WO2022143976A1 - Forme cristalline i, forme cristalline ii et forme cristalline iii de l'oxyde de phénylarsine et procédé de préparation associé - Google Patents

Forme cristalline i, forme cristalline ii et forme cristalline iii de l'oxyde de phénylarsine et procédé de préparation associé Download PDF

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WO2022143976A1
WO2022143976A1 PCT/CN2021/143612 CN2021143612W WO2022143976A1 WO 2022143976 A1 WO2022143976 A1 WO 2022143976A1 CN 2021143612 W CN2021143612 W CN 2021143612W WO 2022143976 A1 WO2022143976 A1 WO 2022143976A1
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crystal form
solvent
solid
preparation
phenylarsenic
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PCT/CN2021/143612
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English (en)
Chinese (zh)
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黄福德
陈磊
刘娟
王来宝
章建刚
万清卫
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江苏挪贝肽医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/66—Arsenic compounds
    • C07F9/70—Organo-arsenic compounds
    • C07F9/74—Aromatic compounds
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/285—Arsenic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to various crystal forms of phenylarsenic oxide as a PI4KIII ⁇ protein inhibitor, in particular, to phenylarsenic oxide crystal form I, crystal form II and crystal form III and a preparation method thereof.
  • Phenylarsine Oxide is a known bioinhibitor, and the arsenic atom in this molecule has a high affinity for the sulfur atom of the sulfhydryl group in biomolecules. Recent studies have found that arsenic oxide is a PI4KIII ⁇ inhibitor that can be used to treat Alzheimer's disease.
  • amorphous has higher solubility and dissolution rate than crystalline form in most cases, it is unstable, has strong hygroscopicity and is prone to crystal form transformation. Therefore, amorphous has problems of processing stability and storage stability, and in the production process, the bulk density of amorphous particles is small, the surface free energy is high, and it is easy to cause a series of preparations such as agglomeration, poor fluidity, and strong elastic deformation. The problem seriously affects the clinical value of amorphous benzene arsenic oxide.
  • the bioavailability of the same drug with different crystal forms may also be different.
  • its stability, fluidity, and compressibility may also be different. These physical and chemical properties have a certain impact on the application of the drug, thereby affecting the efficacy of drugs. Therefore, there is a need for crystalline forms of arsenic phenylene oxide with superior physiochemical properties that can be advantageously used in pharmaceutical processing and pharmaceutical compositions.
  • the crystal form I, crystal form II and crystal form III of the benzene arsenic oxide developed by the invention have excellent stability.
  • the problem to be solved by the present invention is to provide a stable arsenic oxide crystal form, improve its bioavailability, be beneficial to the application in solid medicine, and provide more qualitative and quantitative information for the research on the curative effect of solid medicine.
  • the first aspect of the present invention provides a new crystal form of phenylarsenic oxide, more specifically, a phenylarsenic oxide crystal form I (hereinafter sometimes referred to as a compound represented by formula (I) for short)
  • the crystal form I "PAO crystal form I” or "crystal form I"
  • the crystal form I is characterized in that its X-ray powder diffraction (XRPD) pattern has diffraction peaks at the following 2 ⁇ angles: 8.02° ⁇ 0.2°, 8.83° ⁇ 0.2 °, 9.38° ⁇ 0.2°, 11.57° ⁇ 0.2°, 17.92° ⁇ 0.2°, 18.36° ⁇ 0.2°, 19.89° ⁇ 0.2°, 21.21° ⁇ 0.2°, 22.62° ⁇ 0.2°, 26.40° ⁇ 0.2°,
  • the 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of benzene arsenic oxide crystal form I has diffraction peaks at the following 2 ⁇ angles: 8.02° ⁇ 0.2°, 8.83° ⁇ 0.2°, 9.38° ⁇ 0.2°, 11.57° ⁇ 0.2°, 17.92° ⁇ 0.2 °, 18.36° ⁇ 0.2°, 19.89° ⁇ 0.2°, 21.21° ⁇ 0.2°, 21.68° ⁇ 0.2°, 22.62° ⁇ 0.2°, 25.27° ⁇ 0.2°, 26.40° ⁇ 0.2°, 29.50° ⁇ 0.2°, 30.33° ⁇ 0.2°, 32.49° ⁇ 0.2°, and the 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of the crystal form is basically as shown in FIG. 1 .
  • the crystal form I of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 2-4 in the accompanying drawings.
  • the invention provides a preparation method of benzene arsenic oxide crystal form I, comprising the following steps:
  • phenylarsenic oxide is added to the solvent to obtain a suspension, which is suspended at room temperature;
  • the solvent is selected from water, methanol, acetone, isopropyl acetate, acetonitrile, 4-methyl-2-pentanone, n-heptane, methyl tert-butyl
  • the solvent is water, methanol-water, acetone, isopropyl acetate-acetone, acetonitrile, 4-methyl-2-pentanone-acetonitrile, n-heptane, methyl tert-butyl ether, or isopropyl acetate Propyl ether-tetrahydrofuran.
  • the suspension time is 1 day, 2 days, 3 days, 5 days, 7 days, 10 days or 14 days.
  • the invention provides another preparation method of benzene arsenic oxide crystal form I, comprising the following steps:
  • the solvent is selected from the group consisting of ethyl acetate, dichloromethane, N,N-dimethylformamide, n-heptane and any two or more mixtures thereof. Group. More preferably, the solvent is ethyl acetate, dichloromethane or N,N-dimethylformamide.
  • the invention provides another preparation method of phenylarsenic oxide crystal form I, comprising the following steps:
  • the solvent is selected from isopropanol, acetone, ethyl acetate, isopropyl acetate, n-butanol, acetonitrile, 4-methyl-2-pentanone, The group consisting of heptane, cyclohexane, methyl tert-butyl ether, isopropyl ether, dichloromethane, 1,4-dioxane or 2-methyltetrahydrofuran and mixtures of any two or more thereof.
  • the solvent is isopropyl acetate, acetonitrile or 2-methyltetrahydrofuran-ethyl acetate.
  • the heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C.
  • the low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.
  • the invention provides another preparation method of benzene arsenic oxide crystal form I, comprising the following steps:
  • the solvent is selected from the group consisting of water, acetone, isopropyl acetate, cyclohexane, acetonitrile, ethyl acetate and any two or more mixtures thereof. More preferably, the solvent is water or acetone-acetonitrile.
  • the heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C.
  • the rate of controlled cooling is 5-10°C/h; the temperature is lowered to room temperature, close to 0°C or lower than 0°C.
  • the second aspect of the present invention provides a new crystal form of benzene arsenic oxide, more specifically, benzene arsenic oxide crystal form II (hereinafter sometimes also referred to as "crystal form II of the compound represented by formula (I)” , “PAO crystal form II” or “crystal form II”), characterized in that the XRPD pattern of the crystal form has diffraction peaks at the following 2 ⁇ angles: 8.48° ⁇ 0.2°, 9.44° ⁇ 0.2°, 14.63° ⁇ 0.2°, 15.83° ⁇ 0.2°, 17.28° ⁇ 0.2°, 24.90° ⁇ 0.2°, 25.18° ⁇ 0.2°, 25.89° ⁇ 0.2°, 26.20° ⁇ 0.2°, 31.40° ⁇ 0.2°, among which 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of benzene arsenic oxide crystal form II has diffraction peaks at the following 2 ⁇ angles: 8.48° ⁇ 0.2°, 9.44° ⁇ 0.2°, 12.38° ⁇ 0.2°, 13.00° ⁇ 0.2°, 14.63° ⁇ 0.2° , 15.83° ⁇ 0.2°, 17.28° ⁇ 0.2°, 19.90° ⁇ 0.2°, 20.36° ⁇ 0.2°, 24.90° ⁇ 0.2°, 25.18° ⁇ 0.2°, 25.89° ⁇ 0.2°, 26.20° ⁇ 0.2°, 31.40 ° ⁇ 0.2°, 32.84° ⁇ 0.2°, where the 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of the crystal form is basically as shown in FIG. 6 .
  • the crystal form II of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 7-9 in the accompanying drawings.
  • the invention provides a preparation method of benzene arsenic oxide crystal form II, comprising the following steps:
  • the solvent is selected from methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclic
  • the solvent is methanol, ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, cyclohexane, isopropyl ether or 1,4 -Dioxane.
  • the invention provides another preparation method of benzene arsenic oxide crystal form II, comprising the following steps:
  • phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended at room temperature;
  • the solvent is the group consisting of methyl ethyl ketone, ethanol, cyclohexane, isopropanol, ethyl acetate and any two or more mixtures thereof. More preferably, the solvent is methyl ethyl ketone-ethanol-cyclohexane-isopropanol.
  • the suspension time is 1 day, 2 days, 3 days, 5 days, 7 days, 10 days or 14 days.
  • the invention provides another preparation method of phenylarsenic oxide crystal form II, comprising the following steps:
  • the solvent is selected from methanol, ethanol, isopropanol, n-butanol, methyl ethyl ketone, cyclohexane, dichloromethane, acetone, ethyl acetate, 4-methyl - The group consisting of 2-pentanone, cyclohexane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, and mixtures of any two or more thereof.
  • the solvent is methanol, ethanol, isopropanol-n-butanol, methyl ethyl ketone-cyclohexane, dichloromethane, or n-butanol-methanol.
  • the heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C.
  • the low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.
  • the invention provides another preparation method of benzene arsenic oxide crystal form II, comprising the following steps:
  • the solvent is selected from ethanol, isopropanol, methyl ethyl ketone, isopropyl ether, acetonitrile, dichloromethane, methyl tert-butyl ether, 4-methyl-2- The group consisting of pentanone, n-heptane, 1,4-dioxane, acetone, isopropyl acetate, cyclohexane, dioxane, and mixtures of any two or more thereof.
  • the solvent is ethanol, isopropanol, methyl ethyl ketone-isopropyl ether, acetonitrile, dichloromethane-methyl tert-butyl ether, 4-methyl-2-pentanone-isopropyl ether, n-heptane - cyclohexane, methyl tert-butyl ether-isopropyl ether, or 1,4-dioxane.
  • the heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C.
  • the rate of controlled cooling is 5-10°C/h; the temperature is lowered to room temperature, close to 0°C or lower than 0°C.
  • the third aspect of the present invention provides a new crystal form of benzene arsenic oxide, more specifically, benzene arsenic oxide crystal form III (hereinafter sometimes also referred to as "crystal form III of the compound represented by formula (I)” , “PAO crystal form III” or “crystal form III”), characterized in that the XRPD pattern of the crystal form has diffraction peaks at the following 2 ⁇ angles: 8.39° ⁇ 0.2°, 9.50° ⁇ 0.2°, 16.04° ⁇ 0.2°, 16.56° ⁇ 0.2°, 18.06° ⁇ 0.2°, 19.11° ⁇ 0.2°, 19.44° ⁇ 0.2°, 23.85° ⁇ 0.2°, 25.25° ⁇ 0.2°, 25.70° ⁇ 0.2°, 31.74° ⁇ 0.2° , where the 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of benzene arsenic oxide crystal form II has diffraction peaks at the following 2 ⁇ angles: 8.39° ⁇ 0.2°, 9.50° ⁇ 0.2°, 12.55° ⁇ 0.2°, 13.85° ⁇ 0.2°, 14.55° ⁇ 0.2° , 15.14° ⁇ 0.2°, 16.04° ⁇ 0.2°, 16.56° ⁇ 0.2°, 18.06° ⁇ 0.2°, 19.11° ⁇ 0.2°, 19.44° ⁇ 0.2°, 20.68° ⁇ 0.2°, 22.06° ⁇ 0.2°, 23.85 ° ⁇ 0.2°, 25.25° ⁇ 0.2°, 25.70° ⁇ 0.2°, 29.23° ⁇ 0.2°, 32.10° ⁇ 0.2°, 33.15° ⁇ 0.2°, 33.69° ⁇ 0.2°, 34.51° ⁇ 0.2°, 36.75° ⁇ 0.2°, 39.00° ⁇ 0.2°, 31.74° ⁇ 0.2°, and the 2 ⁇ value error range is ⁇ 0.2° or ⁇ 0.15°.
  • the XRPD pattern of the crystal form is substantially as shown in FIG. 11 .
  • the crystal form III of benzene arsenic oxide according to the present invention has at least one of the following features: a DSC spectrum, a TGA spectrum and a dynamic moisture adsorption spectrum that are substantially the same as those of FIGS. 12-14 in the accompanying drawings.
  • the invention provides a preparation method of benzene arsenic oxide crystal form III, comprising the following steps:
  • the solvent is toluene.
  • the invention provides another preparation method of benzene arsenic oxide crystal form III, comprising the following steps:
  • phenylarsenic oxide is added to the solvent to obtain a suspension, which is stirred and suspended under heating;
  • the solvent is selected from the group consisting of toluene, acetone, ethyl acetate and a mixture of any two or more thereof. More preferably, the solvent is acetone or ethyl acetate.
  • the suspension time is at least 1 day.
  • the heating temperature is preferably 40 to 60°C, and more preferably 50°C.
  • the invention provides another preparation method of phenylarsenic oxide crystal form III, comprising the following steps:
  • the solvent is toluene.
  • the heating temperature does not exceed the boiling point of the solvent, preferably 40-70°C.
  • the low temperature environment temperature is not lower than the melting point of the solvent, preferably -30 to 0°C.
  • the phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention all have excellent stability, which is beneficial to its pharmaceutical processing and use in pharmaceutical compositions, and can provide qualitative and quantitative information, which is useful for further It is of great significance to study the efficacy of such solid drugs.
  • the fourth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention or a combination thereof, and pharmaceutically acceptable excipients, preferably Typically, the pharmaceutically acceptable adjuvants are pharmaceutically acceptable carriers, diluents and/or excipients.
  • the fifth aspect of the present invention provides the use of any one of the crystal form I, crystal form II and crystal form III of phenylarsenic oxide of the present invention or a combination thereof or the pharmaceutical composition of the present invention in preparing a medicine.
  • the medicament is for the treatment or prevention of Alzheimer's disease in a patient.
  • Fig. 1 is the XRPD spectrum of benzene arsenic oxide crystal form I provided by the present invention.
  • Fig. 2 is the DSC spectrum of the benzene arsenic oxide crystal form I provided by the present invention.
  • Fig. 3 is the TGA spectrum of benzene arsenic oxide crystal form I provided by the present invention.
  • Fig. 4 is the DVS spectrum of benzene arsenic oxide crystal form I provided by the present invention.
  • Fig. 5 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form I provided by the present invention, from bottom to top are the control and 2 weeks of light, high temperature, high humidity and accelerated conditions.
  • Fig. 6 is the XRPD spectrum of the benzene arsenic oxide crystal form II provided by the present invention.
  • Fig. 7 is the DSC spectrum of the benzene arsenic oxide crystal form II provided by the present invention.
  • Fig. 8 is the TGA spectrum of the benzene arsenic oxide crystal form II provided by the present invention.
  • Fig. 9 is the DVS spectrum of the benzene arsenic oxide crystal form II provided by the present invention.
  • FIG. 10 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form II provided by the present invention.
  • Fig. 11 is the XRPD pattern of the benzene arsenic oxide crystal form III provided by the present invention.
  • Fig. 12 is the DSC spectrum of the benzene arsenic oxide crystal form III provided by the present invention.
  • FIG. 13 is the TGA spectrum of the benzene arsenic oxide crystal form III provided by the present invention.
  • FIG. 14 is the DVS spectrum of the benzene arsenic oxide crystal form III provided by the present invention.
  • Fig. 15 is the XRPD overlapping pattern of the stability test of the benzene arsenic oxide crystal form III provided by the present invention, from bottom to top, the control and 2 weeks of light, high temperature, high humidity and accelerated conditions.
  • AD Alzheimer's disease
  • Most AD patients have extracellular ⁇ -amyloid plaques in the middle and late stages, and intracellular neurofibrillary tangles composed of Tau protein, or loss of synapses and nerve cells.
  • the disease can be present in both humans and non-human mammalian animals such as dogs.
  • treating means reversing, alleviating or inhibiting the progression of the disease to which the term applies, or one or more symptoms of the disease.
  • the term also includes prophylaxis of disease, including preventing the onset of the disease or any symptoms associated therewith, as well as reducing the severity of the disorder or any condition that precedes the onset, depending on the condition of the patient.
  • patient refers to an animal.
  • the animal is a mammal, for example also referring to primates such as humans (including adults and children, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish , birds, etc.
  • the patient is a primate. In other embodiments, the patient is a human.
  • a crystal form may be considered in the present invention to be characterized by graphical data "depicted" by a graph.
  • These data include, for example, powder X-ray diffraction patterns, Raman spectroscopy, Fourier transform-infrared spectroscopy, DSC curves and solid state NMR spectroscopy.
  • the skilled artisan will appreciate that small changes in the graphical representation of such data (eg peak relative intensities and peak positions) may occur due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to the skilled artisan. Nonetheless, the skilled artisan is able to compare the pattern data in the figures herein with pattern data generated for an unknown crystal form, and can confirm whether the two sets of pattern data characterize the same crystal form.
  • XRPD refers to X-ray powder diffraction.
  • DSC Differential Scanning Thermal Analysis.
  • amorphous or “amorphous form” is intended to mean that the substance, component or product in question lacks a characteristic crystalline shape or crystalline structure, is not substantially crystalline when determined, for example, by XRPD, or The substance, component or product in question, for example, is not birefringent when viewed using a polarized light microscope, or the X-ray powder diffraction pattern has no sharp peaks.
  • a sample comprising an amorphous form of a substance may be substantially free of other amorphous and/or crystalline forms.
  • polymorph As used herein, the terms “polymorph”, “polymorphs”, “crystal modification”, “crystal form”, “crystalline modification”, “Polymorphic form” and “crystalline form” are understood to be synonymous and in the present invention refer to solid crystalline forms of compounds or complexes, including, but not limited to, single-component or multi-component Fractional crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts.
  • Polymorphs can be detected, identified, classified and characterized using techniques well known to those skilled in the art such as, but not limited to: Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), X-ray Powder Diffraction method (XRPD), single crystal X-ray diffraction method, vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (SSNMR), Fourier transform-infrared spectroscopy (FT-IRspectrum) method, Raman spectroscopy (Ramanspectrum) method, thermal Stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility and dissolution rate.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • XRPD X-ray Powder Diffraction method
  • FT-IRspectrum Fourier transform-infrared spectroscopy
  • Raman spectroscopy Raman
  • a crystal form can be described as the ability of a particular compound to crystallize in different crystal modifications while maintaining the same chemical structural formula.
  • Polymorphs of a given substance are chemically equivalent, containing the same atoms bonded to each other in the same way, but in different crystalline forms that affect one or more physical properties, such as dissolution rate ), melting point, bulk density, stability, flow properties, etc.
  • the graphical representation of such data may vary slightly (eg, peak relative intensities and peak positions) due to factors such as changes in instrument response and changes in sample concentration and purity, which are well known to those skilled in the art. Nonetheless, one skilled in the art can compare the pattern data in the figures herein with pattern data generated for an unknown crystal form, and can confirm whether the two sets of pattern data characterize the same crystal form.
  • peak refers to a non-specific peak that can be recognized by one of ordinary skill in the art. Peaks or other special features caused by background noise.
  • X-ray powder diffraction As is well known in the field of X-ray powder diffraction (XRPD), for any given crystal form, the equipment used to obtain the X-ray powder diffraction (XRPD) pattern, humidity, temperature, orientation of powder crystals, and other parameters are all May cause some variability in the appearance, intensity and position of peaks in the diffractogram. See, for example, The United States Pharmacopeia #23, National Formulary #18, pp. 1843-1844, 1995. In the present case, the variability of ⁇ 0.2° 2 ⁇ peak positions takes into account these possible variations without preventing unambiguous identification of the crystal forms shown. Identification of a crystalline form can be based on any unique difference peak (in °2 ⁇ units) or a combination thereof, typically the more pronounced peaks.
  • crystalline compounds of the present invention are characterized by XRPD patterns having certain peak positions having substantially the same characteristics as the XRPD patterns provided in the accompanying figures of the present invention.
  • a crystalline form contains its tautomer, ie the crystalline form is at least 60% pure, or at least 70% pure, or at least 80% pure, or at least 85% pure relative to its tautomer , 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 means that one crystal form may contain another one or more crystal forms, that is, the purity of the crystal form relative to the other one or more crystal forms is at least 60%, or at least 70%, or 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 it means that the crystal form contains other
  • any number with a value of N any number with N ⁇ 0.01, N ⁇ 0.02, N ⁇ 0.03, N ⁇ 0.05, N ⁇ 0.07, N ⁇ 0.08, N ⁇ 0.1, N ⁇ 0.15, N ⁇ 0.2, N ⁇ 1, N ⁇ 1.5, N ⁇ 2, N ⁇ 3, N ⁇ 4, N ⁇ 5, N ⁇ 6, N ⁇ 7, N ⁇ 8, N ⁇ 9, N ⁇ 10, the number of values will be explicitly Disclosure, where " ⁇ " means plus or minus.
  • ⁇ means plus or minus.
  • compositions of the present invention further comprise pharmaceutically acceptable excipients, such as those used in the present invention, including any solvents, solid excipients, diluents, binders agents, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc. etc., suitable for the unique target dosage form.
  • pharmaceutically acceptable excipients such as those used in the present invention, including any solvents, solid excipients, diluents, binders agents, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc. etc., suitable for the unique target dosage form.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphate; glycine; sorbic acid; Potassium sorbate; partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; Vinylpyrrolidones; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxylate Sodium methylcellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients
  • the crystalline compound of the present invention will be applied to, but in no way limited to, using an effective amount of the crystalline compound or pharmaceutical composition of the present invention to be administered to a patient to prevent or treat Alzheimer's disease in a patient, or to alleviate Alzheimer's disease symptoms, or slow the progression or onset of Alzheimer's.
  • An "effective amount”, “therapeutically effective amount” or “effective dose” of a crystalline compound or pharmaceutically acceptable pharmaceutical composition of the present invention refers to an amount that treats or lessens the severity of one or more of the disorders referred to in the present invention. effective amount.
  • the crystalline compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a fairly wide range of dosages. Can be divided into one or several doses.
  • the methods, crystalline compounds and pharmaceutical compositions according to the present invention may be used in any amount and by any route of administration to be effective for treating or reducing the severity of a disease.
  • the exact amount necessary will vary from patient to patient depending on race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like.
  • the benzene arsenic oxide raw material used in all embodiments of the present invention is the applicant (inventor) self-synthesis (F.F.Blicke and F.D.Smith.The action of aromatic Grignard reagents on arylarsine oxides. Journal of the American Chemical Society 1929, Volume 51, Issue 11, 3479-3483.; Nicholas C. Lloyd, Hugh W. Morgan, Brian K. Nicholson, Ron S. Ronimus. Substituted phenylarsonic acids; structures and spectroscopy. Journal of Organometallic Chemistry 2008, Volume 693, Issue 14, 2443-2450 .)
  • the measurement of the X-ray powder diffraction (XRPD) pattern was carried out using a D8 ADVANCE powder X-ray diffractometer from BRUKER.
  • the light source was CuK
  • the X-ray intensity was 40kV/40mA
  • the scanning mode was Theta-theta
  • the scanning angle (2 ⁇ ) ranged from 4° to 40°
  • the step size was 0.05°
  • the scanning speed was 0.5 sec/step. Samples were processed by pressing glass slides directly on the test plate.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis was performed using a Q500 Thermogravimetric Analyzer from TA Instruments. The sample was placed in a platinum sample pan and heated from room temperature to 300°C at a heating rate of 10°C/min under nitrogen flow (50 mL/min). The weight of the solid sample as a function of temperature was recorded.
  • Dynamic Moisture Sorption was performed using the Advantage 1.0 Dynamic Moisture Sorption Meter from Surface Measurement Systems. The temperature was set at 25°C, after drying for 60 minutes under the condition of humidity 0%RH (Relative Humidity), the hygroscopic characteristics of the samples were tested when the humidity changed from 0%-95%RH, and the humidity was changed from 95%-0%RH Dehumidification characteristics of the sample when changing; the humidity change step size is 5% RH, when the value of the mass change rate dm/dt is less than 0.002%, it is regarded as the balance balance, and the mass change rate within 5 minutes is less than 0.01%/min as the detection process. equilibration standard, the longest equilibration time is 2 hours. The isothermal adsorption/desorption water characteristics under the test conditions were recorded.
  • a sample of arsenic oxide of benzene was weighed and placed in a container, a small amount of solvent was added successively, and ultrasonication was performed until the solid was basically completely dissolved, and then filtered into a centrifuge tube using a 0.45 ⁇ m nylon filter membrane. The centrifuge tube was placed open after shading, and the solvent was naturally volatilized at room temperature (20-25° C.), and the precipitated solid sample was characterized by XRPD.
  • a sample of arsenic oxide of benzene was weighed and placed in a container, a solvent was added, the container was heated in a 50° C. water bath and magnetically stirred, and the solid was completely dissolved and kept for 15 minutes.
  • the solution was filtered through a 0.45 ⁇ m nylon filter while still hot, and the filtrate was transferred to a centrifuge tube. Immediately store the centrifuge tubes in a -20°C freezer overnight. The precipitated solid was collected by centrifugation and characterized by XRPD.
  • a sample of arsenic oxide of benzene was weighed and placed in a container, a solvent was added, the container was heated in a 50° C. water bath and magnetically stirred, and the solid was completely dissolved and kept for 15 minutes.
  • the solution was filtered through a 0.45 ⁇ m nylon filter while still hot, and the filtrate was transferred to a centrifuge tube. Slowly cool down to room temperature (20-25°C) at a rate of 6°C/h, and store overnight. If there is no solid precipitation, the temperature is slowly lowered to 0-5°C at a rate of 6°C/h, and then transferred to a -20°C refrigerator for overnight storage.
  • the precipitated solid was collected by centrifugation and characterized by XRPD.
  • sample vials under humidity conditions were sealed with tin foil and placed with holes, while other samples were placed with caps and tightly capped.
  • PAO crystalline form I is a crystalline form without solvent or water, with birefringence phenomenon under polarized light microscope, and a flocculent or short rod-like crystal habit.
  • the initial melting point of this crystal form was measured by DSC to be 105.14°C.
  • the crystalline form loses 0.06% in weight from 26°C to 92°C, which may be a small amount of residual solvent or free water on the solid surface; from 92°C to 133°C, the weight loss is 0.21%, which may be a small amount of solvent or other easily contained in the powder pores. volatile components.
  • the DVS test results show that the crystalline form has only 0.29% hygroscopic weight gain from 0%-80% RH, and less than 1.0% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity.
  • the crystal form remained unchanged before and after DVS test by XRPD.
  • PAO crystal form I has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form.
  • PAO crystal form I is stable under the conditions of high temperature, high humidity, light and acceleration.
  • the error range of the 2 ⁇ value is ⁇ 0.2. After testing, the error range of the 2 ⁇ value can also be ⁇ 0.15.
  • the initial melting point of this crystal form was measured by DSC to be 105.14°C. According to TGA, the crystalline form loses 0.06% in weight from 26°C to 92°C, which may be a small amount of residual solvent or free water on the solid surface; from 92°C to 133°C, the weight loss is 0.21%, which may be a small amount of solvent or other easily contained in the powder pores. Volatile components; Form I is an anhydrous crystal form.
  • the DVS test results show that the crystalline form has only 0.29% hygroscopic weight gain from 0%-80% RH, and less than 1.0% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity. In addition, the crystal form remained unchanged before and after DVS test by XRPD.
  • Embodiment 7 Stability test of benzene arsenic oxide crystal form I
  • phenylarsenic oxide crystal form I prepared by the method described in Examples 1-4, and test the physical stability of PAO crystal form I placed for 2 weeks under four conditions of high temperature, high humidity, light, and acceleration according to the aforementioned stability test method. sex. After 2 weeks, by XRPD detection, PAO crystal form I was stable under high temperature, high humidity, light, and accelerated conditions, as shown in Figure 5.
  • PAO crystalline form II is a crystalline form without solvent or water, and has obvious birefringence phenomenon under polarized light microscope, showing granular or lamellar crystal habit.
  • the initial melting point of this crystal form was measured by DSC to be 152.0°C.
  • the weight loss of this crystal form from 28°C to 183°C measured by TGA was 0.2%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores.
  • DVS test results show that the crystalline form has only 0.13% hygroscopic weight gain from 0%-80% RH, and less than 0.3% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity.
  • the crystal form remained unchanged before and after DVS test by XRPD.
  • PAO crystal form II has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form. According to XRPD detection, PAO crystal form II is stable under the conditions of high temperature, high humidity, light and acceleration.
  • the initial melting point of this crystal form was measured by DSC to be 152.0°C.
  • the weight loss of this crystal form from 28°C to 183°C measured by TGA was 0.2%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores.
  • DVS test results show that the crystalline form has only 0.13% hygroscopic weight gain from 0%-80% RH, and less than 0.3% hygroscopic weight gain from 0%-95% RH, indicating that the crystalline form has no hygroscopicity.
  • the crystal form remained unchanged before and after DVS test by XRPD detection.
  • PAO crystal form III is a crystal form without solvent or water, and has obvious birefringence phenomenon under polarized light microscope, showing a rod-like crystal habit.
  • the initial melting point of this crystal form was measured by DSC to be 142.1°C.
  • the weight loss of this crystal form from 27°C to 170°C measured by TGA was 0.5%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores.
  • the DVS test results show that the crystalline form has only a hygroscopic weight gain of 0.29% from 0%-80% RH, and a hygroscopic weight gain of less than 0.8% from 0%-95% RH, indicating that the crystalline form has no hygroscopicity.
  • the crystal form remained unchanged before and after DVS test by XRPD test.
  • PAO crystal form III has good physical stability under four conditions of high temperature, high humidity, light, and acceleration for 2 weeks, and there is no significant change in appearance and crystal form. According to XRPD detection, PAO crystal form III is stable under the conditions of high temperature, high humidity, light and acceleration.
  • phenylarsenic oxide samples were respectively weighed, solvent was added according to Table 11, ultrasonicated for 5 minutes to disperse the samples evenly, wrapped in aluminum foil to block light, and then beaten in a 50°C water bath for 24 hours.
  • the Form III solid was collected by filtration or centrifugation, and the yield was calculated by weighing.
  • the initial melting point of this crystal form was measured by DSC to be 142.1°C.
  • the weight loss of this crystal form from 27°C to 170°C measured by TGA was 0.5%, which may be a small amount of residual solvent or free water on the solid surface, or a small amount of solvent or other volatile components trapped in the powder pores.
  • the DVS test results show that the crystalline form has only a hygroscopic weight gain of 0.29% from 0%-80% RH, and a hygroscopic weight gain of less than 0.8% from 0%-95% RH, indicating that the crystalline form has no hygroscopicity.
  • the crystal form remained unchanged before and after DVS test by XRPD test.
  • the crystal form I, crystal form II and crystal form III of benzene arsenic oxide can remain stable under high temperature, high humidity, light and accelerated conditions.
  • a stable crystal form has advantages in the production of pharmaceutical formulations. Since arsenic oxide crystal form I, crystal form II and crystal form III have excellent high temperature stability, high humidity stability and light stability, they can remain stable during the drug processing of various solid dosage forms, and it can be determined that the final obtained
  • the crystal form of the active ingredient in the drug can ensure the known bioavailability, and there will be no difference in efficacy due to crystal form transformation.
  • Table 14 the test results of the crystal forms of benzene arsenic oxide crystal form I, crystal form II and crystal form III are shown in Table 14. In addition, three different crystalline forms were dissolved in different types of vegetable oils and the solubility was compared.
  • the phenylarsenic oxide crystal form I, crystal form II and crystal form III of the present invention can be prepared into common solid dosage forms such as tablets, powders, granules, capsules and the like after being pulverized and combined with pharmaceutical excipients.
  • the arsenic oxide crystal form I, crystal form II and crystal form III of the present invention have certain inhibitory and/or therapeutic effects on Alzheimer's disease.
  • medium-chain triglycerides refers to fatty acids (including one or more of caproic acid, caprylic acid, capric acid and lauric acid) having a length of 6 to 12 carbon atoms species) of triglycerides.
  • Medium chain triglycerides have a low freezing point and are liquid at room temperature with low viscosity.
  • the medium chain triglycerides described herein are extracted from the dry hard part of the endosperm of coconut (eg, Cocos nucifera L.) or oil palm (eg, Elaeis guineenis Jacq).
  • Typical medium chain triglycerides refer to saturated caprylic triglycerides or saturated capric triglycerides or saturated caprylic-capric mixed triglycerides.
  • the medium chain triglycerides described herein meet generally recognized pharmacopeia (eg, US Pharmacopoeia, Chinese Pharmacopoeia, or European Pharmacopoeia) standards for medium chain triglycerides.
  • the medium chain triglycerides described herein are of the type 812N medium chain triglycerides.
  • the first group male 101 and female 102 were orally administered with PAO, the vehicle was MCT, and the dose was 0.3 mg/kg/day for 2 consecutive weeks. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after the last day of dosing, and the concentration of the compound in the blood (whole blood, not plasma) was measured.
  • the second group male 301 and female 302 were orally administered with PAO crystal form II, the same vehicle was MCT, and the dose was 0.3 mg/kg. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after administration, and the concentration of the compound in whole blood was also measured. After 5 days of drug withdrawal, PAO was orally administered, the same vehicle was MCT, and the dose was 0.6 mg/kg. Blood was collected at 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in the blood was measured.
  • animal ID 101 102 average value animal ID 301 302 average value Rsq_adj ND ND -- Rsq_adj ND 0.877 -- Points for T 1/2 0.00 0.00 0.00 Points for T 1/2 0.00 5.00 ND Cmax (ng/mL) 172 141 157 Cmax (ng/mL) 75.9 50.7 63.3 Tmax (h) 4.00 4.00 4.00 Tmax (h) 12.0 2.00 7.00 T 1/2 (h) ND ND ND T 1/2 (h) ND 38.6 ND T last (h) 48.0 48.0 48.0 T last (h) 48.0 48.0 48.0 AUC 0-last (ng ⁇ h/mL) 3760 4500 4130 AUC 0-last (ng ⁇ h/mL) 1880 1554 1717 AUC 0-inf (ng.h/mL) ND ND ND AUC 0-inf (ng.h/mL) ND 2823 ND MRT 0-last (h) 26.1 24.8 25.4 MRT 0-last (h
  • animal ID 301 302 average value Rsq_adj 0.883 0.897 -- Points for T 1/2 6.00 6.00 6.00 6.00 Cmax (ng/mL) 126 144 135 Tmax (h) 1.00 1.00 1.00 T 1/2 (h) 23.5 29.9 26.7 T last (h) 48.0 48.0 48.0 AUC 0-last (ng ⁇ h/mL) 2807 3796 3302 AUC 0-inf (ng.h/mL) 3925 6004 4964 MRT 0-last (h) 18.5 19.7 19.1 MRT 0-inf (h) 36.6 46.0 41.3
  • T 1/2 may not be estimated accurately.
  • T 1/2 may not be estimated accurately.
  • the fatty acids in MCT are mainly medium-chain saturated fatty acids, while the fatty acids in sesame oil are mainly long-chain unsaturated fatty acids.
  • the long-chain fatty acids are mainly absorbed through the lymphatic vessels in the intestine, while the medium-chain fatty acids are mainly absorbed through the intestine. mucosal cell uptake. Therefore, we examined the kinetics of an oral sesame oil formulation of PAO in monkeys and compared it with that of intravenous PAO.
  • the first group (C1001 and C1002) was administered PAO by iv injection, the vehicle was 1% DMSO, the actual dose was 0.118 mg/kg (nominal dose: 0.100 mg/kg), a single dose; the second group (C2001 and C2002) Oral administration of PAO, the vehicle is sesame oil, the actual dose is 0.168 mg/kg (nominal dose: 0.200 mg/kg), and it is also a single dose.
  • Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in blood (whole blood, not plasma) was measured.
  • T 1/2 may not be estimated accurately.
  • MRT 0-inf and Vd ss may not be estimated accurately if %AUMC Extra >20%.
  • T 1/2 may not be estimated accurately.
  • PAO can also be absorbed into the blood
  • PAO can also be absorbed into the blood
  • the blood concentration reaches the highest within 4 hours
  • the half-life of PAO in the blood is about 27.5 hours
  • Group 1 (D1001 and D1002), PAO administered by iv injection, vehicle is 1% DMSO, actual dose 0.101mg/kg (nominal dose: 0.100mg/kg) single dose; Group 2 (D2001 and D2002) Oral administration of PAO, the vehicle is sesame oil, the actual dose is 0.169 mg/kg (nominal dose: 0.200 mg/kg), and it is also a single dose. Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after administration, and the concentration of the compound in blood (whole blood, not plasma) was measured.
  • T 1/2 may not be estimated accurately.
  • MRT 0-inf and Vd ss may not be estimated accurately if %AUMC Extra >20%.
  • T 1/2 may not be estimated accurately.
  • mice were divided into two groups with 3 mice in each group.
  • One group was orally administered with PAO (M01, M02 and M03), the vehicle was a 1% DMSO aqueous solution, and the actual dose was 0.0913 mg/kg (nominal dose: 0.100 mg/kg). kg); another group was orally administered the MCT formulation of PAO (N01, N02 and N03), the actual dose was 0.107 mg/kg (nominal dose: 0.100 mg/kg).
  • Blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose and the concentration of the compound in blood (whole blood, not plasma) was measured.
  • T 1/2 may not be estimated accurately.
  • MRT 0-inf and Vd ss may not be estimated accurately if %AUMC Extra >20%.
  • T 1/2 may not be estimated accurately.
  • T 1/2 may not be estimated accurately.
  • MRT 0-inf and Vd ss may not be estimated accurately if %AUMC Extra >20%.
  • T 1/2 may not be estimated accurately.
  • mice As for male mice, every mouse that was orally administered with MCT preparation of PAO at 0.75 mg/kg/day survived, and the weight of each mouse increased slowly, but the weight changes of the other three groups of mice had no obvious regularity; One of the 5 mice that received 1.5 mg/kg/day orally administered PAO in MCT formulation died in the second week of administration; one of the 5 mice that received 0.75 mg/kg/day orally administered PAO in 0.1% DMSO aqueous solution died. At the second week of administration, two of the five mice that received PAO orally in 0.1% DMSO in water at 1.5 mg/kg/day died at the second and sixth week of administration, respectively.

Abstract

La présente invention concerne une forme cristalline I, une forme cristalline II et une forme cristalline III d'un composé représenté par la formule (I). La forme cristalline I, la forme cristalline II et la forme cristalline III de l'oxyde de phénylarsine selon la présente invention a une bonne stabilité à haute température, une stabilité à l'humidité élevée et une grande stabilité sous éclairage, qui sont bénéfiques à l'utilisation de la forme cristalline I, de la forme cristalline II et de la forme cristalline III dans le traitement pharmaceutique et les compositions pharmaceutiques.
PCT/CN2021/143612 2020-12-31 2021-12-31 Forme cristalline i, forme cristalline ii et forme cristalline iii de l'oxyde de phénylarsine et procédé de préparation associé WO2022143976A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016173562A1 (fr) * 2015-04-30 2016-11-03 江苏挪贝肽医药科技有限公司 Application de la protéine pi4kiiiα et du complexe de protéines membranaires associées dans le traitement de la maladie d'alzheimer
CN109966281A (zh) * 2019-04-11 2019-07-05 北京大学 PAO作为Pi4KIIα抑制剂在制备治疗创伤后应激障碍药物中的应用
WO2021004422A1 (fr) * 2019-07-05 2021-01-14 挪贝肽医药科技(上海)有限公司 COMPOSITION D'INHIBITEUR DE PI4KIIIα MICROMOLÉCULAIRE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

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WO2016173562A1 (fr) * 2015-04-30 2016-11-03 江苏挪贝肽医药科技有限公司 Application de la protéine pi4kiiiα et du complexe de protéines membranaires associées dans le traitement de la maladie d'alzheimer
CN109966281A (zh) * 2019-04-11 2019-07-05 北京大学 PAO作为Pi4KIIα抑制剂在制备治疗创伤后应激障碍药物中的应用
WO2021004422A1 (fr) * 2019-07-05 2021-01-14 挪贝肽医药科技(上海)有限公司 COMPOSITION D'INHIBITEUR DE PI4KIIIα MICROMOLÉCULAIRE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

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