Crystal forms of molisum sodium, methods of making and uses thereof

Abstract

The present application relates to a crystal form of sodium morlitset, its preparation method and use. The present application provides two crystal forms of 1-[6-(morpholine-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol sodium (i.e. sodium morlitset), wherein the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values of 17.1°±0.2°, 24.2°±0.2° and 26.6°±0.2°, and the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values of 6.5°±0.2°, 9.7°±0.2°, 16.5°±0.2° and 26.6°±0.2°. The crystal forms of sodium morlitset of the present application all have the advantages of good solubility, good stability, high bioavailability and suitability for industrial production.

Description

[0001] This application claims priority to an earlier application filed on December 6, 2024, with the China National Intellectual Property Administration, patent application number 202411789767.7, entitled "Molistat Sodium Crystal Form, Preparation Method Thereof and Uses"; the entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to the sodium molistat crystal form, its preparation method, and its uses. Background Technology

[0003] Molidustat (trade name: MUSREDO) is a novel hypoxia-induced proline hydroxylase inhibitor developed by Bayer AG. It was launched in Japan on January 22, 2021, for the treatment of anemia in dialysis-dependent chronic kidney disease (DD-CKD) and non-dialysis-dependent chronic kidney disease (NDD-CKD). CN103270031B reports a crystalline form of molidustat sodium containing less than 0.5% by weight of water, exhibiting non-hygroscopicity. Under normal environmental conditions (20-35°C, normal pressure) and even at higher humidity levels (up to 90% rF), its water content changes only minimally, remaining below 0.5% by weight, although its solubility is low.

[0004] Therefore, there is an urgent need to develop new sodium molistat crystal forms suitable for industrial production. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a sodium molistat crystal form that is completely different from the prior art, its preparation method and uses.

[0006] This invention provides two crystal forms of sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazole-5-phenol (i.e., molistat sodium), including crystal form A and crystal form B. The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 17.1°±0.2°, 24.2°±0.2° and 26.6°±0.2°. The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 16.5°±0.2°, and 26.6°±0.2°.

[0007] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 17.1°±0.2°, 24.2°±0.2° and 26.6°±0.2°.

[0008] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 17.1°±0.2°, 21.6°±0.2°, 23.0°±0.2°, 24.2°±0.2°, and 26.6°±0.2°.

[0009] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 23.0°±0.2°, 24.2°±0.2°, and 26.6°±0.2°.

[0010] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A may also have characteristic peaks at 2θ values ​​of 16.5°±0.2°, 26.1°±0.2°, 27.3°±0.2° and / or 28.2°±0.2°.

[0011] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form A is substantially as follows: Figure 1 As shown.

[0012] According to an embodiment of the present invention, the crystal form A has X-ray powder diffraction analysis data as shown in Table 1.

[0013] According to an embodiment of the present invention, the crystal form A may be an anhydrous form, hydrate, or solvate of molistat sodium.

[0014] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 16.5°±0.2° and 26.6°±0.2°.

[0015] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 16.5°±0.2°, 21.1°±0.2°, and 26.6°±0.2°.

[0016] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.1°±0.2°, 14.8°±0.2°, 16.5°±0.2°, 21.1°±0.2°, and 26.6°±0.2°.

[0017] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.1°±0.2°, 14.8°±0.2°, 16.5°±0.2°, 21.1°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 24.3°±0.2°, 26.6°±0.2°, and 29.5°±0.2°.

[0018] According to an embodiment of the present invention, the crystal form B has X-ray powder diffraction analysis data as shown in Table 2.

[0019] According to an embodiment of the present invention, the X-ray powder diffraction pattern of crystal form B is substantially as follows: Figure 2 As shown.

[0020] According to an embodiment of the present invention, the crystal form B may be an anhydrous form, hydrate, or solvate of molistat sodium.

[0021] The present invention also provides a method for preparing molistat sodium crystal form A, which includes the following steps: a solution of molistat sodium and solvent 1 is formed, and then mixed with solvent 2 to crystallize and obtain molistat sodium crystal form A; The solvent 1 is selected from one or more of water, a mixed solvent of water and methanol, a mixed solvent of water and ethanol, a mixed solvent of water and acetonitrile, a mixed solvent of water and acetone, a mixed solvent of water and tetrahydrofuran, and a mixed solvent of water and 1,4-dioxane; the water is preferably purified water. The solvent 2 is selected from one or more of ethanol, n-propanol, isopropanol, isopropyl ether, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, n-heptane, dichloromethane, chloroform, and toluene, preferably one or more of acetonitrile, acetone, 1,4-dioxane, and tetrahydrofuran.

[0022] According to an embodiment of the present invention, the solution formed by molistat sodium and solvent 1 is preferably obtained by stirring and dissolving; the stirring and dissolving temperature is preferably 40°C to 100°C, more preferably 50°C to 80°C or 50°C to 60°C; the stirring and dissolving time is preferably 0.1 hours to 5 hours, more preferably 0.5 hours to 2 hours.

[0023] According to an embodiment of the present invention, the crystallization temperature is preferably -10°C to 10°C, for example, 0°C to 10°C.

[0024] According to an embodiment of the present invention, the crystallization time is preferably 1 hour to 10 hours, for example 4 hours.

[0025] According to an embodiment of the present invention, the preparation method of crystal form A may further include the following post-processing steps: after crystallization, the crystals are filtered and dried to obtain crystal form A of molistat sodium; The drying temperature is preferably 40°C to 50°C, for example, 40°C; The drying time is preferably 1 to 20 hours.

[0026] The present invention also provides a method for preparing molistat sodium crystal form B, which includes the following steps: a solution formed by molistat sodium and a solvent is allowed to stand and evaporate to obtain molistat sodium crystal form B; The solvent is selected from one or more of water, a mixed solvent of water and methanol, a mixed solvent of water and ethanol, a mixed solvent of water and acetonitrile, a mixed solvent of water and acetone, a mixed solvent of water and tetrahydrofuran, and a mixed solvent of water and 1,4-dioxane; the water is preferably purified water; the solvent is preferably a mixed solvent of water and methanol.

[0027] According to an embodiment of the present invention, when a mixed solvent of water and methanol is used, the volume ratio of methanol to water is preferably 1 to 50, for example 10 to 30 or 20.

[0028] According to an embodiment of the present invention, the solution formed by molistat sodium and solvent is preferably obtained by stirring and dissolving; the stirring and dissolving temperature is preferably 40°C to 80°C, more preferably 50°C to 60°C; the stirring and dissolving time is preferably 0.1 hours to 5 hours, more preferably 0.5 hours to 2 hours.

[0029] According to an embodiment of the present invention, the temperature for static evaporation is preferably 40°C to 80°C, for example, 50°C.

[0030] According to an embodiment of the present invention, the settling and evaporation time is preferably 1 to 15 days, for example 5 days.

[0031] The present invention also provides another method for preparing molistat sodium crystal form B, which includes the following steps: adding molistat to (purified) water, stirring at 2~10°C (e.g., stirring for 20~40 min), slowly adding isothermal sodium hydroxide aqueous solution, continuing to stir at 2~10°C (e.g., stirring for 15~20 h), filtering, and drying (e.g., drying at 55~65°C for 8~15 h) to obtain molistat sodium crystal form B.

[0032] The present invention also provides a pharmaceutical composition comprising two crystal forms of the molistat sodium, for example comprising crystal form A and / or crystal form B.

[0033] The pharmaceutical compositions of the present invention may also include pharmaceutically acceptable excipients.

[0034] The present invention also provides the use of two crystal forms of molistat sodium (e.g., molistat sodium crystal form A or molistat sodium crystal form B) in the preparation of medicaments for the treatment and / or prevention of hypoxia-induced proline hydroxylase-mediated diseases.

[0035] According to an embodiment of the present invention, the hypoxia-induced proline hydroxylase-mediated disease can be renal anemia.

[0036] The present invention also provides a method for treating and / or preventing hypoxia-induced proline hydroxylase-mediated diseases, which involves providing patients in need with a therapeutically effective amount of either of the two crystal forms of molistat sodium (e.g., molistat sodium crystal form A or molistat sodium crystal form B) or the pharmaceutical composition thereof.

[0037] Terminology Definitions and Explanations In this invention, the term "solvent" refers to a molecular complex of a drug and one or more solvent molecules (such as ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound to the drug, as in channel solvates and hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex is typically non-stoichiometric.

[0038] In this invention, the term "hydrate" describes a solvate comprising a drug and a stoichiometric or non-stoichiometric amount of water. The term "relative humidity" refers to the ratio, expressed as a percentage, of the amount of water vapor at a specified temperature to the maximum amount of water vapor that can be retained at that temperature and pressure.

[0039] In this invention, the pharmaceutical composition comprises a therapeutically effective amount of the molistat sodium and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to organisms such as humans or other mammals.

[0040] The term "therapeutic effective amount" refers to the amount of the active pharmaceutical ingredient of this invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). Therapeutic effective amount can vary depending on factors such as the intended application (in vitro or in vivo), the subject being treated, and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. The specific dosage will vary depending on factors such as the specific active ingredient selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system used.

[0041] It should be understood that those skilled in the art can adjust the amounts of raw materials and reagents used in the method of the present invention based on their knowledge and experience, including proportionally increasing or decreasing the amount of raw materials, adjusting the ratio of raw materials, reagents, and solvents, and changing the temperature of the present invention. These adjustments are also included in the method of the present invention.

[0042] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0043] The reagents and raw materials used in this invention are all commercially available.

[0044] In this invention, room temperature refers to an ambient temperature of 10℃ to 35℃.

[0045] The term "multiple" refers to two or more kinds, such as two, three or more kinds.

[0046] Beneficial effects The sodium molistat crystal forms A and B provided by this invention both possess comprehensive advantages such as good solubility, high stability (40℃, 60℃, high humidity, light and acceleration), high bioavailability, small angle of repose, low electrostatic induction, excellent flowability and compressibility. These advantages can improve the ease of preparation when it is formulated, and the favorable physical properties can improve the content uniformity during formulation, making it more suitable for industrial production.

[0047] Furthermore, crystal form B can be prepared in water without the need for organic solvents, making it suitable for industrial production. Attached Figure Description

[0048] Figure 1 The XRPD pattern of molistat sodium crystal form A of the present invention; Figure 2The XRPD pattern of sodium molistat B according to the present invention is shown. Detailed Implementation

[0049] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0050] XRPD measurements were performed using a Bruker D2-Phaser X-ray powder diffractometer. The test used CuKα rays as the light source, and the scanning parameters were as follows: voltage 30 kV, current 10 mA, scanning range 5°–50°, scanning step size 0.02°, and continuous scanning mode.

[0051] Example 1: Molistat sodium crystal form A and its preparation 1.6 g of molistat sodium was added to 50 ml of purified water and stirred at 50℃-60℃ for 0.5 h to 2 h until the solution was clear. The solution was then filtered. Subsequently, 300 ml of acetonitrile was slowly added to the filtrate, allowing crystals to slowly crystallize. After the addition was complete, the solution was stirred at 0-10℃ for 4 h. After stirring, the solution was filtered and dried under vacuum at 40℃ for 2 h to obtain 1.3 g of solid molistat sodium (crystal form A), with a yield of 81%. Its XPRD spectrum is shown below. Figure 1 As shown; The specific XPRD data for crystal form A are shown in Table 1 below: Table 1

[0052]

[0053] Example 2 Molistat sodium crystal form B and its preparation 0.1 g of molistat sodium was added to 1 ml of purified water and 20 ml of methanol. The mixture was stirred at 50℃-60℃ for 0.5-2 h until the solution was clear. The solution was then filtered. The filtrate was allowed to stand at 50℃ for 12-24 h to slowly evaporate, yielding solid molistat sodium (crystal form B). Its XPRD spectrum is shown below. Figure 2 As shown.

[0054] The specific XPRD data for crystal form B are shown in Table 2 below: Table 2

[0055]

[0056] Example 3: Preparation of Molistat Sodium Crystal Form B 0.1 g of molistat was added to 2 ml of purified water and stirred at 2-10 °C for 0.5 h. Then, 1.1 eq. of 14% sodium hydroxide aqueous solution was slowly added at the same temperature and stirred at 2-10 °C for 18 h. The mixture was filtered and dried overnight at 60 °C to obtain solid molistat sodium (crystal form B), whose XPRD spectrum was consistent with that of Example 2.

[0057] Test case The original crystal form was prepared according to Example 26 of patent CN104411704B. After verification, the obtained product is the same as the crystal form CN103270031B.

[0058] 1.1 Solubility Test Take an appropriate amount of raw material into a container at 37℃, gradually increase the solvent in the table below, record the amount of solvent consumed during dissolution, calculate the solubility of the corresponding crystal form, and the results are shown in Table 3.

[0059] Table 3

[0060] As shown in the table above, at 37°C, crystal form A and crystal form B have significantly higher solubility than the original crystal form in water, pH 7.4 and pH 6.8 and other near-neutral media, which can promote the absorption of raw materials in the intestine, thereby reducing the dosage, reducing toxic side effects and improving bioavailability.

[0061] 1.2 Cartesian index and angle of repose test Considering that materials with high electrostatic induction, poor flowability, and poor compressibility are usually difficult to process under pharmaceutical technology conditions, which is not conducive to the uniformity of content during formulation mixing and the mechanical strength and formability of tablets, the Karl index (Karl index CI = 100% × (1-BD / TD)) and angle of repose of the crystal form A and crystal form B compounds of the present invention were compared with those of the original crystal form. The results are shown in Tables 4 and 5.

[0062] Table 4

[0063] Table 5

[0064] As shown in the table above, crystal forms A and B have lower Karl quotients and smaller angles of repose compared to the original crystal form. In addition, the original crystal form compound was found to have a certain electrostatic effect during weighing, while no electrostatic effect was observed in crystal forms A and B. Therefore, crystal forms A and B have lower electrostatic induction, better flowability and compression molding properties, which can improve the ease of preparation during formulation and have favorable physical properties to improve the content uniformity during formulation.

[0065] 1.3 Stability Test Sample placement conditions: open and protected from light under high temperature tests at 40℃ and 60℃; open and protected from light under high humidity tests at 75%±5%RH and 90%±5%RH; open and protected from light under accelerated tests at 40℃ / 70%±5%RH; and open under light exposure tests.

[0066] In Table 6-11, ND represents not detected.

[0067] Table 6. Data on factors affecting crystal form A and crystal form B (high temperature 40℃)

[0068] Table 7. Data on factors affecting crystal form A and crystal form B (high temperature 60℃)

[0069] Table 8. Influencing factors of crystal form A and crystal form B (high humidity test (75%±5%RH, 25℃)) data

[0070] Table 9. Influencing factors of crystal form A and crystal form B (high humidity test (90%±5%RH, 25℃)) data

[0071] Table 10. Factors affecting crystal form A and crystal form B (illuminance test (total illuminance not less than 1.2 × 10⁻⁶)) 6 Lux·hr, near-ultraviolet total amplitude not less than 200 W·hr / m 2 ))data

[0072] Table 11. Accelerated data for crystal form A and crystal form B after 1 month (70%±5%RH, 40℃±2℃)

[0073] Table 6-11 shows that crystal form A and crystal form B maintain good stability under conditions of 40℃, 60℃, high humidity, light, and acceleration.

[0074] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. Two crystal forms of molistat sodium, characterized in that: Including crystal form A and crystal form B, The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 17.1°±0.2°, 24.2°±0.2° and 26.6°±0.2°; The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 16.5°±0.2° and 26.6°±0.2°; The molistat sodium has the following structure: 。 2. The two crystal forms of molistat sodium as described in claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 17.1°±0.2°, 24.2°±0.2° and 26.6°±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 17.1°±0.2°, 21.6°±0.2°, 23.0°±0.2°, 24.2°±0.2°, and 26.6°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form A has characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.2°±0.2°, 13.5°±0.2°, 14.0°±0.2°, 14.5°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 21.6°±0.2°, 23.0°±0.2°, 24.2°±0.2°, and 26.6°±0.2°.

3. The two crystal forms of molistat sodium as described in claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form A is shown in Figure 1.

4. The two crystal forms of molistat sodium as described in claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 16.5°±0.2° and 26.6°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 14.1°±0.2°, 16.5°±0.2°, 21.1°±0.2°, and 26.6°±0.2°; Preferably, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.1°±0.2°, 14.8°±0.2°, 16.5°±0.2°, 21.1°±0.2°, and 26.6°±0.2°. Preferably, the X-ray powder diffraction pattern of crystal form B has characteristic peaks at 2θ values ​​of 6.5°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.1°±0.2°, 14.8°±0.2°, 16.5°±0.2°, 21.1°±0.2°, 23.0°±0.2°, 23.8°±0.2°, 24.3°±0.2°, 26.6°±0.2°, and 29.5°±0.2°.

5. The two crystal forms of molistat sodium as described in claim 1, characterized in that: The X-ray powder diffraction pattern of crystal form B is shown in Figure 2.

6. The method for preparing the two crystal forms of molistat sodium according to any one of claims 1 to 5, characterized in that, Choose from any of the following methods: Method 1: Molistat sodium is mixed with solvent 1 to form a solution, and then mixed with solvent 2 to crystallize, thus obtaining the crystal form A; The solvent 1 is selected from one or more of water, a mixed solvent of water and methanol, a mixed solvent of water and ethanol, a mixed solvent of water and acetonitrile, a mixed solvent of water and acetone, a mixed solvent of water and tetrahydrofuran, and a mixed solvent of water and 1,4-dioxane. The solvent 2 is selected from one or more of ethanol, n-propanol, isopropanol, isopropyl ether, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, n-heptane, dichloromethane, chloroform, and toluene; preferably, the solvent 2 is selected from one or more of acetonitrile, acetone, 1,4-dioxane, and tetrahydrofuran. Method 2: A solution of sodium molistat and a solvent is formed, and the solution is allowed to stand and evaporate to obtain the crystal form B. The solvent is selected from one or more of water, a mixed solvent of water and methanol, a mixed solvent of water and ethanol, a mixed solvent of water and acetonitrile, a mixed solvent of water and acetone, a mixed solvent of water and tetrahydrofuran, and a mixed solvent of water and 1,4-dioxane. Method 3: Add molistat to (purified) water and stir at 2-10°C (e.g., stir for 20-40 min). Slowly add isothermal sodium hydroxide aqueous solution and continue stirring at 2-10°C (e.g., stir for 15-20 h). Filter and dry to obtain molistat sodium crystal form B.

7. The preparation method according to claim 6, characterized in that, In Method 1, The crystallization temperature is -10℃ to 10℃; And / or, The crystallization time is 1 hour to 10 hours; And / or, The method one also includes the following post-processing steps: after the reaction is completed, the mixture is filtered and dried to obtain the crystal form A.

8. The preparation method according to claim 6, characterized in that, In method two, The temperature for static crystallization is 40℃~80℃; And / or, The time for static crystallization is 1 to 15 days.

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises crystal form A and / or crystal form B as described in any one of claims 1 to 5.

10. The use of the two crystal forms of molistat sodium (e.g., crystal form A or crystal form B) according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 9, in the preparation of a medicament for treating and / or preventing hypoxia-induced proline hydroxylase-mediated diseases; The hypoxia-induced proline hydroxylase-mediated disease is renal anemia.

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