TWI548630B - 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof - Google Patents

Description

Crystal form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid and preparation method thereof

The present invention relates to a crystalline form of a novel compound represented by the following formula (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) It is suitable as an inhibitor against xanthine oxidase, and a preparation method thereof.

Xanthine oxidase is an enzyme that converts 6-hydroxypurine to form xanthine and further converts the formed xanthine into uric acid. When the body appears too much uric acid, it may cause a variety of different diseases, such as: gout. Gout is a disease in which uric acid crystals accumulate in cartilage, ligaments, and surrounding tissues, causing severe inflammation and pain. The incidence of gout has continued to rise over the past 40 years (N.L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587-2590). In addition, many researchers have confirmed the close relationship between uric acid and heart failure, hypertension, diabetes, kidney disease and cardiovascular disease, and have noticed the importance of controlling uric acid (DIFeig et al., N.Eng. J. Med, 2008, 23, 1811 to 1821). Therefore, substances that inhibit the activity of xanthine oxidase can be effectively used for the treatment of diseases associated with xanthine oxidase, such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation. With joints Disease, inflammatory bowel disease, etc.

On the other hand, in the medical field where high quality and long-term preservation are required, it is important to use a medically and chemically stable drug as an active ingredient. Therefore, the excellent pharmaceutical properties of the active ingredient and its superior pharmacological potency are extremely valuable as the effects of the present invention.

It is an object of the present invention to provide a crystalline form of the novel compound of the formula (1) [hereinafter referred to as the compound (1)], thereby providing excellent pharmaceutical properties (e.g., stability, non-absorbability, ease of handling, etc.), and The pharmacological activity is achieved by selective binding to xanthine oxidase.

The invention is described in more detail below.

The present invention provides a crystalline form of the novel compound (1) (chemical name: 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid), which is suitable for confrontation Inhibitor of xanthine oxidase.

The crystalline form of the compound (1) (i.e., the crystalline form of 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid) exhibits inhibitory activity against xanthine oxidase And the method of its manufacture will be described in more detail in the following process.

Xanthine oxidase is an enzyme that converts 6-hydroxyindole to form xanthine and further converts the formed xanthine into uric acid. When the body appears too much uric acid, it may cause a variety of different diseases, such as: gout. Chemical The crystalline form of the compound (1) selectively inhibits xanthine oxidase.

When analyzed by X-ray powder diffraction (XRD), the crystalline form of Compound (1) showed characteristic peaks (2 θ) of 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6. More specifically, when XRD analysis is used, the characteristic peak (2 θ) of the compound (1) crystal form is 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 20.9°, 23.1°, 24.8°, 25.8° and 26.6°.

Further, when the compound (1) crystal form is analyzed by differential scanning calorimetry, it exhibits an initial endothermic peak caused by the melting point of 263 to 268 ° C, whereby it can be seen that the novel compound (1) crystal form according to the present invention has 263 to High melting point of 268 ° C, very suitable for heat resistance (Figure 2). This can be confirmed by thermal stability data after storage for 12 weeks at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH. Even after 12 weeks of compound storage, the original contents did not decrease at all. In the thermogravimetric analysis, the endothermic section (263 to 268 ° C) (Fig. 3) shown by differential scanning calorimetry confirmed no loss of weight.

Further, the crystalline form of the compound (1) of the present invention is highly suitable for combating moisture. As shown in Fig. 4, it has been confirmed that the crystal form of the present invention exhibits a weight change by moisture influence of only about 0.3% or less in the moisture adsorption isotherm. It is therefore considered that the crystalline form of the present invention is highly suitable for combating moisture.

As described above, the crystal form of the compound (1) according to the present invention has a little or no change in humidity in a wide range of relative humidity, which means that the crystal form does not change with changes in humidity, and is highly suitable for heat resistance. Therefore, it is particularly suitable for stable storage, grinding processing, and the like.

The present invention also provides a process for preparing a crystalline form of the compound (1) by crystallizing the compound (1) from a suitable solvent or solvent mixture. The solvent or solvent mixture is preferably selected from the solvents which have been used in the process for the preparation of the compound (1). The solvent or solvent mixture employed is selected from the group consisting of anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, Tributyl alcohol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, Chloroform, toluene and its mixture. More preferably, the solvent is selected from the group consisting of anhydrous ethanol, tert-butanol, acetone, tetrahydrofuran, acetonitrile, chloroform and mixtures thereof.

The method of crystallizing the compound (1) from a suitable solvent may be, for example, cooling the solution, evaporating the solvent, adding an anti-solvent (solvent which does not dissolve the compound (1), for example, water) until it is supersaturated, and is converted into a slurry liquid. ,and many more.

The crystalline form of Compound (1) employed herein can be administered to a human patient either as the compound itself or as a pharmaceutical composition comprising the compound and other active ingredients for combination therapy or with other suitable carriers or excipients.

The pharmaceutical compositions of the present invention can be prepared by known methods such as conventional mixing, dissolving, granulating, tableting, milling, emulsifying, encapsulating, embedding or freeze drying, and the like.

Thus, the pharmaceutical compositions of the present invention can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Such carriers include excipients or auxiliaries which facilitate the conversion of the active compound into a pharmaceutically acceptable formulation. Suitable formulations may vary depending on the route of administration chosen. Can be known in related art (example For example, "Remington's Pharmaceutical Sciences" technology, carriers and excipients, and methods are suitably selected.

For example, the crystalline form of the compound (1) can be formulated into an injection preparation, an oral preparation, and the like, depending on the purpose of the present invention.

In the preparation of the injectable preparation, the active compound of the present invention can be formulated into a liquid preparation using a pharmaceutically suitable buffer (preferably Hank's solution, Ringer's solution, physiological saline, etc.). . For administration through the mucosa, a penetration enhancer suitable for penetrating the barrier can be used in the formulation. Such penetration enhancers are known to those skilled in the art.

The active compounds of the present invention are readily formulated into a solid dosage form for oral administration by combining the compound with a pharmaceutically acceptable carrier known in the art. By using such carriers, the compounds of the invention may be formulated into lozenges, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like. Capsules, troches, pills, powders and granules are advantageous, and capsules and troches are particularly advantageous. For example, an oral administration dosage form can be obtained by the following method.

The crystalline form of the compound (1) according to the invention is mixed with one or more excipients, and if appropriate, the mixture can be ground. A suitable locus can be added if necessary, and the lozenge or dragee core can be obtained from the granulation mixture. Suitable excipients may include fillers such as lactose, sucrose, mannitol or sorbitol; cellulosic materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, yellow gum, methyl Cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP); and the like. If necessary, a disintegrant can be added as a carrier, such as: cross-linked polyvinylpyrrolidone, agar, Alginic acid or a salt thereof (such as sodium alginate), a lubricant (such as magnesium stearate) and a binder.

Oral preparations may include sealed soft capsules (made of gelatin and a plasticizer such as glycol or sorbitol) and hard capsules (made of gelatin). The hard gelatin capsules may contain a mixture of the active compound with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate. In soft capsules, the active compound can be dissolved or dispersed in a suitable medium such as a fatty acid, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be included. All orally administered formulations may contain an appropriate amount of the active compound.

The active compound (i.e., the crystalline form of the compound (1)) can also be formulated into an injection preparation such as, for example, a bolus injection or a continuous injection for parenteral administration. The injectable preparation may be in the form of a ampule containing a preservative or in a unit dosage form filled in a multi-dose container. The composition may be in the form of a suspension, solution or emulsion contained in an oil or liquid vehicle, and may contain formulation ingredients such as suspending, stabilizing and/or disintegrating agents. The active ingredient can be in the form of a powder which is reconstituted by dissolving in sterile pyrogen-free water just prior to use. The active compound can also be formulated for rectal pharmaceutical compositions such as suppositories or enemas containing conventional suppository bases such as cocoa butter or other glycerides.

The crystalline form of the compound (1) in the pharmaceutical composition according to the present invention contains an amount effective for the purpose of the plan. In particular, the medically effective amount means that the amount of active compound is effective to prolong the survival of the patient being treated, or to prevent, alleviate or ameliorate the symptoms of the disease. Those skilled in the art will be able to determine the medically effective amount, particularly in light of the detailed description provided herein.

When a compound is formulated into a unit dosage form, it is based on a compound per unit dose. The compound (1) preferably has a crystalline form of the compound (1) in an amount of from about 0.1 to 1,000 mg. The dosage depends on the physician's location, such as the patient's weight or age, the nature of the disease, the severity of the disease, and the like. However, the dosage required to treat an adult is usually from about 1 to 1,000 mg per day, depending on the strength and frequency of administration. When administered to an adult via the intramuscular or intravenous route, a total daily dose of about 1 to 500 mg should be sufficient when administered separately in a single dose, although some patients may require a higher daily dose.

The present invention further provides a method of preventing or treating a disease associated with human xanthine oxidase using a medically effective amount of the compound (1) crystalline form. The term "disease associated with human xanthine oxidase" means that the disease can be prevented or treated by inhibiting human xanthine oxidase, including but not limited to: hyperuricemia, gout, heart failure, heart Vascular disease, hypertension, diabetes, diabetic complications, kidney disease, inflammation and joint disease, inflammatory bowel disease, etc. Some examples of such diabetic complications are hyperlipidemia, atherosclerosis, obesity, hypertension, retinal degeneration, renal failure, and the like (Circulation Research, 2006, 98, 169 to 171; Hypertension 2003, 41, 1183 to 1190) . Further, as confirmed by the animal toxicity test data, the crystalline form of the compound (1) of the present invention has no genotoxicity, repeated toxicity, and the like, and is extremely safe.

As used herein, the term "therapeutic" means that when administered to an individual who is beginning to develop symptoms of the disease, it may interfere with or delay the progression of the disease, and the term "prevention" means when administered to a patient who has not yet developed symptoms of the disease but is at risk of developing the symptoms of the disease. Individuals can interfere with or delay the onset of disease symptoms.

The invention will be illustrated in more detail using the following examples and experimental examples. Of course Rather, it is intended to be illustrative only, and is not intended to limit the scope of the invention.

The crystalline form of the compound (1) newly provided by the present invention has pharmacological activity by selectively inhibiting xanthine oxidase, and has excellent medical stability such as thermal stability, storage stability, and the like. The reason why the crystalline form of the compound (1) as a novel substance is suitable is that it has little or no change in humidity over a wide range of relative humidity, and its crystal form does not change with changes in humidity. Furthermore, it is possible to control the preparation of this crystalline form in accordance with the various methods provided by the present invention.

Method: Compound (1) Process 1-1: ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

The title compound was prepared according to the following processes (1), (2) and (3). (1) Method for preparing ethyl 1-(3-methylindolyl-1H-indol-5-yl)pyrazole-4-carboxylate

Toluene chloride (0.56 mL, 6.6 mmol) and N,N-dimethylformamide (0.51 mL, 6.6 mmol) were added sequentially in anhydrous dichloromethane (50 mL). The mixture was stirred at 0 ° C for 30 minutes. A mixture of ethyl 1-(1H-indol-5-yl)pyrazole-4-carboxylate (1.40 g, 5.47 mmol) and dichloromethane (50 mL) was added to the reaction mixture, then at room temperature Stir under reflux for 1 hour. Exclude solvent. Add tetrahydrofuran (100 mL) with 20% acetic acid Aqueous ammonium solution (100 mL) was added to the residue, heated for 30 min and stirred under reflux. After the reaction was completed, the reaction solution was cooled, and ethyl acetate was added. The mixture was washed with aq.

Quality (EI) 284 (M ⁺ +1)

(2) Method for preparing 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester

Ethyl 1-(3-methylindol-1H-indol-5-yl)pyrazole-4-carboxylate obtained from the above step (1) was dissolved in pyridine (150 mL), and hydroxy ammonium chloride was added ( 499 mg, 7.18 mmol). The mixture was heated and stirred under reflux for 5 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was filtered through silica gel using acetone as solvent to give the title compound.

Quality (EI) 299 (M ⁺ +1)

(3) Method for preparing ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate

Ethyl 1-[3-[(E,Z)-hydroxyiminomethyl]-1H-indol-5-yl]pyrazole-4-carboxylic acid ethyl ester obtained from the above step (2) is dissolved in anhydrous Tetrahydrofuran (94 mL). Di(imidazol-1-yl)methylthione (90%, 2.79 g, 14.1 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hr. After the reaction is completed, the reaction dissolves. The liquid was concentrated under reduced pressure. The obtained solid was isolated by column chromatography toiel

NMR: ¹ H-NMR (DMSO-d ₆ ) δ 12.40 (1H, br), 9.20 (1H, s), 8.37 (1H, s), 8.21 (1H, d), 8.14 (1H, s), 7. 1H, dd), 7.68 (1H, d), 4.29 (2H, q), 1.32 (3H, t)

Quality EI) 281 (M ⁺ +1)

Process 1-2: ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate

Ethyl 1-(3-cyano-1H-indol-5-yl)pyrazole-4-carboxylate (13.84 g, 49.38 mmol) from m.p. Cesium carbonate (32.17 g, 98.74 mmol) and 2-iodopropane (19.7 mL, 198 mmol) were added, and the mixture was stirred and stirred under reflux for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained solid compound was purified by column chromatography toield

NMR: ¹ M-NMR (CDCl ₃ ) δ 8.48 (1H, s), 8.16 (1H, s), 8.06 (1H, d), 7.82 (1H, s), 7.78 (1H, dd), 7.57 (1H, d), 4.80-4, 73 (1H, m), 4.38 (2H, q), 1.64 (6H, d), 1.42 (3H, t)

Quality (EI) 323 (M ⁺ +1)

Process 1-3: 1-(3-Cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (compound (1))

Ethyl 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (13.87 g, 43.03 mmol) from 1-2 (m. 140 mL), a solution of methanol (140 mL) and 6N sodium hydroxide (70 mL), then react at room temperature for 1 hour. After the reaction, the organic solvent was removed under reduced pressure and the residual aqueous layer was washed with ethyl acetate. A concentrated hydrochloric acid aqueous solution was added to pH 1. The precipitated solid was filtered, washed with EtOAc EtOAcjjjjj

NMR: ¹ H-NMR (DMSP-d ₆ ) δ 12.55 (1H, br), 9.10 (1H, s), 8.53 (1H, s), 8.16 (1H, d), 8.06 (1H, s), 7.90 ( 1H, dd), 7.86 (1H, d), 4.92-4.86 (1H, m), 1.48 (6H, d)

Quality (EI) 295 (M ⁺ +1)

Example 1: Compound (1) Crystal Forming Method

The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (3.82 kg) obtained was dissolved in acetone (382 L) and then slowly stirred. Slowly add to the water (40 L) at a temperature of 90 °C. After completion of the dropwise addition, the mixture was further stirred for about 12 hours, cooled and filtered to give a crystalline form (3.40 kg) of the compound (1) of the present invention. The obtained compound (1) crystal form was characterized by ¹ H-NMR and IR analysis. The results are shown below.

¹ H-NMR (DMSO-D ₆ , ppm) 1.5 (6H, d), 4.9 (1H, q), 8.6 (1H, s), 8.2 (1H, d), 7.9 (1H, dd), 7.9 (1H , d), 8.1 (1H, s), 9.1 (1H, s), 12.6 (1H, br)

IR (cm ^-1 ) 2500 to 3150, 2215, 1669, 1558, 1502, 1263

Further, as shown in the spectrum of the first graph obtained from XRD, the crystal form of the compound (1) showed characteristic peaks (2 θ) of 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°. The clear values for XRD are shown in Table 1 below.

Example 2

The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (40 mg) was dissolved in tetrahydrofuran (10 ml), slow at room temperature The solvent was slowly evaporated to give the compound (1) crystal form (35 g).

The clear values for XRD are shown in Table 2 below.

Example 3

The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) was added to a tributanol (120 ml). The solvent was evaporated at room temperature to give the compound (1) crystal form (190 g).

The clear values for XRD are shown in Table 3 below.

Example 4

The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) obtained was added to ethanol (60 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (184 g).

The clear values for XRD are shown in Table 4 below.

Example 5

The 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) obtained was added to acetonitrile (70 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (179 g).

The clear values for XRD are shown in Table 5 below.

Example 6

The obtained 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid (200 mg) was added to chloroform (120 ml) and then slurried. The mixture was stirred for 24 hours, and filtered to give Compound (1) crystal form (196 g).

The clear values for XRD are shown in Table 6 below.

Example 7

The obtained sodium 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylate (7.3 kg) was dissolved in a 10N NaOH solution (11.6 L). Hydrochloric acid (12.1 kg) was slowly added dropwise to the solution with stirring. The crystalline form of the compound (1) starts to precipitate. When the pH reached about 1 to 2, the dropwise addition of hydrochloric acid was stopped. The mixture was stirred until it became homogeneous, and then filtered to give a compound (1) crystal form (15.96 kg).

Test example 1 Powder X-ray diffraction analysis

About 40 mg of Compound (1) crystal form from Example 1 was added to a sample holder and mounted on an X'Pert PRO (from Panalytical) to determine a diffraction pattern in the range of 4 to 40 °/2 θ. The result is shown in Fig. 1. The clear conditions of the analytical method are as follows.

Time per step: 99.45 s

Resolution: 0.0394°

Scan mode: continuous

Voltage / current: 45 kV / 40 mA

Cu-palladium (Ni-filter)

Fixed divergence slit

Parallel plate slit: parallel plate 0.04 rad

Detector slit 0.04 rad parallel plate slit, backscatter slit P7.5

It can be confirmed from Fig. 1 that the characteristic peaks (2 θ) of the XRD spectrum measured by the crystal form of the compound (1) of the present invention analyzed at CuK α, 45 Kv, 40 m Å are 12.1°, 13.2°, 15.7°, 18.3. °, 24.8 °, 25.8 ° and 26.6 °.

Test example 2 Differential Scanning Calorimeter (DSC)

The DSC was carried out using the DSC821 ^e from Mettler Toledo. 3 mg of the crystalline form of the compound (1) from Example 1 was placed in an aluminum pan, and the weight was accurately recorded. Cover the aluminum plate. Punch and shape the cover. The aluminum frame is on the instrument. Heated from 25 ° C to 300 ° C at a rate of 10 ° C / min under a nitrogen purge. Indium metal was used as a calibration standard. The results obtained are shown in Fig. 2. As confirmed from Fig. 2, the crystalline form of the compound (1) of the present invention exhibits an initial endothermic peak because its melting point is from 263 to 268 ° C, whereby it can be seen that the crystalline form of the present invention has a high melting point and is stable against heat.

Test Example 3 Thermogravimetric analysis (TGA)

The TGA was carried out at the TGA850 of Mettler Toledo. The crystalline form 5 mg of the compound (1) from Example 1 was placed in an aluminum pan. The aluminum pan was placed on the instrument and then heated from 25 ° C to 300 ° C at a rate of 10 ° C / min under a nitrogen purge. Use of nickel and aluminum (Nickel and Aluminum ^TM) as a calibration standard. The results obtained are shown in Figure 3. As confirmed from Fig. 3, the crystalline form of the compound (1) of the present invention showed no weight loss in the endothermic phase of DSC, and thus it was found that the crystalline form of the present invention can be stably resistant to heat.

Test Example 4 Isothermal moisture adsorption/desorption analysis

The compound (1) crystal form from Example 1 was collected, and moisture adsorption/desorption data was collected on a VTI-SA vapor absorption analyzer (Vapor Sorption Analyzer). The sample was not dried prior to analysis. The adsorption and desorption of moisture was analyzed at intervals of 5% RH while maintaining a temperature of 25 ° C in the range of 5 to 95% relative humidity (RH). The result is shown in Fig. 4. As seen from Fig. 4, the change in weight of the crystalline form of the compound (1) of the present invention is only 0.3% or less based on the change in external humidity in the range of 5 to 95% RH. That is, the crystalline form of the present invention is extremely stable against any change in relative humidity, and the crystal form remains unchanged as humidity changes.

Test Example 5 Thermal stability

Approximately 50 mg of the crystalline form of the invention from Example 1 was placed in a Duma bottle and then stored at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH. After 2 weeks, 8 weeks, and 12 weeks, each sample was taken from the Duma bottle. The sample was dissolved in an acetonitrile/water/0.1 N sodium hydroxide solution = 30/60/10 (v/v/v%) solvent mixture, followed by HPLC analysis. The conditions for HPLC analysis are as follows: Conditions for HPLC analysis

Column: dC18 (4.6 mm I.Dx450 mm L, particle size 5.0 μm, Agilent)

Column temperature: 20 ° C

Mobile phase: MeCN/H ₂ O/TFA=35/65/0.1

Flow rate: 1.0 mL/min.

Detection: 250 nm, UV

Injection volume: 10μl

Total analysis time: 40 min.

The thermal stability results of the crystalline form are shown in Table 8 below.

The data in Table 8 shows that the crystalline form of the compound (1) of the present invention has excellent stability after 12 weeks at 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C, 5 ± 5% RH.

Test Example 6 Estimation of the selectivity of xanthine oxidase

The compound of the present invention (1) was administered to a male mouse (BALB/c) at a dose of 100 or 300 mg/kg. After 24 hours, blood was collected and plasma was separated. The concentration of orotate (OA) and orotidine (OD) in plasma was quantitatively analyzed by LC-MS/MS. The results are shown in Table 9 below. This test attempts to confirm whether the compound (1) crystal form is selective for the main enzyme in pyrimidine metabolism (i.e., orotic acid phosphoribosyltransferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC)). In this in vivo test, OA and OD in blood did not increase (see Table 9 below). The result is predictable, the compound (1) crystal form and xanthine oxidase Selective combination.

Test Example 7 Assessing the availability of animals to animals

In order to evaluate the bioavailability of the crystalline form of the compound (1) of the present invention, a single dose of the compound (1) is administered intravenously and orally to rats, monkeys and dogs. Blood was collected and the concentration of the compound (1) in plasma was quantitatively analyzed by LC-MS/MS. The pharmacokinetic parameters (C _max , AUC _inf , CL, Vd _ss , t _1.2 ) of each route of administration were obtained, and the bioavailability was calculated from the percentage of AUC of the orally administered drug relative to the AUC of the intravenous administration. The bioavailability of rats, monkeys and dogs was analyzed to be 37 to 61%, 23 to 39% and 75%, respectively.

Fig. 1 represents an X-ray powder diffraction method (XRD) pattern of the compound (1) crystal form.

Fig. 2 shows the results of differential scanning calorimetry (DSC) of the crystal form of the compound (1).

Fig. 3 represents the results of thermogravimetric analysis (TGA) of the crystalline form of the compound (1).

Figure 4 represents the moisture adsorption/desorption isotherm of the crystalline form of Compound (1).

Claims (10)

A crystal form of a compound represented by the following formula (1): Among the crystal forms, the characteristic peaks (2 θ) appearing in the X-ray diffraction pattern spectrum are 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°; 12.1°. 13.2°, 15.6°, 18.2°, 24.7°, 25.6° and 26.6°; 12.2°, 13.3°, 15.9°, 18.4°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 18.3 °, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.8°, 18.3°, 24.9°, 25.8° and 26.6°; or 12.1°, 13.3°, 15.8°, 18.3°, 24.9°, 25.8° With 26.7°. As shown in the crystalline form of claim 1, the characteristic peaks (2 θ) appearing in the X-ray diffraction pattern spectrum are 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°. 20.9°, 23.1°, 24.8°, 25.8° and 26.6°; 12.1°, 13.2°, 15.6°, 16.6°, 18.2°, 19.6°, 20.9°, 24.7°, 25.6° and 26.6°; 12.2°, 13.3 °, 15.9°, 16.7°, 18.4°, 19.7°, 21.1°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 20.9°, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.7°, 16.6°, 18.3°, 19.6°, 21.0°, 23.3°, 24.9°, 25.8° and 26.6°; 12.1°, 13.2°, 15.8° , 16.7°, 18.3°, 19.6°, 21.0°, 23.1°, 24.9°, 25.8° and 26.6°; or 12.1°, 13.3°, 15.8°, 16.7°, 18.3°, 19.6°, 21.0°, 23.2°, 24.9°, 25.8° and 26.7°. The crystalline form according to claim 1, wherein the melting temperature of the differential scanning calorimetry curve is 263 to 268 ° C from the initial temperature of the DSC. A process for preparing a crystalline form of a compound of the formula (1), which is obtained by dissolving a compound of the formula (1) as defined in the first aspect of the patent application in a solvent selected from the group consisting of: anhydrous ethanol, 2-methyl Oxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, tert-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, acetic acid And a mixture of the third butyl ester, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene, and the like, wherein the crystalline form is X- The characteristic peaks (2 θ) appearing in the ray diffraction pattern spectrum are as follows: 12.1°, 13.2°, 15.7°, 18.3°, 24.8°, 25.8° and 26.6°; 12.1°, 13.2°, 15.6°, 18.2° 24.7°, 25.6° and 26.6°; 12.2°, 13.3°, 15.9°, 18.4°, 24.7°, 25.9° and 26.7°; 12.1°, 13.2°, 15.7°, 18.3°, 24.9°, 25.8° and 26.6 °; 12.1 °, 13.2 °, 15.8 °, 18.3 °, 24.9 °, 25.8 ° and 26.6 °; or 12.1°, 13.3°, 15.8°, 18.3°, 24.9°, 25.8° and 26.7°. The method for preparing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the crystallization is carried out by a method selected from the group consisting of cooling a solution, evaporating a solvent, and adding an anti-solvent until supersaturation is achieved. And converted into a liquid state. A method for producing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in acetone and then evaporated. A method for producing a crystalline form of the compound of the formula (1) as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in anhydrous ethanol, acetonitrile or chloroform to form a slurry. Then stir and filter. A method for producing a crystalline form of the compound of the formula (1), as described in claim 4, wherein the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in tetrahydrofuran or tert-butanol, and The solvent was evaporated at room temperature. A process for preparing a crystalline form of a compound of the formula (1) according to the first aspect of the invention, wherein the sodium salt of the compound of the formula (1) as defined in the first aspect of the patent application is dissolved in a sodium hydroxide solution. Hydrochloric acid was added dropwise to cause crystallization, and the mixture was stirred until the conversion was uniform. A composition comprising a crystalline form of a compound of formula (1) as defined in claim 1 for the treatment or prevention of a disease associated with xanthine oxidase, the related disease being selected from the group consisting of hyperuricemia, gout , a group of heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and joint disease, and inflammatory bowel disease.