Method for producing heterocyclic derivative compound, composition containing said compound, and hydrate of said compound

Abstract

To provide: a novel hydrochloride 1.5 hydrate of a heterocyclic derivative compound for treatment or prevention of hyperuricemia and gout; a production method thereof; and a pharmaceutical composition containing the hydrochloride 1.5 hydrate.SOLUTION: A hydrochloride 1.5 hydrate of a compound represented by the formula (I) in the figure is provided, which displays characteristic peaks in the powder X-ray diffraction (XRD) analysis at the 2θ positions of 11.48±0.5°, 24.11±0.5°, 24.76±0.5°, 27.99±0.5°, 31.43±0.5°, and 34.20±0.5°.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound represented by the following formula (I): [ka] a novel intermediate compound used in the production method; a composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid, which comprises a compound of formula (I) in an amount of more than 2 mg and not more than 10 mg, and which is orally administered once daily; and a novel hydrochloride 1.5 hydrate of the compound of formula (I). [Background technology]

[0002] Drugs currently used for the treatment or prevention of hyperuricemia and gout include benzbromarone, a urate excretion enhancer that inhibits human urate anion transporter 1 (hURAT1), as well as probenecid and sulfinpyrazone. However, these drugs lack sufficient activity against URAT1. In particular, benzbromarone has been noted to have several drawbacks in terms of side effects. Because benzbromarone exhibits strong inhibitory activity against the 2C9 protein, which is a cytochrome P450 (CYP450) protein, it may cause drug-drug interactions. The formation of reactive metabolites has also been reported in glutathione (GSH) adduct formation experiments (Non-Patent Document 1).

[0003] Furthermore, benzbromarone has a benzofuran skeleton similar to the drug structures of benziodarone, benzarone, and amiodarone, which have been reported to exhibit hepatotoxicity. Therefore, the liver function of patients who plan to take this drug must be tested before administration, and even during administration, it is recommended to monitor for a certain period (6 months) whether hepatotoxicity is induced. Therefore, a drug that solves these problems is needed in the pharmaceutical field (Non-Patent Documents 2, 3, 4, 5).

[0004] Patent Document 1 discloses a compound represented by the following formula (I): [ka] (I) and among the specific examples of the compound, (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (compound 4) is disclosed.

[0005] Patent Document 1 discloses that the heterocyclic derivative compounds exhibit stronger human urate anion transporter 1 (hURAT1) inhibitory activity than conventional inhibitors of hURAT1 activity, and are therefore useful as inhibitors of uric acid reabsorption, particularly as selective inhibitors. Furthermore, it discloses that the heterocyclic derivative compounds exhibit no drug-drug interactions with cytochrome P450 (CYP450), exhibit selectivity among organic anion transporters, have higher solubility and metabolic stability, and exhibit favorable pharmacokinetics, and therefore exhibit superior effects compared to conventional drugs in the treatment or prevention of hyperuricemia, acute gouty arthritis, chronic gouty arthritis, gouty tophi, gouty nephropathy, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, and complications reported to be associated with increased blood uric acid, such as hyperlipidemia, ischemic heart disease, myocardial infarction, arteriosclerosis, cerebral infarction, cerebrovascular disease, diabetes, and hypertension.

[0006] The above-mentioned Patent Document 1 describes an experiment in which the heterocyclic derivative compound was orally administered to capuchin monkeys at doses of 3.75 mg / kg, 7.5 mg / kg, and 15 mg / kg. These doses, when logically converted to doses applicable to humans, amount to approximately 15 mg to 60 mg, and such high doses pose a considerable risk of side effects.

[0007] Furthermore, in the case of the hydrochloride salt of the heterocyclic derivative compound, there is a limit to the preparation of oral preparations by wet granulation due to its hygroscopicity.

[0008] On the other hand, as a method for synthesizing the heterocyclic derivative compound, Patent Document 1 also discloses steps for producing the heterocyclic derivative compound of formula (I): (1) a step of halogenating a compound of formula (VII) below to obtain a compound of formula (X) below, and reacting the obtained compound of formula (X) with a compound of formula (IX) below to obtain a compound of formula (VIII) below, or a step of subjecting a compound of formula (VII) below and a compound of formula (IX) below to a Mitsunobu reaction to obtain a compound of formula (VIII) below; (2) a step of cyclizing the obtained compound of formula (VIII) to obtain a compound of formula (IV); and (3) a step of subjecting the obtained compound of formula (IV) and a compound of formula (III) to a peptide bond reaction. [ka]

[0009] However, among the oxazine derivatives of the formula (IV) obtained as intermediates in the production method, [ka] 3,4-Dihydro-2H-pyrido[4,3-b][1,4]oxazine, which has the formula:

[0001] , is liquid and unstable, and its decomposition produces impurities that are highly likely to be carcinogenic or mutagenic. Because an additional step is required to purify these impurities, the above manufacturing method is not suitable for mass production.

[0010] In addition, the compound of formula (III) in the above-mentioned production method is represented by the following formula: [ka] 3,5-Dibromo-4-methoxy-benzoyl chloride having the formula (III) is obtained from 3,5-dibromo-4-methoxybenzoic acid, which is an expensive starting material. Furthermore, since the process of synthesizing the compound of formula (III) and the oxazine derivative of formula (IV) may involve genetic mutations, a process that can minimize such a possibility is required.

[0011] On the other hand, Patent Document 2 discloses a compound of the following formula, which is effective in treating hyperuricemia, gout, etc. [ka] The present invention discloses oxazine derivative compounds and methods for synthesizing the same. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2009 / 145456 [Patent Document 2] U.S. Patent Application Publication No. 2007-0010670 [Non-patent literature]

[0013] [Non-Patent Document 1] Dermot F. McGinnity et al., Drug Metabolism and Disposition, 33, p1700-1707 (2005) [Non-patent document 2] Hautekeete ML, et al., Liver, 15, p25-29 (1995) [Non-patent document 3] Makoto Arai, et al., Journal of Gastroenterology and Hepatology 17, p625-626 (2002) [Non-patent document 4] Saitama Medical College Magazine, 30, p187-194 (2003) [Non-patent document 5] Priska Kaufmann, et al., HEPATOLOGY, 41, p925-935 (2005) Summary of the Invention [Problem to be solved by the invention]

[0014] Conventional methods for preparing heterocyclic derivative compounds of formula (I) have problems, such as the decomposition of the oxazine derivative obtained as an intermediate, resulting in the generation of impurities that may be carcinogenic or mutagenic, and the synthesis of the oxazine derivative with 3,5-dibromo-4-methoxybenzoyl chloride, resulting in the generation of toxic intermediates that induce genetic mutations. Furthermore, additional purification steps are required at each step to remove impurities, making the preparation process complex and unsuitable for mass production. To address these problems, the present invention aims to provide a novel method for preparing heterocyclic derivative compounds of formula (I), characterized by the use of a novel oxazine derivative HBr salt (dihydrobromide, 2HBr), which is a stabilized form of the oxazine derivative, and a novel benzoic acid intermediate that does not produce toxic substances, allows for in situ reactions, reduces the number of manufacturing steps, and is suitable for mass production.

[0015] The present invention also aims to provide novel intermediate compounds used in the above-mentioned production methods.

[0016] Furthermore, the present invention is intended to provide a composition for use in the treatment or prevention of hyperuricemia, gouty disease, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid, which comprises, as an active ingredient, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amount of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I), and which is orally administered once daily.

[0017] Furthermore, the present invention is intended to provide a novel hydrochloride sesquihydrate of the compound of formula (I). [Means for solving the problem]

[0018] The present invention provides a method for producing a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof, which comprises a step of coupling a compound represented by the following formula (III) with a compound represented by the following formula (IV): [ka] wherein R is hydrogen or tert-butyloxycarbonyl (Boc).

[0019] In one embodiment of the present invention, the compound of formula (III) can be obtained by reacting a compound of formula (II) below with di-tert-butyl dicarbonate and pyridine: [ka]

[0020] In one embodiment of the present invention, the method for preparing the compound of formula (I) may comprise the steps of: (1) reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V): (2) reacting the compound of formula (V) with an alcohol in the presence of an acid to obtain a salt of a compound of formula (I): (3) reacting a salt of a compound of formula (I) first with a base and then with an acid. [ka]

[0021] In one embodiment of the present invention, the steps (1) and (2) can be carried out as in situ reactions.

[0022] In one embodiment of the present invention, the step of obtaining a compound of formula (III) from a compound of formula (II), and the steps (1) and (2) can be carried out as in situ reactions.

[0023] In one embodiment of the present invention, the compound of formula (IV) is prepared by reacting 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine with acetic acid. Kasui It can be obtained by reacting with benzoic acid.

[0024] The present invention also provides a compound represented by the following formula (III): [ka] (wherein R is hydrogen or Boc) The present invention provides an intermediate compound represented by the formula:

[0025] Furthermore, the present invention provides a compound represented by the following formula (IV): [ka] The present invention provides an intermediate compound represented by the formula:

[0026] The present invention also provides a pharmaceutical composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid, which comprises, as an active ingredient, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amount of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I), and which is orally administered once daily.

[0027] Furthermore, the present invention provides use of the compound of formula (I), its pharmaceutically acceptable salt or its hydrate orally administered once daily at a dose of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I) for the treatment or prevention of hyperuricemia, gouty disease, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid.

[0028] The present invention also provides a method for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid in a subject, comprising orally administering to the subject once a day the compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof at a dose of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I).

[0029] In one embodiment of the present invention, the dosage of the compound of formula (I) may be 3 mg to 8 mg of the free base.

[0030] In one embodiment of the present invention, the compound of formula (I) may be the hydrochloride salt of the compound of formula (I) or a sesquihydrate form thereof.

[0031] The present invention also provides a hydrochloride sesquihydrate of the compound of formula (I).

[0032] In one embodiment of the present invention, the hydrochloride sesquihydrate of the compound of formula (I) exhibits characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis: 11.48±0.5°, 24.11±0.5°, 24.76±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°

[0033] In one embodiment of the present invention, the hydrochloride sesquihydrate of the compound of formula (I) further exhibits characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis: 6.89±0.5°, 17.61±0.5°, 21.42±0.5°, 23.27±0.5°

[0034] The present invention also provides a method for producing the hydrochloride sesquihydrate of the compound of formula (I), which comprises the step of reacting the compound of formula (I) with acetic acid, an aqueous hydrochloric acid solution, and acetone to produce crystals.

[0035] The present invention further provides a pharmaceutical composition comprising the hydrochloride sesquihydrate of the compound of formula (I) formulated for oral administration.

[0036] In one embodiment of the present invention, the pharmaceutical composition may be in tablet form. [Effects of the Invention]

[0037] The method for producing the heterocyclic derivative compound of formula (I) according to the present invention solves the problem of the production of impurities that are likely to cause carcinogenesis or mutagenesis by using a stabilized HBr salt (2HBr) form of the oxazine derivative instead of the oxazine derivative. The method for producing the heterocyclic derivative compound of formula (I) according to the present invention solves the problem of the production of impurities that are likely to cause carcinogenesis or mutagenesis by using a novel benzoic acid intermediate instead of 3,5-dibromo-4-methoxybenzoyl chloride. Therefore, the method for producing the heterocyclic derivative compound of formula (I) according to the present invention eliminates the need for additional purification steps to remove impurities at each step and has the advantage of being suitable for mass production by in situ reaction.

[0038] In addition, a dosage regimen in which the compound of formula (I) according to the present invention is orally administered once a day at a dosage of more than 2 mg and not more than 10 mg exhibits significantly excellent effects in the treatment or prevention of hyperuricemia, gouty disease, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or uric acid-related diseases, and minimizes the possibility of side effects.

[0039] Furthermore, in the case of the conventional hydrochloride salt of the compound of formula (I), there was a problem in formulating a preparation for oral administration by wet granulation due to its hygroscopicity. However, the hydrochloride 1.5 hydrate of the compound of formula (I) according to the present invention solves this problem and exhibits stability suitable for preparations for oral administration (particularly tablets). [Brief explanation of the drawings]

[0040] [Figure 1] FIG. 1 shows NMR data of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) of the present invention produced in Example 1. [Figure 2]FIG. 1 shows the results of thermogravimetry (TG) / differential thermal analysis (DTA) of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) of the present invention produced in Example 1. [Figure 3] FIG. 1 shows NMR data of the compound of formula (I) of the present invention produced in Example 2. [Figure 4] FIG. 2 shows the results of powder X-ray diffraction (XRD) analysis of the hydrochloride sesquihydrate of the compound of formula (I) of the present invention prepared in Example 3. [Figure 5] FIG. 1 shows NMR data of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate. [Figure 6] FIG. 1 shows the TG / DTA results of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate. [Figure 7] FIG. 1 shows NMR data for 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine free base form. [Figure 8] FIG. 1 shows the TG / DTA results of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine free base form. [Figure 9] FIG. 1 shows the results of powder X-ray diffraction (XRD) analysis of (a) the non-solvated hydrochloride salt of compound of formula (I) and (b) the sesquihydrate hydrochloride salt of compound of formula (I) of the present invention. [Figure 10] FIG. 1 is a diagram showing the TG / DTA results of (a) a non-solvated hydrochloride salt of the compound of formula (I) and (b) a sesquihydrate hydrochloride salt of the compound of formula (I) of the present invention. [Figure 11] FIG. 1 is a diagram showing water sorption isotherms of (a) the non-solvated hydrochloride salt of compound of formula (I) and (b) the sesquihydrate hydrochloride salt of compound of formula (I) of the present invention. [Figure 12] FIG. 1 is a diagram showing the comparison of the solubility of the hydrochloride 1.5 hydrate of the compound of formula (I) of the present invention with the hydrochloride non-solvate of the same compound. [Figure 13]FIG. 1 shows the percentage (%) of patients whose blood uric acid levels decreased to less than 5.0 mg / dL (right bar) and the percentage (%) of patients whose blood uric acid levels decreased to less than 6.0 mg / dL (left bar) when administered with a compound of formula (I) of the present invention at low doses (0.25 mg, 0.5 mg, 1 mg) and 2 mg. [Figure 14] This figure shows the percentage (%) of patients whose blood uric acid levels decreased to less than 5.0 mg / dL (right bar) and the percentage (%) of patients whose blood uric acid levels decreased to less than 6.0 mg / dL (left bar) when administered with the compound of formula (I) of the present invention at doses within the administration regimen range (3 mg, 5 mg, 7 mg, 10 mg). DETAILED DESCRIPTION OF THE INVENTION

[0041] The present invention will be described in more detail below.

[0042] Method for preparing the compound of formula (I), its salt or hydrate

[0043] The present invention relates to a method for producing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof, which comprises a step of coupling a compound of formula (III) with a compound of formula (IV): <Reaction Scheme 1> [ka] (wherein R is hydrogen or Boc)

[0044] Specifically, a base is added to the compound of formula (III), and the resulting compound is coupled with 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr), a compound of formula (IV). The resulting intermediate compound is then post-treated to give (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone, a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment of the present invention, the compound of formula (III) can be obtained by reacting a compound of formula (II) below with di-tert-butyl dicarbonate and pyridine: <Reaction Scheme 2> [ka]

[0046] Specifically, a solvent is added to a reactor, then 3,5-dibromo-4-hydroxybenzoic acid of formula (II) is added, di-tert-butyl dicarbonate is added, and pyridine is added, and the reaction is carried out to obtain the compound of formula (III).

[0047] The compound of formula (II), 3,5-dibromo-4-hydroxybenzoic acid, used as a low-cost starting material, can be prepared by referring to known methods or purchased commercially from a reagent company.

[0048] Conventional solvents that do not adversely affect the reaction can generally be used. Preferred examples of solvents include ether-based solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon-based solvents such as benzene, toluene, hexane, and xylene; halogenated hydrocarbon-based solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; alcohol-based solvents such as methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol; ester-based solvents such as ethyl acetate, methyl acetate, and butyl acetate; and polar solvents such as acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile. Mixtures of two solvents selected from the above can also be used. Tetrahydrofuran is preferred for this reaction.

[0049] Specifically, tetrahydrofuran (THF) is added to a reactor, followed by the addition of 3,5-dibromo-4-hydroxybenzoic acid (the compound of formula (II)), followed by the addition of di-tert-butyl dicarbonate, and then pyridine under a nitrogen atmosphere to react to obtain the compound of formula (III). The reaction can be carried out at a temperature of 25-30°C for approximately 1-3 hours with stirring.

[0050] The obtained compound of formula (III) is a novel benzoic acid intermediate compound. [ka] (wherein R is hydrogen or Boc) The present invention also includes compounds represented by the following formula:

[0051] The process for preparing the compound of formula (I) of the present invention may comprise the following steps: (1) reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V); (2) reacting a compound of formula (V) with an alcohol in the presence of an acid to obtain a salt of a compound of formula (I); and (3) reacting the salt of the compound of formula (I) first with a base and then with an acid; <Reaction Scheme 3> [ka] (wherein R is hydrogen or Boc)

[0052] In one embodiment of the present invention, the method may further include a step of reacting the compound of formula (II) with di-tert-butyl dicarbonate and pyridine before the step (1). In this case, the method for producing the compound of formula (I) can be represented by the following reaction scheme: <Reaction Scheme 4> [ka] (wherein R is hydrogen or Boc)

[0053] In one embodiment of the present invention, the steps (1) and (2) can be carried out as in situ reactions.

[0054] In one embodiment of the present invention, the step of obtaining a compound of formula (III) from a compound of formula (II), and the steps (1) and (2) can be carried out as in situ reactions.

[0055] "In situ reaction" refers to the continuous chemical reactions carried out in one reactor, and is also called "one-pot reaction." In situ reactions are very economical and suitable for mass production because the next reaction can be carried out immediately without the need for separation and purification steps of intermediate compounds.

[0056] The manufacturing method is described in detail below.

[0057] Step (1) Reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V).

[0058] A base is added to the compound of formula (III), and the compound is reacted with 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr), which is a compound of formula (IV).

[0059] Examples of bases that can be used in the reaction include organic bases such as triethylamine, pyridine, 4-methylaminopyridine, 4-methylmorpholine, piperazine, and N-methylpiperazine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; and potassium phosphate. Triethylamine is preferred for this reaction.

[0060] Specifically, triethylamine was added to the reaction mixture, and then 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) of formula (IV) was added to the reaction mixture, and the reaction mixture was stirred at a temperature of 25-30°C for about 5-7 hours. After removing the formed salt (precipitate), the filtrate was collected and then concentrated at a temperature of 25-30°C to obtain tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, a compound of formula (V).

[0061] Step (2) Reacting the compound of formula (V) with an alcohol in the presence of an acid to obtain a salt of the compound of formula (I).

[0062] An alcohol was added to a reactor containing tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, a compound of formula (V), and the mixture was reacted in the presence of an acid to obtain the salt of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone.

[0063] Examples of acids used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalsulfonic acid. Hydrochloric acid is preferred in this reaction.

[0064] Examples of the alcohol used in the reaction include methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc., and isopropyl alcohol is preferred in this reaction.

[0065] More specifically, isopropyl alcohol was added to a reactor containing tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, a compound of formula (V), at a temperature of 25-30°C. Concentrated hydrochloric acid was then slowly added at 45°C or below, and the reaction mixture was cooled to 25-30°C and stirred for approximately 1-2 hours. Isopropyl alcohol was added to the reaction mixture at 25-30°C, and the mixture was stirred for another hour. The reaction mixture was then cooled to 20-25°C. The resulting crystals were filtered and dried to obtain (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone hydrochloride.

[0066] Step (3) reacting the compound of formula (I) first with a base and then with an acid to obtain the compound of formula (I)

[0067] Water was added to a clean reactor, and the salt of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone was added to the reactor, and the base and acid were reacted successively. The resulting crystals were filtered to obtain (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone, a compound of formula (I).

[0068] Examples of bases that can be used in the reaction include organic bases such as triethylamine, pyridine, 4-methylaminopyridine, 4-methylmorpholine, piperazine, and N-methylpiperazine; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride, or alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogen carbonates such as sodium bicarbonate and potassium bicarbonate; and potassium phosphate. Sodium hydroxide is preferred in this reaction.

[0069] Examples of acids used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid, and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalsulfonic acid. Hydrochloric acid is preferred in this reaction.

[0070] More specifically, water was added to a clean reactor, and the (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone hydrochloride obtained in step (2) was added to the reactor at 25-30°C. The reaction mixture was stirred at 25-30°C for approximately 15 minutes. Aqueous sodium hydroxide solution was slowly added at 25-30°C until the pH reached 10.0. The reaction mixture was filtered, and the filtrate was collected. Ethyl acetate was added to the reactor, and the mixture was stirred to separate the aqueous layer. Aqueous hydrochloric acid solution was added at 20-25°C until the pH reached 6.4-6.7. The resulting crystals were filtered to obtain the compound of formula (I), (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone.

[0071] The above-described method for producing the compound of formula (I) will be explained in more detail in the Examples below.

[0072] Method for preparing the compound of formula (IV)

[0073] In one embodiment of the present invention, the compound of formula (IV) is prepared by reacting 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine with acetic acid. Kasui It can be produced by a production method including a step of reacting with hydrochloric acid.

[0074] In another embodiment of the present invention, the compound of formula (IV) can be prepared by the following steps: <Reaction Scheme 5> [ka]

[0075] Specifically, the manufacturing method is as follows. (1) Add phosphoryloxychloride to 4-hydroxy-nitropyridine to obtain 4-chloro-3-nitropyridine. (2) Methyl glycolate and potassium carbonate are added to 4-chloro-3-nitropyridine to obtain methyl 2-((3-nitropyridin-4-yl)oxy)acetate. (3) Methyl 2-((3-nitropyridin-4-yl)oxy)acetate is added with ammonium chloride (NH4Cl) and iron (Fe) to give 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one. (4) 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one is treated with lithium aluminum hydride (LiAlH4, LAH) to give 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine. (5) 3,4-Dihydro-2H-pyrido[4,3-b][1,4]oxazine in acetic acid Kasui Addition of hydrochloric acid finally gives the compound of formula (IV), 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr).

[0076] Therefore, the present invention provides a compound represented by the following formula (IV): [ka] The present invention also includes a novel intermediate compound represented by the formula:

[0077] The method for producing the intermediate compound of formula (IV) described above will be explained in more detail in the Examples below.

[0078] Use of the compounds of formula (I)

[0079] The present invention also relates to a pharmaceutical composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid, which comprises, as an active ingredient, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof in an amount of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I), and which is orally administered once daily.

[0080] Furthermore, the present invention relates to use of the compound of formula (I), its pharmaceutically acceptable salt or its hydrate, which is orally administered once daily at a dose of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I), for the treatment or prevention of hyperuricemia, gouty disease, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid.

[0081] The present invention also relates to a method for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, nephrolithiasis, uremia, urolithiasis, or a disease associated with uric acid in a subject, comprising orally administering to the subject once a day the compound of formula (I), its pharmaceutically acceptable salt, or its hydrate at a dosage of more than 2 mg and not more than 10 mg relative to the free base of the compound of formula (I).

[0082] In one embodiment of the present invention, the compound of formula (I) contained as an active ingredient in the pharmaceutical composition, use and method may be in the form of a pharmaceutically acceptable salt or hydrate.

[0083] Such pharmaceutically acceptable salts include acid addition salts formed with acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid; and sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalsulfonic acid. These salts also include salts with alkali metals such as sodium and potassium. Other salts may also be formed with other acids or bases that are known and conventionally used in the technical field related to aromatic amidine derivatives or lactam derivatives. The hydrate forms include hemihydrate, monohydrate, 1.5-hydrate, dihydrate, and trihydrate.

[0084] Specifically, the pharmaceutically acceptable salt may be a hydrochloride salt, and the hydrate may be in the form of a sesquihydrate.

[0085] Hyperuricemia is an abnormally high level of uric acid in the blood. It is defined as a condition in which blood uric acid levels are higher than normal (7-8 mg / dl in men, 6 mg / dl in women) due to insufficient kidney excretion or overproduction in the liver. Gout is a condition in which blood uric acid levels are significantly higher than normal (7-8 mg / dl in men, 6 mg / dl in women) due to overproduction or insufficient liver excretion. Uric acid crystals can deposit in connective soft tissues such as joints and ligaments, and needle-shaped uric acid crystals can pierce muscles around joints. The body's immune system then attacks the uric acid crystals, causing severe pain and swelling around the joints. This paroxysmal and inflammatory arthritis is called gout. It has been reported that uric acid crystals are deposited mainly in the metatarsophalangeal joint of the big toe, and rarely in the lumbar spine [Vervaeck M., et al., Clinical Neurology and Neurosurgery, 93, p233-236 (1991)].

[0086] Gout is a very dangerous factor because it can cause complications of various metabolic diseases, such as diabetes, hypertension, heart disease, obesity, nephrolithiasis, and urinary tract stones, in addition to arthritis. The peak incidence of gout is observed mainly in men in their 40s and 50s, and is increasing in postmenopausal women. The incidence is also higher in obese individuals and those who engage in very strenuous exercise.

[0087] The incidence of gout attacks is closely related to patients' long-term hyperuricemia. The incidence of gout attacks has been reported to be 4.9% in patients with uric acid levels of 9 mg / dL or higher, 0.5% in patients with uric acid levels of 7.0-8.9 mg / dL, and 0.1% in patients with uric acid levels of 7.0 mg / dL or lower. The 5-year cumulative incidence of gout attacks was approximately 22% in patients with uric acid levels of 9 mg / dL or higher. [Campion EW et al., Am. J. Med., 82, pp. 421-426 (1987)].

[0088] Lowering blood uric acid (UA) levels to less than <6.0 mg / dL, more preferably less than <5.0 mg / dL, is clinically important for the treatment of patients with severe gout. The administration regimen according to the present invention, in which the compound of formula (I), its pharmaceutically acceptable salt, or its hydrate is orally administered once daily at a dose of more than 2 mg to 10 mg, based on the free base of the compound of formula (I), is significantly effective in lowering blood uric acid levels in patients to less than <5.0 mg / dL.

[0089] Specifically, as can be seen from Experimental Example 4 below, when the dosage regimen of the present invention was administered at 3 mg, 5 mg, 7 mg, and 10 mg, the percentage of patients whose blood uric acid levels decreased to less than 5.0 mg / dL was about 23%, about 64%, about 80%, and about 73%, respectively, ranging from about 23% to about 80% (see Figure 14). However, when the same compound was administered at 0.25 mg, 0.5 mg, and 1 mg, no patients whose blood uric acid levels decreased to less than 5.0 mg / dL were observed, and at the 2 mg dose, the percentage was only about 8% (see Figure 13). These experimental results demonstrate that significant effects are observed at doses exceeding 2 mg, which is the lower limit of the dosage range of the dosage regimen of the present invention.

[0090] Furthermore, an administration regimen in which the compound of formula (I) according to the present invention is orally administered once daily at a dose of more than 2 mg to 10 mg or less exhibits potent inhibitory activity against human urate anion transporter 1 (hURAT1), and is useful for the treatment or prevention of hyperuricemia, gouty diseases such as acute gouty arthritis, chronic gouty arthritis, gouty tophi, and gouty nephropathy; nephritis, chronic renal failure, nephrolithiasis, uremia, and urolithiasis, as well as diseases associated with uric acid, such as hyperlipidemia, ischemic heart disease, myocardial infarction, cerebral infarction, cerebrovascular disease, diabetes, and hypertension.

[0091] In one embodiment of the present invention, the dosage of the compound of formula (I) can vary depending on the patient's disease, condition, age, weight, and dosage form, ranging from more than 2 mg to 10 mg or less when administered orally once daily. Specifically, it can be administered orally at a dosage of 3 mg to 8 mg once daily, more specifically, at a dosage of 3 mg to 6 mg once daily. The dosage range is based on the free base form of the active ingredient, the compound of formula (I), and the compound of formula (I) can be administered in the form of hydrochloride or its sesquihydrate. Specifically, when administered in the form of the hydrochloride sesquihydrate of the compound of formula (I), the dosage can be from more than 2.3 mg to 11.5 mg or less.

[0092] Doses below 2 mg are insufficient to treat the disease, with 10 mg demonstrating the maximum effect. Although doses exceeding 10 mg are effective in lowering uric acid levels, such doses may induce arthralgia, joint swelling, and other symptoms during treatment, potentially causing pain to patients, as well as other potential side effects. These side effects include increased creatinine levels, which can lead to potentially fatal kidney disease. As can be seen from Experimental Example 5 below, doses exceeding 10 mg, the maximum dose for the administration regimen of the present invention, may increase the incidence of adverse events such as arthralgia and joint swelling, as well as the risk of increased urinary creatinine levels.

[0093] The subject for use according to the present invention is an animal, preferably a mammal, most preferably a human.

[0094] Hydrochloride sesquihydrate of the compound of formula (I)

[0095] The present invention also relates to the hydrochloride sesquihydrate of the compound of formula (I).

[0096] The present invention also provides a method for producing the hydrochloride 1.5 hydrate of the compound of formula (I), which comprises the step of reacting the compound of formula (I) with acetic acid, an aqueous hydrochloric acid solution, and acetone to produce crystals.

[0097] Specifically, the compound of formula (I), (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone, was added to a reactor at 25°C. Immediately, acetic acid was added at the same temperature, and water was then added to the reactor. Aqueous hydrochloric acid was added to the reactor at 25°C, and then acetone was added to the reaction solution to form crystals. The resulting crystals were filtered and dried under vacuum to obtain (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate.

[0098] The method for producing the hydrochloride 1.5 hydrate of compound of formula (I) described above will be explained in more detail in the Examples below.

[0099] In one embodiment of the present invention, the hydrochloride sesquihydrate of the compound of formula (I) exhibits characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis: 11.48±0.5°, 24.11±0.5°, 24.76±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°

[0100] In one embodiment of the present invention, the hydrochloride sesquihydrate of the compound of formula (I) further exhibits characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis: 6.89±0.5°, 17.61±0.5°, 21.42±0.5°, 23.27±0.5°

[0101] In one embodiment of the present invention, the hydrochloride sesquihydrate of the compound of formula (I) exhibits characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis: 6.89±0.5°, 10.84±0.5°, 11.48±0.5°, 13.73±0.5°, 15.85±0.5°, 17.61±0.5°, 18.51±0.5°, 19.98±0.5°, 21.42±0.5°, 22.99±0.5°, 23.27±0.5°, 24.11±0.5°, 24.76±0.5°, 27.37±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°

[0102] The present invention also relates to a pharmaceutical composition formulated for oral administration, which comprises the hydrochloride 1.5 hydrate of the compound of formula (I).

[0103] Pharmaceutical compositions according to the present invention can be prepared by mixing an effective amount of the hydrochloride sesquihydrate of compound of formula (I) as an active ingredient with pharmaceutically acceptable carriers, vehicles, binders, stabilizers, and / or diluents. The pharmaceutical compositions of the present invention can be prepared in unit dosage form or in multi-dose containers by formulating them with pharmaceutically acceptable carriers and / or additives according to methods readily practiced by those skilled in the art. The pharmaceutically acceptable carriers can be solid or liquid and can be one or more selected from additives, antioxidants, buffers, bacteriostats, dispersing agents, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, fluidizers, release-modifying agents, wetting agents, stabilizers, suspending agents, and lubricants. The pharmaceutically acceptable carriers can also be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and mixtures thereof.

[0104] The pharmaceutical composition according to the present invention can be prepared in the form of a pharmaceutical preparation suitable for oral administration. The pharmaceutical preparation can be orally administered in the form of powder, granules, tablets, capsules, syrup or suspension, and can be specifically in the form of tablets. In one embodiment, the pharmaceutical preparation can be formulated to coat the active ingredient or protect it from degradation in the stomach.

[0105] The present invention will be described in more detail below through examples, which are intended only to illustrate one or more embodiments and are not intended to limit the scope of the present invention. [Example]

[0106] Example 1 Synthesis of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr), a compound of formula (IV)

[0107] (1) Preparation of 4-chloro-3-nitropyridine

[0108] 50 g (0.356 mmol) of 4-hydroxy-nitropyridine was added to 50 mL (1 T) of DMF (dimethylformamide) and 450 mL (9 T) of ethyl acetate. 42.5 mL of phosphoryloxychloride (POCl3, 1.3 eq) was added, and the mixture was heated to reflux at 70-80 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to 40 °C and 200 mL of water was added to quench the reaction. The separated organic layer was washed with 200 mL of saturated sodium bicarbonate (NaHCO3) and 200 mL of brine, respectively. The combined organic layer was dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure to give 60 g of 4-chloro-3-nitropyridine as pale yellow crystalline solids.

[0109] (2) Preparation of methyl 2-((3-nitropyridin-4-yl)oxy)acetate

[0110] 60 g (0.356 mmol) of 4-chloro-3-nitropyridine obtained in step (1) above was dissolved in 300 mL (5 T) of DMF, 36 mL (1.3 eq) of methyl glycolate and 74 g (1.5 eq) of potassium carbonate (K2CO3) powder were added, and the mixture was heated and reacted at 70-80 °C for 1-2 hours. After the reaction was completed, the mixture was cooled to room temperature, and 150 mL of 10% HCl was added to dissolve and neutralize the mixture, followed by extraction with 500 mL of ethyl acetate. The resulting organic layer was washed with 150 mL of brine, concentrated under reduced pressure, and dried in vacuo to obtain 62 g (82%) of methyl 2-((3-nitropyridin-4-yl)oxy)acetate as a light brown solid.

[0111] (3) Preparation of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0112] 62 g (0.291 mmol) of methyl 2-((3-nitropyridin-4-yl)oxy)acetate obtained in step (2) above was dissolved in 480 mL of acetonitrile (ACN) and 120 mL of water (HO), and 16 g (1.0 eq) of ammonium chloride (NHCl) and 33 g (2.0 eq) of iron (Fe) powder were added. The mixture was heated and reacted at 70-80°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, 30 mL of concentrated hydrochloric acid was added, and the mixture was stirred for 30 minutes. The reaction solution was filtered to remove insoluble matter. The resulting reaction solution was concentrated until a solid was obtained. The concentrate was added to methanol, stirred, and filtered to obtain 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one hydrochloride. After dissolving in water, the mixture was neutralized (pH 6-7) with 10% sodium hydroxide (NaOH), and the resulting solid was filtered and dried to obtain 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0113] 1 H-NMR(300MHz, MeOD-d): δ = 8.06(m, 2H), 6.97(s, 1H), 4.72(s, 2H)

[0114] (4) Preparation of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine

[0115] 38 g (0.251 mmol) of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one obtained in step (3) was added to 570 mL of tetrahydrofuran (THF) (15 T), and the reaction mixture was cooled to 0°C. 15 g (1.5 eq) of lithium aluminum hydride (LiAlH4, LAH) was added several times, and the reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was completed, the mixture was cooled to 0°C, 40 mL of H2O was added dropwise slowly, and the mixture was stirred for 10 minutes. 80 mL of 5% NaOH solution was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered to remove insoluble Al(OH)3. The filtrate was neutralized (pH 7) with 10% HCl, extracted with ethyl acetate, washed with brine, and the organic layer was dried over sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to give 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (30 g, 90%).

[0116] (5) Preparation of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr)

[0117] 100 g (0.666 mol) of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one was stirred in 570 mL of THF (15 T) and the reaction mixture was cooled to 0 °C. 38 g (0.999 mol, 1.5 eq) of lithium aluminum hydride (LiAlH, LAH) was added in portions, and the reaction mixture was heated to room temperature and stirred for 2 h. After completion of the reaction, the mixture was cooled to 0 °C, quenched, filtered, concentrated, stirred with methylene chloride (MC), and filtered. The MC used was 1000 mL (10 v / w) of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one. To the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine / MC solution, 294 g (210 mL) of 33% acetic acid solution containing 1.8 equivalents (1.199 mmol relative to 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one) of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one was added. KasuiTo the resulting solution, benzoic acid (d, 1.40 g / mL) was added dropwise at 20-30°C for 20-30 minutes. The resulting crystalline solution was stirred at room temperature for 1 hour, cooled to 5-10°C, and further stirred for 30 minutes. The crystalline solution was filtered, washed with 300-500 mL of MC, and vacuum dried at room temperature for 5 hours to obtain 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr), a compound of formula (IV) below, in a 95% yield: [ka]

[0118] The NMR data of the compound is shown in FIG. 1, and the thermogravimetric analysis (TG) / differential thermal analysis (DTA) results are shown in FIG.

[0119] Example 2 Synthesis of the compound of formula (I), (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone

[0120] At 25-30°C, 1 L of tetrahydrofuran (THF) was added to a reactor, followed by 139 g (0.470 mol) of 3,5-dibromo-4-hydroxybenzoic acid and 278 g (1.27 mol) of di-tert-butyl dicarbonate. 125 g (1.58 mol) of pyridine was added under a nitrogen atmosphere, and the reaction mixture was stirred at 25-30°C for 2 hours to obtain a reaction mixture containing 3,5-dibromo-4-tert-butoxycarbonyloxybenzoic acid and 3,5-dibromo-4-((tert-butoxycarbonyl)oxy)benzoic acid (tert-butylcarbonyl) anhydride.

[0121] To the reaction mixture, 170 g (1.68 mol) of triethylamine was added at 25 to 30°C, and 100 g of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) prepared in Example 1 was added. The reaction mixture was stirred at 25 to 30°C for 6 hours. The formed salt was removed, and the filtrate was collected and concentrated at 25 to 30°C to obtain tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate.

[0122] 500 mL of isopropyl alcohol was added to a reactor containing tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate at 25-30°C, and 500 mL of concentrated hydrochloric acid was slowly added at 45°C or below. The reaction solution was cooled to 25-30°C and stirred for 1-2 hours. 3 L of isopropyl alcohol was added to the reaction solution at 25-30°C, and after further stirring for 1 hour, the reaction solution was cooled to 20-25°C. The resulting crystals were filtered and dried to obtain (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone hydrochloride.

[0123] Water was added to a clean reactor, and the (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)methanone hydrochloride obtained above was added to the reactor at 25-30°C. The reaction mixture was stirred at 25-30°C for 15 minutes. 100 mL of 4N aqueous sodium hydroxide solution was slowly added at 25-30°C until the pH reached 10.0. The reaction mixture was filtered and the filtrate was collected. Ethyl acetate was added to the reactor, and the mixture was stirred to separate the aqueous layer. 10% aqueous hydrochloric acid was added at 20-25°C until the pH reached 6.4-6.7. The resulting crystals were filtered to obtain the compound of formula (I), (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (yield 60%, purity 98.0% or more). The NMR data of the compound is shown in Figure 3.

[0124] Example 3 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate

[0125] 83 g of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone prepared in Example 2 was added to a reactor at 25°C, and 584 mL of acetic acid was immediately added at the same temperature. 83 mL of water was then added to the reactor. 111 mL of 2 M aqueous hydrochloric acid was added to the reactor at 25°C, and 688 mL of acetone was added to the reaction solution to form crystals. The resulting crystals were filtered and dried under vacuum for 12 hours to obtain (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate (yield 90%, purity 99.9%).

[0126] The powder X-ray diffraction (XRD) analysis results of the obtained (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate are shown in Figure 4. As shown in Figure 4, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate showed characteristic peaks at the following 2θ positions:

[0127] 6.89±0.5°, 10.84±0.5°, 11.48±0.5°, 13.73±0.5°, 15.85±0.5°, 17.61±0.5°, 18.51±0.5°, 19.98±0.5°, 21.42±0.5°, 22.99±0.5°, 23.27±0.5°, 24.11±0.5°, 24.76±0.5°, 27.37±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°

[0128] Experimental Example 1 Stability of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr)

[0129] A stability comparison experiment was conducted between the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) of the present invention prepared in Example 1 and other salts prepared by the same method. 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine phosphate was obtained in a gel form rather than a solid form. 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrochloride was also unstable in a semi-solid form. The solid substances obtained were 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine HBr salt (2HBr) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate.

[0130] As shown in Table 1 below, in the case of the sulfate salt form, not only was the purity of the obtained substance lower than that of the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine free base form, but the phenomenon of the solid melting back into a liquid occurred during the stability test. On the other hand, in the case of the HBr salt form, not only was the purity improved compared to the free base form, but also no significant change was observed in the purity at the start of the 4-week stability test.

[0131] [Table 1]

[0132] In addition, NMR was measured for the HBr salt form, sulfate salt form, and free base form, and thermogravimetric analysis (TG) and differential thermal analysis (DTA) were also performed.

[0133] The NMR data of the HBr salt (2HBr) is shown in FIG. 1, and the thermogravimetry (TG) / differential thermal analysis (DTA) results are shown in FIG.

[0134] The NMR data of the sulfate salt is shown in FIG. 5, and the TG / DTA results are shown in FIG.

[0135] The NMR data of the free base is shown in FIG. 7, and the TG / DTA results are shown in FIG.

[0136] Experimental Example 2 Stability of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate

[0137] The (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate of the present invention prepared in Example 3 and the non-solvated hydrochloride of the same compound were subjected to powder X-ray diffraction (XRD) analysis, TG / DTA, and water adsorption isotherm analysis, and the results are shown in Figures 9 to 11.

[0138] Specifically, the results of powder X-ray diffraction (XRD) analysis of the non-solvate (a) and the sesquihydrate (b) are shown in FIG.

[0139] The results of TG / DAT of the non-solvate (a) and the 1.5 hydrate (b) are shown in FIG.

[0140] The moisture adsorption isotherms of the non-solvate (a) and the sesquihydrate (b) are shown in FIG.

[0141] Furthermore, the physical stability to processing factors during production of the 1.5 hydrate and the non-solvate was compared, and the results are shown in Table 2 below.

[0142] [Table 2] *: The sample was ground using a mortar for approximately 2 minutes. **: After adding 30% v / w solvent, the sample was granulated using a mortar for approximately 2 minutes. The granulated sample was stored in a sealed vial for approximately 1 hour, and then the sample was dried at 50°C for approximately 3 hours. ***: Samples were compressed using a 7 mm thick punch at a pressure of 2 tons for 5 seconds. ****: Crystallinity was evaluated using a powder X-ray diffractometer.

[0143] As shown in Table 2, a comparison of the crystallinity changes during grinding and tableting revealed that the 1.5-hydrate was significantly more stable than the non-solvate. Furthermore, a comparison of the solid forms during granulation revealed that the non-solvate partially transformed into the 1.5-hydrate form, while the 1.5-hydrate showed no change. Therefore, it was found that the 1.5-hydrate exhibits superior physical stability to the non-solvate.

[0144] Experimental Example 3 Solubility of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate

[0145] The solubility of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate of the present invention, prepared in Example 3, and the nonsolvated hydrochloride salt of the same compound were compared. The test was conducted using 50 mL of FeSSIF (pH 5.0) as the medium, a paddle speed of 50 rpm, and an operating condition of 37°C. Solubility was measured using a physical mixture of 10 mg of the compound and 100 mg of lactose as the sample. The results are shown in Figure 12. It was found that the solubility of the nonsolvated hydrochloride sesquihydrate was approximately 125 μg / mL at 240 minutes, while the solubility of the nonsolvated form decreased to approximately 112.5 μg / mL.

[0146] Experimental Example 4 Comparative study of the effects of different doses of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone

[0147] A total of 60 gout patients were administered (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride pentacene hydrate of the present invention, prepared in Example 3. The active ingredient, (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (formula (I)), was orally administered at 0.25 mg (N=12), 0.5 mg (N=12), 1 mg (N=12), and 2 mg (N=12) of the compound, as well as a placebo (N=12), for 14 days, and the efficacy and safety of blood uric acid levels, etc., were evaluated in comparison with the placebo.

[0148] Blood uric acid levels were measured 15 days after administration, and the percentages of patients whose blood uric acid levels fell below <6.0 mg / dL and <5.0 mg / dL were determined and shown in Figure 13. As shown in Figure 13, when administered at doses of 0.25 mg, 0.5 mg, and 1 mg, no patients were observed whose blood uric acid levels fell below <5.0 mg / dL. Only at the 2 mg dose was this observed in only about 8% of patients. These results indicate that doses below 2 mg are not effective in treating diseases such as hyperuricemia and gout.

[0149] Furthermore, a total of 68 gout patients were administered (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride pentacene hydrate of the present invention. The active ingredient, (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (formula (I)), was orally administered at doses of 3 mg (N=13), 5 mg (N=14), 7 mg (N=15), and 10 mg (N=15) of the compound, as well as a placebo (N=11), for 14 days, and the efficacy and safety of blood uric acid levels, etc., were evaluated in comparison with placebo.

[0150] Blood uric acid levels were measured 15 days after administration, and the percentages of patients whose blood uric acid levels fell below <6.0 mg / dL and <5.0 mg / dL were determined and shown in Figure 14. As shown in Figure 14, when administered at doses of 3 mg, 5 mg, 7 mg, and 10 mg, the percentages of patients whose blood uric acid levels fell below <5.0 mg / dL were approximately 23%, approximately 64%, approximately 80%, and approximately 73%, respectively, ranging from approximately 23% to approximately 80%. Patients whose blood uric acid levels fell below <6.0 mg / dL were also observed at all experimental doses.

[0151] The results of the above experiments showed that significant effects were observed at doses above 2 mg, which is the lower end of the dose range for the administration regimen of the present invention.

[0152] Experimental Example 5 Examination of side effects at various doses of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone

[0153] A total of 76 gout patients were administered (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride sesquihydrate of the present invention, prepared in Example 3. The active ingredient, (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (Formula (I)), was orally administered at doses of 3 mg (N=14), 5 mg (N=15), 7 mg (N=17), and 10 mg (N=17), as well as a placebo (N=13), for 14 days, and adverse drug reactions were investigated. As a result, as shown in Table 3 below, the administration regimen did not result in any adverse events, such as joint pain and joint swelling, or the incidence of such events was extremely low.

[0154] [Table 3]

[0155] The urinary creatinine concentrations of the same patients were also measured. The number of cases in which creatinine levels increased by 0.3 mg / dL or more or 1.5 times or more compared to baseline is shown in Table 4 below.

[0156] [Table 4]

[0157] As shown in Table 4, only one case was observed in both the placebo group and the 5 mg dose group, but three cases were observed in the maximum dose group of 10 mg. From these results, it can be inferred that the risk of an increase in urinary creatinine concentration increases when the dose exceeds the maximum dose of 10 mg. The present invention includes the following aspects and embodiments. [1] A step of coupling a compound represented by the following formula (III) with a compound represented by the following formula (IV): [ka] wherein R is hydrogen or tert-butyloxycarbonyl (Boc). A method for producing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising: [2] The compound of formula (III) is obtained by reacting a compound of formula (II) with di-tert-butyl dicarbonate and pyridine: [ka] The method according to [1], characterized in that the compound is obtained by the following steps. [3] (1) reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V): (2) reacting the compound of formula (V) with an alcohol in the presence of an acid to obtain a salt of a compound of formula (I): (3) reacting a salt of a compound of formula (I) first with a base and then with an acid: [ka] The manufacturing method according to [1], characterized in that it comprises: [4] The production method according to [3], wherein the steps (1) and (2) are carried out as in situ reactions. [5] The compound of formula (III) is obtained by reacting a compound of formula (II) with di-tert-butyl dicarbonate and pyridine: [ka] is obtained by The manufacturing method according to [3], characterized in that the steps (1) and (2) are carried out as in situ reactions. [6] The method according to [1], wherein the compound of formula (IV) is obtained by reacting 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine with hydrobromic acid in acetic acid. [7] The following formula (III)

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[10] The pharmaceutical composition according to [9], characterized in that the administration dose is 3 mg to 8 mg.

[11] The pharmaceutical composition according to [9], wherein the active ingredient is the hydrochloride salt of the compound of formula (I) or a 1.5-hydrate thereof.

[12] [9] A hydrochloride 1.5 hydrate of the compound of formula (I) described in [9].

[13] Powder X-ray diffraction (XRD) analysis showed the following: 11.48±0.5°、24.11±0.5°、24.76±0.5°、27.99±0.5°、31.43±0.5°、34.20±0.5° The hydrochloride 1.5 hydrate of the compound of formula (I) according to

[12] , characterized by exhibiting a characteristic peak at the 2θ position.

[14] the below described 6.89±0.5°、17.61±0.5°、21.42±0.5°、23.27±0.5° The hydrochloride 1.5 hydrate of the compound of formula (I) according to

[13] , further exhibiting a characteristic peak at the 2θ position of

[15] The following formula (I)

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[16] A pharmaceutical composition formulated for oral administration, comprising the hydrochloride pentaceous hydrate of the compound of formula (I) according to any one of

[12] to

[14] .

[17] The pharmaceutical composition according to

[16] , which is in tablet form.

Claims

1. The following formula (I) 【Chemistry 1】 wherein the crystals show the following in powder X-ray diffraction (XRD) analysis: １１．４８±０．５°、２４．１１±０．５°、２４．７６±０．５°、２７．９９±０．５°、３１．４３±０．５°、３４．２０±０．５° 1. A crystalline hydrochloride 1.5 hydrate of the compound of formula (I), characterized by exhibiting a characteristic peak at the 2θ position of

2. Powder X-ray diffraction (XRD) analysis revealed the following: ６．８９±０．５°、１７．６１±０．５°、２１．４２±０．５°、２３．２７±０．５° 2. The hydrochloride 1.5 hydrate crystal of the compound of formula (I) according to claim 1, further showing a characteristic peak at the 2θ position of

3. The following formula (I) 【Chemistry 2】 with acetic acid, aqueous hydrochloric acid, and acetone to produce crystals, wherein the crystals exhibit the following properties in powder X-ray diffraction (XRD) analysis: １１．４８±０．５°、２４．１１±０．５°、２４．７６±０．５°、２７．９９±０．５°、３１．４３±０．５°、３４．２０±０．５° The production method is characterized in that the compound exhibits a characteristic peak at the 2θ position of

4. A pharmaceutical composition formulated for oral administration, comprising the hydrochloride sesquihydrate crystals of the compound of formula (I) according to claim 1 or 2.

5. 5. The pharmaceutical composition according to claim 4, which is in tablet form.

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