosterone Synthase (CYP11B2) Inhibitory Activity <Experimental Method> We transfected the Chinese hamster lung fibroblast cell line V79 with the pcDNA3.1-human CYP11B2 plasmid to create a stable expression cell line of the human CYP11B2 gene. These cells were cultured and grown in Dulbecco's modified Eagleham medium supplemented with 10% bovine serum and 1% G418 disulfate solution at 37°C under conditions of 95% air and 5% CO2, and then harvested. Next, mitochondrial fractions were obtained using the method described in Chabre et al. JCE&M 85(11) 4060-68, 2000. Specifically, cells suspended in 5 mmol / L Tris-HCl buffer (pH 7.4) containing 250 mmol / L sucrose were homogenized using a Teflon® Potter-Elbe Gem homogenizer, and the suspension was centrifuged (800 × g for 15 minutes). After separating the supernatant, it was centrifuged again (10000 × g for 15 minutes) to obtain a pellet (mitochondrial fraction). Mitochondrial fractions diluted with a buffer containing 10 mmol / L KH2PO4, 10 mmol / L Tris, 20 mmol / L KCl, 25 mmol / L sucrose, 5 mmol / L MgCl2, and 0.05% bovine serum albumin were dispensed into 96-well plates. 0.5 μmol / L deoxycorticosterone and 150 μmol / L NADPH were added, and the mixture was incubated at room temperature for 1.5–2 hours to produce aldosterone. The amount of aldosterone produced in the solution was measured using the HTRF (Homogeneous Time Resolved Fluorescence) method. The aldosterone production inhibition rate (%) of triazine compound A of the present invention at each concentration was used to perform nonlinear regression using a logistic curve. 50 The (nmol / L) value was calculated. As a result, the IC of triazine compound A of the present invention 50 The concentration was 9.0 nmol / L, and the triazine compound A of the present invention had strong aldosterone synthase inhibitory activity. Furthermore, by performing experiments in the same manner as in this experimental example using the salt and crystals of triazine compound A of the present invention, it can be similarly confirmed that the salt and crystals of triazine compound A of the present invention have strong aldosterone synthase inhibitory activity. [Industrial applicability]

[0114] The novel salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is a salt that yields excellent crystals, and in particular the hydrobromide salt exhibits stable pharmacokinetics under both gastric acid secretion promotion and suppression conditions, and is free of compounds that may have adverse effects on the body from a safety standpoint. Moreover, the novel salt crystals of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine leave no residue from the solvent used, exhibit excellent thermal stability, have minimal weight change with respect to humidity, do not deliquesce, exhibit excellent chemical stability, and are highly safe. Furthermore, these crystals can be obtained reproducibly by industrially suitable methods, making them excellent crystals for use as pharmaceutical raw materials. Furthermore, the method for producing crystals of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is an industrially advantageous method because it does not use manufacturing intermediates that pose explosive and genotoxic risks, allows for the production of the active pharmaceutical ingredient in high yield, and enables the reproducible and high yield of the most stable crystals.

Claims

1. A pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is a hydrobromide salt.

2. The salt crystals according to claim 1.

3. The crystal according to claim 2, wherein the powder X-ray diffraction spectrum has peaks at diffraction angles represented by 2θ, namely 8.8°±0.2°, 18.1°±0.2°, 20.9°±0.2°, and 25.6°±0.2°.

4. The crystal according to claim 2 or 3, having an endothermic peak at 265 to 275°C as determined by differential scanning calorimetry analysis.

5. An aldosterone synthase inhibitor containing the crystal described in any one of claims 2 to 4 as an active ingredient.

6. A pharmaceutical composition comprising the crystal described in any one of claims 2 to 4 and a pharmaceutically acceptable additive.

7. The pharmaceutical composition according to claim 6, in the form of a tablet.

8. A pharmaceutical composition according to claim 6 or 7 for preventing or treating a disease in which improvement of the pathological condition is expected by inhibition of aldosterone synthase, wherein the disease is one or more diseases selected from the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrotic lesions, post-myocardial ischemia, coronary artery disease, myocardial or vascular fibrosis or remodeling, vascular restenosis, vascular wall thickening, arteriosclerosis, acute kidney injury, chronic kidney disease, renal fibrosis, nephropathy, hypokalemia, metabolic syndrome, obesity, sleep apnea syndrome, retinopathy, liver disease, idiopathic and / or periodic edema, and sympathetic nervous system hyperactivity.

9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is intended to be administered in a dose of about 0.01 to 500 mg / person / day.

10. Use of the crystal according to any one of claims 2 to 4 in the manufacture of a pharmaceutical product for preventing or treating a disease in which improvement of the pathological condition is expected by inhibition of aldosterone synthase.

11. A method for producing crystals according to claim 2, characterized in that 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is crystallized by adding 0.9 to 1.1 equivalents of hydrogen bromide to a mixed solvent of water and acetone having a water content of 2.0 to 3.0 volume percent.

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