Triazine compound salt, crystal form thereof, and production method therefor

Abstract

To provide a compound having an inhibitory action against aldosterone synthase and useful as a drug, particularly as a drug for preventing or treating primary aldosteronism and the like.SOLUTION: Specifically, 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 hydrobromide, sulfate, succinate, or tosilate, is provided.SELECTED DRAWING: None

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 drug for preventing or treating primary aldosteronism, etc., a crystalline form thereof, and a method for producing the same. 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, a crystalline form thereof, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient. [Background technology]

[0002] Patent Document 1 discloses several triazine compounds or pharmacologically acceptable salts thereof having aldosterone synthase inhibitory activity, and describes triazine compound A 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 Summary of the Invention [Problem to be solved by the invention]

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

[0005] In order to solve the above problems, the present inventors have conducted extensive research to obtain a drug substance having a certain quality suitable for use as a pharmaceutical, and have attempted to obtain a salt. As a result, they have found that the hydrobromide, sulfate, succinate, or tosylate of triazine compound A is a salt that can give crystals excellent in terms of purity, thermal stability, hygroscopicity, deliquescence, chemical stability, and safety, as well as in terms of handling. Next, the present inventors have conducted extensive studies on the salts of the above-mentioned triazine compound A and have found that the hydrobromide salt of triazine compound A exhibits stable pharmacokinetics both under conditions of gastric acid secretion promotion and gastric acid secretion inhibition. Although the hydrobromide salt of triazine compound A has unexpectedly excellent properties as a drug substance, it has been found to exist in various crystalline forms. The present inventors have found that type A crystals of the hydrobromide salt of triazine compound A are the most preferable crystalline form in terms of stability, etc. However, depending on the amount of hydrogen bromide added during the crystallization process, the crystallization temperature, and the composition of the crystallization solvent, problems such as the inclusion of polymorphs, an increase in impurities, and an increase in residual solvent have been observed, making it impossible to reproducibly and stably obtain the desired crystals. Therefore, the present inventors have extensively investigated the types, amounts, and ratios of reagents and solvents used in crystallization, as well as the crystallization procedure. As a result, they have discovered a method for efficiently obtaining type A crystals of the hydrobromide salt of triazine compound A, which are crystals of a quality suitable for use as a drug substance, and have completed the present invention. Furthermore, they have discovered a method for obtaining stable crystalline forms of good quality for the sulfate, succinate, and tosylate salts of triazine compound A, similar to type A crystals of the hydrobromide salt of triazine compound A.

[0006] Furthermore, compounds (B), (C), and (E), which are production intermediates described in Patent Document 1, were found to be compounds with an explosive risk as a result of differential scanning calorimetry. Furthermore, compounds (B), (C), and (D) were found to be compounds with a potential genotoxic risk as a result of genotoxicity risk assessment using DEREK; MultiCASE. As such, the production method described in Patent Document 1 is disadvantageous for implementation on an industrial scale because it uses compounds with an explosive or genotoxic risk as production intermediates. In addition, triazine compound A is a poorly soluble compound and has similar physical properties to insoluble impurities generated during intermediate processes. Therefore, it is not easy to purify it, such as by isolating it, in the final process. It has become clear that it is difficult to supply triazine compound A of a quality suitable for use as a pharmaceutical active ingredient. Therefore, the present inventors have conducted various studies and have found an industrially advantageous method for producing triazine compound A having a quality suitable for use as a pharmaceutical active ingredient, by using a compound with low explosive and genotoxic risks as a production intermediate and further employing a compound with high solubility as the production intermediate, which makes it possible to easily remove insoluble impurities.

[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 the hydrobromide, sulfate, succinate, or tosylate salt. [2] The salt according to [1], wherein the salt is a hydrobromide salt. [3] [1] A crystal of the salt described in [1]. [4] The crystal according to [3], wherein the salt is a hydrobromide salt. [4-1] The crystal according to [3], wherein the salt is a dihydrobromide salt. [4-2] The crystal according to any one of [3] to [4-1], wherein the salt is a hydrate. [5] The crystal according to any one of [4] to [4-2], which has peaks at diffraction angles represented by 2θ in a powder X-ray diffraction spectrum of 8.8°±0.2°, 18.1°±0.2°, 20.9°±0.2°, and 25.6°±0.2°. [6] The crystal according to any one of [4] to [5], which has an endothermic peak at 265 to 275°C in differential scanning calorimetry analysis. [7] An aldosterone synthase inhibitor comprising the crystal according to any one of [3] to [6] as an active ingredient. [8] A pharmaceutical composition comprising the crystal according to any one of [3] to [6] and a pharmaceutically acceptable additive. [9] The pharmaceutical composition according to [8], for preventing or treating a disease whose pathology is expected to be improved 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 necrosis, post-ischemic myocardial damage, 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 cyclic edema, and sympathetic hyperactivity.

[11] A method for preventing or treating a disease whose pathology is expected to be improved by inhibiting aldosterone synthase, comprising administering to a patient an effective amount of the crystal according to any one of [3] to [6].

[12] Use of the crystal according to any one of [3] to [6] in the manufacture of a pharmaceutical for preventing or treating a disease whose pathology is expected to be improved by inhibiting aldosterone synthase.

[13] The crystal according to any one of [3] to [6], for preventing or treating a disease whose pathology is expected to be improved by inhibiting aldosterone synthase.

[14] The reaction scheme is as follows: [ka] (In the formula, R 1 and R 2 each 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 formula: (Step 1) reacting compound (2) with compound (3) to obtain compound (4) or a salt thereof; (Step 2) a step of subjecting compound (4) or a salt thereof to a deprotection reaction to obtain compound (5) or a salt thereof; (Step 3) reacting compound (5) or a salt thereof with compound (7) to obtain compound (8) or a salt thereof; (Step 4) subjecting compound (8) or a salt thereof to a deprotection reaction to obtain compound (9) or a salt thereof; and (Step 5) A step of reacting compound (9) or a salt thereof with an acetylating agent to obtain compound (10) A manufacturing method comprising:

[15] A method for producing crystals of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine hydrobromide, comprising 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, the water content of which is 2.0 to 3.0% by volume.

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

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

[18] Formula (8) [ka] (In the formula, R 2 indicates an amino protecting group) A compound represented by the formula (I) 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 as active pharmaceutical ingredients, and in particular, their crystals are free of residual solvent, have excellent thermal stability, are stable with little weight change against humidity, do not deliquesce, and are excellent in chemical stability. Thus, the salts of triazine compound A or their crystals are useful as active pharmaceutical ingredients. In particular, the hydrobromide of triazine compound A of the present invention exhibits stable pharmacokinetics both under conditions of gastric acid secretion promotion and gastric acid secretion inhibition, and further, its crystals have excellent stability and purity, and from a safety perspective, a method for stably obtaining crystals that do not contain compounds that may have adverse effects on living bodies has been established. Thus, the hydrobromide of triazine compound A or its crystals is particularly useful as a pharmaceutical active ingredient. In addition, the method for producing triazine compound A of the present invention allows triazine compound A to be obtained in an industrially suitable manner with good reproducibility, and is therefore useful as an industrial production method for pharmaceutical active ingredients with good quality. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the results of powder X-ray diffraction measurement of sulfate B-type crystals of triazine compound A. [Figure 2] FIG. 2 shows the results of differential scanning calorimetry of sulfate B-type crystals of triazine compound A. [Figure 3] FIG. 3 shows the results of powder X-ray diffraction measurement of type C crystals of the tosylate salt of triazine compound A. [Figure 4] FIG. 4 shows the results of differential scanning calorimetry of type C crystals of the tosylate salt of triazine compound A. [Figure 5] FIG. 5 shows the results of powder X-ray diffraction measurement of succinate type A crystals of triazine compound A. [Figure 6] FIG. 6 shows the results of differential scanning calorimetry of succinate A-type crystals of triazine compound A. [Figure 7] FIG. 7 shows the results of powder X-ray diffraction measurement of type F crystals of the hydrobromide salt of triazine compound A. [Figure 8] FIG. 8 shows the results of differential scanning calorimetry of type F crystals of hydrobromide of triazine compound A. [Figure 9] FIG. 9 shows the results of powder X-ray diffraction measurement of N-type crystals of the hydrobromide salt of triazine compound A. [Figure 10] FIG. 10 is a diagram showing the results of differential scanning calorimetry of N-type crystals of the hydrobromide salt of triazine compound A. [Figure 11] FIG. 11 shows the results of powder X-ray diffraction measurement of type A crystals of hydrobromide of triazine compound A. [Figure 12] FIG. 12 is a diagram showing the results of differential scanning calorimetry of the hydrobromide A-type crystals of triazine compound A. [Figure 13] FIG. 13 shows the results of infrared absorption spectrum measurement of hydrobromide type A crystals of triazine compound A. [Figure 14]FIG. 14 is a graph showing the pharmacokinetics of triazine compound A in free form and the hydrobromide of triazine compound A in concomitant use with pentagastrin, a gastric acid secretion promoter, or omeprazole, a gastric acid secretion inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0010] In this specification, the substituents represented by the respective symbols have the following meanings. The "amino-protecting group" includes protecting groups commonly used in the field of organic synthetic chemistry, such as t-butoxycarbonyl, benzyloxycarbonyl, and p-methoxybenzyl groups. Of these, t-butoxycarbonyl and benzyloxycarbonyl groups are preferred.

[0011] Triazine compound A can be prepared as follows. [ka] (In the formula, R 1 represents an amino-protecting group such as a benzyloxycarbonyl group, and R 2 is an amino-protecting group such as a t-butoxycarbonyl group, and R 1 (showing a different amino protecting group from

[0012] Step 1: Step 1 is a step of reacting compound (2) with compound (3) to obtain compound (4) or a salt thereof. Compound (2) and compound (3) are known or can be prepared according to known methods. Examples of salts of compound (4) include acid addition salts, such as inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate. Hydrochloride is preferred. The reaction of compound (2) with compound (3) can be carried out in accordance with the method described in WO 2015 / 163427, for example, by reacting compound (2) with compound (3) and a condensing agent in a solvent in the presence of a base. The condensing agent includes carbodiimides, acid azides, phosphonium-based condensing agents, triazoles, and acid anhydrides, with acid anhydrides being preferred, and propanephosphonic anhydride being particularly preferred. The solvent may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), and ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), and these can also be used in appropriate combinations. Among these, nitriles are preferred, and acetonitrile is particularly preferred. Examples of the base include triethylamine, diisopropylethylamine, and 1,8-diazabichloro[5.4.0]undec-7-ene (DBU), among 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 the salt of compound (5) include acid addition salts, such as inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate. Hydrochloride is preferred. The deprotection reaction of compound (4) can be carried out in accordance with the method described in Theodora W. Greene, Peter G.M. Wuts, “Protective Groups in Organic Synthesis” 4th Ed. / John Wiley & Sons, Inc., 2007, for example, in a solvent in the presence of palladium carbon under a hydrogen atmosphere. The solvent may be any solvent that does not affect the reaction, and examples thereof 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.), and these can also be used in appropriate combinations. Among 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, based on the compound (4) or a salt thereof. This reaction can be carried out at 0 to 30°C.

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

[0015] Step 4: Step 4 is a step of reacting compound (5) or a salt thereof with compound (7) to obtain compound (8) or a salt thereof. Examples of the salt of compound (8) include acid addition salts, such as inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate. Hydrochloride is preferred. This reaction can be carried out in a solvent in the presence of a base. The solvent may be any solvent that does not affect the reaction, and examples thereof 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, dimethoxyethane, etc.), and alcohols (methanol, ethanol, isopropanol, etc.), and these can also be used in appropriate combinations. Among 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 the base include triethylamine, diisopropylethylamine, and 1,8-diazabichloro[5.4.0]undec-7-ene (DBU), among which triethylamine is preferred. The amount of the 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 the salt of compound (9) include acid addition salts, such as inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate. Hydrochloride is preferred. The deprotection reaction of compound (8) can be carried out according to the method described in, for example, Theodora W. Greene, Peter G.M. Wuts, "Protective Groups in Organic Synthesis" 4th Ed. / John Wiley & Sons, Inc., 2007. This reaction can be carried out, for example, in a solvent in the presence of an acid. The solvent may be any solvent that does not affect the reaction, and examples thereof 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.), and these can also be used in appropriate combinations. Of these, water is preferred. Examples of the acid include trifluoroacetic acid, hydrochloric acid, paratoluenesulfonic acid, and methanesulfonic acid, and among these, hydrochloric acid is preferred. The amount of the 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 compound (9) or a salt thereof obtained after the reaction can be used in the next step as is, but it is preferable to use it in the next step after removing insoluble matter. When removing insoluble matter, it is 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, more preferably 30 to 50°C. It is 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 of reacting compound (9) or a salt thereof with an acetylating agent to obtain compound (10). The reaction of compound (9) or a salt thereof with an acetylating agent can be carried out in a solvent. The solvent may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), and alcohols (methanol, ethanol, isopropanol, etc.), and these can also be used in appropriate combinations. Among 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. The acetylating agent includes acetyl chloride and acetic anhydride, of which acetic anhydride is preferred. The amount of the acetylating agent used is 1 to 1.5 equivalents, preferably 1.05 to 1.2 equivalents, relative to compound (9) or a salt thereof. This reaction can be carried out at 40 to 60°C.

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

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

[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, more preferably a hydrobromide of triazine compound A. The molar ratio of the acid to the triazine compound A is not particularly limited, and may be, for example, 1 to 3 equivalents. For example, the hydrobromide of the triazine compound A includes the monohydrobromide of the triazine compound A and the dihydrobromide of the triazine compound A. The salt of triazine compound A may also be a hydrate.

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

[0022] The crystals of the sulfate of triazine compound A are preferably B-type crystals of the sulfate of triazine compound A.

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

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

[0025] A method for producing crystals of the hydrobromide salt of triazine compound A is described below. Crystals of the hydrobromide salt of triazine compound A exist in multiple crystalline forms, but particularly preferred crystalline forms are A-type, F-type, and N-type. Although A-type crystals are particularly preferred, simply adding hydrogen bromide to triazine compound A in a solvent will result in contamination with F-type and N-type crystals. However, by appropriately controlling the amount of hydrogen bromide added, the amount of water present in the system, the crystallization temperature, and the like, the crystal form can be converged to A-type crystals, and only A-type crystals can be obtained stably and efficiently.

[0026] The A-type crystals of the hydrobromide salt of triazine compound A can be prepared 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, followed by crystallization to obtain type A crystals of the hydrobromide salt of triazine compound A. The reaction can be carried out in a solvent. Examples of the solvent 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 combination. A preferred example is a mixed solvent of water and a solvent that is easily miscible with water. More preferred is a mixed solvent in which the water content is 1.0 to 5.0% of the total solvent volume. 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 preferred, and a mixed solvent of water and acetone in which the water content is 2.0 to 3.0% of the total solvent volume is more preferred. This reaction can be carried out at 5 to 55°C, preferably 20 to 55°C, and more preferably 40 to 55°C.

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

[0028] The N-type crystals of the hydrobromide salt of triazine compound A can be prepared as follows. Compound (10) is reacted with 1.2 to 1.5 equivalents of hydrogen bromide, followed by crystallization to obtain N-type crystals of the hydrobromide salt of triazine compound A. The reaction can be carried out in a solvent. Examples of the solvent 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 combination. Water is preferred. This reaction can be carried out at 10 to 50°C, preferably 40 to 50°C.

[0029] Crystals of the sulfate salt of triazine compound A can be prepared as follows.

[0030] The sulfate salt of compound (10) can be obtained as a crystal by reacting compound (10) with sulfuric acid and then crystallizing it. The reaction can be carried out in a solvent. The solvent may be any solvent that does not affect the reaction, and examples thereof include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), alcohols (methanol, ethanol, isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, xylene, etc.), and these can also 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] Crystals of the tosylate salt of triazine compound A can be prepared as follows.

[0032] The compound (10) can be reacted with tosylic acid and crystallized to obtain a crystalline tosylate of the compound (10). The reaction can be carried out in a solvent. The solvent may be any solvent that does not affect the reaction, and examples thereof include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), alcohols (methanol, ethanol, isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, xylene, etc.), and these can also 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] Crystals of the succinate salt of triazine compound A can be prepared as follows.

[0034] Crystals of the succinate salt of compound (10) can be obtained by reacting compound (10) with succinic acid and crystallizing the reaction. The reaction can be carried out in a solvent. The solvent may be any solvent that does not affect the reaction, and examples thereof include water, aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), alcohols (methanol, ethanol, isopropanol, etc.), and aromatic hydrocarbons (benzene, toluene, xylene, etc.), and these can also 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] The triazine compound A and / or hydrogen bromide, sulfuric acid, tosylic acid and succinic acid in the crystal of the present invention may be isotopes (e.g.,3 H, 13 C. 14 C. 15 N, 18 F, 32 This includes compounds labeled with .P) and deuterium conversions.

[0036] In the crystals of the present invention, type A crystals of the hydrobromide salt of triazine compound A contain no remaining molecules other than those used to obtain the crystals, and contain triazine compound A and hydrogen bromide in a molar ratio of 1:1.

[0037] Crystalline form A of the hydrobromide salt of triazine compound A is characterized by one or more of the following: (1) It is preferable that the powder X-ray diffraction pattern is as shown in FIG. 11 and / or the differential scanning calorimetry (DSC) curve is as shown in FIG. (2) Characteristic peaks in the powder X-ray diffraction pattern of the A-type crystals can include peaks at diffraction angles 2θ of 8.8°±0.2° and 25.6°±0.2°. In one embodiment, the A-type crystals have additional peaks at diffraction angles 2θ of 18.1°±0.2° and 20.9°±0.2° in the powder X-ray diffraction pattern. Other characteristic peaks can include peaks at 15.1°±0.2°, 17.5°±0.2°, 21.5°±0.2°, and 25.0°±0.2°. Further, 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°. Form A crystals of the hydrobromide salt of triazine compound A are crystals having a powder X-ray diffraction pattern substantially equivalent to that shown in FIG. (3) The melting point (extrapolated onset temperature) measured by DSC is 265 to 275°C, particularly around 268°C.

[0038] The crystals of the present invention have the advantageous effect of being crystals in which the residual solvent content is below the standard value set by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (hereinafter referred to as ICH). Another advantage is that the crystals have solvent impurities, inorganic impurities, residual metals, residual solvents, genotoxic impurities, etc. below the standard value set by the ICH guidelines.

[0039] The salt of the present invention and the crystal of the present invention have an inhibitory effect on aldosterone synthase and can therefore be used as an active ingredient of an aldosterone synthase inhibitor. Furthermore, the crystal of the present invention and a pharmaceutical composition containing it as an active ingredient are useful for treating or preventing various diseases whose pathological conditions are expected to be improved by inhibiting aldosterone synthase. Such diseases include, for example, 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 tumor, etc.), secondary aldosteronism (hypertension caused by estrogen preparations, renovascular hypertension, pregnancy-induced hypertension, malignant hypertension, pheochromocytoma, congestive heart failure, pseudohypoaldosteronism, chronic liver disease accompanied by ascites (liver cirrhosis, etc.), inappropriate use of drugs such as laxatives and diuretics, or hyperaldosteronism associated with nephrotic syndrome, Bartter syndrome, or Gittelman syndrome, etc.), hypertension (essential hypertension, secondary hypertension (renovascular hypertension, renal parenchymal hypertension, primary aldosteronism, pheochromocytoma, sleep apnea syndrome, etc.)), and group, Cushing's syndrome, drug-induced hypertension, aortic stenosis or hyperparathyroidism, etc.), treatment-resistant hypertension, mineralocorticoid-associated 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 necrosis, post-ischemic myocardial 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, dyslipidemia, sympathetic hyperactivity, idiopathic and / or cyclic edema, headache, anxiety disorder, and depressive disorder.In particular, the hydrobromide crystals of triazine compound A are useful for treating or preventing one or more diseases selected from the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrosis, post-ischemic myocardial 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 cyclic edema, and sympathetic hyperactivity.

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

[0041] The salt of the present invention, the crystal of the present invention, and pharmaceutical compositions containing them as active ingredients can be prepared into 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 depending on the dosage form, such as intravenous administration, oral administration, transdermal administration, etc. The term "patient" as used herein refers to an individual who is a target for prevention or treatment with the crystal of the present invention, and is preferably a mammal, more preferably a human.

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

[0043] In the present invention, "prevention" refers to the act of administering the salt of the present invention, the crystal of the present invention, or a pharmaceutical composition containing the same to an individual who has not developed a disease, disorder, or symptom. Furthermore, "treatment" refers to the act of administering the salt of the present invention, the crystal of the present invention, or a pharmaceutical composition containing the same to an individual who has already developed a disease, disorder, or symptom. Therefore, administering the salt of the present invention, the crystal of the present invention, or a pharmaceutical composition containing the same to an individual who has already developed a disease, disorder, or symptom in order to prevent the worsening of symptoms, attacks, or recurrence is one aspect of "treatment." [Example]

[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 Crystalline Form A of Hydrobromide 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% solution of T3P in acetonitrile was added dropwise over 2 hours and 30 minutes at 16-24°C. After 5 hours, a 10% aqueous potassium carbonate solution (potassium carbonate: 38.40 kg, water: 345.6 kg) was added dropwise over 23 minutes at 19-22°C. The mixture was 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 calcd 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 the atmosphere with an inert gas, the mixture was pressure-filtered. Methanol (235.8 kg) was added, and the mixture was pressure-filtered. The filtrate was concentrated to a volume of 180 L over 9 hours and 20 minutes. Methanol (71.7 kg) was added, yielding 228.1 kg of a methanol solution of compound 5. 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 calcd 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). After drying under reduced pressure at 30°C, 23.7 kg of Compound 7 was obtained (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 calcd 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 mixture was heated 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, and N-methyl-2-pyrrolidone (24.2 kg) was added, followed by stirring 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, 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 calcd 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 heated 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 after the addition of compound 8, the mixture was pressure filtered at 40°C. Water (112.8 L) was then added and pressure filtered. The mixture was cooled to 18°C, and 13.4 wt% aqueous sodium hydroxide 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 resulting solid was dried under reduced pressure at 50°C and crushed. After drying under reduced pressure at 50°C, 42.2 kg of compound 9 was obtained (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 calcd for C 22 H 31 N7O 409.3, found m / z 410 [M+H] + .

[0050] Methanol (55.4 kg), toluene (60.2 kg), and compound 9 (14.4 kg, after correcting for water content: 14.0 kg) were mixed under an inert gas atmosphere 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 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 with purified water (70.0 L). The mixture was dried under reduced pressure at 50°C to obtain 15.0 kg of compound 10. 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 under a nitrogen atmosphere to dissolve compound 10, and then pressurized. Purified water (13.3 L) and methanol (1.2 kg) were added, the mixture was heated to 60°C, and an aqueous solution of 24% sodium hydroxide (8.7 kg) and purified water (45.9 L) was added dropwise at 59-60°C over 50 minutes. 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) and 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 calcd for C 24H 33 N7O2451.3, found m / z 452 [M+H] + .

[0051] Acetone (478.0 kg) and compound 10 (37.8 kg) were mixed under a nitrogen atmosphere and heated to 50°C. 48% hydrobromic acid (13.9 kg), purified water (12.1 kg), and acetone (119.2 kg) were added and stirred at 46-50°C for 2 hours. Acetone (150.7 kg) was then added and stirred at 47-50°C for an additional 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). The crystals were dried under reduced pressure at 50°C for 7 hours to obtain 42.1 kg of compound 1 (hydrobromide of triazine compound A) (yield: 94%). The obtained crystals of hydrobromide of triazine compound A were hydrobromide type A 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 calcd for C 24 H 33 N7O2451.3, found m / z 452 [M+H] + .

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

[0053] [Table 1]

[0054] <X-ray powder diffraction (hereinafter sometimes referred to as XRPD) measurement> Measurement was carried out using a powder X-ray diffractometer X'PertPro (manufactured by PANalytical B.V.) under the following conditions. X-ray generator: X-ray tube (anticathode: copper, tube voltage: 45 kV, tube current: 40 mA) Incident optical system: focusing mirror Light receiving optical system: High-speed semiconductor array detector (X-Celerator), extended light receiving arm Sample stage: HTS sample stage (oscillates in the X-axis direction with a 4 mm amplitude) Number of measurements: 5 (with incident angles changed to -2, -1, 0, 1, and 2°) Measurement range: 2θ=3~40° Scan speed: 0.668451° / sec Step: 0.0167°

[0055] The XRPD results of the hydrobromide type A crystals of triazine compound A are shown in Figure 11. When the peak intensity at a diffraction angle 2θ of 25.6° is taken as 100, the peaks with relative peak intensities of 15 or more (each ±0.2°) are as shown in Table 2 below.

[0056] [Table 2]

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

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

[0059] [Table 3]

[0060] <Single crystal X-ray diffraction measurement> The 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 the crystal structure analysis results were sufficiently reliable.

[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 of the solution was dispensed into each vial of a 96-well plate (approximately 3 mg / vial). One equivalent (70 μL) or two equivalents (140 μL) of a 0.1 mol / L solution of the acid compound was also dispensed. 140 μL of a 0.05 mol / L solution of fumaric acid was dispensed into each vial. After evaporating the solvent with nitrogen, 300 μL of the eight solvents selected as screening solvents was dispensed into each vial, which was then sealed and stirred at room temperature for four days. Precipitates from vials containing precipitates were collected by filtration and analyzed by XRPD. Vials without precipitates were left uncapped and stored at room temperature overnight. If solids were observed, they were collected by filtration and analyzed by XRPD.

[0063] <Result> Crystallization studies were conducted using triazine compound A in mixed solvents prepared using 18 acids and 8 solvents. As a result, new crystals were obtained with 14 acids (hydrobromic acid, 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 alphabets were assigned to each salt in the order in which new XRPD patterns were confirmed. The XRPD results showed that the hydrobromide salt type A crystals of triazine compound A were the same crystals as the hydrobromide salt type A crystals of triazine compound A obtained in Example 1.

[0064] A portion of each of the above crystals was evaluated for thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0065] <Thermal stability evaluation> Measurements and evaluations were carried out under the following conditions using a thermogravimetric / differential thermal simultaneous measurement device TG / DTA7200 (SII NanoTechnology Inc.). Heating rate: 10°C / min Temperature range: 25 to 300°C Atmosphere: Nitrogen 200mL / min

[0066] <Evaluation of moisture absorption and deliquescence> The moisture adsorption measurement device DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited) was used to evaluate the moisture adsorption as follows: Approximately 5 mg of sample was placed on an aluminum dish whose tare weight had been adjusted in advance, and the sample was hung on the precision balance of the device to accurately measure the weight at the start of the measurement. The humidity was gradually changed in a chamber at 25°C, and the weight change was recorded over time, and the equilibrium weight at each humidity was determined. The weight at dry time (0% RH) was used as the base weight, and the rate of weight change and hydration number at each humidity were calculated.

[0067] <Chemical stability evaluation> Approximately 1 mg of each sample stored at 60°C (sealed) and 60°C / 75%RH (open) for one week, as well as the unstorage sample (at the start of the test), was weighed and dissolved in 5 mL of a 1:1 mixture of acetonitrile and water to prepare a sample solution. The test was carried out by liquid chromatography under the following conditions, and the individual peak area percentages were calculated. Measurement was performed using Waters ACQUITY UPLC under the following conditions. Detector: Photodiode array (measurement wavelength 239 nm) Column: Waters ACQUITY BEH C18 (2.1 mm x 100 mm, 1.7 μm) 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 min) 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 change was observed in the 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, for the succinate type A crystals, there was no significant weight change at 25 to 148°C (melting point), confirming that they are crystalline forms with good thermal stability.

[0070] Furthermore, as shown in the hygroscopicity and deliquescence evaluation results in Table 5, no significant increase in related substances was observed in the 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 hygroscopicity and deliquescence. Furthermore, it was confirmed that the sulfate type B crystals have a hydration stage and are in the form of a hydrate at room temperature and a relative humidity of 10 to 95%.

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

[0072] The hydrobromide salt type A crystals, sulfate salt type B crystals, tosylate salt type C crystals, and succinate salt type A crystals had good physical properties such as thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0073] Experimental Example 1: Synthesis of sulfate B crystals 50 mg of triazine compound A was dissolved in 2 mL of chloroform at room temperature. 30 mg (2.7 equivalents) of sulfuric acid was diluted with 2 mL of methanol and added at room temperature. After stirring at room temperature for 0.5 hours, the solvent was evaporated with nitrogen. 3 mL of acetonitrile and 100 μL of water were added to the dried solid to obtain a syrup. Seed crystals were added to the syrup to form a suspension, which was then stirred overnight at room temperature. The precipitate was filtered, washed twice with 0.5 mL of acetonitrile, and 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 50 mg of triazine compound A was dissolved in 2 mL of chloroform at room temperature. 45 mg (2 equivalents) of tosylic acid was dissolved in 2 mL of chloroform and 0.5 mL of methanol and added at room temperature. The solvent was evaporated with nitrogen, and 2.5 mL of 1,2-dimethoxyethane was added and stirred at room temperature overnight. The precipitate was filtered and dried under reduced pressure at 40°C for 3 hours to obtain 70 mg of tosylate type C crystals (yield 79%, calculated as ditosylate).

[0075] Experimental Example 3: Synthesis of succinate 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 form a solution, and the solvent was evaporated by blowing nitrogen. 2.5 mL of toluene was added and the mixture was stirred at room temperature overnight. 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 one succinate salt).

[0076] Experimental Example 4: Synthesis of Hydrobromide Crystalline Form A (Alternative Method) 50 mg of triazine compound A was dissolved in 2 mL of chloroform at room temperature. 39 mg of 25% hydrobromic acid / acetic acid was diluted with 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 dried product and stirred at room temperature overnight. The precipitate was filtered, washed twice with 0.5 mL of acetonitrile, and dried under reduced pressure at 40°C for 3 hours to obtain 50 mg of hydrobromide salt type A crystals (yield 85%).

[0077] Example 3 Polymorphism search for the hydrobromide salt of triazine compound A <Experimental Method> A suspension was obtained by dissolving approximately 500 mg of triazine compound A hydrobromide salt type A crystals in 5.0 mL of chloroform. This suspension was dispensed into vials in 50 μL aliquots in a 96-well plate. The solvent was evaporated to dryness under a nitrogen stream, and then the solvents shown in Table 6 were added in the order of poor solvents (6 types) and 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 suspension was sealed and stirred at room temperature for 5 days. The presence or absence of a suspension was visually confirmed. The suspension vials were filtered through a 96-well filter plate (MultiScreen® HTS+Hi-Flow, FC, Merck Millipore), and the residue on the filter was subjected to XRPD analysis.

[0078] <Result> Polymorphism was investigated using type A crystals of the hydrobromide salt of triazine compound A in a mixed solvent 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 analysis of the obtained crystals revealed the crystals listed in Table 6. The crystal forms were distinguished by XRPD patterns, and alphabets were assigned in the order in which new XRPD patterns were confirmed for each salt. The XRPD results indicate that type A crystals of the hydrobromide salt of triazine compound A are the same as type A crystals of the hydrobromide salt of triazine compound A obtained in Example 1.

[0079] [Table 6]

[0080] Of the 96 conditions shown in Table 6, under 55 conditions, the crystal form remained unchanged from the hydrobromide salt type A crystals, under 11 conditions the crystal form changed from the hydrobromide salt type A crystals to the hydrobromide salt type C crystals of triazine compound A (dimethyl sulfoxide solvate), and under 1 condition the crystal form changed to the hydrobromide salt type D crystals of triazine compound A (N-methylpyrrolidone solvate). Here, "not applicable" indicates that the crystals changed to a solution or other form that cannot be used for powder X-ray diffraction measurement, and "amorphous" indicates that the hydrobromide salt type A crystals changed to an amorphous form. As such, it was found that among the crystals of the hydrobromide salt of triazine compound A, the type A crystals were the most stable.

[0081] Example 4 Polymorphism search of the hydrobromide salt crystals of triazine compound A-2 Polymorphic screening of the hydrobromide salt crystals of triazine compound A was carried out in acetone, water, or a mixed solvent of acetone and water, depending on the hydrogen bromide equivalent or the crystallization temperature. As a result, 11 crystalline forms were obtained. Among the many crystalline forms obtained, type A crystals of the hydrobromide salt of triazine compound A, type F crystals of the hydrobromide salt of triazine compound A, and type N crystals of the hydrobromide salt of triazine compound A had good physical properties such as thermal stability, hygroscopicity, deliquescence, and chemical stability. The crystallization conditions for the hydrobromide A-type crystals of triazine compound A, the hydrobromide F-type crystals of triazine compound A, and the hydrobromide N-type crystals of triazine compound A, which had physical properties suitable for the production of pharmaceuticals, are shown in Table 7. The XRPD measurement device and measurement conditions were the same as those in Example 1. The XRPD results show that the hydrobromide A-type crystals of triazine compound A are the same crystals as the hydrobromide A-type crystals of triazine compound A obtained in Example 1.

[0082] [Table 7]

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

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

[0085] Method (c) yielded N-type crystals of the hydrobromide salt of triazine compound A. 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 by 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, and then 48% aqueous hydrobromic acid solution (7.84 g, 2.1 equivalents) was added and stirred for approximately 20 hours. The mixture was cooled to 10°C and filtered. The wet product was washed with acetone (50 mL) and dried under reduced pressure at 40°C for 24 hours to obtain hydrobromide salt type F crystals (13.45 g).

[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, and then 48% aqueous hydrobromic acid solution (26.19 g, 1.4 equivalents) was added and stirred for about 5 hours. The mixture was cooled to 14°C and filtered. The wet product was washed with acetone (200 mL) and dried under air for 21 hours to obtain hydrobromide salt N-type crystals (57.43 g).

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

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

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

[0092] The results of powder X-ray diffraction measurement of the hydrobromide salt type F crystals and hydrobromide salt type N crystals of the above-mentioned triazine compound A are shown below.

[0093] <Powder X-ray diffraction measurement> Measurement was carried out using a powder X-ray diffractometer X'PertPro (manufactured by PANalytical B.V.) under the following conditions. X-ray generator: X-ray tube (anticathode: copper, tube voltage: 45 kV, tube current: 40 mA) Incident optical system: focusing mirror Light receiving optical system: High-speed semiconductor array detector (X-Celerator), extended light receiving arm Sample stage: HTS sample stage (oscillates in the X-axis direction with a 4 mm amplitude) Number of measurements: 5 (with incident angles changed to -2, -1, 0, 1, and 2°) Measurement range: 2θ=3~40° Scan speed: 0.668451° / sec Step: 0.0167°

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

[0095] [Table 8]

[0096] Characteristic peaks in the powder X-ray diffraction pattern of type F crystals can include 10.0°±0.2° and 27.5°±0.2°, as diffraction angles represented by 2θ. In one embodiment, type F crystals further have peaks at 3.3°±0.2° and 14.4°±0.2°, as diffraction angles represented by 2θ, in the powder X-ray diffraction pattern. Other characteristic peaks can include 17.4°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.6°±0.2°. Further, 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°. Form F crystals of the hydrobromide salt of triazine compound A are crystals having a powder X-ray diffraction pattern substantially equivalent to that shown in FIG.

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

[0098] [Table 9]

[0099] Characteristic peaks in the powder X-ray diffraction pattern of the N-type crystals can include 11.3°±0.2° and 24.3°±0.2°, expressed as diffraction angles 2θ. In one embodiment, the N-type crystals further have peaks at 6.2°±0.2° and 31.9°±0.2°, expressed as diffraction angles 2θ, in the powder X-ray diffraction pattern. Other characteristic peaks can include 11.9°±0.2°, 22.4°±0.2°, 23.8°±0.2°, and 26.8°±0.2°. Further, 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-type crystals of the hydrobromide salt of triazine compound A are crystals having a powder X-ray diffraction pattern substantially equivalent to that shown in FIG.

[0100] Each of the above crystals was evaluated for thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0101] <Thermal stability evaluation> Measurements and evaluations were carried out under the following conditions using a thermogravimetric / differential thermal simultaneous measurement device TG / DTA7200 (SII NanoTechnology Inc.). Heating rate: 10°C / min Temperature range: 30 to 300°C Atmosphere: Nitrogen 200mL / min Or, TGA / DSC1 thermogravimetric analyzer (Mettler-Toledo, STARe system) Measurements and evaluations were carried out under the following conditions. Heating rate: 10°C / min Temperature range: 25 to 300°C Atmosphere: Nitrogen 50mL / min

[0102] <Evaluation of moisture absorption and deliquescence> The moisture adsorption measurement device DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited) was used to evaluate the adsorption properties as follows: The sample was placed in a cell whose tare weight had been adjusted in advance, and the device was hung on a precision balance to precisely measure the weight at the start of the measurement. The weight change was recorded over time as the humidity was gradually changed, and the equilibrium weight at each humidity was determined. The rate of weight change at each humidity was calculated based on the anhydrous weight converted from the moisture content at the start of the measurement, either when dry (0% RH) or confirmed by another method.

[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, and the increase or decrease in related substances before and after storage was calculated from the area percentage of each peak using high-performance liquid chromatography, and the condition after storage was also observed.

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

[0105] Among the many crystalline forms obtained, hydrobromide type A crystals, hydrobromide type F crystals, and hydrobromide type N crystals had good physical properties such as thermal stability, hygroscopicity, deliquescence, and chemical stability. However, hydrobromide type F crystals and hydrobromide type N crystals had a hydration stage and were confirmed to be hydrates at room temperature and relative humidity of 10 to 95%.

[0106] Example 6 Effect of water on the crystallization of hydrobromide salt type A crystals [Table 11]

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

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

[0109] It was confirmed that hydrobromide salt 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 aqueous hydrobromic acid solution, and stirring at 50°C. This method is an industrially advantageous crystallization method for pharmaceuticals.

[0110] Example 7 Comparison of the pharmacokinetics of triazine compound A and the hydrobromide salt of triazine compound A when used in combination with a gastric acid secretion promoter or a gastric acid secretion inhibitor <Experimental Method> The pharmacokinetics of triazine compound A hydrobromide and triazine compound A under controlled gastric acid secretion and intragastric pH were evaluated in dogs treated with a gastric acid secretagogue or gastric acid inhibitor in a two-group, four-period crossover design. Pentagastrin was used as the gastric acid secretion promoter. 2.8 mg of pentagastrin was dissolved in 7.0 mL of dimethyl sulfoxide and 7.0 mL of water for injection. The administration solution was administered intramuscularly in the thigh at a dose of 10 μg / 0.05 mL / kg. Pentagastrin was administered 0.5 hours before and 0.5 hours after the administration of the test substance (hydrobromide of triazine compound A (Compound 1 prepared in Example 1) or triazine compound A (Compound 10 prepared in Example 1)). Omeprazole was used as the gastric acid secretion inhibitor. 90 mg of omeprazole was dissolved in 22.5 mL of a 1:1 mixture of 0.1% aqueous sodium bicarbonate (w / v) and polyethylene glycol 400. The administration solution was administered intramuscularly in the saphenous vein of the hind limb at a dose of 1 mg / 0.25 mL / kg. Omeprazole was administered 1 hour before the administration of the test substance. The hydrobromide of triazine compound A and triazine compound A were orally administered at a dose of 10 mg / capsule (the hydrobromide of triazine compound A was equivalent to the amount of the free salt (10 mg of triazine compound A)) using a syringe equipped with an oral catheter after the rats had drunk 25 mL of water for injection, and then another 25 mL of water for injection was given from the syringe equipped with an oral catheter. The test substance was administered in a fasting state, and the rats were fed for 6 hours after administration. The rats were deprived of water from 1 hour before administration until 2 hours after administration. Six 4-year-old male beagle dogs were divided into two groups of three dogs each. Dogs in Group 1 were administered omeprazole followed by triazine compound A in Period 1, omeprazole followed by triazine compound A hydrobromide in Period 2, pentagastrin followed by triazine compound A in Period 3, and pentagastrin followed by triazine compound A hydrobromide in Period 4. Dogs in Group 2 were administered omeprazole followed by triazine compound A hydrobromide in Period 1, omeprazole followed by triazine compound A in Period 2, pentagastrin followed by triazine compound A hydrobromide in Period 3, and pentagastrin followed by triazine compound A in Period 4. Each period was followed by a 6- or 7-day washout period. 0.6 mL whole blood samples were collected from the cephalic vein using a heparinized syringe under conscious conditions at 15 minutes, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration of triazine compound A hydrobromide or triazine compound A. The whole blood samples were processed to plasma and analyzed for triazine compound A drug concentrations using liquid chromatography tandem mass spectrometry (LC-MS / MS). The area under the plasma concentration-time curve (AUC; the area from time 0 to the time when the final concentration could be measured, AUC) was calculated based on the plasma versus time data. 0-t and the area AUC calculated from time 0 to infinity by extrapolation of the final elimination phase 0-∞ ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max ), and the elimination half-life from plasma (T 1 / 2 ) was calculated 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 was absorbed less under gastric acid suppression conditions than under gastric acid secretion promotion conditions. maxA decrease of approximately 50% was confirmed in both CV% and AUC. Furthermore, under gastric acid suppression conditions, the CV% was large, suggesting that individual differences are more likely to occur. For 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 crystal form of the hydrobromide of triazine compound A used in Example 7 was hydrobromide type A crystal.

[0113] Experimental Example 8 Measurement of aldosterone synthase (hereinafter referred to as CYP11B2) inhibitory activity <Experimental Method> The pcDNA3.1-human CYP11B2 plasmid was transfected into the Chinese hamster lung fibroblast V79 cell line to generate a stable expression line of the human CYP11B2 gene. The cells were cultured and grown in Dulbecco's modified Eagle's Ham medium supplemented with 10% bovine serum and 1% G418 disulfate solution at 37°C in an environment of 95% air and 5% CO2, and then harvested. Next, mitochondria were fractionated according to the method of Chabre et al. JCE&M 85(11) 4060-68, 2000. Specifically, cells were suspended in 5 mmol / L Tris-HCl buffer (pH 7.4) containing 250 mmol / L sucrose and homogenized using a Teflon Potter-Elvehjem homogenizer. The suspension was then centrifuged (800 × g for 15 minutes). The supernatant was collected and centrifuged again (10,000 × g for 15 minutes) to obtain a pellet (mitochondrial fraction). The mitochondrial fraction was 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 and dispensed into a 96-well plate. Aldosterone production was achieved by adding 0.5 μmol / L deoxycorticosterone and 150 μmol / L NADPH and incubating at room temperature for 1.5–2 hours. The amount of aldosterone produced in the solution was measured using homogeneous time-resolved fluorescence (HTRF) analysis. The IC was calculated by performing nonlinear regression using a logistic curve from the aldosterone production inhibition rate (%) of the triazine compound A of the present invention at each concentration. 50 (nmol / L) was calculated. As a result, the IC of the triazine compound A of the present invention 50 The aldosterone synthase inhibitory activity was 9.0 nmol / L, and triazine compound A of the present invention had a strong aldosterone synthase inhibitory activity. Furthermore, by carrying out experiments similar to those in this experimental example using the salt of triazine compound A of the present invention and its crystals, it can be similarly confirmed that the salt of triazine compound A of the present invention and its crystals 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 can yield excellent crystals, and the hydrobromide salt in particular exhibits stable pharmacokinetics both under conditions of stimulated and suppressed gastric acid secretion, and from a safety perspective, is a salt that does not contain compounds that may have adverse effects on living organisms. Furthermore, the novel salt crystal of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is free of residual solvents, has excellent thermal stability, exhibits little weight change with humidity, does not deliquesce, has excellent chemical stability, and is safe. From a safety perspective, it is a crystal that does not contain compounds that may have adverse effects on living organisms, and further, the crystal can be obtained reproducibly by an industrially suitable method, making it an excellent crystal for use as a pharmaceutical active ingredient. Furthermore, the method for producing crystals of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine does not use any intermediates that pose explosive or genotoxic risks, and is capable of producing the active pharmaceutical ingredient with high yield. It is also an industrially advantageous method that can reproducibly produce the most stable crystals in high yield.

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 the hydrobromide, sulfate, succinate, or tosylate salt.

2. 2. The salt of claim 1, wherein the salt is a hydrobromide salt.

3. A salt crystal according to claim 1.

4. The crystal according to claim 3, wherein the salt is a hydrobromide salt.

5. The crystal according to claim 4, which has peaks at diffraction angles represented by 2θ in a powder X-ray diffraction spectrum of 8.8°±0.2°, 18.1°±0.2°, 20.9°±0.2°, and 25.6°±0.2°.

6. The crystal according to claim 4 or 5, which has an endothermic peak at 265 to 275°C in differential scanning calorimetry analysis.

7. An aldosterone synthase inhibitor comprising the crystal according to any one of claims 3 to 6 as an active ingredient.

8. A pharmaceutical composition comprising the crystal according to any one of claims 3 to 6 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition according to claim 8, for preventing or treating a disease whose pathological condition is expected to be improved by inhibiting aldosterone synthase.

10. The pharmaceutical composition of claim 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 necrosis, post-ischemic myocardial 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 cyclic edema, and sympathetic hyperactivity.

11. A method for preventing or treating a disease whose pathology is expected to be improved by inhibiting aldosterone synthase, comprising administering to a patient an effective amount of the crystal according to any one of claims 3 to 6.

12. Use of the crystal according to any one of claims 3 to 6 in the manufacture of a pharmaceutical for preventing or treating a disease whose pathology is expected to be improved by inhibiting aldosterone synthase.

13. The crystal according to any one of claims 3 to 6, for preventing or treating a disease whose pathological condition is expected to be improved by inhibiting aldosterone synthase.

14. The reaction scheme is as follows: 【Chemical 1】 (In the formula, R １ and R ２ each 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 formula: (Step 1) reacting compound (2) with compound (3) to obtain compound (4) or a salt thereof; (Step 2) a step of subjecting compound (4) or a salt thereof to a deprotection reaction to obtain compound (5) or a salt thereof; (Step 3) reacting compound (5) or a salt thereof with compound (7) to obtain compound (8) or a salt thereof; (Step 4) subjecting compound (8) or a salt thereof to a deprotection reaction to obtain compound (9) or a salt thereof; and (Step 5) A step of reacting compound (9) or a salt thereof with an acetylating agent to obtain compound (10). A manufacturing method comprising:

15. A method for producing a crystal of hydrobromide of 3-[4-[[trans-4-(acetamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, comprising 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 in a mixed solvent of water and acetone, the water content of which is 2.0 to 3.0% by volume.

16. Formula (4) 【Chemistry 2】 (In the formula, R １ and R ２ each independently represents an amino-protecting group. A compound represented by the formula (I) or a salt thereof.

17. Formula (5) 【Chemistry 3】 (In the formula, R ２ indicates an amino protecting group) A compound represented by the formula (I) or a salt thereof.

18. Formula (8) 【Chemistry 4】 (In the formula, R ２ indicates an amino protecting group) A compound represented by the formula (I) or a salt thereof.

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