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WO2024027723A1 - Forme cristalline, type de sel et composition d'un composé pyridazine et procédé de préparation correspondant - Google Patents

Forme cristalline, type de sel et composition d'un composé pyridazine et procédé de préparation correspondant Download PDF

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Publication number
WO2024027723A1
WO2024027723A1 PCT/CN2023/110617 CN2023110617W WO2024027723A1 WO 2024027723 A1 WO2024027723 A1 WO 2024027723A1 CN 2023110617 W CN2023110617 W CN 2023110617W WO 2024027723 A1 WO2024027723 A1 WO 2024027723A1
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Prior art keywords
compound
formula
crystal form
preparation
angles
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English (en)
Chinese (zh)
Inventor
贺海鹰
赵乐乐
孙建军
吴艾米丽媛媛
曹兰
童海骏
赵亚男
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to CN202380056182.1A priority Critical patent/CN119677731A/zh
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a crystal form, salt form, composition and preparation method of a pyridazine compound, specifically disclosing the A crystal form, salt form and composition of the compound of formula (I), and the B form of the compound of formula (II). Preparation methods and applications of crystal forms and Form C of the compound of formula (III).
  • the NLRP3 inflammasome is a multi-protein complex that plays an important role in the development of innate immunity and inflammation-related diseases.
  • the NLRP3 inflammasome consists of NOD-like receptors (NLRs), apoptosis-associated speck-like protein containing a CARD (ASC), and caspase 1 (Caspase-1) composition.
  • NLRs NOD-like receptors
  • ASC apoptosis-associated speck-like protein containing a CARD
  • Caspase-1 caspase 1
  • Exogenous pathogens or endogenous risk factors such as mitochondrial reactive oxygen species, oxidized mitochondrial DNA, ⁇ -amyloid or ⁇ -synuclein can activate NLRP3.
  • Activated NLRP3, ASC and Caspase-1 form the activated NLRP3 inflammasome, which further hydrolyzes IL-1 ⁇ precursor (pro-IL-1 ⁇ ) and IL-18 precursor (pro-IL-18) through Caspase-1. It releases active cytokines IL-1 ⁇ and IL-18. The secretion of these cytokines can lead to pyroptosis or neuronal damage.
  • NLRP3 inflammasome plays an important role in the development of various autoimmune diseases, cardiovascular diseases, neurodegenerative diseases and tumors (Nature Reviews Drug Discovery, 2018, 17(8):588-606.).
  • NLRP3 inhibitors There are currently no drug molecules for NLRP3 inhibitors on the market.
  • the preclinical compound MCC950 has a significant inhibitory effect on NLRP3 (Sci. Transl. Med. 10, eaah4066 (2016)).
  • Drugs such as OLT-1177, Inzomelid, Selnoflast and IFM-2427 are in the clinical research stage.
  • the development of NLRP3 inhibitors has broad application prospects.
  • the present invention also provides the A crystal form of the compound of formula (I), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 16.53 ⁇ 0.20° and 18.12 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 13.48 ⁇ 0.20°, 16.53 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20° and 24.06 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20°, 16.53 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20°, 24.06 ⁇ 0.20° and 25.55 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20°, 14.72 ⁇ 0.20°, 15.92 ⁇ 0.20°, 16.53 ⁇ 0.20°, 16.89 ⁇ 0.20°, 18.12 ⁇ 0.20°, 21.44 ⁇ 0.20°, 24.06 ⁇ 0.20°, 25.55 ⁇ 0.20° and 27.12 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 12.72 ⁇ 0.10°, 13.48 ⁇ 0.10°, 14.72 ⁇ 0.10°, 15.92 ⁇ 0.10°, 16.53 ⁇ 0.10°, 16.89 ⁇ 0.10°, 18.12 ⁇ 0.10°, 21.44 ⁇ 0.10°, 24.06 ⁇ 0.10°, 25.55 ⁇ 0.10° and 27.12 ⁇ 0.10°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 12.16 ⁇ 0.20°, 12.72 ⁇ 0.20°, 13.48 ⁇ 0.20° ⁇ 14.72 ⁇ 0.20° ⁇ 15.92 ⁇ 0.20° ⁇ 16.53 ⁇ 0.20° ⁇ 16.89 ⁇ 0.20° ⁇ 17.37 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 21.44 ⁇ 0.20° ⁇ 24.06 ⁇ 0.20° ⁇ 24.84 ⁇ 0.20° ⁇ 25.55 ⁇ 0.20°, 27.12 ⁇ 0.20° and 29.03 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 12.16 ⁇ 0.10°, 12.72 ⁇ 0.10°, 13.48 ⁇ 0.10° ⁇ 14.72 ⁇ 0.10° ⁇ 15.92 ⁇ 0.10° ⁇ 16.53 ⁇ 0.10° ⁇ 16.89 ⁇ 0.10° ⁇ 17.37 ⁇ 0.10° ⁇ 18.12 ⁇ 0.10° ⁇ 21.44 ⁇ 0.10° ⁇ 24.06 ⁇ 0.10° ⁇ 24.84 ⁇ 0.10° ⁇ 25.55 ⁇ 0.10°, 27.12 ⁇ 0.10° and 29.03 ⁇ 0.10°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.20°, 8.41 ⁇ 0.20°, 11.58 ⁇ 0.20°, 12.16 ⁇ 0.20°, 12.72 ⁇ 0.20° ⁇ 13.07 ⁇ 0.20° ⁇ 13.48 ⁇ 0.20° ⁇ 14.72 ⁇ 0.20° ⁇ 15.92 ⁇ 0.20° ⁇ 16.53 ⁇ 0.20° ⁇ 16.89 ⁇ 0.20° ⁇ 17.37 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 18.43 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 21.24 ⁇ 0.20° ⁇ 21.44 ⁇ 0.20° ⁇ 22.41 ⁇ 0.20° ⁇ 23.02 ⁇ 0.20° ⁇ 23.23 ⁇ 0.20° ⁇ 23.52 ⁇ 0.20° ⁇ 24.06 ⁇ 0.20° ⁇ 24.84 ⁇ 0.20° ⁇ 25.34 ⁇ 0.20° ⁇ 25.55 ⁇ 0.20° ⁇ 26.08 ⁇ 0.20° ⁇ 26.49 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80 ⁇ 0.10°, 8.41 ⁇ 0.10°, 11.58 ⁇ 0.10°, 12.16 ⁇ 0.10°, 12.72 ⁇ 0.10° ⁇ 13.07 ⁇ 0.10° ⁇ 13.48 ⁇ 0.10° ⁇ 14.72 ⁇ 0.10° ⁇ 15.92 ⁇ 0.10° ⁇ 16.53 ⁇ 0.10° ⁇ 16.89 ⁇ 0.10° ⁇ 17.37 ⁇ 0.10° ⁇ 18.12 ⁇ 0.10° ⁇ 18.43 ⁇ 0.10° ⁇ 19.11 ⁇ 0.10° ⁇ 21.24 ⁇ 0.10° ⁇ 21.44 ⁇ 0.10° ⁇ 22.41 ⁇ 0.10° ⁇ 23.02 ⁇ 0.10° ⁇ 23.23 ⁇ 0.10° ⁇ 23.52 ⁇ 0.10° ⁇ 24.06 ⁇ 0.10° ⁇ 24.84 ⁇ 0.10° ⁇ 25.34 ⁇ 0.10° ⁇ 25.55 ⁇ 0.10° ⁇ 26.08 ⁇ 0.10° ⁇ 26.49 ⁇ 0.10°
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.80, 8.41, 11.58, 12.16, 12.72, 13.07, 13.48, 14.72, 15.92, 16.53, 16.89, 17.37, 18.12, 18.43, 19.11, 21.24, 21.44, 22.41, 23.02, 23.23, 23.52, 24.06, 24.84, 25.34, 25.55, 26.08, 26.49, 26.89, 27.12, 27.92, 28.62, 29. 03, 29.75, 30.10, 31.21, 32.10, 32.89, 33.26, 34.45, 35.64, 36.06, 37.24, 38.84.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.20°, 16.53 ⁇ 0.20°, and/or 18.12 ⁇ 0.20°, and/or 5.80 ⁇ 0.20°, and/or 11.58 ⁇ 0.20°, and/or 12.16 ⁇ 0.20°, and/or 12.72 ⁇ 0.20°, and/or 13.07 ⁇ 0.20°, and/or 13.48 ⁇ 0.20°, and/or 14.72 ⁇ 0.20 °, and/or 15.92 ⁇ 0.20°, and/or 16.89 ⁇ 0.20°, and/or 17.37 ⁇ 0.20°, and/or 18.43 ⁇ 0.20°, and/or 19.11 ⁇ 0.20°, and/or 21.24 ⁇ 0.20°, and/or 21.44 ⁇ 0.20°, and/or 22.41 ⁇ 0.20°, and/or 23.02 ⁇ 0.20°, and/or 23.23 ⁇ 0.20°, and/or 23.52 ⁇ 0.20
  • the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 8.41 ⁇ 0.10°, 16.53 ⁇ 0.10°, and/or 18.12 ⁇ 0.10°, and/or 5.80 ⁇ 0.10°, and/or 11.58 ⁇ 0.10°, and/or 12.16 ⁇ 0.10°, and/or 12.72 ⁇ 0.10°, and/or 13.07 ⁇ 0.10°, and/or 13.48 ⁇ 0.10°, and/or 14.72 ⁇ 0.10 °, and/or 15.92 ⁇ 0.10°, and/or 16.89 ⁇ 0.10°, and/or 17.37 ⁇ 0.10°, and/or 18.43 ⁇ 0.10°, and/or 19.11 ⁇ 0.10°, and/or 21.24 ⁇ 0.10°, and/or 21.44 ⁇ 0.10°, and/or 22.41 ⁇ 0.10°, and/or 23.02 ⁇ 0.10°, and/or 23.23 ⁇ 0.10°, and/or 23.52 ⁇ 0.10
  • the XRPD pattern of the above-mentioned crystal form A is basically as shown in Figure 1.
  • the differential scanning calorimetry curve of the above-mentioned crystal form A has an endothermic peak starting point at 164.0 ⁇ 5°C.
  • the DSC pattern of the above-mentioned crystal form A is shown in Figure 2.
  • thermogravimetric analysis curve of the above-mentioned crystal form A reaches a weight loss of 1.25% at 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned crystal form A is shown in Figure 3.
  • the present invention also provides compounds of formula (II), whose structural formula is as follows:
  • the present invention also provides the B crystal form of the compound of formula (II), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 14.59 ⁇ 0.20°, 19.11 ⁇ 0.20° and 21.75 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20°, 15.31 ⁇ 0.20°, 19.11 ⁇ 0.20°, 21.75 ⁇ 0.20°, 24.94 ⁇ 0.20° and 25.73 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.62 ⁇ 0.20°, 19.11 ⁇ 0.20°, 21.75 ⁇ 0.20°, 22.23 ⁇ 0.20°, 24.94 ⁇ 0.20°, 25.73 ⁇ 0.20°, 26.22 ⁇ 0.20°, 27.88 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 7.66 ⁇ 0.20°, 8.11 ⁇ 0.20°, 13.89 ⁇ 0.20°, 14.59 ⁇ 0.20° ⁇ 15.31 ⁇ 0.20° ⁇ 16.62 ⁇ 0.20° ⁇ 17.65 ⁇ 0.20° ⁇ 18.35 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 21.75 ⁇ 0.20° ⁇ 22.23 ⁇ 0.20° ⁇ 24.94 ⁇ 0.20° ⁇ 25.73 ⁇ 0.20° ⁇ 26.22 ⁇ 0.20°, 27.88 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 7.66 ⁇ 0.20°, 8.11 ⁇ 0.20°, 11.34 ⁇ 0.20°, 12.21 ⁇ 0.20° ⁇ 13.89 ⁇ 0.20° ⁇ 14.59 ⁇ 0.20° ⁇ 14.84 ⁇ 0.20° ⁇ 15.31 ⁇ 0.20° ⁇ 16.20 ⁇ 0.20° ⁇ 16.62 ⁇ 0.20° ⁇ 17.44 ⁇ 0.20° ⁇ 17.65 ⁇ 0.20° ⁇ 18.35 ⁇ 0.20° ⁇ 19.11 ⁇ 0.20° ⁇ 19.84 ⁇ 0.20° ⁇ 20.43 ⁇ 0.20° ⁇ 21.75 ⁇ 0.20° ⁇ 22.23 ⁇ 0.20° ⁇ 22.46 ⁇ 0.20° ⁇ 23.50 ⁇ 0.20° ⁇ 24.36 ⁇ 0.20° ⁇ 24.94 ⁇ 0.20° ⁇ 25.73 ⁇ 0.20° ⁇ 26.22 ⁇ 0.20° ⁇ 27.43 ⁇ 0.20° ⁇ 27.88 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.10°, 7.66 ⁇ 0.10°, 8.11 ⁇ 0.10°, 11.34 ⁇ 0.10°, 12.21 ⁇ 0.10° ⁇ 13.89 ⁇ 0.10° ⁇ 14.59 ⁇ 0.10° ⁇ 14.84 ⁇ 0.10° ⁇ 15.31 ⁇ 0.10° ⁇ 16.20 ⁇ 0.10° ⁇ 16.62 ⁇ 0.10° ⁇ 17.44 ⁇ 0.10° ⁇ 17.65 ⁇ 0.10° ⁇ 18.35 ⁇ 0.10° ⁇ 19.11 ⁇ 0.10° ⁇ 19.84 ⁇ 0.10° ⁇ 20.43 ⁇ 0.10° ⁇ 21.75 ⁇ 0.10° ⁇ 22.23 ⁇ 0.10° ⁇ 22.46 ⁇ 0.10° ⁇ 23.50 ⁇ 0.10° ⁇ 24.36 ⁇ 0.10° ⁇ 24.94 ⁇ 0.10° ⁇ 25.73 ⁇ 0.10° ⁇ 26.22 ⁇ 0.10°, 27.43 ⁇ 0.10°, 27.88 ⁇ 0.10°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22, 7.66, 8.11, 11.34, 12.21, 13.89, 14.59, 14.84, 15.31, 16.20, 16.62, 17.44, 17.65, 18.35, 19.11, 19.84, 20.43, 21.75, 22.23, 22.46, 23.50, 24.36, 24.94, 25.73, 26.22, 27.43, 27.88, 28.72, 29.14, 30.11, 30.64, 32. 04, 32.87, 33.46, 35.89, 38.78 and 39.28.
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.20°, 8.11 ⁇ 0.20°, and/or 7.66 ⁇ 0.20°, and/or 11.34 ⁇ 0.20°, and/or 12.21 ⁇ 0.20°, and/or 13.89 ⁇ 0.20°, and/or 14.59 ⁇ 0.20°, and/or 14.84 ⁇ 0.20°, and/or 15.31 ⁇ 0.20°, and/or 16.20 ⁇ 0.20 °, and/or 16.62 ⁇ 0.20°, and/or 17.44 ⁇ 0.20°, and/or 17.65 ⁇ 0.20°, and/or 18.35 ⁇ 0.20°, and/or 19.11 ⁇ 0.20°, and/or 19.84 ⁇ 0.20°, and/or 20.43 ⁇ 0.20°, and/or 21.75 ⁇ 0.20°, and/or 22.23 ⁇ 0.20°, and/or 22.46 ⁇ 0.20°, and/or 23.50 ⁇ 0.20°
  • the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.22 ⁇ 0.10°, 8.11 ⁇ 0.10°, and/or 7.66 ⁇ 0.10°, and/or 11.34 ⁇ 0.10°, and/or 12.21 ⁇ 0.10°, and/or 13.89 ⁇ 0.10°, and/or 14.59 ⁇ 0.10°, and/or 14.84 ⁇ 0.10°, and/or 15.31 ⁇ 0.10°, and/or 16.20 ⁇ 0.10 °, and/or 16.62 ⁇ 0.10°, and/or 17.44 ⁇ 0.10°, and/or 17.65 ⁇ 0.10°, and/or 18.35 ⁇ 0.10°, and/or 19.11 ⁇ 0.10°, and/or 19.84 ⁇ 0.10°, and/or 20.43 ⁇ 0.10°, and/or 21.75 ⁇ 0.10°, and/or 22.23 ⁇ 0.10°, and/or 22.46 ⁇ 0.10°, and/or 23.50 ⁇ 0.10°
  • the XRPD pattern of the above-mentioned crystal form B is basically as shown in Figure 4.
  • the XRPD spectrum analysis data of the above-mentioned Form B is shown in Table 2.
  • the differential scanning calorimetry curve of the above-mentioned B crystal form has an endothermic peak at 153.7 ⁇ 3°C.
  • the DSC pattern of the above-mentioned B crystal form is shown in Figure 5.
  • thermogravimetric analysis curve of the above-mentioned B crystal form has a weight loss of 2.88% at 150.0 ⁇ 3°C.
  • the TGA spectrum of the above-mentioned B crystal form is shown in Figure 6.
  • the present invention also provides a compound of formula (III), whose structural formula is as follows:
  • the present invention also provides the C crystal form of the compound of formula (III), whose X-ray powder diffraction pattern (XRPD) has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20° and 20.59 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20°, 16.25 ⁇ 0.20°, 18.12 ⁇ 0.20°, 20.59 ⁇ 0.20°, 21.63 ⁇ 0.20° and 26.50 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20°, 16.25 ⁇ 0.20°, 18.12 ⁇ 0.20°, 20.59 ⁇ 0.20°, 21.63 ⁇ 0.20°, 24.11 ⁇ 0.20°, 26.50 ⁇ 0.20°, 27.75 ⁇ 0.20° and 28.15 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 9.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 15.22 ⁇ 0.20°, 15.80 ⁇ 0.20° ⁇ 16.25 ⁇ 0.20° ⁇ 18.12 ⁇ 0.20° ⁇ 20.59 ⁇ 0.20° ⁇ 21.63 ⁇ 0.20° ⁇ 24.11 ⁇ 0.20° ⁇ 24.91 ⁇ 0.20° ⁇ 25.87 ⁇ 0.20° ⁇ 26.50 ⁇ 0.20° ⁇ 27.75 ⁇ 0.20° ⁇ 28.15 ⁇ 0.20°, 30.73 ⁇ 0.20° and 31.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46, 9.30, 13.19, 15.22, 15.80, 16.25, 18.12, 20.59, 21.63, 24.11, 24.91, 25.87, 26.50, 27.75, 28.15, 30.73 and 31.74.
  • the X-ray powder diffraction pattern of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.46 ⁇ 0.20°, 15.22 ⁇ 0.20°, and/or 9.30 ⁇ 0.20°, and/or 13.19 ⁇ 0.20°, and/or 15.80 ⁇ 0.20°, and/or 16.25 ⁇ 0.20°, and/or 18.12 ⁇ 0.20°, and/or 20.59 ⁇ 0.20°, and/or 21.63 ⁇ 0.20°, and/or 24.11 ⁇ 0.20 °, and/or 24.91 ⁇ 0.20°, and/or 25.87 ⁇ 0.20°, and/or 26.50 ⁇ 0.20°, and/or 27.75 ⁇ 0.20°, and/or 28.15 ⁇ 0.20°, and/or 30.73 ⁇ 0.20°, and/or 31.74 ⁇ 0.20°.
  • the XRPD pattern of the above-mentioned crystal form C is basically as shown in Figure 7.
  • the differential scanning calorimetry curve of the above-mentioned crystal form C has endothermic peaks at 105.1 ⁇ 3°C and 216.0 ⁇ 3°C.
  • the DSC pattern of the above-mentioned C crystal form is shown in Figure 8.
  • the weight loss of the above-mentioned C crystal form in the thermogravimetric analysis curve reaches 8.22% at 150.0 ⁇ 3°C.
  • the present invention also provides a pharmaceutical composition, which contains a therapeutically effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient and pharmaceutically acceptable excipients;
  • the dosage form of the above-mentioned pharmaceutical composition is selected from capsules, granules, injections, pills, syrups, powders, ointments, emulsions, solutions, suspensions or tinctures, and other variables are as defined in the present invention.
  • the above-mentioned auxiliary materials are selected from excipients, fillers, binders, humectants, disintegrants, slow solvents, absorption accelerators, adsorbents, diluents, solubilizers, emulsifiers, lubricants, Wetting agents, glidants, suspending agents, flavoring agents, perfumes or mixtures thereof, other variables are as defined in the present invention.
  • the present invention also provides a preparation method of the compound of formula (I), which is prepared as follows:
  • R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
  • R 1 is selected from Boc, Cbz, Bn and PMB
  • the preparation method of the compound of formula (I) is selected from:
  • the preparation method of the compound of formula (II-3) is selected from:
  • Method one includes:
  • Method two includes:
  • Method three includes:
  • R 1 is selected from H, CH 3 , Boc, Cbz, Bn and PMB;
  • R 2 is selected from Bn, PMB, PNB and MOM
  • R 4 is selected from CH 3 , MOM, Bn, SEM and Ac;
  • R 5 is selected from F, Cl, Br, I, OTf and OCH 2 CF 3 ;
  • R 31 is selected from B(OH) 2 ;, and BF 3K ;
  • R 6 is selected from F, Cl, Br and I.
  • R 7 is selected from Cl, Br, OTf, OCH 2 CF 3 and OTs.
  • the present invention also provides a method for preparing the compound of formula (I),
  • Step 1 React compound EE-3 to obtain compound EE-4,
  • Step 2 react compound EE-4 to obtain compound EE-5,
  • Step 3 React compound EE-5 and compound AA to obtain compound H-1,
  • Step 4 react compound H-1 to obtain the compound of formula (I),
  • the preparation method of the compound of formula (I) above includes the following steps: Step 1: react compound EE-3 with reagents A and B to obtain compound EE-4,
  • Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
  • Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
  • Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, with DMF being preferred.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 2 React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
  • Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
  • Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
  • Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
  • Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, with dioxane being preferred.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 3 React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
  • Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
  • Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 .
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 4 React compound H-1 and reagent K to obtain the compound of formula (I),
  • Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
  • the preparation method of the compound of formula (I) above includes the following steps:
  • Step 1 React compound EE-3 with reagents A and B to obtain compound EE-4,
  • Step 2 React compound EE-4 with reagents D, E, F, and G to obtain compound EE-5,
  • Step 3 React compound EE-5 and compound AA with reagents I and J to obtain compound H-1,
  • Step 4 React compound H-1 and reagent K to obtain the compound of formula (I),
  • Reagent A is selected from the group consisting of methyl chloride, methyl bromide, methyl iodide and methoxymethyl methanesulfonate, with methyl chloride being preferred;
  • Reagent B is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, sodium hydrogen, lithium hexamethyldisilazide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, potassium tert-butoxide , sodium tert-butoxide, sodium hydroxide, lithium hydroxide and potassium hydroxide, preferably potassium carbonate;
  • Solvent C is selected from DMF, DCM, THF, 2-MeTHF, EtOAc, i-PrOAc, NMP and dioxane, preferably DMF;
  • Reagent D is selected from the group consisting of zonacol borane and zonacol borane, preferably zonacol borane;
  • Reagent E is selected from Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , bis(acetonitrile)palladium(II) dichloride, Pd(OAc) 2 and Pd 2 (dba) 3 , preferably Pd (OAc) 2 ;
  • Reagent F is selected from Sphos, Xphos, XantPhos and 2-(dicyclohexylphosphonium)biphenyl, preferably 2-(dicyclohexylphosphonium)biphenyl;
  • Reagent G is selected from potassium acetate, sodium acetate, TEA, DIPEA and potassium 2-ethylhexanoate, with TEA being preferred;
  • Solvent H is selected from dioxane, DMSO, DMF, NMP, DCM, THF, 2-MeTHF and water, preferably dioxane;
  • Reagent I is selected from Pd(OAc) 2 -BINAP, Pd 2 (dba) 3 -Xphos, Brettphos-Pd-G3, Pd(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 CH 2 Cl 2 and Pd(OAc) 2 -Sphos, preferably Pd(dppf)Cl 2 CH 2 Cl 2 ;
  • Reagent J is selected from Cs 2 CO 3 , K 2 CO 3 , Na 2 CO 3 , K 3 PO 4 , KOAc, KF and TEA, preferably K 2 CO 3 ;
  • Reagent K is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, formic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, preferably hydrochloric acid.
  • the invention also provides a method for preparing the intermediate compound of formula (AA):
  • R 51 is selected from F, Cl, Br and I;
  • R 11 is selected from CH 3 , Boc, Cbz, Bn and PMB.
  • the invention also provides a method for preparing the intermediate compound of formula (AA):
  • the preparation method of the compound of formula (I) above is selected from:
  • Method one includes:
  • Method two includes:
  • Method three includes:
  • Method four includes:
  • Method five includes:
  • Method six includes:
  • Method seven includes:
  • Method eight includes:
  • Method nine includes:
  • Method ten includes:
  • Method 11 includes:
  • Method twelve includes:
  • Method thirteen includes:
  • Method fourteen includes:
  • the present invention also provides the above-mentioned compound A crystal form of the formula (I), the above-mentioned compound formula (II), the above-mentioned compound B crystal form of the formula (II), the above-mentioned pharmaceutical composition and the above-mentioned preparation method for the preparation and treatment of NLRP3 inflammation.
  • the above-mentioned NLRP3 inflammasome-related diseases are selected from NLRP3 inflammasome-related neuroinflammatory diseases (such as brain inflammation, brain injury) and neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease). Alzheimer's disease, multiple sclerosis).
  • NLRP3 inflammasome-related neuroinflammatory diseases such as brain inflammation, brain injury
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease. Alzheimer's disease, multiple sclerosis.
  • the above-mentioned NLRP3 inflammasome-related diseases are selected from the group consisting of NLRP3 inflammasome-related neuroinflammatory diseases and neurodegenerative diseases.
  • the above-mentioned NLRP3 inflammasome-related neuroinflammatory disease is selected from brain inflammation and brain injury.
  • the above-mentioned neurodegenerative disease is selected from Parkinson's disease, Alzheimer's disease and multiple sclerosis.
  • the above-mentioned neurodegenerative disease is selected from Parkinson's disease and Alzheimer's disease.
  • the A crystal form of the compound of formula (I) and the B crystal form of the compound of formula (II) of the present invention are easy to obtain, and have relatively high physical and chemical stability. Well, it has high industrial application value and economic value.
  • the process for synthesizing the compound of formula (I) and its intermediates provided by the present invention has the following beneficial effects: the raw materials are cheap and easy to obtain, and overcome the shortcomings of difficulty in separation and purification and difficulty in industrialization.
  • the NLRP3 inhibitor provided by the invention can effectively inhibit the activity of NLRP3 inflammasome and the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ , and has good pharmacokinetic properties and can be used for NLRP3 inflammation.
  • composition means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically acceptable carriers.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • compound of formula (I) or a pharmaceutically acceptable salt thereof described in this application can be a "pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof", and further, it can be “a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof”.
  • compound may also be “a pharmaceutical composition containing a compound of formula (III)”.
  • administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need may be “administering a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need”, and further , may be “administering a pharmaceutical composition containing a compound of formula (II) to an individual in need” or may be “administering a pharmaceutical composition containing a compound of formula (III) to an individual in need”.
  • terapéuticaally effective dose means an amount of a compound sufficient to effect treatment of a disease when administered to a human for the treatment of the disease.
  • solvate refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent bound by non-covalent intermolecular forces.
  • the solvent is water, it is a hydrate.
  • treatment includes inhibiting, slowing, stopping or reversing existing symptoms or the progression or severity of a disease.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • compositions of the present application can be prepared by combining the compounds of the present application with appropriate pharmaceutically acceptable excipients.
  • they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, dragees, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • the intermediate compounds 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, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well 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.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • Boc represents tert-butoxycarbonyl
  • Cbz represents benzyloxycarbonyl
  • Bn represents benzyl
  • PMB p-methoxybenzyl
  • DCM represents dichloromethane
  • DMF represents N, N-bis Methylformamide
  • THF represents tetrahydrofuran
  • DMSO dimethyl sulfoxide
  • EtOH represents ethanol
  • MeOH represents methanol
  • ACN (MeCN) represents acetonitrile
  • EtOAc represents ethyl acetate
  • H 2 O represents water
  • i-PrOH represents isopropyl alcohol
  • Acetone represents acetone
  • IPAc represents isopropyl acetate
  • 2-MeTHF represents 2-methyltetrahydrofuran
  • 1,4-Dioxane represents 1,4-dioxane
  • CHCl 3 represents chloroform
  • Toluene represents toluene
  • test parameters of the X-ray powder diffraction (X-ray powder diffractometer, XRPD) method of the present invention are shown in Table 4.
  • test parameters of the differential scanning calorimeter (DSC) method of the present invention are shown in Table 5.
  • thermogravimetric analyzer (TGA) method of the present invention are shown in Table 6.
  • test parameters of the dynamic vapor adsorption analysis (Dynamic Vapor Sorption, DVS) method of the present invention are shown in Table 7.
  • FIG. 14 Single crystal X-ray diffraction (SC-XRD) three-dimensional structure ellipsoid diagram of the compound of formula (I).
  • the hydrochloride of compound AA-5 (85.0g, 283.69mmol) was dissolved in anhydrous methanol (850mL), and 37% formaldehyde aqueous solution (69.06g, 851mmol) was added to the reaction solution.
  • the reaction solution was heated at 20 The reaction was stirred at 20°C for 0.5 hours.
  • Sodium acetate borohydride (123.97g, 567mmol) was added in batches to the reaction solution at 20°C, and the reaction solution was stirred at 20°C for 11.5 hours.
  • the filtrate was concentrated under reduced pressure to remove dioxane and 2-methyltetrahydrofuran.
  • the remaining aqueous phase was adjusted to pH 4 with hydrochloric acid aqueous solution (1mol/L), extracted with 2-methyltetrahydrofuran (1000mL ⁇ 2), and the aqueous phase was adjusted to pH 10 with sodium hydroxide aqueous solution (1mol/L), and 2- Extract with methyltetrahydrofuran (1000mL ⁇ 1,700mL ⁇ 2), combine the organic phases, concentrate, dissolve the organic phase with 1400ml of dimethyltetrahydrofuran, add modified silica gel (LI-511, 50g) for palladium removal, and stir at 45°C for 6 hours, filter, continue adding modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 12 hours, filter, add modified silica gel (LI-511, 50g) for palladium removal to the filtrate, stir at 50°C for 6 hours
  • the amorphous form of the compound of formula (I) was analyzed by high performance liquid chromatography (chromatographic column: Phenomenex C18 150 ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: [water (hydrochloric acid)-acetonitrile]; B%: 1%-30%, 10 minutes ) to prepare the amorphous form of the compound of formula (III).
  • Acetone 0.5 mL was added to the amorphous form (50.2 mg) of the compound of formula (III), and the resulting suspension was stirred at room temperature for 3 days to obtain the C crystal form of the compound of formula (III).
  • the XRPD, DSC, TGA, and DVS detection results are shown in Figures 7, 8, 9, and 12 in sequence.
  • Example 7 Solid pre-stability test of crystal form A of compound of formula (I) and crystal form of compound B of formula (II)
  • Hygroscopicity evaluation classification table Note: ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • the DVS spectrum of the crystal form A of compound of formula (I) is shown in Figure 10.
  • the DVS results show that the sample absorbs moisture and gains weight by 0.1665% under the conditions of 25°C/80% RH, and the sample has no or almost no hygroscopicity. After completing the DVS test (0-95-0% RH), take out the sample and expose it to the air for XRPD testing. The results show that the crystal form has not changed before and after the DVS test.
  • the DVS spectrum of the crystalline form B of compound (II) is shown in Figure 11.
  • the DVS results showed that the sample gained 7.15% moisture and weight under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH, and the sample was hygroscopic.
  • the DVS spectrum of the crystalline form C of compound (III) is shown in Figure 12.
  • the DVS results show that the sample has a hygroscopic weight gain of 21.09% under the condition of 25°C/80%RH compared with the condition of 25°C/0%RH.
  • the sample is extremely hygroscopic.
  • the crystal form of compound A of formula (I) has no or almost no hygroscopicity at 25 ⁇ 1°C and 80 ⁇ 2%RH, and the crystal form remains unchanged;
  • the crystal form of compound B of formula (II) has no or almost no hygroscopicity at 25 ⁇ 1°C and 80 ⁇ 2% RH. It is hygroscopic at 2% RH;
  • the crystal form C of the compound of formula (III) is extremely hygroscopic at 25 ⁇ 1°C and 80 ⁇ 2% RH.
  • MV average particle size calculated by volume
  • D10 Indicates the particle size corresponding to 10% of the particle size distribution (volume distribution);
  • D50 Indicates the particle size corresponding to 50% of the particle size distribution (volume distribution), also known as the median diameter;
  • D90 Indicates the particle size corresponding to 90% of the particle size distribution (volume distribution);
  • the PSD results of the crystal form of compound A of formula (I) are shown in Figure 13.
  • the volume average particle size of the crystal form of compound A of formula (I) is 12.05 microns.
  • the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • X-ray light source high-intensity micro-focus rotating anode light source, Cu target;
  • Goniometer four axes (Kappa, ⁇ , 2 ⁇ , ) goniometer;
  • Detector Large area photon II detector, the effective area of the detector is 14cm ⁇ 10cm, the distance between the detector and the sample is automatically adjustable by the motor.
  • This experiment used rat primary microglia to study the inhibitory activity of NLRP3 inhibitors on IL-1 ⁇ secretion in rat primary microglia.
  • the cerebral cortex was removed, digested and separated to obtain mixed glial cells, which were inoculated into culture bottles for culture. Change the medium every 3-4 days and culture for about 10 days. After the cells are completely confluent, shake at 37°C, collect microglia by centrifugation, inoculate them into a 96-well cell culture plate and culture them overnight. The cells were replaced with serum-free medium, 50ng/mL LPS was added for 3h, then different concentrations of compounds were added for 0.5h, and then 0.3 ⁇ g/mL Nigericin was added for 1h. Collect the supernatant and store it at -80°C or directly detect the release of IL-1 ⁇ by ELISA and follow the instructions of the kit.
  • Data processing uses the 10 ⁇ M positive compound group as the low value (L) and the DMSO group as the high value (H).
  • the compound of the present invention has significant inhibitory activity on the maturation and secretion of IL-1 ⁇ in rat primary microglia.
  • a central inflammation model was established by injecting LPS into the lateral ventricle of rats, and ELISA was used to evaluate the IL-1 ⁇ levels in cerebrospinal fluid to evaluate the in vivo efficacy of the test compounds.
  • SD male rats aged 10-14 weeks were anesthetized using isoflurane breathing; ensure that the animal's head does not move and adjust the brain surface to be flat; the rat's head is shaved, and a skin incision is made along the sagittal suture.
  • fontanelle position the glass electrode to the anterior fontanelle, reset each axis of the coordinate display to zero, and position according to the coordinates; slowly insert the needle to locate the lateral ventricle, inject 12.5 ⁇ g LPS, and give 5 mg/kg compound of formula (I) 2 hours later.
  • ATP was administered 3 hours later
  • cerebrospinal fluid was collected 3.5 hours later
  • IL-1 ⁇ inhibition level was evaluated by ELISA.
  • SD rats were selected and a Parkinson's disease (PD) model was established by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy.
  • 6-OHDA 6-hydroxydopamine
  • the striatum was collected after treatment with the compound for 5 days, and IL-1 ⁇ was evaluated by ELISA. Inhibition level.
  • test substance compound of formula (I), 5, 10 mg/kg
  • vehicle control solvent stock solution
  • test compound had a significant inhibitory effect on striatal IL-1 ⁇ levels in the 6-hydroxydopamine-induced rat Parkinson model.
  • SD rats were selected to establish a Parkinson's disease (PD) model by injecting 6-hydroxydopamine (6-OHDA) through brain stereotaxy.
  • the compound was administered for 21 days and then related behavioral tests (balance beam test, rotarod test) were conducted. Test) and histological testing [tyrosine hydroxylase (TH), microglia marker (Iba1) immunofluorescence staining] to evaluate the efficacy of the compound to be tested.
  • SD rats were anesthetized with isoflurane breathing to ensure that the animal's head would not move and the brain surface should be adjusted to be flat.
  • the head of the rat was shaved, and a skin incision was made along the sagittal suture to expose the bregma.
  • Position the glass electrode to the bregma reset each axis of the coordinate display to zero, and locate the substantia nigra (SN) and striatum (Str) brain areas according to the coordinates; slowly insert the needle to locate SN and Str, wait 10 minutes, and then inject 0.4 ⁇ L Inject 6-OHDA at a rate of /min. After the drug is administered, stay for another 10 minutes and then slowly withdraw the needle.
  • Balance beam test training period put the animal on the balance beam to adapt for 10 minutes every day, and cross the balance beam twice for each training, for a total of 2 days; the formal test adapts to the environment for 30-60 minutes, place the animal on the balance beam, and record the animal passing the balance beam twice. number of foot slips. Evaluation criteria: The number of foot slides (feet leaving the upper surface of the balance beam) that successfully pass the balance beam twice.
  • Rotarod test muscle strength test: Before testing, animals are placed in the test room to adapt to the environment for 30-60 minutes; adaptation training: Each experimental animal is placed on the rotarod fatigue instrument for adaptive training for 5 minutes.
  • Formal testing The parameters of the rotary rod fatigue meter are set to a rotation speed of 20 rpm/min and a test time of 5 minutes. Rats are placed on the rotary rod in batches for testing. Result analysis: count the time each animal spent on the bar.
  • TH tyrosine hydroxylase
  • Iba1 microglia marker
  • results show that: compared with the compound group of formula (I) and the 6-OHDA modeling group, the rats in the compound group of formula (I) stay on the rod longer than the rats in the 6-OHDA modeling group, and the difference between the two is significant (p ⁇ 0.05) .
  • AD Alzheimer's Disease
  • Table 25 Grouping of experimental animals, model induction and drug administration and treatment
  • Animals were administered orally administered with vehicle or vehicle from the first day.
  • the vehicle group and oA ⁇ 1-42 modeling group were orally administered vehicle, and the third group was orally administered test compound solution twice a day with an interval of 8 hours.
  • Behavioral experiments were conducted on the eighth and tenth days, and the second dose was administered after the behavioral experiment.
  • tissue samples were taken from the mice 2 hours after the first administration.
  • Y maze test Place the mouse at the end of any arm of the Y maze and let it explore freely for 8 minutes.
  • the animal's movement trajectory and behavioral changes are recorded with video, and the following indicators are recorded: 1
  • the total number of entries (the total number of entries) : The number of times an animal enters the arms of the maze (taking all four legs of the mouse into the arms is considered as one arm entry); 2
  • One turn (an alternation): Enter all three arms of the Y maze consecutively once; 3*Number of turns (The number of maximum alternations): The total number of arm advances -2.
  • Mouse behavior was analyzed using the EthosVision-XT8.0 video analysis system.
  • Table 30 Analysis results of Tau protein phosphorylation levels and microglia activation in cortical brain areas 13 days after intracerebroventricular injection of oA ⁇ 1-42 Note: Data are expressed as Mean ⁇ SEM; *: compared with vehicle group, ****p ⁇ 0.0001; # : compared with oA ⁇ 1-42 modeling group, #### p ⁇ 0.0001.

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Abstract

La présente invention concerne une forme cristalline, un type de sel et une composition d'un composé pyridazine et un procédé de préparation correspondant, et concerne spécifiquement un procédé pour préparer une forme cristalline A et une composition du composé de formule (I), une forme cristalline B du composé de formule (II) et une forme cristalline C du composé de formule (III), et l'utilisation associée.
PCT/CN2023/110617 2022-08-01 2023-08-01 Forme cristalline, type de sel et composition d'un composé pyridazine et procédé de préparation correspondant Ceased WO2024027723A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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WO2022135567A1 (fr) * 2020-12-25 2022-06-30 上海拓界生物医药科技有限公司 Composé contenant de la pyridazine et son utilisation médicinale
WO2022166890A1 (fr) * 2021-02-08 2022-08-11 南京明德新药研发有限公司 Dérivés de pyridazine phénol substitués

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WO2022135567A1 (fr) * 2020-12-25 2022-06-30 上海拓界生物医药科技有限公司 Composé contenant de la pyridazine et son utilisation médicinale
WO2022166890A1 (fr) * 2021-02-08 2022-08-11 南京明德新药研发有限公司 Dérivés de pyridazine phénol substitués

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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