Crystals of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione compound and method for preparing the same.

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to crystalline 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione compounds and methods for preparing the same, and more particularly to crystalline compounds represented by formula (1), methods for preparing crystalline compounds represented by formula (1), compositions and formulations containing the crystalline compounds, and the use of the crystalline compounds or compositions and formulations containing the crystalline compounds in the preparation of agents for lowering uric acid, resisting inflammation, and / or treating and / or preventing uric acid-related diseases and / or gouty diseases. [Formula 1] TIFF2026510570000013.tif44168

Description

[Technical Field]

[0001] The present invention belongs to the field of medical technology and, more specifically, relates to crystals of the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, compositions and formulations containing said crystals, methods for preparing them, and the use of said crystals or compositions or formulations containing said crystals in the manufacture of pharmaceuticals for lowering uric acid, reducing inflammation, and / or treating and / or preventing uric acid disease or gout. [Background technology]

[0002] Hyperuricemia is a metabolic disorder caused by impaired purine metabolism, leading to elevated blood uric acid levels. When blood uric acid levels remain consistently high, the body's uric acid concentration becomes excessively high, leading to the formation of uric acid crystals. These crystals can trigger an inflammatory response, potentially causing a gout attack. Therefore, some gout sufferers develop symptoms after progressing from asymptomatic hyperuricemia through this crystal formation process.

[0003] Uric acid crystals typically form in the joints, kidneys, and soft tissues, causing persistent and long-term pain in patients, thus requiring long-term treatment with uric acid-lowering drugs. When gout patients begin taking uric acid-lowering drugs, fluctuations in blood uric acid levels can partially dissolve tophi and the surface of uric acid crystals, potentially triggering gout attacks. The greater the decrease in blood uric acid levels, the higher the likelihood of a gout attack. This process causes significant distress to patients, sometimes leading to them being unable to continue medication. Combining acute gout attack medications with uric acid-lowering drugs often fails to adequately alleviate patient suffering.

[0004] Currently, gout treatments mainly include drugs for treating acute gout attacks (colchicine, nonsteroidal anti-inflammatory drugs, glucocorticoids), uric acid synthesis inhibitors (allopurinol, febuxostat, etc.), and uric acid excretion promoters (probenecid, benzbromarone, etc.). Colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids are primarily used during acute gout attacks. In uric acid-lowering therapy, uric acid synthesis inhibitors and uric acid excretion promoters are mainly used, but these drugs have drawbacks such as insufficient efficacy and significant side effects.

[0005] Plasma concentrations of uric acid-lowering drugs are thought to be associated with the degree of reduction in blood uric acid levels, and the degree of reduction in blood uric acid levels is thought to be associated with the frequency of gout attacks (Dalbeth, Nicola, et al. “2020 American College of Rheumatology Guideline for the Management of Gout.” Arthritis Care & Research 72.6 (2020)). To reduce the risk of acute gout attacks during initial treatment with uric acid-lowering drugs, it is crucial to control fluctuations in the plasma concentrations of these drugs. Clinical guidelines and medical practice recommend a stepwise dosing regimen for uric acid-lowering therapy (e.g., allopurinol, febuxostat, benzbromarone), starting with a low dose and gradually increasing it. Furthermore, controlling fluctuations in plasma drug concentrations after uric acid-lowering drugs have reached a steady state is even more important in reducing the frequency of gout attacks. Therefore, uric acid-lowering drugs with long half-lives that can reduce the peak-to-trough ratio of plasma drug concentrations have significant clinical importance in the treatment of gout.

[0006] International Publication No. 2016 / 119570A1 discloses a series of compounds useful for lowering uric acid, reducing inflammation, and preventing or treating uric acid-related diseases or gout. Among these, compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (formula (1)) has excellent uric acid-lowering effects. [ka]

[0007] International Publication No. 2016 / 119570A1 discloses a method for preparing and separating 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione using column chromatography, ultimately yielding a pale yellow solid (Example 2). The crystalline form of the compound is not examined in this document.

[0008] International Publication No. 2005 / 077950A2 relates to a drug having HM74A activity. Although the drug mentioned in this document is not associated with uric acid reduction, the preparation of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione is also disclosed, ultimately yielding a white solid (Example 12). The crystalline form of the compound is not examined in this document either.

[0009] To maximize the effectiveness of drugs with HM74A activity, C max The rise and T max It is necessary to achieve a reduction in [unclear]. Therefore, based on International Publication No. 2005 / 077950A2, C max The rise and T max To reduce [unclear], International Publication No. 2010 / 068581A1 discloses the crystalline form of 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-diontris(hydroxymethyl)aminomethane. This crystalline form is used to treat diseases resulting from insufficient activation of the HM74A receptor, or diseases in which activation of the HM74A receptor is beneficial. It is more stable and soluble than free acid, and C max The rise and T max This shows a decrease in absorption by the patient.

[0010] However, with uric acid-lowering drugs, excessive fluctuations in drug concentration from peak to trough are undesirable in order to avoid side effects such as gout attacks caused by a rapid decrease in blood uric acid levels. Further research has shown that the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione has a significant uric acid-lowering effect. Therefore, uric acid-lowering drugs with a long half-life can mitigate the problem of gout attacks caused by fluctuations in drug concentration.

[0011] Furthermore, each tris(hydroxymethyl)aminomethane molecule has three hydroxyl groups. Due to the high polarity of the hydroxyl groups, 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione is considered to be highly hygroscopic, which is a disadvantage for its use as a pharmaceutical. On the other hand, while the molecular weight of tri(hydroxymethyl)aminomethane is relatively high, the molecular weight of its parent compound, 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, is not very high. Therefore, when 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione is converted to tris(hydroxymethyl)aminomethane, the amount of active ingredient in the formulation decreases significantly, leading to a decline in patient medication compliance. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] International Publication No. 2016 / 119570A1 [Patent Document 2] International Publication No. 2005 / 077950A2 [Patent Document 3] International Publication No. 2010 / 068581A1 [Non-patent literature]

[0013] [Non-Patent Document 1] Dalbeth, Nicola, et al. “2020 American College of Rheumatology Guideline for the Management of Gout.” Arthritis Care & Research 72.6 (2020)

Summary of the Invention

Problems to be Solved by the Invention

[0014] Therefore, it is an important task to find crystals of the stable and pharmaceutically acceptable compound of formula (1) having a relatively long half-life for use in the preparation of pharmaceuticals for reducing uric acid levels, reducing inflammation, treating and / or preventing uric acid diseases and / or gouty diseases.

Means for Solving the Problems

[0015] (Summary of the Invention) In the research and development process of the compound of formula (1), it has been found that the free acid of the compound of formula (1) can be easily (or partially) converted into other forms by a hydration reaction in the main preparation process. In order to obtain crystals with high purity, high content and good stability and suitable for industrial production, the inventors have conducted extensive research on the crystals of the compound of formula (1) and obtained the crystals of the compound of formula (1).

[0016] The first object of the present invention is to provide crystals of the compound of formula (1).

[0017] The second object of the present invention is to provide pharmaceutically acceptable crystals of the compound of formula (1).

[0018] The third object of the present invention is to provide a method for preparing crystals of the compound of formula (1) and a method for the interconversion of said crystals.

[0019] Another object of the present invention is to provide the use of crystals of a compound of formula (1) in the manufacture of a medicament for reducing uric acid, reducing inflammation, and / or treating and / or preventing uric acid diseases and / or gouty diseases, wherein the uric acid diseases include hyperuricemia, uric acid nephropathy, etc., and the gouty diseases include gout, gouty inflammation, etc.

[0020] Another object of the present invention is to provide crystals of a compound of formula (1) with an extended half-life, thereby minimizing the problem of gout attacks caused by fluctuations in plasma drug concentrations and improving patient medication compliance.

[0021] Crystals of the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione represented by formula (1)

Chemical formula

[0022] (1) Types I, II, III, IV, V, and VI crystals The inventors have conducted extensive research on crystals of the compound of formula (1) and discovered types I, II, III, IV, V, and VI crystals of the compound of formula (1). In particular, it is pointed out that these six different crystals cannot be predicted based on the chemical formula of the compound of formula (1), and neither the structure nor the properties of any of these crystals can be predicted.

[0023] The crystals of the compound of formula (1) have the following characteristics: The X-ray powder diffraction pattern of type I crystals shown in FIG. 1; The X-ray powder diffraction pattern of type II crystals shown in FIG. 2; The X-ray powder diffraction pattern of type III crystals shown in FIG. 3; The X-ray powder diffraction pattern of type IV crystals shown in FIG. 4; and The X-ray powder diffraction pattern of type V crystals shown in FIG. 5.

[0024] This study revealed that type I crystals are monohydrates, while type II crystals are anhydrous.

[0025] Type III crystals are highly crystalline monohydrates. When Type III crystals are heated to 95°C in a water-alcohol or ketone system (e.g., C1-C3 alcohols or acetone), held for 10 minutes, and then cooled to ambient conditions (20-25°C, 70-80% RH), they are converted to Type II crystals.

[0026] Type IV crystals are highly crystalline monohydrates. They can be obtained by heating Type I crystals to 150°C and then cooling them to ambient conditions (20-25°C, 70-85% RH), or by placing Type V crystals at ambient conditions (25-30°C, 70-85% RH) for approximately 10 hours.

[0027] Type V crystals are anhydrous and are obtained by heating Type I crystals to 100°C and holding them for 30 minutes. Type V crystals have moderate crystallinity and are metastable crystals, so they convert to Type IV crystals when left under ambient conditions (25-30°C, 70-85% RH) for about 10 hours.

[0028] Type VI crystals are obtained in methanol. After drying, they are converted to Type III crystals and finally to anhydrous Type II crystals.

[0029] In summary, not all of the type I, II, III, IV, V, and VI crystals of the compound in formula (1) meet the requirements for a pharmaceutical product. Of these, type V and VI crystals are in a metastable state and cannot meet clinical requirements.

[0030] (2) Medicinally acceptable crystals Based on the above research, the present invention provides stable type I, type II, type III, and type IV crystals of the compound of formula (1).

[0031] A preferred technical solution of the present invention is as follows:

[0032] The crystalline compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, represented by formula (1), has an X-ray powder diffraction pattern that, when measured using Cu-Kα radiation, includes the following characteristic peak expressed at 2θ degrees; Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 19.0°±0.2°, 21.0°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 15.5°±0.2°, 27.6°±0.2°; Type III crystal: 6.8°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 10.2°±0.2°, 14.1°±0.2°.

[0033] When measured using Cu-Kα radiation, the crystalline compound of formula (1) exhibits an X-ray powder diffraction pattern containing the following characteristic peaks, expressed at 2θ degrees: Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 19.0°±0.2°, 21.0°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 17.1°±0.2°, 27.6°±0.2°; Type III crystal: 6.8°±0.2°, 9.7°±0.2°, 11.1°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 19.3°±0.2°.

[0034] When measured using Cu-Kα radiation, the crystalline compound of formula (1) exhibits an X-ray powder diffraction pattern containing the following characteristic peaks, expressed at 2θ degrees: Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 24.4°±0.2°, 29.1°±0.2°, 30.1°±0.2°; or Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 24.4°±0.2°, 26.1°±0.2°, 29.1°±0.2°; or Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 24.4°±0.2°, 26.1°±0.2°, 29.1°±0.2°, 30.1°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 17.1°±0.2°, 20.0°±0.2°, 24.1°±0.2°, 27.6°±0.2°, 29.4°±0.2°, 31.6°±0.2°; Type III crystal: 6.8°±0.2°, 9.7°±0.2°, 11.1°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°, 27.3°±0.2°, 27.6°±0.2°, 29.2°±0.2°, 31.4°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 9.3°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.0°±0.2°, 19.3°±0.2°, 27.6°±0.2°.

[0035] When measured using Cu-Kα radiation, the crystalline compound of formula (1) exhibits an X-ray powder diffraction pattern containing the following characteristic peaks, expressed at 2θ degrees: Type I crystals: 6.3°±0.1°, 9.6°±0.1°, 10.9°±0.1°, 12.6°±0.1°, 14.9°±0.1°, 19.0°±0.1°, 21.0°±0.1°, 24.4°±0.1°, 29.1°±0.1°, 30.1°±0.1°; or Type I crystals: 6.3°±0.1°, 9.6°±0.1°, 10.9°±0.1°, 12.6°±0.1°, 14.9°±0.1°, 19.0°±0.1°, 21.0°±0.1°, 24.4°±0.1°, 26.1°±0.1°, 29.1°±0.1°; or Type I crystals: 6.3°±0.1°, 9.6°±0.1°, 10.9°±0.1°, 12.6°±0.1°, 14.9°±0.1°, 19.0°±0.1°, 21.0°±0.1°, 24.4°±0.1°, 26.1°±0.1°, 29.1°±0.1°, 30.1°±0.1°; Type II crystals: 6.7°±0.1°, 11.0°±0.1°, 13.3°±0.1°, 15.5°±0.1°, 17.1°±0.1°, 20.0°±0.1°, 24.1°±0.1°, 27.6°±0.1°, 29.4°±0.1°, 31.6°±0.1°; Type III crystal: 6.8°±0.1°, 9.7°±0.1°, 11.1°±0.1°, 13.5°±0.1°, 20.3°±0.1°, 21.3°±0.1°, 27.3°±0.1°, 27.6°±0.1°, 29.2°±0.1°, 31.4°±0.1°; Type IV crystals: 6.2°±0.1°, 6.6°±0.1°, 9.3°±0.1°, 10.2°±0.1°, 12.5°±0.1°, 14.1°±0.1°, 15.5°±0.1°, 17.0°±0.1°, 19.3°±0.1°, 27.6°±0.1°.

[0036] The crystalline form of the compound of formula (1) has the following characteristics: The differential scanning calorimetry thermogram of a type I crystal shows an endothermic peak in the range of 270-295°C, preferably with an onset temperature of 284.5°C and a peak temperature of 285.1°C. The differential scanning calorimetry thermogram of a type II crystal shows an endothermic peak in the range of 275-293°C, preferably with an onset temperature of 283.6°C and a peak temperature of 285.2°C. The differential scanning calorimetry thermogram of the type III crystal shows an endothermic peak in the range of 270 to 295°C, preferably with an onset temperature of 284.0°C and a peak temperature of 285.4°C.

[0037] The crystalline form of the compound of formula (1) has the following characteristics: Type I crystal: X-ray powder diffraction pattern shown in Figure 1; Type II crystal: X-ray powder diffraction pattern shown in Figure 2; Type III crystal: X-ray powder diffraction pattern shown in Figure 3; and Type IV crystal: X-ray powder diffraction pattern shown in Figure 4.

[0038] The present invention also provides a method for preparing type I, type II, type III, and type IV crystals of the compound of formula (1), the following steps: The compound of formula (1) is placed in a solvent such as a lower alcohol, tetrahydrofuran, or a mixed solution of acetonitrile and water, and a method including suspension / slurry washing, volatilization and / or cooling is used to obtain type I crystals; The compound of formula (1) is placed in a solvent such as an anhydrous lower alcohol or tetrahydrofuran, heated until dissolved, and then cooled to obtain type II crystals; The compound of formula (1) is placed in a lower alcohol, the mixture is heated until dissolved, water is added, the mixture is cooled to below 20°C, and filtered to obtain type III crystals; or The steps include heating a type I crystal of the compound of formula (1) to above 100°C to obtain a metastable type V crystal, and then converting the type V crystal to a type IV crystal by placing it at ambient temperature and humidity. Includes.

[0039] The method for preparing type I, type II, type III, and type IV crystals of the compound of formula (1) is as follows: A step of obtaining type I crystals by placing a compound of formula (1) in a lower alcohol, tetrahydrofuran, or a mixed solution of acetonitrile and water (preferably tetrahydrofuran), and performing a suspension / slurry washing, volatilization, and / or cooling, wherein the compound is preferably heated until dissolved (e.g., to 50-60°C, e.g., 55°C), cooled (e.g., to 20-40°C, e.g., 30°C), and vacuum-dried at 20-40°C, e.g., 30°C for 1-24 hours (e.g., 4-8 hours); The compound of formula (1) is placed in a solvent such as an anhydrous lower alcohol or tetrahydrofuran, preferably tetrahydrofuran, the mixture is heated until dissolved, then cooled, preferably the compound is heated until dissolved (e.g., 50-60°C, e.g., up to 55°C), then cooled to 15-25°C (e.g., room temperature 25°C), filtered, and the resulting solid is vacuum dried at 45-55°C, e.g., 50°C for 1-24 hours (e.g., 4-8 hours) to obtain type II crystals; A compound of formula (1), for example, a type I crystalline compound, is dissolved in a lower alcohol (for example, C1-3 alcohols such as methanol, ethanol, and propanol), the mixture is heated until dissolved (for example, 50-60°C, e.g., up to 55°C), optionally filtered, and the resulting solution or filtrate is left at 15-25°C (e.g., room temperature 25°C) to slowly evaporate the solvent and produce type III crystals, or a compound of formula (1), for example, a type I crystalline compound, is dissolved in a lower alcohol (for example, The process involves dissolving a C1-6 alcohol (e.g., methanol, ethanol, and propanol) in a mixture of water (with a mass ratio of alcohol to water of 1:5-5:1, e.g., 1:3), cooling the mixture to below 20°C (e.g., 5-20°C, e.g., 5°C), adding the type III crystal species, stirring the mixture for 1-24 hours (e.g., 4-8 hours), then filtering the mixture, and vacuum-drying the resulting solid at 25-40°C, e.g., 30°C, for 1-24 hours (e.g., 4-8 hours) to obtain type III crystals; The steps involve heating a type I crystal of the compound of formula (1) to 100°C or higher (e.g., 100-150°C, e.g., 100°C) to obtain a metastable type V crystal, and then converting the type V crystal to a type IV crystal by leaving it at ambient temperature (e.g., 15-35°C, e.g., 25-30°C) and a predetermined humidity (e.g., RH=30-90%, e.g., RH=70-85%) for 1-24 hours (e.g., 4-8 hours). Includes.

[0040] The present invention also provides a pharmaceutical composition comprising a crystalline form of the compound of formula (1) and a pharmaceutically acceptable carrier, wherein the crystalline form includes type I crystals, type II crystals, type III crystals, and type IV crystals, and combinations thereof. Based on the weight of the pharmaceutical composition, the crystalline form of the compound of formula (1) accounts for 1 to 99% by weight, for example 20 to 80% by weight, 30 to 70% by weight, or 45 to 55% by weight, and the pharmaceutically acceptable carrier accounts for 99 to 1% by weight, for example 80 to 20% by weight, 70 to 30% by weight, or 55 to 45% by weight.

[0041] The pharmaceutical composition of the present invention includes the presence of the crystalline material in a pure form, with a content of 94.5% by weight or more, 95% by weight or more, 96% by weight or more, 98% by weight or more, or 99% by weight or more of type I crystals, type II crystals, or type III crystals, or combinations thereof, and includes, but is not limited to, the presence of impurities in amounts of less than about 5.5% by weight, less than about 5% by weight, less than about 4% by weight, less than about 2% by weight or less than about 1% by weight, for example. Such impurities include, but are not limited to, decomposition products, oxidation products, epimers, solvents, and / or other undesirable impurities.

[0042] The present invention also provides a pharmaceutical formulation in any pharmaceutically acceptable dosage form, comprising crystalline form of the compound of formula (1) and one or more pharmaceutically acceptable carriers and / or diluents. In the pharmaceutical formulation of the present invention, the crystalline form of the compound of formula (1) comprises 1 to 99% by weight, for example, 20 to 80% by weight, 30 to 70% by weight, or 45 to 55% by weight, and the pharmaceutically acceptable carriers and / or diluents comprises 99 to 1% by weight, for example, 80 to 20% by weight, 70 to 30% by weight, or 55 to 45% by weight. The present invention also provides that crystalline form of the compound of formula (1) can be formulated into a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers. The pharmaceutical formulation refers to a conventional clinically used formulation that can be administered orally or parenterally to a patient in need of treatment. Oral administration is preferred, and the pharmaceutical formulation is preferably an oral formulation. The pharmaceutical formulation includes conventional solid formulations, conventional liquid formulations, and the like. For oral administration, the crystalline material can be formulated into conventional solid dosage forms such as tablets, capsules, pills, and granules. It can also be formulated into oral liquid preparations such as oral liquids, oral suspensions, and syrups. For parenteral administration, the crystalline material can be formulated into injectable preparations such as injections, sterile powders for injection, concentrated solutions for injection, and suspensions for injection. For rectal administration, the crystalline material can be formulated into suppositories or the like. For pulmonary administration, the crystalline material can be formulated into inhalants, sprays, and the like. For topical or transdermal administration, the crystalline material can be formulated into ointments, pastes, creams, lotions, gels, powders, solutions, or transdermal patches. These preparations can be prepared by conventional methods, such as adding pharmaceutically acceptable carriers like excipients, binders, humectants, disintegrants, and thickeners, where the crystalline material includes type I, type II, type III, and type IV crystals, as well as combinations thereof.

[0043] The present invention also provides the use of crystalline compounds of formula (1) in the manufacture of pharmaceuticals for the treatment and / or prevention of uric acid diseases and / or gouty diseases, wherein the crystalline compounds include type I crystals, type II crystals, type III crystals and type IV crystals, and combinations thereof.

[0044] Compared to the prior art, the crystalline compound of formula (1) of the present invention has the following advantages: (1) The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, or combinations thereof, have good stability. In particular, the stability of the type I crystal is superior to that of the type II, type III, and type IV crystals, and the thermal stability of the type I crystal is superior to that of the type II, type III, and type IV crystals; (2) The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, or combinations thereof, have low residual solvent content and low toxicity and side effects; (3) The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, or combinations thereof, have good physicochemical properties, stable quality, and uniform particle size distribution, making them suitable for large-scale industrial production; (4) The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, or combinations thereof, are particularly suitable for the preparation of pharmaceuticals aimed at lowering uric acid, reducing inflammation, and / or treating and / or preventing uric acid-related diseases and / or gouty diseases, and can improve patient medication compliance.

[0045] Experiments have shown that for pharmaceutical applications, type I and type II crystals are advantageous in terms of thermodynamic stability, while type III crystals are not optimal. Furthermore, investigations into crystallization kinetics have revealed that type I crystals are more beneficial for pharmaceutical applications. Studies on kinetic stability in the solid state have shown that type I crystals remained unchanged after more than 6 years of storage at 10°C to 30°C in double-sealed aluminum packaging and self-sealing plastic bags. This result indicates that type I crystals have good kinetic stability in the solid state. In this invention, the dehydration risk of monohydrate crystals was also evaluated using VT-XRPD (Variable Temperature X-ray Powder Diffraction). The results showed that the dehydration risk of type I crystals is extremely low. In this invention, the stability of type I crystals in formulations was also evaluated. After storage at 40°C / 75%RH for 6 months or at 25°C / 60%RH for 9 months, the content of type III crystals in the formulations was below the LOD (Limit of Detection). This indicates that type I crystals also exhibit good physical stability without being converted to type III crystals in the formulation. In this invention, the stability of type I and type IV crystals in the solid state was also investigated. As a result, it was confirmed that after storage for one month under accelerated conditions (25°C / 92.5%RH, open container) or accelerated conditions (40°C / 75%RH, open container), type I crystals did not convert, but type IV crystals converted to type I crystals.

[0046] Based on these results, Type I crystals exhibit relatively high crystallinity, relatively high dehydration temperatures, and good manufacturability. The solid maintains good kinetic stability even when stored at room temperature for several years, and also shows good stability in formulations. Therefore, the risk of polymorphic transformation of Type I crystals is very low.

[0047] The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, or combinations thereof, are characterized by physical properties such as stability, solubility, hygroscopicity, and dissolution rate that are suitable for clinical and therapeutic dosage forms. They also have physical properties such as crystal morphology, compressibility, particle size, and hardness that are suitable for the preparation of solid dosage forms. The above properties can be measured using techniques known in the art, such as X-ray diffraction, microscopy, IR spectroscopy, thermal analysis, and hygroscopicity analysis.

[0048] The crystalline structure of a compound can affect its solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, brittleness, compressibility, and the safety and efficacy of pharmaceuticals based on that compound. Therefore, it is crucial to prepare and market pure pharmaceuticals that possess the thermodynamically most stable crystalline form and are substantially free of other crystalline structures.

[0049] Crystalline compounds with optimal physical and chemical properties facilitate the development of active pharmaceutical compounds. Most useful physical and chemical properties include ease of manufacture and reproducibility, crystallinity, non-hygroscopicity, water solubility, stability to visible and ultraviolet light, low degradation rates under accelerated stability conditions of temperature and humidity, low isomerization rates between isomers, and long-term safety in humans.

[0050] The type I, type II, type III, and type IV crystals of the compound of formula (1) of the present invention, as well as combinations thereof, exhibit storage stability, compressibility, density, particle size stability, solubility, and other properties advantageous for the preparation and formulation of the compound of formula (1), its use in formulations, and its bioavailability.

[0051] The type I, type II, type III, type IV, and type V crystals (including mixed crystals thereof) of the compound of formula (1) of the present invention can be interconverted under certain conditions. The present invention further discloses the conversion relationships between type I, type II, type III, type IV, and type V crystals. [Brief explanation of the drawing]

[0052] [Figure 1] The XRPD pattern of the type I crystal of the compound of formula (1) is shown. [Figure 2] The XRPD pattern of the type II crystal of the compound of formula (1) is shown. [Figure 3] The XRPD pattern of the type III crystal of the compound of formula (1) is shown. [Figure 4] The XRPD pattern of the type IV crystal of the compound of formula (1) is shown. [Figure 5] The XRPD pattern of the V-type crystal of the compound of formula (1) is shown. [Figure 6] The DSC thermogram of the type I crystal of the compound of formula (1) is shown. [Figure 7] The TGA curve for the type I crystal of the compound of formula (1) is shown. [Figure 8] The DSC thermogram of the type II crystal of the compound of formula (1) is shown. [Figure 9] The TGA curve for the type II crystal of the compound of formula (1) is shown. [Figure 10] The DSC thermogram of the type III crystal of the compound of formula (1) is shown. [Figure 11] The TGA curve for the type III crystal of the compound of formula (1) is shown. [Figure 12] The DSC thermogram of the type IV crystal of the compound of formula (1) is shown. [Figure 13] The TGA curve for the type IV crystal of the compound of formula (1) is shown. [Figure 14]This diagram shows the interconversion relationships between type I, type II, type III, type IV, and type V crystals of the compound of formula (1). Here, 1. When a solution of type I crystals in tetrahydrofuran is evaporated using a rotary evaporator, type II crystals are obtained. Alternatively, type II crystals can be obtained by freeze-drying type I crystals in 1,4-dioxane; 2. Suspend in cumene at 5°C and 25°C and separate; 3. Heat to 95°C, then cool to ambient conditions at 10-40°C in a lower alcohol or ketone aqueous solution (aw ≤ 0.3); 4. Suspend in nitromethane at 5°C and 25°C and separate; 5. Slowly evaporate in methanol and rapidly cool in tetrahydrofuran and water (1:1, v / v); 6. Hold in a methanol / water system (aw ≥ 0.4) at 30-40°C; 7. Completely dehydrate type I crystals at 100°C to convert to type V crystals; 8. Dry type I crystals under vacuum at 60°C for 24 hours to convert to type V crystals; 1. Suspend in acetone / water system (aw≧0.2) at room temperature, acetone / water system (aw≧0.4) or methanol / water system (aw≧0.4) at 50°C, or acetonitrile / water system (aw≧0.6) or water at 70°C, and separate; 9. Heat to 150°C, then cool to ambient temperature; 10. Convert after leaving at 25°C / 92.5%RH or 40°C / 75%RH for 1 month, or at 25°C / 60%RH for 30 days; 11. Convert from type V crystals to type IV crystals after leaving under ambient conditions (25~30°C, 70~85%RH) for about 10 hours; 12. Leave at 60°C for 5 days or 1 month; 13. Suspend and separate in ethyl acetate / acetone at room temperature; suspend and separate in acetone / aqueous system (aw=0~0.2) at 50°C; or suspend and separate in acetonitrile / aqueous system (aw=0~0.4) at 70°C. [Modes for carrying out the invention]

[0053] In this specification, "slurry washing" refers to the process of stirring and washing a large amount of solid with a small amount of solvent.

[0054] As used herein, the term "lower alcohol" refers to alcohols having 1 to 6 carbon atoms, including methanol, ethanol, propanol, isopropanol, butanol, isobutanol, n-butanol, pentanol, hexanol, etc.

[0055] (Detailed Description of Embodiments) The following specific embodiments are examples for further elaborating on the above content of the present invention. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. Any technical solutions implemented based on the above content of the present invention fall within the scope of the present invention.

Example

[0056] Example 1: Preparation of 8-Chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione Referring to the method described in International Publication No. WO2016 / 119570A1, the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione monohydrate (60 g) was synthesized with a yield of 67.7%. Molecular formula: C 10 H 15 ClN4O3; Molecular weight: 274.1; Mass spectrum (M+H): 257.1 1 1H-NMR (DMSO-d6, 400 MHz): 0.84 - 0.86 (t, 3H), 1.28 (m, 4H), 1.63 (m, 2H), 3.85 (t, 2H), 11.22 (s, 1H), 14.38 (br.s, 1H).

[0057] Example 2: Preparation of Crystal Form I of the Compound 8-Chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 10 g of the compound of formula (1) prepared in Example 1 was added to 150 g of tetrahydrofuran. The mixture was heated to 55 °C while stirring until dissolved. 150 g of water was added, and after cooling the mixture to 30 °C, it was filtered. The resulting solid was placed in a vacuum drying oven and vacuum dried at 30 °C overnight to obtain Crystal Form I.

[0058] Detection by the Karl Fischer (KF) method revealed that the type I crystals contained approximately 1.1 equivalents (7.6 wt%) of water. DSC showed that the type I crystals began to dehydrate at approximately 30°C. TGA showed a weight loss of approximately 6.6% at 100°C. The melting point was 284.5°C.

[0059] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of a type I crystal. The main parameters are as follows: TIFF2026510570000004.tif112168

[0060] The DSC thermogram and TGA curve of the type I crystal of the compound of formula (1) are shown in Figures 6 and 7, respectively.

[0061] Example 3: Preparation of Type II crystals of compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione Five g of the compound of formula (1) prepared in Example 1 was added to 50 g of tetrahydrofuran. The mixture was heated to 55°C with stirring until dissolved, cooled to room temperature, and filtered. The resulting solid was placed in a vacuum drying oven and vacuum dried overnight at 50°C to obtain type II crystals. The melting point was 283.6°C.

[0062] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of a type II crystal. The main parameters are as follows: TIFF2026510570000005.tif124168

[0063] The DSC thermogram and TGA curve of the type II crystal of the compound of formula (1) are shown in Figures 8 and 9, respectively.

[0064] Example 4: Preparation of Type III crystals of compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione Method 1: 50 mg of type I crystals prepared in Example 2 were completely dissolved in 10 mL of methanol, filtered, and then slowly evaporated at ambient temperature. The solid obtained by evaporation was recovered as type III crystals.

[0065] Method 2: 1 g of type I crystals prepared in Example 2 was placed in a mixed solvent of 10 g of methanol and water (methanol / water = 1:3, w / w). The mixture was cooled to 5°C and stirred for 1-2 hours. Then, 10 mg of type III crystals were added and stirring continued overnight. The mixture was filtered. The resulting solid was placed in a vacuum drying oven and vacuum dried overnight at 30°C to obtain crystal type III. The melting point was 284.0°C.

[0066] Figure 3 shows the X-ray powder diffraction (XRPD) pattern of a type III crystal. The main parameters are as follows: TIFF2026510570000006.tif141168

[0067] The DSC thermogram and TGA curve of the type III crystal of the compound of formula (1) are shown in Figures 10 and 11, respectively.

[0068] Example 5: Preparation of type IV crystals of compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione One g of the type I crystal prepared in Example 2 was completely dehydrated at 100°C. The resulting substance was converted to type IV crystals by being left under ambient conditions (25-30°C, relative humidity 70-85%) for approximately 10 hours.

[0069] The X-ray powder diffraction (XRPD) pattern of the type IV crystal is shown in Figure 4. The main parameters are as follows: TIFF2026510570000007.tif160168

[0070] The DSC thermogram and TGA curve of the type IV crystal of the compound of formula (1) are shown in Figures 12 and 13, respectively.

[0071] The beneficial effects of the compound of the present invention will be described in more detail below through stability tests in various crystalline forms, but this should not be interpreted as meaning that the compound of the present invention has only the following beneficial effects.

[0072] Test Example 1: Stability of various crystalline forms of the compound of the present invention

[0073] Test sample: Type I and Type II crystals of the compound of formula (1) were prepared according to the above examples.

[0074] Test conditions for investigating influencing factors:

[0075] High humidity test: Type I and Type II crystals of the compound of formula (1) were placed on a dry, clean watch glass and kept at 40°C ± 2°C and 75% RH ± 5% for 10 days. Samples were taken on day 5 and day 10, respectively. The purity of the compound of formula (1) and the content of related substances were measured and compared with the sample taken on day 0.

[0076] Lightstability test: Type I and Type II crystals of the compound of formula (1) were placed on a dry, clean watch glass and kept in a light-irradiated chamber with an illuminance of 5000 Lx ± 500 Lx for 10 days. Samples were taken on day 5 and day 10, respectively. The purity of the compound of formula (1) and the content of related substances were measured and compared with the sample taken on day 0. The test results are shown in Table 1 below.

[0077] [Table 1]

[0078] The test results showed that the purity / related substance content of the type I and type II crystals of the compound of formula (1) remained almost unchanged under high humidity and light exposure, demonstrating high stability. This facilitates the preparation, storage, and transport of the drug, ensuring its efficacy and safety.

[0079] Test Example 2: In vivo PK properties of the crystalline compound of the present invention in SD rats

[0080] Test sample: The compound represented by formula (1), as well as type I and type II crystals of the compound of formula (1), were prepared according to Examples 1 to 3. Tris (i.e., tris(hydroxymethyl)aminomethane) salt crystals of the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione were prepared in reference to International Publication 2010 / 068581A1.

[0081] TIFF2026510570000009.tif31168

[0082] Data processing method: The concentrations of the test substances were output using AB Sciex's Analyst 1.6.2 software. Parameters such as the mean, standard deviation, and coefficient of variation were calculated using Microsoft Excel (parameters directly output by Analyst 1.6.2 were not recalculated). PK parameters were calculated using Pharsight Phoenix 6.2 software (NCA model).

[0083] The test results are shown in Table 2 below.

[0084] [Table 2]

[0085] From the test results, the type I and type II crystals of the present invention have longer half-lives (t 1 / 2 It became clear that this indicates...

[0086] Test Example 3: Hygroscopicity test (based on Chinese Pharmacopoeia's Guidelines for Drug Hygroscopicity Testing, at 25±1℃ and 80%±2% relative humidity)

[0087] Appropriate samples were taken from the examples and subjected to a hygroscopicity test. The results were as follows.

[0088] TIFF2026510570000011.tif29168

[0089] The test results revealed that the Type I and Type II crystals of the present invention exhibit extremely low hygroscopicity.

[0090] Furthermore, the hygroscopic properties of type I, type II, type III, and type IV crystals were investigated in detail using a dynamic vapor adsorption (DVS) apparatus, and the stability of type III and type IV crystals was investigated using the method of Test Example 1. Comparative tests showed that type I and type II crystals are more beneficial for pharmaceutical applications.

Claims

1. Formula (1): 【Chemistry 1】 A crystalline form of the compound 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, A crystalline material characterized by having an X-ray powder diffraction pattern that includes the following characteristic peak, expressed at 2θ degrees, when measured using Cu-Kα rays: Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 19.0°±0.2°, 21.0°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 15.5°±0.2°, 27.6°±0.2°; Type III crystal: 6.8°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 10.2°±0.2°, 14.1°±0.2°.

2. A crystalline compound of formula (1) according to claim 1, characterized in that, when measured using Cu-Kα radiation, it has an X-ray powder diffraction pattern including the following characteristic peak represented by 2θ degrees: Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 19.0°±0.2°, 21.0°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 17.1°±0.2°, 27.6°±0.2°; Type III crystal: 6.8°±0.2°, 9.7°±0.2°, 11.1°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 19.3°±0.2°.

3. A crystalline compound of formula (1) according to claim 1 or 2, characterized in that, when measured using Cu-Kα rays, it has an X-ray powder diffraction pattern including the following characteristic peak represented by 2θ degrees: Type I crystals: 6.3°±0.2°, 9.6°±0.2°, 10.9°±0.2°, 12.6°±0.2°, 14.9°±0.2°, 19.0°±0.2°, 21.0°±0.2°, 24.4°±0.2°, 29.1°±0.2°, 30.1°±0.2°; Type II crystals: 6.7°±0.2°, 11.0°±0.2°, 13.3°±0.2°, 15.5°±0.2°, 17.1°±0.2°, 20.0°±0.2°, 24.1°±0.2°, 27.6°±0.2°, 29.4°±0.2°, 31.6°±0.2°; Type III crystal: 6.8°±0.2°, 9.7°±0.2°, 11.1°±0.2°, 13.5°±0.2°, 20.3°±0.2°, 21.3°±0.2°, 27.3°±0.2°, 27.6°±0.2°, 29.2°±0.2°, 31.4°±0.2°; Type IV crystals: 6.2°±0.2°, 6.6°±0.2°, 9.3°±0.2°, 10.2°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 15.5°±0.2°, 17.0°±0.2°, 19.3°±0.2°, 27.6°±0.2°.

4. The type I crystal has the X-ray powder diffraction pattern shown in Figure 1. The type II crystal has the X-ray powder diffraction pattern shown in Figure 2. The Type III crystal has the X-ray powder diffraction pattern shown in Figure 3. A crystalline body of the compound of formula (1) according to any one of claims 1 to 3, characterized in that the type IV crystal has the X-ray powder diffraction pattern shown in Figure 4.

5. Type I crystals exhibit an endothermic peak in the range of 270-295°C in differential scanning calorimetry thermograms. Type II crystals exhibit an endothermic peak in the range of 275–293°C in differential scanning calorimetry thermograms. A crystalline body of the compound of formula (1) according to any one of claims 1 to 4, characterized in that the type III crystal has an endothermic peak in the range of 270 to 295°C in a differential scanning calorimetry thermogram.

6. A method for preparing a crystalline form of the compound of formula (1) described in any one of claims 1 to 5, The compound of formula (1) is placed in a lower alcohol, tetrahydrofuran, or a mixed solution of acetonitrile and water, and type I crystals are obtained by suspension, slurry washing, evaporation, cooling, etc. The compound of formula (1) is placed in a solvent such as an anhydrous lower alcohol or tetrahydrofuran, the mixture is heated until dissolved, and then cooled to obtain type II crystals; The compound of formula (1) is placed in a lower alcohol, the mixture is heated until dissolved, water is added, the mixture is cooled to below 20°C, and filtered to obtain type III crystals; or The type I crystal of the compound of formula (1) is heated to 100°C or higher to obtain a metastable type V crystal, and the type V crystal is converted to a type IV crystal by placing it at ambient temperature and humidity. A method characterized by the following.

7. A pharmaceutical composition comprising a crystalline compound of formula (1) as described in any one of claims 1 to 5 and a pharmaceutically acceptable carrier, wherein the crystalline compound is selected from type I crystals, type II crystals, type III crystals, type IV crystals, and combinations thereof.

8. A pharmaceutical formulation comprising a crystalline compound of formula (1) as described in any one of claims 1 to 5, and a pharmaceutically acceptable carrier and / or diluent, wherein the crystalline compound is selected from type I crystals, type II crystals, type III crystals, type IV crystals, and combinations thereof.

9. The pharmaceutical preparation according to claim 8, wherein the pharmaceutical preparation is an oral preparation.

10. Use of a crystalline compound of formula (1) according to any one of claims 1 to 5 in the manufacture of a pharmaceutical product for reducing uric acid or reducing inflammation, wherein the crystalline compound is selected from type I crystals, type II crystals, type III crystals and type IV crystals, and combinations thereof.

11. Use of a crystalline compound of formula (1) according to any one of claims 1 to 5 in the manufacture of a pharmaceutical product for treating and / or preventing uric acid disease and / or gouty disease, wherein the crystalline compound is selected from type I crystals, type II crystals, type III crystals and type IV crystals, and combinations thereof.

12. A crystalline compound of formula (1) according to any one of claims 1 to 5, for use in lowering uric acid or reducing inflammation, wherein the crystalline material is selected from type I crystals, type II crystals, type III crystals, and type IV crystals, and combinations thereof.

13. A crystalline compound of formula (1) according to any one of claims 1 to 5, for use in treating and / or preventing uric acid disease and / or gouty disease, wherein the crystalline material is selected from type I crystals, type II crystals, type III crystals and type IV crystals, and combinations thereof.

14. A method for lowering uric acid or reducing inflammation, comprising administering a crystalline form of the compound of formula (1) described in any one of claims 1 to 5 to a subject in need, wherein the crystalline form is selected from type I crystals, type II crystals, type III crystals, and type IV crystals, and combinations thereof.

15. A method for treating and / or preventing uric acid disease and / or gouty disease, the method comprising administering a crystalline form of the compound of formula (1) described in any one of claims 1 to 5 to a subject in need, wherein the crystalline form is selected from type I crystals, type II crystals, type III crystals and type IV crystals, and combinations thereof.

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