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EP-4092014-B1 - CRYSTALLINE FORM OF FLUVATINIB METHANESULFONATE AND PREPARATION METHOD THEREFOR

EP4092014B1EP 4092014 B1EP4092014 B1EP 4092014B1EP-4092014-B1

Inventors

  • HE, Shuai
  • ZHANG, YANG
  • LIU, QIANG
  • CHEN, Zhengxia
  • DAI, Meibi
  • FAN, BIN
  • XIE, Peiyu

Dates

Publication Date
20260506
Application Date
20210316

Claims (6)

  1. A crystalline form I of fluvatinib mesylate, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 9.60±0.2°, 22.49±0.2° and 23.07±0.2'; preferably, its X-ray powder diffraction pattern further has characteristic diffraction peaks at 2θ degrees of 10.74±0.2°, 16.79±0.2°, 17.51±0.2°, 18.50±0.2°, 20.64±0.2°, 20.85±0.2°, 21.51±0.2°, 23.73±0.2°, 24.84±0.2°, 26.51±0.2°, 27.05±0.2°, 27.88±0.2°, 28.60±0.2° and 29.74±0.2°.
  2. A crystalline form III of fluvatinib mesylate, wherein its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°; preferably, its X-ray powder diffraction pattern further has characteristic diffraction peaks at 2θ degrees of 10.25±0.2°, 14.44±0.2°, 15.28±0.2°, 18.91±0.2°, 19.98±0.2°, 20.86±0.2°, 21.77±0.2°, 22.78±0.2°, and 24.98±0.2°.
  3. A method of preparing the crystalline form I of fluvatinib mesylate according to claim 1, comprising obtaining a mixed solution of fluvatinib mesylate with ethanol, stirring the mixed solution at a temperature of 20-30°C for 1h, filtering to obtain a solid, and drying the solid to obtain the crystalline form I of fluvatinib mesylate.
  4. A method of preparing the crystalline form III of fluvatinib mesylate according to claim 2, comprising obtaining a mixed solution of fluvatinib mesylate with ethanol, stirring the mixed solution at a temperature of 20-30 °C for 16-48 h, or at a temperature of 40 °C for 3-4 h or at a temperature of 55-65 °C for 2-3 h, filtering to obtain a solid, and drying the solid to obtain the crystalline form III of fluvatinib mesylate.
  5. A pharmaceutical composition, comprising the crystalline form I of fluvatinib mesylate according to claim 1 or the crystalline form III of fluvatinib mesylate according to claim 2, and a pharmaceutically acceptable adjuvant.
  6. The composition according to claim 5 for use in treating a tumor.

Description

This application claims the priority to Chinese Patent Application No. 202010063033.6, titled "CRYSTALLINE FORM OF FLUVATINIB OR FLUVATINIB METHANESULFONATE AND PREPARATION METHOD THEREFOR", filed on January 19, 2020 with the China National Intellectual Property Administration. FIELD The present disclosure relates to the field of medicinal chemistry, and specifically relates to a crystalline form of fluvatinib mesylate and preparation method thereof. BACKGROUND Liver cancer is a common malignant tumor in China. The database reported by the National Cancer Center in 2017 showed that the number of new liver cancer cases reached 362,000, and the incidence rate ranked third in China; the number of liver cancer deaths reached 316,000, ranking second. Hepatocellular carcinoma (HCC) occurs insidiously without obvious symptoms in early stage, so most of patients have missed the opportunity for surgery when they are diagnosed. Surgery, interventional therapy and chemotherapy all are not satisfactory for the treatment of liver cancer. Currently, 5-year survival rate of liver cancer is still very low. Targeted drug therapy for HCC was born with the development of science and technology. The current target drugs for liver cancer mainly include epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VEGFR) antagonists, multikinase inhibitors, the PI3K/Akt/mTOR signaling pathway, hepatocyte growth factor receptor (Met) inhibitors, and TGFβ receptor inhibitors. Currently approved TKI-targeting drugs mainly include sorafenib, lenvatinib and regorafenib. Thus, therapeutic drugs are very limited. CN109134365 discloses an active compound or pharmaceutically acceptable salt thereof that acts on multi-targets including VEGFR 1-3 types, fibroblast growth factor receptor 1-3 types, RET, Kit and PDGFR, having a chemical structural formula I: Its chemical name is 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy) -7-methoxy-6-quinolinecarboxamide, and drug name is fluvatinib. The compound is highly active and provides a potential new treatment option for patients with tumors such as liver and kidney. A methanesulfonate salt form of fluvatinib is disclosed in Embodiment 1 of EP3689351A1, which is demonstrated to be useful for treating a disease related to tyrosine kinase inhibitors. However, the inventors have found that the free base and pharmaceutically acceptable salts of fluvatinib, especially the methanesulfonate salt, all exhibit polymorphism, which greatly affects drug quality control, since different crystalline forms have polymorphic properties, such as different stability, solubility, and druggability. Therefore, it needs to develop a crystalline form with good stability and druggability. SUMMARY The objective of the present disclosure is to provide a crystalline form of fluvatinib methanesulfonate salt. Fluvatinib is represented by formula I, and its full name is 4-(2-fluoro-3-chloro-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide. The fluvatinib methanesulfonate (also called as "fluvatinib mesylate",which refers to the same compound) is the compound represented by formula II, According to the present disclosure, a crystalline form I of fluvatinib mesylate is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 9.60±0.2°, 22.49±0.2° and 23.07±0.2°, and further its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 10.74±0.2°, 16.79±0.2°, 17.51±0.2°, 18.50±0.2°, 20.64±0.2°, 20.85±0.2°, 21.51±0.2°, 23.73±0.2°, 24.84±0.2°, 26.51±0.2°, 27.05±0.2°, 27.88±0.2°, 28.60±0.2° and 29.74±0.2°. According to the present disclosure, a crystalline form III of fluvatinib mesylate is provided, and its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 6.28±0.2°, 10.65±0.2°, 17.87±0.2°, 19.48±0.2°, 23.57±0.2°, and 24.38±0.2°, and further its X-ray powder diffraction pattern has characteristic diffraction peaks at 2θ degrees of 10.25±0.2°, 14.44±0.2°, 15.28±0.2°, 18.91±0.2°, 19.98±0.2°, 20.86±0.2°, 21.77±0.2°, 22.78±0.2°, and 24.98±0.2°. In another aspect, the present disclosure provides methods of preparing the crystalline form I and III of fluvatinib mesylate as set out in the appended set of claims In an embodiment, the present disclosure provides a crystalline form I of fluvatinib mesylate, which exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at 2θ degrees of 9.60±0.2°, 22.49±0.2° and 23.07±0.2°. Further, the above-mentioned crystalline form I of fluvatinib mesylate exhibits an X-ray powder diffraction pattern having characteristic diffraction peaks at 2θ (±0.2°) degrees of 10.74, 16.79, 17.51, 18.50, 20.64, 20.85, 21.51, 23.73, 24.84, 26.51, 27.05, 27.88, 28.60 and 29.74. Preferably, the crystalline form I of fluvatinib mesylate exhibits an X-ray powder diffraction pattern having characteristic diffrac