WO2023093812A1 - Forme cristalline de composé de triazolone et son utilisation - Google Patents

Forme cristalline de composé de triazolone et son utilisation Download PDF

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Publication number
WO2023093812A1
WO2023093812A1 PCT/CN2022/134142 CN2022134142W WO2023093812A1 WO 2023093812 A1 WO2023093812 A1 WO 2023093812A1 CN 2022134142 W CN2022134142 W CN 2022134142W WO 2023093812 A1 WO2023093812 A1 WO 2023093812A1
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crystal form
compound
formula
present
ray powder
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PCT/CN2022/134142
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Chinese (zh)
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陈正霞
孙继奎
张杨
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南京明德新药研发有限公司
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Publication of WO2023093812A1 publication Critical patent/WO2023093812A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings

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  • the present invention relates to the crystal form of triazolone compounds and applications thereof, in particular to the crystal form of the compound of formula (I), the crystal form of the compound of formula (I), the compound of formula (II) and its crystal form, the compound of formula (III) Compound and crystal form thereof, compound of formula (IV) and crystal form thereof.
  • DHODH Dihydroorotate dehydrogenase
  • DHODH has been confirmed as a therapeutic target for various diseases, such as cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc.
  • diseases such as cancer, viral infection, autoimmune diseases (rheumatoid arthritis and multiple sclerosis), etc.
  • the virus needs a large amount of nucleosides in the host cell to complete replication, so blocking the host's DHODH pyrimidine synthesis pathway can effectively inhibit virus replication.
  • the demand for pyrimidine nucleotides is far greater than that of normal cells, and it will rely on de novo synthesis. Blocking DHODH can effectively prevent tumor cell proliferation.
  • Studies have shown that DHODH is highly expressed in a variety of tumors and is positively correlated with the poor prognosis of clinical tumor patients. Inhibiting the expression of DHODH can inhibit tumor proliferation.
  • Inhibiting DHODH activity can effectively inhibit the proliferation of activated lymphocytes and the secretion of cytokines. Activated lymphocytes also require a large amount of nucleic acid for proliferation and metabolism, and are more sensitive to the inhibition of DHODH activity. DHODH inhibitors such as leflunomide and teriflunomide are also effective drugs for the treatment of autoimmune diseases, such as rheumatoid arthritis, intestinal inflammation and other diseases.
  • DHODH has not only become a potential target for anti-tumor therapy, but also an effective target for broad-spectrum anti-viral infection and treatment of autoimmune diseases.
  • the development and research of specific inhibitors for it is of great significance.
  • the present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 21.535 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 4, 5, 6, 7 or 8 characteristic diffraction peaks selected from the following: 5.741 ⁇ 0.20° , 11.431 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20 °, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A contains at least 6, 7, 8, 9, 10 or 11 characteristic diffraction peaks selected from the following: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.2 0°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.967 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 28.055 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.856 ⁇ 0.20°, 17.386 ⁇ 0.20°, 16.717 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 28.055 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.532 ⁇ 0.20°, 15.856 ⁇ 0.20°, 16.717 ⁇ 0.20°, 17.152 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.785 ⁇ 0.20°, 17.967 ⁇ 0.20°, 18.344 ⁇ 0.20°, 18.538 ⁇ 0.20 °, 18.845 ⁇ 0.20°, 19.114 ⁇ 0.20°, 20.728 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.580 ⁇ 0.20°, 22.916 ⁇ 0.20°, 24.311 ⁇ 0.20°, 25.175 ⁇ 0.20°, 25.529 ⁇ 0.20 °, 28.055 ⁇ 0.20°, 32.907 ⁇ 0.20°, 33.735 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741°, 11.431°, 12.681°, 13.366°, 14.953°, 15.532°, 15.856°, 16.717 °, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 20.728°, 20.923°, 21.535°, 22.580°, 22.916°, 24.311°, 25.175° , 25.529°, 28.055°, 32.907°, 33.735°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, 8.685 ⁇ 0.20°, 9.257 ⁇ 0.20°, 11.431 ⁇ 0.20°, 12.681 ⁇ 0.20°, 13.366 ⁇ 0.20°, 13.956 ⁇ 0.20°, 14.953 ⁇ 0.20°, 15.532 ⁇ 0.20°, 15.856 ⁇ 0.20°, 16.717 ⁇ 0.20°, 17.152 ⁇ 0.20°, 17.386 ⁇ 0.20°, 17.785 ⁇ 0.20 °, 17.967 ⁇ 0.20°, 18.344 ⁇ 0.20°, 18.538 ⁇ 0.20°, 18.845 ⁇ 0.20°, 19.114 ⁇ 0.20°, 19.615 ⁇ 0.20°, 20.728 ⁇ 0.20°, 20.923 ⁇ 0.20°, 21.535 ⁇ 0.20°, 22.580 ⁇ 0.20 °, 22.916 ⁇ 0.20°, 23.721 ⁇ 0.20°, 24.311 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741°, 8.685°, 9.257°, 11.431°, 12.681°, 13.366°, 13.956°, 14.953 °, 15.532°, 15.856°, 16.717°, 17.152°, 17.386°, 17.785°, 17.967°, 18.344°, 18.538°, 18.845°, 19.114°, 19.615°, 20.728°, 20.923°, 21.535° , 22.580°, 22.916°, 23.721°, 24.311°, 25.175°, 25.529°, 26.282°, 26.496°, 26.806°, 26.983°, 27.191°, 27.625°, 28.055°, 28.682°, 29.338°, 29.862°, 3 0.168°, 30.567° , 30.821
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, and/or 11.431 ⁇ 0.20°, and/or 12.681 ⁇ 0.20°, and /or 13.366 ⁇ 0.20°, and/or 14.953 ⁇ 0.20°, and/or 15.532 ⁇ 0.20°, and/or 15.856 ⁇ 0.20°, and/or 16.717 ⁇ 0.20°, and/or 17.152 ⁇ 0.20°, and/or 17.386 ⁇ 0.20°, and/or 17.785 ⁇ 0.20°, and/or 17.967 ⁇ 0.20°, and/or 18.344 ⁇ 0.20°, and/or 18.538 ⁇ 0.20°, and/or 18.845 ⁇ 0.20°, and/or 19.114 ⁇ 0.20°, and/or 20.728 ⁇ 0.20°, and/or 20.923 ⁇ 0.20°, and/or 21.535 ⁇ 0.20°, and/or 22.580 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.741 ⁇ 0.20°, and/or 11.431 ⁇ 0.20°, and/or 8.685 ⁇ 0.20°, and /or 9.257 ⁇ 0.20°, and/or 12.681 ⁇ 0.20°, and/or 13.366 ⁇ 0.20°, and/or 13.956 ⁇ 0.20°, and/or 14.953 ⁇ 0.20°, and/or 15.532 ⁇ 0.20°, and/or 15.856 ⁇ 0.20°, and/or 16.717 ⁇ 0.20°, and/or 17.152 ⁇ 0.20°, and/or 17.386 ⁇ 0.20°, and/or 17.785 ⁇ 0.20°, and/or 17.967 ⁇ 0.20°, and/or 18.344 ⁇ 0.20°, and/or 18.538 ⁇ 0.20°, and/or 18.845 ⁇ 0.20°, and/or 19.114 ⁇ 0.20°, and/or 19.615 ⁇ 0.20°
  • the XRPD pattern of the crystal form A of the compound of formula (I) is shown in FIG. 1 .
  • thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 0.66% at 130°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 2 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C ⁇ 3°C.
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 152.4°C ⁇ 5°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°;
  • the present invention also provides crystal form B of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 19.654 ⁇ 0.20°, 25.131 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B contains at least 4, 5, 6 or 7 characteristic diffraction peaks selected from the following: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B contains at least 4, 5, 6, 7, 8 or 9 characteristic diffraction peaks selected from the following: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form, represented by 2 ⁇ angle at least includes 6, 7, 8, 9, 10, 11, 12, 13, 14 selected from the following , 15 or 16 feature diffraction peaks: 9.954 ⁇ 0.20 °, 14.658 ⁇ 0.20 °, 16.079 ⁇ 0.20 °, 16.727 ⁇ 0.20 °, 17.496 ⁇ 0.20 °, 19.189 ⁇ 0.20 °, 19.654 ⁇ 0.20 °, 20.722 ⁇ 0 0 .20 °, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20°, 26.729 ⁇ 0.20°, 31.415 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, 14.658 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 17.496 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20°, 20.722 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 25.131 ⁇ 0.20°, 26.024 ⁇ 0.20 °, 26.729 ⁇ 0.20°, 31.415 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022 ⁇ 0.20°, 9.954 ⁇ 0.20°, 11.191 ⁇ 0.20°, 12.474 ⁇ 0.20°, 14.658 ⁇ 0.20°, 15.040 ⁇ 0.20°, 15.335 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 16.996 ⁇ 0.20°, 17.266 ⁇ 0.20°, 17.496 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20 °, 19.928 ⁇ 0.20°, 20.415 ⁇ 0.20°, 20.722 ⁇ 0.20°, 20.962 ⁇ 0.20°, 21.151 ⁇ 0.20°, 22.376 ⁇ 0.20°, 22.923 ⁇ 0.20°, 24.212 ⁇ 0.20°, 24.757 ⁇ 0.20°, 25.131 ⁇ 0.20 °, 26.196 ⁇ 0.20°, 26.024 ⁇ 0.20°, 26.729 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022°, 9.954°, 11.191°, 12.474°, 14.658°, 15.040°, 15.335°, 16.079 °, 16.727°, 16.996°, 17.266°, 17.496°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722°, 20.962°, 21.151°, 22.376°, 22.923°, 24.212°, 24.757° , 25.131°, 26.196°, 26.024°, 26.729°, 26.977°, 29.549°, 29.970°, 30.456°, 30.694°, 31.415°, 32.010°, 32.396°, 35.702°.
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.213 ⁇ 0.20°, 6.458 ⁇ 0.20°, 8.022 ⁇ 0.20°, 9.954 ⁇ 0.20°, 11.191 ⁇ 0.20°, 12.474 ⁇ 0.20°, 12.852 ⁇ 0.20°, 13.180 ⁇ 0.20°, 14.658 ⁇ 0.20°, 15.040 ⁇ 0.20°, 15.335 ⁇ 0.20°, 16.079 ⁇ 0.20°, 16.727 ⁇ 0.20°, 16.996 ⁇ 0.20 °, 17.266 ⁇ 0.20°, 17.496 ⁇ 0.20°, 18.389 ⁇ 0.20°, 18.693 ⁇ 0.20°, 19.189 ⁇ 0.20°, 19.654 ⁇ 0.20°, 19.928 ⁇ 0.20°, 20.415 ⁇ 0.20°, 20.722 ⁇ 0.20°, 20.962 ⁇ 0.20 °, 21.151 ⁇ 0.20°, 21.710 ⁇ 0.20°, 21.928 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 6.213°, 6.458°, 8.022°, 9.954°, 11.191°, 12.474°, 12.852°, 13.180 °, 14.658°, 15.040°, 15.335°, 16.079°, 16.727°, 16.996°, 17.266°, 17.496°, 18.389°, 18.693°, 19.189°, 19.654°, 19.928°, 20.415°, 20.722° , 20.962°, 21.151°, 21.710°, 21.928°, 22.376°, 22.923°, 24.212°, 24.757°, 25.131°, 25.447°, 26.024°, 26.196°, 26.729°, 26.977°, 27.649°, 28.899°, 2 9.549°, 29.970° , 30.456°
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 8.022 ⁇ 0.20°, and/or 9.954 ⁇ 0.20°, and/or 11.191 ⁇ 0.20°, and /or 12.474 ⁇ 0.20°, and/or 14.658 ⁇ 0.20°, and/or 15.040 ⁇ 0.20°, and/or 15.335 ⁇ 0.20°, and/or 16.079 ⁇ 0.20°, and/or 16.727 ⁇ 0.20°, and/or 16.996 ⁇ 0.20°, and/or 17.266 ⁇ 0.20°, and/or 17.496 ⁇ 0.20°, and/or 19.189 ⁇ 0.20°, and/or 19.654 ⁇ 0.20°, and/or 19.928 ⁇ 0.20°, and/or 20.415 ⁇ 0.20°, and/or 20.722 ⁇ 0.20°, and/or 20.962 ⁇ 0.20°, and/or 21.151 ⁇ 0.20°, and/or 22.376 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 9.954 ⁇ 0.20°, and/or 19.654 ⁇ 0.20°, and/or 6.213 ⁇ 0.20°, and /or 6.458 ⁇ 0.20°, and/or 8.022 ⁇ 0.20°, and/or 11.191 ⁇ 0.20°, and/or 12.474 ⁇ 0.20°, and/or 12.852 ⁇ 0.20°, and/or 13.180 ⁇ 0.20°, and/or 14.658 ⁇ 0.20°, and/or 15.040 ⁇ 0.20°, and/or 15.335 ⁇ 0.20°, and/or 16.079 ⁇ 0.20°, and/or 16.727 ⁇ 0.20°, and/or 16.996 ⁇ 0.20°, and/or 17.266 ⁇ 0.20°, and/or 17.496 ⁇ 0.20°, and/or 18.389 ⁇ 0.20°, and/or 18.693 ⁇ 0.20°, and/or 19.189 ⁇ 0.20°
  • the XRPD spectrum of the crystal form B of the compound of formula (I) is shown in FIG. 4 .
  • thermogravimetric analysis curve of the above crystal form B reaches a weight loss of 1.06% at 130.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in FIG. 5 .
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an onset value of an endothermic peak at 143.8°C ⁇ 3°C.
  • the differential scanning calorimetry curve of the above-mentioned crystal form B has an endothermic peak at 143.8°C ⁇ 5°C.
  • the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 6 .
  • the present invention provides a compound of formula (II),
  • the invention also provides crystal form C of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 16.434 ⁇ 0.20°, 24.235 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 21.270 ⁇ 0.20°, 24.235 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 21.270 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.051 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 18.979 ⁇ 0.20°, 21.270 ⁇ 0.20°, 23.636 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 25.851 ⁇ 0.20°, 27.099 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.117 ⁇ 0.20°, 13.051 ⁇ 0.20°, 13.942 ⁇ 0.20°, 14.871 ⁇ 0.20°, 16.434 ⁇ 0.20°, 17.670 ⁇ 0.20°, 18.979 ⁇ 0.20°, 21.270 ⁇ 0.20°, 23.636 ⁇ 0.20°, 24.235 ⁇ 0.20°, 24.992 ⁇ 0.20°, 25.851 ⁇ 0.20°, 27.099 ⁇ 0.20°, 28.565 ⁇ 0.20 °, 30.135 ⁇ 0.20°, 31.174 ⁇ 0.20°.
  • the XRPD spectrum of the crystal form C of the compound of formula (II) is shown in FIG. 7 .
  • the present invention also provides a compound of formula (III),
  • the invention also provides crystal form D of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.549 ⁇ 0.20°, 16.867 ⁇ 0.20°, 22.037 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 8.549 ⁇ 0.20°, 16.867 ⁇ 0.20°, 17.461 ⁇ 0.20°, 18.061 ⁇ 0.20°, 20.239 ⁇ 0.20°, 22.037 ⁇ 0.20°.
  • the XRPD pattern of the crystal form D of the compound of formula (III) is shown in FIG. 8 .
  • the invention also provides crystal form E of the compound of formula (III), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 16.970 ⁇ 0.20°, 25.361 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 15.667 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 17.994 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°, 30.468 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 8.528 ⁇ 0.20°, 14.332 ⁇ 0.20°, 15.667 ⁇ 0.20°, 16.099 ⁇ 0.20°, 16.970 ⁇ 0.20°, 17.583 ⁇ 0.20°, 17.994 ⁇ 0.20°, 19.124 ⁇ 0.20°, 20.892 ⁇ 0.20°, 22.187 ⁇ 0.20°, 24.189 ⁇ 0.20°, 25.361 ⁇ 0.20°, 26.348 ⁇ 0.20°, 30.468 ⁇ 0.20 °.
  • the XRPD pattern of the crystal form E of the compound of formula (III) is shown in FIG. 9 .
  • the present invention provides a compound of formula (IV),
  • the present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 16.652 ⁇ 0.20°;
  • the present invention also provides the crystal form F of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.883 ⁇ 0.20°, 16.652 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 8.365 ⁇ 0.20°, 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 12.701 ⁇ 0.20°, 16.652 ⁇ 0.20°, 17.735 ⁇ 0.20°, 18.278 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 8.365 ⁇ 0.20°, 8.883 ⁇ 0.20°, 11.157 ⁇ 0.20°, 12.701 ⁇ 0.20°, 16.652 ⁇ 0.20°, 17.735 ⁇ 0.20°, 18.278 ⁇ 0.20°, 21.347 ⁇ 0.20°, 22.359 ⁇ 0.20°, 25.352 ⁇ 0.20°.
  • the XRPD pattern of the crystal form F of the compound of formula (IV) is shown in FIG. 10 .
  • the present invention also provides crystal form G of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 12.879 ⁇ 0.20°, 23.105 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 23.105 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 14.337 ⁇ 0.20°, 16.833 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 20.635 ⁇ 0.20°, 23.105 ⁇ 0.20°, 25.950 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 7.043 ⁇ 0.20°, 8.978 ⁇ 0.20°, 11.517 ⁇ 0.20°, 12.879 ⁇ 0.20°, 14.337 ⁇ 0.20°, 16.058 ⁇ 0.20°, 16.833 ⁇ 0.20°, 17.318 ⁇ 0.20°, 18.995 ⁇ 0.20°, 19.849 ⁇ 0.20°, 20.635 ⁇ 0.20°, 23.105 ⁇ 0.20°, 25.950 ⁇ 0.20°, 26.131 ⁇ 0.20 °.
  • the XRPD pattern of the crystal form G of the compound of formula (IV) above is shown in FIG. 11 .
  • the present invention also provides the crystal form H of the compound of formula (IV), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 23.443 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 18.330 ⁇ 0.20°, 21.690 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 18.330 ⁇ 0.20°, 18.981 ⁇ 0.20°, 21.690 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form H has characteristic diffraction peaks at the following 2 ⁇ angles: 7.303 ⁇ 0.20°, 9.362 ⁇ 0.20°, 14.560 ⁇ 0.20°, 15.502 ⁇ 0.20°, 17.858 ⁇ 0.20°, 18.330 ⁇ 0.20°, 18.981 ⁇ 0.20°, 19.721 ⁇ 0.20°, 21.690 ⁇ 0.20°, 22.373 ⁇ 0.20°, 23.443 ⁇ 0.20°, 24.600 ⁇ 0.20°, 25.793 ⁇ 0.20°.
  • the XRPD pattern of the crystal form H of the compound of formula (IV) is shown in FIG. 12 .
  • the present invention also provides the compound of formula (II), compound of formula (II), compound of formula (IV), crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, and crystal form G .
  • the above enteritis includes ulcerative enteritis and Crohn's disease.
  • the crystal form of the present invention has the characteristics of good stability and excellent PK properties, and has excellent therapeutic effect on enteritis.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • X-ray powder diffraction can detect information such as changes in crystal forms, crystallinity, and crystal structure state, and is a common method for identifying crystal forms.
  • the peak positions of an XRPD pattern mainly depend on the structure of the crystalline form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • 2-MeTHF 2-methyl Tetrahydrofuran
  • Dioxane represents dioxane
  • ACN represents acetonitrile
  • Toluene represents toluene
  • Acetone represents acetone
  • EtOAc represents ethyl acetate
  • THF represents tetrahydrofuran
  • H 2 O represents water
  • TosOH represents p-toluenesulfonic acid
  • Pd(dppf)Cl 2 Represents 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride.
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 30kV
  • phototube current 10mA
  • Anti-scatter slit 2.50mm
  • Step size 0.5 seconds
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under N2 conditions, heat the sample from 25°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min.
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under N2 conditions, heat the sample from room temperature to 350°C at a heating rate of 10°C/min or lose 20% of its weight.
  • Figure 1 is the Cu-K ⁇ radiation XRPD spectrum of (I) compound crystal form A.
  • Fig. 2 is the TGA spectrogram of (I) compound crystal form A.
  • Fig. 3 is the DSC spectrogram of (I) compound crystal form A.
  • Fig. 4 is the Cu-K ⁇ radiation XRPD spectrum of (I) compound crystal form B.
  • Fig. 5 is the TGA spectrogram of (I) compound crystal form B.
  • Fig. 6 is the DSC spectrogram of (I) compound crystal form B.
  • Fig. 7 is the Cu-K ⁇ radiation XRPD spectrum of (II) compound crystal form C.
  • Fig. 8 is the Cu-K ⁇ radiation XRPD spectrum of the crystal form D of compound (III).
  • Fig. 9 is the Cu-K ⁇ radiation XRPD spectrum of (III) compound crystal form E.
  • Fig. 10 is the Cu-K ⁇ radiation XRPD spectrum of (IV) compound crystal form F.
  • Fig. 11 is the Cu-K ⁇ radiation XRPD spectrum of (IV) compound crystal form G.
  • Fig. 12 is the Cu-K ⁇ radiation XRPD spectrum of Form H of compound (IV).
  • Figure 13 is the amorphous spectrum of compound (I).
  • Figure 14 is a graph of body weight changes.
  • Fig. 15 is a graph showing the evaluation results of DAI (Daily Illness Index).
  • Figure 16 is a graph of colon density at the end point of the experiment.
  • Embodiment 1 Preparation of formula (I) compound crystal form A
  • step 1
  • Acetonitrile (900mL), 2,4,5-trifluorobenzonitrile (50.39g, 320.78mmol, 1eq), compound 5 (90g, 320.78mmol, 1eq) were added to the reaction flask, and stirring was started; then anhydrous potassium phosphate (136.18g, 641.56mmol, 2eq) was added thereto, the temperature was raised to 70°C, and the reaction was carried out for 15 hours.
  • N-methylpyrrolidone (472mL), potassium tert-butylate (21.87g, 194.94mmol, 1.3eq) into the reaction flask and start stirring; , 1,1-trifluoropropan-2-ol (18.81g, 164.95mmol, 1.1eq) was added to it, raised to room temperature 10-15°C, reacted for 0.5 hours, and then lowered the temperature to 0-5°C, then Compound 6 (59g, 149.95mmol, 92.6% purity, 1eq) was dissolved in N-methylpyrrolidone (236mL), added dropwise thereto, and reacted for 1 hour.
  • the reaction solution was concentrated under reduced pressure at 45°C, and then extracted by adding 500 mL of methyl tert-butyl ether; adding hydrochloric acid (1M) to the obtained aqueous phase to adjust the pH value to 5-6 After that, add methyl tert-butyl ether for extraction (700mL/time x 3 times); the obtained organic phase was washed with saturated brine (1L/time x 1 time), dried by adding anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure at °C to obtain a crude product.
  • 1,4-dioxane (580mL), compound 8 (29g, 57.71mmol), bisanalyl borate (48.36g, 190.44mmol) were added to the reaction flask, and stirring was started; then triethylamine (438.58mmol, 61.05mL,), palladium acetate (2.59g, 11.54mmol, 0.2eq), pivalic anhydride (26.87g, 144.27mmol,), 1,4-bis(diphenylphosphine)butane (4.92g , 11.54mmol) was added therein, under the protection of nitrogen, the reaction was carried out at 100°C for 12 hours.
  • Embodiment 2 the preparation of formula (I) compound amorphous
  • Embodiment 3 Preparation of formula (I) compound crystal form B
  • the crystal form B of the compound of formula (I) was obtained.
  • the amorphous compound (50 mg) of formula (I) was dissolved in ethyl acetate (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
  • the amorphous compound (50 mg) of formula (I) was dissolved in ethanol (0.3 mL), and stirred at 20-25°C for 12 hours. The reaction solution was directly filtered, and the obtained solid was concentrated under reduced pressure at 45°C. The crystal form B of the compound of formula (I) was obtained.
  • the compound of formula (I) was amorphous (50mg), methanol (0.9mL), water (0.3mL), stirred at 50°C for 14hr, and then the system was filtered to collect the filter cake, which was decompressed at 45°C with an oil pump Concentration gives the compound of formula (I) in Form B.
  • Embodiment 4 Preparation of formula (II) compound crystal form C
  • Embodiment 5 the preparation of formula (III) compound crystal form D
  • Embodiment 6 the preparation of formula (III) compound crystal form E
  • Embodiment 7 Preparation of formula (IV) compound crystal form F
  • Embodiment 8 Preparation of formula (IV) compound crystal form G
  • Embodiment 9 Preparation of formula (IV) compound crystal form H
  • Embodiment 10 the solid stability test of formula (I) compound crystal form A
  • Embodiment 11 solid stability test of formula (I) compound crystal form B
  • Embodiment 1 enzymatic experiment
  • the DHODH inhibitory activity of the compounds was detected by the following experimental methods.
  • DHODH uses flavin mononucleotide (FMN) to catalyze the oxidation of dihydroorotic acid DHO to orotic acid, and the re-oxidation of FMN requires the participation of coenzyme CoQ.
  • FMN flavin mononucleotide
  • Resazurin dye replaces CoQ as the enzyme activity
  • Resazurin solution is blue, and the resorufin produced after reduction has red fluorescence, and its fluorescence signal can be detected under the conditions of excitation wavelength 535nm and emission wavelength 590nm.
  • the reaction buffer components used in the experiment were 100mM Hepes pH 7.0, 150mM NaCl, 0.3% CHAPS, 0.5mg/ml BSA, 0.1 ⁇ M FMN, 1% DMSO.
  • the final concentration of the DHODH enzyme in the reaction system was 5 nM
  • the final concentration of the substrate L-DHO was 15 ⁇ M
  • the final concentration of the indicator Resazurin was 80 ⁇ M.
  • the components of the reaction termination buffer were 100mM Hepes pH7.0 and 5mM Orotate.
  • the compound of the present invention has excellent DHODH enzyme inhibitory activity.
  • the compound of the present invention has excellent metabolic stability (Cl) in vivo, IV and PO all show longer half-life (T 1/2 ); formula (I) crystal form A and crystal form B all have excellent oral absorption Drug exposure (AUC), and high oral bioavailability (>60%).
  • mice were anesthetized with 0.25 mL of anesthetic (1.25% Avertin, Easycheck, M2910).
  • the mice in the vehicle group and the compound dosage administration group were perfused with 150 ⁇ L of 1.5% TNBS solution (final concentration 50% ethanol) in the rectum.
  • the mice in the negative group were perfused with an equal volume of 50% ethanol in their rectums.
  • the first group is the negative group, the animals are given vehicle, the second group is the vehicle group (i.e. the modeling group), the animals are given the vehicle, the 3rd, 4th and 5th groups are the compound dosage administration groups, the animals are given different Dosage of crystal form A of formula (I), the solvent is 5% DMSO/10% Solutol solution/0.2% Tween80/84.8% aqueous solution, once a day.
  • the recording frequency was once a day (QD), days -1-7.
  • DAI Disease Activity Index
  • the recording frequency is once a day, on days -1-7, and is graded into 4 levels according to the following criteria:
  • Bloody stool (0, negative; 1, weakly positive for occult blood; 2, positive for occult blood; 3, obvious blood in stool; 4, massive blood in stool);
  • Colon tissue was divided longitudinally into two parts, and one part was fixed in the form of "Swiss" roll immersed in 10% neutral paraformaldehyde.
  • the other part was quick-frozen in liquid nitrogen first, and then stored in a -80°C refrigerator for the detection and analysis to be selected.
  • the experimental data should be expressed as mean ⁇ standard error (mean ⁇ S.E.M.).
  • the data were analyzed by ANOVA statistical method using GraphPad Prism. Compared with the vehicle group, *p ⁇ 0.05**p ⁇ 0.01***p ⁇ 0.005****p ⁇ 0.0001, P ⁇ 0.05 was considered statistically different.
  • DAI Daily Illness Index
  • the crystalline form A of the compound of formula (I) exhibited significant anti-inflammatory effects. It can significantly slow down the weight loss of mice with enteritis, improve the disease score (DAI) associated with diarrhea and blood in the stool, and can improve the increase in colon density caused by inflammation, which is consistent with the results of the DAI score.
  • DAI disease score

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Abstract

L'invention concerne une forme cristalline d'un composé de triazolone et son utilisation. L'invention concerne spécifiquement une forme cristalline d'un composé de formule (I), un composé de formule (II) et une forme cristalline de celui-ci, un composé de formule (III) et une forme cristalline de celui-ci, et un composé de formule (IV) et une forme cristalline de celui-ci.
PCT/CN2022/134142 2021-11-26 2022-11-24 Forme cristalline de composé de triazolone et son utilisation WO2023093812A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110023302A (zh) * 2016-10-27 2019-07-16 拜耳股份有限公司 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮
CN110248937A (zh) * 2016-10-27 2019-09-17 拜耳股份有限公司 4,5-环状1,2,4-三唑酮
WO2021238881A1 (fr) * 2020-05-29 2021-12-02 南京明德新药研发有限公司 Composé de triazolone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110023302A (zh) * 2016-10-27 2019-07-16 拜耳股份有限公司 用作dhodh抑制剂的2,4,5-三取代的1,2,4-三唑酮
CN110248937A (zh) * 2016-10-27 2019-09-17 拜耳股份有限公司 4,5-环状1,2,4-三唑酮
WO2021238881A1 (fr) * 2020-05-29 2021-12-02 南京明德新药研发有限公司 Composé de triazolone

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