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CN-114685492-B - Crystal form of TAS-116, preparation method, pharmaceutical composition and application thereof

CN114685492BCN 114685492 BCN114685492 BCN 114685492BCN-114685492-B

Abstract

The invention relates to the technical field of drug crystal forms, in particular to a crystal form of TAS-116, and a preparation method, a drug composition and application thereof. The crystal form of the TAS-116 has the advantages of better solubility, dissolution speed, crystal form stability, difficult moisture absorption and the like.

Inventors

  • SHENG XIAOHONG
  • SHENG XIAOXIA
  • WU TAO
  • LV KANGLE
  • YU PENG
  • HU CHENYANG

Assignees

  • 杭州领业医药科技有限公司

Dates

Publication Date
20260505
Application Date
20211231
Priority Date
20201231

Claims (11)

  1. 1. A crystal form III of a compound TAS-116 with a structural formula shown as a formula (I), Formula (I) Characterized in that Cu-K alpha radiation is used, and the X-ray powder diffraction pattern of the crystal form III has a2 theta value of 3.20 ±0.2 、6.39 ±0.2 、10.40 ±0.2 、11.41 ±0.2 、12.94 ±0.2 And 19.48 ±0.2 With characteristic peaks.
  2. 2. Form III according to claim 1, characterized in that the X-ray powder diffraction pattern of form III is 3.20 at 2-theta values using Cu-ka radiation ±0.2 、6.39 ±0.2 、10.40 ±0.2 、11.41 ±0.2 、12.94 ±0.2 、17.58 ±0.2 、18.26 ±0.2 、19.48 ±0.2 、21.71 ±0.2 、22.69 ±0.2 And 23.65 ±0.2 With characteristic peaks.
  3. 3. Form III according to claim 2, characterized in that the X-ray powder diffraction pattern of form III has characteristic peaks at the following diffraction angles using Cu-ka radiation, the 2-theta values and relative intensities of which are shown in the table below:
  4. 4. A form III according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern of form III is substantially as shown in figure 4.
  5. 5. A form III according to any of claims 1-3, wherein the fourier infrared spectrum of form III has characteristic peaks at wavenumbers 1650 cm -1 ±2 cm -1 、1569 cm -1 ±2 cm -1 、1504 cm -1 ±2 cm -1 、1424cm -1 ±2 cm -1 、1272cm -1 ±2 cm -1 、1030cm -1 ±2 cm -1 、823cm -1 ±2 cm -1 、812 cm -1 ±2 cm -1 、748cm -1 ±2 cm -1 、711cm -1 ±2 cm -1 、668 cm -1 ±2 cm -1 and 653 cm -1 ±2 cm -1 .
  6. 6. The preparation method of the crystal form III according to any one of claims 1 to 4, comprising any one of the following methods: (1) Forming suspension of compound TAS-116 solid in solvent 1, stirring, separating solid, drying to obtain crystal form III, Wherein the solvent 1 is selected from dioxane; the mass volume ratio of the compound TAS-116 solid to the solvent 1 is 10-200:1; the stirring time is 10-168 hours; The stirring is carried out at room temperature; Heating the obtained solid at the temperature of 60-150 ℃ for 5 minutes-16 hours after drying; (2) Forming a solution of a compound TAS-116 solid in a solvent 2, cooling, separating the solid, drying to obtain a crystal form III, Wherein the solvent 2 is selected from tetrahydrofuran and chloroform; the mass volume ratio of the solute to the solvent 2 in the solution is 5-100:1; the temperature of the formed solution is 60-80 ℃; cooling to 10-50 ℃; The stirring time is 2-24 hours.
  7. 7. The process for preparing form III according to claim 6, wherein, in the process (1), The stirring time is 16-72 hours; And heating the obtained solid at the temperature of 80-130 ℃ for 5 minutes-16 hours after drying.
  8. 8. The process for preparing form III according to claim 6, wherein, in the process (2), And cooling to 10-40 ℃.
  9. 9. The process for preparing form III according to claim 6 or 8, wherein, in the process (2), Adding crystal form III seed crystal of TAS-116 in the cooling process; The seed crystal addition amount is 10% -30% of the TAS-116 solid.
  10. 10. A pharmaceutical composition comprising the crystalline form III of any one of claims 1-5, or the crystalline form III obtained by the process of any one of claims 6-9, and at least one pharmaceutically acceptable carrier.
  11. 11. Use of the crystalline form III according to any one of claims 1 to 5, the crystalline form III according to any one of claims 6 to 9, or the pharmaceutical composition according to claim 10 for the manufacture of a medicament for the treatment of cancer selected from oesophageal cancer, stomach cancer, colon cancer, rectal cancer.

Description

Crystal form of TAS-116, preparation method, pharmaceutical composition and application thereof Technical Field The present application relates to the field of pharmaceutical chemistry. In particular, the application relates to a crystal form of TAS-116, a preparation method, a pharmaceutical composition and application thereof. Background TAS-116 is a selective heat shock protein 90 (HSP 90) inhibitor for treating gastrointestinal cancer such as colon cancer and gastric stromal tumor. Currently, TAS-116 is being developed for clinical studies in patients with gastrointestinal cancer. TAS-116 is 3-ethyl-4- { 3-isopropyl-4- (4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl) -1H-pyrazolo [3,4-b ] pyridin-1-yl } benzamide, also known as THS-1593, of formula C 25H26N8 O and of molecular weight 454.53, of formula: patent CN102471335B discloses a general structure comprising TAS-116 compounds. Patent CN104710420B discloses a specific structure of TAS-116 and discloses a process for preparing TAS-116 in free form, referring to TAS-116 as a white solid. Patent CN107531707B discloses form I crystals (hereinafter referred to simply as "form I") and form II crystals (hereinafter referred to simply as "form II") of TAS-116, wherein form I has only an XRPD pattern, the oral absorbability of form I is problematic, form II is an anhydrate, and the patent also states that form II is a form superior to form I. The inventors found during the course of the study that the sample of TAS-116 prepared according to example 102 of patent CN104710420B was crystalline form II and that the DMSO (dimethylsulfoxide) residue of the obtained sample was very high, and still had more residue when washed with diethyl ether. The inventors found that form I appeared after more than 2 hours of form II sample remained in the solvent of example 102, indicating that form II had a problem with stability. The inventors have also found during the course of the study that crystal form I of TAS-116 prepared according to CN107531707B is unstable and readily undergoes a form transformation to form II upon standing at room temperature (20-30 ℃). Form I requires more severe storage conditions to stabilize, indicating that its pharmaceutically acceptable value is not high. The present inventors have also found during the course of the study that the stability of crystal form II of TAS-116 prepared according to the CN107531707B patent is greatly limited, and that in addition to the instability in the solvent of example 102 in CN104710420B described above, there are also various other environments in which crystal transformation occurs, and different degrees of crystal form I occur. In view of the deficiencies of the prior art, particularly in respect of stability, there is a need in the art to develop a more stable solid form of TAS-116 with more advantageous properties. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide a TAS-116 crystal form with better physicochemical properties, and a preparation method, a pharmaceutical composition and application thereof. Compared with the known TAS-116 compound, the TAS-116 crystal form has better crystal form stability, has other unexpected effects, mainly shows better solubility and dissolution speed, better particle morphology, higher crystallinity, better hygroscopicity and the like, and is further considered to have better flowability, preparation processability and bioavailability. According to an object of the present invention, a first aspect of the present invention provides a TAS-116 form, hereinafter referred to as form III. The crystal form III of the invention is an anhydrous substance, and the structural formula is shown as the formula (I): Using Cu-ka radiation, the X-ray powder diffraction pattern of form III has characteristic peaks at 2θ values of 6.39 ° ± 0.2 °, 10.40 ° ± 0.2 °, 12.94 ° ± 0.2 ° and 19.48 ° ± 0.2 °. Preferably, using Cu-ka radiation, the X-ray powder diffraction pattern of form III has characteristic peaks at 2θ values of 3.20 ° ± 0.2 °, 6.39 ° ± 0.2 °, 10.40 ° ± 0.2 °, 11.41 ° ± 0.2 °, 12.94 ° ± 0.2 ° and 19.48 ° ± 0.2 °. More preferably, using Cu-ka radiation, the X-ray powder diffraction pattern of form III has characteristic peaks at 2 theta values of 3.20°±0.2°、6.39°±0.2°、10.40°±0.2°、11.41°±0.2°、12.94°±0.2°、17.58°±0.2°、18.26°±0.2°、19.48°±0.2°、21.71°±0.2°、22.69°±0.2° and 23.65 ° ± 0.2 °. Further preferably, using Cu-ka radiation, the X-ray powder diffraction pattern of form III has characteristic peaks at the following diffraction angles, with 2 theta values and relative intensities as shown in the following table: without limitation, the X-ray powder diffraction (XRPD) pattern of form III is substantially as shown in figure 4. Without limitation, the Differential Scanning Calorimetric (DSC) profile of form III is shown in figure 5. The melting point set value of the crystal form III is 269 ℃, and the peak value is 270 ℃. Without limitati