WO2019105388A1 - Forme cristalline d'un médicament agoniste du récepteur de l'adénosine a3, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un médicament agoniste du récepteur de l'adénosine a3, son procédé de préparation et son utilisation Download PDF

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WO2019105388A1
WO2019105388A1 PCT/CN2018/117958 CN2018117958W WO2019105388A1 WO 2019105388 A1 WO2019105388 A1 WO 2019105388A1 CN 2018117958 W CN2018117958 W CN 2018117958W WO 2019105388 A1 WO2019105388 A1 WO 2019105388A1
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solvent
crystal form
crystalline form
preparation
ray powder
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PCT/CN2018/117958
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English (en)
Chinese (zh)
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陈敏华
张炎锋
刘启月
罗敏
张晓宇
杨朝惠
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苏州科睿思制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the invention relates to the field of medicinal chemistry. Specifically, it relates to a crystalline form of an A3 adenosine receptor agonist drug, a preparation method thereof and use thereof.
  • CF-101 was developed by Kan-Fete Biomedical Co., Ltd. By the end of 2018, CF-101 is in clinical phase III for the treatment of autoimmune diseases such as rheumatoid arthritis, osteoarthritis and psoriasis, as well as glaucoma.
  • CF-101 is an A3 adenosine receptor (A3AR) agonist, and adenosine plays an important role in limiting inflammation through its receptor.
  • Adenosine can produce anti-inflammatory effects by inhibiting TNF-a, interleukin-1, and interleukin-6.
  • Studies have shown that A3AR agonists are in different experimental autoimmune models, such as rheumatoid arthritis, Crohn's disease, and silver swarf. In the disease, it acts as an anti-inflammatory agent by improving the inflammatory process.
  • CF-101 1-deoxy-I-(6- ⁇ [(3-iodophenyl)methyl]amino ⁇ -9H-fluoren-9-yl)-N-methyl-bD-ribofuranose Carbonamide (hereinafter referred to as "Compound I”) has the following structural formula:
  • a crystal form is a solid in which a compound molecule is orderedly arranged in a microstructure to form a crystal lattice, and a drug polymorphism phenomenon means that two or more different crystal forms of a drug exist.
  • crystal forms of drugs may have different dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent; especially for poorly soluble solid drugs, the crystal form will have greater influence. Therefore, the drug crystal form is inevitably an important part of drug research and an important part of drug quality control. Most importantly, the study of crystal forms is beneficial to find a crystal form that is clinically therapeutically meaningful and has stable and physicochemical properties.
  • Amorphous is generally not suitable as a medicinal form, and the molecules in the amorphous material are disorderly arranged, so they are in a thermodynamically unstable state. Amorphous solids are in a high-energy state, and generally have poor stability.
  • amorphous drugs are prone to crystal transformation, which leads to the loss of consistency in drug bioavailability, dissolution rate, etc., resulting in changes in the clinical efficacy of the drug.
  • amorphous preparation is usually a rapid kinetic solid precipitation process, which easily leads to excessive residual solvents, and its particle properties are difficult to control by the process, making it a challenge in the practical application of the drug.
  • Crystalline CS1 has advantages in physical and chemical properties, especially physical and chemical stability, low wettability, good solubility and good mechanical stability. It provides a new and better choice for the development of drugs containing CF-101, which is very important. The meaning.
  • the main object of the present invention is to provide a new crystal form of CF-101 and a preparation method and use thereof.
  • the present invention provides the crystal form CS1 of the compound I (hereinafter referred to as "crystal form CS1").
  • the crystal form CS1 is a hydrate.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at a diffraction angle 2 ⁇ value of 13.2° ⁇ 0.2°, 18.7° ⁇ 0.2°, and 21.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 23.6° ⁇ 0.2°, 26.6° ⁇ 0.2°, and 24.0° ⁇ 0.2°. Peak; preferably, the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at three points in the diffraction angle 2 ⁇ of 23.6° ⁇ 0.2°, 26.6° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has characteristics at one, or two, or three points in the diffraction angle 2 ⁇ value of 25.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 34.3° ⁇ 0.2°. Peak; preferably, the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at three points in the diffraction angle 2 ⁇ of 25.2° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 34.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a diffraction angle 2 ⁇ values of 13.2° ⁇ 0.2°, 18.7° ⁇ 0.2°, 21.8° ⁇ 0.2°, 23.6° ⁇ 0.2°, Any 3, or 4, or 5, or 6, or 7 of 26.6 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °, 25.2 ° ⁇ 0.2 °, 16.9 ° ⁇ 0.2 °, 34.3 ° ⁇ 0.2 ° , or 8 or 9 has characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CS1 is substantially as shown in FIG.
  • the crystal form CS1 provided by the present invention when subjected to differential scanning calorimetry, starts to have a first endothermic peak near 118 ° C, and two endothermic peaks appear near 174 ° C.
  • the DSC chart is shown in Figure 3.
  • the crystalline form CS1 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 3.7% when heated to about 120 ° C, and its TGA corresponds to the weight loss of moisture, as shown in FIG. 4 .
  • the present invention also provides a method for preparing a crystal form CS1 of CF-101, characterized in that the method comprises:
  • the nitrile solvent is preferably acetonitrile, and the ketone solvent is preferably acetone.
  • CF-101 is dissolved in a positive solvent to obtain a positive solvent solution, and then the anti-solvent is slowly added dropwise to the positive solvent solution, and stirred and crystallized at room temperature to obtain.
  • the positive solvent is preferably a cyclic ether, a ketone or a sulfoxide solvent, and the antisolvent is preferably water;
  • the cyclic ether solvent is preferably tetrahydrofuran or 1,4-dioxane
  • the ketone solvent is preferably N-methylpyrrolidone
  • the sulfoxide solvent is dimethyl sulfoxide.
  • the present invention also provides a crystal form CS3 of CF-101 (hereinafter referred to as "crystal form CS3").
  • crystal form CS3 is an acetic acid solvate.
  • the X-ray powder diffraction of the crystal form CS3 has a characteristic peak at a diffraction angle 2 ⁇ value of 13.9° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 5.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 18.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 6.7° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at three points in the diffraction angle 2 ⁇ values of 18.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, and 6.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 8.2° ⁇ 0.2°, 25.8° ⁇ 0.2°, and 15.7° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS3 has characteristic peaks at three points in the diffraction angle 2 ⁇ values of 8.2° ⁇ 0.2°, 25.8° ⁇ 0.2°, and 15.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS3 is at a diffraction angle 2 ⁇ of 13.9° ⁇ 0.2°, 21.0° ⁇ 0.2°, 5.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.5. Any 3, or 4, or 5, or 6 of ° ⁇ 0.2 °, 6.7 ° ⁇ 0.2 °, 8.2 ° ⁇ 0.2 °, 25.8 ° ⁇ 0.2 °, 15.7 ° ⁇ 0.2 °, 25.0 ° ⁇ 0.2 ° There are characteristic peaks at, or at 7, or 8, or at 9, or at 10.
  • the X-ray powder diffraction pattern of Form CS3 is substantially as shown in FIG.
  • the crystal form CS3 provided by the present invention when subjected to differential scanning calorimetry, starts to have an endothermic peak when heated to around 161 ° C, and a second endothermic peak appears near the temperature of 178 ° C, and its DSC The figure is shown in Figure 8.
  • the crystalline form CS3 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 10.5% when heated to about 160 ° C, corresponding to a theoretical weight loss of about 10.5% of a single acetic acid molecule, and its TGA. As shown in Figure 9.
  • the present invention also provides a method for preparing a crystal form CS3 of CF-101, characterized in that the method comprises:
  • CF-101 is added to acetic acid or a mixed system of acetic acid and water, and stirred at a certain temperature.
  • the volume ratio of acetic acid to water is preferably from 20:1 to 1:20, more preferably, the volume ratio is 2:1;
  • the stirring temperature is preferably 20 to 50 ° C, and more preferably, the temperature is room temperature.
  • the present invention also provides a crystal form CS4 of CF-101 (hereinafter referred to as "crystal form CS4").
  • crystal form CS4 is a chloroform solvate.
  • the X-ray powder diffraction pattern of Form CS4 is substantially as shown in FIG.
  • the present invention also provides a crystal form CS2 of CF-101 (hereinafter referred to as "crystal form CS2").
  • crystal form CS2 is an amorphous type.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ value of 20.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 6.9° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the crystalline form CS2 has a characteristic of 1 ⁇ 4 or 2, or 3 ⁇ in the diffraction è 2 ⁇ value of 24.0° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 25.5° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystal form CS1 has characteristic peaks at three points in the diffraction angle 2 ⁇ values of 24.0° ⁇ 0.2°, 24.9° ⁇ 0.2°, and 25.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has a diffraction angle 2 ⁇ values of 20.9° ⁇ 0.2°, 18.4° ⁇ 0.2°, 10.7° ⁇ 0.2°, 6.9° ⁇ 0.2°, 25.5. There are characteristic peaks at any three, or four, or five, or six, or seven of ° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS2 is substantially as shown in FIG.
  • crystal form CS2 when subjected to differential scanning calorimetry, starts to have an endothermic peak near 172 ° C, and its DSC chart is shown in FIG.
  • the crystalline form CS2 provided by the present invention when subjected to thermogravimetric analysis, has a mass loss of about 0.3% when heated to 120 ° C, and its TGA is as shown in FIG.
  • the present invention also provides a method for preparing a crystal form CS2 of CF-101, characterized in that the method comprises:
  • CF-101 is dissolved in a single solvent or a mixed solvent system of alcohols, nitriles, ketones, cyclic ethers, sulfoxides, esters, and volatilized at a certain temperature;
  • the alcohol solvent is preferably methanol, ethanol or isopropanol
  • the nitrile solvent is preferably acetonitrile
  • the ketone solvent is preferably acetone
  • the cyclic ether solvent is preferably tetrahydrofuran
  • the sulfoxide solvent is preferably dimethyl sulfoxide or ester.
  • the solvent is preferably ethyl acetate;
  • the temperature is preferably from 5 to 60 ° C;
  • the temperature is 50 ° C ⁇ 5 ° C.
  • CS2 is obtained by heating a hydrate or solvate of CF-101 to a temperature of dehydration or desolvation.
  • the hydrate is preferably the crystalline form CS1 of the present invention
  • the solvate is preferably the crystalline forms CS3 and CS4 of the present invention
  • the heating method comprises heating with TGA, DSC or a hot stage.
  • the crystal form CS1 provided by the invention has the following beneficial effects:
  • the crystal form CS1 provided by the present invention has lower wettability than amorphous.
  • the test results show that the wettability of the crystalline form CS1 of the present invention is less than 1% of the amorphous.
  • the crystal form CS1 has a weight gain of 0.02% at 80% relative humidity, while the amorphous weight gain reaches 2.07%.
  • the hygroscopicity directly affects the physicochemical stability of the drug, and the high wettability tends to cause chemical degradation and crystal transformation.
  • high moisture permeability will reduce the fluidity of the drug, thereby affecting the processing of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which imposes higher requirements on production and requires high costs.
  • high moisture permeability is likely to cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the low moisture absorbing crystal form is not demanding on the environment, which reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CS1 provided by the present invention has good physical and chemical stability. When placed at 25 ° C / 60% relative humidity, the crystal form did not change for at least 7 months, and the purity remained basically unchanged during storage. It shows that the crystalline CS1 drug substance has good long-term stability and is beneficial to the storage of drugs. At the same time, under the condition of 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity, the crystal form did not change for at least 7 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline CS1 drug substance has good acceleration stability. The accelerated stability of the drug substance is critical to the drug. From bulk drugs to drugs, they need to go through storage, transportation, and formulation processes. These processes often encounter harsh conditions, most often high temperatures and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
  • the transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug.
  • the reduced purity of the drug during storage will result in a significantly lower drug content or decreased activity, with a significant increase in toxic side effects.
  • the crystalline form CS1 has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and the preparation, and maximally reducing the drug effect change and even toxic side effects caused by the crystal form change or impurity generation.
  • the crystalline CS1 bulk drug has good mechanical stability.
  • the crystalline CS1 raw material has good physical stability after grinding. Grinding and pulverizing of the drug substance is often required in the preparation process, and good physical stability can reduce the risk of crystal transformation of the drug substance in the preparation process.
  • the crystal form CS1 provided by the present invention has good solubility in a simulated biological medium.
  • Good solubility is beneficial to improve the absorption of drugs in the human body, improve bioavailability, and make drugs play a better therapeutic role.
  • good solubility can reduce the dose of drugs while reducing the side effects of drugs while ensuring the efficacy of drugs. And improve the safety of drugs.
  • the crystal form CS1 provided by the invention has almost no solvent residue and meets the requirements of medicinal requirements, while the residual amount of the amorphous solid solvent exceeds the standard and cannot be directly used as a pharmaceutical raw material.
  • Many organic solvents have certain harm to the environment and the human body. Therefore, in order to ensure the safety of the drug and control the quality of the product, it is necessary to strictly control and control the organic solvent residue of the drug substance.
  • the crystal form CS2 provided by the invention has the following beneficial effects:
  • the crystal form CS1 provided by the present invention has lower wettability than amorphous.
  • the test results show that the wettability of the crystalline form CS2 of the present invention is less than 42% of the amorphous.
  • the weight gain of the crystalline form CS1 at 80% relative humidity was 0.86%, while the amorphous weight gain reached 2.07%.
  • the hygroscopicity directly affects the physicochemical stability of the drug, and the high wettability tends to cause chemical degradation and crystal transformation.
  • high moisture permeability will reduce the fluidity of the drug, thereby affecting the processing of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which imposes higher requirements on production and requires high costs.
  • high moisture permeability is likely to cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the low moisture absorbing crystal form is not demanding on the environment, which reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CS2 provided by the present invention has good physical and chemical stability. When placed at 25 ° C / 60% relative humidity, the crystal form did not change for at least 7 months, and the purity remained basically unchanged during storage. It shows that the crystalline CS2 drug substance has good long-term stability and is beneficial for drug storage. At the same time, under the condition of 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity, the crystal form did not change for at least 7 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline CS2 drug substance has good acceleration stability. The accelerated stability of the drug substance is critical to the drug.
  • the transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug.
  • the reduced purity of the drug during storage will result in a significantly lower drug content or decreased activity, with a significant increase in toxic side effects.
  • the crystalline form CS2 has good physical and chemical stability, ensures that the quality of the drug substance and the preparation is consistent and controllable, and minimizes the drug effect change and even toxic side effects caused by the crystal form change or impurity generation.
  • the crystalline form CS2 provided by the present invention has good solubility in a simulated biological medium.
  • Good solubility is beneficial to improve the absorption of drugs in the human body, improve bioavailability, and make drugs play a better therapeutic role.
  • good solubility can reduce the dose of drugs while reducing the side effects of drugs while ensuring the efficacy of drugs. And improve the safety of drugs.
  • the crystal form CS2 provided by the invention has almost no solvent residue and meets the requirements of medicinal requirements, while the residual amount of the technical solid solvent exceeds the standard and cannot be directly used as a pharmaceutical raw material.
  • Many organic solvents have certain harm to the environment and the human body. Therefore, in order to ensure the safety of the drug and control the quality of the product, it is necessary to strictly control and control the organic solvent residue of the drug substance.
  • the crystal form CS3 provided by the invention has the following beneficial effects:
  • the crystal form CS3 provided by the present invention has lower wettability than amorphous.
  • the test results show that the wettability of the crystalline form CS3 of the present invention is less than 12% of the amorphous.
  • the weight gain of the crystalline form CS1 at 80% relative humidity was 0.24%, while the amorphous weight gain reached 2.07%.
  • the hygroscopicity directly affects the physicochemical stability of the drug, and the high wettability tends to cause chemical degradation and crystal transformation.
  • high moisture permeability will reduce the fluidity of the drug, thereby affecting the processing of the drug.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which imposes higher requirements on production and requires high costs.
  • high moisture permeability is likely to cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the low moisture absorbing crystal form is not demanding on the environment, which reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CS3 provided by the present invention has good physical and chemical stability. When placed at 25 ° C / 60% relative humidity, the crystal form did not change for at least 2 months, and the purity remained basically unchanged during storage. It shows that the crystalline CS3 drug substance has good long-term stability and is beneficial to the storage of drugs. At the same time, under the condition of 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity, the crystal form did not change for at least 2 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline CS3 drug substance has good acceleration stability. The accelerated stability of the drug substance is critical to the drug.
  • the transformation of the crystal form can lead to changes in the absorption of the drug, affecting the bioavailability, and even causing the toxic side effects of the drug.
  • the reduced purity of the drug during storage will result in a significantly lower drug content or decreased activity, with a significant increase in toxic side effects.
  • the crystalline form CS3 has good physical and chemical stability, ensuring consistent controllable quality of the drug substance and the preparation, and maximally reducing the drug effect change and even toxic side effects caused by the crystal form change or impurity generation.
  • the crystalline CS3 bulk drug has good mechanical stability.
  • the crystalline CS3 bulk drug has good physical stability after grinding. Grinding and pulverizing of the drug substance is often required in the preparation process, and good physical stability can reduce the risk of crystal transformation of the drug substance in the preparation process.
  • the crystalline form CS3 provided by the present invention has good solubility in a simulated biological medium.
  • Good solubility is beneficial to improve the absorption of the drug in the human body, improve the bioavailability, and make the drug play a better therapeutic effect.
  • good solubility can reduce the dose of the drug while reducing the side effect of the drug while ensuring the efficacy of the drug. And improve the safety of drugs.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form CS1, a crystalline form CS2, a crystalline form CS3 or any mixture thereof and a pharmaceutically acceptable carrier, diluted Agent or auxiliary.
  • the present invention provides the use of a crystalline form CS1, a crystalline form CS2, a crystalline form CS3, or any mixture thereof, in the preparation of a pharmaceutical preparation of an A3 adenosine receptor agonist.
  • the present invention provides the use of the crystalline form CS1, the crystalline form CS2, the crystalline form CS3 of CF-101 or any mixture thereof in the preparation of a pharmaceutical preparation for the treatment of rheumatoid arthritis, psoriasis, osteoarthritis or glaucoma.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • the crystallization method of the anti-solvent addition generally means a method in which a solid is dissolved in a positive solvent to form a clear solution, and an anti-solvent is slowly added to the clear solution to precipitate a solid to obtain a crystal.
  • the crystallization method of the reverse anti-solvent addition generally means a method in which a solid is dissolved in a positive solvent to form a clear solution, and a clear solution is slowly added to the anti-solvent to precipitate a solid to obtain a crystal.
  • the positive solvent in the above is generally a good solvent for the solid, and the antisolvent is a poor solvent for the solid.
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern (XRPD pattern).
  • XRPD pattern X-ray powder diffraction pattern
  • XRPD patterns will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the XRPD pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensities of the peaks in the XRPD pattern are related to the preferred orientation of the crystal.
  • the peak intensities shown herein are illustrative and not absolute.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Any crystal form having the same or similar pattern as the characteristic peaks in these XRPD patterns is within the scope of the present invention.
  • One skilled in the art will be able to compare the XRPD pattern listed herein with an XRPD pattern of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS1 of the present invention is pure, substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Figure 1 is an XRPD pattern of a crystal form CS1 obtained according to Example 1 of the present invention.
  • Example 2 is an XRPD pattern of a crystal form CS1 obtained according to Example 2 of the present invention.
  • Figure 3 is a DSC diagram of a crystalline form CS1 in accordance with the present invention.
  • Figure 4 is a TGA diagram of a crystalline form CS1 in accordance with the present invention.
  • Figure 5 is an XRPD pattern of a crystal form CS1 obtained according to Example 4 of the present invention.
  • Figure 6 is an XRPD pattern of a crystalline form CS3 obtained according to Example 7 of the present invention.
  • Figure 7 is a 1 H NMR spectrum of the crystalline form CS3 obtained according to Example 7 of the present invention.
  • Figure 8 is a DSC chart of a crystalline form CS3 obtained according to Example 7 of the present invention.
  • Figure 9 is a TGA diagram of a crystalline form CS3 obtained in accordance with Example 7 of the present invention.
  • Figure 10 is an XRPD pattern of a crystalline form CS4 obtained in accordance with Example 8 of the present invention.
  • Figure 11 is an XRPD pattern of a crystalline form CS2 obtained according to Example 15 of the present invention.
  • Figure 12 is an XRPD pattern of a crystalline form CS2 obtained in accordance with Example 17 of the present invention.
  • Figure 13 is a DSC chart of a crystalline form CS2 obtained in accordance with Example 17 of the present invention.
  • Figure 14 is a TGA diagram of a crystalline form CS2 obtained in accordance with Example 17 of the present invention.
  • Figure 15 is an XRPD overlay of the crystalline form CS1 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower figure is before placement, the upper figure is after placement).
  • Figure 16 is an XRPD overlay of the crystalline form CS1 of the present invention before and after placement at 40 ° C / 75% relative humidity (the lower figure is before placement, the upper figure is after placement).
  • Fig. 17 is an XRPD diagram of the crystal form CS1 of the present invention before and after polishing (the figure below is before polishing, and the figure above is after polishing).
  • Figure 18 is an XRPD overlay of the crystalline form CS3 of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower figure is before placement, the upper figure is after placement).
  • Figure 19 is an XRPD overlay of the crystalline form CS3 of the present invention before and after placement at 40 ° C / 75% relative humidity (the lower figure is before placement, the upper figure is after placement).
  • Fig. 20 is an XRPD diagram of the crystal form CS3 before and after polishing according to the present invention (the figure below is before polishing, and the figure above is after polishing).
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • room temperature is not a specific temperature value and refers to a temperature range of 10-30 °C.
  • the CF101 as a raw material is in the form of a solid (crystalline or amorphous), semi-solid, wax or oil.
  • the compound I as a raw material is in the form of a solid powder.
  • Form CS3 has a single peak at 1.91, corresponding to the hydrogen chemical shift of the acetic acid molecule. According to the nuclear magnetic data, the molar ratio of acetic acid molecule to CF-101 is 1:1, and its 1 H NMR is shown in FIG.
  • the DSC (heating rate of 2 ° C / min) of the crystal form CS3 obtained in Example 7 was as shown in FIG. 8 , and the first endothermic peak appeared near the temperature of 161 ° C, which was attributed to the loss of the acetic acid molecule near the temperature. A second endothermic peak began to appear near 178 °C.
  • the TGA of Form CS3 obtained in Example 7 is shown in Figure 9. It has a mass loss of about 10.5% when heated to around 160 °C, corresponding to a theoretical weight loss of about 10.5% for a single acetic acid molecule. From the TGA and nuclear magnetic data, it is known that about 1 mole of acetic acid is contained per mole of CF-101.
  • the crystal form CS2 obtained in Example 17 was selected for test characterization, and the XRPD data thereof is shown in Fig. 12 and Table 10.
  • the DSC of the crystalline form CS2 obtained in Example 17 was as shown in Fig. 13, and an endothermic peak began to appear near 172 °C.
  • the TGA of the crystal form CS2 obtained in Example 17 was as shown in Fig. 14, and when heated to 120 ° C, it had a mass loss of about 0.3%.
  • Example 20 Comparison of the wettability of crystalline CS1 and amorphous
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the wettability weight gain of the crystalline form CS1 under the condition of 80% RH is 0.02%, which is none or almost no wettability, while the amorphous weight gain is 2.07% under the condition of 80% RH, which is hygroscopic. Crystal form CS1 has better wettability than amorphous form.
  • Example 21 Stability study of crystalline form CS1
  • the crystal form CS1 was placed open at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 7 months, and then XRPD was sampled and tested for purity by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the XRPD overlay before and after placement at 25 ° C / 60% relative humidity is shown in Figure 15, and the XRPD overlay before and after placement at 40 ° C / 75% relative humidity is shown in Figure 16.
  • the results are shown in Table 12.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated fed-feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated fed-feeding intestinal fluid
  • the crystal form CS1 was placed in a mortar, manually ground for 5 minutes, and subjected to an XRPD test before and after the grinding.
  • the test results are shown in Fig. 17 (the figure below is before grinding, the above figure is after grinding), and the results show that the crystal form CS1 is not changed before and after grinding, and has good grinding stability.
  • the solvent residual amount of the crystalline form CS1 of the present invention and the amorphous solid was separately tested.
  • the test results showed that the crystalline form CS1 of the present invention had almost no solvent residue, and the solvent residual amount of tetrahydrofuran in the amorphous solid was 54600 ppm.
  • ICH International Coordinating Committee
  • tetrahydrofuran is the second type of solvent in pharmaceuticals and the solvent residue must not exceed 720 ppm. It can be seen that the residual amount of the tetrahydrofuran solvent in the amorphous solid significantly exceeds the limit prescribed by ICH, and is not suitable for direct use as a pharmaceutical raw material.
  • Example 25 Comparison of the wettability of crystalline form CS2 with amorphous
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the wettability weight gain of the crystalline form CS2 under the condition of 80% RH is 0.86%, which is slightly wetted, while the amorphous weight gain is 2.07% under the condition of 80% RH, which is hygroscopic. Crystal form CS2 has better wettability than amorphous form.
  • Example 26 Stability study of crystalline form CS2
  • the crystal form CS2 was placed at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 7 months.
  • the XRPD was sampled and tested by high performance liquid chromatography (HPLC). The results are shown in the table. 15 is shown.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated fed-feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated fed-feeding intestinal fluid
  • Example 28 Study on crystalline CS2 and amorphous solvent residues
  • the solvent residual amount of the crystalline form CS2 of the present invention and the amorphous solid was separately tested.
  • the test results show that the crystalline form CS2 of the present invention has almost no solvent residue, and the solvent residual amount of tetrahydrofuran in the amorphous solid is 54611 ppm.
  • ICH International Coordinating Committee's
  • tetrahydrofuran is the second type of solvent in pharmaceuticals and the solvent residue must not exceed 720 ppm. It can be seen that the residual amount of the tetrahydrofuran solvent in the amorphous solid significantly exceeds the limit prescribed by ICH, and is not suitable for direct use as a pharmaceutical raw material.
  • Example 29 Comparison of the wettability of crystalline CS3 with amorphous
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the wettability weight gain of the crystalline form CS3 was 0.24% under the condition of 80% RH, which was slightly wetted, while the amorphous weight gain was 2.07% under the condition of 80% RH, which was hygroscopic. Crystalline CS3 has better wettability than amorphous.
  • Example 30 Stability study of crystalline form CS3
  • the crystalline form CS3 was placed in an open position at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 7 months, and then XRPD was sampled and tested for purity by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the XRPD overlay before and after placement at 25 ° C / 60% relative humidity is shown in Figure 18, and the XRPD overlay before and after placement at 40 ° C / 75% relative humidity is shown in Figure 19.
  • the results are shown in Table 18.
  • Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated fed-feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated fed-feeding intestinal fluid
  • Example 31 Study on the grinding stability of crystalline form CS3
  • the crystal form CS3 was placed in a mortar, manually ground for 5 minutes, and subjected to an XRPD test before and after the grinding.
  • the test results are shown in Fig. 20 (the lower figure is before grinding, the upper figure is after grinding), and the results show that the crystal form CS3 is not changed before and after grinding, and has good grinding stability.

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Abstract

La présente invention concerne une nouvelle forme cristalline du composé I et son procédé de préparation, une composition pharmaceutique comprenant la forme cristalline et une utilisation de la forme cristalline dans la préparation d'un agoniste du récepteur de l'adénosine A3 et une préparation pharmaceutique permettant de traiter la polyarthrite rhumatoïde, le psoriasis, l'ostéoarthrite ou le glaucome. La forme cristalline du composé I de la présente invention présente une ou plusieurs propriétés améliorées par comparaison à l'état de la technique, et est d'une grande valeur pour l'optimisation et le développement de médicaments.
PCT/CN2018/117958 2017-11-29 2018-11-28 Forme cristalline d'un médicament agoniste du récepteur de l'adénosine a3, son procédé de préparation et son utilisation WO2019105388A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002604A1 (fr) * 1993-07-13 1995-01-26 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Agonistes du recepteur de l'adenosine a¿3?
WO2003029264A2 (fr) * 2001-10-01 2003-04-10 University Of Virginia Patent Foundation Analogues de 2-propynyle adenosine presentant une activite agoniste de a2a et compositions en contenant
CN101646685A (zh) * 2007-03-14 2010-02-10 坎-菲特生物药物有限公司 合成ib-meca的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002604A1 (fr) * 1993-07-13 1995-01-26 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Agonistes du recepteur de l'adenosine a¿3?
WO2003029264A2 (fr) * 2001-10-01 2003-04-10 University Of Virginia Patent Foundation Analogues de 2-propynyle adenosine presentant une activite agoniste de a2a et compositions en contenant
CN101646685A (zh) * 2007-03-14 2010-02-10 坎-菲特生物药物有限公司 合成ib-meca的方法

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