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EP-4741394-A1 - CRYSTAL FORM OF [1,2,4]TRIAZOLO[4,3-B]PYRIDAZINE COMPOUND, AND PREPARATION METHOD THEREFOR AND USE THEREOF

EP4741394A1EP 4741394 A1EP4741394 A1EP 4741394A1EP-4741394-A1

Abstract

A crystal form of a [1,2,4]triazolo[4,3-b]pyridazine compound, and a preparation method therefor and a use thereof. The crystal form is a crystal form of a free base and can be used for treating tumor diseases, and a crystal form B has the characteristic of storage stability. Additionally, the crystal form B has a relatively low incipient melting temperature, and when the crystal form B is used in a hot-melt extrusion process, the content of impurities of a related substance in a prepared sampled is low, thereby facilitating improvement of the quality of drugs.

Inventors

  • SONG, Weizhou
  • LI, GANG
  • ZHANG, Peilong
  • SHI, Hepeng

Assignees

  • Beijing Pearl Biotechnology Limited Liability Company
  • Beijing Avistone Biotechnology Co., Ltd.

Dates

Publication Date
20260513
Application Date
20230704

Claims (11)

  1. A crystal form B of 6-(1-cyclopropyl-1-hydro-pyrazol-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazol-5-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine represented by formula (I), wherein with Cu-Kα radiation, the crystal form B has characteristic peaks at 2θ values of 8.38°, 15.99°, 18.73°, 24.86°, 28.96°, and 29.83° in a X-ray powder diffraction pattern expressed in 2θ angles, with a 2θ error range of ± 0.2°,
  2. The crystal form B according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form B shows characteristic peaks at 2θ values of 8.38°, 15.57°, 15.99°, 18.73°, 24.86°, 25.30°, 28.96°, and 29.83°, with a 2θ error range of ± 0.2°; and preferably, the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 5.
  3. The crystal form B according to claim 1 or 2, wherein a thermogravimetric analysis (TGA) thermogram of the crystal form B shows a weight loss of up to 0.50% from room temperature to 200 °C; preferably, a TGA thermogram of the crystal form B is shown in FIG. 6; preferably, a differential scanning calorimetry (DSC) thermogram of the crystal form B shows an endothermic peak value at 203.00 °C; and preferably, a DSC thermogram of the crystal form B is shown in FIG. 7.
  4. A preparation method for the crystal form B according to any one of claims 1 to 3, comprising: adding the compound of formula (I) to a mixture of a normal solvent B1 and an anti-solvent B2, heating until dissolution, filtering and cooling, cultivating crystals, adding the anti-solvent B2, and cooling to 0 °C to obtain the crystal form B, wherein preferably, the normal solvent B1 is acetone, preferably, the anti-solvent B2 is water, preferably, a heating temperature is 0 °C to 60 °C, preferably 60 °C, preferably, before cultivating the crystals, a cooling temperature is 40 °C to 0 °C, preferably 30 °C, and preferably, in the mixture of the normal solvent B1 and the anti-solvent B2, a volume ratio of the normal solvent B1 to the anti-solvent B2 is 4/1 to 1/1, preferably 3/1; or adding the compound of formula (I) to a mixture of a normal solvent B1 and an anti-solvent B2, heating until dissolution, filtering and cooling to obtain the crystal form B, wherein preferably, the normal solvent B1 is acetone, preferably, the anti-solvent B2 is water, preferably, a heating temperature is 0 °C to 60 °C, preferably 60 °C, preferably, a cooling temperature is 0 °C to 30 °C, preferably 0 °C to 10 °C, and preferably, in the mixture of the normal solvent B1 and the anti-solvent B2, a volume ratio of the normal solvent B1 to the anti-solvent B2 is 3/1 to 4/1, preferably 4/1.
  5. A crystal form A of 6-(1-cyclopropyl-1-hydro-pyrazol-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazol-5-yl)methyl)[1,2,4]triazolo[4,3-b]pyridazine represented by formula (I), wherein with Cu-Kα radiation, the crystal form A has characteristic peaks at 2θ values of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 24.25°, and 25.43° in a X-ray powder diffraction pattern expressed in 2θ angles, with a 2θ error range of ± 0.2°,
  6. The crystal form A according to claim 5, wherein the X-ray powder diffraction pattern of the crystal form A shows characteristic peaks at 2θ values of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 17.54°, 17.85°, 18.15°, 20.39°, 24.25°, 25.43°, 25.97° and 26.43°, with a 2θ error range of ± 0.2°; and preferably, the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1.
  7. The crystal form A according to claim 5 or 6, wherein a thermogravimetric analysis (TGA) curve of the crystal form A shows no weight loss from room temperature to a melting point; preferably, a TGA thermogram of the crystal form A is shown in FIG. 2; preferably, a differential scanning calorimetry (DSC) curve of the crystal form A shows an endothermic peak value at 222.27 °C; and preferably, a DSC thermogram of the crystal form A is shown in FIG. 3.
  8. A preparation method for the crystal form A according to any one of claims 5 to 7, comprising: dissolving the compound of formula (I) in a normal solvent A1 at 0 °C to 70 °C, filtering, adding the resulting clear filtrate dropwise to an anti-solvent A2 to obtain the crystal form A, wherein preferably, the normal solvent A1 is acetic acid, preferably, the anti-solvent A2 is ethanol, preferably, a volume ratio of the normal solvent A1 to the anti-solvent A2 is 1/6 to 1/1, more preferably 1/4 or 1/3, and preferably, a temperature at which the compound of formula (I) is dissolved in the normal solvent A1 is 20 °C to 40 °C, more preferably 35 °C, to enable clear dissolution of the compound of formula (I) in the normal solvent A1; or dissolving the compound of formula (I) in a normal solvent A1, filtering, and adding an anti-solvent A2 dropwise to the resulting clear filtrate to obtain the crystal form A; and preferably, the normal solvent A1 is acetic acid, preferably, the anti-solvent A2 is ethanol, preferably, a volume ratio of the normal solvent A1 to the anti-solvent A2 is 1/6 to 1/1, more preferably 1/4 or 1/3, and preferably, a temperature at which the compound of formula (I) is dissolved in the normal solvent A1 is 20 °C to 50 °C, more preferably 35 °C; or dissolving the compound of formula (I) in a certain volume of solvent or mixed solvent, heating until complete dissolution, and filtering and slow cooling to obtain the crystal form A, and preferably, a warming temperature is 20 °C to 70 °C, more preferably 50 °C, preferably, the solvent is acetonitrile, methanol or acetic acid, preferably, the mixed solvent is a mixture of acetic acid and ethanol, and preferably, a volume ratio of the mixed solvent is 1/6 to 1/1, more preferably 1/4 or 1/3.
  9. A pharmaceutical preparation or a pharmaceutical composition, comprising the crystal form B according to any one of claims 1 to 3 or the crystal form A according to any one of claims 5 to 7, and a pharmaceutically acceptable carrier and/or vehicle; and preferably, the pharmaceutical preparation or the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, or spray.
  10. Use of the crystal form B according to any one of claims 1 to 3, or the crystal form A according to any one of claims 5 to 7, or the pharmaceutical preparation or the pharmaceutical composition according to claim 9 in preparation of a medicament for treating c-Met abnormality-mediated diseases, wherein preferably, the c-Met abnormality-mediated diseases are tumor diseases; and preferably, the tumor diseases comprise: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, stomach cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis, or pulmonary fibrosis.
  11. A method for treating c-Met abnormality-mediated diseases, comprising administering the crystal form B according to any one of claims 1 to 3, or the crystal form A according to any one of claims 5 to 7, or the pharmaceutical preparation or the pharmaceutical composition according to claim 9 to a subject in need thereof, wherein preferably, the c-Met abnormality-mediated diseases are tumor diseases; and preferably, the tumor diseases comprise: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, stomach cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, cholangiocarcinoma, endometrial cancer, multiple myeloma or mesothelioma, atherosclerosis, or pulmonary fibrosis.

Description

TECHNICAL FIELD The present invention relates to the field of chemical medicine, and in particular to crystal form of a [1,2,4]triazolo[4,3-b]pyridazine compound as c-Met inhibitor, and preparation method therefor and use thereof. BACKGROUND Hepatocyte growth factor receptor (c-Met) is a transmembrane protein encoded by the MET gene and belongs to the tyrosine kinase receptor superfamily, with the predominant expression in epithelial cells. Hepatocyte growth factor (HGF), also known as scatter factor (SF), is currently the main ligand for c-Met with a high ligand/receptor affinity. It is widely present in various human tissues and organs and is mainly expressed in interstitial cells. When HGF binds to c-Met in an extracellular domain, it triggers c-Met dimerization and promotes the transphosphorylation of two catalytic active sites Tyr1234 and Tyr1235 in a c-Met activation loop, which in turn leads to autophosphorylation of Tyr1349 and Tyr1356 in the C terminus of the receptor protein, thereby recruiting a variety of downstream cellular effectors and effector molecules, activating a series of downstream signaling pathways, such as PI3K-Akt, Ras-MAPK, STAT and Wnt/β-catenin etc. c-Met/HGF is crucial for promoting cell proliferation, cell growth, cell migration, vascular invasion and angiogenesis, c-Met gene abnormalities mainly include three types, namely: MET exon 14 skipping mutation, MET gene amplification and c-Met protein overexpression, c-Met gene abnormalities may cause abnormal activation of the c-Met pathway, leading to overactivation of downstream pathways to induce cancer. At present, c-Met small-molecule kinase inhibitors are the most prevalent and therapeutically promising method for blocking the c-Met/HGF signaling pathway . These small-molecule kinase inhibitors can act on the catalytic domain within the membrane to prevent protein phosphorylation, thereby blocking signal transduction and achieving targeted cancer treatment. 6-(1-Cyclopropyl-1-hydro-pyrazol-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazol-5-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine is a highly selective c-Met inhibitor for treating cancers caused by c-Met gene abnormalities. It has been granted breakthrough therapy designation by China National Medical Products Administration (NMPA) for the treatment of nonsmall cell lung cancer patients with c-Met exon 14 mutations. Its structural formula is represented by formula (I) as follows: At present, there are no published reports on the crystal forms of the free base of the compound represented by formula (I). SUMMARY OF THE INVENTION In order to overcome the defects of the prior art, the present invention provides crystal form of a [1,2,4]triazolo[4,3-b]pyridazine compound as a c-Met inhibitor, and preparation method therefor and use thereof. The crystal forms of the present invention are free base and used for treating tumor diseases. The crystal forms of the present invention have good chemical and physical stability and low hygroscopicity, and are less affected by heat, humidity, and light, thereby facilitating storage. Most importantly, a crystal form B of the present invention has a relatively low incipient melting temperature, and when the crystal form B is used in a hot-melt extrusion process, a sample preparation process is smooth, and a prepared solid dispersion has a low impurity content of related substance, which is beneficial to improving the quality of pharmaceuticals. The present invention provides a crystal form A of 6-(1-cyclopropyl-1-hydro-pyrazol-4-yl)-3-(difluoro(6-fluoro-2-methyl-(dihydro-indazol-5-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazine represented by formula (I), wherein with Cu-Kα radiation, the crystal form A has characteristic peaks at 2θvalues of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 24.25°, and 25.43° in a X-ray powder diffraction pattern expressed in 2θ angles, with a 2θ error range of ± 0.2°, In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A shows characteristic peaks at 2θ values of 7.47°, 10.30°, 12.47°, 14.18°, 17.19°, 17.54°, 17.85°, 18.15°, 20.39°, 24.25°, 25.43°, 25.97°, and 26.43°, with a 2θ error range of ± 0.2°. In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1. In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form A shows characteristic peaks having 2θ values shown in the table below, with a 2θ error range of ± 0.2°. No.2θ angle (°)No.2θ angle (°)No.2θ angle (°)No.2θ angle (°)17.47°1217.54°2322.90°3428.57°28.20°1317.85°2423.18°3529.27°310.30°1418.15°2523.76°3629.75°411.26°1518.86°2624.25°3731.93°512.47°1619.31°2724.75°3833.91°613.79°1719.752825.43°3935.50°714.18°1820.10°2925.97°4036.94°814.89°1920.39°3026.43°4137.46°915.86°2020.98°3127.08°4238.36°1016.36°2121.97°3227.53°//1117.19°2222.48°3328.01°// In some embodiments of the present invention, a thermogravim