Crystal forms of quinolinone compounds and their uses

Abstract

The present invention relates to crystalline forms of quinolinone compounds and uses thereof. The present invention further relates to pharmaceutical compositions containing the crystalline forms and uses of the crystalline forms or pharmaceutical compositions in the manufacture of medicaments for treating or preventing HIF-related and / or EPO-related diseases (e.g., anemia).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from Chinese Patent Application No. 201911187714.7, filed on November 28, 2019, the entire contents of which are hereby incorporated by reference.

[0002] The present invention belongs to the technical field of medicine and relates to a crystalline form of a quinolinone compound and its use, in particular to a crystalline form of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid and its use, and further to a pharmaceutical composition containing said crystalline form. [Background technology]

[0003] In cases of anemia, trauma, tissue necrosis and loss, tissues or cells are always in a hypoxic state. Hypoxia induces the expression of a series of transcription factors involved in angiogenesis, iron and glucose metabolism, cell growth and proliferation. Hypoxia inducible factor (HIF) is a transcription factor activated in somatic cells in the event of oxygen reduction, and is widely distributed in various parts of the body, especially in the vascular intima, heart, brain, kidney, liver, etc. HIF is a heterodimer containing an oxygen-regulated α-subunit (HIF α) and a constitutively expressed β-subunit (HIF β / ARNT). In oxygen-containing cells (where oxygen content is normal), the HIF α subunit is rapidly degraded by von Hippel-Lindau tumor suppressor (pVHL) E3 through the mechanism of ubiquitination of the enzyme complex. Under hypoxic conditions, HIF α is not degraded and active HIF α / β complexes accumulate in the nucleus and activate the expression of a variety of genes, including glycolytic enzymes, glucose transport proteins, erythropoietin (EPO) and vascular endothelial growth factor (VEGF).

[0004] Erythropoietin (EPO) is a naturally occurring hormone produced in conjunction with HIFα that stimulates the production of red blood cells (red blood cells) that carry oxygen throughout the body. EPO is typically secreted by the kidneys, and endogenous EPO is increased under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduced ability of the blood to carry oxygen, and therefore have similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, easy fatigue, and drowsiness, leading to a reduced quality of life. Anemia is generally associated with a medical condition in which there is a deficiency of red blood cells or hemoglobin in the blood. Common causes of anemia include iron, vitamin B 12 and folate deficiency, which may lead to complications of chronic diseases, such as inflammatory diseases, including those with concomitant inflammatory suppression of the bone marrow. Anemia is also associated with impaired renal function, and many patients with renal failure who frequently undergo dialysis suffer from chronic anemia.

[0005] Prolyl hydroxylase domain (PHD) is an important factor regulating HIF. Under normal oxygen conditions, PHD can hydroxylate two important proline residues, Pro402 and Pro564, of HIF α to increase its affinity with pVHL and accelerate the degradation process. Under hypoxic and other pathological conditions, the HIF reaction catalyzed by PHD is inhibited, and the degradation rate of proteases is reduced, so that HIF α accumulates in cells and further triggers a series of adaptive responses to hypoxia in cells. Inhibiting PHD with a PHD inhibitor can prolong the action of HIF and further improve the expression of genes such as EPO, effectively treating and preventing HIF-related and / or EPO-related diseases, such as anemia, ischemia and hypoxia.

[0006] International Application WO2016034108A1 discloses a compound (compound represented by formula (I)) which is 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid, and can treat or alleviate HIF-related and / or EPO-related diseases such as anemia, etc. However, there are no research reports on the crystalline form of the compound in the prior art. [ka]

[0007] Drug polymorphism is a common phenomenon in drug research and is an important factor that affects drug quality. The same drug may have a large difference in appearance, solubility, melting point, dissolution rate, biological efficacy, etc. depending on the crystal structure, which may have various effects on drug stability, bioavailability, therapeutic effect, etc. Therefore, the problem of drug polymorphism should be considered comprehensively in drug development. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2016034108 Summary of the Invention

[0009] The present invention provides a crystalline form of the compound represented by formula (I), and said crystalline form, especially crystalline form I, can obviously improve the properties of the compound such as stability and pharmacokinetics, and thus has excellent pharmaceutical potential.

[0010] In particular, the present invention relates to a crystalline form of the compound of formula (I) and the use of said crystalline form of said compound or said pharmaceutical composition in the manufacture of a medicament for treating or preventing HIF-related and / or EPO-related diseases. The crystalline form according to the present invention may be in the form of a solvate, for example a hydrate form.

[0011] In one aspect, the present invention provides a crystalline form of a compound of formula (I). [ka]

[0012] In some embodiments, the crystalline form of the compound of formula (I) according to the present invention is crystalline form I or crystalline form II.

[0013] In some embodiments, the crystalline form I of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form I has diffraction peaks at 2θ angles of 6.20°±0.2°, 18.16°±0.2°, 19.30°±0.2°, 26.89°±0.2°, and 27.31°±0.2°.

[0014] In another embodiment, the crystalline form I of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form I has diffraction peaks at 2θ angles of 6.20°±0.2°, 9.05°±0.2°, 18.16°±0.2°, 19.30°±0.2°, 26.89°±0.2° and 27.31°±0.2°.

[0015] In another embodiment, the crystalline form I of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form I has diffraction peaks at 2θ angles of 6.20°±0.2°, 9.05°±0.2°, 13.72°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, 22.06°±0.2°, 26.89°±0.2° and 27.31°±0.2°.

[0016] In some embodiments, the crystalline form I of the present invention has an X-ray powder diffraction pattern of 6.20°±0.2°, 7.32°±0.2°, 9.05°±0.2°, 13.72°±0.2°, 14.66°±0.2°, 15.18°±0.2°, 16.55°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, 20.28°±0.2°, 21.78°±0.2°, 22.06°±0.2°, 22.76°±0.2°, 23.39°±0.2°, 25.36°±0.2°, 25.6 The sample is characterized by having diffraction peaks at 2θ angles of 8°±0.2°, 26.89°±0.2°, 27.31°±0.2°, 29.15°±0.2°, 29.49°±0.2°, 30.85°±0.2°, 31.39°±0.2°, 33.27°±0.2°, 34.36°±0.2°, 36.33°±0.2°, 37.15°±0.2°, 37.87°±0.2°, 38.43°±0.2°, 39.44°±0.2°, 40.71°±0.2°, 42.56°±0.2°, 42.94°±0.2°, 43.62°±0.2°, and 44.25°±0.2°.

[0017] In some embodiments, the crystalline form I of the present invention has an X-ray powder diffraction pattern of 6.20°±0.2°, 7.32°±0.2°, 9.05°±0.2°, 13.72°±0.2°, 14.66°±0.2°, 15.18°±0.2°, 16.55°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, 20.28°±0.2°, 20.88°±0.2°, 21.78°±0.2°, 22.06°±0.2°, 22.76°±0.2°. 27.31°±0.2°, 29.15°±0.2°, 29.49°±0.2°, 30.85°±0.2°, 31.39°±0.2°, 33.27°±0.2°, 34.36°±0.2°, 36.33°±0.2°, 40.71°±0.2°, 42.56°±0.2°, 42.94°±0.2°, 43.62°±0.2°, and 44.25°±0.2°.

[0018] In another embodiment, the crystalline form I of the present invention has an X-ray powder diffraction pattern of 6.20°±0.2°, 7.32°±0.2°, 9.05°±0.2°, 12.44°±0.2°, 13.72°±0.2°, 14.66°±0.2°, 15.18°±0.2°, 16.55°±0.2°, 18.16°±0.2°, 18.70°± 0.2°, 19.30°±0.2°, 19.92°±0.2°, 20.28°±0.2°, 20.88°±0.2°, 21.78°±0.2°, 22.06°±0.2°, 22.76°±0.2°, 23.39°±0.2°, 25.36°±0.2°, 25.68°±0.2°, 26.89°±0.2°, 27.31°±0.2°, 29.15°±0.2°, 29.25°±0.2°, 30.0°±0.2°, 31.0°±0.2°, 32.0°±0.2°, 33.0°±0.2°, 34.0°±0.2°, 35.0°±0.2°, 36.0°±0.2°, 37.0°±0.2°, 38.0°±0.2°, 39.0°±0.2°, 40.0°±0.2°, 41.0°±0.2°, 42.0°±0.2°, 43.0°±0.2°, 44.0°±0.2°, 45.0°±0.2°, 46.0°±0.2°, 47.0°±0.2°, 48.0°±0.2°, 49.0°±0.2°, 50.0°±0.2°, 51.0°±0.2°, 52.0°±0.2°, 53.0°±0.2°, 54.0°±0.2°, 55.0°±0.2°, 56.0°±0.2° °±0.2°, 29.49°±0.2°, 30.85°±0.2°, 31.39°±0.2°, 33.27°±0.2°, 34.36°±0.2°, 36.33°±0.2°, 37.15°±0.2°, 37.87°±0.2°, 38.43°±0.2°, 39.44°±0.2°, 40.71°±0.2°, 42.56°±0.2°, 42. It is characterized by having diffraction peaks at 2θ angles of 94°±0.2°, 43.62°±0.2°, 44.25°±0.2°, 45.46°±0.2°, 46.60°±0.2°, 48.43°±0.2°, 49.75°±0.2°, 52.66°±0.2°, 55.45°±0.2°, 56.36°±0.2°, and 57.93°±0.2°.

[0019] In some embodiments, crystalline Form I of the present invention is characterized in that said crystalline Form I has an X-ray powder diffraction pattern substantially as shown in FIG.

[0020] In some embodiments, the crystalline form I of the present invention is characterized in that the differential scanning calorimetry pattern of said crystalline form I comprises an endothermic peak at 222.82°C ± 3°C.

[0021] In some embodiments, crystalline Form I of the present invention is characterized in that said crystalline Form I has a differential scanning calorimetry pattern substantially as shown in FIG.

[0022] In some embodiments, the crystalline form I of the present invention is characterized in that said crystalline form I has a weight loss of 1.315% in the range of about 70° C. to 150° C., and said weight loss rate has a margin of error of ±0.1%.

[0023] In some embodiments, the crystalline form II of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form II has diffraction peaks at 2θ angles of 5.23°, 13.61°, and 25.90°, and the allowable error of said diffraction peaks is ±0.2°.

[0024] In some embodiments, the crystalline form II of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form II has diffraction peaks at 2θ angles of 5.23°, 13.61°, 17.42°, 18.06°, 20.29°, 25.90°, and 27.94°, with a tolerance of ±0.2° for said diffraction peaks.

[0025] In some embodiments, the crystalline form II of the present invention is characterized in that the X-ray powder diffraction pattern of said crystalline form II has diffraction peaks at 2θ angles of 5.23°, 8.73°, 10.12°, 10.52°, 13.61°, 15.80°, 17.42°, 18.06°, 19.99°, 20.29°, 20.93°, 21.54°, 22.72°, 24.08°, 25.18°, 25.90°, 27.94°, 30.04°, 32.19°, 33.13°, 35.21°, 35.99°, 36.95°, 40.09°, 41.17°, 45.55°, 48.48°, 51.97°, and 55.75°, with a tolerance of ±0.2° for said diffraction peaks.

[0026] In some embodiments, crystalline Form II of the present invention is characterized by having an X-ray powder diffraction pattern substantially as shown in FIG.

[0027] In some embodiments, the crystalline form II of the present invention is characterized in that the differential scanning calorimetry pattern of said crystalline form II comprises an endothermic peak at 223.69°C ± 3°C.

[0028] In some embodiments, crystalline Form II of the present invention is characterized by having a differential scanning calorimetry pattern substantially as shown in FIG.

[0029] In some embodiments, the crystalline form II of the present invention is characterized by a weight loss of 0.406% in the range of 70° C. to 160° C., with a margin of error for said weight loss rate of ±0.1%.

[0030] In another embodiment, a pharmaceutical composition according to the present invention comprises any of the crystalline forms according to the present invention and a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0031] In one aspect, the use of any of the crystalline forms or pharmaceutical compositions according to the present invention in the manufacture of a medicament, wherein the medicament is used to prevent, treat or alleviate a hypoxia inducible factor-associated and / or erythropoietin-associated disorder in a patient.

[0032] In some embodiments, the disease according to the present invention is anemia, ischemia, vascular disease, angina, myocardial ischemia, myocardial infarction, metabolic disorders, or wound healing.

[0033] In another embodiment, the use of any of said crystalline forms or said pharmaceutical compositions according to the invention in the manufacture of a medicament, wherein said medicament is used to prevent, treat or alleviate at least a portion of a disease in a patient that is mediated by hypoxia inducible factor prolyl hydroxylase.

[0034] In some embodiments, the disease according to the present invention is anemia, ischemia, vascular disease, angina, myocardial ischemia, myocardial infarction, metabolic disorders, or wound healing.

[0035] According to one aspect of the invention, a method for preventing, treating or ameliorating a hypoxia inducible factor-associated and / or erythropoietin-associated disorder in a patient comprises administering to the patient a crystalline form or pharmaceutical composition according to the invention in a pharma- ceutically acceptable effective dose.

[0036] In another aspect, the present invention further relates to a process for preparing a crystalline form of a compound of formula (I).

[0037] The solvent used in the method for preparing the crystal form of the present invention is not particularly limited, and any solvent that dissolves the starting material to some extent and does not affect its properties is included in the present invention. However, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, combinations of solvents, and various ratios of combining solvents in the field are all considered to be within the scope of the present invention. The present invention provides preferred solvents for use in each reaction step.

[0038] The preparation experiment of the crystal form of the present invention is described in detail in the Examples section. At the same time, the present invention provides activity test experiments (such as pharmacokinetic experiments), solubility experiments, stability tests and hygroscopicity tests of the crystal form. The experiments prove that the crystal form I of the present invention has higher biological activity, solubility and stability than the crystal form II. In terms of stability, the crystal form II is unstable and tends to undergo crystal transition and transform into a mixed crystal when left standing under normal temperature and pressure conditions, and eventually becomes the stable crystal form I, whereas the crystal form I of the present invention is very stable, does not undergo crystal transition under general conditions, and is stable even under high temperature and high humidity conditions, with little change in appearance and purity. Therefore, the crystal form I of the present invention has excellent biological activity, excellent solubility and high stability, and is suitable for pharmaceutical use.

[0039] In addition, according to the results of the hygroscopicity experiment, the crystalline form I according to the present invention is unlikely to deliquesce under the influence of high humidity, and can be easily stored for a long period of time as a drug. Definitions and General Terms

[0040] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and published publications related to this invention are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this invention, the preferred methods, devices and materials are described herein.

[0041] "Crystal form" or "crystalline morphology" refers to a solid having a highly ordered chemical structure, including, but not limited to, single or multi-component crystals and / or crystalline polymorphs of a compound, solvates, hydrates, clathrates, eutectics, salts, solvates of salts, and hydrates of salts. Crystalline forms of a substance can be obtained by many methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces such as nanopores or capillaries, crystallization on surfaces or templates such as polymers, crystallization in the presence of additives such as co-crystallized counter molecules, solvent removal, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding, and solvent drop grinding.

[0042] "Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents that may be used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0043] "Anti-solvent" means a fluid that promotes precipitation of the product (or product precursor) from the solvent. Anti-solvents can include cold gases, or fluids that promote precipitation by chemical reaction, or fluids that reduce the solubility of the product in the solvent, which may be the same liquid as the solvent but at a different temperature, or may be a different liquid than the solvent.

[0044] "Solvate" refers to a compound having a solvent on the surface, in the lattice, or on the surface and in the lattice, and the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butyl alcohol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. One specific example of a solvate is a hydrate, and the solvent on the surface, in the lattice, or on the surface and in the lattice is water. The hydrate may or may not have other solvents other than water on the surface, in the lattice, or on the surface and in the lattice of the material.

[0045] Crystalline forms can be identified by a variety of techniques, such as, for example, X-ray powder diffraction (XRPD), infrared spectroscopy (IR), melting point, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate.

[0046] X-ray powder diffraction (XRPD) can measure information such as changes in crystal form, crystallinity, and crystal structure state, and is a common means of identifying crystal forms. The peak positions of the XRPD pattern mainly depend on the structure of the crystal form and are relatively insensitive to experimental details, and the relative peak heights depend on many factors related to sample preparation and instrument geometry. Thus, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern having several peak positions, which are substantially as shown in the XRPD patterns provided in the drawings of the present invention. In addition, the above values ​​of 2θ cannot be considered absolute, since there may be experimental errors in the measurement of 2θ in the XRPD pattern, and the measurement of 2θ in the XRPD pattern by different instruments and different samples may be slightly different. According to the conditions of the instrument used in this test, the allowable error of the diffraction peaks is ±0.2°C.

[0047] Differential scanning calorimetry (DSC) is a method for measuring the temperature of a sample and an inert reference (typically α-Al) by continuously heating or cooling the sample under controlled conditions. 2 O 3 ) with temperature. The endothermic peak height of the DSC curve depends on many factors related to the sample preparation and the instrument geometry, but the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms according to the present invention are characterized by DSC patterns having characteristic peak positions, which are substantially as shown in the DSC diagrams provided in the drawings of the present invention. In addition, since there are experimental errors in the DSC patterns, and the peak positions and peak values ​​of the DSC spectra from different instruments and different samples may be slightly different, the numerical values ​​of the peak positions or peak values ​​of the DSC endothermic peaks mentioned above cannot be considered absolute. According to the conditions of the instrument used in this test, the tolerance of the endothermic peak is ±3°C.

[0048] Thermogravimetric analysis (TGA) is a technique to measure the mass change of a substance with temperature under procedural control, which is suitable for examining the process of solvent loss in crystallization or sublimation and decomposition of a sample, and can infer the presence of crystal water or crystal solvent in the crystal. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument, and the mass change detected by TGA with different instruments and different samples will be slightly different. According to the conditions of the instrument used in this test, the allowable error of the mass change is ±0.1℃.

[0049] In the context of the present invention, all 2θ values ​​in an X-ray powder diffraction diagram are in degrees (°).

[0050] The term "substantially as shown in the figure" means that at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern, DSC pattern, Raman spectral pattern, or infrared spectral pattern are represented in the figure.

[0051] As used herein, when referring to data shown in spectra and / or graphs, the term "peak" refers to a feature that one of skill in the art would recognize as not being attributable to background noise.

[0052] The new crystalline forms of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid according to the present invention, for example, crystalline forms I or II, exist in substantially pure crystalline form.

[0053] "Substantially pure" means that one crystalline form is substantially free from one or more other crystalline forms, i.e., the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or that the crystalline form contains other crystalline forms, but the percentage of the other crystalline forms relative to the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0054] By "substantially free" is meant that the percentage of one or more other crystalline forms relative to the total volume or weight of the crystalline forms is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0055] "Relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strongest peak to the intensity of other peaks, when the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction (XRPD) pattern is taken as 100%.

[0056] In the context of the present invention, whether or not words such as "about" or "approximately" are used, it means within 10%, preferably within 5%, particularly within 1% of a given value or range. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. When a number having a value N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% is expressly disclosed, where "+ / -" means plus or minus.

[0057] In the present invention, "room temperature" refers to about 10 o C to about 40 o C. In some embodiments, "room temperature" refers to a temperature of about 20 o About 30 from C o In some other embodiments, "room temperature" refers to a temperature of 20 o C, 22.5 o C, 25 o C, 27.5 o It means C etc.

[0058] Compositions, Formulations, Administration and Uses of the Crystalline Forms of the Invention The pharmaceutical composition of the present invention is characterized by comprising a crystalline form of the compound of formula (I) and a pharma- ceutically acceptable carrier, adjuvant, or excipient, and the amount of the crystalline form of the compound in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate a patient's HIF-related and / or EPO-related disease.

[0059] As described in the present invention, the pharma- ceutically acceptable composition of the present invention further comprises a pharma- ceutically acceptable carrier, adjuvant, or excipient, which may be used in the present invention includes any of solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, or lubricants, etc., suitable for a specific target dosage form. The contents of the following references, in combination with those of the literature In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, reveal various carriers that can be used in the formulation of pharma- ceutical acceptable compositions and their known preparation methods. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as producing any undesired biological effects or interacting in a deleterious manner with any other component of the pharma-ceutically acceptable composition, such use is included within the scope of the present invention.

[0060] Pharmaceutically acceptable carrier substances include ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salts or electrolytes such as zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylic esters, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and sodium carboxymethylcellulose, ethylcellulose and These include, but are not limited to, derivatives such as cellulose acetate, auxiliary materials such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, diol compounds such as propylene glycol and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline solution, Ringer's solution, ethanol, phosphate buffer solution, and other non-toxic and suitable lubricants, colorants, release agents, coating agents, sweeteners, flavorings, perfumes, preservatives and antioxidants such as sodium lauryl sulfate and magnesium stearate.

[0061] The pharmaceutical compositions of the present invention may be in the form of capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions and may be administered orally, by injection, aerosol inhalation, topically, rectally, nasally, sublingually, vaginally, or via an implantable drug injection device.

[0062] Oral administration can be in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, etc., and topical administration can be in the form of ointments, gels, drug-containing tapes, etc.

[0063] Preferably, the crystalline form of the present invention is prepared as a dosage unit form depending on the formulation method for dosage reduction and dosage uniformity. The term "dosage unit form" herein means a physically separate unit of drug required for proper treatment of a patient. However, it should be understood that the total daily use of the compound of formula (I) of the present invention or its crystalline form, or the pharmaceutical composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level will depend on many factors for any particular patient or organism, including the disease and severity of the disease being treated, the activity of the specific compound or its crystalline form, the specific composition used, the age, weight, health, sex and dietary habits of the patient, the time of administration, the route of administration and the excretion rate of the specific compound or crystalline form used, the duration of treatment, the co-administration of drugs or combinations with compounds or their crystalline forms having special effects, and several other factors known in the pharmaceutical arts.

[0064] The effective dosage of the active ingredient used may vary depending on the compound or its crystalline form used, the mode of administration and the severity of the disease being treated. However, in general, the compound of the present invention or its crystalline form can achieve the desired effect when administered at a daily dose of approximately 0.25-1000 mg / kg of animal body weight, preferably administered in 2-4 divided doses daily or in a sustained release manner. This dosage regimen can be adjusted to provide an optimal therapeutic response. Also, depending on the treatment situation, it can be administered in multiple divided doses daily or the dosage can be proportionally reduced.

[0065] The compound or crystalline form thereof according to the present invention, and the pharmaceutical composition of the present invention regulate the stability and / or activity of HIF by inhibiting HIF hydroxylase activity, thereby activating HIF and regulating gene expression. The compound or crystalline form thereof, or the pharmaceutical composition can be used in a method for treating, preemptively treating, or delaying the onset or progression of HIF-related diseases, including, but not limited to, diseases related to anemia, ischemia, and hypoxia.

[0066] Specifically, the compound or crystalline form thereof according to the present invention is used to increase endogenous erythropoietin (EPO). The compound or crystalline form thereof can be applied to prevent, preemptively treat or treat EPO-related diseases, including anemia and nervous system disorders, etc. Anemia-related diseases include, but are not limited to, acute or chronic nephropathy, diabetes, cancer, ulcers, viral (e.g., HIV), bacterial or parasitic infections, inflammation, etc. Anemia diseases may further be associated with procedures or treatments, including, for example, radiation therapy, chemotherapy, dialysis, and surgery. Anemia is associated with hemoglobin and / or red blood cell abnormalities, such as abnormalities found in disorders such as microcytic anemia, hypochromic anemia, and aplastic anemia. [Brief description of the drawings]

[0067] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form I of the compound of formula (I). [Diagram 2] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form I of the compound of formula (I). [Diagram 3] FIG. 2 is a thermogravimetric (TGA) analysis diagram of crystalline form I of the compound represented by formula (I). [Figure 4] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form II of compound of formula (I). [Diagram 5] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form II of compound of formula (I). [Figure 6] FIG. 2 is a thermogravimetric (TGA) analysis diagram of crystalline form II of compound of formula (I). [Figure 7] FIG. 2 is a dynamic moisture sorption (DVS) diagram of crystalline form I of compound of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0068] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the above examples.

[0069] The X-ray powder diffraction analysis method used in the present invention is as follows: X-ray powder diffraction patterns are obtained using Cu-Kα radiation (45 KV, 40 mA) on an Empyrean diffractometer. A thin layer is made from the powdered sample on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed within the range of 3°-60° with a 0.0167° step size. Data is collected with Data Collector software, processed with HighScore Plus software, and read with Data Viewer software.

[0070] The differential scanning calorimetry (DSC) analysis method used in this invention is to perform differential scanning calorimetry using a TAQ2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample was accurately weighed into a specially made aluminum crucible with a cover and heated at 10°C / min using a linear heating device from room temperature to approximately 300°C. During use, the DSC cell is purged with dry nitrogen.

[0071] The thermal weight loss (TGA) analysis method used in this invention is as follows: Thermal weight loss analysis is performed using a TAQ500 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of sample is accurately weighed into a platinum sample disk and heated at 10°C / min using a linear heating device from room temperature to approximately 300°C. During use, the TGA furnace chamber is purged with dry nitrogen gas.

[0072] The solubility of the present invention is measured using an Agilent 1200 high performance liquid chromatograph DAD / VWD instrument, and the model of the chromatography column is Agilent XDB-C18 (4.6×50 mm, 5 μm). The wavelength is 266 nm, the flow rate is 1.0 mL / min, the column temperature is 35° C., the mobile phase A is acetonitrile-0.01M ammonium acetate=10:90 (V:V), and the analysis method is acetonitrile-mobile phase A=70:30 (V:V), and the operation time is 10 minutes.

[0073] The hygroscopicity of the present invention is measured by a dynamic moisture and gas sorption analyzer, DVS INT-Std type, from Surface Measurement Systems, Ltd., UK. The humidity test range is 0% to 95%, the gas flow is 200 mL / min, and the temperature is 25 o C and one test point is taken at 5% humidity per liter. Specific Examples

[0074] For a specific synthesis method of the compound 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid represented by formula (I), please refer to Example 1 in International Application WO2016034108A1. Working Example Example 1 Crystalline Form I of the Present Invention

[0075] 1. Preparation of Crystal Form I Regarding method 1, 1,4-dioxane (1.5 mL) is added to 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid (40.0 mg) prepared according to the conventional method, and after the solid is completely dissolved, water (1.5 mL) is added dropwise. After crystallization, the crystals are filtered by suction, and the filter cake is vacuum dried at room temperature to obtain a gray-white solid (38.8 mg, 97.0%).

[0076] Regarding method 2, Methanol (6.0 mL) was added to 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid (26.3 mg) prepared according to the conventional method, and the mixture was heated to 60°C to completely dissolve the solid. The mixture was then kept warm for 30 minutes and then rapidly cooled to -10°C to precipitate crystals, which were then suction filtered. The filter cake was vacuum dried at room temperature to obtain an off-white solid (12.2 mg, 46.4%).

[0077] 2. Identification of Crystal Form I (1) X-ray powder diffraction (XRPD) analysis by Empyrean identified using Cu-Kα radiation at 6.20°, 7.32°, 9.05°, 12.44°, 13.72°, 14.66°, 15.18°, 16.55°, 18.16°, 18.70°, 19.30°, 19.92°, 20.28°, 20.88°, 21.78°, 22.06°, 22.76°, 23.39°, 25.36°, 25.68°, 26.89°, 27.31°, 29. It has characteristic peaks represented by 2θ angles of 15°, 29.49°, 30.85°, 31.39°, 33.27°, 34.36°, 36.33°, 37.15°, 37.87°, 38.43°, 39.44°, 40.71°, 42.56°, 42.94°, 43.62°, 44.25°, 45.46°, 46.60°, 48.43°, 49.75°, 52.66°, 55.45°, 56.36° and 57.93° with a tolerance of ±0.2°C.

[0078] (2) Analysis of differential scanning calorimetry (DSC) by TAQ2000. The scan rate was 10℃ / min, including the endothermic peak at 222.82℃, with a tolerance of ±3℃.

[0079] (3) Thermogravimetric analysis (TGA) by TAQ500. The heating rate is 10°C / min, the weight loss range is 1.315%, and the tolerance is ±0.1%. Example 2 Crystalline Form II of the Present Invention

[0080] 1. Preparation of Crystal Form II Regarding method 1, 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid (50.7 mg) prepared according to the conventional method is added to dimethylformamide (2.0 mL) for dissolution, water (1.5 mL) is added dropwise, crystals are precipitated, and then the precipitate is filtered by suction. The filter cake is vacuum dried at room temperature to obtain a gray-white solid (39.7 mg, 78.3%).

[0081] Regarding method 2, 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid (75.1 mg) produced according to the conventional method is dissolved in dimethylformamide (1.0 mL), and water (5.0 mL) is added dropwise to the reaction solution to precipitate crystals, which are then suction filtered and vacuum dried at room temperature to obtain a gray-white solid (64.5 mg, 85.9%).

[0082] 2. Identification of Crystal Form II (1) X-ray powder diffraction (XRPD) analysis by Empyrean for identification, using Cu-Kα radiation, has characteristic peaks represented by angles 2θ of 5.23°, 8.73°, 10.12°, 10.52°, 13.61°, 15.80°, 17.42°, 18.06°, 19.99°, 20.29°, 20.93°, 21.54°, 22.72°, 24.08°, 25.18°, 25.90°, 27.94°, 30.04°, 32.19°, 33.13°, 35.21°, 35.99°, 36.95°, 40.09°, 41.17°, 45.55°, 48.48°, 51.97° and 55.75°. The tolerance is ±2°C.

[0083] (2) For the analysis and identification of differential scanning calorimetry (DSC) by TAQ2000, the scanning rate was 10℃ / min, including the endothermic peak at 223.69℃, and the tolerance was ±3℃.

[0084] (3) For the analysis and identification of thermogravimetric loss (TGA) by TAQ500, the heating rate is 10°C / min, the range of weight loss is 0.406%, and the tolerance is ±0.1%. Example 3 Pharmacokinetics Experiment of the Crystal Form of the Present Invention

[0085] Filled capsules of the crystalline form of the compound of formula (I) according to the invention are administered orally.

[0086] Three male Beagle dogs weighing 8-12 kg were orally administered capsules containing the test sample at a dose of 10 mg / kg, and blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h. Based on the sample concentration, a standard curve with an appropriate range was established, and the concentration of the test sample in the plasma sample was measured using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Based on the drug concentration-time curve, the pharmacokinetic parameters were calculated using the non-compartmental model method with WinNonLin 6.3 software. The experimental results are shown in Table 1.

[0087] Table 1. Pharmacokinetic experimental data of the crystal forms according to the present invention [Table 1] Test conclusion: As can be seen from Table 1, the crystalline form I of the present invention has a high exposure in the body of beagle dogs and has excellent pharmacokinetic properties. Example 4 Stability test of the crystalline form according to the present invention

[0088] (1) High temperature test: Put an appropriate amount of the test sample into a flat weighing bottle, spread it into a thin layer with a thickness of 5 mm or less, and leave it at a temperature of 60℃±2℃ for 30 days. On the 6th, 10th and 30th days, take samples and measure according to the key stability investigation items, observe the color change of the sample, and measure the purity of the sample by HPLC. The experimental results are shown in Table 2.

[0089] (2) High humidity test: Place an appropriate amount of the test sample in a flat weighing bottle, spread it into a thin layer less than 5 mm thick, and then heat it for 25o C, leave it under RH 90%±5% for 30 days, sample it on the 6th, 10th and 30th days and detect it according to the key stability considerations, observe the color change of the sample, and measure the purity of the sample by HPLC. The experimental results are shown in Table 2.

[0090] (3) Light irradiation test: Put an appropriate amount of the test sample into a flat weighing bottle, spread it into a thin layer with a thickness of 5 mm or less, open it, and place it in a light irradiation test box (with an ultraviolet lamp). The illuminance is 4500 ± 500 lx, and the ultraviolet light is ≧ 0.7 w / m 2 The mixture was left to stand for 30 days under the above conditions, and samples were taken on the 6th, 13th, and 30th days, and the purity of the samples was measured by HPLC. The experimental results are shown in Table 2.

[0091] (4) Accelerated test: A suitable amount of sample from one batch is wrapped in single layer PE and then wrapped in aluminum foil, and left to stand under the conditions of 40±2℃ / 75%±5%RH for 6 months. Samples are taken at 1, 2, 3 and 6 months, and the color change of the sample is observed, the purity of the sample is measured by HPLC, and the moisture content is tested by TGA. The experimental results are shown in Table 3.

[0092] Table 2. Results of high temperature, high humidity and light irradiation experiments of the crystalline form I of the present invention [Table 2] Table 3. Results of accelerated testing (40±2°C / 75%±5%RH) of crystalline form I of the present invention [Table 3] Test conclusion: As can be seen from the experimental results in Table 2, when left standing for 30 days under high temperature (60°C), high humidity (25°C, RH90%±5%) and light irradiation conditions, the appearance and purity of the crystalline form I of the present invention do not change obviously.

[0093] As can be seen from the experimental results in Table 3, under the accelerated test conditions, the appearance, purity and water content of the crystalline form I of the present invention do not change obviously.

[0094] From the above, the crystalline form I according to the present invention has high stability under each static condition and is suitable for pharmaceutical use. Example 5 Hygroscopicity test of the crystalline form according to the present invention

[0095] A suitable amount of the test sample is tested for its moisture absorption using a dynamic moisture sorption apparatus.

[0096] The hygroscopicity test DVS pattern of the crystalline form I of the present invention is substantially as shown in Figure 7, and the specific experimental results are as shown in Table 4. Based on the description of hygroscopicity characteristics and the definition of hygroscopic mass increase (Chinese Pharmacopoeia 2015 Edition, Annex 9103, Guideline of Drug Hygroscopicity, details are shown in Table 5), the crystalline form I of the present invention is slightly hygroscopic and not easily deliquesced under the influence of high humidity.

[0097] Table 4 Hygroscopicity test of crystalline form I of the present invention [Table 4] Table 5. Description of hygroscopic characteristics and definition of hygroscopic mass increase (25°C ± 1°C, 80% ± 2% relative humidity) [Table 5] The above is a basic description of the concept of the present invention, and any equivalent transformation made based on the technical solutions of the present invention should fall within the protection scope of the present invention.

[0098] In the description of this specification, the reference terms "one embodiment", "several embodiments", "examples", "specific examples" or "several examples" mean that the specific features, structures, materials or features described in the combination of the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the exemplary expressions of the above terms are not necessarily limited to the same embodiment or example. And, the specific features, structures, materials or features described can be combined in any suitable manner in any one or more embodiments or examples. In addition, unless mutually inconsistent, a person skilled in the art can combine or combine different embodiments or examples described in this specification and features of different embodiments or examples.

[0099] Although the embodiments of the present invention have been illustrated and described above, it should be understood that the above embodiments are merely illustrative and should not be construed as limiting the present invention, and that those skilled in the art may make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A crystal of the compound of formula (I) which is crystalline form I, characterized in that the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 6.20°±0.2°, 18.16°±0.2°, 19.30°±0.2°, 26.89°±0.2°, and 27.31°±0.2°. 【Chemistry 1】

2. The crystal according to claim 1, characterized in that the X-ray powder diffraction pattern of the crystal has diffraction peaks at 2θ angles of 6.20°±0.2°, 9.05°±0.2°, 13.72°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, 22.06°±0.2°, 26.89°±0.2°, and 27.31°±0.2°.

3. The X-ray powder diffraction pattern of the crystal is 6.20°±0.2°, 7.32°±0.2°, 9.05°±0.2°, 13.72°±0.2°, 14.66°±0.2°, 15.18°±0.2°, 16.55°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, 20.28°±0.2°, 21.78°±0.2°, 22.06°±0.2°, 22.76°±0.2°, 23.39°±0.2°, 25.36°±0.2°, 25.68°±0.2°, 26.89°±0.2° 3. The crystal according to claim 1 or 2, characterized in that it has diffraction peaks at 2θ angles of 27.31°±0.2°, 29.15°±0.2°, 29.49°±0.2°, 30.85°±0.2°, 31.39°±0.2°, 33.27°±0.2°, 34.36°±0.2°, 36.33°±0.2°, 37.15°±0.2°, 37.87°±0.2°, 38.43°±0.2°, 39.44°±0.2°, 40.71°±0.2°, 42.56°±0.2°, 42.94°±0.2°, 43.62°±0.2°, and 44.25°±0.2°.

4. The X-ray powder diffraction pattern of the crystal is 6.20°±0.2°, 7.32°±0.2°, 9.05°±0.2°, 12.44°±0.2°, 13.72°±0.2°, 14.66°±0.2°, 15.18°±0.2°, 16.55°±0.2°, 18.16°±0.2°, 18.70°±0.2°, 19.30°±0.2°, 19.92°±0.2°, ±0.2°, 20.28°±0.2°, 20.88°±0.2°, 21.78°±0.2°, 22.06°±0.2°, 22.76°±0.2°, 23.39°±0.2°, 25.36°±0.2°, 25.68°±0.2°, 26.89°±0.2°, 27.31°±0.2°, 29.15°±0.2°, 29.49°±0.2°, 30 . 85°±0.2°, 31.39°±0.2°, 33.27°±0.2°, 34.36°±0.2°, 36.33°±0.2°, 37.15°±0.2°, 37.87°±0.2°, 38.43°±0.2°, 39.44°±0.2°, 40.71°±0.2°, 42.56°±0.2°, 42.94°±0.2°, 43.62°±0.2 The crystal according to any one of claims 1 to 3, characterized in that it has diffraction peaks at 2θ angles of 44.25°±0.2°, 45.46°±0.2°, 46.60°±0.2°, 48.43°±0.2°, 49.75°±0.2°, 52.66°±0.2°, 55.45°±0.2°, 56.36°±0.2°, and 57.93°±0.2°.

5. The crystal according to any one of claims 1 to 4, characterized in that the differential scanning calorimetry pattern of the crystal includes an endothermic peak at 222.82°C ± 3°C.

6. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 5 and a pharma- ceutically acceptable carrier, excipient, diluent, adjuvant, or a combination thereof.

7. A crystal described in any one of claims 1 to 5 or a pharmaceutical composition described in claim 6 for use in preventing, treating or alleviating a hypoxia-inducible factor-associated and / or erythropoietin-associated disease in a patient.

8. 8. The crystal or pharmaceutical composition of claim 7, wherein the disease is anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing.

9. A crystal described in any one of claims 1 to 5 or a pharmaceutical composition described in claim 6 for use in preventing, treating or alleviating at least some of the diseases mediated by hypoxia-inducible factor prolyl hydroxylase in at least some patients.

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