KR20120114174A - 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid crystalline form and the producing method thereof - Google Patents

Abstract

PURPOSE: A crystalline form of a compound and a method for preparing the same are provided to selectively suppress xanthine oxidase and to ensure thermal stability and storage stability. CONSTITUTION: A crystalline form of 1-(3-cyano-1-isopropyl-indole-5-yl)pyrazole-4-carboxylic acid is denoted by formula 1. A method for preparing the crystalline form of the compound of formula 1 comprises a step of dissolving the compound of chemical formula 1 in a solvent and crystallizing. The solvent includes anhydrous ethanol, 2-methoxy ethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofurane, acetonitrile, chloroform, toluene, or a mixture thereof.

Description

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

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

[Formula 1]

Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and xantine formed to uric acid. When too much uric acid is present in the body, it causes a variety of diseases, and the typical gout. Gout refers to a condition in which uric acid crystals accumulate in the cartilage, ligaments, and surrounding tissues of the joints, causing severe inflammation and pain, and the incidence has increased steadily over the past 40 years (NL Edwards, Arthritis). & Rheumatism, 2008, 58, 2587-2590). In addition, many researchers have confirmed that there is a 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). Thus, 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, inflammatory and joint diseases, inflammatory bowel disease, and the like.

On the other hand, the chemical and physical stability of the drug used as an active ingredient in the pharmaceutical field to ensure a high quality and maintain it for a long time is very important. The pharmaceutical excellence of these active ingredients is of great value as an effect of the invention with the excellence of pharmacological effects.

An object of the present invention is to provide a crystalline pharmacological activity and stability, non-hygroscopicity, ease of handling and the like, which are achieved by selectively binding to xanthine oxidase by providing a crystalline form of Formula 1 as a novel substance.

Hereinafter, the present invention will be described in detail.

The present invention relates to a compound of formula 1 which is a novel substance useful as an xanthine oxidase inhibitor (Compound name: 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid ) Gives the crystalline form.

[Formula 1]

The crystalline form of the compound of Formula 1, that is, the crystalline form of 1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid, exhibits inhibitory activity against xanthine oxidase, and the preparation method thereof is It is explained in detail in the preparation examples below.

Xanthine oxidase is an enzyme that converts hypoxanthine to xanthine and xantine to uric acid. When too much uric acid is present in the body, it causes a variety of diseases, and the typical gout. The crystalline form of the compound of formula 1 selectively inhibits xanthine oxidase.

The crystalline form of the compound of formula 1 of the present invention shows a characteristic peak (2θ) at 12.1 °, 13.2 °, 15.7 °, 18.3 °, 24.8 °, 25.8 °, and 26.6 ° when analyzed by X-ray powder diffraction (XRD). More specifically, the crystalline form of the compound of formula 1 is at 12.1 °, 13.2 °, 15.7 °, 16.6 °, 18.3 °, 19.6 °, 20.9 °, 23.1 °, 24.8 °, 25.8 °, 26.6 ° in X-ray powder diffraction analysis. The characteristic peak 2θ is shown.

In addition, the crystalline form of the compound of formula 1 of the present invention exhibits an endothermic peak due to melting point at 263 ~ 268 ℃ as an onset value, when analyzed by differential scanning calorimetry, from which It can be seen that the crystalline form of Compound 1 as a substance is a very stable crystalline form that exhibits a high melting point of 263 to 268 캜 (FIG. 2). This can be confirmed by the thermal stability obtained after 12 weeks of storage at a high temperature of 40 ± 2 ℃, 75 ± 5% RH or 60 ± 2 ℃, 5 ± 5% RH. Residual content of the compound stored for 12 weeks is not lost at all compared to the content initially stored. In the analysis using thermogravimetric analysis, it was confirmed that no weight loss was observed in the endothermic section (263-268 ° C.) of the differential scanning calorimetry (FIG. 3).

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

As described above, the crystalline form of the compound of formula 1 of the present invention shows little change in weight according to humidity change in a wide range of relative humidity, no change in crystalline form due to humidity change, and is very stable to heat, such as storage stability or milling. It is especially useful from a viewpoint of a process.

The present invention also provides a process for preparing the 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 is anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl 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.

Crystallization of a compound of formula 1 from a suitable solvent may be, for example, by cooling the solution, evaporating the solvent, or supersaturating by adding an anti-solvent (a solvent in which the formula 1 compound is poorly soluble, such as water, etc.) , 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 as such or as a pharmaceutical composition mixed with other active ingredients or with a suitable carrier or excipient, such as in combination therapy.

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

Accordingly, the pharmaceutical composition according to the invention comprises one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. Can be prepared by conventional methods. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, known carriers and excipients, and means known in the art, for example Remingston's Pharmaceutical Sciences, can be suitably used.

For example, in the present invention, a crystalline form of the compound of Formula 1 may be formulated into an injectable preparation, an oral preparation, and the like as desired.

For injection, the components of the present invention may be formulated in liquid solution, preferably in a pharmaceutically suitable buffer such as Hank's solution, Ringer's solution, or physiological saline. For mucosal permeation administration, penetration aids suitable for the barrier to pass through are 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 the active compound. Such carriers allow the compounds of the 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 medications can be prepared, for example, as follows.

The crystalline form of the compound of formula 1 and one or more excipients according to the invention are mixed, optionally pulverized such mixtures and, if necessary, added with appropriate auxiliaries, followed by treating the mixture of granules to obtain a tablet or sugar core. Can be. Suitable excipients include fillers such as lactose, sucrose, mannitol or sorbitol; Cellulose based materials such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone (PVP) Etc. can be mentioned. If necessary, a disintegrating agent such as crosslinked polyvinyl pyrrolidone, urticaria, or a salt thereof such as alginic acid or sodium alginate, a lubricant such as magnesium stearate, a carrier such as a binder, or the like may be added.

Formulations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycol or sorbitol, as well as pushed capsules made of gelatin. The push-fix capsule 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 compounds may be dissolved or dispersed in suitable media, such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be included. All preparations for oral administration can be prepared in amounts suitable for such administration.

Crystalline forms of the compound of formula 1, ie the active compound, may also be formulated for parenteral infusion by injection, eg, by large pill injection or continuous infusion. Injectable formulations may be presented in unit dosage form, eg, in ampoules or in multi-dos containers, with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants. The active compound may be in the form of a powder for combination with a suitable vehicle, such as sterilized pyrogen-free water, prior to use. The active compounds may also be formulated in rectal dosage compositions such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.

The pharmaceutical composition according to the present invention contains a crystalline form of the compound of formula 1 in an amount effective to achieve its intended purpose. In particular, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

When formulated in unit dosage form, the crystalline form of the compound of formula 1 as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg based on the compound of formula 1. 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, dosages required for adult treatment typically range from 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, usually separated by a single dose for intramuscular or intravenous administration to an adult, will be sufficient, but for some patients a higher daily dosage may be desirable.

The present invention also provides a method of treating or preventing a human xanthine oxidase related disease using a therapeutically effective amount of a crystalline form of a compound of formula 1. “Human xanthine oxidase related disease” is a disease that can be treated or prevented by inhibiting human xanthine oxidase, for example, hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, diabetes-related complications, kidney disease, Inflammation and joint diseases, inflammatory bowel disease, and the like, but are not limited thereto. Examples of the diabetes-related complications include hyperlipidemia, arteriosclerosis, obesity, hypertension, retinopathy, renal failure, and the like (Circulation Research, 2006, 98, 169-171; Hypertension 2003, 41, 1183-90). In addition, the crystalline form of the compound of formula 1 of the present invention has no safety risks such as genotoxicity or repetitive toxicity as a result of toxicity testing in animals.

The term "treatment" means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms of onset, and the term "preventing" means stopping or delaying the onset of disease when used in a subject who does not exhibit symptoms but has a high risk of developing the disease. It means to let.

Hereinafter, the present invention will be described in more detail based on the following Examples and Test Examples. However, these examples and test examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples and test examples.

The present invention, i.e., a crystalline form of the compound of formula 1 as a novel substance, has the necessary pharmacological activity as a medicament which can be achieved by selectively inhibiting xanthine oxidase and at the same time, excellent pharmaceutical properties such as stability, for example, thermal stability and storage stability. Has an effect. As a novel substance, the crystalline form of the compound of formula 1 is useful because it shows little change in weight according to humidity change over a wide range of relative humidity, and no change in crystalline form due to humidity change. It is also possible to control the preparation of these crystalline forms according to the various methods provided herein.

1 is an X-ray powder diffraction (XRD) pattern of the crystalline form of the compound of formula 1 of the present invention.
Figure 2 is a differential scanning calorimetry (DSC) analysis of the crystalline form of the compound of formula 1 of the present invention.
Figure 3 is a thermogravimetric analysis (TGA) of the crystalline form of the compound of formula 1 of the present invention.
4 is an isothermal hygroscopic curve and isothermal dehumidification curve of the crystalline form of the compound of formula 1 of the present invention.

Manufacturing example  Preparation of the Compound of Formula 1

Manufacturing example  1-1: 1- (3- Cyano -1H-indole-5-day) 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, and N, N-dimethylformamide (0.51 mL, 6.6 mmol) was added at 0 ° C., and stirred at 0 ° C. for 30 minutes. To this reaction mixture, a mixture of compound 1- (1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester (1.40 g, 5.47 mmol) and 50 mL of dichloromethane was added and stirred at reflux for 1 hour at room temperature. After removing the solvent. 100 mL of tetrahydrofuran and 100 mL of 20% aqueous ammonium acetate solution were added thereto, and the mixture was heated and refluxed for 30 minutes. After completion of the reaction, the reaction solution was cooled, ethyl acetate was added, the reaction solution was washed with aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound.

Mass (EI) 284 (M ⁺ +1)

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

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

Mass (EI) 299 (M ⁺ +1)

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

1- [3-[(E, Z) -hydroxyiminomethyl] -1H-indol-5-yl] pyrazole-4-carboxylic acid ethyl ester obtained in step (2) was added to 94 mL of anhydrous tetrahydrofuran. After dissolving, di (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 solution 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 -Indole-5-day) Pyrazole -4- Carboxylic acid  Preparation of Ethyl Ester

1- (3-cyano-1H-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester (13.84 g, 49.38 mmol) obtained in Preparation Example 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 added thereto, followed by heating to reflux 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 give 13.87 g (43.03 mmol, 87% yield) of the title compound.

Manufacturing example  1-3: 1- (3- Cyano -One- Isopropyl -Indole-5-day) Pyrazole -4- Of carboxylic acids (compound 1)  Produce

1- (3-cyano-1-isopropyl-indol-5-yl) pyrazole-4-carboxylic acid ethyl ester (13.87 g, 43.03 mmol) obtained in Preparation Example 1-2 was diluted with 140 mL of tetrahydrofuran, To 140 mL of methanol and 70 mL of 6N sodium hydroxide solution were added and 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 the addition of concentrated hydrochloric acid, and the precipitated solid compound was filtered, washed with distilled water and dried to give 12.09 g (41.08 mmol, 95% yield) of the title compound.

Example  One: Equation 1 Preparation of Crystalline Forms of Compounds

3.82 kg of prepared 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was dissolved in 382 L of acetone, which was slowly added dropwise to 40 L of 90 ° C. water while stirring. After the addition was completed, the mixture was stirred for about 12 hours, further cooled and filtered to obtain 3.40 kg of crystalline form of the compound of formula 1 of the present invention. About the crystalline form of obtained Formula 1 compound, ¹ H-NMR and IR were measured and 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 ) 2500-3150, 2215, 1669, 1558, 1502, 1263

In addition, as measured by XRD, the crystal forms of the compound of formula 1 of the present invention showed a characteristic peak (2θ) at 12.1, 13.2, 15.7, 18.3, 24.8, 25.8, and 26.6 ° as measured in the spectrum shown in FIG. In addition, specific values of XRD are shown in Table 1 below.

Example  2

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

Example  3

200 mg of prepared 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 the compound of Formula 1 of the present invention. 190 g of crystalline form was obtained. Specific values of XRD are shown in Table 3 below.

Example  4

200 mg of the prepared 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was added to 60 ml of ethanol, and stirred for 24 hours in a slurry state, followed by filtration. 184 g of crystalline form of 1 compound was obtained. Specific values of XRD are shown in Table 4 below.

Example  5

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

Example  6

200 mg of the prepared 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid was added to 120 ml of chloroform, and stirred for 24 hours in a slurry state, followed by filtration. 196 g of crystalline form of 1 compound was obtained. Specific values of XRD are shown in Table 6 below.

Example  7

Dissolve 7.3 kg of the sodium salt of 1- [3-cyano-1-isopropyl-indol-5-yl] pyrazole-4-carboxylic acid in 11.6 L of 10N NaOH solution, and hydrochloric acid 12.1 while stirring the solution. kg was slowly added dropwise. The crystal form of the compound of formula 1 of the present invention began to precipitate. When the pH was about 1 to 2, the dropwise addition of hydrochloric acid was stopped and stirred until the mixture was uniform, followed by filtration to give 15.96 kg of 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 obtained in Example 1 was charged to a sample holder, mounted on X'Pert PRO from Panalytical Inc., and the diffraction pattern was measured in the range of 4-40 ° / 2θ. 1 is shown. 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

As can be seen in Figure 1, when analyzing the crystalline form of the compound of formula 1 of the present invention, the characteristic peak value (2θ) of the XRD spectrum measured at CuKα, 45kV, 40mPa is 12.1, 13.2, 15.7, 18.3, 24.8, 25.8 , 26.6 °.

Test Example  2

Differential scanning Calorimetry  ( DSC )

Differential Scanning Calorimetry (DSC) was performed using DSC821 ^e from Mettler Toledo. 3 mg of the crystalline form of the compound of formula 1 obtained in Example 1 was placed in an aluminum pan and the weight was recorded accurately. Cover the pan with a punched lid and hold the mold. The fan was mounted to the apparatus and heated at 25 ° C. to 300 ° C. at a rate of 10 ° C./min under a nitrogen purge. Indium metal was used as calibration standard. The obtained result is shown in FIG. As confirmed in Figure 2, the crystalline form of the compound of formula 1 of the present invention exhibits an endothermic peak by the melting point as an Onset value at 263 ~ 268 ℃, it can be seen that the melting point is a stable crystal form at high temperatures.

Test Example  3

Thermogravimetric analysis  ( TGA )

Thermogravimetric Analysis (TGA) was performed using a Mettler Toledo TGA850. 5 mg of the crystalline form of the compound of formula 1 obtained in Example 1 was added to an aluminum pan and mounted in an apparatus. Heated at a rate of 10 ° C./min to 25-300 ° C. under a nitrogen purge. Nickel and Aluminum ™ were used as calibration standards. The obtained result is shown in FIG.

As can be seen in Figure 3, it was confirmed that the crystalline form of the compound of formula 1 of the present invention does not show a weight loss in the endothermic section of the differential scanning calorimetry. From this, it was confirmed that the crystalline form of the compound of formula 1 of the present invention was a heat stable crystalline form.

Test Example  4

Isothermal Hygroscopic Of Dehumidification  Analysis method

For the crystalline form of the compound of formula 1 obtained in Example 1, moisture absorption / desorption data was collected on a VTI-SA Vapor Sorption Analyzer. The samples were not dried prior to analysis, and were absorbed and dehumidified at 5% RH intervals at a relative humidity (RH) of 5 to 95% while maintaining 25 ° C. The results are shown in FIG. As can be seen from Figure 4, it can be seen that the crystalline form of the compound of formula 1 of the present invention exhibits a weight change of only 0.3% or less with respect to an external humidity change of 5 to 95% RH. That is, the crystalline form according to the present invention is very stable against the relative humidity change, and there was no change of the crystalline form due 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., 5 ± 5% RH. After 2, 8 and 12 weeks, each sample was taken out of Duma bottle, dissolved in acetonitrile / water / 0.1 N sodium hydroxide solution = 30/60/10 (v / v / v%) mixed solvent and analyzed by HPLC. HPLC analysis conditions are as follows.

HPCL analysis conditions

Column: dC18 (4.6mm I.D x 450mm L, Particle Size 5.0㎛, Agilent)

Column temperature: 20 ℃

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 40 min.

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

As shown in Table 8, the crystalline form of the compound of formula 1 of the present invention was confirmed to exhibit excellent stability up to 12 weeks at 40 ± 2 ℃, 75 ± 5% RH or 60 ± 2 ℃, 5 ± 5% RH.

Test Example  6

Xanthine  Oxidase ( xanthine oxidase Selectivity Identification Enzyme Test

The crystalline form of the compound of Formula 1 was administered to male mice (BALB / c species) at doses of 100 and 300 mg / kg, and blood was collected at 24 hours to separate plasma and ortho acid (OA; orotic acid in plasma). ), Orotidine (OD) and the concentrations of the compounds were quantitatively analyzed using LC-MS / MS and the results are shown in Table 9 below. This test shows that the crystalline form of the compound of formula 1 is orthotate phosphoribosy ltransferase (OPRT; orotidine monophosphate decarboxylase), which is a major enzyme involved in pyrimidine metabolism. As a result of conducting the present in vivo test, there was no increase in blood OA and OD as shown in Table 9. From this, the crystalline form of the compound of formula 1 was xanthine oxidase. It was confirmed to bind selectively to.

Test Example  7

Bioavailability Assessment in Animals

In order to evaluate the bioavailability of the crystalline form of the compound of formula 1 of the present invention, the rats, monkeys, and dogs were subjected to a single intravenous oral administration of the crystalline form of the compound of formula 1, and blood was collected to determine the concentration of the crystalline form of the compound of formula 1 in plasma. Quantification using MS / MS. After obtaining the pharmacokinetic parameters _{(C max, AUC inf, CL} , Vd ss, t 1 .2) at each administration route it was determined as a percentage of AUC The bioavailability upon oral administration to the AUC when administered intravenously. Bioavailability in rats, monkeys, and dogs was 37-61%, 23-39%, and 75%, respectively.

Claims (11)

Crystalline Form Of A Compound Of Formula 1
[Formula 1]

The crystalline form according to claim 1, wherein the characteristic peaks (2θ) of the X-ray diffraction pattern spectrum appear at 12.1 °, 13.2 °, 15.7 °, 18.3 °, 24.8 °, 25.8 °, and 26.6 °. The characteristic peak (2θ) of the X-ray diffraction pattern spectrum according to claim 1, wherein the characteristic peaks 2θ are 12.1 °, 13.2 °, 15.7 °, 16.6 °, 18.3 °, 19.6 °, 20.9 °, 23.1 °, 24.8 °, 25.8 °, 26.6 ° Crystalline form, characterized by appearing in. The crystalline form according to claim 1, wherein a differential scanning calorimetry curve having a melting point of 263 to 268 ° C is shown as an Onset value of DSC. Formula 1 compound of claim 1 is anhydrous ethanol, 2-methoxyethanol, isobutanol, n-butanol, n-octanol, n-propanol, isopropanol, t-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate 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. Crystallization from to prepare a crystalline form of the compound of formula 1. The method according to claim 5, wherein the crystallization is performed by a method selected from the group consisting of a method of cooling a solution, a method of evaporating a solvent, a supersaturation by adding an antisolvent, or a method of slurry conversion. How to make. The method of claim 5, wherein the compound of formula 1 is dissolved in acetone, and then evaporated to prepare the crystalline form of the compound of formula 1. The method of claim 5, wherein the compound of formula 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. The method of 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. The method according to claim 5, wherein the sodium salt of the compound of formula 1 is dissolved in a sodium hydroxide solution, and then hydrochloric acid is added dropwise to form a crystal, and the mixture is stirred until homogeneous to prepare a crystalline form of the compound of formula 1 Way. Xanthine oxyazase-related diseases selected from the group consisting of hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes mellitus, kidney disease, inflammatory and joint diseases, and inflammatory bowel disease, including the crystalline form of the compound of claim 1 Therapeutic or prophylactic composition.

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