Salt of triazine compound, crystal form thereof, and manufacturing method

Abstract

The present application provides a salt of a triazine compound having an inhibitory action against aldosterone synthase, which is useful as a medicine, particularly a prophylactic or therapeutic agent for primary aldosteronism and the like, a crystal thereof, and a production method thereof. Specifically, the present application provides a pharmaceutically acceptable salt of 3-[4-[[trans-4-(acetylamino)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is a hydrobromide, a sulfate, a succinate, or a p-toluenesulfonate, or the like.

Description

Technical Field

[0001] This invention relates to salts of triazine compounds having inhibitory effects on aldosterone synthase and useful as medicines, especially for the prevention or treatment of primary aldosteronism, as well as their crystal forms and methods of manufacture. More specifically, it relates to 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine (hereinafter, sometimes referred to as "triazine compound A") or pharmaceutically acceptable salts thereof, their crystal forms, methods of manufacture, and pharmaceutical compositions containing them as active ingredients. Background Technology

[0002] Patent Document 1 discloses various triazine compounds or their pharmacologically acceptable salts that have aldosterone synthase inhibitory activity, and Triazine Compound A is described in Example 48. However, Patent Document 1 does not describe or suggest a specific salt or crystal form of Triazine Compound A.

[0003] In addition, Patent Document 1 discloses the following method for manufacturing triazine compound A.

[0004] [Chemical Formula 1]

[0005]

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: International Publication No. 2015 / 163427 Summary of the Invention

[0009] The problem that the invention aims to solve

[0010] The present invention provides a novel salt of triazine compound A for the prevention or treatment of primary aldosteronism, its crystal form, and an industrially advantageous method for manufacturing the compound.

[0011] Methods for solving problems

[0012] To address the aforementioned issues, the inventors of this application conducted in-depth research to obtain a raw material with suitable qualities for use as a drug, and attempted to obtain a salt. As a result, hydrobromide, sulfate, succinate, or p-toluenesulfonate of triazine compound A were discovered as salts that are excellent in terms of purity, thermal stability, hygroscopicity, deliquescence, chemical stability, and safety, and are also excellent in terms of handling.

[0013] Next, the inventors of this application conducted in-depth research on the salt of the above-mentioned triazine compound A, and found that the hydrobromide of triazine compound A exhibits stable pharmacokinetics under both gastric acid secretion promotion and gastric acid secretion inhibition conditions.

[0014] Thus, the hydrobromide of triazine compound A, as a pharmaceutical technical material, possesses unexpectedly excellent properties, but multiple crystal forms have been identified. The inventors of this application discovered that, in particular, the A-type crystal of the hydrobromide of triazine compound A is the most preferred crystal form from a stability perspective. However, depending on the amount of hydrogen bromide added during the crystallization step, the crystallization temperature, and the composition of the crystallization solvent, issues such as the introduction of polymorphs, the increase of impurities, and the increase of residual solvent were observed, making it impossible to obtain the target crystal with good reproducibility and stability. Therefore, in addition to in-depth research on the types, amounts, and ratios of reagents and solvents used in crystallization, the inventors of this application also conducted in-depth research on the crystallization steps. As a result, a method for efficiently obtaining the A-type crystal of the hydrobromide of triazine compound A, suitable for pharmaceutical technical materials, was discovered, thus completing this invention. Furthermore, similarly to the A-type crystal of the hydrobromide of triazine compound A, methods for obtaining stable crystal forms of good quality for the sulfate, succinate, and p-toluenesulfonate of triazine compound A were also discovered.

[0015] Furthermore, based on the results of differential scanning calorimetry, compounds (B), (C), and (E) described in Patent Document 1 were confirmed to be compounds with explosive risks. Additionally, based on the results of the DEREK; MultiCASE genotoxicity risk assessment, compounds (B), (C), and (D) were confirmed to be compounds with potential genotoxic risks. As stated above, the manufacturing method described in Patent Document 1 uses compounds with explosive and genotoxic risks as manufacturing intermediates, and is therefore unfavorable for industrial-scale implementation.

[0016] Furthermore, triazine compound A is a poorly soluble compound, similar in properties to insoluble impurities produced in intermediate steps. Therefore, it is known that it is not easy to separate or purify it in the final step, making it difficult to supply triazine compound A of suitable quality as a pharmaceutical raw material.

[0017] Therefore, the inventors of this application conducted various studies and discovered an industrially advantageous method for manufacturing triazine compound A with qualities suitable for use as a pharmaceutical ingredient, which allows for the easy removal of insoluble impurities by using compounds with low explosive and genotoxic risks as manufacturing intermediates and by using compounds with high solubility as manufacturing intermediates.

[0018] That is, the present invention is as follows.

[0019] [1] Pharmaceutically acceptable salts of 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, wherein the salt is a hydrobromide, sulfate, succinate, or p-toluenesulfonate.

[0020] [2] The salt as described in [1], wherein the salt is a hydrobromide.

[0021] [3][1] The salt crystals described.

[0022] [4] Crystals as described in [3], wherein the salt is a hydrobromide.

[0023] [4-1] Crystals as described in [3], wherein the salt is 2-hydrobromate.

[0024] [4-2] The crystal as described in any one of [3] to [4-1], wherein the salt is a hydrate.

[0025] [5] The crystal as described in any one of [4] to [4-2], wherein, in the X-ray powder diffraction spectrum, it has 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.

[0026] [6] The crystal as described in any one of [4] to [5], wherein, in differential scanning calorimetry analysis, it has an endothermic peak at 265 to 275 °C.

[0027] [7] An aldosterone synthase inhibitor, which contains any one of the crystals described in [3] to [6] as an active ingredient.

[0028] [8] A pharmaceutical composition comprising any one of [3] to [6] crystals and pharmaceutically acceptable additives.

[0029] [9] The pharmaceutical composition described in [8] is used for the prevention or treatment of a disease in which the pathological condition is expected to be improved by the inhibition of aldosterone synthase.

[0030]

[10] The pharmaceutical composition as described in [9], wherein the disease is selected from one or more diseases in the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrosis, myocardial ischemia-reperfusion injury, coronary artery disease, myocardial or vascular fibrosis or remodeling, 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.

[0031]

[11] Methods for the prevention or treatment of diseases in which the pathological condition is expected to be improved by the inhibition of aldosterone synthase include administering to the patient an effective amount of any one of [3] to [6].

[0032] The use of any one of the crystals described in

[12] [3] to [6] in the manufacture of a medicament for the prevention or treatment of a disease in which the condition is expected to be improved by the inhibition of aldosterone synthase.

[0033]

[13] The crystal as described in any one of [3] to [6], which is used for the prevention or treatment of diseases that are expected to be improved by the inhibition of aldosterone synthase.

[0034]

[14] The method for producing compound (10) 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is represented by the following reaction formula.

[0035] [Chemical Formula 2]

[0036]

[0037] (where R is in the formula) 1 and R 2 Each group independently represents an amino protecting group.

[0038] The manufacturing method includes the following steps:

[0039] (Step 1) The step of reacting compound (2) with compound (3) to obtain compound (4) or its salt;

[0040] (Step 2) The step of subjecting compound (4) or its salt to a deprotection reaction to obtain compound (5) or its salt;

[0041] (Step 3) The step of reacting compound (5) or its salt with compound (7) to obtain compound (8) or its salt;

[0042] (Step 4) The step of subjecting compound (8) or its salt to a deprotection reaction to obtain compound (9) or its salt; and

[0043] (Step 5) The step of reacting compound (9) or its salt with an acetylation agent to obtain compound (10).

[0044]

[15] A method for manufacturing crystals of hydrobromide of 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine, characterized in that 0.9 to 1.1 equivalents of hydrogen bromide are added to a mixed solvent of water and acetone with a water content of 2.0 to 3.0 volume % to crystallize 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine.

[0045]

[16] The compound or its salt represented by formula (4).

[0046] [Chemical Formula 3]

[0047]

[0048] (where R is in the formula) 1 and R 2 Each group independently represents an amino protecting group.

[0049]

[17] The compound or its salt represented by formula (5).

[0050] [Chemical Formula 4]

[0051]

[0052] (where R is in the formula) 2 (Indicates amino protecting group)

[0053]

[18] The compound or its salt represented by formula (8).

[0054] [Chemical Formula 5]

[0055]

[0056] (where R is in the formula) 2 (Indicates amino protecting group)

[0057] The effects of the invention

[0058] The hydrobromide, sulfate, succinate, and p-toluenesulfonate salts of the triazine compound A of the present invention are all excellent salts for use as pharmaceutical technical materials. In particular, their crystals do not leave solvent residues, exhibit excellent thermal stability, show little and stable weight change relative to humidity, do not deliquesce, and possess excellent chemical stability. Thus, the salts of triazine compound A or its crystals are useful as pharmaceutical technical materials.

[0059] In particular, the hydrobromide of triazine compound A of the present invention exhibits stable pharmacokinetics under both gastric acid secretion-promoting and gastric acid secretion-inhibiting conditions, and its crystals possess excellent stability and purity. Furthermore, a method for stably obtaining crystals free of compounds that may have adverse effects on organisms from a safety perspective has been established. Thus, the hydrobromide of triazine compound A or its crystals are particularly useful as a pharmaceutical technical material.

[0060] Furthermore, the method for manufacturing triazine compound A of the present invention can reproducibly produce triazine compound A in an industrially suitable manner, and is therefore useful as an industrial manufacturing method for a pharmaceutical technical material with good quality. Attached Figure Description

[0061] [ Figure 1 ] Figure 1 The figure shows the results of X-ray powder diffraction analysis of type B sulfate crystals of triazine compound A.

[0062] [ Figure 2 ] Figure 2 A graph showing the results of differential scanning calorimetry (DSC) measurements of type B sulfate crystals of triazine compound A.

[0063] [ Figure 3 ] Figure 3 A graph showing the results of X-ray powder diffraction analysis of p-toluenesulfonate C-type crystals of triazine compound A.

[0064] [ Figure 4 ] Figure 4 A graph showing the results of differential scanning calorimetry (DSC) determination of p-toluenesulfonate C-type crystals of triazine compound A.

[0065] [ Figure 5 ] Figure 5 A graph showing the results of X-ray powder diffraction measurements of succinate type A crystals of triazine compound A.

[0066] [ Figure 6 ] Figure 6 A graph showing the results of differential scanning calorimetry (DSC) measurements of succinate type A crystals of triazine compound A.

[0067] [ Figure 7 ] Figure 7 A graph showing the results of X-ray powder diffraction measurements of F-type crystals of triazine compound A hydrobromide.

[0068] [ Figure 8 ] Figure 8 A graph showing the results of differential scanning calorimetry (DSC) determination of F-type crystals of triazine compound A hydrobromide.

[0069] [ Figure 9 ] Figure 9 A graph showing the results of X-ray powder diffraction measurements of the N-type hydrobromide crystals of triazine compound A.

[0070] [ Figure 10 ] Figure 10 A graph showing the results of differential scanning calorimetry (DSC) measurements of N-type hydrobromide crystals of triazine compound A.

[0071] [ Figure 11 ] Figure 11 A graph showing the results of X-ray powder diffraction measurements of the hydrobromide type A crystals of triazine compound A.

[0072] [ Figure 12 ] Figure 12 A graph showing the results of differential scanning calorimetry (DSC) measurements of type A hydrobromide crystals of triazine compound A.

[0073] [ Figure 13 ] Figure 13 The figure shows the results of infrared absorption spectroscopy measurements of the hydrobromide type A crystals of triazine compound A.

[0074] [ Figure 14 ] Figure 14 A diagram illustrating the pharmacokinetics of free triazine compound A and its hydrobromide in combination with pentagastrin, a gastric acid secretion promoter, or omeprazole, a gastric acid secretion inhibitor. Detailed Implementation

[0075] In this specification, the substituents represented by each symbol have the following meanings.

[0076] Examples of "amino protecting groups" commonly used in organic synthesis chemistry include tert-butoxycarbonyl, benzyloxycarbonyl, and p-methoxybenzyl. Among these, tert-butoxycarbonyl and benzyloxycarbonyl are preferred.

[0077] Triazine compound A can be manufactured in the following manner.

[0078] [Chemical Formula 6]

[0079]

[0080] (where R is in the formula) 1 R represents amino protecting groups such as benzyloxycarbonyl. 2 This indicates an amino protecting group such as tert-butyloxycarbonyl, and is related to R. 1 Different amino protecting groups)

[0081] Step 1:

[0082] Step 1 is the 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 manufactured by known methods. Examples of salts of compound (4) include acid addition salts, inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate or maleate. Hydrochloride is preferred.

[0083] The reaction of compound (2) with compound (3) can be carried out in accordance with the method described in International Publication No. 2015 / 163427, for example, by reacting compound (2) and compound (3) and condensing agent in a solvent in the presence of a base.

[0084] Examples of condensing agents include carbodiimides, acyl azides, phosphonium-based condensing agents, triazoles, and acid anhydrides, with acid anhydrides being preferred, and propanephosphonic anhydride being particularly preferred.

[0085] As a solvent, any solvent that does not affect the reaction can be used. 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 solvents can also be used in appropriate combinations. Nitriles are preferred, and acetonitrile is particularly preferred.

[0086] Examples of bases include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), among which diisopropylethylamine is preferred.

[0087] The amount of compound (3) used relative to compound (2) is 1.0 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents. The amount of condensing agent used relative to compound (2) is 0.9 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents. The amount of base used relative to compound (2) is 1.0 to 1.5 equivalents, preferably 1.0 to 1.3 equivalents. This reaction can be carried out at 0 to 30°C.

[0088] Step 2:

[0089] Step 2 is the step of subjecting compound (4) or its salt to a deprotection reaction to obtain compound (5) or its salt. Examples of salts of compound (5) include acid addition salts, inorganic acid salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or maleate. Hydrochloride is preferred.

[0090] The deprotection reaction of compound (4) can be carried out in a solvent, in the presence of palladium on carbon, or under a hydrogen atmosphere, as described in Theodora W. Greene, Peter GMWuts, “Protective Groups in Organic Synthesis” 4th Ed. / John Wiley & Sons, Inc., 2007.

[0091] As a solvent, any solvent that does not affect the reaction can be used, including 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 solvents can also be used in appropriate combinations. Alcohols are preferred, and methanol is more preferred.

[0092] The amount of palladium on carbon used relative to compound (4) or its salt is 0.1 to 10% by weight, preferably 0.5 to 10% by weight. The reaction can be carried out at 0 to 30°C.

[0093] Step 3:

[0094] Step 3 is the step of chlorinating compound (6) to obtain compound (7). Compound (6) is known or can be manufactured by known methods. The chlorination reaction of compound (6) can be carried out in a solvent in the presence of a chlorinating agent. It can also be carried out in the presence of a catalyst if necessary.

[0095] As a solvent, any solvent that does not affect the reaction can be used. 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 solvents can also be used in appropriate combinations. Among these, ethers are preferred, and dimethoxyethane is more preferred.

[0096] Examples of chlorinating agents include thionyl chloride, phosphorus oxychloride, and oxaloyl chloride, with thionyl chloride being the preferred option.

[0097] The amount of chlorinating agent used relative to compound (6) is 1.0 to 3.0 equivalents, preferably 1.8 to 2.2 equivalents.

[0098] N,N-dimethylformamide is preferred as a catalyst.

[0099] The amount of catalyst used relative to compound (6) is 0.01 to 0.5 equivalents, preferably 0.05 to 0.1 equivalents.

[0100] This reaction can be carried out at 50–100°C, preferably 70–80°C.

[0101] Step 4:

[0102] Step 4 is a step of reacting compound (5) or its salt with compound (7) to obtain compound (8) or its salt. Examples of salts of compound (8) include acid addition salts, inorganic acid salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or maleate. Hydrochloride is preferred.

[0103] This reaction can be carried out in a solvent and in the presence of a base.

[0104] As a solvent, any solvent that does not affect the reaction can be used, including 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 solvents can also be used in appropriate combinations. Preferably, aprotic solvents and alcohols are used, more preferably N-methyl-2-pyrrolidone and methanol, and even more preferably a mixture of N-methyl-2-pyrrolidone and methanol.

[0105] Examples of bases include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), among which triethylamine is preferred.

[0106] The amount of base used relative to compound (7) is 1 to 5 equivalents, preferably 2 to 3 equivalents. The reaction can be carried out at 50 to 100°C, preferably 50 to 70°C.

[0107] Step 5:

[0108] Step 5 is the step of subjecting compound (8) or its salt to a deprotection reaction to obtain compound (9) or its salt. Examples of salts of compound (9) include acid addition salts, inorganic acid salts such as hydrochloride, sulfate, phosphate, or hydrobromide, and organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or maleate. Hydrochloride is preferred.

[0109] The deprotection reaction of compound (8) can be carried out according to the method described in Theodora W. Greene, Peter GMWuts, “Protective Groups in Organic Synthesis” 4th Ed. / John Wiley & Sons, Inc., 2007, etc. This reaction can be carried out, for example, in a solvent or in the presence of an acid.

[0110] As a solvent, any solvent that does not affect the reaction can be used, including 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 solvents can also be used in appropriate combinations. Among them, water is preferred.

[0111] Examples of acids include trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, and methanesulfonic acid, with hydrochloric acid being the preferred choice.

[0112] The amount of acid used relative to compound (8) is 3 to 10 equivalents, preferably 3 to 5 equivalents. This reaction can be carried out at 30 to 50°C.

[0113] The resulting mixture containing compound (9) or its salt can be used directly in the next step, but it is preferred to use it in the next step after removing insoluble matter. If insoluble matter is removed, it is further preferred to filter the mixture. When filtering the mixture, it is preferred to use the same solvent as during the reaction. The temperature during filtration is preferably 5–95°C, more preferably 30–50°C. It is further preferred to crystallize the filtrate to obtain compound (9) in solid form before using it in the next step.

[0114] Step 6:

[0115] Step 6 is the step of reacting compound (9) or its salt with an acetylation agent to obtain compound (10). The reaction of compound (9) or its salt with the acetylation agent can be carried out in a solvent.

[0116] As a solvent, any solvent that does not affect the reaction can be used. 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 solvents can also be used in appropriate combinations. Among these, aromatic hydrocarbons and alcohols are preferred, toluene and methanol are more preferred, and a mixture of toluene and methanol is even more preferred.

[0117] Examples of acetylation agents include acetyl chloride and acetic anhydride, with acetic anhydride being the preferred choice.

[0118] The amount of acetylation agent used relative to compound (9) or its salt is 1 to 1.5 equivalents, preferably 1.05 to 1.2 equivalents. The reaction can be carried out at 40 to 60°C.

[0119] Compounds (4), (5), and (8) are novel manufacturing intermediates for the production of compound (10).

[0120] This invention relates to the salt, crystals, and methods for manufacturing triazine compound A.

[0121] The salt of the present invention is a salt of triazine compound A, preferably a hydrobromide, sulfate, p-toluenesulfonate, or succinate of triazine compound A, and more preferably a hydrobromide of triazine compound A.

[0122] The molar ratio of the acid to triazine compound A is not particularly limited; for example, the molar ratio of the acid to triazine compound A can be 1 to 3 equivalents. For example, the hydrobromide salts of triazine compound A include dihydrobromide salt and dihydrobromide salt of triazine compound A, etc.

[0123] In addition, the salts of triazine compound A can be hydrates.

[0124] 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 p-toluenesulfonate 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 crystals of type A hydrobromide of triazine compound A.

[0125] The preferred crystals of the sulfate of triazine compound A are type B crystals of the sulfate of triazine compound A.

[0126] The preferred crystal form of the p-toluenesulfonate of triazine compound A is the C-type crystal of the p-toluenesulfonate of triazine compound A.

[0127] The preferred crystals of the succinate of triazine compound A are type A crystals of the succinate of triazine compound A.

[0128] The following describes a method for manufacturing crystals of the hydrobromide of triazine compound A. The hydrobromide of triazine compound A exists in various crystal forms, with A-type, F-type, and N-type being particularly preferred. A-type crystals are especially preferred; however, if only hydrogen bromide is added to the solvent, F-type and N-type crystals may also be mixed into the triazine compound A. However, by appropriately managing the amount of hydrogen bromide added, the amount of water present in the system, and the crystallization temperature, the crystal form can be concentrated into A-type crystals, resulting in stable and efficient production of only A-type crystals.

[0129] Type A crystals of the hydrobromide of triazine compound A can be produced in the following manner.

[0130] 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 is performed to obtain type A crystals of the hydrobromide of triazine compound A. This reaction can be carried out in a solvent.

[0131] Examples of solvents include water, ketones (acetone and methyl ethyl ketone, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). Two or more solvents can also be appropriately combined. A mixed solvent containing water and a solvent easily miscible with water is preferred. A mixed solvent containing 1.0 to 5.0% water by volume is further preferred. A mixed solvent of water and acetone containing 1.0 to 5.0% water by volume is particularly preferred, and a mixed solvent of water and acetone containing 2.0 to 3.0% water by volume is even more preferred.

[0132] This reaction can be carried out at 5–55°C, preferably at 20–55°C, and even more preferably at 40–55°C.

[0133] The F-type crystals of hydrobromide of triazine compound A can be prepared in the following manner.

[0134] Compound (10) is reacted with 2.0–2.2 equivalents of hydrogen bromide and crystallized to obtain F-type crystals of the hydrobromide of triazine compound A. This reaction can be carried out in a solvent.

[0135] Examples of solvents include water, ketones (acetone and methyl ethyl ketone, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). Two or more solvents can also be used in appropriate combinations, with a mixture of water and acetone being preferred.

[0136] This reaction can be carried out at 10–50°C, preferably at 40–50°C.

[0137] The N-type crystals of hydrobromide of triazine compound A can be prepared in the following manner.

[0138] Compound (10) is reacted with 1.2 to 1.5 equivalents of hydrogen bromide and crystallized to obtain N-type crystals of the hydrobromide of triazine compound A. This reaction can be carried out in a solvent.

[0139] Examples of solvents include water, ketones (acetone and methyl ethyl ketone, etc.), and alcohols (methanol, ethanol, and isopropanol, etc.). Two or more solvents can also be used in appropriate combinations. Water is preferred.

[0140] This reaction can be carried out at 10–50°C, preferably at 40–50°C.

[0141] Crystals of the sulfate of triazine compound A can be produced in the following manner.

[0142] Compound (10) is reacted with sulfuric acid and crystallized to obtain crystals of the sulfate of compound (10). This reaction can be carried out in a solvent.

[0143] As a solvent, any solvent that does not affect the reaction can be used, including 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.), etc., and can also be used in appropriate combinations.

[0144] The amount of sulfuric acid used relative to compound (10) is 1 to 10 equivalents, preferably 1 to 5 equivalents. This reaction can be carried out at 10 to 60°C.

[0145] Crystals of p-toluenesulfonate of triazine compound A can be produced in the following manner.

[0146] Compound (10) is reacted with p-toluenesulfonic acid and crystallized to obtain crystals of p-toluenesulfonate of compound (10). This reaction can be carried out in a solvent.

[0147] As a solvent, any solvent that does not affect the reaction can be used, including 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.), etc., and can also be used in appropriate combinations.

[0148] The amount of p-toluenesulfonic acid used relative to compound (10) is 1 to 10 equivalents, preferably 1 to 5 equivalents. This reaction can be carried out at 10 to 60°C.

[0149] Crystals of the succinate of triazine compound A can be produced in the following manner.

[0150] Compound (10) is reacted with succinic acid and crystallized to obtain crystals of the succinate of compound (10). This reaction can be carried out in a solvent.

[0151] As a solvent, any solvent that does not affect the reaction can be used, including 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.), etc., and can also be used in appropriate combinations.

[0152] The amount of succinic acid used relative to compound (10) is 1 to 10 equivalents, preferably 1 to 5 equivalents. This reaction can be carried out at 10 to 60°C.

[0153] The triazine compound A and / or hydrogen bromide, sulfuric acid, toluenesulfonic acid, and succinic acid in the crystals of the present invention include isotopes (e.g., 3 H, 13 C 14 C 15 N、 18 F, 32 Compounds labeled with P and deuterium conversion products.

[0154] In the crystals of the present invention, for the type A crystals of the hydrobromide of triazine compound A, no other molecules used in obtaining the crystals remain, and triazine compound A and hydrogen bromide are contained in a 1:1 molar ratio.

[0155] The A-type crystals of the hydrobromide of triazine compound A are characterized by one or more of the following:

[0156] (1) Preferably having Figure 11 The X-ray powder diffraction pattern shown and / or Figure 12 The differential scanning calorimetry (DSC) curve shown is shown.

[0157] (2) For characteristic peaks in the X-ray powder diffraction pattern of the type A crystal, diffraction angles represented by 2θ include 8.8°±0.2° and 25.6°±0.2°. In one embodiment, the type A crystal also has peaks in the X-ray powder diffraction pattern at diffraction angles represented by 2θ at 18.1°±0.2° and 20.9°±0.2°. Other characteristic peaks include 15.1°±0.2°, 17.5°±0.2°, 21.5°±0.2°, and 25.0°±0.2°. In addition, 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 crystals of the hydrobromide of triazine compound A have the same... Figure 11 Crystals with essentially the same X-ray powder diffraction pattern.

[0158] (3) The melting point (extrapolated starting temperature) based on DSC is 265-275℃, especially around 268℃.

[0159] The crystals of this invention have an advantageous effect in that the residual solvent content is below the reference values ​​specified by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Other advantages include that the crystals contain solvent impurities, inorganic impurities, residual metals, residual solvents, genotoxic impurities, etc., below the reference values ​​specified in the ICH guidelines.

[0160] The salt and crystals of the present invention have an inhibitory effect on aldosterone synthase, and therefore can be used as an active ingredient in aldosterone synthase inhibitors. In addition, the crystals of the present invention and pharmaceutical compositions containing them as active ingredients are useful for the treatment or prevention of various diseases that are expected to improve pathological conditions 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 multinodular 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 with ascites (cirrhosis, etc.), inappropriate use of laxatives and diuretics, or nephrotic syndrome, Bartter syndrome, or Gitelman's syndrome. Hyperaldosteronism (as seen in hyperaldosteronism due to syndromes), hypertension (primary hypertension, secondary hypertension (renovascular hypertension, renal parenchymal hypertension, primary aldosteronism, pheochromocytoma, sleep apnea syndrome, Cushing's syndrome, drug-induced hypertension, aortic stenosis or hyperparathyroidism, etc.), refractory hypertension, mineralocorticoid-related hypertension, etc.), heart failure (congestive heart failure, left ventricular failure, right ventricular failure, systolic failure, diastolic failure, etc.), cardiomyopathy, cardiac hypertrophy (left ventricular hypertrophy, etc.), myocardial infarction, myocardial necrosis, etc. Myocardial ischemia-induced injury, coronary artery disease, myocardial or vascular fibrosis or remodeling (cardiovascular fibrosis and remodeling accompanied by hypertension and / or endothelial dysfunction, etc.), restenosis, thickening of the vessel wall, 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 abnormalities, sympathetic hyperactivity, idiopathic and / or periodic edema, headache, anxiety, and depressive disorders, etc.In particular, the 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 necrosis, post-myocardial ischemia injury, coronary artery disease, myocardial or vascular fibrosis or remodeling, 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.

[0161] Pharmaceutical compositions containing the salt or crystals of the present invention as active ingredients can be obtained by mixing the salt or crystals of the present invention with pharmaceutically acceptable additives, such as diluents, binders (syrups, gum arabic, gelatin, sorbitol, tragacanth gum, and polyvinylpyrrolidone, etc.), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbitol, and glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, and silicon dioxide, etc.), disintegrants (potato starch, etc.), and humectants (sodium lauryl sulfate, etc.).

[0162] The salts, crystals, and pharmaceutical compositions containing them as active ingredients of the present invention can be administered to a patient after being prepared into a suitable form of administration (e.g., powder, injection, tablet, capsule, and topical preparation) by a suitable method of administration corresponding to that form of administration (e.g., intravenous administration, oral administration, and percutaneous administration). The term "patient" in this invention refers to an individual who is the object of prevention or treatment by the crystals of the present invention, preferably a mammal, and more preferably a human.

[0163] Regarding the dosage, it can be determined based on factors such as the patient's age, weight, general health condition, sex, diet, administration time, administration method, excretion rate, combination of drugs, and the severity of symptoms being treated at the time of administration, taking into account these or other factors. The salt of the present invention, the crystals of the present invention, and pharmaceutical compositions containing them as active ingredients have low toxicity and can be used safely. The daily dosage (i.e., the effective dose) varies depending on the patient's condition, weight, and route of administration. For example, in the case of non-oral administration, it is desirable to administer 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. In the case of oral administration, it is desirable to administer about 0.01 to 1000 mg / person / day, preferably about 0.01 to 500 mg / person / day.

[0164] In this invention, "prevention" refers to the act of administering the salt, crystal, or pharmaceutical composition containing the present invention to an individual who has not yet developed a disease or symptoms. Conversely, "treatment" refers to the act of administering the salt, crystal, or pharmaceutical composition containing the present invention to an individual who has already developed a disease or symptoms. Therefore, administering such treatment to an individual who has already developed a disease or symptoms in order to prevent the worsening of symptoms, the onset of disease, or the recurrence of disease is a form of "treatment."

[0165] Example

[0166] The present invention will now be described in detail through examples and experimental cases, but the present invention is not limited thereto. It should be noted that, in this specification, "equivalent" refers to "molar equivalent".

[0167] Example 1: Synthesis of Type A crystals of hydrobromide of triazine compound A

[0168] [Chemical Formula 7]

[0169]

[0170] 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 at 16–24 °C for 2 hours and 30 minutes. After 5 hours, a 10% potassium carbonate aqueous solution (potassium carbonate: 38.40 kg, water: 345.6 kg) was added dropwise at 19–22 °C for 23 minutes, followed by cooling to 15 °C and stirring 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 then dried under reduced pressure at 50 °C to obtain 67.1 kg of compound 4 (yield: 93%).

[0171] 1 H NMR(DMSO-d6,500MHz): 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(b r,1H),3.42(br,4H),3.45-3.51(m,1H),5.07(s,2H),6.70(d,J=7.8Hz,1H),7.30-7.39(m,5H),7.52(d,J=8.2Hz,1H).

[0172] MS calcd for C 25 H 38N4O5 474.3, found m / z 475 [M+H] + .

[0173] Methanol (471.6 kg), Compound 4 (59.7 kg), and 10% palladium on carbon (6.0 kg) were mixed at 15–17 °C under an inert gas atmosphere, with hydrogen supplied at 0.2 MPa, and stirred at 17–23 °C for 3 hours and 40 minutes. After replacing the mixture with an inert gas, the mixture was pressure filtered. Further addition of methanol (235.8 kg) and pressure filtration were performed, and the filtrate was concentrated to a volume of 180 L after 9 hours and 20 minutes. Adding methanol (71.7 kg) yielded 228.1 kg of a methanol solution of Compound 5.

[0174] 1 H NMR(CDCl3,500MHz): δ1.19-1.30(m,4H),1.44(s,9H),1.97-2.04(m,4H),2.46(br,4H),2.89(t, J=4.9Hz,4H),2.94(s,2H),3.43(br,1H),3.70-3.77(m,1H),4.39(br,1H),6.99(d,J=8.4Hz,1H).

[0175] MS calcd for C 17 H 32 N4O3 340.2, found m / z 341 [M+H] + .

[0176] Under an inert gas atmosphere, 237.5 kg of 1,2-dimethoxyethane, 42.0 kg of compound 6, and 1.64 kg of dimethylformamide were mixed at 15–16 °C and heated to 74 °C over 1 hour. Thionyl chloride (53.4 kg) was added dropwise over 1 hour at 73–79 °C, and the mixture was stirred at 71–77 °C for 5 hours. After cooling to 20 °C, 210.0 L of water was added dropwise over 2 hours and 30 minutes at 20–22 °C, 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, 99.5 kg of ethanol was mixed with the crystals 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%).

[0177] 1H NMR (DMSO-d6, 500MHz): δ2.43 (s, 3H), 7.46 (d, J = 7.9Hz, 2H), 8.25 (d, J = 8.3Hz, 2H), 10.12 (s, 1H).

[0178] MS calcd for C 10 H8ClN3 205.0,found m / z 206[M+H] + .

[0179] 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 N-methyl-2-pyrrolidone (96.8 kg) of compound 7 (23.5 kg) was added dropwise at 57–62 °C. After adding N-methyl-2-pyrrolidone (24.2 kg), 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. The mixture was 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%).

[0180] 1 H NMR (CDCl3, 500MHz): δ1.22-1.34(m,4H),1.44(s,9H),2.01-2.06(m,4H),2.44(s,3H),2.64(t,J=5.2Hz,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=8.6Hz,1H),7.32(d,J=8.0Hz,2H),8.00(d,J=8.2Hz,2H),9.00(s,1H).

[0181] MS calcd for C 27 H 39 N7O3 509.3, found m / z 510 [M+H] + .

[0182] Under an inert gas atmosphere, water (564.0 L) and 35% hydrochloric acid (133.1 kg) were mixed at 19–24 °C, and the mixture was heated to 37 °C. Compound 8 (56.4 kg) was added in batches at 37–41 °C for 1 hour. Dilute hydrochloric acid, prepared from water (141.0 L) and 35% hydrochloric acid (33.3 kg), was 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. Water (112.8 L) was further 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 then dried under reduced pressure at 50°C, and the resulting solid was pulverized. Further drying under reduced pressure at 50°C yielded 42.2 kg of compound 9 (yield: 93%).

[0183] 1 H NMR (CD3OD, 500MHz): δ1.22-1.41(m,4H),1.92(d,J=6.3Hz,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=5.0Hz,4H),7.36(d,J=8.1Hz,2H),8.10(d,J=8.3Hz,2H),9.06(s,1H).

[0184] MS calcd for C 22 H 31 N7O 409.3, found m / z 410 [M+H] + .

[0185] Under an inert gas atmosphere, methanol (55.4 kg), toluene (60.2 kg), and compound 9 (14.4 kg, weight of compound 9 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 further 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 at 50°C over 40 minutes. 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), followed by further washing with purified water (70.0 L). Compound 10 was dried under reduced pressure at 50°C to obtain 15.0 kg. 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. Purified water (13.3 L) and methanol (1.2 kg) were further added, and the temperature was raised to 60°C. 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. The mixture was stirred at 59–60°C for 40 minutes, 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%).

[0186] 1 H NMR (CDCl3, 500MHz): δ1.24-1.38(m,4H),1.97(s,3H),2.02-2.06(m,4H),2.44(s,3H),2.65(t,J=5.1Hz,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=8.6Hz,1H),7.32(d,J=8.0Hz,2H),8.00(d,J=8.3Hz,2H),9.00(s,1H).

[0187] MS calcd for C 24 H 33 N7O2 451.3, found m / z 452 [M+H] + .

[0188] Under a nitrogen atmosphere, acetone (478.0 kg) and Compound 10 (37.8 kg) were mixed and the temperature was raised 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 further stirred at 47 - 50 °C for 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).减压干燥 was carried out at 50 °C for 7 hours to obtain 42.1 kg of Compound 1 (hydrobromide of triazine compound A) (yield: 94%). At this time, the crystals of the hydrobromide of triazine compound A obtained were hydrobromide A-type crystals.

[0189] 1 H NMR(CDCl3,500MHz):δ1.24 - 1.38(m,4H),1.97(s,3H),2.02 - 2.06(m,4H),2.44(s,3H),2.66(t,J = 5.1Hz,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 = 8.6Hz,1H),7.32(d,J = 8.0Hz,2H),8.00(d,J = 8.3Hz,2H),9.01(s,1H).

[0190] MS calcd for C 24 H 33 N7O2 451.3,found m / z 452[M + H] + .

[0191] The results of elemental analysis determination are shown in Table 1 below.

[0192] [Table 1]

[0193] Table 1 Results of elemental analysis determination of hydrobromide A-type crystals of triazine compound A

[0194] C H N Br Measured values 53.89 6.39 18.18 15.17 Theoretical value 53.98 6.46 18.13 15.22

[0195] (The theoretical values represent the theoretical values when 0.1 equivalent of acetone is attached.)

[0196] <X-ray powder diffraction (hereinafter sometimes referred to as XRPD) determination>

[0197] Using an X-ray powder diffraction apparatus X’PertPro (manufactured by PANalyical B.V.), the measurement was carried out under the following conditions.

[0198] It should be noted that the "减压干燥" in the original text seems to be an incorrect or incomplete expression. It might be "vacuum drying" in a more accurate context.X-ray generating device: X-ray tube (cathode: copper, tube voltage: 45kV, tube current: 40mA)

[0199] Incident optical system: Condensing lens

[0200] Light-receiving optical system: High-speed semiconductor array detector (X-Celerator), extended light-receiving arm

[0201] Sample stage: HTS sample stage (vibrates at a width of 4mm in the X-axis direction)

[0202] Total number of attempts: 5 (the incident angles were changed to -2°, -1°, 0°, 1°, and 2° respectively).

[0203] Measurement range: 2θ = 3~40°

[0204] Scanning speed: 0.668451° / second

[0205] Step size: 0.0167°

[0206] The XRPD results of the type A hydrobromide crystals of triazine compound A are shown in... Figure 11 The peaks with relative peak intensities of 15 or higher (each ±0.2°) when the peak intensity represented by 2θ at a diffraction angle of 25.6° is set to 100 are shown in Table 2 below.

[0207] [Table 2]

[0208] Table 2

[0209] 2θ(deg) relative strength 8.8 85 13.0 47 13.1 34 13.8 23 15.1 67 15.4 28 17.5 85 18.1 88 19.6 25 20.9 89 21.5 77 22.9 27 25.0 87 25.6 100 26.2 41 26.3 56 28.2 43

[0210] Differential Scanning Calorimetry (DSC) Measurement

[0211] The measurements were performed using a differential scanning calorimeter X-DSC7000 (SII NanoTechnology Co., Ltd.) under the following conditions.

[0212] Heating rate: 10℃ / minute (30℃~300℃)

[0213] Atmosphere: Nitrogen 100 mL / min

[0214] The results of obtaining type A crystals of hydrobromide from triazine compound A are shown in... Figure 12 An endothermic peak was also observed at approximately 265–275 °C.

[0215] <Infrared Absorption Spectroscopy Measurement>

[0216] The potassium bromide pellet method of infrared absorption spectroscopy was used to conduct experiments, and the obtained infrared absorption spectra were compared.

[0217] The results of the hydrobromide A-type crystal of triazine compound A are shown in Figure 13 . The attribution results of the infrared absorption spectrum are shown in Table 3 below.

[0218] [Table 3]

[0219] Table 3: Attribution Results of Infrared Absorption Spectrum of Hydrobromide A-Type Crystal of Triazine Compound A

[0220] <![CDATA[Wave number (cm -1 )]]> Belonging 3360.05 NH stretching vibration (amide) 2934.74 CH stretching vibration (benzene ring) 2567.30 NH stretching vibration (NH+) 1663.63 C=O stretching vibration (amide) 1527.65 C=O stretching vibration (benzene ring) 824.58 CH out-of-plane bending vibration (1,4-disubstituted benzene)

[0221] <X-ray Single Crystal Diffraction Determination>

[0222] Using an X-ray single crystal diffractometer R-AXIS RAPID / R (Rigaku Corporation) (CuKα line), the lattice constants were determined and the diffraction peak intensities were measured at -40 °C. Then, the phase was determined using the direct method, the structure was refined based on the full matrix least squares method, and the analysis was performed. The obtained crystallographic data and the results of the crystal structure analysis are shown in Table 4. It should be noted that the reliability factor (R value) is 12.35%, and various other parameters also indicate that this crystal structure analysis is a result with a sufficiently high reliability.

[0223] [Table 4]

[0224] Table 4: Crystallographic Data and Results of Crystal Structure Analysis of Hydrobromide A-Type Crystal of Triazine Compound A

[0225]

[0226] Example 2 Study on the Salt Crystallization of Triazine Compound A

[0227] <Experimental Method>

[0228] Dissolve about 600 mg of triazine compound A in 40 mL of chloroform, and dispense 200 μL (about 3 mg / well) into each well (vial) of a 96-well plate. In addition, 1 equivalent (70 μL) or 2 equivalents (140 μL) of a 0.1 moL / L solution of an acid compound was dispensed separately. For fumaric acid, 140 μL of a 0.05 moL / L solution was dispensed separately. After the solvent was evaporated by nitrogen blowing, 300 μL of 8 solvents selected as screening solvents were dispensed into each well, sealed, and stirred at room temperature for 4 days. For the wells with precipitates, the precipitates were filtered out and XRPD measurement was performed. For the wells without precipitates, the lids were opened and stored at room temperature overnight. In the case where solids were observed, they were filtered out and XRPD measurement was performed.

[0229] <Results>

[0230] Crystallization studies were conducted using triazine compound A in a mixed solvent prepared with 18 acids and 8 solvents. Novel crystals were obtained from 14 acids (hydrobromic acid, hydrochloric acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, citric acid, fumaric acid, tartaric acid, malic acid, succinic acid, glutaric acid 2-oxoacetic acid, and glycolic acid). Crystal forms were distinguished by XRPD patterns, with each salt labeled in the order in which the novel XRPD pattern was identified. The XRPD results showed that the hydrobromide A-type crystals of triazine compound A were identical to those obtained in Example 1.

[0231] For a portion of each of the aforementioned crystals, evaluate their thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0232] <Evaluation of Thermal Stability>

[0233] The following measurements and evaluations were performed using a simultaneous thermogravimetric / differential calorimetry (TGC / DTA7200) device (SII NanoTechnology Co., Ltd.).

[0234] Heating rate: 10℃ / minute

[0235] Temperature range: 25~300℃

[0236] Atmosphere: Nitrogen 200 mL / min

[0237] <Evaluation of hygroscopicity and deliquescence>

[0238] The evaluation was performed using a moisture adsorption assay apparatus, either the DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited), as follows: Approximately 5 mg of sample was placed in a pre-calibrated aluminum dish. The apparatus was then attached to a precision balance, and the initial weight was precisely measured. The weight change was recorded over time as humidity was varied in stages within a chamber at 25°C, and the equilibrium weight at each humidity level was determined. Using the weight at dryness (0% RH) as a baseline, the rate of weight change and hydration number at each humidity level were calculated.

[0239] <Chemical Stability Evaluation>

[0240] For samples stored at 60℃ (sealed) and 60℃ / 75%RH (open) for one week, as well as unstored samples (at the start of the test), approximately 1 mg was measured and dissolved in 5 mL of an acetonitrile / water (1:1) mixture to prepare a sample solution. The test was performed using liquid chromatography under the following conditions, and the peak areas were determined.

[0241] Use Waters ACQUITY UPLC and perform the determination under the following conditions.

[0242] Detector: Photodiode array (measurement wavelength 239nm)

[0243] Column: Waters ACQUITY BEH C18 (2.1mm×100mm, 1.7μm)

[0244] Column temperature: a constant temperature around 40℃

[0245] Mobile phases: Solution A: Water / TFA (2000:1); Solution B: Acetonitrile / TFA (2000:1)

[0246] Concentration gradient control: B%2 → 100% (15 minutes)

[0247] Flow rate: 0.5 mL / min

[0248] Injection volume: 2 μL

[0249] The results are shown in Table 5.

[0250] [Table 5]

[0251] Table 5. Results of solid property determination of triazine compound A salt crystals

[0252]

[0253] *1: Has a hydration stage

[0254] As shown in Table 5, no significant weight changes were observed in hydrobromide type A crystals, hydrochloride type A crystals, sulfate type B crystals, p-toluenesulfonate type B crystals, p-toluenesulfonate type C crystals, methanesulfonate type A crystals, maleate type A crystals, maleate type B crystals, and citrate type A crystals, confirming them as crystal forms with good thermal stability. Furthermore, succinate type A crystals showed no significant weight changes between 25 and 148 °C (melting point), thus confirming them as a crystal form with good thermal stability.

[0255] Furthermore, as shown in Table 5 regarding the evaluation results of hygroscopicity and deliquescence, no significant increase in similar substances was observed in hydrobromide type A crystals, sulfate type B crystals, p-toluenesulfonate type B crystals, p-toluenesulfonate type C crystals, succinate type A crystals, and glycolate type A crystals, confirming them as good crystal forms with low hygroscopicity and deliquescence. Additionally, it was confirmed that sulfate type B crystals have a hydration stage and are hydrated under conditions of room temperature and relative humidity of 10–95%.

[0256] Furthermore, as shown in the chemical stability test results in Table 5, no significant increase of similar substances was observed in hydrobromide type A crystals, hydrochloride type A crystals, sulfate type B crystals, p-toluenesulfonate type B crystals, p-toluenesulfonate type C crystals, maleate type A crystals, citrate type A crystals, succinate type A crystals, and glycolate type A crystals, confirming that they are crystal forms with good chemical stability.

[0257] Hydrobromide type A crystals, sulfate type B crystals, p-toluenesulfonate type C crystals, and succinate type A crystals possess good thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0258] Experimental Example 1: Synthesis of Sulfate Type B Crystals

[0259] 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 under nitrogen. 3 mL of acetonitrile and 100 μL of water were added to the dried solid to obtain a sugar-like substance. Seed crystals were added to the sugar-like substance 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).

[0260] Experimental Example 2: Synthesis of p-Toluenesulfonate C-type Crystals

[0261] Dissolve 50 mg of triazine compound A in 2 mL of chloroform at room temperature. Dissolve 45 mg (2 equivalents) of p-toluenesulfonic acid in 2 mL of chloroform and 0.5 mL of methanol, and add the solution at room temperature. Evaporate the solvent with nitrogen, add 2.5 mL of 1,2-dimethoxyethane, and stir overnight at room temperature. Filter the precipitate and dry under reduced pressure at 40 °C for 3 hours to give 70 mg of p-toluenesulfonate C-type crystals (yield 79%, calculated as 2 p-toluenesulfonate).

[0262] Experimental Example 3: Synthesis of Succinate Type A Crystals

[0263] 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 prepare a solution. The solvent was then evaporated by nitrogen blowing, and 2.5 mL of toluene was added. 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 give 43 mg of succinate type A crystals (yield 85%, calculated as 1 succinate).

[0264] Experimental Example 4: Synthesis of Hydrobromide Type A Crystals (Another Method)

[0265] Dissolve 50 mg of triazine compound A in 2 mL of chloroform at room temperature. Dilute 39 mg of 25% hydrobromic acid / acetic acid with 1 mL of methanol and add the solution at room temperature. Stir at room temperature for 1 hour, then evaporate the solvent with nitrogen. Add 2.5 mL of acetonitrile to the dried solid and stir overnight at room temperature. Filter the precipitate, wash the filter twice with 0.5 mL of acetonitrile, and dry under reduced pressure at 40 °C for 3 hours to obtain 50 mg of hydrobromide type A crystals (yield 85%).

[0266] Example 3: Polymorphism Search of Hydrobromate of Triazine Compound A

[0267] <Experimental Methods>

[0268] Approximately 500 mg of triazine compound A hydrobromide type A crystals were dissolved in 5.0 mL of chloroform to obtain a suspension. 50 μL of this suspension was dispensed into each well of a 96-well plate. After the solvent dried under a nitrogen stream, the solvents listed in Table 6 were added in the order of unsuitable solvents (6 types) and good solvents (4 types), bringing the total volume to 200 μL. Acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene were selected as unsuitable solvents. Methanol, benzyl alcohol, N-methylpyrrolidone, and dimethyl sulfoxide were selected as good solvents. The plate was sealed and stirred at room temperature for 5 days. The presence of suspension was visually confirmed. For wells showing suspension, the plate was filtered through a 96-well filter plate (MultiScreen HTS+Hi-Flow, FC, Merck Millipore), and the XRPD of the residue on the filter was determined.

[0269] <Results>

[0270] Using the hydrobromide A-type crystals of triazine compound A, polymorphism searching was performed using a mixed solvent prepared with six unsuitable solvents (acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene) and four good solvents (methanol, benzyl alcohol, N-methylpyrrolidone, and dimethyl sulfoxide). X-ray powder diffraction (XRPD) was performed on the obtained crystals, and the results are shown in Table 6. The crystal forms were distinguished by XRPD patterns, and for each salt, letters were labeled in the order in which the novel XRPD pattern was confirmed. The XRPD results show that the hydrobromide A-type crystals of triazine compound A are the same as those obtained in Example 1.

[0271] [Table 6]

[0272] Table 6: Results of polymorph search for hydrobromide crystals of triazine compound A - 1

[0273]

[0274] Of the 96 conditions shown in Table 6, the A-type hydrobromide crystals did not undergo a change in crystal form under 55 conditions, changed to the C-type hydrobromide crystals (dimethyl sulfoxide) of triazine compound A under 11 conditions, and changed to the D-type hydrobromide crystals (N-methylpyrrolidone) of triazine compound A under 1 condition. Here, "not conforming" indicates a change to a form such as a solution that cannot be measured by X-ray powder diffraction, and "amorphous" indicates a change from the A-type hydrobromide crystals to an amorphous substance. Therefore, it can be concluded that the A-type hydrobromide crystals of triazine compound A are the most stable.

[0275] Example 4: Polymorphism Search of Hydrobromide Crystals of Triazine Compound A - 2

[0276] Using triazine compound A, polymorphisms of the hydrobromide crystals of triazine compound A were searched in acetone, water, or a mixture of acetone and water by means of hydrogen bromide equivalent or crystallization temperature. As a result, 11 polymorphs were obtained.

[0277] Among the many crystal forms obtained, the A-type crystal of triazine compound A, the F-type crystal of triazine compound A, and the N-type crystal of triazine compound A exhibit good thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0278] The crystallization conditions for triazine compound A hydrobromide type A crystals, triazine compound A hydrobromide type F crystals, and triazine compound A hydrobromide type N crystals, which have suitable physical properties for pharmaceutical manufacturing, are shown in Table 7. The XRPD apparatus and measurement conditions were the same as in Example 1. The XRPD results show that the triazine compound A hydrobromide type A crystals are the same as those obtained in Example 1.

[0279] [Table 7]

[0280] Table 7 Crystallization methods for hydrobromide crystals of triazine compound A

[0281]

[0282] In method (a), type A crystals of hydrobromide of triazine compound A were obtained. It was determined that the crystals contained 1.0 equivalent of hydrobromic acid.

[0283] In method (b), F-type crystals of the hydrobromide of triazine compound A were obtained. It was determined that the crystal contained 2.0 equivalents of hydrobromic acid.

[0284] In method (c), N-type crystals of the hydrobromide of triazine compound A were obtained. It was determined that the crystal contained 1.0 equivalent of hydrobromic acid.

[0285] Experimental Example 5

[0286] (a) Experimental example of the method

[0287] Crystals were obtained using the crystallization method described in Example 1.

[0288] Experimental Example 6

[0289] (b) Experimental examples of the method

[0290] Triazine compound A (10.0 g) was suspended in acetone (300 mL) at 50 °C, and 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 dried under reduced pressure at 40 °C for 24 hours to obtain hydrobromide F-type crystals (13.45 g).

[0291] Experimental Example 7

[0292] (c) Experimental example of the method

[0293] Triazine compound A (50.0 g) was suspended in water (450 mL) at 50 °C, and 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 mixture was washed with acetone (200 mL) and dried under reflux for 21 hours to obtain N-type hydrobromide crystals (57.43 g).

[0294] Example 5: Comparison of triazine compound A hydrobromide type A crystals, triazine compound A hydrobromide type F crystals, and triazine compound A hydrobromide type N crystals.

[0295] In the comparative test results shown below, the hydrobromide A-type crystals of triazine compound A represent the results obtained using the method described in Example 1.

[0296] In the comparative test results shown below, the F-type crystals of triazine compound A hydrobromide represent the crystals obtained using the method described in Experimental Example 6.

[0297] In the comparative test results shown below, the N-type crystals of triazine compound A hydrobromide represent the crystals obtained using the method described in Experimental Example 7.

[0298] The results of X-ray powder diffraction measurements for the F-type and N-type hydrobromide crystals of the aforementioned triazine compound A are shown below.

[0299] <X-ray Powder Diffraction Measurement>

[0300] The measurements were performed using an X-ray powder diffractometer, X'PertPro (manufactured by PANalyical B.V.), under the following conditions.

[0301] X-ray generating device: X-ray tube (cathode: copper, tube voltage: 45kV, tube current: 40mA)

[0302] Incident optical system: Condensing lens

[0303] Light-receiving optical system: High-speed semiconductor array detector (X-Celerator), extended light-receiving arm

[0304] Sample stage: HTS sample stage (vibrates at a width of 4mm in the X-axis direction)

[0305] Total number of attempts: 5 (the incident angles were changed to -2°, -1°, 0°, 1°, and 2° respectively).

[0306] Measurement range: 2θ = 3~40°

[0307] Scanning speed: 0.668451° / second

[0308] Step size: 0.0167°

[0309] The XRPD results of the F-type crystals of hydrobromide of triazine compound A are shown in... Figure 7 The peaks (each ±0.2°) are shown in Table 8 below.

[0310] [Table 8]

[0311] Table 8

[0312] 2θ(deg) 3.3 10.0 14.1 14.4 14.9 16.5 17.4 18.5 20.6 21.2 21.8 24.3 24.7 25.6 27.5 28.5 29.6

[0313] For characteristic peaks in the X-ray powder diffraction pattern of the F-type crystal, diffraction angles represented by 2θ include 10.0°±0.2° and 27.5°±0.2°. In one embodiment, the F-type crystal also exhibits peaks in the X-ray powder diffraction pattern at diffraction angles represented by 2θ at 3.3°±0.2° and 14.4°±0.2°. Other characteristic peaks include 17.4°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.6°±0.2°. In addition, 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-type crystals of the hydrobromide of triazine compound A exhibit similar characteristics to... Figure 7 Crystals with essentially the same X-ray powder diffraction pattern.

[0314] The XRPD results of the N-type crystals of hydrobromide of triazine compound A are shown in... Figure 9 The peaks (each ±0.2°) are shown in Table 9 below.

[0315] [Table 9]

[0316] Table 9

[0317] 2θ(deg) 6.2 9.8 11.3 11.9 14.0 15.6 16.2 18.8 19.1 20.4 20.9 22.1 22.4 23.8 24.3 26.8 31.9

[0318] For characteristic peaks in the X-ray powder diffraction pattern of an N-type crystal, examples of diffraction angles represented by 2θ include 11.3°±0.2° and 24.3°±0.2°. In one embodiment, the N-type crystal also exhibits peaks at 6.2°±0.2° and 31.9°±0.2°, representing diffraction angles of 2θ in the X-ray powder diffraction pattern. Other characteristic peaks include 11.9°±0.2°, 22.4°±0.2°, 23.8°±0.2°, and 26.8°±0.2°. In addition, 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 of triazine compound A exhibit characteristics similar to... Figure 9 Crystals with essentially the same X-ray powder diffraction pattern.

[0319] For each of the above crystals, evaluate their thermal stability, hygroscopicity, deliquescence, and chemical stability.

[0320] <Evaluation of Thermal Stability>

[0321] The following measurements and evaluations were performed using a simultaneous thermogravimetric / differential calorimetry (TGC / DTA7200) device (SII NanoTechnology Co., Ltd.).

[0322] Heating rate: 10℃ / minute

[0323] Heating range: 30~300℃

[0324] Atmosphere: Nitrogen 200 mL / min

[0325] or,

[0326] The following measurements and evaluations were performed using a TGA / DSC1 thermogravimetric analyzer (Mettler-Toledo, STARe system) under the following conditions.

[0327] Heating rate: 10℃ / minute

[0328] Temperature range: 25~300℃

[0329] Atmosphere: Nitrogen 50 mL / min

[0330] <Evaluation of Hygroscopicity and Deliquescence>

[0331] The evaluation was performed using a moisture adsorption measuring device, either the DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited). The sample was placed in a pre-calibrated tare dish, and the device was attached to a precision balance. The initial weight was precisely measured. The weight change was recorded over time as humidity levels changed, and the equilibrium weight at each humidity level was determined. The rate of change of weight at each humidity level was calculated using the dry condition (0% RH) or an anhydrous sample converted from the initial moisture content confirmed by other methods as a baseline.

[0332] <Chemical Stability Evaluation>

[0333] The sample was stored at 60℃ in a sealed state and at 60℃ and 75%RH for one week. The increase or decrease of similar substances before and after storage was calculated by high performance liquid chromatography based on the area percentage of each peak, and then the state after storage was observed.

[0334] The results are shown in Table 10.

[0335] [Table 10]

[0336] Table 10

[0337]

[0338] *1: Hydration phase

[0339] Among the many crystal forms obtained, hydrobromide type A crystals, hydrobromide type F crystals, and hydrobromide type N crystals exhibit good thermal stability, hygroscopicity, deliquescence, and chemical stability. However, hydrobromide type F crystals and hydrobromide type N crystals have a hydration stage, confirming that they are hydrates under conditions of room temperature and relative humidity of 10–95%.

[0340] Example 6: The effect of water during the crystallization of hydrobromide type A crystals

[0341] [Table 11]

[0342] Table 11

[0343]

[0344] <Experimental Methods>

[0345] Triazine compound A was added to acetone and water mixtures with varying water contents, along with one equivalent of aqueous hydrobromic acid. The mixture was stirred at 50°C. After 1 hour, 19 hours, and 45 hours of stirring, portions of the reaction solution were filtered off, and the filtrates were subjected to X-ray powder diffraction analysis. The transition rate to type A crystals in acetone and water mixtures with varying water contents was confirmed.

[0346] <Results>

[0347] The results are shown in Table 11.

[0348] In a mixed solvent with a water content of 0.64% (entry 1), after 19 hours of stirring, it is a mixture of hydrobromide type A crystals, hydrobromide type F crystals and triazine compound A, but after 45 hours of stirring, it converges into hydrobromide type A crystals.

[0349] In a mixed solvent with a water content of 2–5% (items 2–5), after stirring for 1 hour, it converged into hydrobromide type A crystals. Furthermore, it was confirmed that when the water content was 2–3%, the inclusion rate of triazine compound A in the mother liquor was good, ranging from 0.6% to 1.1%, but when the water content was 5%, the inclusion rate of triazine compound A in the mother liquor increased to 5.5%.

[0350] It has been confirmed that by adding triazine compound A to a mixed solvent of acetone and water with a water content of 2.0–3.0%, followed by the addition of 1 equivalent of aqueous hydrobromic acid, and stirring at 50°C, the stirring time can be shortened, and hydrobromide type A crystals can be obtained with high recovery. This method is an industrially advantageous crystallization method for pharmaceuticals.

[0351] Example 7: Comparison of the pharmacokinetics of triazine compound A and its hydrobromide when used in combination with a gastric acid secretion promoter or gastric acid secretion inhibitor.

[0352] <Experimental Methods>

[0353] In dogs treated with gastric acid secretion promoters or gastric acid secretion inhibitors, a two-group, four-phase crossover method was used to evaluate the hydrobromide content of triazine compound A under gastric acid secretion and gastric pH regulation, as well as the pharmacokinetics of triazine compound A.

[0354] In the treatment of gastric acid secretion stimulants, pentagastrin was used. The administration solution was prepared by dissolving 2.8 mg of pentagastrin in dimethyl sulfoxide (7.0 mL) and water for injection (7.0 mL), and administered intramuscularly to the thigh muscle 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 prepared in Example 1), or triazine compound A (compound 10 prepared in Example 1)). In the treatment of gastric acid secretion inhibitors, omeprazole was used. The administration solution was prepared by dissolving 90 mg of omeprazole in 22.5 mL of a 1:1 mixture of 0.1% sodium bicarbonate aqueous solution (w / v) and polyethylene glycol 400, and administered intravenously to the saphenous vein of the hind limb at a dose of 1 mg / 0.25 mL / kg. Omeprazole should be administered 1 hour before the test substance.

[0355] Using a syringe with an oral cannula, after the dog drinks 25 mL of water for injection, it is forcibly administered orally at a dose of 10 mg / capsule (the equivalent amount of the free salt of triazine compound A (10 mg based on triazine compound A)). The dog is then given another 25 mL of water for injection to drink from the syringe with the oral cannula. The test substance is administered while the dog is fasting, and feeding resumes 6 hours after administration. Water is withheld from 1 hour before to 2 hours after administration of the test substance.

[0356] Six 4-year-old male beagle dogs were divided into two groups of three. For group 1, the administration sequence was: (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. For group 2, the same sequence was administered: (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 withdrawal period for each phase was 6 or 7 days. At 15 minutes, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration of triazine compound A hydrobromide or triazine compound A, 0.6 mL whole blood samples were collected from the cephalic vein using a heparin sodium syringe while the patient was awake. The whole blood samples were processed into plasma, and the concentration of triazine compound A was analyzed 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 at which the final concentration can be measured) based on plasma-time data was calculated using Phoenix WinNonlin Software Ver. 6.3 (Certara LP). 0-t And the area AUC from time 0 to infinity calculated by extrapolation through the final elimination of the phase. 0-∞ ), maximum blood concentration (C max Time to peak plasma concentration (T) max ), and the elimination half-life (T) in plasma 1 / 2 ).

[0357] <Results>

[0358] The results are shown in Table 12 and Figure 14 .

[0359] [Table 12]

[0360] Table 12

[0361]

[0362] The absorption of triazine compound A was inhibited under conditions of gastric acid inhibition, and compared with conditions of gastric acid secretion promotion, the absorption of C was confirmed. max Both the concentrations of triazine compound A and its AUC decreased by approximately 50%. Furthermore, this suggests that under conditions of gastric acid suppression, the CV% is high, making individual variability more likely. The blood concentration of hydrobromide in triazine compound A remained unchanged under gastric acid conditions, confirming that it is unaffected by gastric pH.

[0363] It should be noted that the hydrobromide of triazine compound A used in Example 7 is in the form of hydrobromide type A crystal.

[0364] Experimental Example 8: Determination of the inhibitory activity of aldosterone synthase (hereinafter CYP11B2)

[0365] <Experimental Methods>

[0366] The pcDNA3.1-human CYP11B2 plasmid was transfected into the Chinese hamster lung fibroblast V79 cell line to create a stable expression line of the human CYP11B2 gene.

[0367] The cells were cultured and proliferated in Dulbecco modified Eagle Ham medium supplemented with 10% bovine serum and 1% G418 disulfide solution at 37°C, 95% air, and 5% CO2. The cells were then recovered.

[0368] Next, following the method of Chabre et al., JCE&M 85(11)4060-68, 2000, mitochondrial fractions were obtained. Specifically, cells suspended in 5 mmol / L Tris-HCl buffer (pH 7.4) containing 250 mmol / L sucrose were homogenized using a Teflon homogenizer, and the suspension was then centrifuged (800×g for 15 minutes). The supernatant was collected and centrifuged again (10000×g for 15 minutes) to obtain particles (mitochondrial fractions).

[0369] 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 aliquoted into 96-well plates. 0.5 μmol / L deoxycorticosterone and 150 μmol / L NADPH were added, and the plates were incubated at room temperature for 1.5–2 hours to produce aldosterone. The amount of aldosterone produced in the solution was determined using HTRF (Homogeneous Time-Resolved Fluorescence).

[0370] Based on the aldosterone production inhibition rate (%) of the triazine compound A of the present invention at various concentrations, a nonlinear regression based on logistic curves was performed to calculate the IC. 50 (nmol / L).

[0371] As a result, the IC50 of the triazine compound A of the present invention... 50 With a concentration of 9.0 nmol / L, the triazine compound A of the present invention exhibits strong aldosterone synthase inhibitory activity.

[0372] Furthermore, experiments were conducted using the salt of the triazine compound A of the present invention and its crystals, in the same manner as in this experimental example. Thus, it was also confirmed that the salt of the triazine compound A of the present invention and its crystals have strong aldosterone synthase inhibitory activity.

[0373] Industrial availability

[0374] The novel salts of 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine are salts that yield excellent crystals. In particular, the hydrobromide salt exhibits stable pharmacokinetics under both gastric acid secretion-promoting and gastric acid secretion-inhibiting conditions, and is free of compounds that could potentially have adverse effects on organisms from a safety perspective. Furthermore, the crystals of the novel salts of 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine are characterized by: no solvent residue, excellent thermal stability, minimal and stable weight change relative to humidity, non-hygroscopicity, excellent chemical stability, and excellent safety profile. They are free of compounds that could potentially have adverse effects on organisms from a safety perspective. Moreover, since these crystals can be readily obtained using industrially suitable methods, they are excellent crystals for use as pharmaceutical technical materials.

[0375] Furthermore, the method for manufacturing crystals of 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine is an industrially advantageous method that does not use manufacturing intermediates with explosive or genotoxic risks, can produce the active ingredient in good yield, and can reproducibly obtain the most stable crystals in high yield.

Claims

1. 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine hydrobromide crystals, wherein, In X-ray powder diffraction spectra, peaks, represented by 2θ, are observed at 8.8°±0.2°, 13.0°±0.2°, 13.1°±0.2°, 13.8°±0.2°, 15.1°±0.2°, 15.4°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 19.6°±0.2°, 20.9°±0.2°, 21.5°±0.2°, 22.9°±0.2°, 25.0°±0.2°, 25.6°±0.2°, 26.2°±0.2°, 26.3°±0.2°, and 28.2°±0.2°.

2. The crystal as claimed in claim 1, wherein, In differential scanning calorimetry analysis, an endothermic peak is observed at 265–275 °C.

3. An aldosterone synthase inhibitor, comprising the crystals described in claim 1 or 2 as an active ingredient.

4. A pharmaceutical composition comprising the crystals as described in claim 1 or 2 and pharmaceutically acceptable additives.

5. The pharmaceutical composition of claim 4, wherein it is in tablet form.

6. Use of the pharmaceutical composition of claim 4 or 5 in the manufacture of a medicament for treating hypertension.

7. Use of the pharmaceutical composition of claim 4 or 5 in the manufacture of a medicament for the prevention or treatment of a disease for which improvement is expected through inhibition of aldosterone synthase.

8. The use as described in claim 6, wherein, The pharmaceutical composition is administered at a dose of 0.01 to 500 mg per person per day.

9. The use as described in claim 7, wherein, The pharmaceutical composition is administered at a dose of 0.01 to 500 mg per person per day.

10. Use of the crystal as described in claim 1 or 2 in the manufacture of a medicament for the prevention or treatment of a disease for which improvement is expected through inhibition of aldosterone synthase.

11. The method for manufacturing the crystal according to claim 1 or 2, characterized in that, In a mixed solvent of water and acetone with a water content of 2.0–3.0% by volume, 0.9–1.1 equivalents of hydrogen bromide are added to crystallize 3-[4-[[trans-4-(acetamido)cyclohexyl]carbamoylmethyl]piperazin-1-yl]-5-(p-tolyl)-1,2,4-triazine.

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