CN111269178A - Crystal forms of quinolinones - Google Patents

Abstract

The invention relates to a crystal form of quinolinone compounds. The invention also relates to a pharmaceutical composition comprising said crystalline form and to the use of said crystalline form or said pharmaceutical composition for the preparation of a medicament for the treatment and prevention of hypoxia inducible factor prolyl hydroxylase mediated diseases.

Description

Crystal forms of quinolinones

technical field

The invention belongs to the technical field of medicine, and relates to a crystal form of quinolinone compounds, in particular to 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline -The crystalline form I of 3-formamido)acetic acid and the use thereof, and further relate to the pharmaceutical composition comprising the crystalline form I.

Background technique

In the case of anemia, trauma, tissue necrosis and defect, tissue or cells are often in a state of hypoxia. Hypoxia leads to the expression of a series of transcription-inducing factors involved in angiogenesis, iron, glucose metabolism, and cell growth and proliferation. Among them, hypoxia inducible factor (HIF) is a transcription factor initiated by somatic cells when oxygen is reduced, and is widely distributed in various parts of the body, especially the vascular intima, heart, brain, kidney, liver, etc. . HIF is a heterodimer containing an oxygen-regulated α-subunit (HIFα) and a constitutively expressed β-subunit (HIFβ/ARNT). In oxygenated (normoxic) cells, the HIFα subunit is rapidly degraded by a mechanism of ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex . Under hypoxic conditions, HIFα is not degraded, and active HIFα/β complexes accumulate in the nucleus and activate the expression of various genes, including glycolytic enzymes, glucose transporters, erythropoietin (EPO), and blood vessels Endothelial Growth Factor (VEGF).

Prolyl hydroxylase domain (PHD) is a key factor in the regulation of HIF. Under normoxia, PHD can hydroxylate the two key proline residues Pro402 and Pro564 of HIFα, increasing its affinity with pVHL and accelerating the degradation process. Under hypoxia and other pathological conditions, the HIF reaction catalyzed by PHD is blocked and the degradation rate of protease is slowed down, resulting in the accumulation of HIFα in cells, which in turn causes a series of adaptive responses of cells to hypoxia. Inhibiting PHD by PHD inhibitors prolongs the effect of HIF, thereby increasing the expression of genes such as EPO, can effectively treat and prevent HIF-related and/or EPO-related disorders, such as anemia, ischemia and hypoxia.

Patent application WO 2016034108 A1 discloses the compound 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid (formula ( The compound shown in I)), which can treat or alleviate diseases mediated by hypoxia-inducible factor prolyl hydroxylase, such as anemia and the like.

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug research and development, the problem of polymorphism of drugs should be fully considered.

SUMMARY OF THE INVENTION

The present invention provides the crystal form I of the compound represented by formula (I), wherein, the crystal form I can obviously improve the stability and pharmacokinetic properties of the compound, thereby having better druggability.

Specifically, the present invention relates to the crystalline form of the compound represented by formula (I), and the crystalline form of the compound or the pharmaceutical composition used in the preparation for the treatment or prevention of hypoxia-inducible factor prolyl hydroxylase-mediated Use in medicines for diseases. The crystalline forms of the present invention may also be in the form of solvates, such as dimethyl sulfoxide solvate.

In one aspect, the present invention provides the crystal form I of the compound represented by formula (I),

It is characterized in that, the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 8.52°±0.2°, 15.79°±0.2°, 18.50°±0.2°, 19.28°±0.2°, 22.33° ±0.2°, 28.83°±0.2°.

In some embodiments, the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 8.52°±0.2°, 12.51°±0.2° ,15.79°±0.2°,18.50°±0.2°,19.28°±0.2°,20.37°±0.2°,21.97°±0.2°,22.33°±0.2°,24.19°±0.2°,25.78°±0.2°,28.83 °±0.2°.

In other embodiments, the crystal form I of the present invention is characterized in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 4.28°±0.2°, 8.52°±0.2 °,10.16°±0.2°,12.51°±0.2°,12.83°±0.2°,13.58°±0.2°,15.79°±0.2°,17.08°±0.2°,18.50°±0.2°,19.28°±0.2°, 20.13°±0.2°, 20.37°±0.2°, 21.06°±0.2°, 21.97°±0.2°, 22.33°±0.2°, 23.43°±0.2°, 24.19°±0.2°, 24.50°±0.2°, 25.11° ±0.2°, 25.78°±0.2°, 27.38°±0.2°, 28.83°±0.2°, 29.69°±0.2°, 30.77°±0.2°, 31.57°±0.2°, 32.87°±0.2°, 34.77°±0.2 °, 36.25°±0.2°, 38.11°±0.2°, 41.13°±0.2°.

In some embodiments, the crystal form I of the present invention is characterized in that the crystal form I has an X-ray powder diffraction pattern as shown in FIG. 1 .

In some embodiments, the crystal form I of the present invention is characterized in that the differential scanning calorimetry of the crystal form I comprises an endothermic peak at 145.61°C ± 3°C.

In some embodiments, the crystal form I of the present invention is characterized in that the crystal form I has a differential scanning calorimetry diagram as shown in FIG. 2 .

In some embodiments, the crystal form I of the present invention is characterized in that the crystal form I loses 17.39% in weight in the range of 50°C-170°C, and the weight loss ratio has an error tolerance of ±0.1%.

In some embodiments, the crystal form I of the present invention can be a solvate, wherein the solvate is a dimethyl sulfoxide solvate.

In another aspect, the present invention relates to a pharmaceutical composition comprising the crystal form I of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.

In one aspect, the present invention relates to the use of the crystalline form I or the pharmaceutical composition in the preparation of a medicament for preventing, treating or reducing hypoxia-inducible factor-related and/or erythropoietin-related disease.

On the other hand, the present invention relates to the use of the crystal form I or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating the following diseases: anemia, ischemia, vascular disease, angina pectoris , myocardial ischemia, myocardial infarction, metabolic disorders or wound healing.

In another aspect, the present invention relates to the use of said crystalline form I or said pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating at least partial prolyl hydroxylation of a patient by hypoxia-inducible factor Enzyme-mediated diseases.

In some embodiments, the disease described herein is anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorder, or wound healing.

The solvent used in the preparation method of the crystal form of the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications in the art, equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention. The present invention provides the preferred solvent used in each reaction step.

The present invention provides a pharmacological property test (such as a pharmacokinetic test), a solubility test, a stability test, a hygroscopicity test and the like of the crystal form I. The experimental results show that the crystal form I of the present invention has better biological activity, solubility and stability, and is suitable for pharmaceutical use.

Definitions and General Terms

Unless otherwise defined, 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 publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or identical to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described herein.

"Crystalline" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts. Crystalline forms of materials can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.

"Solvate" means a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, the solvent may 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-dimethylmethane Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, in the lattice, or both on the surface and in the lattice.

Crystal forms can be identified by various 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 Resonance method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention. At the same time, there may be experimental errors in the measurement of the 2θ of the XRPD spectrum, and the measurement of the 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of the 2θ cannot be regarded as absolute. According to the condition of the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

Differential Scanning Calorimetry (DSC) is a technique for measuring the energy difference between a sample and an inert reference (commonly α-Al ₂ O ₃ ) as a function of temperature by continuously heating or cooling under program control. The endothermic peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention. At the same time, the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. Depending on the condition of the instrument used in this test, there is a tolerance of ±3°C for the endothermic peak.

Thermogravimetric analysis (TGA) is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples. Depending on the condition of the instrumentation used for this test, there is a ±0.1% error tolerance for mass variation.

In the context of the present invention, the 2Θ values in an X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" means at least 50%, or at least 60%, or at least 70%, or at least 80%, of an X-ray powder diffraction pattern or DSC pattern or Raman spectrum or infrared spectrum, or At least 90%, or at least 95%, or at least 99% of the peaks are shown in their graph.

When referring to a spectrum or/and data appearing in a graph, a "peak" refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.

The present invention relates to a novel crystalline form of said 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid, such as , Form I or a solvate thereof, which exists in substantially pure crystalline form.

"Substantially pure" means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, 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, said The percentage of other crystal forms 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%.

"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form 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%.

The "relative intensity" (or "relative peak height") in the XRPD pattern means that when the intensity of the first strong peak among all diffraction peaks in the X-ray powder diffraction pattern (XRPD) is 100%, the intensities of other peaks are the same as those of the first peak. The ratio of the intensities of the strong peaks.

In the context of the present invention, when or whether the words "about" or "about" are used, it means within 10%, suitably within 5%, especially within 1% of the given value or range . Alternatively, to those of ordinary skill in the art, the terms "about" or "about" mean within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within the /-10% value are explicitly disclosed, where "+/-" means plus or minus.

In the present invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, and the like.

Compositions, Formulations, Administration and Uses of the Crystal Forms of the Invention

The characteristics of the pharmaceutical composition of the present invention include the crystal form of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the compound crystalline form in the pharmaceutical composition of the present invention is effective to detectably treat or alleviate a HIF-related and/or EPO-related disease in a patient.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in: 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, a synthesis of the contents of this document, shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional carrier vehicle is incompatible with the crystalline form of the compound of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of the pharmaceutically acceptable composition effects, their uses are also within the scope of the present invention.

Substances that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; Potassium acid; partial glyceride mixture 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; polyethylene Pyrrolidones; 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 Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants 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; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; Coatings; Sweeteners; Flavourings; Perfumes; Preservatives and Antioxidants.

The pharmaceutical composition of the present invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; it can be administered by the following routes: oral administration, injection administration, spray inhalation, topical administration, Rectal, nasal, buccal, vaginal or via an implantable kit.

Oral administration can be administered in the following forms: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs, etc.; topical administration can be administered in the following forms: ointments, gels, Medicated tape, etc.

The crystalline form of the present invention is preferably formulated into dosage unit form to reduce administration amount and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug required for a patient to receive appropriate treatment. However, it should be understood that the total daily usage of a compound of formula (I) of the present invention or a crystalline form thereof, or a pharmaceutical composition of the present invention will be determined by the attending physician according to sound medical judgment. The specific effective dosage level for any one particular patient or organism will depend on a number of factors including the condition being treated and the severity of the condition, the activity of the particular compound or crystalline form thereof, the particular composition employed, the age, weight, Health status, gender and dietary habits, time of administration, route of administration and excretion rate of the specific compound or crystalline form used, duration of treatment, use of the drug in combination or in combination with a specific compound or crystalline form, and Other factors well known in the field of pharmacy.

The effective dose of active ingredient employed may vary with the compound employed or its crystalline form, the mode of administration, and the severity of the disease to be treated. Generally, however, satisfactory results are obtained when a compound of the present invention or a crystalline form thereof is administered in a daily dose of about 0.25-1000 mg/kg of animal body weight, preferably in 2-4 divided doses per day, or Administered in 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 active compound or a crystalline form thereof. Dosage forms suitable for oral administration contain about 0.25-500 mg of the active compound or a crystalline form thereof in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide optimal therapeutic response. In addition, several divided doses may be administered daily or the dose may be proportionally reduced depending upon the condition being treated.

The compounds of the present invention or their crystal forms, and the pharmaceutical compositions of the present invention can be used to inhibit HIF hydroxylase activity, thereby regulating the stability and/or activity of HIF and activating the expression of HIF-regulated genes. Said compound or its crystalline form or said pharmaceutical composition can be used in a method of treating, pre-treating or delaying the onset or progression of HIF-related disorders, including but not limited to anemia and ischemia and deficiency. Aspects of Oxygen Disorders.

Description of drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of the crystal form I of the compound represented by formula (I).

Figure 2 is a differential scanning calorimetry (DSC) chart of crystal form I of the compound represented by formula (I).

Fig. 3 is a thermal gravimetric (TGA) analysis chart of the crystal form I of the compound represented by formula (I).

Detailed ways

The present invention is further described below by way of examples, and therefore the present invention is not limited to the scope of the described examples.

The X-ray powder diffraction analysis method used in the present invention is: Empyrean diffractometer, using Cu-Kα radiation (45KV, 40mA) to obtain the X-ray powder diffraction pattern. Powdered samples were prepared as thin layers on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0167° steps over a range of 3°-60°. Data was collected using Data Collector software, processed by HighScore Plus software, and read by Data Viewer software.

The differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5 mg of sample was accurately weighed into a special aluminum crucible with a lid, and the sample was analyzed from room temperature to about 300°C using a 10°C/min line heating device. During use, the DSC cell was purged with dry nitrogen.

The thermogravimetric (TGA) analysis method used in the present invention is: using a TA Q500 module with a thermal analysis controller to conduct thermogravimetric loss. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10 mg of the sample was accurately weighed into a platinum sample pan, and the sample was analyzed from room temperature to approximately 300°C using a linear heating device at 10°C/min. During use, the TGA oven chamber was purged with dry nitrogen.

Specific implementation method

Example

Example 1 Crystal Form I

1. Preparation of Form I

Preparation 1:

To 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid (refer to the implementation in international application WO 2016034108 A1 Prepared by the method of Example 1) (35.5 mg) was added with dimethyl sulfoxide (1.0 mL), slurried at room temperature for three days, filtered with suction, and the filter cake was vacuum dried at room temperature to obtain a white solid (23.8 mg, 67.04%).

Preparation 2:

To 2-(4-hydroxy-1-methyl-2-oxo-7-phenoxy-1,2-dihydroquinoline-3-carboxamido)acetic acid (refer to the example in international application WO 2016034108A1 1) (700.5 mg) was added with dimethyl sulfoxide (10.0 mL), the insolubles were filtered off after stirring for 1.5 hours, water (5.0 mL) was added dropwise to the filtrate, crystallization was performed for 3.5 hours, and the filter cake was filtered at room temperature. Drying in vacuo gave a white solid (505 mg, 72.09%).

2. Identification of Form I

(1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks represented by angle 2θ, as shown in Figure 1: 4.28°, 8.52°, 10.16°, 12.51°, 12.83 °,13.58°,15.79°,17.08°,18.50°,19.28°,20.13°,20.37°,21.06°,21.97°,22.33°,23.43°,24.19°,24.50°,25.11°,25.78°,27.38°, 28.83°, 29.69°, 30.77°, 31.57°, 32.87°, 34.77°, 36.25°, 38.11°, 41.13°, 46.16°, 50.46°, 52.18° and 53.56°, with an error tolerance of ±0.2°.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis, as shown in Figure 2: the scanning speed is 10°C/min, the endothermic peak at 145.61°C is included, and there is an error tolerance of ±3°C.

(3) Thermal weight loss (TGA) analysis and identification by TA Q500, as shown in Figure 3: the heating rate is 10°C/min, the weight loss range is 17.39%, and there is an error tolerance of ±0.1%.

Example 2 Pharmacokinetic experiment

The crystal form of the compound represented by the formula (I) of the present invention is filled with capsules for oral administration.

Three 8-12kg male Beagle dogs were taken orally administered capsules containing the test sample at a dose of 10mg/kg, and blood was collected at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h. A standard curve with a suitable range was established according to the sample concentration. Using AB SCIEX API4000 LC-MS/MS, the concentration of the test sample in the plasma sample was determined in the MRM mode, and the quantitative analysis was carried out. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters. The experimental results are shown in Table 1. It can be seen from the data in Table 1 that the crystal form I of the present invention has a larger exposure in beagle dogs and has better pharmacokinetic properties.

Table 1 Pharmacokinetic experimental data of the crystal form of the present invention

Test sample T_max(h) C_max(ng/ml) AUC_last(h*ng/ml) Embodiment 1 (crystal form I) 1.25 746 1950

Example 3 Stability Experiment

(1) High temperature experiment : Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thick, and place it at 40°C±2°C and 60°C±2°C for 30 days. , 30-day sampling is tested according to the key stability inspection items: observe the color change of the sample, and test the purity of the sample by HPLC.

(2) High- humidity experiment : Take a batch of the test sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thick, and place it for 30 days at 25°C and RH 90%±5% for 30 days. 10th and 30th day sampling shall be tested according to the key stability inspection items, the color change of the sample shall be observed, and the purity of the sample shall be tested by HPLC.

(3) Illumination test : Take a batch of the test sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thick, and place it in a light box (with an ultraviolet lamp) with an open mouth. The illumination is 4500±500lx, Under the condition of ultraviolet light ≥0.7w/m ² for 30 days, samples were taken on the 6th, 13th and 30th days, and the purity of the samples was tested by HPLC.

The experimental results show that the crystal form I of the present invention has good stability under various setting-out conditions, and is suitable for pharmaceutical use.

The above content is only a basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

1. the crystal form I of the compound shown in formula (I), it is characterised in that the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 8.52°±0.2°, 15.79°±0.2°, 18.50°±0.2°, 19.28°±0.2°, 22.33°±0.2°, 28.83°±0.2°;

2. The crystal form I according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 8.52°±0.2°, 12.51°±0.2°, 15.79° °±0.2°, 18.50°±0.2°, 19.28°±0.2°, 20.37°±0.2°, 21.97°±0.2°, 22.33°±0.2°, 24.19°±0.2°, 25.78°±0.2°, 28.83°± 0.2°. 3. The crystal form I according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ angles: 4.28°±0.2°, 8.52°±0.2° ,10.16°±0.2°,12.51°±0.2°,12.83°±0.2°,13.58°±0.2°,15.79°±0.2°,17.08°±0.2°,18.50°±0.2°,19.28°±0.2°,20.13 °±0.2°, 20.37°±0.2°, 21.06°±0.2°, 21.97°±0.2°, 22.33°±0.2°, 23.43°±0.2°, 24.19°±0.2°, 24.50°±0.2°, 25.11°± 0.2°, 25.78°±0.2°, 27.38°±0.2°, 28.83°±0.2°, 29.69°±0.2°, 30.77°±0.2°, 31.57°±0.2°, 32.87°±0.2°, 34.77°±0.2° , 36.25°±0.2°, 38.11°±0.2°, 41.13°±0.2°. 4. The crystal form I according to any one of claims 1-3, wherein the crystal form I has an X-ray powder diffraction pattern as shown in FIG. 1 . 5 . The crystal form I according to claim 1 , wherein the differential scanning calorimetry of the crystal form I comprises an endothermic peak at 145.61° C.±3° C. 6 . 6. The crystal form I according to any one of claims 1-5, wherein the crystal form I has a differential scanning calorimetry diagram as shown in FIG. 2 . 7. A pharmaceutical composition comprising the crystal form I of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent or a combination thereof. 8. a pharmaceutical preparation, it is the capsule, tablet, pill, powder, granule, aqueous suspension, solution, the crystal form I described in any one of claims 1-6 and pharmaceutical adjuvants made, Ointment or gel. 9. the crystal form I described in any one of claim 1-6 or the purposes of the pharmaceutical composition described in claim 7 or the pharmaceutical preparation described in claim 8 in the preparation of medicine, and described medicine is used for prevention, treatment Or alleviate the following diseases in patients: anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing. 10. the purposes of the crystal form I described in any one of claim 1-6 or the pharmaceutical composition described in claim 7 or the pharmaceutical preparation described in claim 8 in the preparation of medicine, and described medicine is used for prevention, treatment Or alleviate a disease in a patient mediated at least in part by hypoxia-inducible factor prolyl hydroxylase.

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