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WO2024213088A1 - Cristal de dérivé tricyclique de pyrimidine et son utilisation - Google Patents

Cristal de dérivé tricyclique de pyrimidine et son utilisation Download PDF

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Publication number
WO2024213088A1
WO2024213088A1 PCT/CN2024/087396 CN2024087396W WO2024213088A1 WO 2024213088 A1 WO2024213088 A1 WO 2024213088A1 CN 2024087396 W CN2024087396 W CN 2024087396W WO 2024213088 A1 WO2024213088 A1 WO 2024213088A1
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compound
crystal
formula
ray powder
present application
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PCT/CN2024/087396
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English (en)
Chinese (zh)
Inventor
尹晓华
张国利
罗云富
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正大天晴药业集团股份有限公司
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Publication of WO2024213088A1 publication Critical patent/WO2024213088A1/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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application relates to a crystal and use of a pyrimidine tricyclic derivative, and specifically to a crystal of a compound of formula (I), a preparation method and use thereof.
  • Soluble guanylate cyclase is widely present in the cytosol of mammals and is a heterodimer composed of two subunits, ⁇ and ⁇ . Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After being activated in vivo, sGC catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
  • GTP guanosine triphosphate
  • cGMP cyclic guanosine monophosphate
  • cGMP is an important secondary messenger molecule that activates a variety of downstream effector molecules, such as cGMP-dependent protein kinase G and cGMP-gated ion channels, thereby triggering a series of downstream cascade reactions. It plays an important physiological function in the gastrointestinal system, cardiovascular system, and central nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, cell apoptosis and inflammation, and participating in neurotransmission.
  • the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction.
  • abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
  • sGC stimulators have a dual mechanism of action: they can be independent of NO, but they need to rely on the heme cofactor containing Fe 2+ to directly activate the sGC-cGMP signaling pathway; they can also enhance the sensitivity of sGC to endogenous NO, thereby producing a synergistic effect with NO. Therefore, sGC stimulators are heme-dependent and NO-independent sGC stimulators. Stimulating sGC to produce more cGMP can regulate a variety of important physiological processes: promoting vascular smooth muscle relaxation, inhibiting platelet aggregation, etc. At the same time, activating sGC can also regulate other signaling pathways, such as TGF- ⁇ , to exert anti-fibrosis and anti-tumor effects.
  • TGF- ⁇ signaling pathways
  • sGC stimulators can be used as a potential therapeutic method for the treatment of cardiovascular diseases (heart failure, pulmonary hypertension, angina pectoris, myocardial infarction) and fibrotic diseases (renal fibrosis, systemic sclerosis).
  • cardiovascular diseases heart failure, pulmonary hypertension, angina pectoris, myocardial infarction
  • fibrotic diseases renal fibrosis, systemic sclerosis.
  • crystals of the compound of formula (I) described in the present application may be in the form of a non-solvate or a solvate, such as a hydrate.
  • the crystal of the compound of formula (I) is selected from:
  • the crystal E of the compound of formula (I) has an X-ray powder diffraction pattern with diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 10.01 ⁇ 0.20°, 15.71 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the present application also provides crystal A of the compound of formula (I), wherein the X-ray powder diffraction pattern of crystal A has diffraction peaks at the following 2 ⁇ angles: 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 14.54 ⁇ 0.20° and 17.36 ⁇ 0.20°.
  • the crystal A of the compound of the above formula (I) has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 2, 3, 4 or 5 diffraction peaks selected from the following: 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 14.54 ⁇ 0.20° and 17.36 ⁇ 0.20°.
  • the crystalline A of the compound of the above formula (I) has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 6, 7, 8 or 9 diffraction peaks selected from the following: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 14.54 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20° and 21.72 ⁇ 0.20°.
  • the crystalline A of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 14.54 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20° and 21.72 ⁇ 0.20°.
  • the crystalline A of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 14.54 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20° and 21.72 ⁇ 0.20°.
  • the crystal A of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and comprises at least 10, 11, 12, 13 or 14 diffraction peaks selected from the following: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.66 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20°, 20.45 ⁇ 0.20°, 21.72 ⁇ 0.20°, 24.15 ⁇ 0.20° and 26.32 ⁇ 0.20°.
  • the crystal A of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction patterns at the following 2 ⁇ angles: Emission peaks: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.66 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20°, 20.45 ⁇ 0.20°, 21.72 ⁇ 0.20°, 26.32 ⁇ 0.20°.
  • the crystalline A of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.66 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 19.13 ⁇ 0.20°, 20.45 ⁇ 0.20°, 21.72 ⁇ 0.20°, 24.15 ⁇ 0.20° and 26.32 ⁇ 0.20°.
  • the crystal A of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 15, 16, 17, 18 or 19 diffraction peaks selected from the following: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.80 ⁇ 0.20°, 16.70 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.50 ⁇ 0.20°, 19.70 ⁇ 0.20°, 20.80 ⁇ 0.20°, 21.30 ⁇ 0.20°, 22.50 ⁇ 0.20°, 23.50 ⁇ 0.20°, 24.50 ⁇ 0.20°, 25.50 ⁇ 0.20°, 26.50 ⁇ 0.20°, 27.50 ⁇ 0.20°, 28.50 ⁇ 0.20°, 29.
  • the crystalline A of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 15.66 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 17.95 ⁇ 0.20°, 19.13 ⁇ 0.20°, 20.45 ⁇ 0.20°, 21.72 ⁇ 0.20°, 24.15 ⁇ 0.20° and 26.32 ⁇ 0.20°.
  • the crystal A of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 14.80 ⁇ 0.20°, 15.66 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.01 ⁇ 0.20°, 17.36 ⁇ 0.20°, 17.95 ⁇ 0.20°, 19.13 ⁇ 0.20°, 20.45 ⁇ 0.20°, 21.72 ⁇ 0.20°, 24.15 ⁇ 0.20°, 25.59 ⁇ 0.20° and 26.32 ⁇ 0.20°.
  • the crystal A of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 8.34 ⁇ 0.20°, 9.74 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.92 ⁇ 0.20°, 13.10 ⁇ 0.20°, 13.69 ⁇ 0.20°, 13.95 ⁇ 0.20°, 14.54 ⁇ 0.20°, 14.80 ⁇ 0.20°, 15.66 ⁇ 0.20°, 16.22 ⁇ 0.20°.
  • the XRPD pattern of the crystal A of the compound of formula (I) is shown in FIG1 .
  • the differential scanning calorimetry curve of the crystal A of the compound of formula (I) above has the starting values of the endothermic peaks at: 172.95°C ⁇ 5°C and 236.77°C ⁇ 5°C, respectively.
  • the DSC spectrum of the crystal A of the compound of formula (I) is shown in FIG2 .
  • thermogravimetric analysis curve of the crystal A of the compound of formula (I) above shows no obvious step weight loss.
  • the TGA spectrum of the crystal A of the compound of formula (I) is shown in FIG3 .
  • the crystal A of the compound of formula (I) may exist in the form of a solvate crystal.
  • the present application also provides a method for preparing the crystal A of the compound of formula (I), comprising the step of slurrying the compound of formula (I) in a solvent, and further comprising a separation step.
  • the solvent is selected from one or a mixed solvent of two or more of acetonitrile, isopropanol, acetone and water; preferably, the solvent is selected from acetonitrile.
  • the method for preparing the crystal A of the compound of formula (I) above comprises:
  • the mass volume ratio of the compound of formula (I) to acetonitrile in step (1) is 1 g: 2-10 mL; preferably 1 g: 2-5 mL; more preferably 1 g: 4-5 mL.
  • the temperature of the slurry stirring in step (1) is 5-40°C, preferably 10-30°C, and more preferably 20-25°C.
  • the present application also provides a crystalline C of the compound of formula (I), whose X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.61 ⁇ 0.20° and 16.47 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 3, 4, 5 or 6 diffraction peaks selected from the following: 7.91 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.61 ⁇ 0.20° and 16.47 ⁇ 0.20°.
  • the crystalline C of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and comprises at least 7, 8, 9, 10, 11, 12 or 13 diffraction peaks selected from the following: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.26 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°, 16.58 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 15.26 ⁇ 0.20°, 16.47 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystalline C of the compound of the above formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystalline C of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.26 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.47 ⁇ 0.20°, 16.58 ⁇ 0.20°, 20.63 ⁇ 0.20° and 22.17 ⁇ 0.20°.
  • the crystal C of the compound of formula (I) has an X-ray powder diffraction pattern of at least 13, 14, 15, 16, 17, 18 or 19 diffraction peaks selected from the following: 7.91 ⁇ 0.20°, 8.07 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.26 ⁇ 0.20°, 16.80 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.10 ⁇ 0.20°, 19.80 ⁇ 0.20°, 20.80 ⁇ 0.20°, 21.30 ⁇ 0.20°, 22.80 ⁇ 0.20°, 23.90 ⁇ 0.20°, 24.80 ⁇ 0.20°, 25.80 ⁇ 0.20°, 26.80 ⁇ 0.20°, 27.80 ⁇ 0.20°, 28.80 ⁇ 0.20°, 29.
  • the crystal C of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.07 ⁇ 0.20°, 8.69 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.69 ⁇ 0.20°, 14.39 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.26 ⁇ 0.20°, 15.61 ⁇ 0.20°, 1 6.47 ⁇ 0.20°, 16.15 ⁇ 0.20°, 16.58 ⁇ 0.20°, 17.02 ⁇ 0.20°, 17.34 ⁇ 0.20°, 18.04 ⁇ 0.20°, 19.02 ⁇ 0.20°, 19.36 ⁇ 0.20°, 19.88 ⁇ 0.20°, 20.63 ⁇ 0.20°, 21.38 ⁇ 0.20°, 22.17 ⁇ 0.20°, 23.46 ⁇ 0.20° and 27.26 ⁇ 0.20°.
  • the crystal C of the compound of formula (I) above, the X-ray powder diffraction pattern of the crystal is represented by 2 ⁇ angle and contains at least 20, 21, 22, 23 or 24 diffraction peaks selected from the following: 7.91 ⁇ 0.20°, 8.07 ⁇ 0.20°, 8.69 ⁇ 0.20°, 9.74 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.23 ⁇ 0.20°, 12.80 ⁇ 0.20°, 13.71 ⁇ 0.20°, 14.97 ⁇ 0.20°, 15.30 ⁇ 0.20°, 16.70 ⁇ 0.20°, 17.91 ⁇ 0.20°, 18.60 ⁇ 0.20°, 19.70 ⁇ 0.20°, 20.80 ⁇ 0.20°, 21.70 ⁇ 0.20°, 22.60 ⁇ 0.20°, 23.70 ⁇ 0.20°, 24.90 ⁇ 0.20°, 25.90 ⁇ 0.20°, 26.90 ⁇ 0.20°, 27.90 ⁇ 0.20°, 28.
  • the crystal C of the compound of formula (I) has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.91 ⁇ 0.20°, 8.07 ⁇ 0.20°, 8.69 ⁇ 0.20°, 9.74 ⁇ 0.20°, 10.31 ⁇ 0.20°, 10.65 ⁇ 0.20°, 11.23 ⁇ 0.20°, 11.69 ⁇ 0.20°, 12 .54 ⁇ 0.20°, 13.02 ⁇ 0.20°, 13.27 ⁇ 0.20°, 13.63 ⁇ 0.20°, 14.39 ⁇ 0.20°, 14.78 ⁇ 0.20°, 15.26 ⁇ 0.20°, 15.61 ⁇ 0.20°, 16.15 ⁇ 0.20°, 16.47 ⁇ 0.20°, 16.
  • the X-ray powder diffraction pattern of the crystalline C of the compound of formula (I) is shown in FIG4 .
  • the crystalline C of the above-mentioned compound (I), the spectrum analysis data of the diffraction peaks in its X-ray powder diffraction (XRPD) spectrum are shown in Table 2:
  • the differential scanning calorimetry curve of the crystal C of the compound of formula (I) above has an onset value of the endothermic peak at 256.71°C ⁇ 5°C.
  • the DSC spectrum of the crystal C of the compound of formula (I) is shown in FIG5 .
  • thermogravimetric analysis curve of the crystal C of the compound of formula (I) above shows no obvious step weight loss.
  • the TGA spectrum of the crystal C of the compound of formula (I) is shown in FIG6 .
  • the crystalline C of the compound of formula (I) may exist in the form of a solvate crystal.
  • the present application also provides a method for preparing the above-mentioned crystal C of the compound of formula (I), comprising the step of stirring the compound of formula (I), the crystal A of the compound of formula (I) or the crystal E of the compound of formula (I) in water. Furthermore, it also includes a separation step.
  • the method for preparing the crystalline C of the compound of formula (I) comprises:
  • the mass volume ratio of the crystal A or crystal E of the compound of formula (I) and water in step (1) is 1g:5-20mL; preferably 1g:5-15mL; more preferably 1g:5-10mL.
  • the stirring time in step (1) in water is 10-20 hours, preferably 10-15 hours, and more preferably 10-12 hours.
  • the step (1) further comprises a cooling step, wherein the cooling step is to 10-30°C, preferably 10-25°C.
  • the present application also provides a crystalline E of the compound of formula (I), whose X-ray powder diffraction pattern has a diffraction peak at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 10.01 ⁇ 0.20°, 15.71 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 15.71 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 2, 3 or 4 diffraction peaks selected from the following: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 15.71 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and comprises at least 5, 6, 7, 8 or 9 diffraction peaks selected from the following: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 19.56 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20° and 19.56 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 19.56 ⁇ 0.20° and 20.80 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and comprises at least 9, 10, 11 or 12 diffraction peaks selected from the following: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.80 ⁇ 0.20°, 22.48 ⁇ 0.20°, 26.19 ⁇ 0.20° and 30.43 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.80 ⁇ 0.20°, 22.48 ⁇ 0.20°, 26.19 ⁇ 0.20° and 30.43 ⁇ 0.20°.
  • the crystal E of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles and contains at least 13, 14, 15, 16 or 17 diffraction peaks selected from the following: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 1 6.61 ⁇ 0.20°, 17.51 ⁇ 0.20°, 17.73 ⁇ 0.20°, 18.48 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.04 ⁇ 0.20°, 20.36 ⁇ 0.20°, 20.80 ⁇ 0.20°, 22.48 ⁇ 0.20°, 25.35 ⁇ 0.20°, 26.19 ⁇ 0.20°, 28.41 ⁇ 0.20° and 30.43 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.61 ⁇ 0.20°, 17.51 ⁇ 0.20°, 17.73 ⁇ 0.20°, 18.48 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.04 ⁇ 0.20°, 20.36 ⁇ 0.20°, 20.80 ⁇ 0.20°, 22.48 ⁇ 0.20°, 25.35 ⁇ 0.20°, 26.19 ⁇ 0.20°, 28.41 ⁇ 0.20° and 30.43 ⁇ 0.20°.
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern represented by 2 ⁇ angles comprising at least 18, 19, 20, 21 or 22 diffraction peaks selected from the following: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 10.67 ⁇ 0.20°, 11.31 ⁇ 0.20°, 12.12 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 14.80 ⁇ 0.20°, 15.70 ⁇ 0.20°, 16.90 ⁇ 0.20°, 17.10 ⁇ 0.20°, 18.81 ⁇ 0.20°, 19.70 ⁇ 0.20°, 20.81 ⁇ 0.20°, 21.70 ⁇ 0.20°, 22.81 ⁇ 0.20°, 23.67 ⁇ 0.20°, 24.67 ⁇ 0.20°, 25.67 ⁇ 0.20°, 26.67 ⁇ 0.20°, 27.67 ⁇ 0.20°, 28.67 ⁇ 0.20°, 29.67 ⁇ 0.20°, 30.67 ⁇ 0.20°, 31.31 ⁇ 0.20°, 32
  • the crystalline E of the compound of formula (I) above has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 7.87 ⁇ 0.20°, 9.03 ⁇ 0.20°, 10.01 ⁇ 0.20°, 10.67 ⁇ 0.20°, 11.31 ⁇ 0.20°, 12.12 ⁇ 0.20°, 12.44 ⁇ 0.20°, 13.75 ⁇ 0.20°, 14.72 ⁇ 0.20°, 15.71 ⁇ 0.20°, 16.29 ⁇ 0.20°, 16.61 ⁇ 0.20°, 17.51 ⁇ 0.20°, 17.73 ⁇ 0.20°, 18.25 ⁇ 0.20°, 18.48 ⁇ 0.20°, 19.56 ⁇ 0.20°, 20.04 ⁇ 0.20°, 20.36 ⁇ 0.20°, 20.80 ⁇ 0.20°, 22.48 ⁇ 0.20°, 23.27 ⁇ 0.20°, 23.57 ⁇ 0.20°, 24.03 ⁇ 0.20°, 24.49 ⁇ 0.20°, 25.35 ⁇ 0.20°, 26.19 ⁇ 0.20°, 26.77 ⁇ 0.20°,
  • the XRPD pattern of the crystal E of the compound of formula (I) is shown in FIG. 7 .
  • the differential scanning calorimetry curve of the crystal E of the compound of formula (I) above has the starting values of the endothermic peaks at: 185.51°C ⁇ 5°C, 236.70°C ⁇ 5°C and 257.64°C ⁇ 5°C, respectively.
  • the DSC spectrum of the crystal E of the compound of formula (I) is shown in FIG8 .
  • thermogravimetric analysis curve of the crystal E of the compound of formula (I) above shows a weight loss of 0.52% at 250°C.
  • the TGA spectrum of the crystal E of the compound of formula (I) is shown in FIG9 .
  • the crystalline E of the compound of formula (I) may exist in the form of a solvate crystal.
  • the present application also provides a method for preparing the above-mentioned crystal E of the compound of formula (I): comprising the step of slurrying the crystal A of the compound of formula (I) in a solvent. Further, a separation step is also included.
  • the solvent is selected from one or a mixed solvent of two or more selected from isopropyl ether, cyclohexane, n-heptane or tetrahydrofuran, preferably n-heptane.
  • the method for preparing the crystalline E of the compound of formula (I) comprises:
  • the mass volume ratio of the crystal A of the compound of formula (I) and n-heptane in step (1) is 1 g: 5-20 mL; preferably 1 g: 5-15 mL; more preferably 1 g: 5-10 mL.
  • the stirring temperature in step (1) in n-heptane is 20-80°C, preferably 30-50°C, and more preferably 40-50°C.
  • the stirring time in step (1) in n-heptane is 10-20 hours, preferably 10-15 hours, and more preferably 10-12 hours.
  • the step (1) further comprises a cooling step, wherein the cooling step is to 10-30°C, preferably 10-25°C.
  • the present application also provides a solvate of the compound of formula (I), wherein the solvate includes: isopropyl ether solvate, n-heptane solvate, ethyl acetate solvate or methanol solvate, preferably methanol solvate.
  • the present application also provides a crystalline solvate of the compound of formula (I), wherein the solvate includes: isopropyl ether solvate, n-heptane solvate, ethyl acetate solvate or methanol solvate, preferably methanol solvate.
  • the solvate of the crystalline compound of formula (I) includes the solvate of crystalline compound A of formula (I), or the solvate of crystalline compound E of formula (I), or the solvate of crystalline compound C of formula (I);
  • the present application also provides a methanol solvate of the compound of formula (I), as shown in the compound of formula (II),
  • the present application also provides a crystal B of the compound of formula (II), and the XRPD spectrum of the crystal B is shown in FIG. 14 .
  • the crystal B of the compound of formula (II) is a single crystal.
  • the crystal B of the compound of formula (II) is a single crystal, and the ellipsoid diagram of the single crystal molecular structure is shown in FIG13 .
  • the present application also provides an amorphous form of the compound of formula (I).
  • the XRPD spectrum of the amorphous form of the compound of formula (I) is shown in FIG. 15 .
  • the present application provides a crystalline composition
  • a crystalline composition comprising Crystal A, Crystal C or Crystal E of the compound of formula (I), wherein the Crystal A, Crystal C or Crystal E respectively accounts for more than 50% of the weight of the crystalline composition, preferably more than 80%, more preferably more than 90%, and most preferably more than 95%.
  • the present application provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of Crystal A, Crystal C or Crystal E of the compound of formula (I) described in the present application, or the above-mentioned crystalline composition.
  • the pharmaceutical composition of the present application may contain or not contain a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the present application provides a method for treating a disease associated with an sGC agonist or stimulator, the method comprising administering to an individual in need thereof a therapeutically effective amount of Crystal A, Crystal C or Crystal E of the compound of formula (I) described in the present application, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition.
  • the present application provides the use of Crystal A, Crystal C or Crystal E of the compound of formula (I), or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating diseases associated with sGC agonists or stimulants.
  • the present application provides use of Crystal A, Crystal C or Crystal E of the compound of formula (I), or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition in treating diseases associated with sGC agonists or stimulators.
  • the present application provides a crystalline compound of the above formula (I) for treating diseases associated with sGC agonists or stimulants A, Crystal C or Crystal E, or the above-mentioned crystalline composition, or the above-mentioned pharmaceutical composition.
  • the disease associated with sGC agonists or stimulators is selected from heart failure or hypertension.
  • crystal preparation of the compound of formula (I) of the present application is simple, has good solubility, physical stability and chemical stability, and has good pharmacokinetic properties, and is suitable for use as a drug.
  • crystal A, crystal C and crystal E of the compound of formula (I) of the present application have good stability, low hygroscopicity, and are easy to make into medicine; they can effectively stimulate sGC, significantly increase cGMP levels, have good apparent distribution volume and half-life, have good cardiac distribution and no risk of entering the brain.
  • the relative intensity of the diffraction peaks can change due to the preferred orientation caused by factors such as crystal morphology, which is well known in the field of crystallography. Where there is a preferred orientation effect, the peak intensity changes, but the diffraction peak position of the crystal form cannot be changed. In addition, for any given crystal form, there may be a slight error in the position of the peak, which is also well known in the field of crystallography. For example, due to changes in temperature when analyzing a sample, movement of the sample, or calibration of the instrument, the position of the peak can move, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.20 degrees. Therefore, it is well known to those skilled in the art that this error should be taken into account when determining each crystalline structure.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to changes in its crystalline structure or melting of the crystal.
  • the error of thermal transition temperature and melting point is typically within about 5°C or 3°C.
  • DSC peak or melting point this refers to the DSC peak or melting point ⁇ 5°C or ⁇ 3°C.
  • DSC provides an auxiliary method for distinguishing different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be pointed out that for mixtures, their DSC peaks or melting points may vary over a larger range.
  • the melting temperature is related to the heating rate.
  • the TGA weight loss temperature may vary due to factors such as the measuring instrument, measuring method/conditions, etc.
  • the weight loss temperature may have an error of about ⁇ 5°C or about ⁇ 3°C.
  • the "pharmaceutically acceptable excipients” refer to inert substances that are administered together with the active ingredients and are conducive to the administration of the active ingredients, including but not limited to any glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that are acceptable for use in humans or animals (such as livestock) and approved by the State Food and Drug Administration.
  • crystalline composition refers to a mixture of the crystal of formula (I) or formula (II) of the present application and other crystalline forms or amorphous forms or other impurities of the compound.
  • the crystalline composition of crystal A of the compound of formula (I) contains other crystalline forms or amorphous forms or other impurities of the compound of formula (I) in addition to crystal A of the compound of formula (I).
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • the therapeutic dosage of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means an amount of the compound of the present application that (i) treats a specific disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • references to “one embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” throughout this specification are intended to include in at least one embodiment the specific referenced elements, structures or features described in connection with that embodiment.
  • the phrases “in one embodiment” or “in an embodiment” or “in another embodiment” or “in certain embodiments” appearing in different places throughout the specification do not necessarily all refer to the same embodiment.
  • the specific elements, structures or features may be combined in any appropriate manner in one or more embodiments.
  • the intermediate compounds of the present application can be prepared by a variety of synthesis 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 equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • the structure of the compounds of the present application can be confirmed by conventional methods known to those skilled in the art. If the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, with the light source being CuK ⁇ radiation and the scanning mode being: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffraction
  • the solvents used in this application are commercially available and can be used without further purification.
  • HPLC high performance liquid chromatography
  • °C stands for degrees Celsius
  • h stands for hour
  • mL stands for milliliter
  • mM stands for millimole per liter
  • mmol stands for millimole
  • ⁇ mol stands for micromole
  • 1 H NMR stands for hydrogen nuclear magnetic resonance
  • MS stands for mass spectrometry
  • min stands for minute
  • pH stands for negative logarithm of molar concentration of hydrogen ions
  • DMSO dimethyl sulfoxide.
  • the compounds are named by conventional naming methods in the art or The software names were used, and commercially available compounds were named using the supplier's catalog names.
  • Test method About 3-10 mg of sample was used for XRPD detection.
  • Test method Take an appropriate amount of sample powder for XRPD detection.
  • Test conditions Take a sample (30-50 mg) and place it in the DVS sample tray for testing.
  • the moisture absorption evaluation is classified as follows:
  • ⁇ W% indicates the weight gain due to moisture absorption at 25 ⁇ 1°C and 80 ⁇ 2% RH.
  • This application uses the Differential Scanning Calorimeter (DSC) method
  • a sample (1-3 mg) was placed in a covered aluminum crucible under the protection of 50 mL/min dry nitrogen for testing.
  • the method was: heating from 25°C to the set test temperature at a heating rate of 10°C/min.
  • Test method Take a sample (1-5 mg) and place it in an uncovered aluminum crucible under the protection of 60 mL/min dry nitrogen for testing. The method is: from 25°C to the set test temperature, the heating rate is 10°C/min.
  • Test method The sample was dissolved in 480 ⁇ L methanol at room temperature, and the sample solution was placed in a 4 mL semi-sealed sample bottle and slowly evaporated at room temperature. Colorless block crystals were obtained the next day.
  • Area detector a HyPix-6000HE area detector.
  • Cu 50W, micro-focus source with multi-layer mirror ( ⁇ -CMF).
  • Tube current 1mA.
  • FIG1 is a Cu-K ⁇ radiation XRPD spectrum of crystal A of compound of formula (I);
  • Figure 2 is a DSC spectrum of crystal A of compound of formula (I);
  • FIG. 3 is a TGA spectrum of crystal A of compound of formula (I);
  • FIG4 is a Cu-K ⁇ radiation XRPD spectrum of crystal C of compound of formula (I);
  • Figure 5 is a DSC spectrum of the crystal C of the compound of formula (I);
  • Figure 6 is a TGA spectrum of crystal C of compound of formula (I);
  • FIG7 is a Cu-K ⁇ radiation XRPD spectrum of crystal E of compound of formula (I);
  • FIG8 is a DSC spectrum of the crystal E of the compound of formula (I);
  • Figure 9 is a TGA spectrum of the crystal E of the compound of formula (I);
  • FIG10 is a DVS adsorption and desorption curve of the crystal C of the compound of formula (I);
  • Figure 11 is a single crystal image of the compound of formula (II);
  • Figure 12 is a molecular structure diagram of the compound of formula (II);
  • Figure 13 is an ellipsoid diagram of the molecular structure of the compound of formula (II);
  • Figure 14 is a Cu-K ⁇ radiation XRPD spectrum of crystalline B of compound of formula (II).
  • FIG. 15 is a Cu-K ⁇ radiation XRPD spectrum of the amorphous form of the compound of formula (I).
  • compound 1-8 (660 mg, 1.32 mmol) was added to tetrahydrofuran (6 mL) and acetonitrile (3 mL), followed by methanol (169.39 mg, 5.29 mmol), potassium monopersulfate (1.63 g, 2.64 mmol), potassium dihydrogen phosphate (359.73 mg, 2.64 mmol) and cuprous bromide (37.92 mg, 264.33 ⁇ mol), and the reaction solution was stirred at 80 ° C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL ⁇ 2), and the organic phases were combined.
  • the compound of formula (I) prepared by the method of Example 1 was concentrated and freeze-dried.
  • the compound of formula (I) (2.0 g) was added to an eggplant-shaped glass bottle, acetonitrile (20 mL) was added, and the mixture was suspended and stirred at 50° C. for 12 hours, cooled to room temperature, and the solid was filtered to obtain Crystal A of the compound of formula (I).
  • the compound of formula (I) prepared by the method of Example 1 was concentrated and freeze-dried, and about 200 mg of the compound of formula (I) was weighed, and ethyl acetate (about 1 mL) was added at room temperature (about 15° C.) to obtain a clear solution, and evaporated and crystallized at room temperature to obtain a solid.
  • the solid was characterized by XRPD and determined to be amorphous. The XRPD spectrum is shown in Figure 15.
  • the weight gain of the crystal C of the compound of formula (I) at 80% RH was 0.66% compared with the initial 0% RH, indicating that the sample was slightly hygroscopic.
  • the crystals of compound C of formula (I) were spread into a thin layer, and completely exposed to high temperature (60°C), normal temperature and high humidity (25°C/92.5%RH), light (illuminance ⁇ 5000Lux/near ultraviolet ⁇ 90 ⁇ w/ cm2 , open), high temperature and high humidity (40°C/75%RH or 60°C/75%RH) conditions, and samples were taken at the prescribed time to detect XRPD, appearance, content and related substances, and compared with the results of the 0-day sample.
  • the experimental results are shown in Table 4.
  • Crystalline C of compound of formula (I) has good stability under high temperature, normal temperature and high humidity, light, and high temperature and high humidity conditions.
  • mice 2 male Sprague Dawley rats aged 9-10 weeks
  • Experimental procedures The pharmacokinetic characteristics of rodents after oral administration of the compound were tested according to the standard protocol.
  • the candidate compound was prepared into a uniform suspension solution (the solvent for oral administration preparation was 0.5% MC + 0.2% Tween80/H 2 O), and a single oral administration of 0.2 mg/mL concentration of the compound of formula (I) crystal C was given.
  • the animal weight was weighed before administration.
  • the body weight at the beginning of the experiment was 320-230 g.
  • the administration volume was calculated based on the body weight and the oral administration (1 mg/kg) was given.
  • Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration.
  • the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the plasma drug concentration data of the metabolites of the compound of the present application were processed by non-compartmental model using Phoenix WinNonlin 6.3 software.
  • the linear logarithmic trapezoidal method was used to calculate relevant pharmacokinetic parameters, such as peak concentration (C max ), half-life (T 1/2 ), area under the concentration-time curve (AUC), time to peak (T max ), etc.
  • relevant pharmacokinetic parameters such as peak concentration (C max ), half-life (T 1/2 ), area under the concentration-time curve (AUC), time to peak (T max ), etc.
  • C max peak concentration
  • T 1/2 half-life
  • AUC area under the concentration-time curve
  • T max time to peak
  • LNCap culture medium RPMI1640 + 10% fetal bovine serum + 1% double antibody.
  • cGMP standard curve Use Graphpad prism to make a standard curve based on the cGMP concentration and the ratio of 665/615.
  • the MEC value of the sGC stimulating activity of the compound of formula (I) of the present application is: 214 nM.
  • MEC Minimum effective concentration that stimulates cGMP production (three times greater than basal value) in lnCap cells.
  • Purpose To test the distribution ratio of the compound in plasma, heart, cerebrospinal fluid and brain tissue under oral administration.
  • This project used 6 male SD rats for oral administration, with a dose of 1 mg/kg and a concentration of 0.2 mg/mL. Cerebrospinal fluid, brain, heart tissue and plasma samples were collected 2, 6 and 12 hours after administration, and then the collected samples were analyzed by LC-MS/MS and data was collected. The collected analysis data were used to calculate the relevant pharmacokinetic parameters using Phoenix WinNonlin 6.3 software.

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Abstract

La présente invention concerne un cristal d'un dérivé tricyclique de pyrimidine et une utilisation, et concerne plus précisément un cristal d'un composé de formule (I), ainsi qu'un procédé de préparation et une utilisation de celui-ci.
PCT/CN2024/087396 2023-04-13 2024-04-12 Cristal de dérivé tricyclique de pyrimidine et son utilisation WO2024213088A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103180327A (zh) * 2010-07-09 2013-06-26 拜耳知识产权有限责任公司 稠环的4-氨基嘧啶及其作为可溶性鸟甘酸环化酶的刺激物的用途
CN103619845A (zh) * 2011-04-21 2014-03-05 拜耳知识产权有限责任公司 氟烷基取代的吡唑并吡啶及其用途
CN103906752A (zh) * 2011-07-06 2014-07-02 拜耳知识产权有限责任公司 杂芳基取代的吡唑并吡啶及其用作可溶性鸟苷酸环化酶刺激剂的用途
CN107964018A (zh) * 2016-10-19 2018-04-27 中国人民解放军军事医学科学院毒物药物研究所 取代嘌呤酮类衍生物及其医药用途
CN108727340A (zh) * 2017-04-11 2018-11-02 广东东阳光药业有限公司 氟取代的吲唑类化合物及其用途
WO2021219088A1 (fr) * 2020-04-30 2021-11-04 正大天晴药业集团股份有限公司 Composé tricyclique à base de pyrimidine et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103180327A (zh) * 2010-07-09 2013-06-26 拜耳知识产权有限责任公司 稠环的4-氨基嘧啶及其作为可溶性鸟甘酸环化酶的刺激物的用途
CN103619845A (zh) * 2011-04-21 2014-03-05 拜耳知识产权有限责任公司 氟烷基取代的吡唑并吡啶及其用途
CN103906752A (zh) * 2011-07-06 2014-07-02 拜耳知识产权有限责任公司 杂芳基取代的吡唑并吡啶及其用作可溶性鸟苷酸环化酶刺激剂的用途
CN107964018A (zh) * 2016-10-19 2018-04-27 中国人民解放军军事医学科学院毒物药物研究所 取代嘌呤酮类衍生物及其医药用途
CN108727340A (zh) * 2017-04-11 2018-11-02 广东东阳光药业有限公司 氟取代的吲唑类化合物及其用途
WO2021219088A1 (fr) * 2020-04-30 2021-11-04 正大天晴药业集团股份有限公司 Composé tricyclique à base de pyrimidine et son utilisation

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