Salts of quinolinone compounds and uses thereof

Abstract

The present invention relates to salts of quinolinone compounds and uses thereof. In particular, the present invention relates to salts of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid and pharmaceutical compositions comprising said salts, further to their use in the manufacture of a medicament for the treatment and prevention of HIF-related and / or EPO-related diseases, such as anemia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to salts of quinolinone compounds and their uses, specifically to salts of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamide)acetic acid and pharmaceutical compositions comprising said salts, and further to their use in the preparation of pharmaceuticals. Background Technology

[0002] In cases of anemia, trauma, tissue necrosis, and defects, tissues or cells are often in a state of hypoxia. Hypoxia leads to the expression of a series of transcription inducible factors, which are involved in angiogenesis, iron and glucose metabolism, and cell growth and proliferation. Among them, hypoxia-inducible factor (HIF) is a transcription factor that is initiated by somatic cells under conditions of reduced oxygen. It is widely distributed in various parts of the body, especially the vascular endothelium, heart, brain, kidneys, and liver. HIF is a heterodimer containing an oxygen-regulated α-subunit (HIFα) and a constitutively expressed β-subunit (HIFβ / ARNT). In oxygen-containing (normal oxygen levels) cells, the HIFα subunit is rapidly degraded through the ubiquitination mechanism of the von Hippel-Lindau tumorsuppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFα is not degraded, and the active HIFα / β complex accumulates in the nucleus, activating the expression of various genes, including glycolytic enzymes, glucose transporters, erythropoietin (EPO), and vascular endothelial growth factor (VEGF).

[0003] Erythropoietin (EPO) is a naturally occurring hormone produced in conjunction with HIFα, stimulating the production of red blood cells (erythrocytes) that carry oxygen throughout the body. EPO is normally secreted by the kidneys, and endogenous EPO increases under conditions of reduced oxygen (hypoxia). All types of anemia are characterized by a reduced oxygen-carrying capacity of the blood, resulting in similar signs and symptoms, including pale skin and mucous membranes, weakness, dizziness, fatigue, and drowsiness, leading to a decreased quality of life. Anemia is usually associated with a lack of red blood cells or hemoglobin in the blood. Common causes of anemia include iron deficiency and vitamin B deficiency. 12 Folic acid deficiency can also occur as a complication of chronic diseases, such as inflammatory diseases, including those with secondary myelosuppression. Anemia is also associated with kidney dysfunction; most patients with kidney failure who undergo regular dialysis have chronic anemia.

[0004] Prolyl hydroxylase (PHD) is a key factor regulating HIF. Under normoxic conditions, PHD can hydroxylate two key proline residues, Pro402 and Pro564, of HIFα, increasing its affinity for pVHL and accelerating its degradation. Under hypoxic and other pathological conditions, the PHD-catalyzed HIF reaction is inhibited, the protease degradation rate slows down, and HIFα accumulates intracellularly, leading to a series of adaptive responses of the cell to hypoxia. Inhibiting PHD with PHD inhibitors prolongs the action of HIF, thereby increasing the expression of genes such as EPO, which can effectively treat and prevent HIF-related and / or EPO-related conditions, such as anemia, ischemia, and hypoxia.

[0005] International application WO 2016034108 A1 discloses compound 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamide)acetic acid (I), which can treat or alleviate HIF-related and / or EPO-related diseases, such as anemia. This compound suffers from poor solubility, suboptimal absorption in animals, and poor stability, which pose significant challenges to subsequent formulation development.

[0006] Summary of the Invention

[0007] This invention provides salts of the compounds shown in formula (I). Specifically, this invention provides diethanolamine salts of the compounds shown in formula (I), wherein the diethanolamine salt, particularly crystal form A, can significantly improve the stability and pharmacokinetic properties of the compounds, thereby exhibiting superior drug-like properties.

[0008] Specifically, the present invention relates to salts of compounds of formula (I), pharmaceutical compositions comprising said salts, and their use in the preparation of medicaments for the treatment or prevention of HIF-related and / or EPO-related diseases. The salts of the present invention may also be in solvate form, such as hydrate form.

[0009] On the one hand, the present invention provides a salt of the compound shown in formula (I);

[0010]

[0011] In some embodiments, the salts of the compounds represented by formula (I) of the present invention include, but are not limited to, sodium salts, potassium salts, magnesium salts, diethanolamine salts, ethanolamine salts, imidazole salts, arginine salts, diethylaminoethanol salts, N,N-dimethylethanolamine salts, ethylenediamine salts, or diethylamine salts.

[0012] In some embodiments, the salt of the compound represented by formula (I) of the present invention is the diethanolamine salt of the compound represented by formula (I).

[0013] In some embodiments, the diethanolamine salt of the compound represented by formula (I) of the present invention is crystal form A of the diethanolamine salt of the compound represented by formula (I).

[0014]

[0015] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the diethanolamine salt of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 6.49±0.2°, 9.75±0.2°, 16.41±0.2°, 19.62±0.2° and 25.41±0.2°.

[0016] In other embodiments, the X-ray powder diffraction pattern of crystal form A of the diethanolamine salt of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 6.49±0.2°, 9.75±0.2°, 16.41±0.2°, 16.92±0.2°, 19.62±0.2°, 23.16±0.2°, 25.41±0.2°, 26.27±0.2°, 27.88±0.2° and 29.64±0.2°.

[0017] In other embodiments, the X-ray powder diffraction pattern of crystal form A of the diethanolamine salt of the compound shown in formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 6.49±0.2°, 9.75±0.2°, 10.84±0.2°, 12.38±0.2°, 13.04±0.2°, 14.05±0.2°, 14.47±0.2°, 16.41±0.2°, 16.92±0.2°, 17.86±0.2°, 19.62±0.2°, 20.87±0.2°, 21.94±0.2°, 22.95±0.2°, 23.16± 0.2°, 23.85±0.2°, 24.93±0.2°, 25.41±0.2°, 26.27±0.2°, 27.88±0.2°, 29.64±0.2°, 31.73±0.2° and 33.04±0.2°.

[0018] In some embodiments, the crystal form A of the diethanolamine salt of the compound represented by formula (I) of the present invention has substantially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0019] In some embodiments, the differential scanning calorimetry (DSC) of crystal form A of the diethanolamine salt of the compound represented by formula (I) of the present invention contains an endothermic peak at 148.89 °C ± 3 °C.

[0020] In some embodiments, the crystal form A of the diethanolamine salt of the compound represented by formula (I) of the present invention has substantially the following characteristics: Figure 2 The differential scanning calorimeter shown is a thermal image.

[0021] In some embodiments, the diethanolamine salt of the compound represented by formula (I) of the present invention is crystal form B of the diethanolamine salt of the compound represented by formula (I).

[0022] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the diethanolamine salt of the compound shown in formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 4.77±0.2°, 7.17±0.2°, 7.68±0.2°, 9.55±0.2°, 11.31±0.2°, 12.05±0.2°, 12.99±0.2°, 13.40±0.2°, 14.36±0.2°, 15.57±0.2°, 17.49±0.2°, 19.18±0.2°, 20.57°±0.2°, 21.65±0.2°, 21.82±0.2°. 22.49±0.2°, 22.75±0.2°, 24.36±0.2°, 25.38±0.2°, 26.55±0.2°, 27.20±0.2°, 28.98±0.2°, 29.63±0.2°, 31.41±0.2°, 32.84±0.2°, 33.95±0.2°, 34.48±0.2°, 36.22±0.2° and 38.54±0.2°

[0023] In some embodiments, the crystal form B of the diethanolamine salt of the compound represented by formula (I) of the present invention has substantially the following characteristics: Figure 3 The X-ray powder diffraction pattern shown.

[0024] In some embodiments, the differential scanning calorimetry (DSC) of crystal form B of the diethanolamine salt of the compound represented by formula (I) of the present invention contains an endothermic peak at 166.56 °C ± 3 °C.

[0025] In some embodiments, the crystal form B of the diethanolamine salt of the compound represented by formula (I) of the present invention has substantially the following characteristics: Figure 4 The differential scanning calorimeter shown is a thermal image.

[0026] In some embodiments, the salt of the compound represented by formula (I) of the present invention is the sodium salt of the compound represented by formula (I).

[0027] In some embodiments, the sodium salt of the compound represented by formula (I) of the present invention is crystal form A of the sodium salt of the compound represented by formula (I).

[0028] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the sodium salt of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 3.29±0.2°, 6.45±0.2°, 9.82±0.2°, 11.65±0.2°, 13.14±0.2°, 13.74±0.2°, 15.63±0.2°, 16.22±0.2°, 17.29±0.2°, 17.91±0.2°, 19.01±0.2°, 19.74±0.2°, 23.19±0.2°, 25.03±0.2°, 26.92±0.2°, 28.63± 0.2°, 29.83±0.2°, 33.05±0.2°, 34.52±0.2° and 36.53±0.2°.

[0029] In some embodiments, the crystal form A of the sodium salt of the compound of formula (I) described in this invention has substantially the following characteristics: Figure 5 The X-ray powder diffraction pattern shown.

[0030] In some embodiments, the differential scanning calorimetry (DSC) of the sodium salt of the compound of formula (I) of the present invention includes endothermic peaks at 140.99 °C ± 3 °C and 259.59 °C ± 3 °C and an exothermic peak at 176.06 °C ± 3 °C.

[0031] In some embodiments, the crystal form A of the sodium salt of the compound of formula (I) described in this invention has substantially the following characteristics: Figure 6 The differential scanning calorimeter shown is a thermal image.

[0032] In some embodiments, the sodium salt of the compound represented by formula (I) of the present invention is crystal form C of the sodium salt of the compound represented by formula (I).

[0033] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the sodium salt of the compound of formula (I) of the present invention contains the following diffraction peaks at the 2θ angle: 7.16±0.2°, 10.77±0.2°, 14.38±0.2°, 15.57±0.2°, 16.08±0.2°, 16.30±0.2°, 16.72±0.2°, 17.15±0.2°, 17.55±0.2°, 18.04±0.2°, 18.88±0.2°, 19.56±0.2°, 20.02±0.2°, 20.94±0.2°, 21.69±0.2°, 22.43 ±0.2°, 22.78±0.2°, 23.45±0.2°, 25.38±0.2°, 26.19±0.2°, 27.30±0.2°, 28.06±0.2°, 29.07±0.2°, 30.30±0.2°, 31.66±0.2°, 32.36±0.2°, 32.83±0.2°, 33.41±0.2°, 33.81±0.2°, 34.49±0.2°, 34.76±0.2°, 35.77±0.2° 36.29±0.2°, 36.72±0.2°, 37.83±0.2°, 38.14±0.2°, 38.59±0.2° and 39.21±0.2°.

[0034] In some embodiments, the crystal form C of the sodium salt of the compound of formula (I) of the present invention has substantially the following characteristics: Figure 7 The X-ray powder diffraction pattern shown.

[0035] In some embodiments, the differential scanning calorimetry (DSC) of the sodium salt of the compound of formula (I) of the present invention contains an endothermic peak at 261.96 °C ± 3 °C.

[0036] In some embodiments, the crystal form C of the sodium salt of the compound of formula (I) of the present invention has substantially the following characteristics: Figure 8 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0037] In some embodiments, the sodium salt of the compound represented by formula (I) of the present invention is of crystal form D.

[0038] In some embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) of the present invention, crystal form D, contains the following diffraction peaks at the 2θ angle: 3.34±0.2°, 6.54±0.2°, 9.20±0.2°, 10.28±0.2°, 14.64±0.2°, 15.44±0.2°, 16.49±0.2°, 17.06±0.2°, 20.75±0.2°, 22.40±0.2°, 23.32±0.2°, 25.42±0.2°, 27.48±0.2°, and 28.33±0.2°.

[0039] In some embodiments, the crystal form D of the sodium salt of the compound of formula (I) of the present invention has substantially the following characteristics: Figure 9 The X-ray powder diffraction pattern shown.

[0040] In some embodiments, the differential scanning calorimetry (DSC) of the sodium salt of the compound of formula (I) of the present invention contains an endothermic peak at 262.65 °C ± 3 °C.

[0041] In some embodiments, the crystal form D of the sodium salt of the compound of formula (I) of the present invention has substantially the following characteristics: Figure 10 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0042] In some embodiments, the sodium salt of the compound represented by formula (I) is crystal form E of the sodium salt of the compound represented by formula (I).

[0043] In some embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound of formula (I) of the present invention, crystal form E, contains the following diffraction peaks at the 2θ angle: 3.55±0.2°, 7.01±0.2°, 9.80±0.2°, 11.08±0.2°, 13.27±0.2°, 15.30±0.2°, 16.72±0.2°, 17.98±0.2°, 18.44±0.2°, 18.84±0.2°, 19.80±0.2°, 20.84±0.2°, 22.22±0.2°, 22.62±0.2°, 23.95±0.2°, 24.52± 0.2°, 25.58±0.2°, 26.60±0.2°, 29.91±0.2°, 31.86±0.2°, 34.03±0.2°, 36.66±0.2° and 39.49±0.2°.

[0044] In some embodiments, the crystal form E of the sodium salt of the compound of formula (I) described in this invention has substantially the following characteristics: Figure 11 The X-ray powder diffraction pattern shown.

[0045] In some embodiments, the differential scanning calorimetry (DSC) of the sodium salt of the compound of formula (I) of the present invention contains an endothermic peak at 231.51 °C ± 3 °C.

[0046] In some embodiments, the crystal form E of the sodium salt of the compound of formula (I) described in this invention has substantially the following characteristics: Figure 12 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0047] In some embodiments, the potassium salt of the compound represented by formula (I) of the present invention is its potassium salt crystal form A.

[0048] In some embodiments, the X-ray powder diffraction pattern of the potassium salt of the compound of formula (I) of the present invention, crystal form A, contains the following diffraction peaks at the 2θ angle: 3.28±0.2°, 6.45±0.2°, 9.66±0.2°, 11.53±0.2°, 12.87±0.2°, 13.59±0.2°, 15.63±0.2°, 16.06±0.2°, 16.21±0.2°, 17.33±0.2°, 17.76±0.2°, 18.74±0.2°, 18.98±0.2°, 19.51±0.2°, 20.21±0.2°, 21.58± 0.2°, 22.57±0.2°, 22.87±0.2°, 23.23±0.2°, 24.03±0.2°, 24.54±0.2°, 25.04±0.2°, 25.82±0.2°, 26.54±0.2°, 26.91±0.2°, 27.41±0.2°, 28.53±0.2°, 29.11±0.2°, 30.09±0.2°, 30.72±0.2°, 31.51±0.2°, 31.77±0.2°, 32.15 ±0.2°, 32.44±0.2°, 33.19±0.2°, 33.82±0.2°, 34.39±0.2°, 35.29±0.2°, 35.79±0.2°, 36.93±0.2°, 37.95±0.2°, 38.72±0.2° and 39.14±0.2°.

[0049] In some embodiments, the potassium salt of the compound of formula (I) of the present invention has a crystal form A that is substantially as follows: Figure 13 The X-ray powder diffraction pattern shown.

[0050] In some embodiments, the differential scanning calorimetry (DSC) of the potassium salt of the compound of formula (I) of the present invention contains endothermic peaks at 170.58 °C ± 3 °C and 279.49 °C ± 3 °C.

[0051] In some embodiments, the potassium salt of the compound of formula (I) of the present invention has a crystal form A that is substantially as follows: Figure 14 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0052] In some embodiments, the salt of the compound represented by formula (I) of the present invention is the magnesium salt of the compound represented by formula (I).

[0053] In some embodiments, the magnesium salt of the compound represented by formula (I) of the present invention is crystal form A of the magnesium salt of the compound represented by formula (I). In some embodiments, the X-ray powder diffraction pattern of crystal form A of the magnesium salt of the compound represented by formula (I) of the present invention contains the following diffraction peaks at 2θ angles: 3.20±0.2°, 6.27±0.2°, 9.44±0.2°, 12.59±0.2°, 14.23±0.2°, 15.74±0.2°, 16.18±0.2°, 18.04± 0.2°, 18.63±0.2°, 18.82±0.2°, 19.33±0.2°, 19.97±0.2°, 21.26±0.2°, 21.57±0.2°, 22.43±0.2°, 22.92±0.2°, 23.92±0.2°, 25.23±0.2°, 27.21±0.2°, 27.57±0.2°, 28.34±0.2°, 29.49±0.2°, 31.00±0.2°, 32.12±0.2°, 32.92±0.2°, 34.56±0.2°, 35.83±0.2°, 37.21±0.2° and 38.50±0.2°.

[0054] In some embodiments, the magnesium salt of the compound of formula (I) of the present invention has a crystal form A that is substantially as follows: Figure 15 The X-ray powder diffraction pattern shown.

[0055] In some embodiments, the differential scanning calorimetry (DSC) of the magnesium salt of the compound represented by formula (I) of the present invention contains an endothermic peak at 175.18 °C ± 3 °C.

[0056] In some embodiments, the magnesium salt of the compound of formula (I) of the present invention has a crystal form A that is substantially as follows: Figure 16 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0057] On the other hand, the present invention relates to a pharmaceutical composition comprising the salt described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0058] On one hand, the present invention relates to the use of the salt or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of hypoxia-inducible factor-related and / or erythropoietin-related diseases in patients.

[0059] In some embodiments, the diseases described in this invention are anemia, ischemia, vascular diseases, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders, or wound healing.

[0060] On the other hand, the present invention relates to the use of the salt or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of a disease in which a patient is at least partially mediated by hypoxia-inducible factor prolyl hydroxylase.

[0061] In some embodiments, the diseases described in this invention are anemia, ischemia, vascular diseases, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders, or wound healing.

[0062] One aspect of this invention relates to methods for preventing, treating, or alleviating hypoxia-inducible factor-related and / or erythropoietin-related diseases in patients, including administering medication to patients using a pharmaceutically acceptable and effective dose of the salt or pharmaceutical composition described herein.

[0063] On the other hand, the present invention also relates to a method for preparing salts of the compounds shown in formula (I).

[0064] The solvents used in the salt preparation method described in this invention are not particularly limited; any solvent capable of dissolving the starting material to a certain extent without affecting its properties is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0065] The preparation experiments of the salt or its crystal form described in this invention are described in detail in the Examples section. Furthermore, this invention provides pharmacological testing experiments (such as pharmacokinetic experiments) and stability experiments for the salt or its crystal form. Experiments have demonstrated that the salt or its crystal form described in this invention possesses good stability and pharmacokinetic properties.

[0066] Definitions and general terms

[0067] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0068] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0069] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, 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, etc.

[0070] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0071] A "solvent" is a compound that has a solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which water is the solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. A hydrate may or may not have other solvents besides water on its surface, in its crystal lattice, or both on its surface and in its crystal lattice.

[0072] Crystal forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0073] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0074] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3° for the endothermic peaks.

[0075] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0076] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks are shown in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum.

[0077] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0078] This invention relates to salts of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid and their crystal forms, for example, crystal form A of diethanolamine salt, which exist in substantially pure crystalline form.

[0079] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal 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 the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal 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%.

[0080] "Substantially free of" means that one or more other crystal forms account for 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% of the total volume or weight of the crystal form.

[0081] The "relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in the X-ray powder diffraction pattern (XRPD) is 100%.

[0082] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of 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 explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0083] In this invention, "room temperature" refers to a temperature ranging from approximately 10°C to approximately 40°C. In some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0084] Pharmaceutical compositions, formulations, administration and uses of the salts of the compounds described in this invention.

[0085] The pharmaceutical compositions of the present invention are characterized by a salt of a compound of formula (I) and a pharmaceutically acceptable carrier, excipient, or excipient. The amount of the salt of the compound in the pharmaceutical compositions of the present invention can effectively and detectably treat or alleviate HIF-related and / or EPO-related diseases in patients.

[0086] As described in this invention, pharmaceutically acceptable compositions of this invention further comprise pharmaceutically acceptable carriers, excipients, or excipients, such as those used in this invention, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a particular target dosage form. As described in the following literature: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are summarized herein demonstrate that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except for any conventional carrier media that are incompatible with the salts or crystal forms of the compounds of the present invention, such as those that produce any adverse biological effects or interactions with any other component of a pharmaceutically acceptable composition in a harmful manner, their use is also within the scope of this invention.

[0087] Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols 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 salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0088] The pharmaceutical compositions of the present invention may be capsules, tablets, pills, powders, granules, and aqueous suspensions or solutions; and may be administered via the following routes: oral administration, injection administration, inhalation spray, topical administration, rectal administration, nasal administration, sublingual administration, vaginal administration, or via implantable cassette.

[0089] Oral administration can be in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, etc.; topical administration can be in the following forms: ointments, gels, medicated plasters, etc.

[0090] The salts or crystal forms thereof of the present invention are preferably formulated in a dosage unit form to reduce the uniformity of dosage and administration. The term "dosage unit form" here refers to the physical dispersion unit of the drug required for the patient to receive adequate treatment. However, it should be understood that the total daily dosage of the salts or crystal forms thereof of the compounds of formula (I) of the present invention, or the pharmaceutical compositions of the present invention, will be determined by the attending physician based on reliable medical judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and its severity, the activity of the salts or crystal forms thereof of the specific compound, the specific composition used, the patient's age, weight, health status, sex and dietary habits, the time of administration, the route of administration and the excretion rate of the salts or crystal forms thereof of the specific compound used, the duration of treatment, whether the drug is used in combination therapy or in combination with salts or crystal forms thereof of a specific compound, and other factors known in the pharmaceutical field.

[0091] The effective dose of the active ingredient used can vary depending on the salt or crystal form of the compound used, the administration method, and the severity of the disease being treated. However, generally, satisfactory effects are obtained when the salt or crystal form of the compound of the present invention is administered daily at a dose of about 0.25-1000 mg / kg of animal body weight, preferably in 2-4 separate doses daily, or in a sustained-release form. For most large mammals, the total daily dose is about 1-100 mg / kg, preferably about 2-80 mg / kg of the salt or crystal form of the active compound. Suitable oral dosage forms comprise about 0.25-500 mg of the salt or crystal form of the active compound, closely mixed with a pharmaceutically acceptable solid or liquid carrier. This dosage regimen can be adjusted to provide the optimal therapeutic response. Additionally, depending on the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0092] The salts of the compounds or their crystal forms, and the pharmaceutical compositions of the present invention, may be used to inhibit HIF hydroxylase activity, thereby regulating the stability and / or activity of HIF and activating the expression of HIF regulatory genes. The salts of the compounds or their crystal forms, or the pharmaceutical compositions thereof, may be used in methods for treating, pre-treating, or delaying the onset or progression of HIF-related conditions, including but not limited to anemia, ischemia, and hypoxia.

[0093] Specifically, salts of the compounds or their crystal forms involved in this invention can be used to increase endogenous erythropoietin (EPO). Salts of said compounds or their crystal forms can be administered to prevent, pre-treat, or treat EPO-related conditions, including, for example, anemia and neurological disorders. Conditions associated with anemia include, but are not limited to: acute or chronic kidney disease, diabetes, cancer, ulcers, viral (e.g., HIV), bacterial or parasitic infections; inflammation, etc. Anemia can be further associated with procedures or treatments including, for example, radiotherapy, chemotherapy, dialysis, and surgery. Additionally, anemia is associated with hemoglobin and / or red blood cell abnormalities, such as those seen in microcytic anemia, hypochromic anemia, aplastic anemia, and other disorders. Attached Figure Description

[0094] Figure 1 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form A of the diethanolamine salt of the compound shown in formula (I).

[0095] Figure 2 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the diethanolamine salt of the compound shown in formula (I).

[0096] Figure 3 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form B of the diethanolamine salt of the compound shown in formula (I).

[0097] Figure 4 The differential scanning calorimetry (DSC) curve is shown for crystal form B of the diethanolamine salt of the compound shown in formula (I).

[0098] Figure 5 The image shows the X-ray powder diffraction (XRPD) pattern of crystal form A of the sodium salt of the compound shown in formula (I).

[0099] Figure 6 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the sodium salt of the compound shown in formula (I).

[0100] Figure 7 The image shows the X-ray powder diffraction (XRPD) pattern of the crystal form C of the sodium salt of the compound shown in formula (I).

[0101] Figure 8 The differential scanning calorimetry (DSC) curve is shown for the crystal form C of the sodium salt of the compound shown in formula (I).

[0102] Figure 9 The image shows the X-ray powder diffraction (XRPD) pattern of the crystal form D of the sodium salt of the compound shown in formula (I).

[0103] Figure 10 The differential scanning calorimetry (DSC) curve is shown for the crystal form D of the sodium salt of the compound shown in formula (I).

[0104] Figure 11 The image shows the X-ray powder diffraction (XRPD) pattern of the crystal form E of the sodium salt of the compound shown in formula (I).

[0105] Figure 12 The differential scanning calorimetry (DSC) curve is shown for the crystal form E of the sodium salt of the compound shown in formula (I).

[0106] Figure 13 The image shows the X-ray powder diffraction (XRPD) pattern of the potassium salt of the compound shown in formula (I) with crystal form A.

[0107] Figure 14 The differential scanning calorimetry (DSC) curve is shown for the potassium salt of the compound represented by formula (I), which is crystal form A.

[0108] Figure 15 The image shows the X-ray powder diffraction (XRPD) pattern of the magnesium salt of the compound shown in formula (I) with crystal form A.

[0109] Figure 16 The differential scanning calorimetry (DSC) curve is shown for crystal form A of the magnesium salt of the compound shown in formula (I). Detailed Implementation

[0110] The present invention will be further illustrated by means of embodiments below, but the invention is not limited to the scope of the embodiments described herein.

[0111] The X-ray powder diffraction analysis method used in this invention is as follows: An Empyrean diffractometer was used, employing Cu-Kα radiation (45 kV, 40 mA) to obtain the X-ray powder diffraction pattern. The powdered sample was prepared into a thin layer on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0168° steps within a range of 3°–40°. Data was collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0112] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: Differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a specially designed aluminum crucible with a lid, and sample analysis is performed using a linear heating device at 10°C / min, from room temperature to approximately 300°C. During use, the DSC chamber is purged with dry nitrogen.

[0113] Specific implementation methods

[0114] The compound 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamide)acetic acid shown in formula (I) was synthesized according to the method of Example 1 in International Application WO 2016034108A1.

[0115] Example

[0116] Example 1 Crystal form A of diethanolamine salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid

[0117] 1. Preparation of crystal form A of diethanolamine salt

[0118] Add acetonitrile (2.0 mL) to 50 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid and stir until suspended. Add 16 mg of diethanolamine dissolved in 0.5 mL of ethanol dropwise to the reaction flask. Stir for 6 hours and then filter. Dry the filter cake under vacuum at 60 °C to obtain a white solid (29 mg, yield 44.8%).

[0119] 2. Identification of crystal form A of diethanolamine salt

[0120] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks are expressed in terms of angle 2θ: 6.49°, 9.75°, 10.84°, 12.38°, 13.04°, 14.05°, 14.47°, 16.41°, 16.92°, 17.86°, 19.62°, 20.87°, 21.94°, 22.95°, 23.16°, 23.85°, 24.93°, 25.41°, 26.27°, 27.88°, 29.64°, 31.73° and 33.04°, with an error tolerance of ±0.2°.

[0121] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 2 As shown, there is an endothermic peak at 148.89℃, with an error tolerance of ±3℃.

[0122] Example 2. Crystal form B of diethanolamine salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0123] 1. Preparation of crystal form B of diethanolamine salt

[0124] Methanol (5.0 mL) was added to 80 mg of diethanolamine salt A of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid. The mixture was heated to 60 °C to dissolve the raw material. After filtering the solution through a membrane while hot, the reaction solution was cooled to -10 °C. After crystallization for 6 hours, the mixture was filtered under vacuum and the filter cake was dried under vacuum at room temperature to obtain a white solid (16 mg, yield 20.3%).

[0125] 2. Identification of crystal form B of diethanolamine salt

[0126] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 4.77°, 7.17°, 7.68°, 9.55°, 11.31°, 12.05°, 12.99°, 13.40°, 14.36°, 15.57°, 17.49°, 19.18°, 20.57°, 21.65°. The following angles are given: 21.82°, 22.49°, 22.75°, 24.36°, 25.38°, 26.55°, 27.20°, 28.98°, 29.63°, 31.41°, 32.84°, 33.95°, 34.48°, 36.22°, and 38.54°, with an error tolerance of ±0.2°.

[0127] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 4 As shown, there is an endothermic peak at 166.56℃, with an error tolerance of ±3℃.

[0128] Example 3. Crystal form A of sodium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0129] 1. Preparation of sodium salt crystal form A

[0130] Add 1.5 mL of N,N-dimethylacetamide to 100 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid, then add dropwise sodium isooctanoate (47 mg) dissolved in 1.0 mL of N,N-dimethylacetamide. Heat to 100 °C and maintain the temperature for 8 hours. Stop heating, cool to room temperature, filter, and dry the filter cake under vacuum at room temperature to give a white solid (40 mg, yield 39.0%).

[0131] 2. Identification of crystal form A of sodium salt

[0132] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks are expressed in terms of angle 2θ: 3.29°, 6.45°, 9.82°, 11.65°, 13.14°, 13.74°, 15.63°, 16.22°, 17.29°, 17.91°, 19.01°, 19.74°, 23.19°, 25.03°, 26.92°, 28.63°, 29.83°, 33.05°, 34.52° and 36.53°, with an error tolerance of ±0.2°.

[0133] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 6 As shown, it includes endothermic peaks at 140.99℃ and 259.59℃ and an exothermic peak at 176.06℃, with an error tolerance of ±3℃.

[0134] Example 4. Crystal form C of sodium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0135] 1. Preparation of the crystal form C of sodium salts

[0136] Dimethyl sulfoxide (24.0 mL) was added to 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid (1.99 g) and sodium hydroxide (228 mg). The mixture was heated to 80 °C, and the solid dissolved. The mixture was kept at this temperature for 0.5 h, and a large amount of white solid precipitated. Heating was stopped, and the mixture was cooled to 60 °C in a gradient of 10 °C / h. The mixture was then filtered, and the filter cake was washed with dimethyl sulfoxide (1.0 mL × 2). The filter cake was dried under vacuum at 70 °C for 12 h to give a white solid (1.56 g, yield 74.4%).

[0137] 2. Identification of the crystal form C of sodium salts

[0138] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 7.16°, 10.77°, 14.38°, 15.57°, 16.08°, 16.30°, 16.72°, 17.15°, 17.55°, 18.04°, 18.88°, 19.56°, 20.02°, 20.94°, 21.69°, 22.43°, 22.78°, 23.45°, 25.38°, 26.19°, 27.30°, 28.06°, 29.07°, 30.30°, 31.66°, 32.36°, 32.83°. For the angles 33.41°, 33.81°, 34.49°, 34.76°, 35.77°, 36.29°, 36.72°, 37.83°, 38.14°, 38.59° and 39.21°, there is an error tolerance of ±0.2°.

[0139] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 8 As shown, there is an endothermic peak at 261.96℃, with an error tolerance of ±3℃.

[0140] Example 5. Crystal form D of sodium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0141] 1. Preparation of crystal form D of sodium salt

[0142] Methanol (2.0 mL) was added to 151 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid and 17 mg of sodium hydroxide. The mixture was heated to reflux and held at that temperature for 2 hours. Heating was stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was stirred for 12 hours, filtered, and the filter cake was washed with methanol (1.0 mL × 2). The cake was dried under vacuum at 70 °C for 12 hours. Under nitrogen protection, the solid powder was heated to 190 °C and held at that temperature for 3 hours. After cooling to room temperature, the nitrogen was removed to obtain an off-white solid (102 mg, yield 66.5%).

[0143] 2. Identification of crystal form D of sodium salt

[0144] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks are expressed in terms of angle 2θ: 3.34°, 6.54°, 9.20°, 10.28°, 14.64°, 15.44°, 16.49°, 17.06°, 20.75°, 22.40°, 23.32°, 25.42°, 27.48° and 28.33°, with an error tolerance of ±0.2°.

[0145] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 10 As shown, there is an endothermic peak at 262.65℃, with an error tolerance of ±3℃.

[0146] Example 6. Crystal form E of sodium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0147] 1. Preparation of crystal form E of sodium salt

[0148] Methanol (3.0 mL) was added to 110 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamide)acetic acid and 50 mg of sodium isooctanoate. The mixture was heated to 60 °C and maintained at that temperature for 9.5 hours. Heating was then stopped, and the mixture was allowed to cool naturally to room temperature. The mixture was stirred for 12 hours, filtered, and the filter cake was washed with methanol (1.0 mL × 2). The mixture was then dried under vacuum at room temperature to give an off-white solid (81 mg, yield 72.2%).

[0149] 2. Identification of the crystal form E of sodium salts

[0150] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks are expressed in terms of angle 2θ: 3.55°, 7.01°, 9.80°, 11.08°, 13.27°, 15.30°, 16.72°, 17.98°, 18.44°, 18.84°, 19.80°, 20.84°, 22.22°, 22.62°, 23.95°, 24.52°, 25.58°, 26.60°, 29.91°, 31.86°, 34.03°, 36.66° and 39.49°, with an error tolerance of ±0.2°.

[0151] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 12 As shown, there is an endothermic peak at 231.51℃, with an error tolerance of ±3℃.

[0152] Example 7. Crystal form A of potassium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0153] 1. Preparation of crystal form A of potassium salt

[0154] Method 1: Add tetrahydrofuran (1.0 mL) to 49 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid. After complete dissolution, add potassium hydroxide (10 mg) dissolved in a small amount of water. After crystals precipitate, filter the solution and dry the filter cake under vacuum at room temperature to obtain a white solid (52 mg, yield 96.5%).

[0155] Method 2: Add water (2.0 mL) to 104 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formamido)acetic acid, stir until a uniform suspension is formed, then add potassium hydroxide (19 mg) and water (1.0 mL) to make up the difference. Stir overnight, and crystals will precipitate. Filter the mixture and dry the filter cake under vacuum at room temperature to obtain a white solid (104 mg, yield 91.4%).

[0156] 2. Identification of crystal form A of potassium salt

[0157] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 3.28°, 6.45°, 9.66°, 11.53°, 12.87°, 13.59°, 15.63°, 16.06°, 16.21°, 17.33°, 17.76°, 18.74°, 18.98°, 19.51°. For the following angles: 20.21°, 21.58°, 22.57°, 22.87°, 23.23°, 24.03°, 24.54°, 25.04°, 25.82°, 26.54°, 26.91°, 27.41°, 28.53°, 29.11°, 30.09°, 30.72°, 31.51°, 31.77°, 32.15°, 32.44°, 33.19°, 33.82°, 34.39°, 35.29°, 35.79°, 36.93°, 37.95°, 38.72°, and 39.14°, there is an error tolerance of ±0.2°.

[0158] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 14 As shown, there are endothermic peaks at 170.58℃ and 279.49℃, with an error tolerance of ±3℃.

[0159] Example 8. Crystal form A of magnesium salt of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-formylamino)acetic acid.

[0160] 1. Preparation of magnesium salt crystal form A

[0161] Add water (2.0 mL) to 54 mg of 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid, stir until a uniform suspension is formed, then add magnesium acetate (31 mg) dissolved in a small amount of water, stir overnight, filter, and dry the filter cake under vacuum at room temperature to obtain a white solid (57 mg, yield 86.5%).

[0162] 2. Identification of crystal form A of magnesium salts

[0163] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 3.20°, 6.27°, 9.44°, 12.59°, 14.23°, 15.74°, 16.18°, 18.04°, 18.63°, 18.82°, 19.33°, 19.97°, 21.26°, 21.57°, 22.43°, 22.92°, 23.92°, 25.23°, 27.21°, 27.57°, 28.34°, 29.49°, 31.00°, 32.12°, 32.92°, 34.56°, 35.83°. There is an error tolerance of ±0.2° for 37.21° and 38.50°.

[0164] (2) Identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10℃ / min, and the obtained DSC curves are as follows: Figure 16 As shown, there is an endothermic peak at 175.18℃, with an error tolerance of ±3℃.

[0165] Pharmacokinetic experiments of the salt described in this invention

[0166] Experimental methods:

[0167] The salt of the compound of formula (I) of the present invention is filled into capsules for oral administration.

[0168] Male Beagle dogs weighing 8-12 kg were divided into two groups of three. Each group was orally administered capsules containing the test sample at a dose of 10 mg / kg. Blood samples were collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours. A standard curve was established based on the sample concentration. The concentration of the test sample in plasma samples was determined using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curve. The experimental results are shown in Table 1.

[0169] Table 1. Pharmacokinetic experimental data of the salt described in this invention.

[0170]

[0171] Experimental conclusion:

[0172] As shown in Table 1, the diethanolamine salt crystal form A of the present invention has a higher exposure level in beagle dogs and has better pharmacokinetic properties than other salt crystal forms such as potassium salt crystal form A.

[0173] Stability test of the salt described in this invention

[0174] Experimental methods:

[0175] (1) High temperature experiment Take an appropriate amount of the test sample and place it in a flat weighing bottle, spread it into a thin layer of ≤5mm thickness, and place it at 60℃±2℃ for 30 days. Take samples on the 5th, 11th and 30th days and test them according to the key stability test items: observe the color change of the sample and detect the purity of the sample by HPLC.

[0176] (2) High humidity test Take an appropriate amount of the test sample and place it in a flat weighing bottle, spread it into a thin layer of ≤5mm thickness, and place it at 25℃ and RH 90%±5% for 30 days. Take samples on the 5th, 11th and 30th days and test them according to the key stability test items. Observe the color change of the sample and detect the purity of the sample by HPLC.

[0177] (3) Light test Take an appropriate amount of the test sample and place it in a flat weighing bottle, spreading it into a thin layer ≤5mm thick. Place the bottle open in a light box (equipped with a UV lamp) at an illuminance of 4500±500lx and a UV light intensity ≥0.7w / m². 2 The samples were placed under the specified conditions for 30 days, and samples were taken on days 5, 13 and 30. The purity of the samples was determined by HPLC.

[0178] (4) Accelerated Experiments Take an appropriate amount of the test sample, package it in a single-layer PE package with aluminum foil, and place it at 40±2℃ / 75%±5%RH for 6 months. Take samples at 1, 2, 3 and 6 months, observe the color change of the sample, detect the purity of the sample by HPLC, and test the moisture by TGA.

[0179] The experimental results show that after being placed under high temperature (60℃), high humidity (25℃, RH 90%±5%), and light conditions for 30 days, the appearance and purity of the crystal form of the salt described in this invention did not change significantly. Under accelerated experimental conditions, the appearance, purity, and water content of the crystal form of the salt described in this invention did not change significantly.

[0180] In summary, the diethanolamine salt of the present invention exhibits good stability under high temperature, high humidity and light conditions, making it suitable for pharmaceutical applications.

[0181] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

[0182] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0183] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. The crystal form A of the diethanolamine salt of the compound shown in formula (I), characterized in that, The X-ray powder diffraction pattern of crystal form A contains the following diffraction peaks at the 2θ angle: 6.49 ± 0.2°, 9.75 ± 0.2°, 16.41 ± 0.2°, 19.62 ± 0.2° and 25.41 ± 0.2°; (I)。 2. Crystal form A according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A contains the following diffraction peaks at the 2θ angle: 6.49 ± 0.2°, 9.75 ± 0.2°, 16.41 ± 0.2°, 16.92 ± 0.2°, 19.62 ± 0.2°, 23.16 ± 0.2°, 25.41 ± 0.2°, 26.27 ± 0.2°, 27.88 ± 0.2°, and 29.64 ± 0.2°.

3. Crystal form A according to claim 1 or 2, characterized in that, The X-ray powder diffraction pattern of crystal form A contains the following diffraction peaks at the 2θ angle: 6.49 ± 0.2°, 9.75 ± 0.2°, 10.84 ± 0.2°, 12.38 ± 0.2°, 13.04 ± 0.2°, 14.05 ± 0.2°, 14.47 ± 0.2°, 16.41 ± 0.2°, 16.92 ± 0.2°, 17.86 ± 0.2°, 19.62 ± 0.2°, 20.87 ± 0.2°, 21.94 ± 0.2°, 22.95 ± 0.2°, 23.16 ± 0.2°, 23.85 ± 0.2°, 24.93 ± 0.2°, 25.41 ± 0.2°, 26.27 ±0.2°, 27.88 ± 0.2°, 29.64 ± 0.2°, 31.73 ± 0.2° and 33.04 ± 0.2°.

4. The crystal form A according to claim 1, characterized in that, The crystal form A has an X-ray powder diffraction pattern that is substantially as shown in Figure 1.

5. Crystal form A according to claim 1, characterized in that, The differential scanning calorimetry (DSC) of crystal form A contains an endothermic peak at 148.89°C ± 3°C.

6. The crystal form A according to claim 1, characterized in that, The crystal form A has a differential scanning calorimeter that is substantially as shown in Figure 2.

7. A pharmaceutical composition comprising crystal form A as described in any one of claims 1-6, and a pharmaceutically acceptable excipient.

8. Use of crystal form A according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for the prevention, treatment or relief of hypoxia-inducible factor-related and / or erythropoietin-related diseases in patients.

9. The use according to claim 8, wherein, The diseases mentioned are anemia, ischemia, vascular disease, angina pectoris, myocardial infarction, or metabolic disorders.

10. Use of crystal form A according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for the prevention, treatment or relief of a patient’s disease mediated at least in part by hypoxia-inducible factor prolyl hydroxylase.

11. The use according to claim 9, wherein the ischemia is myocardial ischemia.

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