CN111269177A - Crystal forms of quinolinone compounds - Google Patents
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- CN111269177A CN111269177A CN201911195230.7A CN201911195230A CN111269177A CN 111269177 A CN111269177 A CN 111269177A CN 201911195230 A CN201911195230 A CN 201911195230A CN 111269177 A CN111269177 A CN 111269177A
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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
Technical Field
The invention belongs to the technical field of medicines, relates to a crystal form of a quinolinone compound, and particularly relates to a crystal form III of 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-formamido) acetic acid and an application thereof, and further relates to a pharmaceutical composition containing the crystal form III.
Background
In the case of anemia, trauma, tissue necrosis and defects, etc., tissues or cells are often in a hypoxic state, hypoxia causes the expression of a series of transcription-inducing factors, which are involved in angiogenesis, iron, sugar metabolism and cell growth and proliferation, among which, hypoxia-inducing factor (HIF), a transcription factor that body cells initiate in the presence of reduced oxygen, is widely distributed in various parts of the body, particularly the intima, heart, brain, kidney, liver, etc., HIF is a heterodimer containing an oxygen-regulated α -subunit (387 α) and a constitutively expressed HIF 2-subunit (β/ARNT), in oxygen-containing (normoxic) cells, the HIF α subunit is rapidly degraded by the mechanisms of ubiquitin complexing with von Hippel-Lindau turgorson, vhl) 3 ligase (ubiquitin) under hypoxic conditions, and the activities of the HIF are not degraded by the endoenzyme, VEGF α, and expressed in the vascular endothelial growth factor (36 α, EPO), including the endoglycosylvestris (VEGF) and EPO (EPO) genes.
Under hypoxia and other pathological conditions, the HIF reaction catalyzed by PHD is blocked, the degradation speed of the protease is reduced, the HIF α is accumulated in cells, and a series of adaptive responses of the cells to hypoxia are caused.
Patent application WO 2016034108a1 discloses the compound 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-carboxamido) acetic acid (compound of formula (I)) which can treat or alleviate hypoxia-inducible factor prolyl hydroxylase mediated diseases, such as anemia and the like.
Drug polymorphism is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in aspects such as appearance, solubility, melting point, dissolution rate, bioavailability and the like, and also have different influences on aspects such as stability, bioavailability, curative effect and the like of the drug. Therefore, in drug development, the problem of polymorphism of drugs should be considered comprehensively.
Disclosure of Invention
The invention provides a crystal form III of a compound shown in a formula (I), wherein the crystal form III can obviously improve the properties of the compound such as stability, pharmacokinetics and the like, so that the compound has more excellent druggability.
In particular, the invention relates to a crystal form of a compound shown as a formula (I), and application of the crystal form of the compound or the pharmaceutical composition in preparing a medicament for treating or preventing hypoxia-inducible factor prolyl hydroxylase mediated diseases. The crystalline forms of the present invention may also be in the form of solvates.
In one aspect, the invention provides a crystalline form III of a compound of formula (I),
characterized in that the X-ray powder diffraction pattern of the crystal form III has diffraction peaks at the following 2 theta angles: 4.50 ° ± 0.2 °,8.97 ° ± 0.2 °,15.32 ° ± 0.2 °,17.94 ° ± 0.2 °,27.24 ° ± 0.2 °.
In some embodiments, form III of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.50 ° ± 0.2 °,8.97 ° ± 0.2 °,13.41 ° ± 0.2 °,15.32 ° ± 0.2 °,17.94 ° ± 0.2 °,19.01 ° ± 0.2 °,23.97 ° ± 0.2 °,27.00 ° ± 0.2 °,27.24 ° ± 0.2 °,31.60 ° ± 0.2 °.
In other embodiments, form III of the present invention is characterized by an X-ray powder diffraction pattern having diffraction peaks at the following 2 Θ angles: 4.50 ° ± 0.2 °,8.97 ° ± 0.2 °,11.40 ° ± 0.2 °,12.15 ° ± 0.2 °,13.41 ° ± 0.2 °,15.32 ° ± 0.2 °,17.94 ° ± 0.2 °,19.01 ° ± 0.2 °,19.68 ° ± 0.2 °,20.79 ° ± 0.2 °,21.21 ° ± 0.2 °,21.95 ° ± 0.2 °,22.46 ° ± 0.2 °,22.99 ° ± 0.2 °,23.97 ° ± 0.2 °,24.93 ° ± 0.2 °,26.01 ° ± 0.2 °,27.00 ° ± 0.2 °,27.24 ° ± 0.2 °,28.44 ° ± 0.2 °,30.27 ° ± 0.2 °,31.60 ° ± 0.2 °,34.79 ° ± 0.2 °, 36 35.61 ° ± 0.2 °,37.65 ° ± 0.2 °.
In some embodiments, the crystalline form III of the present invention, wherein the crystalline form III has an X-ray powder diffraction pattern as shown in figure 1.
In some embodiments, form III of the present invention is characterized by a differential scanning calorimetry trace comprising endothermic peaks at 195.61 ℃ ± 3 ℃ and 206.17 ℃ ± 3 ℃.
In some embodiments, form III of the present invention, wherein the form III has a differential scanning calorimetry trace as shown in figure 2.
In some embodiments, form III of the present invention, wherein the form III has a weight loss of 6.088% in the range of 120 ℃ to 220 ℃, and the weight loss ratio has a margin of error of ± 0.1%.
In another aspect, the present invention relates to a pharmaceutical composition comprising the crystalline form III of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.
In one aspect, the invention relates to the use of said crystalline form III or said pharmaceutical composition for the preparation of a medicament for preventing, treating or alleviating hypoxia-inducible factor-related and/or erythropoietin-related diseases in a patient.
In another aspect, the invention relates to the use of said crystalline form III or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of a disease or a disorder of: anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing.
In another aspect, the invention relates to the use of said crystalline form III or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of a disease or a disorder mediated at least in part by the hypoxia inducible factor prolyl hydroxylase in a patient.
In some embodiments, the disease of the invention is anemia, ischemia, vascular disease, angina, myocardial ischemia, myocardial infarction, metabolic disorder, or wound healing.
The solvent used in the method for producing the crystalline form of the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.
The invention provides a pharmacological property test experiment (such as a pharmacokinetic experiment), a solubility experiment, a stability experiment, a hygroscopicity experiment and the like of the crystal form III. Experimental results show that the crystal form III has good biological activity, solubility and stability, and is suitable for pharmaceutical application.
Definitions and general terms
Unless defined otherwise, 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 equivalent 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 form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance 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 a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"solvate" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. Diffraction peaks were found to have a margin of error of + -0.2 deg. depending on the condition of the instrument used in the experiment.
Differential Scanning Calorimetry (DSC) is carried out by continuously heating or cooling under program control to measure sample and inert reference substance (usually α -Al)2O3) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
In the context of the present invention, the 2 θ values in the X-ray powder diffraction pattern are all in degrees (°).
The term "substantially 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 in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.
When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.
The present invention relates to novel crystalline forms of said 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-carboxamido) acetic acid, e.g. form III or solvates thereof, which exist in substantially pure crystalline form.
By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or 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%.
"relative intensity" (or "relative peak height") in an XRPD pattern refers to the ratio of the intensity of the first strong peak to the intensity of the other peaks when the intensity of the first strong peak is 100% of all the diffraction peaks in the X-ray powder diffraction pattern (XRPD).
In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to 20 ℃, 22.5 ℃, 25 ℃, 27.5 ℃, and the like.
Compositions, formulations, administration and uses of the crystalline forms of the invention
The pharmaceutical composition of the invention is characterized by comprising a crystal form of the compound shown in the formula (I) and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the crystalline form of the compound in the pharmaceutical compositions of the invention is effective to detectably treat or ameliorate HIF-related and/or EPO-related conditions in a subject.
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 excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: 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.Swarbrickand J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, indicate that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the crystalline form of the compound of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.
Materials 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; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures 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; polyacrylate esters; a wax; 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 sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; 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; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants.
The pharmaceutical composition of the invention can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions; administration can be by the following route: oral administration, injection administration, spray inhalation, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable kit.
Oral administration may be in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, elixirs and the like; administration by external application may be in the form of: ointment, gel, medicated plaster, etc.
The crystalline forms of the invention are preferably formulated as unit dosage forms to reduce the dosage and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units of a drug required for proper treatment of a patient. It will be appreciated, however, that the total daily usage of a compound of formula (I) or a crystalline form thereof, or a pharmaceutical composition of the invention, will be determined by the attending physician, within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the severity of the condition and disorder being treated, the activity of the specific compound or crystalline form thereof, the specific composition employed, the age, body weight, health, sex, and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the specific compound or crystalline form employed, the duration of the treatment, the drug regimen or combination with the specific compound or crystalline form thereof, and other factors well known in the pharmaceutical arts.
The effective dosage of the active ingredient employed may vary with the compound or crystalline form thereof employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention or crystalline forms thereof are administered daily at a dose of about 0.25 to 1000mg/kg animal body weight, preferably 2 to 4 divided doses per day, or in sustained release form. For the majority of large mammals, the total daily dose is from about 1 to about 100mg/kg, preferably from about 2 to about 80mg/kg, of the active compound or crystalline form thereof. A dosage form suitable for oral administration comprising about 0.25 to 500mg of the active compound or crystalline form thereof in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the best therapeutic response. In addition, due to the differences in the treatment conditions, several divided doses may be given daily, or the doses may be proportionally reduced.
The compounds or crystalline forms thereof, and pharmaceutical compositions of the invention are useful for inhibiting HIF hydroxylase activity, thereby modulating the stability and/or activity of HIF and activating expression of HIF regulatory genes. The compounds, or crystalline forms thereof, or the pharmaceutical compositions described can be used in methods of treating, pretreating, or delaying the onset or progression of a HIF-associated condition, including, but not limited to, anemia and ischemia, as well as conditions associated with hypoxia.
Drawings
Figure 1 is an X-ray powder diffraction (XRPD) pattern of form III of the compound of formula (I).
FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of form III of the compound of formula (I).
FIG. 3 is a thermogravimetric analysis (TGA) of the crystalline form III of the compound of formula (I).
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The X-ray powder diffraction analysis method used by the invention is that an Empyrean diffractometer obtains an X-ray powder diffraction pattern by using Cu-K α radiation (45KV,40mA), a powdery sample is prepared into thin layers on a monocrystalline silicon sample rack, the thin layers are placed on a rotary sample table, analysis is carried out in 0.0167 DEG step size within the range of 3-60 DEG, Data Collector software is used for collecting Data, HighScore Plus software is used for processing the Data, and Data Viewer software is used for reading the Data.
The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.
The Thermal Gravimetric Analysis (TGA) method used in the invention is as follows: the thermogravimetric loss was performed using a TA Q500 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10mg of the sample was accurately weighed into a platinum sample pan and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the TGA furnace chamber was purged with dry nitrogen.
Detailed description of the invention
Examples
Example 1 form III
1. Preparation of form III
Preparation 1:
to 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-carboxamido) acetic acid (prepared by the method of example 1 in international application WO 2016034108a 1) (30mg) was added N, N-dimethylformamide (1.0mL), heated to 90 ℃, and then L-hydroxyproline (20mg) was dissolved in water (0.5mL), and the above solution was added, and after incubation for 16 hours, slowly cooled to room temperature, filtered, and the filter cake was vacuum dried at room temperature to give a white solid (22.2mg, 74%).
Preparation 2:
to 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-carboxamido) acetic acid (prepared by the method of example 1 in International application WO 2016034108A 1) (30mg) was added N, N-dimethylformamide (1.0mL), heated to 90 deg.C, and then L-valine (20mg) was dissolved in water (0.5mL) and the above solution was added, and after 16 hours of incubation, slowly cooled to room temperature, filtered, and the filter cake was vacuum dried at room temperature to give a white solid (22.6mg, 75.3%).
Preparation 3:
to 2- (4-hydroxy-1-methyl-2-oxo-7-phenoxy-1, 2-dihydroquinoline-3-carboxamido) acetic acid (prepared by the method of example 1 in International application WO 2016034108A 1) (30mg) was added N, N-dimethylformamide (1.0mL), heated to 90 deg.C, then L-aspartic acid (11.5mg) was dissolved in water (0.5mL) and the solution was added, incubated for 16 hours and slowly cooled to room temperature, filtered and the filter cake was vacuum dried at room temperature to give a white solid (25.9mg, 86.3%).
2. Identification of form III
(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis as having the following characteristic peaks expressed in degrees 2 θ using Cu-K α radiation, as shown in FIG. 1, 4.50 °,8.97 °,11.40 °,12.15 °,13.41 °,15.32 °,17.94 °,19.01 °,19.68 °,20.79 °,21.21 °,21.95 °,22.46 °,22.99 °,23.97 °,24.93 °,26.01 °,27.00 °,27.24 °,28.44 °,30.27 °,31.60 °,34.79 °,35.61 °,37.65 °,39.38 °,41.03 °,42.45 °,43.48 °,45.82 °,46.89 °,49.61 ° and 51.43 °, with a tolerance of error of + -0.2 °.
(2) Identified by TA Q2000 Differential Scanning Calorimetry (DSC) analysis, as shown in figure 2: the scan rate was 10 ℃/min, contained endothermic peaks at 195.61 ℃ and 206.17 ℃, with a margin of error of ± 3 ℃.
(3) Thermogravimetric analysis (TGA) was performed by TA Q500, as shown in figure 3: the heating rate is 10 ℃/min, the weight loss range is 6.088%, and error tolerance of +/-0.1% exists.
Example 2 pharmacokinetic experiments
The crystal form filling capsule of the compound shown in the formula (I) is used for oral administration.
3 male Beagle dogs (8-12 kg) were orally administered to capsules containing test samples at a dose of 10mg/kg, and blood was 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 of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. The results are shown in Table 1.
Table 1 pharmacokinetic data of the crystalline forms of the invention
| Test sample | AUClast(h*ng/ml) | Cmax(ng/ml) | Tmax(h) |
| Crystal form III | 7090 | 1910 | 1.33 |
And (4) conclusion:
experimental results show that the crystal form III has larger exposure in beagle dogs and better pharmacokinetic property.
Example 3 stability test
(1)High temperature experiment: taking a proper amount of a sample to be tested, putting the sample into a flat weighing bottle, spreading the sample into a thin layer with the thickness of less than or equal to 5mm, standing the sample at the temperature of 60 +/-2 ℃ for 30 days, sampling the sample in the 5 th, 10 th and 30 th days, and detecting according to the stability key examination items: the color change of the sample is observed, and the purity of the sample is detected by HPLC. The results are shown in Table 2.
TABLE 2 high temperature experiments of the crystalline forms of the present invention
And (4) conclusion:
experimental results show that under the high-temperature condition, the appearance and the total impurity content of the crystal form III are not obviously changed, and the stability effect is good.
(2)High humidity experiment: taking a proper amount of a batch of test samples, putting the test samples into a flat weighing bottle, spreading the test samples into a thin layer with the thickness of less than or equal to 5mm, placing the test samples for 30 days at 25 ℃ under the condition of RH 90% +/-5%, sampling the test samples for 5 days, 10 days and 30 days according to the key stability study items, observing the color change of the samples, and detecting the purity of the samples by HPLC. The results are shown in Table 3.
Table 3 high humidity experiment of the crystalline form of the invention
And (4) conclusion:
experimental results show that under the high-humidity condition, the appearance and the total impurity content of the crystal form III are not obviously changed, and the stability effect is good.
(3)Light test: taking a proper amount of a batch of samples, placing into a flat weighing bottle, spreading into a thin layer with thickness of less than or equal to 5mm, placing in a light box (with an ultraviolet lamp) with an opening, and irradiating at an illuminance of 4500 + -500 lx and an ultraviolet light of more than or equal to 0.7w/m2Was left under the conditions of (1) for 30 days, and samples were taken on days 6, 13 and 30, and purity of the samples was checked by HPLC. Experimental results show that the crystal form III has good stability effect under the illumination condition.
In conclusion, the crystal form III disclosed by the invention has better stability under various lofting conditions and is suitable for pharmaceutical application.
The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
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, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Form III of a compound of formula (I), characterized in that the form III has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.50 +/-0.2 degrees, 8.97 +/-0.2 degrees, 15.32 +/-0.2 degrees, 17.94 +/-0.2 degrees and 27.24 +/-0.2 degrees;
2. form III according to claim 1, characterized in that the form III has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.50 ° ± 0.2 °,8.97 ° ± 0.2 °,13.41 ° ± 0.2 °,15.32 ° ± 0.2 °,17.94 ° ± 0.2 °,19.01 ° ± 0.2 °,23.97 ° ± 0.2 °,27.00 ° ± 0.2 °,27.24 ° ± 0.2 °,31.60 ° ± 0.2 °.
3. Form III according to claim 1 or 2, characterized in that the form III has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.50 ° ± 0.2 °,8.97 ° ± 0.2 °,11.40 ° ± 0.2 °,12.15 ° ± 0.2 °,13.41 ° ± 0.2 °,15.32 ° ± 0.2 °,17.94 ° ± 0.2 °,19.01 ° ± 0.2 °,19.68 ° ± 0.2 °,20.79 ° ± 0.2 °,21.21 ° ± 0.2 °,21.95 ° ± 0.2 °,22.46 ° ± 0.2 °,22.99 ° ± 0.2 °,23.97 ° ± 0.2 °,24.93 ° ± 0.2 °,26.01 ° ± 0.2 °,27.00 ° ± 0.2 °,27.24 ° ± 0.2 °,28.44 ° ± 0.2 °,30.27 ° ± 0.2 °,31.60 ° ± 0.2 °,34.79 ° ± 0.2 °, 36 35.61 ° ± 0.2 °,37.65 ° ± 0.2 °.
4. The crystalline form III according to any one of claims 1-3, characterized in that the crystalline form III has an X-ray powder diffraction pattern as shown in figure 1.
5. A crystalline form III according to any one of claims 1 to 4, characterized in that the differential scanning calorimetry trace of form III comprises endothermic peaks at 195.61 ℃ ± 3 ℃ and 206.17 ℃ ± 3 ℃.
6. A crystalline form III according to any one of claims 1 to 5, characterized in that it has a differential scanning calorimetry trace as shown in figure 2.
7. A pharmaceutical composition comprising the crystalline form III of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, or combination thereof.
8. A pharmaceutical preparation which is the crystalline form III according to any one of claims 1 to 6, in combination with a pharmaceutically acceptable excipient, in the form of a capsule, tablet, pill, powder, granule, aqueous suspension, solution, ointment or gel.
9. Use of the crystalline form III according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 or the pharmaceutical formulation according to claim 8 for the preparation of a medicament for the prevention, treatment or alleviation of the following diseases in a patient: anemia, ischemia, vascular disease, angina pectoris, myocardial ischemia, myocardial infarction, metabolic disorders or wound healing.
10. Use of the crystalline form III according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 or the pharmaceutical formulation according to claim 8 for the preparation of a medicament for the prevention, treatment or alleviation of a disease or a disorder mediated at least in part by the hypoxia inducible factor prolyl hydroxylase in a patient.
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| WO2021104353A1 (en) * | 2019-11-28 | 2021-06-03 | 广东东阳光药业有限公司 | Crystal form of quinolinone compound and use thereof |
| CN115010662A (en) * | 2021-03-05 | 2022-09-06 | 广东东阳光药业有限公司 | Crystal form of quinolinone compound and application thereof |
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| WO2022184159A1 (en) * | 2021-03-05 | 2022-09-09 | 广东东阳光药业有限公司 | Crystal form of quinolinone compound and use thereof |
| CN115010662B (en) * | 2021-03-05 | 2023-12-08 | 广东东阳光药业股份有限公司 | Crystal forms of quinolinone compounds and application thereof |
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Application publication date: 20200612 Assignee: Nianyan Pharmaceutical (Shanghai) Co.,Ltd. Assignor: SUNSHINE LAKE PHARMA Co.,Ltd. Contract record no.: X2021980013023 Denomination of invention: Crystal forms of quinolone compounds License type: Exclusive License Record date: 20211124 |
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