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WO2024255833A1 - Co-cristal d'oxynitrure de pyridine et d'acide fumarique, composition le comprenant, utilisation et procédé de préparation associés - Google Patents

Co-cristal d'oxynitrure de pyridine et d'acide fumarique, composition le comprenant, utilisation et procédé de préparation associés Download PDF

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Publication number
WO2024255833A1
WO2024255833A1 PCT/CN2024/099157 CN2024099157W WO2024255833A1 WO 2024255833 A1 WO2024255833 A1 WO 2024255833A1 CN 2024099157 W CN2024099157 W CN 2024099157W WO 2024255833 A1 WO2024255833 A1 WO 2024255833A1
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crystal
fumaric acid
ray powder
powder diffraction
diffraction pattern
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Chinese (zh)
Inventor
张勇
程宏明
王明力
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Shanghai Jemincare Pharmaceuticals Co Ltd
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Shanghai Jemincare Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention relates to a co-crystal of a compound of formula (I) and fumaric acid, a pharmaceutical composition containing the same, and an application of the co-crystal as a voltage-gated sodium channels (NaV) blocker.
  • Drug cocrystals refer to crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a certain ratio. By forming cocrystals, drugs can improve their physical and chemical properties and enhance their clinical therapeutic effects on the one hand, and on the other hand, cocrystals can enrich their crystal forms. However, the development of drug cocrystals is difficult, and in-depth research and evaluation are required on cocrystal ligand selection, preparation process, and physical property characterization.
  • the present invention provides a co-crystal of a compound of formula (I) and fumaric acid, wherein the co-crystal is formed by a non-covalent bond between the compound of formula (I) and fumaric acid in a molar ratio of 1:(0.4-0.6), and the molar ratio is preferably 1:(0.45-0.55) or 1:(0.48-0.51);
  • the co-crystal is formed by non-covalent bonding of the compound of formula (I) and fumaric acid at a molar ratio of 1:0.5.
  • the co-crystal of the compound of formula (I) and fumaric acid is co-crystal A
  • the X-ray powder diffraction pattern of co-crystal A has characteristic diffraction peaks at the following 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the co-crystal A further comprises the following one, two or more 2 ⁇ angles: Characteristic diffraction peaks: 14.99 ⁇ 0.2°, 16.86 ⁇ 0.2°, 17.65 ⁇ 0.2°, 18.00 ⁇ 0.2°, 18.61 ⁇ 0.2°, 19.35 ⁇ 0.2°, 21.27 ⁇ 0.2°, 26.40 ⁇ 0.2°, 27.02 ⁇ 0.2°, 27.90 ⁇ 0.2°, 28.62 ⁇ 0.2°, 28.83 ⁇ 0.2°, 29.22 ⁇ 0.2°, 31.07 ⁇ 0.2°.
  • the co-crystal A has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the X-ray powder diffraction pattern analysis data of the cocrystal A is shown in Table 1 below.
  • the co-crystal of the compound of formula (I) and fumaric acid is co-crystal B, and the X-ray powder diffraction pattern of co-crystal B has characteristic diffraction peaks at the following 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the cocrystal B further includes the following one, two or more characteristic diffraction peaks at 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the co-crystal B has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
  • the X-ray powder diffraction pattern analysis data of the cocrystal B is shown in Table 2 below.
  • the co-crystal of the compound of formula (I) and fumaric acid is co-crystal C, and the X-ray powder diffraction pattern of co-crystal C has characteristic diffraction peaks at the following 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the cocrystal C further includes the following one, two or more characteristic diffraction peaks at 2 ⁇ angles:
  • the X-ray powder diffraction pattern of the co-crystal C has an X-ray powder diffraction pattern substantially as shown in FIG. 14 .
  • the X-ray powder diffraction pattern analysis data of the cocrystal C is shown in Table 3 below.
  • the co-crystal of the compound of formula (I) and fumaric acid is a single crystal of the triclinic system
  • the space group is P-1
  • the single crystal has a three-dimensional structural ellipsoid diagram as shown in FIG. 1 .
  • the single crystal has a unit cell stacking projection diagram along the b-axis direction as shown in FIG. 2 .
  • the atomic coordinates and isotropic temperature factor of the single crystal are shown in Table 4 below.
  • the bond length of the single crystal is and bond angles (°) are shown in Table 5 below.
  • twist angle (°) of the single crystal is shown in Table 6 below.
  • the hydrogen bond list of the co-single crystal ( °) are shown in Table 7 below.
  • the present invention also provides a pharmaceutical composition, comprising a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid, such as co-crystal A, co-crystal B, co-crystal C, or a single crystal.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the present invention also provides the use of a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to inhibit voltage-gated sodium channels.
  • a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid e.g., co-crystal A, co-crystal B, co-crystal C, single crystal
  • the drug is used to inhibit voltage-gated sodium channels.
  • the voltage-gated sodium channel is Nav1.8.
  • the present invention also provides the use of a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid (e.g., co-crystal A, co-crystal B, co-crystal C, single crystal) or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent and/or alleviate and/or relieve a disease, wherein the disease is preferably pain or cough.
  • a co-crystal of any of the above-mentioned compounds of formula (I) and fumaric acid e.g., co-crystal A, co-crystal B, co-crystal C, single crystal
  • the drug is used to treat and/or prevent and/or alleviate and/or relieve a disease, wherein the disease is preferably pain or cough.
  • the disease is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and cardiac arrhythmia.
  • the present invention also provides a method for preparing the above co-crystal, the preparation method comprising the following steps:
  • the free compound of formula (I) and fumaric acid are mixed in a solvent, stirred, filtered, and dried under vacuum at room temperature to obtain the co-crystal.
  • the preparation method-1 of the above-mentioned co-crystal A comprises the following steps:
  • the free compound of formula (I) and a certain amount of fumaric acid are mixed in solvent-1, stirred and then a certain amount of fumaric acid is added, the stirring is continued, the mixture is filtered and dried under vacuum at room temperature to obtain the cocrystal A.
  • Solvent-1 is selected from a mixed solvent of ethanol and n-heptane, a mixed solvent of n-propanol and n-heptane, a mixed solvent of acetone and n-heptane, and a mixed solvent of 2-methyltetrahydrofuran and n-heptane; preferably, it is a mixed solvent of ethanol and n-heptane in a volume ratio of 2:3;
  • the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.
  • the preparation method 1 of co-crystal A is specifically as follows:
  • the preparation method 2 of the above-mentioned co-crystal A comprises the following steps:
  • the mixed product was added into solvent-3, stirred at room temperature, filtered, and dried in vacuo to obtain the co-crystal A.
  • Solvent-2 is selected from ethyl acetate
  • solvent-3 is selected from methanol
  • the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.
  • the preparation method 2 of cocrystal A is specifically as follows:
  • the preparation method-1 of the above-mentioned co-crystal B comprises the following steps:
  • the co-crystal A was added into the solvent-4, stirred at room temperature, filtered, and dried in vacuo to obtain the co-crystal B.
  • Solvent-4 is selected from acetone.
  • the preparation method 1 of cocrystal B is specifically as follows:
  • the preparation method 2 of the above-mentioned co-crystal B comprises the following steps:
  • Solvent-5 is selected from n-propanol and ethanol
  • solvent-6 is selected from n-heptane
  • cooling is 0-10°C for 5h;
  • the amount of seed crystal added is 0.5%-0.7%
  • the temperature for dissolving, adding in portions, and stirring is 50-60°C or 45-55°C;
  • the molar ratio of the free compound of formula (I) to fumaric acid is 1:0.4-1.0, preferably 1:0.5.
  • the preparation method of the above-mentioned co-crystal C comprises the following steps:
  • the co-crystal B is added to the solvent-7, and the solvent-8 is gradually added dropwise, and the mixture is stirred at room temperature and/or allowed to stand in a refrigerator and/or allowed to stand in an open container for evaporation until a solid is precipitated, and the mixture is centrifuged to obtain the co-crystal C.
  • Solvent-7 is selected from cyclohexane
  • solvent-8 is selected from tetrahydrofuran.
  • the preparation method of co-crystal C is specifically as follows:
  • co-crystal B 20 mg was added to cyclohexane, and tetrahydrofuran was gradually added dropwise.
  • the mixture was stirred at room temperature and/or allowed to stand in a refrigerator and/or allowed to stand in an open container for evaporation until a solid was precipitated.
  • the mixture was centrifuged to obtain the co-crystal C.
  • the method for preparing the single crystal comprises the following steps:
  • solvent-9 is selected from methanol.
  • the amount of cocrystal B is 10 mg;
  • the amount of methanol used is 0.5 mL.
  • the present invention provides a co-crystal of a compound of formula (I) and fumaric acid, including co-crystal A, co-crystal B, co-crystal C, and a single crystal.
  • the co-crystal has good stability in different solvents and has good stability under high temperature, high humidity, light and accelerated conditions.
  • API or “free state” refers to the free base form of the compound represented by formula (I).
  • Eutectoid refers to a single-phase crystalline material comprising two or more components in a specific stoichiometric ratio, wherein the arrangement in the crystal lattice is not based on ionic bonds (such as those formed with a salt) and at least two of the components are solid at room temperature.
  • the term "the molar ratio of the compound of formula (I) and fumaric acid is approximately 1:0.5” means that the compound of formula (I) and fumaric acid co-crystal has a stoichiometric ratio of about 1:0.5 of the compound of formula (I): fumaric acid; for example, 1:(0.4-0.6), 1:(0.45-0.55), 1:(0.48-0.51) or 1:0.5.
  • Crystal form or “crystalline form” refers to a solid having 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 of compounds.
  • the crystalline form of a substance can be obtained by many methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
  • an additive such as a co-crystallization countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, grinding and solvent drop grinding, etc.
  • Amorphous or “amorphous form” refers to a substance formed when the particles (molecules, atoms, ions) of a substance are arranged in a three-dimensional space without periodicity, and is characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.
  • the amorphous form of a substance can be obtained by many methods known in the art. This method includes, but is not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion technology, etc.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, 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, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, tolu
  • Anti-solvent refers to a fluid that promotes precipitation of a product (or a product precursor) from a solvent.
  • the anti-solvent may include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid from the solvent.
  • Solidvate means that the crystal has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, wherein 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-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-acetone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof
  • 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. Hydrates may or may not have other solvents other than water on the surface of the substance, in the crystal lattice, or on the surface and in the crystal lattice.
  • Crystalline or amorphous forms can be identified by a variety of technical means, 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, solution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • solution calorimetry scanning electron microscopy
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, and crystal structure states, and is a common means of identifying crystal forms.
  • the peak position of the XRPD spectrum depends mainly on the structure of the crystal form, is relatively insensitive to experimental details, and its relative peak height depends 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 substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention.
  • the measurement of 2 ⁇ of the XRPD spectrum may have experimental errors, and the measurement of 2 ⁇ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of 2 ⁇ cannot be regarded as absolute. According to the instrument conditions used in the test of the present invention, there is an error tolerance of ⁇ 0.2° for the diffraction peak.
  • DSC Differential Scanning Calorimetry
  • an inert reference usually ⁇ -Al 2 O 3
  • the height of the melting peak of 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 of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention.
  • DSC spectra may have experimental errors, and the peak positions and peak values of DSC spectra may vary slightly between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the melting peak has an error tolerance of ⁇ 3°C.
  • Glass transition refers to the transition between the highly elastic state and the glassy state of an amorphous material, which is an inherent property of the material; its corresponding transition temperature is the glass transition temperature (Tg), which is an important physical property of an amorphous material.
  • Tg glass transition temperature
  • the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details, etc. According to the instrument conditions used in the test of the present invention, the glass transition temperature has an error tolerance of ⁇ 3°C.
  • DSC Differential scanning calorimetry
  • Solids with the same chemical composition often form isomers with different crystal structures, or variants, under different thermodynamic conditions. This phenomenon is called polymorphism or polyphase phenomenon.
  • crystal transformation When the temperature and pressure conditions change, the variants will transform into each other, which is called crystal transformation. Due to the crystal transformation, the mechanical, electrical, magnetic and other properties of the crystal will change greatly.
  • DSC differential scanning calorimetry
  • this transformation process can be observed on the differential scanning calorimetry (DSC) graph, characterized in that the DSC graph has an exothermic peak reflecting this transformation process, and at the same time has two or more endothermic peaks, which are the characteristic endothermic peaks of different crystal forms before and after the transformation.
  • the crystal form or amorphous form of the compound of the present invention can undergo crystal transformation under appropriate conditions.
  • Thermogravimetric analysis is a technique for measuring the mass change of a substance with temperature under program control. It is suitable for checking the loss of solvent in crystals or the process of sample sublimation and decomposition, and can infer the presence of crystal water or crystallization solvent in the crystals.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. According to the instrument conditions used in the test of the present invention, the mass change has an error tolerance of ⁇ 0.3%.
  • the moisture adsorption/desorption isotherm measurement is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of a solid object under various relative humidity conditions.
  • a peak refers to a feature that can be identified by one skilled in the art and which cannot be attributed to background noise.
  • 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 the DSC pattern or the TGA results are shown in the pattern thereof.
  • substantially pure means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystalline form contains other crystalline forms, and the percentage of the 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 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%.
  • “Relative intensity” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.
  • FIG1 is an ellipsoid diagram of the three-dimensional structure of a single crystal of a eutectic body according to an embodiment of the present invention
  • FIG2 is a unit cell stacking projection diagram of a single crystal of a eutectic along the b-axis direction according to an embodiment of the present invention
  • FIG3 is an XRPD diagram of a free state of a compound of formula (I) according to an embodiment of the present invention.
  • FIG4 is a DSC and TGA diagram of the free state of the compound of formula (I) according to an embodiment of the present invention.
  • FIG5 is an NMR diagram of the free state of the compound of formula (I) according to an embodiment of the present invention.
  • FIG6 is an XRPD diagram of co-crystal A according to an embodiment of the present invention.
  • FIG7 is a DSC and TGA graph of co-crystal A according to an embodiment of the present invention.
  • FIG8 is a comparison of NMR of (a) and free state of co-crystal A according to an embodiment of the present invention. (b) NMR graph;
  • FIG9 is (a) a DVS curve of co-crystal A according to an embodiment of the present invention. (b) a comparison diagram of XRPD of the sample before and after the DVS test;
  • FIG10 is an XRPD pattern of co-crystal B according to an embodiment of the present invention.
  • FIG11 is a DSC and TGA graph of co-crystal B according to an embodiment of the present invention.
  • FIG12 is a comparison of NMR of (a) and free state of co-crystal B according to an embodiment of the present invention. (b) NMR graph;
  • FIG13 is (a) a DVS curve of co-crystal B according to an embodiment of the present invention; (b) a comparison diagram of XRPD of the sample before and after the DVS test;
  • FIG14 is an XRPD pattern of co-crystal C according to an embodiment of the present invention.
  • FIG15 is a DSC and TGA graph of co-crystal C according to an embodiment of the present invention.
  • FIG16 is a NMR comparison diagram of (a) co-crystal C and co-crystal A according to an embodiment of the present invention. (b) NMR diagram;
  • FIG17 is an XRPD diagram of the stability study of co-crystal A according to an embodiment of the present invention.
  • FIG. 18 is an XRPD pattern of a stability study of co-crystal B according to an embodiment of the present invention.
  • the solid samples obtained in the experiment were analyzed by X-ray powder diffractometer Bruker D8 Advance (Bruker, GER). The 2 ⁇ scanning angle was from 3° to 45°, the scanning step was 0.02°, and the exposure time was 0.08 seconds.
  • the test method was Cu target K ⁇ 1 radiation, voltage 40kV, current 40mA, and the sample pan was a zero background sample pan.
  • thermogravimetric analyzer is TA Discovery 550 (TA, US). 2-5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, and the nitrogen purge rate at the sample was 60 mL/min and the nitrogen purge rate at the balance was 40 mL/min.
  • the model of the differential scanning calorimeter was TA Discovery 250 (TA, US). 1-2 mg of sample was accurately weighed and placed in a DSC Tzero sample pan with holes and heated to the final temperature at a rate of 10 °C/min. The nitrogen purge rate in the furnace was 50 mL/min.
  • Dynamic moisture adsorption and desorption analysis was performed using DVS Intrinsic (SMS, UK).
  • the test used a gradient mode with a humidity change of 0%-95%-0%.
  • the humidity change for each gradient in the range of 0% to 90% was 10%.
  • the gradient endpoint was determined using the dm/dt method, with dm/dt less than 0.002% and maintained for 10 minutes as the gradient endpoint, or each gradient maintained for up to 180 minutes.
  • the sample was analyzed by XRPD to confirm whether the solid morphology had changed.
  • HPLC model was Waters Acquity Arc (Waters, US), and the test conditions were shown in Table 8.
  • the preparation process of the biological medium is shown in the table. Samples of different crystal forms were added to the biological medium and water and shaken at a constant temperature of 37°C for 24 hours. Samples were taken at 0.5h, 2h and 24h, respectively. The sampled solutions were filtered with a 0.22 ⁇ m water filter membrane. Some samples with higher concentrations were appropriately diluted with diluents. The signal peak area of the solution was measured by HPLC. Finally, the concentration of the compound in the solution was calculated based on the peak area, the HPLC standard curve of the free raw material and the dilution multiple. In addition, the pH value of the supernatant after 24h was tested, and the remaining solid was tested by XRPD.
  • the starting materials of the free compound of formula (I) used in the following examples can be prepared according to the prior art. For example, they can be prepared according to the method described in patent application publication WO2021047622A1, but the starting materials are not limiting conditions for preparing the co-crystals of the present invention.
  • the XRPD results ( Figure 3) of the free state of the compound of formula (I) show that it is a solid with good crystallinity.
  • the TGA results ( Figure 4) show that the free state has a weight loss of 0.8% during heating to 150°C, and decomposition may occur above 300°C.
  • the DSC results ( Figure 4) show that the free state has an endothermic signal at about 94°C and a melting endothermic peak at about 150°C. No obvious residual organic solvent signal peak is found in the NMR results ( Figure 5), and the NMR results are used as a reference for subsequent comparison.
  • XRPD results show that cocrystal A is a solid with good crystallinity.
  • TGA results show that cocrystal A has almost no weight loss during heating to 150°C, and may decompose above 225°C.
  • DSC results show that cocrystal A has a melting endothermic peak at 170°C.
  • NMR results show that the integral of the peak corresponding to the free state of the sample is consistent with the API, and the active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm.
  • the XRPD results show that cocrystal B is a solid with good crystallinity.
  • the TGA results show that cocrystal B has almost no weight loss during heating to 150°C, and may decompose above 225°C.
  • the DSC results show that cocrystal B has a melting endothermic peak at 169°C.
  • the NMR results show that the integral of the peak corresponding to the free state of the sample is consistent with the API, and the active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm.
  • XRPD results show that cocrystal C is a solid with good crystallinity.
  • TGA results show that cocrystal C loses 0.1% of its weight when heated to 150°C, and may decompose above 225°C.
  • DSC results show that cocrystal C has endothermic and exothermic signals at 162°C and 164°C, and a melting endothermic peak at around 170°C.
  • NMR results Figure 16) show that the NMR peak shift of this sample is consistent with that of cocrystal A, and the integral of the corresponding free state peak is consistent with the API.
  • the active hydrogen of fumaric acid can be seen around 13.1ppm, and the characteristic signal peak of fumaric acid can be seen around 6.6ppm. From the integral value, it can be obtained that the molar ratio of the API and fumaric acid is approximately 1:0.5; no obvious residual organic solvent signal peak is observed.
  • cocrystal C is anhydrous crystalline.
  • the stability of the compound of formula (I) fumaric acid co-crystal A and co-crystal B was studied under high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), and accelerated (40°C/75%RH) conditions.
  • Samples were taken for HPLC testing and XRPD characterization at 7 days and 15 days, respectively. The results are shown in Tables 13 to 15, Figures 17 and 18.
  • the XRPD results show that co-crystal A and co-crystal B are stable under high temperature, high humidity, light, and accelerated conditions for 7 days and 15 days, and no crystal transformation occurs, and the appearance does not change significantly.
  • the HPLC results show that the chemical purity of co-crystal A and co-crystal B does not change significantly after being placed under the above conditions for 7 days and 15 days.
  • the free state II can be obtained according to the preparation method of the crystalline form A of the compound of formula (I) disclosed in patent application publication TW202300147A.
  • the single crystal has a three-dimensional structure ellipsoid diagram as shown in FIG1 , and a unit cell stacking projection diagram along the b-axis direction as shown in FIG2 .
  • the atomic coordinates and isotropic temperature factor of the single crystal are shown in Table 4.
  • the bond angles (°) are shown in Table 5
  • the torsion angles (°) are shown in Table 6, and the hydrogen bond list ( °) as shown in Table 7.
  • Plasma samples were stored in a -80°C refrigerator before analysis.
  • ⁇ LC-MS/MS was used to determine the concentration of the target analyte in beagle dog plasma.
  • Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters based on the blood drug concentration data at different time points, providing parameters such as AUC 0-t , AUC 0- ⁇ , C max , T max , and T 1/2 and their mean and standard deviation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un co-cristal d'un composé représenté par la formule (I) et de l'acide fumarique, une composition pharmaceutique et une utilisation associées. Plus particulièrement, la présente invention concerne un co-cristal formé par un composé représenté par la formule (I) et de l'acide fumarique dans un rapport molaire de 1 : 0,4 à 0,6, la structure du co-cristal étant telle que représentée dans la formule (II) ; et la présente invention concerne en outre un procédé de préparation du co-cristal du composé représenté par la formule (I) et de l'acide fumarique.
PCT/CN2024/099157 2023-06-14 2024-06-14 Co-cristal d'oxynitrure de pyridine et d'acide fumarique, composition le comprenant, utilisation et procédé de préparation associés Pending WO2024255833A1 (fr)

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CN202310705175.1 2023-06-14
CN202310705175 2023-06-14
CN202410750805.1 2024-06-11
CN202410750805 2024-06-11

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112479996A (zh) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2022188872A1 (fr) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Forme cristalline d'un composé d'oxyde d'azote de pyridine et son utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112479996A (zh) * 2019-09-12 2021-03-12 上海济煜医药科技有限公司 吡啶氮氧化合物及其制备方法和用途
WO2022188872A1 (fr) * 2021-03-11 2022-09-15 上海济煜医药科技有限公司 Forme cristalline d'un composé d'oxyde d'azote de pyridine et son utilisation

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