Process for preparation of heterocyclic derivative compounds, compositions containing said compounds, and hydrates of said compounds

Abstract

The invention relates to a novel preparation method of a heterocyclic derivative compound of a chemical formula I; a novel intermediate compound for use in the preparation process; a composition for treating or preventing hyperuricemia, gout disease, nephritis, chronic renal failure, kidney stone, uremia, lithangiuria or uric acid-related diseases, the composition comprising a compound of formula I in an administration dose of more than 2 mg to 10 mg or less, orally administered once a day; the invention also discloses a hydrochloride 1.5 hydrate of the novel compound of the chemical formula I.

Description

[0001] This application is a divisional application of a Chinese patent application filed on May 24, 2018, with Chinese patent application number 201880034458.5 and invention name “Method for preparing heterocyclic derivative compounds, compositions containing the compounds and hydrates of the compounds”, and this application claims priority to Korean application number 10-2017-0064914. Technical Field

[0002] The present invention relates to a novel preparation method of a heterocyclic derivative compound of the following chemical formula I; a novel intermediate compound used in the preparation method; a composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary tract stones or uric acid-related diseases, wherein the composition comprises the compound of chemical formula I in an administration dose of more than 2 mg to less than 10 mg and is orally administered once a day; and a novel hydrochloride 1.5 hydrate of the compound of chemical formula I.

[0003] Background Art

[0004] At present, the therapeutic agent or preventive agent of hyperuricemia and gout uses benzbromarone, which is a uricosuric agent with the effect of hindering the activity of human urate anion transporter 1 (hURAT1). In addition, agents such as probenecid and sulfinpyrazone are also used, but the activity of URAT1 is not sufficient enough. In particular, benzbromarone has several disadvantages in terms of side effects. Benzbromarone shows a strong inhibitory effect on the 2C9 protein in cytochrome P450 (CYP450) protein, so it has the possibility of causing drug-drug interaction, and there is also a report about generating reactive metabolites (reactive metabolites) by glutathione (GSH) adduct generation experiment (reference [Dermot F.McGinnity et al., Drug Metabolism and Disposition, 33, p1700-1707 (2005)]).

[0005] In addition, benzbromarone has the same drug structure as the hepatotoxic drugs benziodarone, benzarone and amiodarone, and is also a drug having a benzofuran skeleton, so it has the problem of side effects of reducing liver function and inducing hepatotoxicity and causing death. Therefore, patients who intend to take this drug must have their liver function checked before administration, and during treatment, it is recommended to confirm whether liver toxicity is induced within a certain period (6 months) while taking the drug. Therefore, drugs that improve the above problems are needed in the medical field (references [Hautekeete ML, et al., Liver, 15, p25-29 (1995)]; reference [Makoto Arai, et al., Journal of Gastroenterology and Hepatology 17, p625-626 (2002)]; reference [Saitama Medical University Journal, 30, 187-194 (2003)]; reference [Priska Kaufmann, et al., HEPATOLOGY, 41, p925-935 (2005)]).

[0006] International patent publication WO2009 / 145456 (C&C New Drug Research Institute) discloses the following heterocyclic derivative compound of [Chemical Formula I], and as a specific example of the compound, (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-yl)-methanone (Compound 4) is disclosed.

[0007] [Chemical formula I]

[0008]

[0009] International patent publication WO2009 / 145456 discloses that the heterocyclic derivative compound shows strong inhibitory activity on human urate anion transporter 1 (hURAT1) compared with conventional hURAT1 activity inhibitors, and can therefore be effectively used as a uric acid reuptake inhibitor, especially a selective inhibitor, has no drug-drug interaction with cytochrome P450 (CYP450), shows selectivity between organic anion transporters, and shows effective pharmacokinetic properties due to higher solubility and metabolic stability. Therefore, it shows superior effects to existing drugs in the treatment or prevention of the following diseases: hyperuricemia, acute gouty arthritis, chronic gouty arthritis, gouty nodules, gouty nephropathy, nephritis, chronic renal failure, kidney stones, uremia, urinary stones and complications reported to be accompanied by increased uric acid in the blood, such as hyperlipidemia, ischemic heart disease, myocardial infarction, arteriosclerosis, cerebral infarction, cerebrovascular disease, diabetes, hypertension, etc.

[0010] The above document records an experiment in which the heterocyclic derivative compound was orally administered to Cebus monkeys at 3.75 mg / kg, 7.5 mg / kg, and 15 mg / kg. Theoretically, these doses are about 15 to 60 mg when converted to dosage values ​​suitable for humans. At such high doses, the risk of side effects is very high.

[0011] In addition, in the case of the hydrochloride of the heterocyclic derivative compound, there are limitations in formulating it into an oral administration preparation by a wet granulation method due to hygroscopicity.

[0012] In addition, as a synthesis method of the heterocyclic derivative compound, the above document discloses the following preparation method of the heterocyclic derivative compound of Chemical Formula I, which comprises the following steps: (1) halogenating the compound of Chemical Formula VII to obtain the compound of Chemical Formula X, and then reacting the obtained compound of Chemical Formula X with the compound of Chemical Formula IX to obtain the compound of Chemical Formula VIII, or subjecting the compound of Chemical Formula VII to Mitsunobu reaction with the compound of Chemical Formula IX to obtain the compound of Chemical Formula VIII; (2) cyclizing the obtained compound of Chemical Formula VIII to obtain the compound of Chemical Formula IV; and (3) performing a peptide coupling reaction between the obtained compound of Chemical Formula IV and the compound of Chemical Formula III.

[0013]

[0014]

[0015] However, among the oxazine derivatives of [Chemical Formula IV] obtained as intermediates in the preparation method, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine having the following structure is liquid and unstable, and thus generates impurities with carcinogenicity or mutagenic potential during decomposition, requiring an additional purification process for these impurities, and is therefore not suitable for mass production.

[0016]

[0017] In addition, the starting material 3,5-dibromo-4-methoxybenzoic acid of 3,5-dibromo-4-methoxy-benzoyl chloride having the following structure as the compound of [Chemical Formula III] in the preparation method is expensive, and there is a possibility of inducing gene mutation during the synthesis of the compound of [Chemical Formula III] and the oxazine derivative of [Chemical Formula IV], so a process that can minimize this possibility is required.

[0018]

[0019] In addition, US Patent Publication No. US2007-0010670A1 (Japan Tabacco Inc.) discloses an oxazine derivative compound having the following structural formula, which is effective for treating hyperuricemia, gout, and the like, and a method for synthesizing the same.

[0020] Summary of the invention

[0021] Technical issues to be solved

[0022] In order to solve the following problems and disadvantages, namely, the problem that the oxazine derivatives obtained as intermediates in the existing preparation methods of heterocyclic derivative compounds of Chemical Formula I generate impurities with the possibility of carcinogenicity or inducing mutations when decomposed, the problem that the oxazine derivatives generate toxic intermediates that induce gene mutations when synthesized with 3,5-dibromo-4-methoxy-benzoyl chloride, and the disadvantage that an additional purification process is required to remove impurities in each step, so the preparation method needs to go through multiple steps and is not suitable for mass production. The object of the present invention is to provide a new preparation method for heterocyclic derivative compounds of Chemical Formula I, characterized in that a new oxazine derivative hydrobromide (dihydrobromide, 2HBr) in a stable form of the oxazine derivative and a new benzoic acid intermediate are used, and the new benzoic acid intermediate does not generate toxic substances and can undergo in situ reactions to reduce the preparation steps, and is therefore suitable for mass production.

[0023] In addition, the present invention aims to provide novel intermediate compounds used in the preparation method.

[0024] In addition, the present invention aims to provide a composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, which comprises the compound of Chemical Formula I, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient at an administration dose of more than 2 mg to less than 10 mg based on the free base of the compound of Chemical Formula I, and is orally administered once a day.

[0025] In addition, the present invention aims to provide a novel hydrochloride 1.5 hydrate of the compound of formula I.

[0026] Technical Solution

[0027] The present invention provides a method for preparing a compound of chemical formula I, a pharmaceutically acceptable salt thereof or a hydrate thereof, comprising the step of coupling a compound of the following chemical formula III with a compound of the following chemical formula IV.

[0028]

[0029] In the formula, R is hydrogen or tert-butyloxycarbonyl (Boc).

[0030] In a specific embodiment of the present invention, the compound of the chemical formula III can be obtained by reacting the compound of the following chemical formula II with di-tert-butyl dicarbonate and pyridine.

[0031]

[0032] In a specific embodiment of the present invention, the method for preparing the compound of formula I may include the following steps:

[0033] (1) reacting a compound of formula III with a compound of formula IV to obtain a compound of formula V;

[0034] (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; and

[0035] (3) The salt of the compound of formula I is reacted with a base for the first time and with an acid for the second time.

[0036]

[0037] In one embodiment of the present invention, step (1) and step (2) can be performed as an in situ reaction.

[0038] In a specific embodiment of the present invention, the step of obtaining the compound of Chemical Formula III from the compound of Chemical Formula II, the step (1) and the step (2) can be carried out as an in situ reaction.

[0039] In a specific embodiment of the present invention, the compound of formula IV can be obtained by reacting 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine with bromic acid in acetic acid.

[0040] In addition, the present invention provides an intermediate compound of the following chemical formula III.

[0041]

[0042] In the formula, R is hydrogen or Boc.

[0043] In addition, the present invention provides an intermediate compound of the following chemical formula IV.

[0044]

[0045] In addition, the present invention provides a pharmaceutical composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, which is based on the free base of the compound of Chemical Formula I, contains the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate as an active ingredient at an administration dose of more than 2 mg to less than 10 mg, and is orally administered once a day.

[0046] In addition, the present invention provides the use of the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate in the treatment or prevention of hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, wherein the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate is orally administered once a day at a dosage of more than 2 mg to less than 10 mg based on the free base of the compound of Chemical Formula I.

[0047] In addition, the present invention provides a method for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary tract stones or uric acid-related diseases in a subject, comprising: orally administering the compound of Chemical Formula I, a pharmaceutically acceptable salt thereof or a hydrate thereof to the subject once a day at an administration dose of more than 2 mg to less than 10 mg, based on the free base of the compound of Chemical Formula I.

[0048] In a specific embodiment of the present invention, the dosage of the compound of Formula I can be 3 to 8 mg based on the free base.

[0049] In a specific embodiment of the present invention, the compound of Formula I may be the hydrochloride salt or 1.5 hydrate form of the compound of Formula I.

[0050] In addition, the present invention provides the hydrochloride 1.5 hydrate of the compound of formula I.

[0051] In one specific embodiment of the present invention, the hydrochloride 1.5 hydrate of the compound of Formula I shows characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis:

[0052] 11.48±0.5°, 24.11±0.5°, 24.76±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°.

[0053] In a specific embodiment of the present invention, the hydrochloride 1.5 hydrate of the compound of Formula I further shows characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis:

[0054] 6.89±0.5°, 17.61±0.5°, 21.42±0.5°, 23.27±0.5°.

[0055] In addition, the present invention provides a method for preparing a hydrochloride 1.5 hydrate of a compound of formula I, comprising the step of reacting the compound of formula I with acetic acid, aqueous hydrochloric acid solution and acetone to form crystals.

[0056] In addition, the present invention provides a pharmaceutical composition formulated as an oral administration preparation, which comprises a hydrochloride 1.5 hydrate of the compound of Chemical Formula I.

[0057] In a specific embodiment of the present invention, the pharmaceutical composition may be in the form of a tablet.

[0058] Beneficial Effects

[0059] In the preparation method of the heterocyclic derivative compound of Chemical Formula I of the present invention, the stable hydrobromide (2HBr) form of the oxazine derivative is used to replace the oxazine derivative, thereby solving the problem of generating impurities with the possibility of carcinogenicity or inducing mutations, and the new benzoic acid intermediate is used to replace 3,5-dibromo-4-methoxy-benzoyl chloride, thereby solving the problem of generating toxic intermediates that induce gene mutations. Therefore, there is no need for additional purification processes for removing impurities in each step, and the method has the advantage of being suitable for mass production through in situ reaction.

[0060] In addition, the dosage regimen of orally administering the compound of Chemical Formula I of the present invention once a day at an administration dose of more than 2 mg to less than 10 mg shows significantly excellent effects in the treatment or prevention of hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, and minimizes the possibility of side effects.

[0061] In addition, the existing hydrochloride salt of the compound of Chemical Formula I has problems in formulation into oral preparations by a wet granulation method due to its hygroscopicity, but the hydrochloride 1.5 hydrate of the compound of Chemical Formula I of the present invention solves this problem and shows stability suitable for oral dosage forms (especially, tablets). BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 NMR data of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of the present invention prepared in Example 1 are shown.

[0063] Figure 2 Thermogravimetric (TG) / differential thermal analysis (DTA) results of the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of the present invention prepared in Example 1 are shown.

[0064] Figure 3 The NMR data of the compound of Chemical Formula I of the present invention prepared in Example 2 are shown.

[0065] Figure 4 The results of powder X-ray diffraction (XRD) analysis of the hydrochloride 1.5 hydrate of the compound of Chemical Formula I prepared in Example 3 are shown.

[0066] Figure 5 NMR data for 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate is shown.

[0067] Figure 6 Shown are the TG / DTA results for 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate.

[0068] Figure 7 NMR data for the free base form of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine is shown.

[0069] Figure 8 TG / DTA results are shown for the free base form of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine.

[0070] Fig. 9 The results of powder X-ray diffraction (XRD) analysis of the hydrochloride ansolvate (a) of the compound of Formula I and the hydrochloride 1.5 hydrate (b) of the compound of Formula I of the present invention are shown.

[0071] Fig.10The TG / DTA results of the hydrochloride ansolvate (a) of the compound of Formula I and the hydrochloride 1.5 hydrate (b) of the compound of Formula I of the present invention are shown.

[0072] Fig.11 The water sorption isotherms of the hydrochloride ansolvate (a) of the compound of Formula I and the hydrochloride 1.5 hydrate (b) of the compound of Formula I of the present invention are shown.

[0073] Fig.12 This is a graph showing the solubility comparison between the hydrochloride 1.5 hydrate of the compound of Formula I of the present invention and the hydrochloride ansolvate of the same compound.

[0074] Fig.13 It is a graph showing the proportion (%) of patients whose blood uric acid levels are reduced to less than 5.0 mg / dL when the compound of Chemical Formula I of the present invention is administered at low doses (0.25 mg, 0.5 mg, 1 mg) and when administered at 2 mg (right column) and the proportion (%) of patients whose blood uric acid levels are reduced to less than 6.0 mg / dL (left column).

[0075] Fig.14 It is a graph showing the proportion (%) of patients whose blood uric acid levels are reduced to less than 5.0 mg / dL (right column) and the proportion (%) of patients whose blood uric acid levels are reduced to less than 6.0 mg / dL (left column) when the compound of Chemical Formula I of the present invention is administered within the dosage range (3 mg, 5 mg, 7 mg, 10 mg). DETAILED DESCRIPTION

[0076] Hereinafter, the present invention will be described in more detail.

[0077] Preparation method of the compound of formula I, its salt or hydrate

[0078] The present invention relates to a method for preparing a compound of chemical formula I, a pharmaceutically acceptable salt thereof or a hydrate thereof, comprising the step of coupling a compound of the following chemical formula III with a compound of the following chemical formula IV.

[0079] [Reaction formula 1]

[0080]

[0081] In the formula, R is hydrogen or Boc.

[0082] Specifically, a base is added to the compound of chemical formula III, and a coupling reaction is carried out with the compound of chemical formula IV, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr). The obtained intermediate compound is post-treated to obtain the compound of chemical formula I (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazine-4-yl)-methanone or a pharmaceutically acceptable salt thereof.

[0083] In a specific embodiment of the present invention, the compound of the chemical formula III can be obtained by reacting the compound of the following chemical formula II with di-tert-butyl dicarbonate and pyridine.

[0084] [Reaction 2]

[0085]

[0086] Specifically, a solvent may be added to a reactor, and 3,5-dibromo-4-hydroxybenzoic acid of Chemical Formula II is added, and then di-tert-butyl dicarbonate and pyridine are added to react, thereby obtaining the compound of Chemical Formula III.

[0087] The compound 3,5-dibromo-4-hydroxybenzoic acid of the chemical formula II used as a low-cost starting material can be prepared by referring to a known method, or can be commercially purchased from a reagent company.

[0088] The solvent can generally use a conventional solvent that does not adversely affect the reaction. Examples of preferred solvents include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme, hydrocarbon solvents such as benzene, toluene, hexane, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, alcohol solvents such as methanol, ethanol, isopropanol, and tert-butanol, ester solvents such as ethyl acetate, methyl acetate, and butyl acetate, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, and other polar solvents. A mixed solvent of two of these solvents can also be used. In this reaction, tetrahydrofuran is preferably used.

[0089] Specifically, tetrahydrofuran (THF) can be added to the reactor, and the compound of chemical formula II, 3,5-dibromo-4-hydroxybenzoic acid, is added, and then di-tert-butyl dicarbonate is added, and pyridine is added under a nitrogen atmosphere to react to obtain the compound of chemical formula III. At this time, the reaction can be stirred at a temperature of 25 to 30° C. for about 1 to 3 hours.

[0090] The generated compound of chemical formula III is a new benzoic acid intermediate compound. Therefore, the present invention also includes the compound of the following chemical formula III.

[0091]

[0092] In the formula, R is hydrogen or Boc.

[0093] The preparation method of the compound of formula I of the present invention may comprise the following steps:

[0094] (1) reacting a compound of formula III with a compound of formula IV to obtain a compound of formula V;

[0095] (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; and

[0096] (3) The salt of the compound of formula I is reacted with a base for the first time and with an acid for the second time.

[0097] [Reaction 3]

[0098]

[0099] In the formula, R is hydrogen or Boc.

[0100] In a specific embodiment of the present invention, the step (1) may further include a step of reacting the compound of formula II with di-tert-butyl dicarbonate and pyridine. The preparation method of the compound of formula I may be represented by the following reaction formula.

[0101] [Reaction 4]

[0102]

[0103] In the formula, R is hydrogen or Boc.

[0104] In one embodiment of the present invention, step (1) and step (2) can be performed as an in situ reaction.

[0105] In a specific embodiment of the present invention, the step of obtaining the compound of Chemical Formula III from the compound of Chemical Formula II, the step (1) and the step (2) can be carried out as an in situ reaction.

[0106] "In situ reaction" refers to a continuous chemical reaction in one reactor, also known as "one-pot reaction". In situ reaction can immediately carry out the next reaction without the need for separation and purification of intermediate compounds, so it is very economical and suitable for mass production.

[0107] The preparation method will be described in more detail below.

[0108] (1) reacting a compound of formula III with a compound of formula IV to obtain a compound of formula V

[0109] A base is added to the compound of Chemical Formula III, and the mixture is reacted with the compound of Chemical Formula IV, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr).

[0110] The base used in the reaction can be listed as triethylamine, pyridine, 4-methylaminopyridine, 4-methylmorpholine, piperazine, N-methylpiperazine and other organic bases, or lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and other alkali metal hydroxides, or sodium hydride, potassium hydride and other alkali metal hydrides, or sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, or sodium bicarbonate, potassium bicarbonate and other alkali metal bicarbonates, and potassium phosphate. In this reaction, triethylamine is preferably used.

[0111] Specifically, triethylamine is added to the reaction solution, and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of chemical formula IV is added to the reaction solution, and the reaction solution is stirred at a temperature of 25 to 30° C. for about 5 to 7 hours. The formed salt is removed and the filtrate is collected, and then the filtrate is concentrated at a temperature of 25 to 30° C. to obtain the compound of chemical formula V, tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate.

[0112] (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

[0113] Alcohol is added to a reactor containing the compound of chemical formula V, tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, and the reaction is carried out in the presence of an acid to obtain a salt of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone.

[0114] The acid used in the reaction can be listed 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 or 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 naphthalenesulfonic acid. Preferably, hydrochloric acid is used in this reaction.

[0115] Examples of the alcohol used in the reaction include methanol, ethanol, isopropanol, tert-butanol, and the like. In the present reaction, isopropanol is preferably used.

[0116] More specifically, isopropanol is added to a reactor containing the compound of formula V, tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, at a temperature of 25 to 30°C, and concentrated hydrochloric acid is slowly added at a temperature below 45°C, and then the reaction solution is cooled to 25 to 30°C and stirred for about 1 to 2 hours. At 25 to 30°C, isopropanol is added to the reaction solution, stirred for about 1 hour, and then the reaction solution is cooled to 20 to 25°C. The generated crystals are 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.

[0117] (3) reacting the salt of the compound of formula I with a base for the first time and with an acid for the second time to obtain the compound of formula I

[0118] Add water to a clean reactor, and add a salt of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone to the reactor, then react with a base and an acid in sequence, filter the generated crystals, and obtain the compound of chemical formula I (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone.

[0119] The base used in the reaction can be listed as triethylamine, pyridine, 4-methylaminopyridine, 4-methylmorpholine, piperazine, N-methylpiperazine and other organic bases, or lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and other alkali metal hydroxides, or sodium hydride, potassium hydride and other alkali metal hydrides, or sodium carbonate, potassium carbonate, cesium carbonate and other alkali metal carbonates, or sodium bicarbonate, potassium bicarbonate and other alkali metal bicarbonates, and potassium phosphate. In this reaction, sodium hydroxide is preferably used.

[0120] The acid used in the reaction can be listed 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 or 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 naphthalenesulfonic acid. Preferably, hydrochloric acid is used in this reaction.

[0121] More specifically, water is added to a clean reactor, and (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride obtained in step (2) is added to the reactor at 25-30°C, and then the reaction solution is stirred at 25-30°C for about 15 minutes. An aqueous sodium hydroxide solution is slowly added at 25-30°C until the pH reaches 10.0, and then the reaction solution is filtered and the filtrate is collected. Ethyl acetate is added to the reactor and stirred to separate the water layer, and an aqueous hydrochloric acid solution is added at 20-25°C until the pH reaches 6.4-6.7. The generated crystals are 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.

[0122] The preparation method of the compound of the above-described chemical formula I is described in more detail in the examples described below.

[0123] Preparation method of compound of formula IV

[0124] In a specific embodiment of the present invention, the compound of formula IV can be prepared by a preparation method comprising the step of reacting 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine with bromic acid in acetic acid.

[0125] In another specific embodiment of the present invention, the compound of formula IV can be prepared by the following steps.

[0126] [Reaction 5]

[0127]

[0128] Specifically, the preparation method is as follows.

[0129] (1) Phosphorus oxychloride is added to 4-hydroxy-nitropyridine to obtain 4-chloro-3-nitropyridine.

[0130] (2) Methyl glycolate and potassium carbonate are added to 4-chloro-3-nitropyridine to obtain methyl 2-((3-nitropyridin-4-yl)oxy)acetate.

[0131] (3) Ammonium chloride (NH4Cl) and iron (Fe) are added to methyl 2-((3-nitropyridin-4-yl)oxy)acetate to obtain 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0132] (4) Lithium aluminum hydride (LiAlH4, LAH) is added to 2H-pyrido[4,3-b][1,4]oxazine-3(4H)-one to obtain 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine.

[0133] (5) Adding bromic acid in acetic acid to 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine, finally obtaining the compound 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of formula IV.

[0134] Therefore, the present invention also includes novel intermediate compounds of the following chemical formula IV.

[0135]

[0136] The method for preparing the intermediate compound of the above-described chemical formula IV will be described in more detail in the examples described below.

[0137] Use of the compounds of formula I

[0138] In addition, the present invention relates to a pharmaceutical composition for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, which is based on the free base of the compound of Chemical Formula I, contains the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate as an active ingredient at an administration dose of more than 2 mg to less than 10 mg, and is orally administered once a day.

[0139] In addition, the present invention relates to the use of the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate in the treatment or prevention of hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases, wherein the compound of Chemical Formula I, its pharmaceutically acceptable salt or its hydrate is orally administered once a day at a dosage of more than 2 mg to less than 10 mg based on the free base of the compound of Chemical Formula I.

[0140] In addition, the present invention relates to a method for treating or preventing hyperuricemia, gout, nephritis, chronic renal failure, kidney stones, uremia, urinary stones or uric acid-related diseases in a subject, comprising: orally administering the compound of Chemical Formula I, a pharmaceutically acceptable salt thereof or a hydrate thereof to the subject once a day at a dosage of more than 2 mg to less than 10 mg, based on the free base of the compound of Chemical Formula I.

[0141] In a specific 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 thereof.

[0142] Such pharmaceutically acceptable salts include acid addition salts formed by acids, wherein the acid forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, wherein the acid is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, organic carboxylic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, and also includes salts with alkali metals such as sodium and potassium. In addition, salts with other acids or bases known and used in the technical field to which aromatic amidine derivatives or lactam derivatives belong may also be included. In addition, the hydrate form may include hemihydrate, monohydrate, 1.5 hydrate, dihydrate, trihydrate, etc.

[0143] Specifically, the pharmaceutically acceptable salt may be a hydrochloride, and the hydrate may be a 1.5 hydrate form.

[0144] Hyperuricemia, in which uric acid in the blood is increased, refers to a state in which the uric acid level is higher than normal (7-8 mg / dl for men and 6 mg / dl for women) when the uric acid excretion rate in the kidneys is reduced or the uric acid synthesis is increased. Gout disease refers to a disease in which uric acid crystals are deposited in soft tissues such as joints and ligaments in patients whose blood uric acid level is significantly higher than normal (7-8 mg / dl for men and 6 mg / dl for women) due to excessive production of uric acid or reduced excretion of uric acid. When the needle-shaped uric acid crystals pierce the muscles around the joints, the body's immune organs attack the uric acid crystals, causing paroxysmal and inflammatory arthritis with severe pain and swelling around the joints. The deposition of uric acid crystals mainly occurs in the metatarsophalangeal joint of the big toe and, in rare cases, in the lumbar spine (reference [Vervaeck M., et al., Clinical Neurology and Neurosurgery, 93, p233-236 (1991)]).

[0145] Gout is a risk factor because, in addition to causing arthritis, it is likely to cause complications of various metabolic diseases such as diabetes, hypertension, heart disease, obesity, kidney stones, urinary stones, etc., and the incidence mainly occurs in male patients aged 40 to 50, and the incidence of female patients increases after menopause. In addition, the frequency of gout is high in obese people and those who exercise vigorously.

[0146] Long-term neglect of hyperuricemia is closely related to the incidence of gout. According to reports, when the uric acid level in the body is above 9 mg / dl, the incidence of gout is 4.9%, when the uric acid level is 7.0-8.9 mg / dl, the incidence of gout is 0.5%, when the uric acid level is below 7.0 mg / dl, the incidence of gout is 0.1%, and the cumulative incidence of gout in patients with uric acid levels above 9 mg / dl within five years is about 22% (reference [Campion EW et al., Am. J. Med., 82, p421-426 (1987)]).

[0147] In order to treat patients with severe gout, reducing the serum uric acid level to less than 6.0 mg / dL, more preferably to less than 5.0 mg / dL is clinically significant. The compound of the chemical formula I of the present invention, its pharmaceutically acceptable salt or its hydrate is administered orally once a day at a dosage of more than 2 mg to less than 10 mg based on the free base of the compound of the chemical formula I has a significant effect in reducing the serum uric acid level of the patient to less than 5.0 mg / dL.

[0148] Specifically, as confirmed in Experimental Example 4 described later, when 3 mg, 5 mg, 7 mg and 10 mg were administered according to the usage of the present invention, the percentages of patients whose blood uric acid levels were reduced to less than 5.0 mg / dL were approximately 23%, 64%, 80% and 73%, respectively. Fig.14 On the other hand, when the same compound was administered at doses of 0.25 mg, 0.5 mg, and 1 mg, no patient was observed to have a blood uric acid level lowered to less than 5.0 mg / dL, and only about 8% of patients were observed at a dose of 2 mg (reference Fig.13 ). It can be seen from the above experimental results that when the dosage exceeds the lower limit of 2 mg of the dosage range of the present invention, a significant effect is produced.

[0149] In addition, the compound of Chemical Formula I of the present invention is orally administered once a day at a dosage of more than 2 mg to less than 10 mg, showing a strong inhibitory activity on human urate anion transporter 1 (hURAT1), and is effective in treating or preventing the following diseases: hyperuricemia, such as gout diseases such as acute gouty arthritis, chronic gouty arthritis, gouty nodules, gouty nephropathy, nephritis, chronic renal failure, kidney stones, uremia, urinary stones and uric acid-related diseases such as hyperlipidemia, ischemic heart disease, myocardial infarction, cerebral infarction, cerebrovascular disease, diabetes, hypertension, etc.

[0150] In a specific embodiment of the present invention, the dosage of the compound of Formula I is administered orally once a day, and varies in the range of more than 2 mg to less than 10 mg according to the patient's disease, state, age, weight and administration form. Specifically, it can be administered orally once a day at a dosage of 3 to 8 mg, and more specifically, it can be administered orally once a day at a dosage of 3 to 6 mg. The dosage range is based on the free base form of the compound of Formula I as the active ingredient, and can be administered in the form of the hydrochloride of the compound of Formula I or its 1.5 hydrate. Specifically, when the hydrochloride 1.5 hydrate form of the compound of Formula I is administered, the dosage can be more than 2.3 mg to less than 11.5 mg.

[0151] When the dosage is below 2 mg, it cannot show sufficient effect on the treatment of the disease. When the dosage is 10 mg, it has shown the maximum effect. When the dosage is above 10 mg, although it has the effect of reducing uric acid concentration, it causes arthralgia (Arthralgia), joint swelling (joint swelling), etc. during the treatment process, making the patient receiving the treatment feel painful, and other side effects may occur. This side effect has an increase in the numerical value of creatinine, etc., and the increase in the numerical value of creatinine can especially cause fatal diseases to the kidney. As confirmed in Experimental Example 5 described later, when the maximum dosage of 10 mg of the usage of the present invention is exceeded, it can be inferred that the incidence of adverse events such as arthralgia, joint swelling and the risk of increased concentration of creatinine in urine are high.

[0152] The subject of the use of the present invention is an animal, preferably a mammal, and most preferably a human.

[0153] The hydrochloride 1.5 hydrate of the compound of formula I

[0154] In addition, the present invention relates to the hydrochloride 1.5 hydrate of the compound of formula I.

[0155] In addition, the present invention provides a method for preparing a hydrochloride 1.5 hydrate of a compound of formula I, comprising the step of reacting the compound of formula I with acetic acid, aqueous hydrochloric acid solution and acetone to form crystals.

[0156] Specifically, the compound (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone of chemical formula I can be added into a reactor at 25°C, acetic acid is immediately added at the same temperature, water is added into the reactor, and aqueous hydrochloric acid solution is added into the reactor at 25°C, and then acetone is added into the reaction solution to generate crystals, and then the generated crystals are filtered and vacuum dried to obtain (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride 1.5 hydrate.

[0157] The preparation method of the hydrochloride 1.5 hydrate of the compound of the above-described chemical formula I will be described in more detail in the examples described below.

[0158] In one specific embodiment of the present invention, the hydrochloride 1.5 hydrate of the compound of Formula I shows characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis:

[0159] 11.48±0.5°, 24.11±0.5°, 24.76±0.5°, 27.99±0.5°, 31.43±0.5°, 34.20±0.5°.

[0160] In a specific embodiment of the present invention, the hydrochloride 1.5 hydrate of the compound of Formula I further shows characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis:

[0161] 6.89±0.5°, 17.61±0.5°, 21.42±0.5°, 23.27±0.5°.

[0162] In one specific embodiment of the present invention, the hydrochloride 1.5 hydrate of the compound of Formula I shows characteristic peaks at the following 2θ positions in powder X-ray diffraction (XRD) analysis:

[0163] 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°.

[0164] In addition, the present invention relates to a pharmaceutical composition in the form of an oral administration preparation, which comprises the hydrochloride 1.5 hydrate of the compound of Chemical Formula I.

[0165] The pharmaceutical composition of the present invention can be prepared by mixing a pharmaceutically acceptable carrier, a receptor, a binder, a stabilizer and / or a diluent with an effective amount of the hydrochloride 1.5 hydrate of the compound of formula I as an active ingredient. For the pharmaceutical composition of the present invention, according to the method that can be easily implemented by a person with ordinary knowledge in the technical field to which the present invention belongs, a pharmaceutically acceptable carrier and / or an excipient is used for formulation, so that it can be prepared in a unit dose form or added to a multi-dose container. The pharmaceutically acceptable carrier can be solid or liquid, and can be selected from one or more of an excipient, an antioxidant, a buffer, an antibacterial agent, a dispersant, an adsorbent, a surfactant, a binder, a preservative, a disintegrant, a sweetener, a flavoring agent, a glidant, a release regulator, a wetting agent, a stabilizer, a suspending agent and a lubricant. In addition, the pharmaceutically acceptable carrier can be selected from physiological saline, sterile water, Ringer's solution, buffered physiological saline, glucose solution, maltodextrin solution, glycerol, ethanol and mixtures thereof.

[0166] The pharmaceutical composition of 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 a powder, granule, tablet, capsule, syrup or suspension, and can be specifically in the form of a tablet. In addition, in a specific embodiment, the pharmaceutical preparation can be formulated in a manner that the active agent is coated or protected from decomposition in the stomach.

[0167] The present invention will be described in more detail below by way of examples. However, these examples are only used to exemplify one or more specific embodiments, and the scope of the present invention is not limited thereto.

[0168] Example 1

[0169] The compound of formula IV, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) become

[0170] (1) Preparation of 4-chloro-3-nitropyridine

[0171] 50g (0.356mmol) of 4-hydroxy-nitropyridine was stirred in 50mL (1T) of DMF (dimethylformamide) and 450mL (9T) of ethyl acetate, 42.5mL of phosphorus oxychloride (POCl3, 1.3eq) was added, the temperature was raised and heated to reflux at 70-80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to 40°C and 200mL of water was added to terminate the reaction. The separated organic layer was washed with 200mL of saturated sodium bicarbonate (NaHCO3) and 200mL of brine, and the collected organic layer was dried with magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure to obtain 60g of light yellow concentrated crystals of 4-chloro-3-nitropyridine.

[0172] (2) Preparation of methyl 2-((3-nitropyridin-4-yl)oxy)acetate

[0173] 60g (0.356mmol) of 4-chloro-3-nitropyridine obtained in the step (1) was dissolved in 300mL (5T) of DMF, 36mL (1.3eq) of methyl glycolate and 74g (1.5eq) of potassium carbonate (K2CO3) powder were added, the temperature was raised and reacted at 70-80°C for 1-2 hours. After the reaction was completed, it was cooled to room temperature, 150mL of 10% HCl was added to dissolve and neutralize, and extracted with 500mL of ethyl acetate. The obtained organic layer was washed with 150mL of brine, and then the obtained organic layer was concentrated under reduced pressure and dried in vacuo to obtain 62g (82%) of 2-((3-nitropyridine-4-yl)oxy)acetic acid methyl ester as a light brown solid.

[0174] (3) Preparation of 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0175] 62g (0.291mmol) of 2-((3-nitropyridin-4-yl)oxy)acetic acid methyl ester obtained in the step (2) was dissolved in 480mL of acetonitrile (ACN) and 120mL of water (H2O), 16g (1.0eq) of ammonium chloride (NH4Cl) and 33g (2.0eq) of iron (Fe, Iron) powder were added, and the temperature was raised and reacted at 70-80°C for 2 hours. After the reaction was completed, it was cooled to room temperature, 30mL of concentrated hydrochloric acid (conc-HCl) was added and stirred for 30 minutes. The reaction solution was filtered to remove insoluble matter. The obtained reaction solution was added and concentrated until a solid was obtained, added to methanol, stirred and filtered, and 2H-pyrido [4,3-b] [1,4] oxazine-3 (4H) -one hydrochloride was obtained. The product was dissolved in water and then neutralized with 10% sodium hydroxide (NaOH) (pH 6-7). The generated solid was filtered and dried to obtain 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0176] 1 H-NMR (300MHz, MeOD-d): δ = 8.06 (m, 2H), 6.97 (s, 1H), 4.72 (s, 2H).

[0177] (4) Preparation of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine

[0178] 38g (0.251mmol) of 2H-pyrido [4,3-b] [1,4] oxazine-3 (4H) -one obtained in step (3) was stirred in 570mL of tetrahydrofuran (THF) (15T), the temperature of the reaction solution was cooled to 0°C, and then 15g (1.5eq) of lithium aluminum hydride (LiAlH4, LAH) was added in several portions, and the reaction solution was warmed to room temperature and stirred for 2 hours. After the reaction was completed, it was cooled to 0°C, 40mL of H2O was slowly added dropwise and stirred for 10 minutes, and then 80mL of 5% -NaOH solution was added dropwise and stirred for 30 minutes to room temperature. The reaction solution was filtered to remove Al (OH) 3 insoluble matter. The filtrate was neutralized with 10% -HCl (pH 7), then extracted with ethyl acetate, and the organic layer washed with brine (brine) was dried with sodium sulfate (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to obtain 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (30 g, 90%).

[0179] (5) Preparation of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr)

[0180] 100g (0.666mol) of 2H-pyrido [4,3-b] [1,4] oxazine-3 (4H) -one was stirred in 570mL of THF (15T), the temperature of the reaction solution was cooled to 0°C, and then 38g (0.999mol, 1.5eq) of lithium aluminum hydride (LiAlH4, LAH) was added in several portions, and the reaction solution was heated to room temperature and stirred for 2 hours. After the reaction was completed, it was cooled to 0°C and quenched, and then filtered and concentrated, stirred and filtered with methylene chloride (MC). The MC used at this time was 1000mL (10v / w) of 2H-pyrido [4,3-b] [1,4] oxazine-3 (4H) -one. At 20-30°C, 1.8 equivalents (1.199 mmol based on 2H-pyrido[4,3-b][1,4]oxazine-3(4H)-one) of 294 g (210 mL) of 33% bromic acid (d, 1.40 g / mL) in acetic acid was added dropwise to the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine / MC solution for 20-30 minutes. The resulting crystal solution was stirred at room temperature for 1 hour, cooled to 5-10°C, and then stirred for another 30 minutes. The crystal solution was filtered, washed with 300-500 mL of MC, and then vacuum dried at room temperature for 5 hours to obtain the compound 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of the following chemical formula IV in a yield of 95%.

[0181]

[0182] Figure 1 The NMR data of the compound are shown in Figure 2 The thermogravimetric (TG) / differential thermal analysis (DTA) results of the compounds are shown in FIG.

[0183] Example 2

[0184] The compound of formula I (3,5-dibromo-4-hydroxyphenyl) (2,3-dihydro-4H-pyrido[4,3-b][1,4]oxadiazine) Synthesis of (4-oxazine-4-yl)-methanone

[0185] At 25-30° C., 1 L of tetrahydrofuran (THF) was added to the reactor, and 139 g (0.470 mol) of 3,5-dibromo-4-hydroxybenzoic acid was added, and then 278 g (1.27 mol) of di-tert-butyl dicarbonate was added to the reactor. 125 g (1.58 mol) of pyridine was added under a nitrogen atmosphere, and the reaction solution was stirred at 25-30° C. for 2 hours to obtain a reaction solution containing 3,5-dibromo-4-tert-butoxycarbonyloxy-benzoic acid and 3,5-dibromo-4-((tert-butoxycarbonyl)oxy)benzoic acid (tert-butylcarbonyl) anhydride.

[0186] At a temperature of 25 to 30° C., 170 g (1.68 mol) of triethylamine was added to the reaction solution, and 100 g of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) prepared in Example 1 was added to the reaction solution, and the reaction solution was stirred at a temperature of 25 to 30° C. for 6 hours. The formed salt was removed and the filtrate was collected, and then the filtrate was concentrated at a temperature of 25 to 30° C. to obtain tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate.

[0187] 500 mL of isopropanol was added to a reactor at a temperature of 25 to 30° C. containing tert-butyl-(2,6-dibromo-4-(1,2,3,4-tetrahydro-1,7-naphthyridine-1-carbonyl)phenyl)carbonate, and 500 mL of concentrated hydrochloric acid was slowly added at a temperature below 45° C., and then the reaction solution was cooled to 25 to 30° C. and stirred for 1 to 2 hours. 3 L of isopropanol was added to the reaction solution at 25 to 30° C., and stirred for another hour, and then the reaction solution was cooled to 20 to 25° C. The generated 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.

[0188] Add water to a clean reactor, and add the obtained (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride in the reactor at 25-30°C, and then stir the reaction solution at 25-30°C for 15 minutes. Slowly add 100 mL of 4N sodium hydroxide aqueous solution at 25-30°C until the pH reaches 10.0, and then filter the reaction solution and collect the filtrate. Add ethyl acetate to the reactor and stir to separate the water layer, and add 10% hydrochloric acid aqueous solution at 20-25°C until the pH reaches 6.4-6.7. Filter the generated crystals 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 is 60%, purity is 98.0% or more). Figure 3 The NMR data of the compound are shown in .

[0189] Example 3

[0190] (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone Synthesis of Hydrochloride 1.5 Hydrate

[0191] At 25°C, 83 g of (3,5-dibromo-4-hydroxyphenyl) (2,3-dihydro-4H-pyrido [4,3-b] [1,4] oxazine-4-yl) -methanone prepared in Example 2 was added to the reactor, and 584 mL of acetic acid was immediately added at the same temperature, and then 83 mL of water was added to the reactor, and 111 mL of 2M hydrochloric acid aqueous solution was added to the reactor at 25°C, and then 688 mL of acetone was added to the reaction solution to generate crystals, and then the generated crystals were filtered and vacuum dried for 12 hours to obtain (3,5-dibromo-4-hydroxy-phenyl) -(2,3-dihydro-pyrido [4,3-b] [1,4] oxazine-4-yl) -methanone hydrochloride 1.5 hydrate (yield 90%, purity 99.9%).

[0192] Figure 4 The results of powder X-ray diffraction (XRD) analysis of the obtained (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazine-4-yl)-methanone hydrochloride 1.5 hydrate are shown in FIG. Figure 4 As shown, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone hydrochloride 1.5 hydrate shows characteristic peaks at the following 2θ positions:

[0193] 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°.

[0194] Experimental Example 1

[0195] Stability of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr)

[0196] The stability of the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) of the present invention prepared in Example 1 and other salts prepared by the same method were compared. The obtained 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine phosphate was in a gel type rather than a solid form, and the 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrochloride was also in a semi-solid form and had an unstable form. The substances obtained in a solid form were 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine hydrobromide (2HBr) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine sulfate.

[0197] As shown in Table 1 below, in the case of the sulfate form, not only was the purity of the obtained substance lower than that of the free base form of 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine, but also the solid melted back into liquid during the stability test. On the other hand, in the case of the hydrobromide form, not only was the purity improved compared to the free base form, but the results of the 4-week stability test showed no significant change from the initial purity.

[0198] [Table 1] Stability comparison test results

[0199]

[0200]

[0201] In addition, NMR, thermogravimetric (TG) analysis and differential thermal analysis (DTA) were performed on the hydrobromide salt form, sulfate salt form and free base form.

[0202] Figure 1 The NMR data of the hydrobromide salt (2HBr) are shown in Figure 2 Thermogravimetric (TG) / differential thermal analysis (DTA) results are shown in FIG.

[0203] in addition, Figure 5 The NMR data of sulfate are shown in Figure 6 TG / DTA results are shown in .

[0204] in addition, Figure 7 The NMR data of the free base are shown in Figure 8 TG / DTA results are shown in .

[0205] Experimental Example 2

[0206] (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone Stability of hydrochloride 1.5 hydrate

[0207] The hydrochloride 1.5 hydrate of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone prepared in Example 3 of the present invention and the hydrochloride non-solvate of the same compound were subjected to powder X-ray diffraction (XRD) analysis and TG / DTA analysis, and the water absorption isotherm was measured. The results are shown in Figures 9 to 11 middle.

[0208] Specifically, Fig. 9 The results of powder X-ray diffraction (XRD) analysis of the ansolvate (a) and the 1.5-hydrate (b) are shown in FIG.

[0209] Fig.10 TG / DTA results of the ansolvate (a) and the 1.5-hydrate (b) are shown in FIG.

[0210] Fig.11 The isothermal moisture absorption curves of the ansolvate (a) and the 1.5-hydrate (b) are shown in FIG.

[0211] In addition, a comparative experiment was conducted on the physical stability (Physical Stability to Processing Factors) during the preparation of the 1.5-hydrate and the non-solvate. The results are shown in Table 2 below.

[0212] [Table 2] Comparison of physical stability during preparation

[0213]

[0214]

[0215] *: Grind the sample using a mortar for about 2 minutes.

[0216] **: The sample was granulated using a mortar for about 2 minutes after adding 30% v / w of solvent. The granulated sample was stored in a sealed vial for about 1 hour, and then the sample was dried at 50°C for about 3 hours.

[0217] ***: Using a 7 mm plat-faced punch, press the sample at 2 tons for 5 seconds.

[0218] ****: Crystallinity was evaluated using a powder X-ray diffractometer.

[0219] As shown in Table 2 above, the results of comparing the changes in crystallinity during grinding and tableting showed that the 1.5-hydrate was much more stable than the ansolvate, and the results of comparing the solid forms during granulation showed that a part of the ansolvate was converted into the form of the 1.5-hydrate, but the 1.5-hydrate did not show any changes, indicating that the 1.5-hydrate showed superior physical stability compared to the ansolvate.

[0220] Experimental Example 3

[0221] (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone Solubility of hydrochloride 1.5 hydrate

[0222] The solubility of the hydrochloride 1.5 hydrate of (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone of the present invention prepared in Example 3 and the hydrochloride ansolvate of the same compound were compared. The medium used was 50 mL of FeSSIF (pH 5.0), the paddle speed was set to 50 rpm, and the test was carried out under the operating conditions of 37°C. A physical mixture of 10 mg of the compound and 100 mg of lactose was used as a sample to measure the solubility. The results are shown in Fig.12 It can be seen that the solubility of the hydrochloride 1.5 hydrate at 240 minutes was about 125 μg / mL, but the solubility of the ansolvate decreased to about 112.5 μg / mL.

[0223] Experimental Example 4

[0224] (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone Comparative experiment on the effects of different doses

[0225] A total of 60 gout patients were selected as subjects, and the hydrochloride 1.5 hydrate form of the (3,5-dibromo-4-hydroxyphenyl) (2,3-dihydro-4H-pyrido [4,3-b] [1,4] oxazin-4-yl) -methanone of the present invention prepared in Example 3 was provided. Based on the active ingredient (3,5-dibromo-4-hydroxyphenyl) (2,3-dihydro-4H-pyrido [4,3-b] [1,4] oxazin-4-yl) -methanone (chemical formula I), 0.25 mg (N = 12), 0.5 mg (N = 12), 1 mg (N = 12), 2 mg (N = 12) and placebo (N = 12) were orally administered for 14 days. The placebo was used as a control to evaluate the effectiveness and safety on serum uric acid level (serum UA level) and the like.

[0226] The blood uric acid level was measured on the 15th day after administration, and the percentage of the number of patients whose blood uric acid level decreased to less than 6.0 mg / dL and less than 5.0 mg / dL was determined and shown in Fig.13In. Fig.13 As shown, when the dosage was 0.25mg, 0.5mg, and 1mg, no patient with blood uric acid value lowered to less than 5.0mg / dL was observed, and only about 8% was observed at a dosage of 2mg. From the above results, it can be seen that when the dosage is below 2mg, it has no effect on the treatment of diseases such as hyperuricemia and gout.

[0227] In addition, a total of 68 gout patients were provided with the hydrochloride 1.5 hydrate form of the present invention (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone, and 3 mg (N=13), 5 mg (N=14), 7 mg (N=15), 10 mg (N=15) and placebo (N=11) of the active ingredient (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (chemical formula I) were orally administered for 14 days, and the placebo was used as a control to evaluate the effectiveness and safety on blood uric acid levels, etc.

[0228] The blood uric acid level was measured on the 15th day after administration, and the percentage of the number of patients whose blood uric acid level decreased to less than 6.0 mg / dL and less than 5.0 mg / dL was determined and shown in Fig.14 In. Fig.14 As shown, when the dosage of 3mg, 5mg, 7mg, and 10mg was used, the percentage of the number of patients whose blood uric acid value was reduced to less than 5.0mg / dL was about 23%, 64%, 80%, and 73%, respectively, and it was observed in the range of about 23-80%. Patients whose blood uric acid value was reduced to less than 6.0mg / dL also appeared in all experimental doses.

[0229] It can be seen from the above experimental results that when the dosage exceeds the lower limit of 2 mg in the dosage range of the present invention, a significant effect is produced.

[0230] Experimental Example 5

[0231] (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone Analysis of side effects at different doses

[0232] A total of 76 gout patients were provided with the hydrochloride 1.5 hydrate form of the present invention (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone prepared in Example 3, and 3 mg (N=14), 5 mg (N=15), 7 mg (N=17), 10 mg (N=17) and placebo (N=13) of the active ingredient (3,5-dibromo-4-hydroxyphenyl)(2,3-dihydro-4H-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (chemical formula I) were orally administered for 14 days, and the adverse drug reaction results were investigated. As shown in Table 3 below, the above-mentioned usage had no incidence of adverse events such as joint pain and joint swelling, or the incidence of such adverse events was extremely low.

[0233] [Table 3] Adverse drug reactions

[0234] type Placebo (N=13) 3mg(N=14) 5mg(N=15) 7mg(N=17) 10 mg (N=17) Joint pain 0 0 0 0 2 people (11.76%) [3 cases] Swollen joints 0 0 0 0 1 person (5.88%) [1 case]

[0235] In addition, the urinary creatinine concentration was measured for the same patients. The number of cases in which creatinine increased by 0.3 mg / dL or more or increased by 1.5 times or more compared to the baseline is shown in Table 4 below.

[0236] [Table 4] Number of cases where creatinine increased by 0.3 mg / dL or more or increased by 1.5 times or more compared to baseline

[0237] dose Number of incidents Placebo 1 5mg 1 10mg 3

[0238] As shown in Table 4, only one case was observed in the placebo group and the 5 mg dose group, but three cases were observed in the group administered with the maximum dose of 10 mg. Based on the above results, it can be inferred that the risk of increased urinary creatinine concentration is high when the maximum dose exceeds 10 mg.

Claims

1. The hydrochloride 1.5 hydrate (sesquihydrate) of the compound of the following chemical formula I:

2. The hydrochloride 1.5 hydrate of the compound of formula I according to claim 1, characterized in that: In powder X-ray diffraction (XRD) analysis, characteristic peaks were shown at the following 2θ positions: 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°.

3. The hydrochloride 1.5 hydrate of the compound of formula I according to claim 2, characterized in that: The powder X-ray diffraction (XRD) analysis further showed characteristic peaks at the following 2θ positions: 6.89±0.5°, 17.61±0.5°, 21.42±0.5°, and 23.27±0.5°.

4. A method for preparing a hydrochloride 1.5 hydrate of a compound of the following chemical formula I, which comprises reacting the compound of the chemical formula I with acetic acid, aqueous hydrochloric acid solution and acetone to form crystals, 5. A pharmaceutical composition in the form of an oral administration preparation, comprising the hydrochloride 1.5 hydrate of the compound of formula I according to any one of claims 1 to 3.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is in the form of tablets.

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