The amount of palladium carbon to be used is 0.1 to 10% by weight, and preferably 0.5 to 10% by weight, relative to the Compound (4) or a salt thereof. The present reaction may be carried out at 0 to 30° C.

Step 3:

Step 3 is a step of chlorinating the Compound (6) to produce the Compound (7). The Compound (6) is known, or may be produced according to known method(s). The chlorinating reaction of the Compound (6) may be carried out in a solvent in the presence of a chlorinating agent. The reaction may also be carried out in the presence of a catalyst as needed.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), and ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), and they may also be used in an appropriate combination with each other. Among them, ethers are preferable, and dimethoxyethane is more preferable.

Examples of the chlorinating agent include thionyl chloride, phosphorus oxychloride, and oxalyl chloride, and among them, thionyl chloride is preferable.

The amount of the chlorinating agent to be used is 1.0 to 3.0 equivalent(s), and preferably 1.8 to 2.2 equivalents, relative to the Compound (6).

Preferable examples of the catalyst include N,N-dimethylformamide.

The amount of the catalyst to be used is 0.01 to 0.5 equivalent, and preferably 0.05 to 0.1 equivalent, relative to the Compound (6).

The present reaction may be carried out at 50 to 100° C., and preferably at 70 to 80° C.

Step 4:

Step 4 is a step of reacting the Compound (5) or a salt thereof with the Compound (7) to produce the Compound (8) or a salt thereof. Examples of the salt of the Compound (8) include acid addition salts, and specific examples thereof include 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. Preferable examples thereof include hydrochloride.

The present reaction may be carried out in a solvent in the presence of a base.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), and alcohols (for example, methanol, ethanol, and isopropanol), and they may also be used in an appropriate combination with each other. Among them, aprotic solvents and alcohols are preferable, N-methyl-2-pyrrolidone and methanol are more preferable, and a mixed solvent of N-methyl-2-pyrrolidone and methanol is still more preferable.

Examples of the base include triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and among them, triethylamine is preferable.

The amount of the base to be used is 1 to 5 equivalent(s), and preferably 2 to 3 equivalents, relative to the Compound (7). The present reaction may be carried out at 50 to 100° C., and preferably 50 to 70° C.

Step 5:

Step 5 is a step of subjecting the Compound (8) or a salt thereof to a deprotection reaction to produce the Compound (9) or a salt thereof. Examples of the salt of the Compound (9) include acid addition salts, and specific examples thereof include 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. Preferable examples thereof include hydrochloride.

The deprotection reaction of the Compound (8) may be carried out according to the method(s) disclosed in Theodora W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4th. Ed./John Wiley & Sons, Inc., 2007 or the like. For example, the present reaction may be carried out in a solvent in the presence of an acid.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include water, aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), and alcohols (for example, methanol, ethanol, and isopropanol), and they may also be used in an appropriate combination with each other. Among them, water is preferable.

Examples of the acid include trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, and methanesulfonic acid, and among them, hydrochloric acid is preferable.

The amount of the acid to be used is 3 to 10 equivalents, and preferably 3 to 5 equivalents, relative to the Compound (8). The present reaction may be carried out at 30 to 50° C.

The mixture comprising the resulting Compound (9) or a salt thereof after the reaction may be directly used in the next step, but it is preferable to use said mixture in the next step after insoluble matters are removed. When the insoluble matters are removed, it is more preferable to filter the mixture. When the mixture is filtered, it is preferable to use the same solvent as that used in the reaction. The temperature at the filtration is preferably 5 to 95° C., and more preferably 30 to 50° C. It is more preferable to carry out crystallization from the filtrate to obtain the Compound (9) as solids, and then use them in the next step.

Step 6:

Step 6 is a step of reacting the Compound (9) or a salt thereof with an acetylating agent to produce the Compound (10). The reaction of the Compound (9) or a salt thereof with an acetylating agent may be carried out in a solvent.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include aromatic hydrocarbons (for example, benzene, toluene, and xylene), aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), and alcohols (for example, methanol, ethanol, and isopropanol), and they may also be used in an appropriate combination with each other. Among them, aromatic hydrocarbons and alcohols are preferable, toluene and methanol are more preferable, and a mixed solvent of toluene and methanol is still more preferable.

Examples of the acetylating agent include acetyl chloride and acetic anhydride, and among them, acetic anhydride is preferable.

The amount of the acetylating agent to be used is 1 to 1.5 equivalent(s), and preferably 1.05 to 1.2 equivalents, relative to the Compound (9) or a salt thereof. The present reaction may be carried out at 40 to 60° C.

The Compound (4), the Compound (5), and the Compound (8) are novel production intermediate compounds for producing the Compound (10).

The present invention relates to salts of the Triazine compound A, crystals thereof, and a method for producing the same.

The salts of the present invention are salts of the Triazine compound A, preferably hydrobromide, sulfate, tosylate, and succinate of the Triazine compound A, and more preferably hydrobromide of the Triazine compound A.

The molar ratio of the acid relative to the Triazine compound A is not specifically limited. For example, the molar ratio of the acid relative to the Triazine compound A may be 1 to 3 equivalent (s). For example, hydrobromide of the Triazine compound A includes monohydrobromide of the Triazine compound A, dihydrobromide of the Triazine compound A, and the like.

Also, the salt of the Triazine compound A may be hydrate.

The crystals of the present invention are crystals of salts of the Triazine compound A, preferably a crystal of hydrobromide of the Triazine compound A, a crystal of sulfate of the Triazine compound A, a crystal of tosylate of the Triazine compound A, and a crystal of succinate of the Triazine compound A, more preferably a crystal of hydrobromide of the Triazine compound A, and still more preferably Hydrobromide Form A crystal of the Triazine compound A.

The crystal of sulfate of the Triazine compound A is preferably a Sulfate Form B crystal of the Triazine compound A.

The crystal of tosylate of the Triazine compound A is preferably a Tosylate Form C crystal of the Triazine compound A.

The crystal of succinate of the Triazine compound A is preferably a Succinate Form A crystal of the Triazine compound A.

A method for producing a crystal of hydrobromide of the Triazine compound A is described below. The crystal of hydrobromide of the Triazine compound A has a plurality of crystal forms, and especially preferable crystal forms are Form A, Form F, and Form N crystals. Among them, the Form A crystal is more especially preferable. However, the simple addition of hydrogen bromide to Triazine compound A in a solvent also produces Form F crystals and Form N crystals. In this regard, the appropriate control of the amount of hydrogen bromide to be added, the amount of water present in the reaction system, the crystallization temperature, and the like makes the crystal forms to converge on Form A crystals, to stably and efficiently produce Form A crystals only.

The Hydrobromide Form A crystal of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with 0.9 to 1.1 equivalent(s) of hydrogen bromide, preferably 0.95 to 1.05 equivalent(s) of hydrogen bromide, and the resulting mixture is subjected to crystallization to produce Hydrobromide Form A crystals of the Triazine compound A. Said reaction may be carried out in a solvent.

Examples of the solvent include water, ketones (for example, acetone and methyl ethyl ketone), and alcohols (for example, methanol, ethanol, and isopropanol), and two or more kinds of solvents may also be used in an appropriate combination with each other. Preferable examples thereof include a mixed solvent of water and a water-miscible solvent. More preferable examples thereof include a mixed solvent having a water content of 1.0 to 5.0% relative to whole solvent volume. Especially, a mixed solvent of water and acetone having a water content of 1.0 to 5.0% relative to whole solvent volume in the reaction system is preferable, and a mixed solvent of water and acetone having a water content of 2.0 to 3.0% relative to whole solvent volume is more preferable.

The present reaction may be carried out at 5 to 55° C., preferably at 20 to 55° C., and more preferably at 40 to 55° C.

The Hydrobromide Form F crystal of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with 2.0 to 2.2 equivalents of hydrogen bromide, and the resulting mixture is subjected to crystallization to produce Hydrobromide Form F crystals of the Triazine compound A. Said reaction may be carried out in a solvent.

Examples of the solvent include water, ketones (for example, acetone and methyl ethyl ketone), and alcohols (for example, methanol, ethanol, and isopropanol), and two or more kinds of solvents may also be used in an appropriate combination. Preferable examples thereof include a mixed solvent of water and acetone.

The present reaction may be carried out at 10 to 50° C., and preferably at 40 to 50° C.

The Hydrobromide Form N crystal of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with 1.2 to 1.5 equivalents of hydrogen bromide, and the resulting mixture is subjected to crystallization to produce Hydrobromide Form N crystals of the Triazine compound A. Said reaction may be carried out in a solvent.

Examples of the solvent include water, ketones (for example, acetone and methyl ethyl ketone), and alcohols (for example, methanol, ethanol, and isopropanol), and two or more kinds of solvents may also be used in an appropriate combination with each other. Preferable examples thereof include water.

The present reaction may be carried out at 10 to 50° C., and preferably at 40 to 50° C.

The crystal of sulfate of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with sulfuric acid, and the resulting mixture is subjected to crystallization to produce crystals of sulfate of the Compound (10). Said reaction may be carried out in a solvent.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include water, aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), alcohols (for example, methanol, ethanol, and isopropanol), and aromatic hydrocarbons (for example, benzene, toluene, and xylene), and they may also be used in an appropriate combination with each other.

The amount of sulfuric acid to be used is 1 to 10 equivalent(s), and preferably 1 to 5 equivalent(s), relative to the Compound (10). The present reaction may be carried out at 10 to 60° C.

The crystal of tosylate of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with tosic acid, and the resulting mixture is subjected to crystallization to produce crystals of tosylate of the Compound (10). Said reaction may be carried out in a solvent.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include water, aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), alcohols (for example, methanol, ethanol, and isopropanol), and aromatic hydrocarbons (for example, benzene, toluene, and xylene), and they may also be used in an appropriate combination with each other.

The amount of tosic acid to be used is 1 to 10 equivalent(s), and preferably 1 to 5 equivalent(s), relative to the Compound (10). The present reaction may be carried out at 10 to 60° C.

The crystal of succinate of the Triazine compound A may be produced as follows.

The Compound (10) is reacted with succinic acid, and the resulting mixture is subjected to crystallization to produce crystals of succinate of the Compound (10). Said reaction may be carried out in a solvent.

The solvent is not limited as long as it does not affect the present reaction, and examples thereof include water, aprotic solvents (for example, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone), nitriles (for example, acetonitrile), ketones (for example, acetone and methyl ethyl ketone), esters (for example, ethyl acetate), ethers (for example, diethyl ether, tetrahydrofuran, and dimethoxyethane), alcohols (for example, methanol, ethanol, and isopropanol), and aromatic hydrocarbons (for example, benzene, toluene, and xylene), and they may also be used in an appropriate combination with each other.

The amount of succinic acid to be used is 1 to 10 equivalent(s), and preferably 1 to 5 equivalent(s), relative to the Compound (10). The present reaction may be carried out at 10 to 60° C.

The Triazine compound A and/or hydrogen bromide, sulfuric acid, tosic acid, and succinic acid in the crystal of the present invention encompass(es) compounds labeled with isotopes (for example, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, and ³²P) or the like, and deuterated products.

In the crystal of the present invention, the Hydrobromide Form A crystal of the Triazine compound A does not comprise other residual molecules used in producing the crystal, and comprises the Triazine compound A and hydrogen bromide at a molar ratio of 1:1.

The Hydrobromide Form A crystal of the Triazine compound A is characterized by one or more of the followings.

- (1) It preferably has a powder X-ray diffraction pattern indicated in FIG. 11 and/or a differential scanning calorimetry (DSC) curve indicated in FIG. 12.
- (2) Characteristic peaks in a powder X-ray diffraction pattern of the Form A crystals include 8.8°±0.2° and 25.6°±0.2° as diffraction angles expressed in 2θ. In one embodiment, the Form A crystals have additional peaks at 18.1°±0.2° and 20.9°±0.2° as diffraction angles expressed in 2θ in a powder X-ray diffraction pattern. Other characteristic peaks thereof include 15.1°±0.2°, 17.5°±0.2°, 21.5°±0.2°, and 25.0°±0.2°. Still other characteristic peaks thereof 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 Hydrobromide Form A crystal of the Triazine compound A is a crystal having substantially the same powder X-ray diffraction pattern as FIG. 11.
- (3) The melting point measured by DSC (extrapolated onset temperature) is 265 to 275° C., and especially about 268° C.

The crystal of the present invention has an advantageous effect in that the amount of residual solvent(s) is below the standard value determined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (hereinafter referred to as “ICH”). Also, other effects include that the amounts of solvent impurities, inorganic impurities, residual metals, residual solvents, genotoxic impurities, and the like are below the standard values determined in the guideline of ICH.

The salts of the present invention and the crystals of the present invention have inhibitory actions against aldosterone synthase, and thus may be used as active ingredients of aldosterone synthase inhibitors, and the crystals of the present invention and pharmaceutical compositions comprising the same as active ingredients are useful for the treatment or prevention of various diseases of which pathological conditions are expected to be improved by the inhibition of aldosterone synthase. Examples of such diseases include primary aldosteronism (for example, unilateral or bilateral adrenal adenomas, unilateral or bilateral adrenal hyperplasia, aldosterone-producing adrenal carcinoma, unilateral adrenal multiple nodules aldosteronism, glucocorticoid reactive aldosteronism, familial aldosteronism, and ectopic aldosterone-producing tumors), secondary aldosteronism (for example, hypertension caused by an estrogen preparation, renal vascular hypertension, pregnancy hypertension, malignant hypertension, pheochromocytoma, congestive heart failure, pseudohypoaldosteronism, chronic liver disease associated with ascites (for example, hepatic cirrhosis), inappropriate use of a medicament such as a laxative and a diuretic, and hyperaldosteronemia associated with nephrotic syndrome, Bartter's syndrome, or Gitelman's syndrome), hypertension (for example, essential hypertension, secondary hypertension (for example, renal vascular hypertension, renal parenchymal hypertension, primary aldosteronism, pheochromocytoma, sleep apnea syndrome, Cushing's syndrome, drug induced hypertension, aortostenosis, and hyperparathyroidism), treatment-resistant hypertension, and mineralocorticoid-related hypertension), heart failure (for example, congestive heart failure, left ventricular failure, right ventricular failure, systolic dysfunction, and diastolic dysfunction), cardiomyopathy, cardiac hypertrophy (for example, left ventricular hypertrophy), myocardial infarction, myocardial necrosis lesion, disorder after myocardial ischemia, coronary artery disease, fibrosis or remodeling of myocardium or blood vessel (for example, cardiovascular fibrosis and remodeling caused by hypertension and/or vascular endothelial function disorder), vascular restenosis, blood vessel wall thickening, arterial sclerosis, renal failure (for example, chronic renal failure), acute renal disorder, chronic kidney disease, renal fibrosis, nephropathy (for example, diabetic nephropathy), hypokalemia, obesity, metabolic syndrome, sleep apnea syndrome, retinopathy (for example, diabetic retinopathy), hepatic disease, abnormal lipid metabolism, sympathetic hyperactivity, idiopathic and/or cyclic edema, headache, anxiety, and depressive disorder. In particular, a crystal of hydrobromide of the Triazine compound A is useful for the treatment or prevention of one or more disease(s) selected from the group consisting of primary aldosteronism, secondary aldosteronism, hypertension, heart failure, cardiomyopathy, cardiac hypertrophy, myocardial infarction, myocardial necrosis lesion, disorder after myocardial ischemia, coronary artery disease, fibrosis or remodeling of myocardium or blood vessel, vascular restenosis, blood vessel wall thickening, arterial sclerosis, acute renal disorder, chronic kidney disease, renal fibrosis, nephropathy, hypokalemia, metabolic syndrome, obesity, sleep apnea syndrome, retinopathy, hepatic disease, idiopathic and/or cyclic edema, and sympathetic hyperactivity.

A pharmaceutical composition comprising a salt of the present invention or a crystal of the present invention as an active ingredient may be prepared by mixing a salt of the present invention or a crystal thereof with pharmaceutically acceptable additive(s) such as a diluent, a binder (for example, syrup, gum arabic, gelatin, sorbitol, tragacanth, and polyvinylpyrrolidone), an excipient (for example, lactose, sucrose, corn starch, potassium phosphate, sorbit, and glycine), a lubricant (for example, magnesium stearate, talc, polyethylene glycol, and silica), a disintegrant (for example, potato starch), and a wetting agent (for example, sodium lauryl sulfate).

The salt of the present invention, the crystal of the present invention, and pharmaceutical composition comprising the same as an active ingredient may be prepared into an appropriate dosage form such as powder, injection, tablet, capsule, and topical preparation, and then administered to a patient by using an appropriate method of administration in accordance with the dosage form such as intravenous administration, oral administration, and percutaneous administration. The term “patient” used in the present invention is an individual to be prevented or treated by the crystal of the present invention, preferably a mammal, and more preferably a human.

The dose may be determined depending on the patient's age, body weight, general health condition, sex, diet, time of administration, method of administration, excretion rate, a combination of drugs, and the severity of the disease state of the patient under treatment at the time of administration, in consideration of these or other factors. The salt of the present invention, the crystal of the present invention, and the pharmaceutical composition comprising the same as an active ingredient have low toxicity and can be safely used. The daily dose (i.e., effective amount) thereof may vary depending on the condition or body weight of the patient, the administration route, or the like. For example, in the case of parenteral administration, the salt of the present invention, the crystal of the present invention, and the pharmaceutical composition comprising the same as an active ingredient is desirably administered at a dose of approximately 0.0001 to 1000 mg/person/day, preferably approximately 0.01 to 1000 mg/person/day, and especially preferably approximately 0.01 to 500 mg/person/day, and in the case of oral administration, the salt of the present invention, the crystal of the present invention, and the pharmaceutical composition comprising the same as an active ingredient is desirably administered at a dose of approximately 0.01 to 1000 mg/person/day, preferably approximately 0.01 to 500 mg/person/day.

In the present invention, the term “prevention (or prevent)” means an action to administer the salt of the present invention, the crystal of the present invention, or the pharmaceutical composition comprising the same to an individual who has not developed an illness, a disease, or a symptom. Also, the term “treatment (or treat)” means an action to administer the salt of the present invention, the crystal of the present invention, or the pharmaceutical composition comprising the same to an individual who has already developed an illness, a disease, or a symptom. Accordingly, an action to administer the salt of the present invention, the crystal of the present invention, or the pharmaceutical composition comprising the same to an individual who has already developed an illness, a disease, or a symptom in order to prevent the deterioration, attack, or relapse of the symptom and the like is one aspect of “treatment (or treat)”.

EXAMPLES

Hereinafter, the present invention is illustrated more in detail by Examples and Experimental Examples, but the present invention is not limited by them. In the present description, “equivalent(s)” means “molar equivalent(s)”.

Example 1: Synthesis of Hydrobromide Form A Crystal of the Triazine Compound A

[Image Omitted]

Under inert gas atmosphere, acetonitrile (112.30 kg), the Compound 2 (48.00 kg), diisopropylethylamine (78.80 kg), and the Compound 3 (39.20 kg) were mixed, and a solution of 50% T3P in acetonitrile was added dropwise thereto at 16 to 24° C. over 2 hours and 30 minutes. After 5 hours, a 10% aqueous solution of potassium carbonate (potassium carbonate: 38.40 kg, water: 345.6 kg) was added dropwise thereto at 19 to 22° C. over 23 minutes, then the resulting mixture was cooled to 15° C., and stirred at 9 to 15° C. for 16 hours and 30 minutes. The resulting mixture was filtered, and the resulting crystals were washed with water (240 kg). The crystals were dried under reduced pressure at 50° C. to give the Compound 4 (67.1 kg, Yield: 93%).

¹H 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 C₂₅H₃₈N₄O₅474.3, found m/z 475 [M+H]⁺.

Under inert gas atmosphere, methanol (471.6 kg), the Compound 4 (59.7 kg), and 10% palladium carbon (6.0 kg) were mixed at 15 to 17° C., hydrogen was supplied thereto under 0.2 MPa, and the resulting mixture was stirred at 17 to 23° C. for 3 hours and 40 minutes. After the gas was replaced with inert gas, the mixture was filtered under pressure. Methanol (235.8 kg) was additionally added thereto, the resulting mixture was filtered under pressure, and the resulting filtrate was concentrated over 9 hours and 20 minutes until the volume became 180 L. Methanol (71.7 kg) was added thereto to give a solution of the Compound 5 in methanol (228.1 kg).

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 C₁₇H₃₂N₄O₃340.2, found m/z 341 [M+H]⁺.

Under inert gas atmosphere, 1,2-dimethoxyethane (237.5 kg), the Compound 6 (42.0 kg), and dimethylformamide (1.64 kg) were mixed at 15 to 16° C., and the resulting mixture was warmed to 74° C. over 1 hour. Thionyl chloride (53.4 kg) was added dropwise thereto at 73 to 79° C. over 1 hour, and the resulting mixture was stirred at 71 to 77° C. for 5 hours. After cooled to 20° C., water (210.0 L) was added dropwise thereto at 20 to 22° C. over 2 hours and 30 minutes, and the resulting mixture was stirred at 21 to 22° C. for 13 hours and 30 minutes. The resulting mixture was filtered, and the resulting crystals were washed with water (630.0 L). Under inert gas atmosphere, ethanol (99.5 kg) and the crystals were mixed at 19° C., and the resulting mixture was stirred at 19 to 21° C. for 2 hours. The resulting mixture was filtered, and the crystals were washed with ethanol (99.5 kg). The crystals were dried under reduced pressure at 30° C. to give the Compound 7 (23.7 kg, Yield: 51%).

¹H NMR (DMSO-d6, 500 MHz): 52.43 (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 C₁₀H₈ClN₃205.0, found m/z 206 [M+H]⁺.

Under inert gas atmosphere, to a solution of the Compound 5 in methanol was added triethylamine (23.1 kg) at 18 to 20° C., and the resulting mixture was warmed to 57° C. A solution of the Compound 7 (23.5 kg) in N-methyl-2-pyrrolidone (96.8 kg) was added dropwise thereto at 57 to 62° C., N-methyl-2-pyrrolidone (24.2 kg) was added thereto, and then the resulting mixture was stirred at 59 to 61° C. for 2 hours. Water (470.0 L) was added thereto at 54 to 58° C., the resulting mixture was stirred at 54 to 55° C. for 35 minutes, then cooled to 30° C., and the resulting mixture was stirred at 24 to 30° C. for 13 hours and 45 minutes. The resulting mixture was filtered, and the resulting crystals were washed with water (235.0 kg). The crystals were dried under reduced pressure at 50° C. to give the Compound 8 (56.6 kg, Yield: 97%).

¹H 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 C₂₇H₃₉N₇O₃509.3, found m/z 510 [M+H]⁺.

Under inert gas atmosphere, water (564.0 L) and 35% hydrochloric acid (133.1 kg) were mixed at 19 to 24° C., and the resulting mixture was warmed to 37° C. The Compound 8 (56.4 kg) was added dividedly thereto at 37 to 41° C. over 1 hour. Dilute hydrochloric acid was prepared from water (141.0 L) and 35% hydrochloric acid (33.3 kg), and added thereto at 39 to 41° C. 1 hour after the addition of the Compound 8. After the resulting mixture was stirred for 17 hours and 40 minutes from the addition of the Compound 8, the mixture was filtered under pressure at 40° C. In addition, water (112.8 L) was added thereto, and the resulting mixture was filtered under pressure. After cooled to 18° C., a 13.4 wt % aqueous solution of sodium hydroxide (480.95 kg; prepared from 48% sodium hydroxide (156.2 kg) and water (402.1 L)) was added thereto at 18 to 23° C. to adjust the pH value of the resulting solution to 11.51. After the resulting mixture was stirred at 20 to 21° C. for 45 minutes, a seed crystal of the Compound 9 (0.11 kg) was added thereto at 20° C. After stirred at 19 to 20° C. for 16 hours and 50 minutes, the resulting mixture was filtered, and the resulting crystals were washed with water (564.0 kg). The crystals were dried under reduced pressure at 50° C., and the resulting solids were crushed. The resulting product was dried under reduced pressure at 50° C. to give the Compound 9 (42.2 kg, Yield: 93%).

¹H NMR (CD₃OD, 500 MHz): δ1.22-1.41 (m, 4H), 1.92 (d, J=6.3 Hz, 4H), 2.43 (s, 3H), 2.60-2.65 (m, 5H), 3.07 (s, 2H), 3.66-3.72 (m, 1H), 4.02 (t, J=5.0 Hz, 4H), 7.36 (d, J=8.1 Hz, 2H), 8.10 (d, J=8.3 Hz, 2H), 9.06 (s, 1H).

MS calcd for C₂₂H₃₁N₇O 409.3, found m/z 410 [M+H]⁺.

Under inert gas atmosphere, methanol (55.4 kg), toluene (60.2 kg), and the Compound 9 (14.4 kg, the Compound 9 weight after moisture correction: 14.0 kg) were mixed to dissolve the Compound 9. Active carbon (0.28 kg) was added thereto, the resulting mixture was stirred at 20° C. for 1 hour and 50 minute, and then filtered under pressure. A mixed solution of methanol (22.1 kg) and toluene (25.1 kg) was additionally added thereto, and the resulting mixture was warmed to 47° C. Acetic anhydride (4.19 kg) was added thereto at 47 to 50° C., and the resulting mixture was stirred at 50 to 51° C. for 2 hours. Purified water (56.0 L) and 24% sodium hydroxide (6.8 kg) were mixed, and added to said mixture at 50° C. over 40 minutes. After the resulting mixture was stirred at 50° C. for 1 hour, it was cooled to 15° C., and stirred at 15 to 11° C. for 13 hours and 20 minutes. The resulting mixture was filtered, the resulting crystals were washed with methanol (33.2 kg), and then further washed with purified water (70.0 L). The crystals were dried under reduced pressure at 50° C. to give the Compound 10 (15.0 kg). Under nitrogen atmosphere, purified water (119.9 L), maleic acid (5.3 kg), the Compound 10 (14.8 kg), and methanol (10.5 kg) were mixed at 24° C. to dissolve the Compound 10, and then the resulting solution was pressured. Purified water (13.3 L) and methanol (1.2 kg) were additionally added thereto, the resulting mixture was warmed to 60° C., and a mixed aqueous solution of 24% sodium hydroxide (8.7 kg) and purified water (45.9 L) was added dropwise thereto at 59 to 60° C. over 50 minutes. The resulting mixture was stirred at 59 to 60° C. for 40 minutes, cooled to 25° C., and stirred at 20 to 25° C. for 14 hours and 30 minutes. The resulting mixture was filtered, and the resulting crystals were washed with purified water (74.0 L). The crystals were dried under reduced pressure at 50° C. to give the Compound (14.5 kg, 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 C₂₄H₃₃N₇O₂451.3, found m/z 452 [M+H]⁺.

Under nitrogen atmosphere, acetone (478.0 kg) and the Compound 10 (37.8 kg) were mixed, and the resulting mixture was warmed to 50° C. 48% Hydrobromic acid (13.9 kg), purified water (12.1 kg), and acetone (119.2 kg) were added thereto, and the resulting mixture was stirred at 46 to 50° C. for 2 hours. Acetone (150.7 kg) was additionally added thereto, and the resulting mixture was stirred at 47 to 50° C. for 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 resulting crystals were washed with acetone (596.4 kg). The crystals were dried under reduced pressure at 50° C. for 7 hours to give the Compound 1 (hydrobromide of the Triazine compound A) (42.1 kg, Yield: 94%). In this time, the resulting crystals of hydrobromide of the Triazine compound A were Hydrobromide Form 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 C₂₄H₃₃N₇O₂451.3, found m/z 452 [M+H]⁺.

The elemental analysis measurement result is shown in the following Table 1.

TABLE 1

Elemental analysis measurement result of Hydrobromide

Form A crystal of the Triazine compound A

C
H
N
Br

Measured
53.89
6.39
18.18
15.17

value

Theoretical
53.98
6.46
18.13
15.22

value

(The theoretical value represents a theoretical value when 0.1 equivalent of acetone is attached.)

XRPD was measured by using a powder X-ray diffraction device X'PertPro (manufactured by PANalyical B.V.) under the following conditions.

- X-ray generator: X-ray tube (Anticathode: copper, Tube voltage: 45 kv, Tube current: 40 mA)
- Incidence optical system: Focusing condensing mirror
- Light-receiving optical system: High-speed semiconductor array detector (X-Celerator), Extended light-receiving side arm
- Sample stage: HTS sample stage (oscillated at the range of 4 mm in the X-axis direction)
- Cumulated number: 5 times (each incidence angle was changed by −2, −1, 0, 1, and 2°, respectively)
- Measurement range: 2θ=3 to 40°
- Scan speed: 0.668451°/sec
- Step: 0.0167°

A XRPD result obtained from the Hydrobromide Form A crystals of the Triazine compound A is shown in FIG. 11. When the peak intensity at 25.6° as a diffraction angle expressed in 2θ is set to be 100, peaks (±0.2°, respectively) having 15 or more as the relative peak intensity are shown in the following Table 2.

TABLE 2

Relative

2θ (deg)
intensity

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

DSC was measured by using a differential scanning calorimetry device X-DSC7000 (SII NanoTechnology Inc.) under the following conditions.

- Rate of temperature increase: 10° C./min (30° C. to 300° C.) Atmosphere: nitrogen 100 mL/min

The result obtained from Hydrobromide Form A crystals of the Triazine compound A is shown in FIG. 12. An endothermic peak was also observed at about 265 to 275° C.

A test was carried out according to potassium bromide tablet method of infrared absorption spectrum method, and the resulting infrared absorption spectra were compared.

A result obtained from Hydrobromide Form A crystals of the Triazine compound A is shown in FIG. 13. The assignment result of the infrared absorption spectrum is shown in the following Table 3.

TABLE 3

Assignment result of infrared absorption spectrum obtained from

Hydrobromide Form A crystals of the Triazine compound A

Wavenumber (cm⁻¹)
Assignment

3360.05
N—H stretching vibration (amide)

2934.74
C—H stretching vibration (benzene ring)

2567.30
N—H stretching vibration (NH⁺)

1663.63
C═O stretching vibration (amide)

1527.65
C═C stretching vibration (benzene ring)

824.58
C—H out-of-plane bending vibration

(1,4-disubstituted benzene)

A single crystal X-ray diffraction analysis was carried out by using a single crystal X-ray diffraction device R-AXIS RAPID/R (Rigaku Corporation) (CuKα radiation) to determine lattice constants at −40° C. and measure diffraction peak intensities, subsequently determine the phases by direct method, and carry out a structure refinement by full matrix least square method. The resulting crystallographic data and crystal structure analysis result are shown in Table 4. The reliability factor (R factor) was 12.35%, and the other several parameters also demonstrated that the present crystal structure analysis was a sufficiently highly reliable analysis result.

TABLE 4

crystallographic data and crystal structure analysis result obtained

from Hydrobromide Form A crystals of the Triazine compound A

Molecular formula
C₂₄H₃₃N₇O₂•HBr

Molecular weight
532.48

Lattice constant
a = 7.1256 (9) Å

b = 12.360 (2) Å

c = 15.286 (2) Å

α = 96.489 (7)°

β = 102.173 (7)°

γ = 103.345 (7)°

V = 1261.8 (3) Å³

Crystal system
Triclinic

Space group
P-1

Z value
2

Number of unique reflections
4522

Density D_calc
1.401 g/cm³

R factor
12.35% (I > 2.0 sigma)

Example 2: Crystallization Study of Salt of the Triazine Compound A
Experimental Method

The Triazine compound A (about 600 mg) was dissolved into chloroform (40 mL), and each 200 μL thereof was dispensed in each vial of a 96 well plate (about 3 mg/vial). Also, regarding each acid compound, each 1 equivalent (70 μL) or 2 equivalents (140 μL) of a 0.1 moL/L solution thereof was dispensed in each vial. Regarding fumaric acid, each 140 μL of a 0.05 moL/L solution thereof was dispensed in each vial. After each solvent was allowed to evaporate by spraying nitrogen, each 300 μL of 8 kinds of solvents selected as screening solvents was dispensed in each vial, and each vial was sealed and stirred at room temperature for 4 days. Regarding the vials having precipitates, the precipitates were collected by filtration, and each XRPD thereof was measured. Regarding the vials having no precipitate, the vials were open, stored at room temperature overnight, and if solids were observed, the solids were collected by filtration, and each XRPD thereof was measured.

Crystallization of the Triazine compound A was studied by using a mixed solvent prepared by using 18 kinds of acids and 8 kinds of solvents. As a result, novel crystals were obtained from 14 kinds of acids (hydrobromic acid, hydrochloric acid, sulfuric acid, tosic acid, mesylic acid, benzenesulfonic acid, maleic acid, citric acid, fumaric acid, tartaric acid, malic acid, succinic acid, 2-oxoglutaric acid, and glycolic acid). Crystal forms were distinguished by XRPD patterns with each other, and alphabet was assigned to crystal forms having novel XRPD patterns in the order they were found for each salt. The Hydrobromide Form A crystal of the Triazine compound A in the result of XRPD refers to the same crystal as the Hydrobromide Form A crystal of the Triazine compound A produced in Example 1.

Regarding a part of the above each crystal, thermal stability, hygroscopicity, deliquescency, and chemical stability were evaluated.

Thermal stability was measured and evaluated by using a thermogravimetry/differential thermal analyzer TG/DTA7200 (SII NanoTechnology Inc.) under the following conditions.

- Rate of temperature increase: 10° C./min
- Range of temperature increase: 25 to 300° C.
- Atmosphere: nitrogen 200 mL/min
  
  <Hygroscopicity or Deliquescency Evaluation>

Hygroscopicity or deliquescency was evaluated as follows by using a moisture adsorption measurement device DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited). Each sample (about 5 mg) was placed into an aluminum plate of which the tare weight had been corrected in advance, and the plate was hung on the precision balance of said device to precisely measure the weight at the start of measurement. The humidity was changed in a stepwise manner in a chamber at 25° C., the weight change was recorded with time, and the equilibrium weight was calculated at each humidity. On the basis of the weight at a dried condition (0% RH), the weight change rate and hydration number at each humidity were calculated.

Each about 1 mg of a sample stored at 60° C. (sealed) or 60° C./75% RH (open) for 1 week and an unstored sample (at the start of test) was dissolved into a mixed solution of acetonitrile/water (1:1) (5 mL) to obtain each sample solution. A test was carried out by liquid chromatographic method under the following conditions to measure each peak area (%).

Each peak area (%) was measured by using Waters ACQUITY UPLC under the following conditions.

- Detector: Photodiode array (measurement wavelength: 239 nm)
- Column: Waters ACQUITY BEH C18 (2.1 mm×100 mm, 1.7 μm)
- Column temperature: constant temperature about 40° C.
- Mobile phase: Solution A; water/TEA (2000:1), Solution B;
- Acetonitrile/TFA (2000:1)
- Concentration gradient control: B % 2→100% (15 minutes)
- Flow rate: 0.5 mL/min
- Injection volume: 2 μL

The results are shown in Table 5.

TABLE 5

Solid physical property measurement results of

crystals of salts of the Triazine compound A

Thermal
Hygroscopicity

Chemical

stability
or
Chemical
stability

TG:
Deliquescency
stability
60° C.,

weight
Weight change
60° C.
75% RH, 1

Sample
change
at 90% RH
(sealed)
week (open)
Remarks

Hydrobromide
0.9%
1.0%
−0.01%
0.01%
1.0

Form A
25-274° C.

equivalent of

crystal

hydrobromide

Hydrochloride
0.4%
7.5%
−0.01%
−0.01%
1.0

Form A
25-160° C.

equivalent of

crystal

hydrochloride

Hydrochloride
No data
5.5%
No data
No data
2.0

Form B

equivalents of

crystal

hydrochloride

Sulfate
No data
8%
No data
No data
2.5

Form A

equivalents of

crystal

sulfate

Sulfate
4.3%
5%*¹
0%
0.13%
2.5

Form B
25-93° C.

equivalents of

crystal
1.6%

sulfate

93-105° C.

Tosilate
0.7%
7.5%
−0.07%
−0.05%
1.0

Form B
25° C.-

equivalent of

crystal
melting point

tosilate

Tosilate
1.2%
1.4%
0.04%
0.39%
1.0

Form C
25° C.-

equivalent of

crystal
melting point

tosilate

Mesilate
0.8%
17%
−0.13%
5.73%
1.0

Form A
120° C.

equivalent of

crystal

mesilate

Maleate
0.0%
22%
0.01%
0.12%
1.0

Form A

equivalent of

crystal

maleate

Maleate
0.4%
7.5%
0.02%
9.66%
1.0

Form B
25-90° C.

(deliquescent)
equivalent of

crystal
17.6%

maleate

120-260° C.

Citrate
2.2%
7.6%
−0.03%
0.03%
1.0

Form A
25° C.-

equivalent of

crystal
melting point

citrate

Malate
21.2%
15%
No data
No data
1.0

Form A
25-280° C.

equivalent of

crystal

citrate

Succinate
0.0%
0.4%
0.04%
0.02%
1.2

Form A
25-148° C.

equivalents of

crystal
23.7%

succinate

148-210° C.

Glycolate
14.4%
1.9%
0.02%
0.02%
1.0

Form A
70° C.-

(free body was
equivalent of

crystal
melting point

observed at
glycolate

60° C., 75%

RH, 1 week)

*¹with hydration stage

As shown in the thermal stability results in Table 5, the Hydrobromide Form A crystal, Hydrochloride Form A crystal, Sulfate Form B crystal, Tosylate Form B crystal, Tosylate Form C crystal, Mesilate Form A crystal, Maleate Form A crystal, Maleate Form B crystal, and Citrate Form A crystal did not show a significant weight change, and thus these crystal forms were confirmed to have excellent thermal stability. Further, the Succinate Form A crystal did not show a significant weight change at 25 to 148° C. (melting point), and thus said crystal form was confirmed to have excellent thermal stability.

Also, as shown in the hygroscopicity or deliquescency evaluation results in Table 5, the Hydrobromide Form A crystal, Sulfate Form B crystal, Tosylate Form B crystal, Tosylate Form C crystal, Succinate Form A crystal, and Glycolate Form A crystal did not show a significant increase of related substances, and these crystal forms were confirmed to be excellent in the reduced hygroscopicity or deliquescency. Also, the Sulfate Form B crystal had a hydration stage, and was confirmed to be a hydrate at normal temperature under relative humidity of 10 to 95%.

Further, as shown in the chemical stability test results in Table 5, the Hydrobromide Form A crystal, Hydrochloride Form A crystal, Sulfate Form B crystal, Tosylate Form B crystal, Tosylate Form C crystal, Maleate Form A crystal, Citrate Form A crystal, Succinate Form A crystal, and Glycolate Form A crystal did not show a significant increase of related substances, and these crystal forms were confirmed to have excellent chemical stability.

The Hydrobromide Form A crystal, Sulfate Form B crystal, Tosylate Form C crystal, and Succinate Form A crystal had excellent physical properties in thermal stability, hygroscopicity, deliquescency, and chemical stability.

Experimental Example 1: Synthesis of Sulfate Form B Crystal

The Triazine compound A (50 mg) was dissolved into chloroform (2 mL) at room temperature. Sulfuric acid (30 mg, 2.7 equivalents) was diluted with methanol (2 mL), and the resulting solution was added to the above solution at room temperature. The resulting mixture was stirred at room temperature for 0.5 hour, and then solvents were allowed to evaporate by nitrogen. To the resulting dried solids were added acetonitrile (3 mL) and water (100 μL) to give a syrup. To the syrup was added a seed crystal to give a suspension, and then the resulting mixture was stirred at room temperature overnight. The resulting precipitates were filtered, filtered residue was washed with acetonitrile (0.5 mL) twice, and dried under reduced pressure at 40° C. for 2.5 hours to give the Sulfate Form B crystals (75 mg, Yield: 92%, calculated as 2.5 sulfate 2 hydrate).

Experimental Example 2: Synthesis of Tosylate Form C Crystal

The Triazine compound A (50 mg) was dissolved into chloroform (2 mL) at room temperature. Tosic acid (45 mg, 2 equivalents) was dissolved into chloroform (2 mL) and methanol (0.5 mL), and the resulting solution was added to the above solution at room temperature. Solvents were allowed to evaporate by nitrogen, 1,2-dimethoxyethane (2.5 mL) was added thereto, and the resulting mixture was stirred at room temperature overnight. The resulting precipitates were filtered, and dried under reduced pressure at 40° C. for 3 hours to give the Tosylate Form C crystal (70 mg, Yield: 79%, calculated as 2 Tosylate).

Experimental Example 3: Synthesis of Succinate Form a Crystal

The Triazine compound A (40 mg) was dissolved into chloroform (2 mL) at room temperature. Succinic acid (12 mg, 1 equivalent) was dissolved into tetrahydrofuran (1 mL), and the resulting solution was added to the above solution at room temperature. After stirred for 0.5 hour, to the reaction solution was added methanol (1 mL) to give a solution, then solvents were allowed to evaporate by spraying nitrogen, toluene (2.5 mL) was added thereto, and the resulting mixture was stirred at room temperature overnight. The resulting precipitates were filtered, washed with toluene, and dried under reduced pressure at 40° C. for 2 hours to give the Succinate Form A crystal (43 mg, Yield: 85%, calculated as 1 succinate).

Experimental Example 4: Synthesis of Hydrobromide Form a Crystal (Alternative Method)

The Triazine compound A (50 mg) was dissolved into chloroform (2 mL) at room temperature. 25% Hydrobromic acid/acetic acid (39 mg) was diluted with methanol (1 mL), and the resulting mixture was added to the above solution at room temperature. After stirred at room temperature for 1 hour, solvents were allowed to evaporate by nitrogen. To the resulting dried solids was added acetonitrile (2.5 mL), and the resulting mixture was stirred at room temperature overnight. The resulting precipitates were filtered, filtered residue was washed with acetonitrile (0.5 mL) twice, and dried under reduced pressure at 40° C. for 3 hours to give the Hydrobromide Form A crystal (50 mg, Yield: 85%).

Example 3: Polymorph Search of Hydrobromide of the Triazine Compound A
Experimental Method

Hydrobromide Form A crystal of the Triazine compound A (about 500 mg) was dissolved into chloroform (5.0 mL) to give a suspension. Each 50 μL of the suspension was dispensed in each vial of a 96 well plate, solvent was dried under nitrogen stream to give solids, and then solvents shown in Table 6 were added thereto in the order of anti-solvents (6 kinds) and good-solvents (4 kinds) so that the total volume became 200 μL. As the anti-solvents, acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene were selected. As the good-solvent, methanol, benzyl alcohol, N-methylpyrrolidone, and dimethylsulfoxide were selected. The plate was sealed, stirred at room temperature for 5 days, the presence or absence of suspension was visually observed, the vials containing suspensions were filtered by a 96 well filtration filter plate (MultiScreen (registered trademark) HTS+Hi-Flow, FC, Merck Millipore), and XRPD of residues on the filter were measured.

The Hydrobromide Form A crystal of the Triazine compound A was subjected to polymorph search by using a mixed solvent prepared by using 6 kinds of anti-solvents (acetone, tetrahydrofuran, ethyl acetate, diisopropyl ether, acetonitrile, and toluene) and 4 kinds of good-solvents (methanol, benzyl alcohol, N-methylpyrrolidone, and dimethylsulfoxide). As a result of measuring each powder X-ray diffraction of resulting crystals, each crystal described in Table 6 was obtained. Crystal forms were distinguished by XRPD patterns with each other, and alphabet was assigned to crystal forms having novel XRPD patterns in the order they were found for each salt. The Hydrobromide Form A crystal of the Triazine compound A in the result of XRPD refers to the same crystal as the Hydrobromide Form A crystal of the Triazine compound A produced in Example 1.

TABLE 6

Polymorph search results 1 of crystals of hydrobromide of the Triazine compound A

Anti-solvents

Ethyl
Diisopropyl

Good-solvents
Acetone
Tetrahydrofuran
acetate
ether
Acetonitrile
Toluene

Methanol
A
Not
Not
A
Not
A

(140 μL)

applicable
applicable

applicable

Methanol
A
Not
A
A
Not
A

(100 μL)

applicable

applicable

Methanol
A
A
A
A
A
A

(60 μL)

Methanol
A
A
A
A
A
A

(20 μL)

Benzyl alcohol
Not
Amorphous
Not
Not
Not
Not

(140 μL)
applicable

applicable
applicable
applicable
applicable

Benzyl alcohol
Amorphous
A
A
Not
Not
Not

(100 μL)

applicable
applicable
applicable

Benzyl alcohol
Amorphous
A
A
A
A
A

(60 μL)

Benzyl alcohol
Amorphous
A
A
A
A
A

(20 μL)

N-Methylpyrrolidone
Amorphous
Not
A
A
Amorphous
A

(140 μL)

applicable

N-Methylpyrrolidone
A
A
A
A
A
A

(100 μL)

N-Methylpyrrolidone
A
A
A
A
A
A

(60 μL)

N-Methylpyrrolidone
A
A
A
D
A
A

(20 μL)

Dimethylsulfoxide
Not
Not
Not
Not
Not
Not

(140 μL)
applicable
applicable
applicable
applicable
applicable
applicable

Dimethylsulfoxide
Not
Not
C
Not
C
C

(100 μL)
applicable
applicable

applicable

Dimethylsulfoxide
A
C
C
C
C
C

(60 μL)

Dimethylsulfoxide
A
A
C
C
A
C

(20 μL)

Among the 96 conditions indicated in Table 6, crystal form was not changed from the Hydrobromide Form A crystal in 55 conditions, crystal form was changed from the Hydrobromide Form A crystal to the Hydrobromide Form C crystal of the Triazine compound A (dimethylsulfoxide adduct) in 11 conditions, and crystal form was changed to Hydrobromide Form D crystal of the Triazine compound A in 1 condition (N-methylpyrrolidone adduct). Here, the term of “Not applicable” means that the Triazine compound A was changed to a form of solution or the like which cannot be subjected to a powder X-ray diffraction measurement, and the term of “Amorphous” means that the Triazine compound A was changed to the Hydrobromide Form A crystal to the amorphous form. As descried above, among crystals of hydrobromide of the Triazine compound A, the Form A crystal was proved to be the most stable.

Example 4: Polymorph Search 2 of Crystals of Hydrobromide of the Triazine Compound A

The polymorph search of crystals of hydrobromide of the Triazine compound A was carried out by using the Triazine compound A in acetone, water, or a mixed solvent of acetone and water, with several equivalent(s) of hydrogen bromide, or at several crystallize temperature. As a result, 11 kinds of crystal forms were produced.

Among many resulting crystal forms, the Hydrobromide Form A crystal of the Triazine compound A, Hydrobromide Form F crystal of the Triazine compound A, and Hydrobromide Form N crystal of the Triazine compound A had excellent physical properties in thermal stability, hygroscopicity, deliquescency, and chemical stability.

The crystallization conditions of the Hydrobromide Form A crystal of the Triazine compound A, Hydrobromide Form F crystal of the Triazine compound A, and Hydrobromide Form N crystal of the Triazine compound A having appropriate physical properties for producing a medicament are shown in Table 7. The XRPD measurement device and measurement conditions are the same as used in Example 1. The Hydrobromide Form A crystal of the Triazine compound A in the result of XRPD refers to the same crystal as the Hydrobromide Form A crystal of the Triazine compound A produced in Example 1.

TABLE 7

Crystallization method of crystals of hydrobromide of the Triazine compound A

Hydrogen

Equivalent(s)

bromide

of

Experiment
Material
(equivalent)
Solvent
Temperature
Crystal form
hydrobromide

(a)
Triazine
hydrogen
acetone/water
50° C.
Hydrobromide
1.0 equivalent

compound A
bromide

Form A crystal

(1.0 equivalent)

(b)
Triazine
hydrogen
acetone/water
50° C.
Hydrobromide
2.0 equivalents

compound A
bromide

Form F crystal

(2.1 equivalents)

(c)
Triazine
hydrogen
water
50° C.
Hydrobromide
1.0 equivalent

compound A
bromide

Form N crystal

(1.4 equivalents)

In the method (a), the Hydrobromide Form A crystal of the Triazine compound A was produced. This crystal was proved to comprise 1.0 equivalent of hydrobromic acid.

In the method (b), the Hydrobromide Form F crystal of the Triazine compound A was produced. This crystal was proved to comprise 2.0 equivalents of hydrobromic acid.

In the method (c), the Hydrobromide Form N crystal of the Triazine compound A was produced. This crystal was proved to comprise 1.0 equivalent of hydrobromic acid.

Experimental Example 5
Experimental Example of Method (a)

Crystals were produced according to the crystallization method described in Example 1.

Experimental Example 6
Experimental Example of Method (b)

The Triazine compound A (10.0 g) was suspended in acetone (300 mL) at 50° C., then a 48% aqueous solution of hydrobromic acid (7.84 g, 2.1 equivalents) was added thereto, and the resulting mixture was stirred for about 20 hours. The mixture was cooled to 10° C., and filtered. The resulting wet body was washed with acetone (50 mL), and dried under reduced pressure at 40° C. for 24 hours to give the Hydrobromide Form F crystal (13.45 g).

Experimental Example 7
Experimental Example of Method (c)

The Triazine compound A (50.0 g) was suspended in water (450 mL) at 50° C., then a 48% aqueous solution of hydrobromic acid (26.19 g, 1.4 equivalents) was added thereto, and the resulting mixture was stirred for about 5 hours. The mixture was cooled to 14° C., and filtered. The resulting wet body was washed with acetone (200 mL), and draught drying was carried out for 21 hours to give the Hydrobromide Form N crystal (57.43 g).

Example 5: Comparison of Hydrobromide Form a Crystal of the Triazine Compound a, Hydrobromide Form F Crystal of the Triazine Compound a, and Hydrobromide Form N Crystal of the Triazine Compound A

In the following Comparative test results, the “Hydrobromide Form A crystal of the Triazine compound A” refers to results of crystals obtained from the method described in Example 1.

In the following Comparative test results, the “Hydrobromide Form F crystal of the Triazine compound A” refers to results of crystals obtained from the method described in Experimental Example 6.

In the following Comparative test results, the “Hydrobromide Form N crystal of the Triazine compound A” refers to results of crystals obtained from the method described in Experimental Example 7.

The powder X-ray diffraction measurement results obtained from the above Hydrobromide Form F crystal and Hydrobromide Form N crystal of the Triazine compound A are shown below.

XRPD was measured by using a powder X-ray diffraction device X′PertPro (manufactured by PANalyical B.V.) under the following conditions.

- X-ray generator: X-ray tube (Anticathode: copper, Tube voltage: 45 kv, Tube current: 40 mA)
- Incidence optical system: Focusing condensing mirror
- Light-receiving optical system: High-speed semiconductor array detector (X-Celerator), Extended light-receiving side arm
- Sample stage: HTS sample stage (oscillated at the range of 4 mm in the X-axis direction)
- Cumulated number: 5 times (each incidence angle was changed by −2, −1, 0, 1, and 2°, respectively)
- Measurement range: 2θ=3 to 40°
- Scan speed: 0.668451°/sec
- Step: 0.0167°

A XRPD result obtained from the Hydrobromide Form F crystals of the Triazine compound A is shown in FIG. 7. The peaks (±0.2°, respectively) are shown in the following Table 8.

TABLE 8

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

The characteristic peaks in the powder X-ray diffraction pattern of the Form F crystals include 10.0°±0.2° and 27.5°±0.2° as diffraction angles expressed in 2θ. In one embodiment, the Form F crystals have further peaks at 3.3°±0.2° and 14.4°±0.2° as diffraction angles expressed in 2θ in the powder X-ray diffraction pattern. Other characteristic peaks thereof include 17.4°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 25.6°±0.2°. Still other characteristic peaks thereof 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 Hydrobromide Form F crystal of the Triazine compound A is a crystal having substantially the same powder X-ray diffraction pattern as FIG. 7.

The XRPD result of the Hydrobromide Form N crystals of the Triazine compound A is shown in FIG. 9. The peaks (±0.2°, respectively) are shown in the following Table 9.

TABLE 9

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

The characteristic peaks in the powder X-ray diffraction pattern of the Form N crystals include 11.3°±0.2° and 24.3°±0.2° as diffraction angles expressed in 2θ. In one embodiment, the Form N crystals further have peaks at 6.2°±0.2° and 31.9°±0.2° as diffraction angles expressed in 2θ in the powder X-ray diffraction pattern. Other characteristic peaks thereof include 11.9°±0.2°, 22.4°±0.2°, 23.8°±0.2°, and 26.8°±0.2°. Still other characteristic peaks thereof 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 Hydrobromide Form N crystal of the Triazine compound A is a crystal having substantially the same powder X-ray diffraction pattern as FIG. 9.

The above each crystal was evaluated for thermal stability, hygroscopicity, deliquescency, and chemical stability.

Thermal stability was measured and evaluated by using a thermogravimetry/differential thermal analyzer TG/DTA7200 (SII NanoTechnology Inc.) under the following conditions

- Rate of temperature increase: 10° C./min
- Range of temperature increase: 30 to 300° C.
- Atmosphere: nitrogen 200 mL/min
- or
- using a TGA/DSC1 thermogravimetric analyzer (manufactured by Mettler Toledo, STARe system) under the following conditions.
- Rate of temperature increase: 10° C./min
- Range of temperature increase: 25 to 300° C.
- Atmosphere: nitrogen 50 mL/min
  
  <Hygroscopicity or Deliquescency Evaluation>

Hygroscopicity or deliquescency was evaluated as follows by using a moisture adsorption measurement device DVS-1 or DVS-intrinsic (Surface Measurement Systems Limited). Each sample was placed into a cell of which the tare weight had been corrected in advance, and the cell was hung on the precision balance of said device to precisely measure the weight at the start of measurement. The humidity was changed in a stepwise manner, the weight change was recorded with time, and the equilibrium weight was calculated at each humidity. On the basis of the weight of anhydride converted from the amount of water at a dried condition (0% RH) or at the start of measurement observed by an alternative method, the weight change rate at each humidity was calculated.

Each sample was stored at 60° C. under a sealed condition and at 60° C. under 75% RH for 1 week, and an increase or decrease of related substance(s) after the storage was calculated by high-performance liquid chromatographic method on the basis of the area percentage of each peak. Also, the condition of each sample after the storage was observed.

The results are shown in Table 10.

TABLE 10

Hygroscopicity or

Chemical

Thermal
Deliquescency
Chemical
stability

stability
Weight
stability
60° C., 75%

TG: weight
change at
60° C.
RH, 1 week

Sample
change
90% RH
(sealed)
(open)
Remarks

Hydrobromide
0.98
1.0%
−0.01%
0.01%
comprising 1.0

Form A
25-274° C.

equivalent of

crystal

hydrobromic acid

Hydrobromide
4.8%
3.5%*¹
0.02%
0.12%
comprising 2.0

Form F
room

equivalents of

crystal
temperature-200° C.

hydrobromic acid

Hydrobromide
6.2%
7.2%*¹
No data
0.00%
comprising 1.0

Form N
25-242° C.

equivalent of

crystal

hydrobromic acid

*¹with hydration stage

Among the resulting many crystal forms, the Hydrobromide Form A crystal, Hydrobromide Form F crystal, and Hydrobromide Form N crystal had excellent physical properties in thermal stability, hygroscopicity, deliquescency, and chemical stability. Also, the Hydrobromide Form F crystal and Hydrobromide Form N crystal had a hydration stage, and thus were confirmed to be hydrate at normal temperature under relative humidity of 10 to 95%.

Example 6: Effect of Water at the Crystallization of Hydrobromide Form a Crystal

TABLE 11

Mix rate of

the Triazine

Water
Stirring hour(s)
compound A in

Entry
content
1 hour
19 hours
45 hours
mother liquor

1
0.64%
Form F crystal
Form F crystal
Form A crystal
0.2%

Form A crystal
Form A crystal

Triazine compound A
Triazine compound A

2
2.0%
Form A crystal
Form A crystal
Form A crystal
0.6%

3
2.5%
Form A crystal
Form A crystal
Form A crystal
0.6%

4
3.0%
Form A crystal
Form A crystal
Form A crystal
1.1%

5
5.0%
Form A crystal
Form A crystal
Form A crystal
5.5%

Experimental Method

The Triazine compound A was added to mixed solvents of acetone and water having several water contents, an aqueous solution of hydrobromic acid (1 equivalent) was added thereto, and the resulting mixture was stirred at 50° C. After 1 hour, 19 hours, and 45 hours from the start of stirring, a part of the reaction solution was collected by filtration, and the filtered residue was subjected to a powder X-ray diffraction measurement. The transition rates to the Form A crystal in the mixed solvents of acetone and water having several water contents were confirmed.

The results are shown in Table 11.

In the mixed solvent having the water content of 0.64% (Entry 1), a mixture of the Hydrobromide Form A crystal, the Hydrobromide Form F crystal, and the Triazine compound A was obtained after 19 hours from the start of stirring, while the crystals converged on the Hydrobromide Form A crystals after 45 hours from the start of stirring.

In the mixed solvents having water contents of 2 to 5% (Entries 2 to 5), crystals converged on the Hydrobromide Form A crystals after 1 hour from the start of stirring. Further, in the water contents of 2 to 3%, the mix rates of the Triazine compound A in the mother liquors were excellent (0.6 to 1.1%), while in the water content of 5%, the mix rate of the Triazine compound A in the mother liquor was confirmed to increase (5.5%).

It was confirmed that the Hydrobromide Form A crystals may be obtained in short stirring hour(s) at a high recovery rate by adding the Triazine compound A to a mixed solvent of acetone and water having water content of 2.0 to 3.0%, adding an aqueous solution of hydrobromic acid (1 equivalent) thereto, and stirring the resulting mixture at 50° C. This method is an industrially advantageous crystallization method of a medicament.

Example 7: Comparison of Pharmacokinetics of the Triazine Compound a with Pharmacokinetics of the Hydrobromide of the Triazine Compound a at the Combined Use with a Promotor of Gastric Acid Secretion or an Inhibitor of Gastric Acid Secretion
Experimental Method

The pharmacokinetics of hydrobromide of the Triazine compound A and the Triazine compound A under gastric acid secretion and gastric pH adjustment was evaluated by using dogs treated with a promotor of gastric acid secretion or an inhibitor of gastric acid secretion according to a crossover method of 2 groups with 4 phases.

Pentagastrin was used in the treatment of a promotor of gastric acid secretion. Pentagastrin (2.8 mg) was dissolved into dimethylsulfoxide (7.0 mL) and water for injection (7.0 mL) to prepare an administration solution, and administered into a muscle in the thigh at a dose of 10 μg/0.05 mL/kg. Pentagastrin was administered 0.5 hour before and 0.5 hour after the administration of each test material (hydrobromide of the Triazine compound A (Compound 1 prepared in Example 1) or the Triazine compound A (Compound 10 prepared in Example 1)). Omeprazole was used in the treatment of an inhibitor of gastric acid secretion. Omeprazole (90 mg) was dissolved into a 1:1 mixed solution (22.5 mL) of a 0.1% aqueous solution of sodium hydrogen carbonate (w/v) and polyethyleneglycol 400 to prepare an administration solution, and administered into a 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 each test material.

After 25 mL of water for injection was administered to each dog by using a syringe having an oral catheter, the hydrobromide of the Triazine compound A or the Triazine compound A was forcedly orally administered to each dog at a dose of 10 mg/capsule (in case of hydrobromide of the Triazine compound A, free form equivalent (i.e., 10 mg in terms of the Triazine compound A)), and additional 25 mL of water for injection was administered to each dog through the syringe having an oral catheter. Each test material was administered under fasting state, and each dog was fed 6 hours after the administration. Each dog was deprived of water from 1 hour before the administration of each test material to 2 hours after the administration.