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EP-4740944-A2 - SOLID FORMS OF 3-(5-FLUOROBENZOFURAN-3-YL)-4-(5-METHYL-5H-[1,3]DIOXOLO[4,5-F]INDOL-7-YL)PYRROLE-2,5-DIONE

EP4740944A2EP 4740944 A2EP4740944 A2EP 4740944A2EP-4740944-A2

Abstract

The present disclosure relates to solid forms of 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione, processes for preparation thereof, pharmaceutical compositions thereof, and uses thereof in treating disease.

Inventors

  • ZHANG, Yamin

Assignees

  • Actuate Therapeutics Inc.

Dates

Publication Date
20260513
Application Date
20181016

Claims (11)

  1. A solid form, which is crystalline Form II of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione (9-ING-41).
  2. The solid form of claim 1, characterized by an X-ray powder diffraction pattern comprising a peak at 7.8 ± 0.2 degrees 2-theta, on the 2-theta scale with lambda = 1.54 angstroms (Cu Kα).
  3. The solid form of claim 1, characterized by an X-ray powder diffraction pattern comprising peaks at 7.8, 12.9, 15.8, 18.1, 18.9, 19.5, 22.1, 22.7, 28.0, and 28.5, ± 0.2 degrees 2-theta, on the 2-theta scale with lambda = 1.54 angstroms (Cu Kα).
  4. The solid form of claim 1, characterized by : (i) an X-ray powder diffraction pattern comprising peaks at 7.8, 12.9, 15.8, and 18.9, ± 0.2 degrees 2-theta, on the 2-theta scale with lambda = 1.54 angstroms (Cu Kα); or (ii) an X-ray powder diffraction pattern comprising peaks at 12.9, 18.1, 28.0, and 28.5, ± 0.2 degree 2-theta, on the 2-theta scale with lambda = 1.54 angstroms (Cu Kα); or (iii) an X-ray powder diffraction pattern comprising peaks at three or more of 7.8, 12.9, 15.8, 18.1, 18.9, 19.5, 22.1, 22.7, 28.0, and 28.5, ± 0.2 degrees 2-theta, on the 2-theta scale with lambda = 1.54 angstroms (Cu Kα).
  5. A process for preparing the solid form of any one of claims 1 to 4, comprising (i) dissolving 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione in a warm solvent to form a solution; and (ii) cooling the solution.
  6. The process of claim 5, comprising: (i) mixing 150 ml of a 10:1 (vol/vol) mixture of isoamyl alcohol:acetonitrile with 2.0 g of Form I 9-ING-41; (ii) heating the mixture to 90 °C to give a solution; (iii) filtering the solution and seeding same with Form II 9-ING-41; and (iv) cooling to room temperature with stirring to obtain crystalline Form II 9-ING-41.
  7. An amorphous solid of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrol-2,5-dione (9-ING-41), wherein the amorphous solid is obtained using a method comprising one of: (a) heating 9-ING-41 Form II to 260°C at a rate of 10°C/min to melt same, then holding at 0°C for 15 minutes; or (b) heating 9-ING-41 Form II to 260°C at a rate of 10°C/min, then cooling to -40°C, then reheating to 260°C at a rate of 10°C/min, and then cooling to 40°C.
  8. A pharmaceutical composition comprising the amorphous solid of claim 7 and a pharmaceutically acceptable excipient.
  9. The amorphous solid of claim 7 for use in treating cancer.
  10. The amorphous solid for use according to claim 9, wherein the cancer is brain, lung, breast, ovarian, bladder, neuroblastoma, renal, or pancreatic cancer.
  11. The amorphous solid of claim 7 for use in treating traumatic brain injury in a patient.

Description

Cross-Reference To Related Application The application claims the benefit of priority to United States Provisional Application No. 62/572,603, filed on October 16, 2017, the entirety of which is incorporated by reference herein. Field of the Disclosure The present disclosure relates to solid forms of 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione, processes for preparation thereof, pharmaceutical compositions thereof, and uses thereof in treating disease. Background of the Disclosure 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione ("9-ING-41") has the following chemical structure: 9-ING-41 has been reported as being useful for the treatment of cancers, including brain, lung, breast, ovarian, bladder, neuroblastoma, renal, and pancreatic cancers, as well as for treatment of traumatic brain injury. The structure, properties, and/or biological activity of 9-ING-41 are set forth in U.S. Patent Number 8,207,216; Gaisina et al., From a Natural Product Lead to the Identification of Potent and Selective Benzofuran-3-yl-(indol-3-yl)maleimides as Glycogen Synthase Kinase 3β Inhibitors That Suppress Proliferation and Survival of Pancreatic Cancer Cells, J. Med. Chem. 2009, 52, 1853-1863; and Hilliard, et al., Glycogen synthase kinase 3β inhibitors induce apoptosis in ovarian cancer cells and inhibit in-vivo tumor growth, Anti-Cancer Drugs 2011, 22:978-985. There is a need for novel solid forms (including polymorphs and solvates) of 9-ING-41. Summary of the Disclosure The present disclosure relates to solid forms of 9-ING-41, processes for preparing solid forms of 9-ING-41, pharmaceutical compositions comprising solid forms of 9-ING-41, and methods of treatment comprising administering solid forms of 9-ING-41. In some aspects, the present disclosure is directed to a solid form which is crystalline Form II of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione ("9-ING-41"). The present disclosure also provides processes for preparing solid forms of 9-ING-41. The present disclosure also provides pharmaceutical compositions comprising the solid forms of 9-ING-41. The present disclosure also provides methods of treating disease comprising administering to a patient in need thereof a therapeutically effective amount of a disclosed solid form of 9-ING-41. Brief Description of the Figures Figure 1 shows an X-ray powder diffractogram (XRPD) of Form II of 9-ING-41.Figure 2 shows an X-ray powder diffractogram (XRPD) of Form II of 9-ING-41.Figure 3 shows a differential scanning calorimetry (DSC) profile of Form II of 9-ING-41.Figure 4 shows a thermogravimetric analysis (TGA) profile of Form II of 9-ING-41. Detailed Description of the Invention The present disclosure relates to solid forms of 9-ING-41, processes for preparation thereof and pharmaceutical compositions comprising the solid state form(s). The disclosure also relates to the conversion of the described solid state forms of 9-ING-41 to other solid state forms of 9-ING-41, 9-ING-41 salts and their solid state forms thereof. The name "9-ING-41" is another name for 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione, and the two names are used interchangeably herein. The solid state forms of 9-ING-41 according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents and advantageous processing and handling characteristics such as compressibility, or bulk density. A crystal form may be referred to herein as being characterized by graphical data "as shown in" or "as characterized by" a Figure. Such data include, for example, powder X-ray diffractograms (XRPD), Differential Scanning Calorimetry (DSC) thermograms, thermogravimetric analysis (TGA) profiles, and differential vapor sorption profiles (DVS). As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form which can not necessarily be described by reference to numerical values or peak positions alone. Thus, the term "substantially as shown in" when referring to graphical data in a Figure herein means a pattern that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations, when considered by one of ordinary skill in the art. The skilled person would readily be able to compare the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of gra