KR101424013B1 - 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof - Google Patents

Abstract

The present invention relates to a crystal form of the compound of the formula 1 and a process for producing the same.
[Chemical Formula 1]

Description

Crystalline Forms of 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic Acid and Method for its Preparation {1- (3-cyano-1-isopropyl-indol- ) pyrazole-4-carboxylic acid crystalline form and the resulting method thereof.

The present invention relates to a crystalline form of a compound of the following formula 1 (compound: 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid) useful as an inhibitor of xanthine oxidase And a process for producing the same.

[Formula 1]

Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and also converts the formed xanthine to uric acid. If too much uric acid is present in the body, it can lead to various diseases, typically gout. Gout is a condition in which urate crystals accumulate in the cartilage, ligaments, and surrounding tissues of the joints, causing severe inflammation and pain, and the incidence has steadily increased over the last 40 years (NL Edwards, Arthritis &Amp; Rheumatism, 2008, 58, 2587-2590). In addition, many researchers have confirmed the close correlation between uric acid and heart failure, hypertension, diabetes, kidney disease, and cardiovascular disease, and the importance of uric acid management has been noted (DI Feig et al., N. Eng. J. Med., 2008, 23, 1811-1821). Therefore, a substance that inhibits the activity of xanthine oxidase can effectively treat xanthine oxidase-related diseases such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and joint disease, inflammatory bowel disease and the like.

On the other hand, the chemical and physical stability of drugs used as active ingredients is very important in the field of pharmaceuticals, which must maintain high quality and maintain them for a long period of time. The pharmaceutical superiority of such an active ingredient is of great value as an effect of the invention, together with its superior pharmacological effect.

It is an object of the present invention to provide pharmaceutical superiority such as stability, non-hygroscopicity, and ease of handling achieved by providing a crystal form of formula 1 as a novel substance and selectively binding to xanthine oxidase.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel compound useful as an inhibitor of xanthine oxidase, which is a compound of formula 1 (compound: 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole- ). ≪ / RTI >

[Formula 1]

The crystal form of the compound of formula 1, that is, the crystal form of 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid exhibits an inhibitory activity against xanthine oxidase, It is described in detail in the following Production Examples.

Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and also converts the formed xanthine to uric acid. If too much uric acid is present in the body, it can lead to various diseases, typically gout. The crystalline form of the compound of formula 1 selectively inhibits xanthine oxidase.

The crystal form of the compound of Formula 1 of the present invention exhibits characteristic peaks (2?) At 12.1 °, 13.2 °, 15.7 °, 18.3 °, 24.8 °, 25.8 ° and 26.6 ° in X-ray powder diffraction (XRD) analysis. More concretely, the crystal form of the compound of Formula 1 was observed at an X-ray powder diffraction analysis at 12.1, 13.2, 15.7, 16.6, 18.3, 19.6, 20.9, 23.1, 24.8, 25.8 and 26.6 Characteristic peak (2?).

The crystal form of the compound of Formula 1 of the present invention shows an endothermic peak due to melting point at 263 to 268 ° C as an onset value in the analysis using differential scanning calorimetry, It can be seen that the crystalline form of Compound 1 as a material is a crystalline form that is very stable to heat with a high melting point of 263 to 268 DEG C (FIG. 2). This can be confirmed as a result of thermal stability obtained after storage for 12 weeks at a high temperature of 40 ± 2 ° C, 75 ± 5% RH or 60 ± 2 ° C and 5 ± 5% RH. The residual content of the compound stored for 12 weeks does not disappear at all relative to the initial storage. In the analysis using the thermogravimetric analysis, it was confirmed that the weight loss was not observed in the endothermic period (263 to 268 ° C) of the differential scanning calorimetry (FIG. 3).

Further, the crystal form of the compound of Formula 1 of the present invention is very stable with respect to water. As shown in Fig. 4, weight change due to moisture within only about 0.3% was observed even at isothermal moisture absorption, and it was confirmed that it was a crystal form very stable against moisture.

As described above, the crystal form of the compound of formula (I) of the present invention hardly shows a change in weight due to humidity change in a wide range of relative humidity, has no change in crystal form due to humidity change, and is very stable against heat. And the like.

The present invention also provides a process for preparing a crystalline form of the compound of formula 1 by crystallizing the compound of formula 1 from a suitable solvent or solvent mixture. The solvent or solvent mixture is preferably selected from the solvents already used in the process for preparing the compound of formula 1. The solvent or solvent mixture used may be an anhydrous organic solvent such as anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, , Propyl acetate, t-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene and mixtures thereof. More preferably, the solvent is selected from the group consisting of anhydrous ethanol, t-butanol, acetone, tetrahydrofuran, acetonitrile, chloroform and mixtures thereof.

Crystallisation of the compound of formula 1 from a suitable solvent can be effected, for example, by cooling the solution, evaporating the solvent or by supersaturation with the addition of a reverse-solvent (a solvent in which the compound of formula 1 is poorly soluble, , Slurry conversion, and the like.

The crystalline form of the compound of formula 1 of the present invention may be administered to a human patient either as such, or as a pharmaceutical composition mixed with other active ingredients, such as in a combination therapy, or with a suitable carrier or excipient.

The pharmaceutical composition of the present invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, tableting, pulverizing, emulsifying, encapsulating, trapping or lyophilizing processes.

The pharmaceutical compositions according to the invention thus comprise one or more pharmaceutically acceptable carriers consisting of excipients or auxiliaries which facilitate the treatment of the active compounds with pharmaceutically usable formulations, And can be prepared by conventional methods. Suitable formulations depend on the route of administration chosen. Known techniques, known carriers and excipients, and any means known in the art, for example, Remingston's Pharmaceutical Sciences, can be used as appropriate.

For example, in the present invention, the crystal form of the compound of Formula 1 may be formulated into injectable preparations and oral preparations according to the purpose.

For injection, the components of the present invention may be formulated as a liquid solution, preferably a pharmaceutically suitable buffer, such as a Hank solution, Ringer's solution, or physiological saline. For mucosal permeation administration, a penetration aid suitable for the barrier to be passed is used in the formulation. Such penetration aids are generally known in the art.

For oral administration, the active compound can be easily formulated by combining a pharmaceutically acceptable carrier known in the art with an active compound. Such carriers enable the compounds of the present invention to be formulated into tablets, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Preferably, capsules, tablets, pills, powders and granules are used, in particular, capsules and tablets are useful. Oral medicaments can be prepared, for example, as follows.

It is possible to mix the crystalline form of the compound of formula 1 according to the invention with one or more excipients and, if appropriate, to mill this mixture and, if necessary, add the appropriate auxiliaries and then to treat the mixture of granules to obtain tablets or sugar cores . Suitable excipients include fillers such as lactose, sucrose, mannitol or sorbitol; Cellulose materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, gut tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone (PVP) And the like. If necessary, a carrier such as a disintegrating agent such as crosslinked polyvinylpyrrolidone, marigold, or a salt thereof such as alginic acid or sodium alginate, a lubricant such as magnesium stearate, a binder and the like may be added.

Formulations that can be used orally may include soft, sealed capsules made of gelatin and a plasticizer such as glycol or sorbitol, as well as push-fix capsules made of gelatin. The push-fit capsules may contain the active ingredients as a mixture 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 may be dissolved or dispersed in a suitable medium such as fatty acid, liquid paraffin, or liquid polyethylene glycol. A stabilizer may also be included. All formulations for oral administration may be prepared in suitable amounts for such administration.

The crystalline form of the compound of formula 1, that is, the active compound, may also be formulated for parenteral administration by injection, for example by parenteral injection or continuous infusion. The injectable formulations may be presented in unit dosage form, for example, in ampoules or in multi-dose containers with added preservatives. The compositions may take such forms as suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain components for the formulation, such as suspending, stabilizing and / or dispersing agents. The active compound may be in the form of a powder for combination with an appropriate vehicle such as sterilized pyrogen-free water prior to use. The active compound may be formulated into a rectally administered composition, such as a suppository or rectum, containing conventional suppository bases such as, for example, cocoa butter or other glycerides.

The pharmaceutical composition according to the present invention contains the crystalline form of the compound of formula 1 in an amount effective to achieve its intended purpose. Specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prolong the survival of an object to be treated or to prevent, alleviate or alleviate symptoms of the disease. The determination of a therapeutically effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein.

When formulated in unit dose form, it is preferable that the crystalline form of the compound of Formula 1 as the active ingredient be contained in a unit dose of about 0.1 to 1,000 mg based on the compound of Formula 1. The dosage depends on the physician's prescription based on factors such as the patient's weight, age, and the particular nature and severity of the disease. However, the dosage required for adult therapy is usually in the range of about 1 to 1000 mg per day, depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, separated by a single dose at the time of intramuscular or intravenous administration to an adult would suffice, although in some patients a higher daily dose may be desirable.

The present invention also provides a method of treating or preventing a disease associated with human xanthine oxidase using a therapeutically effective amount of a crystalline form of the compound of formula 1. Refers to a disease that can be treated or prevented by inhibiting human xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes related complications, kidney disease, Inflammatory and joint diseases, inflammatory bowel disease, and the like, but are not limited thereto. Examples of the diabetes-related complications include hyperlipemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure and the like (Circulation Research, 2006, 98, 169-171; Hypertension 2003, 41, 1183-90). In addition, the crystal form of the compound of the formula 1 of the present invention has no safety concerns such as genotoxicity and repeated toxicity as a result of a toxicity test on an animal, and is highly safe.

The term " treatment " as used herein refers to stopping or delaying the progression of a disease when used in an object exhibiting an onset symptom. The term " prevention " means stopping or delaying the onset symptom .

Hereinafter, the present invention will be described more specifically based on the following examples and test examples. However, these examples and test examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited to these examples and test examples in any sense.

The present invention, that is, the novel crystalline form of the compound of Formula 1 as a novel substance, has the necessary pharmacological activity as a medicament that can be achieved by selectively inhibiting xanthine oxidase, and at the same time has excellent pharmacological activities such as stability, Effect. As a novel material, the crystalline form of the compound of Formula 1 is useful because it shows little weight change due to humidity change over a wide range of relative humidity, and there is no change in crystal form with humidity change. It is also possible to control the production of these crystal forms according to the various methods provided in the present invention.

Figure 1 is an X-ray powder diffraction (XRD) pattern of the crystalline form of the compound of formula 1 of the present invention.
2 shows the results of DSC analysis of the crystalline form of the compound of formula 1 of the present invention.
Fig. 3 shows the results of the thermogravimetric analysis (TGA) of the crystalline form of the compound of formula 1 of the present invention.
4 is an isothermal moisture absorption curve and an isothermal dehumidification curve of the crystalline form of the compound of formula 1 of the present invention.

Manufacturing example  : Preparation of compound of formula 1

Manufacturing example  1-1: 1- (3- Cyano Indol-5-yl) Pyrazole -4- Carboxylic acid  Preparation of ethyl ester

The title compound was obtained through the following procedures (1), (2) and (3).

(1) Preparation of 1- (3-formyl-1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester

Oxalyl chloride (0.56 mL, 6.6 mmol) was added to 50 mL of anhydrous dichloromethane, N, N-dimethylformamide (0.51 mL, 6.6 mmol) was added at 0 ° C, and the mixture was stirred at 0 ° C for 30 minutes. To this reaction solution was added a mixed solution of compound 1- (1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester (1.40 g, 5.47 mmol) and 50 mL of dichloromethane and refluxed at room temperature for 1 hour The solvent was removed. 100 mL of tetrahydrofuran and 100 mL of a 20% ammonium acetate aqueous solution were added, and the mixture was refluxed with stirring for 30 minutes. After completion of the reaction, the reaction solution was cooled, ethyl acetate was added thereto, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.

Mass (EI) 284 (M ^& lt ^; + & gt ^; +1)

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

(3- formyl-1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester obtained in the above step (1) was dissolved in pyridine (150 mL), and hydroxyammonium chloride (499 mg, 7.18 mmol) . The mixture was heated and refluxed for 5 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and the residue was filtered through silica gel using acetone as a solvent to obtain the title compound.

Mass (EI) 299 (M ^& lt ^; + & gt ^; +1)

(3) Preparation of 1- (3-cyano-1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester

(E, Z) -hydroxyiminomethyl] -1H-indol-5-yl] pyrazole-4-carboxylic acid ethyl ester obtained in the above step (2) was dissolved in 94 mL of anhydrous tetrahydrofuran (Imidazol-1-yl) methanethione (90%, 2.79 g, 14.1 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting solid compound was separated by column chromatography to obtain 1.32 g (4.71 mmol, 86% yield) of the title compound.

Manufacturing example  1-2: 1- (3- Cyano -One- Isopropyl -Indol-5-yl) Pyrazole -4- Carboxylic acid  Preparation of ethyl ester

(3-cyano-1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester (13.84 g, 49.38 mmol) obtained in Preparation 1-1 was dissolved in 200 mL of acetonitrile. Cesium carbonate (32.17 g, 98.74 mmol) and 2-iodopropane (19.7 mL, 198 mmol) were placed, heated and refluxed with stirring for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting solid compound was separated by column chromatography to obtain 13.87 g (43.03 mmol, 87% yield) of the title compound.

Manufacturing example  1-3: 1- (3- Cyano -One- Isopropyl -Indol-5-yl) Pyrazole -4- The carboxylic acid (compound of formula 1)  Produce

Pyrazole-4-carboxylic acid ethyl ester (13.87 g, 43.03 mmol) obtained in Preparation Example 1-2 was dissolved in 140 mL of tetrahydrofuran, 140 mL of methanol and 70 mL of 6N sodium hydroxide, and the mixture was reacted at room temperature for 1 hour. After the reaction, the organic solvent was removed under reduced pressure, and the remaining aqueous layer was washed with ethyl acetate. The aqueous solution was acidified to pH 1 by adding concentrated hydrochloric acid, and the precipitated solid compound was filtered, washed with distilled water and dried to obtain 12.09 g (41.08 mmol, 95% yield) of the title compound.

Example  One: Equation 1 Preparation of crystalline form of compound

3.82 kg of the prepared 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was dissolved in 382 L of acetone and slowly added dropwise to 40 L of water at 90 ° C under stirring. After the addition was completed, stirring was continued for about 12 hours, followed by cooling and filtration to obtain 3.40 kg of a crystalline form of the compound of formula 1 of the present invention. ¹ H-NMR and IR were measured for the crystal form of the obtained compound of formula 1, and 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 , 8.1 (1H, s), 9.1 (1H, s), 12.6 (1H, br)

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

As a result of XRD measurement, the crystal form of the compound of Formula 1 of the present invention showed characteristic peaks (2?) At 12.1, 13.2, 15.7, 18.3, 24.8, 25.8 and 26.6 ° And specific values of XRD are shown in Table 1 below.

Example  2

40 mg of the obtained 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was dissolved in 10 ml of tetrahydrofuran, and the solvent was slowly evaporated at room temperature, 35 g of a crystalline form of the compound was obtained. Specific values of XRD are shown in Table 2 below.

Example  3

The obtained 200 mg of 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was added to 120 ml of t-butanol and the solvent was evaporated at room temperature to obtain 190 g of crystal form was obtained. Specific values of XRD are shown in Table 3 below.

Example  4

Yl] pyrazole-4-carboxylic acid (200 mg) was added to 60 ml of ethanol, stirred in a slurry state for 24 hours, and filtered to obtain the compound of formula 1 < / RTI > compound was obtained. Specific values of XRD are shown in Table 4 below.

Example  5

The obtained 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid (200 mg) was added to 70 ml of acetonitrile, stirred in a slurry state for 24 hours, 179 g of a crystalline form of the compound of formula 1 of the present invention was obtained. Specific values of XRD are shown in Table 5 below.

Example  6

100 mg of 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was added to 120 ml of chloroform, stirred for 24 hours in a slurry state, 1 < / RTI > Specific values of XRD are shown in Table 6 below.

Example  7

7.3 kg of the prepared sodium salt of 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was dissolved in 11.6 L of 10 N NaOH solution, kg < / RTI > The crystal form of the compound of Formula 1 of the present invention began to precipitate. When the pH reached about 1 to 2, the dropping of the hydrochloric acid was stopped and the mixture was stirred until uniform and filtered to obtain 15.96 kg of the crystalline form of the compound of formula 1 of the present invention.

Test Example  One

Powder X-ray Diffraction test

About 40 mg of the crystalline form of the compound of formula 1 of the present invention obtained in Example 1 was charged into a sample holder and mounted on a X'Pert PRO manufactured by Panalytical, and the diffraction pattern was measured in the range of 4 to 40 ° / 2? Respectively. The detailed analysis conditions are as follows.

ime per Step: 99.45s

Stepsize: 0.0394 °

Scan Mode: Continuous

Voltage / Current: 45kV / 40mA

Cu-target (Ni-filter)

Fixed Divergence Slit

Soller Slit: Soller 0.04 rad

Detector Slits 0.04 rad Soller slits, anti-scatter slit P7.5

1, when the crystal form of the compound of Formula 1 of the present invention was analyzed, characteristic peaks (2?) Of XRD spectra measured at CuK ?, 45 kV and 40 m? Were 12.1, 13.2, 15.7, 18.3, 24.8 and 25.8 , 26.6 °.

Test Example  2

Differential injection Calorimetric method  ( DSC )

A differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC821 ^e a. 3 mg of the crystalline form of the compound of formula 1 obtained in Example 1 was added to an aluminum pan and the weight was accurately recorded. I covered the fan with a hole lid and grabbed the frame. The pan was mounted on the apparatus and heated to 25-300 ° C at a rate of 10 ° C / min under nitrogen purge. Indium metal was used as the calibration standard. The obtained results are shown in Fig. As can be seen from FIG. 2, the crystal form of the compound of Formula 1 of the present invention shows an endothermic peak due to melting point as an Onset value at 263 to 268 ° C, from which it can be seen that it is a column-stable crystalline form showing a melting point at a high temperature.

Test Example  3

Thermogravimetric analysis  ( TGA )

Thermogravimetric analysis (TGA) was performed using Mettler Toledo TGA850. 5 mg of the crystalline form of the compound of formula 1 of the present invention obtained in Example 1 was placed in an aluminum pan and mounted on the apparatus. And heated at 25 ° C to 300 ° C at a rate of 10 ° C / min under nitrogen purge. Nickel and Aluminum ™ were used as calibration standards. The obtained results are shown in Fig.

As can be seen from FIG. 3, it was confirmed that the crystal form of the compound of Formula 1 of the present invention did not show any weight reduction in the endothermic section of the differential scanning calorimetry. From this, it was confirmed that the crystal form of the compound of the formula 1 of the present invention was a crystal form stable to heat.

Test Example  4

Isothermal Absorption / Dehumidification  Analysis method

Moisture / dehumidification data were collected on the VTI-SA Vapor Sorption Analyzer for the crystal form of the compound of Formula 1 of the present invention obtained in Example 1. The samples were not dried prior to analysis and were subjected to moisture absorption and dehumidification at 5% RH in a relative humidity (RH) range of 5 to 95% at 25 ° C. The results are shown in Fig. As can be seen from FIG. 4, the crystal form of the compound of formula 1 of the present invention shows a weight change of only 0.3% or less with respect to the change of external humidity of 5 to 95% RH. That is, the crystal form according to the present invention is very stable against changes in relative humidity, and there is no change in the crystal form according to the humidity change.

Test Example  5

Thermal stability

About 50 mg of the crystalline form of the present invention obtained in Example 1 was placed in a Duma bottle and stored at 40 ± 2 ° C., 75 ± 5% RH or 60 ± 2 ° C. and 5 ± 5% RH. After 2 weeks, 8 weeks and 12 weeks, each sample was taken out of Dumas bottle and dissolved in acetonitrile / water / 0.1 N sodium hydroxide solution = 30/60/10 (v / v / v%) mixed solvent and analyzed by HPLC. The HPLC analysis conditions are as follows.

HPCL analysis conditions

Column: dC18 (4.6 mm ID x 450 mm L, Particle Size 5.0 mu m, Agilent)

Column temperature: 20 DEG C

Mobile phase: MeCN / H2O / TFA = 35/65/0.1

Flow rate: 1.0 mL / min.

Detection: 250 nm, UV

Injection volume: 10 μl

Total analysis time: 40min.

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

As shown in Table 8, it was confirmed that the crystalline form of the compound of Formula 1 of the present invention exhibited excellent stability up to 12 weeks at 40 ± 2 ° C., 75 ± 5% RH or 60 ± 2 ° C. and 5 ± 5% RH.

Test Example  6

Xanthine  Oxidase ( xanthine oxidase ) Selectivity test for enzyme

The plasma form of the compound of formula 1 of the present invention was administered to male mice (BALB / c species) at a dose of 100, 300 mg / kg, and the blood was collected for 24 hours. Plasma was isolated from the blood and the orotic acid ), Orotidine (OD) and compound concentration were quantitatively analyzed using LC-MS / MS, and the results are shown in Table 9 below. This test was conducted in the same manner as in Example 1 except that the crystal form of the compound of Formula 1 was replaced by orotate phosphoribosyl transferase (OPRT), orrotidine monophosphate decarboxylase (OMPDC), which is a main enzyme involved in pyrimidine metabolism, As shown in the following Table 9, OA and OD in the blood did not increase. From this, it was found that the crystal form of the compound of Formula 1 was the same as that of xanthine oxidase . ≪ / RTI >

Test Example  7

Evaluation of bioavailability in animals

In order to evaluate the bioavailability of the crystalline form of the compound of formula 1 of the present invention, a single type of compound of formula 1 was administered intravenously and orally in rats, monkeys, and dogs, and blood was collected to determine the concentration of the crystal form of formula 1 in plasma -MS / MS. ≪ / RTI > The pharmacokinetic parameters (C _max , AUC _inf , CL, Vd _ss , t _{1 .2} ) in each route of administration were obtained and the bioavailability was determined as a percentage of AUC at the time of intravenous administration to AUC. The rates of bioavailability in rats, monkeys and dogs were 37-61%, 23-39% and 75%, respectively.

Claims (11)

The characteristic peak (2?) Of the X-ray diffraction pattern spectrum is
1) 12.1, 13.2, 15.7, 18.3, 24.8, 25.8, 26.6;
2) 12.1, 13.2, 15.6, 18.2, 24.7, 25.6, 26.6;
3) 12.2, 13.3, 15.9, 18.4, 24.7, 25.9, 26.7;
4) 12.1, 13.2, 15.7, 18.3, 24.9, 25.8, 26.6;
5) 12.1, 13.2, 15.7, 18.3, 24.9, 25.8, 26.6;
6) 12.1, 13.2, 15.8, 18.3, 24.9, 25.8, 26.6; or
7) 12.1, 13.3, 15.8, 18.3, 24.9, 25.8, 26.7; Of the compound of formula < RTI ID = 0.0 > 1 < / RTI >
[Formula 1]

. delete The method according to claim 1, wherein the characteristic peak (2?) Of the X-ray diffraction pattern spectrum is
1) 12.1, 13.2, 15.7, 16.6, 18.3, 19.6, 20.9, 23.1, 24.8, 25.8, 26.6;
2) 12.1, 13.2, 15.6, 16.6, 18.2, 19.6, 20.9, 24.7, 25.6, 26.6;
3) 12.2, 13.3, 15.9, 16.7, 18.4, 19.7, 21.1, 24.7, 25.9, 26.7;
4) 12.1, 13.2, 15.7, 16.6, 18.3, 19.6, 20.9, 24.9, 25.8, 26.6;
5) 12.1, 13.2, 15.7, 16.6, 18.3, 19.6, 21.0, 23.3, 24.9, 25.8, 26.6;
6) 12.1, 13.2, 15.8, 16.7, 18.3, 19.6, 21.0, 23.1, 24.9, 25.8, 26.6; or
7) 12.1 °, 13.3 °, 15.8 °, 16.7 °, 18.3 °, 19.6 °, 21.0 °, 23.2 °, 24.9 °, 25.8 °, 26.7 °. The crystalline form according to claim 1, which shows a differential scanning calorimetry curve having a melting point of 263 to 268 캜 as an Onset value of DSC. The compound of formula 1 of claim 1 is dissolved in anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate Is dissolved in a solvent selected from the group consisting of propyl acetate, t-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene and mixtures thereof, To form a crystalline form of the compound of formula (1). The method according to claim 5, wherein the crystallization is carried out by a method selected from the group consisting of a method of cooling a solution, a method of evaporating a solvent, a method of supersaturation by adding an adverse solvent, Lt; / RTI > The method according to claim 5, wherein the compound of formula (1) is dissolved in acetone and then evaporated to prepare a crystalline form of the compound of formula (1). The method according to claim 5, wherein the compound of the formula 1 of claim 1 is dissolved in ethanol, acetonitrile or chloroform to obtain a slurry, which is stirred and filtered to prepare a crystalline form of the compound of formula 1. 6. The method according to claim 5, wherein the compound of formula (1) is dissolved in tetrahydrofuran or t-butanol, and the solvent is evaporated at room temperature to prepare a crystalline form of the compound of formula (1). 6. The method according to claim 5, wherein the sodium salt of the compound of the formula (1) is dissolved in a sodium hydroxide solution, hydrochloric acid is added dropwise to form crystals, and the mixture is stirred until uniform, Way. A method for treating or ameliorating a disease associated with xanthine oxidase selected from the group consisting of hyperlipidemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammatory and joint disease, inflammatory bowel disease, / RTI >

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