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

Abstract

To provide 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 their preparation, and pharmaceutical compositions thereof.SOLUTION: Provided is a solid 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), wherein the solid is solvate 1, solvate 2, solvate 3, solvate 4, solvate 5, solvate 6, solvate 7, solvate 8, or solvate 9, or a mixture thereof.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 544,277, filed August 11, 2017, which is incorporated herein by reference in its entirety.

[0002] 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 its preparation, pharmaceutical compositions thereof, and its use in the treatment of disease.

[0003] 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: [ka]

[0004] 9-ING-41 is reported to be useful in the treatment of cancer, including brain, lung, breast, ovarian, bladder, neuroblastoma, kidney, and pancreatic cancer, as well as in the treatment of traumatic brain injury.

[0005] The structure, properties, and / or biological activity of 9-ING-41 are described in U.S. Pat. No. 8,207,216, Gaisina et al. (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. (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).

[0006] There is a need for new solid forms of 9-ING-41, including polymorphs and solvates. Summary of the Invention

[0007] 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.

[0008] In some embodiments, the disclosure relates to a solid form that is crystalline Form I 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"). In other embodiments, the disclosure relates to a solid form that is Solvate 1, Solvate 2, Solvate 3, Solvate 4, Solvate 5, Solvate 6, Solvate 7, Solvate 8, or Solvate 9 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"). In yet another aspect, the present disclosure relates to amorphous 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”).

[0009] The present disclosure also provides a process for preparing.

[0010] The present disclosure also provides pharmaceutical compositions comprising solid forms of 9-ING-41, as well as methods for their preparation.

[0011] The present disclosure also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of the disclosed solid form of 9-ING-41. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the X-ray powder diffractogram (XRPD) of Form I of 9-ING-41. [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) profile of Form I of 9-ING-41. [Figure 3] FIG. 3 shows the thermogravimetric analysis (TGA) profile of Form I of 9-ING-41. [Figure 4] FIG. 4 shows the dynamic vapor sorption ("DVS") profile of Form I of 9-ING-41. [Figure 5]FIG. 5 shows the X-ray powder diffraction diagram (XRPD) of 9-ING-41 solvate 6. [Figure 6] FIG. 6 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 6. [Figure 7] FIG. 7 shows the X-ray powder diffraction diagram (XRPD) of 9-ING-41 solvate 7. [Figure 8] FIG. 8 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 7. [Figure 9] FIG. 9 shows the X-ray powder diffraction diagram (XRPD) of 9-ING-41 solvate 8. [Figure 10] FIG. 10 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 8. [Figure 11] FIG. 11 shows the X-ray powder diffraction diagram (XRPD) of 9-ING-41 solvate 9. [Figure 12] FIG. 12 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 9. [Figure 13] FIG. 13 shows the X-ray powder diffractogram (XRPD) of 9-ING-41 solvate 3. [Figure 14] FIG. 14 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 3. [Figure 15] FIG. 15 shows the X-ray powder diffractogram (XRPD) of 9-ING-41 solvate 1. [Figure 16] FIG. 16 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 1. [Figure 17] FIG. 17 shows the X-ray powder diffractogram (XRPD) of 9-ING-41 solvate 2. [Figure 18] FIG. 18 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 2. [Figure 19] FIG. 19 shows the X-ray powder diffractogram (XRPD) of 9-ING-41 solvate 4. [Figure 20] FIG. 20 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 4. [Figure 21] FIG. 21 shows the X-ray powder diffractogram (XRPD) of 9-ING-41 solvate 5. [Figure 22] FIG. 22 shows the thermogravimetric analysis (TGA) profile of 9-ING-41 solvate 5. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure relates to solid forms of 9-ING-41, processes for preparing same, and pharmaceutical compositions having the solid state forms. The present 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 those solid state forms.

[0014] The name "9-ING-41" is an alternative name for 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl]-2,5-dihydro-1H-pyrrole-2,5-dione, which is an alternative name for 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione. These names are used interchangeably herein.

[0015] The solid 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, chemical stability with respect to polymorphic transformation, thermal and mechanical stability, stability such as stability with respect to dehydration and / or storage stability, low hygroscopicity, low residual solvent content, advantageous processing and handling properties such as compressibility and bulk density.

[0016] As used herein, crystalline forms may be referred to as being characterized by graphical data as "shown" in a figure. Such data include, for example, X-ray powder diffractograms (XRPDs), differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA) profiles, and dynamic vapor sorption profiles (DVS). As is well known in the art, graphical data may provide additional technical information that further defines each solid form, which cannot necessarily be described by reference to numerical values ​​or peak positions alone. Thus, the term "substantially shown" when referring to graphical data in the figures herein does not necessarily mean that the data is identical to that depicted herein, but that it falls within the range of experimental error or deviation, as considered by those skilled in the art. Those skilled in the art will be able to easily compare the graphical data in the figures herein with graphical data generated for an unknown crystalline form and determine whether the two sets of graphical data characterize the same crystalline form or two different crystalline forms.

[0017] As used herein, solid, crystalline forms may be referred to as "polymorphically pure" or "substantially free of other forms." As used herein in this context, the phrase "substantially free of other forms" is understood to mean that the solid form contains about 20% or less, about 10% or less, about 5% or less, about 2% or less, about 1% or less, or 0% of other forms of the subject compound, as measured, for example, by XRPD. Thus, a solid form of 9-ING-41 described herein as being substantially free of other solid forms is understood to contain about 80% (w / w) or more, about 90% (w / w) or more, about 95% (w / w) or more, about 98% (w / w) or more, about 99% (w / w) or more, or about 100% of the subject solid form of 9-ING-41. Thus, in some embodiments of the present disclosure, the described solid forms of 9-ING-41 may contain about 1% to about 20% (w / w), about 5% to about 20% (w / w), or about 5% to about 10% (w / w) of one or more other solid forms of 9-ING-41.

[0018] As used herein, unless otherwise stated, XRPD peaks reported herein are measured using CuKα radiation, λ=1.5419 Å.

[0019] The modifier "about" should be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses a range of "2 to 4." When used to modify a single number, the term "about" refers to plus or minus 10% of and includes the recited number. For example, "about 10%" indicates a range of 9% to 11%, and "about 1" means 0.9 to 1.1.

[0020] As used herein, the term "solvate" refers to a crystalline form that incorporates a solvent into the crystalline structure, unless otherwise specified. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in the solvate may be present in a stoichiometric or non-stoichiometric amount.

[0021] In some aspects, the present disclosure relates to solid forms of 9-ING-41.

[0022] In some embodiments, the solid form is crystalline Form I of 9-ING-41. In other embodiments, the solid form is crystalline Form I of 9-ING-41 substantially free of other solid forms of 9-ING-41. Crystalline Form I of 9-ING-41 exhibits an XRPD pattern substantially as shown in FIG.

[0023] The XRPD of crystalline Form I of 9-ING-41 shown in FIG. 1 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacings (d values), and relative intensities as shown in Table 1. [Table 1] TIFF2026012715000004.tif239112TIFF2026012715000005.tif237168

[0024] In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising a peak at one of the angles listed in Table 1 above. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising a plurality of peaks at one of the angles listed in Table 1 above. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising two peaks selected from the angles listed in Table 1 above. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising three peaks selected from the angles listed in Table 1 above. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising four peaks selected from the angles listed in Table 1 above. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising five peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising six peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising seven peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising eight peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising nine peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising ten peaks selected from the angles listed in Table 1 above. In another embodiment, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern comprising more than ten peaks selected from the angles listed in Table 1 above.

[0025] In some embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at 5.5 degrees ± 0.2 degrees 2-theta. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at 20.4, 22.1, and 24.7 degrees ± 0.2 degrees 2-theta. In other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at 17.7, 18.4, 18.9, and 20.8 degrees ± 0.2 degrees 2-theta. In yet other embodiments, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at 5.5, 9.4, 11.8, 13.4, 15.3, 24.7, and 29.3 degrees ± 0.2 degrees 2-theta.

[0026] In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at three or more of the following angles: 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ± 0.2 degrees two-theta. In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at four or more of the following angles: 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ± 0.2 degrees two-theta. In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at five or more of the following angles: 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ± 0.2 degrees two-theta. In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at six or more of the following angles: 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ± 0.2 degrees two-theta. In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at seven or more of the following angles: 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ±0.2 degrees two-theta.

[0027] Crystalline Form I of 9-ING-41 can be characterized by a DSC thermogram substantially as shown in Figure 2. As Figure 2 shows, crystalline Form I of 9-ING-41 exhibits an endothermic peak at 228.00°C. When heated at a rate of 10°C / min, the peak onset temperature is 226.75°C with a melting enthalpy of 76.29 J / g. In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by a DSC thermogram with an endothermic peak at about 228°C. In other embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by a DSC melting enthalpy of about 76 J / g.

[0028] Crystalline Form I of 9-ING-41, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 3. As shown in Figure 3, crystalline Form I of 9-ING-41 lost about 1% of its weight when heated between about 150°C and about 235°C when heated at a rate of 10°C / min.

[0029] Crystalline Form I of 9-ING-41 can be characterized by a DVS profile substantially as shown in Figure 4. As Figure 4 shows, crystalline Form I of 9-ING-41 gained approximately 0.23 wt % at 80% relative humidity.

[0030] In some embodiments of the present disclosure, crystalline Form I of 9-ING-41 is characterized by an XRPD pattern with peaks at 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ±0.2 degrees two-theta, and a DSC thermogram with an endothermic peak at about 228° C. when heated at a rate of 10° C. / min.

[0031] In another embodiment of the present disclosure, the solid form of 9-ING-41 is a solvate. In a preferred embodiment, the solid form of 9-ING-41 is solvate 6. In another embodiment, the solid form is 9-ING-41 solvate 6, which is substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 6 is characterized by an XRPD substantially as shown in Figure 5.

[0032] The XRPD of 9-ING-41 solvate 6 shown in FIG. 5 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 2. [Table 2] TIFF2026012715000007.tif71114

[0033] In some embodiments of the present disclosure, 9-ING-41 solvate 6 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 2 above.

[0034] In some embodiments, 9-ING-41 solvate 6 is characterized by an XRPD pattern with a peak at 8.3 degrees ± 0.2 degrees 2-theta. In other embodiments, 9-ING-41 solvate 6 is characterized by an XRPD pattern with one, two, three, four, or five peaks selected from 8.3, 14.7, 16.7, 22.2, and 24.6 degrees ± 0.2 degrees 2-theta.

[0035] 9-ING-41 solvate 6 can be characterized by a TGA profile substantially as shown in Figure 6. As Figure 6 shows, solvate 6 lost approximately 4.5% by weight upon heating between 120°C and 150°C when heated at a rate of 10°C / min.

[0036] In another embodiment of the present disclosure, the solid form is 9-ING-41 solvate 7. In another embodiment, the solid form is 9-ING-41 solvate 7 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 7 may be characterized by an XRPD substantially as shown in FIG.

[0037] The XRPD of 9-ING-41 solvate 7 shown in FIG. 7 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 3. [Table 3]

[0038] In some embodiments of the present disclosure, 9-ING-41 solvate 7 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 3 above.

[0039] In some embodiments, 9-ING-41 solvate 7 is characterized by an XRPD pattern with a peak at 8.2 degrees ± 0.2 degrees 2-theta. In other embodiments, 9-ING-41 solvate 7 is characterized by an XRPD pattern with one, two, three, or four peaks selected from 8.2, 16.5, 24.6, and 24.8 degrees ± 0.2 degrees 2-theta.

[0040] 9-ING-41 solvate 7, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 8. As Figure 8 shows, solvate 7 lost approximately 5% by weight upon heating between 100°C and 160°C when heated at a rate of 10°C / min.

[0041] In another embodiment of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 8. In another embodiment, the solid form is 9-ING-41 solvate 8 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 8 may be characterized by an XRPD substantially as shown in Figure 9.

[0042] The XRPD of 9-ING-41 solvate 8 shown in FIG. 9 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 4. [Table 4] TIFF2026012715000010.tif73162

[0043] In some embodiments of the present disclosure, 9-ING-41 solvate 8 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 4 above.

[0044] In some embodiments, 9-ING-41 solvate 8 is characterized by an XRPD pattern with a peak at 6.2 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 8 is characterized by an XRPD pattern with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks selected from 6.2, 11.5, 12.5, 12.9, 15.0, 16.6, 18.8, 21.8, 25.2, and 27.2 ± 0.2 degrees two-theta.

[0045] 9-ING-41 solvate 8 may be characterized by a TGA profile substantially as shown in Figure 10. As Figure 10 shows, solvate 8 lost approximately 11.25 wt % when heated between 90°C and 120°C, and an additional 2.5 wt % between 130°C and 150°C when heated at a rate of 10°C / min.

[0046] In other embodiments of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 9. In other embodiments, the solid form is 9-ING-41 solvate 9 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 9 can be characterized by an XRPD substantially as shown in Figure 11.

[0047] The XRPD of 9-ING-41 solvate 9 shown in FIG. 11 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 5. [Table 5]

[0048] In some embodiments of the present disclosure, 9-ING-41 solvate 9 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 5 above.

[0049] In some embodiments, 9-ING-41 solvate 9 is characterized by an XRPD pattern with a peak at 7.2 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 9 is characterized by an XRPD pattern with one, two, three, four, five, six, or more peaks selected from 7.2, 14.5, 15.7, 19.0, 22.4, 25.2, and 26.2 ± 0.2 degrees two-theta.

[0050] 9-ING-41 solvate 9, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 12. As Figure 12 shows, solvate 9 lost approximately 7.5% by weight upon heating between 100°C and 160°C when heated at a rate of 10°C / min.

[0051] In another embodiment of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 3. In another embodiment, the solid form is 9-ING-41 solvate 3 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 3 may be characterized by an XRPD substantially as shown in Figure 13.

[0052] The XRPD of 9-ING-41 solvate 3 shown in FIG. 13 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 6. [Table 6] TIFF2026012715000013.tif143169

[0053] In some embodiments of the present disclosure, 9-ING-41 solvate 3 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 6 above.

[0054] In some embodiments, 9-ING-41 solvate 3 is characterized by an XRPD pattern with a peak at 8.0 ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 3 is characterized by an XRPD pattern with 1, 2, 3, 4, 5, 6, 7, or 8 peaks selected from 8.0, 14.6, 16.2, 16.3, 21.7, 23.0, 24.3, and 25.9 ± 0.2 degrees two-theta.

[0055] 9-ING-41 solvate 3, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 14. As Figure 14 shows, solvate 3 lost approximately 5.7% by weight upon heating between 100°C and 140°C when heated at a rate of 10°C / min.

[0056] In other embodiments of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 1. In other embodiments, the solid form is 9-ING-41 solvate 1 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 1 may be characterized by an XRPD substantially as shown in Figure 15.

[0057] The XRPD of 9-ING-41 solvate 1 shown in FIG. 15 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 7. [Table 7]

[0058] In some embodiments of the present disclosure, 9-ING-41 solvate 1 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 7 above.

[0059] In some embodiments, 9-ING-41 solvate 1 is characterized by an XRPD pattern with a peak at 7.2 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 1 is characterized by an XRPD pattern with one, two, three, four, five, or six peaks selected from 7.2, 11.0, 14.6, 14.8, 15.6, and 22.3 ± 0.2 degrees two-theta.

[0060] 9-ING-41 solvate 1, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 16. As Figure 16 shows, solvate 1 lost approximately 7.5% by weight upon heating between 80°C and 160°C when heated at a rate of 10°C / min.

[0061] In other embodiments of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 2. In other embodiments, the solid form is 9-ING-41 solvate 2 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 2 may be characterized by an XRPD substantially as shown in Figure 17.

[0062] The XRPD of 9-ING-41 solvate 2 shown in Figure 17 has reflection angles (degrees 2-theta ± 0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 8. [Table 8] TIFF2026012715000016.tif158169

[0063] In some embodiments of the present disclosure, 9-ING-41 solvate 2 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 8 above.

[0064] In some embodiments, 9-ING-41 solvate 2 is characterized by an XRPD pattern with a peak at 8.0 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 2 is characterized by an XRPD pattern with 1, 2, 3, 4, 5, 6, 7, or 8 peaks selected from 7.3, 8.0, 9.1, 10.1, 19.1, 19.3, 21.3, and 24.2 ± 0.2 degrees two-theta.

[0065] 9-ING-41 solvate 2, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 18. As Figure 18 shows, solvate 2 lost approximately 6% by weight upon heating between 90°C and 150°C when heated at a rate of 10°C / min.

[0066] In another embodiment of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 4. In another embodiment, the solid form is 9-ING-41 solvate 4 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 4 may be characterized by an XRPD substantially as shown in Figure 19.

[0067] The XRPD of 9-ING-41 solvate 4 shown in Figure 19 has reflection angles (degrees 2-theta ± 0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 9. [Table 9]

[0068] In some embodiments of the present disclosure, 9-ING-41 solvate 4 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 9 above.

[0069] In some embodiments, 9-ING-41 solvate 4 is characterized by an XRPD pattern with a peak at 21.2 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 4 is characterized by an XRPD pattern with one, two, three, four, five, six, or seven peaks selected from 9.8, 10.1, 10.9, 17.3, 20.9, 21.2, and 22.6 ± 0.2 degrees two-theta.

[0070] 9-ING-41 solvate 4, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 20. As Figure 20 shows, solvate 4 lost approximately 4.5% by weight upon heating between 60°C and 160°C when heated at a rate of 10°C / min.

[0071] In another embodiment of the present disclosure, the solid form of 9-ING-41 is 9-ING-41 solvate 5. In another embodiment, the solid form is 9-ING-41 solvate 5 substantially free of other solid forms of 9-ING-41. 9-ING-41 solvate 5 may be characterized by an XRPD substantially as shown in Figure 21.

[0072] The XRPD of 9-ING-41 solvate 5 shown in FIG. 21 has reflection angles (degrees 2-theta ±0.2 degrees 2-theta), line spacing (d-values), and relative intensities as shown in Table 10. [Table 10] TIFF2026012715000019.tif82166

[0073] In some embodiments of the present disclosure, 9-ING-41 solvate 5 is characterized by an XRPD pattern having a peak at one of the angles listed in Table 10 above.

[0074] In some embodiments, 9-ING-41 solvate 5 is characterized by an XRPD pattern with a peak at 8.1 degrees ± 0.2 degrees two-theta. In other embodiments, 9-ING-41 solvate 5 is characterized by an XRPD pattern with one, two, three, four, five, or six peaks selected from 5.4, 8.1, 14.8, 16.3, 21.6, and 24.0 ± 0.2 degrees two-theta.

[0075] 9-ING-41 solvate 5, when heated at a rate of 10°C / min, can be characterized by a TGA profile substantially as shown in Figure 22. As Figure 22 shows, solvate 1 lost approximately 2.5% by weight upon heating between 115°C and 130°C when heated at a rate of 10°C / min.

[0076] In some embodiments, the present disclosure relates to amorphous 9-ING-41, which is characterized by the absence of discernible peaks in an XRPD diffractogram.

[0077] In some embodiments, the present disclosure relates to a process for preparing the disclosed solid forms of 9-ING-41, hi some embodiments, the process comprises concentrating a solution of 9-ING-41 dissolved in a solvent or solvent mixture.

[0078] In some aspects, the present disclosure relates to a process for preparing crystalline Form I of 9-ING-41. In some embodiments, the process comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 dissolved in a mixture of ethyl acetate / dichloromethane / petroleum ether. In some embodiments, the volume ratio of ethyl acetate to dichloromethane to petroleum ether is about 1:1:5.

[0079] In other embodiments, the process for preparing crystalline Form I of 9-ING-41 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in ethyl acetate; 2-propanol / ethyl acetate in about a 1:1 volume ratio; 2-methyl-1-propanol / ethyl acetate in about a 1:1 volume ratio; 1-butanol / ethyl acetate in about a 1:1 volume ratio; 3-methylbutanol / tetrahydrofuran (THF) in about a 1:1 volume ratio; 3-methylbutanol / ethyl acetate in about a 1:1 volume ratio; THF / water in about a 1:1 volume ratio; acetonitrile / water in about a 1:1 volume ratio; methyl t-butyl ether (MTBE) / ethyl acetate in about a 1:1 volume ratio; or water / ethyl acetate in about a 1:1 volume ratio.

[0080] In yet another embodiment, the process for preparing crystalline Form I of 9-ING-41 comprises heating one or more solvates 1-9 at a sufficient temperature for a sufficient time to remove the solvent and produce Form I.

[0081] The present disclosure also encompasses processes for preparing 9-ING-41 solvates, particularly solvates 1-9. In some embodiments, the process for preparing 9-ING-41 solvate 6 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in about 1:1 volumetric ethanol / acetone or about 1:1 volumetric ethanol / ethyl acetate. In other embodiments, the process for preparing 9-ING-41 solvate 6 comprises slurrying 9-ING-41 Form I in ethanol.

[0082] In another embodiment, the process for preparing 9-ING-41 solvate 7 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in about 1:1 volumetric ratio of methanol / THF; about 1:1 volumetric ratio of methanol / acetonitrile; about 1:1 volumetric ratio of methanol / MTBE; about 1:1 volumetric ratio of methanol / acetone; and about 1:1 volumetric ratio of methanol / ethyl acetate. In another embodiment, the process for preparing 9-ING-41 solvate 7 comprises slurrying 9-ING-41 Form I in methanol.

[0083] In another embodiment, the process for preparing 9-ING-41 solvate 8 comprises slurrying 9-ING-41 Form I in ethyl acetate.

[0084] In another embodiment, the process for preparing 9-ING-41 solvate 9 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in acetone, acetonitrile / acetone in a volume ratio of about 1:1; MTBE / acetone in a volume ratio of about 1:1; or acetone / water in a volume ratio of about 1:1. In another embodiment, the process for preparing 9-ING-41 solvate 8 comprises slurrying 9-ING-41 Form I in acetone.

[0085] In other embodiments, the process for preparing 9-ING-41 solvate 3 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in about a 1:1 volume ratio of 2-methyl-1-propanol / acetone; or about a 1:1 volume ratio of 1-butanol / acetone.

[0086] In another embodiment, the process for preparing 9-ING-41 solvate 1 comprises concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in about a 1:1 volume ratio of acetone / ethyl acetate. In another embodiment, the process for preparing 9-ING-41 solvate 2 comprises concentrating a solution of 9-ING-41 in about a 1:1 volume ratio of acetone / toluene. In another embodiment, the process for preparing 9-ING-41 solvate 4 comprises concentrating a solution of 9-ING-41 in about a 1:1 volume ratio of 2-propanol / THF. In another embodiment, the process for preparing 9-ING-41 solvate 5 comprises concentrating a solution of 9-ING-41 in about a 1:1 volume ratio of 2-propanol / acetone.

[0087] The present disclosure also encompasses processes for preparing amorphous 9-ING-41. In some embodiments, amorphous 9-ING-41 is prepared by a process comprising rapidly cooling molten 9-ING-41 to about 0° C. In other embodiments, amorphous 9-ING-41 is prepared by a process comprising heating 9-ING-41 to about 260° C. at a rate of 10° C. / min, then cooling the sample to about −40° C., then reheating to about 260° C. at a rate of 10° C. / min, and then cooling to about 40° C. In yet other embodiments, amorphous 9-ING-41 is prepared by a process comprising concentrating (e.g., in vacuo or by evaporation) a solution of 9-ING-41 in about 1:1 volumetric ratio of ethanol / acetonitrile; about 1:1 volumetric ratio of ethanol / toluene; about 1:1 volumetric ratio of 2-propanol / acetonitrile; about 1:1 volumetric ratio of 2-methyl-1-propanol / acetonitrile; or about 1:1 volumetric ratio of MTBE / toluene.

[0088] The present disclosure encompasses pharmaceutical compositions comprising a solid form of 9-ING-41 of the present disclosure and at least one pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients will be known to those skilled in the art. The pharmaceutical composition can be administered in any convenient dosage form. Exemplary dosage forms include tablets, capsules, caplets, reconstitutable powders, elixirs, liquids, colloidal or other types of suspensions, emulsions, beads, beadlets, granules, microparticles, nanoparticles, and combinations thereof. The amount of the composition administered will depend on the subject being treated, the subject's weight, the severity of the condition being treated, the method of administration, and the judgment of the prescribing physician. In some embodiments, the pharmaceutical composition comprises crystalline Form I of 9-ING-41 and at least one pharmaceutically acceptable excipient.

[0089] The present disclosure also encompasses sterile aqueous or organic solution formulations of 9-ING-41, where the formulation is prepared from a solid form of 9-ING-41 of the present disclosure. Thus, in some aspects, the present disclosure encompasses a process for preparing a pharmaceutical composition that is a solution comprising 9-ING-41. In some embodiments, the method for preparing a pharmaceutical composition that is a solution of 9-ING-41 comprises dissolving a solid form of 9-ING-41 of the present disclosure in a solvent or solvent mixture. In some embodiments, the method comprises dissolving crystalline Form I of 9-ING-41 in an aqueous solvent, a non-aqueous solvent, or a mixture of aqueous and / or non-aqueous solvents. In embodiments, the aqueous solvent, non-aqueous solvent, or a mixture of aqueous and / or non-aqueous solvents can include other dissolving components, such as, for example, polyethylene glycol, benzyl alcohol, polysorbate, tocopheryl polyethylene glycol succinate, as well as other surfactants, solubilizers, or other pharmaceutically acceptable excipients. Thus, in some embodiments, the process comprises dissolving crystalline Form I of 9-ING-41 in an aqueous solvent.

[0090] The solid state forms of 9-ING-41 as defined herein, as well as pharmaceutical compositions or formulations thereof, can be used as medicaments for the treatment of cancer, including, inter alia, brain tumors, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, and pancreatic cancer, as well as the treatment of traumatic brain injury.

[0091] Although the present disclosure has been described with reference to certain preferred embodiments, other embodiments will become apparent to those skilled in the art from consideration of the specification. The present disclosure is further illustrated by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

[0092] Analysis method

[0093] XRPD analysis XRPD analysis was carried out using an X-ray diffractometer (Bruker D8 Advance) equipped with a LynxEye detector. The instrument parameters were as follows: Scan: 3°(2θ)~40°(2θ) Increment: 0.02° (2θ) Scan speed: 0.3 seconds / step Voltage: 40KV Current: 40mA Rotation: On Sample Hold: Zero background sample holder

[0094] TGA analysis TGA analysis was performed on a TA Instruments TGA Q500. Samples were placed in tarred open aluminum pans and heated from room temperature to the final temperature at a rate of 10°C / min.

[0095] DSC analysis DSC analysis was performed on a TA Instruments Q200. A weighted sample was placed in the TA DSC pan and heated at a rate of 10°C / min to the final temperature.

[0096] DVS analysis DVS analysis was performed on an IGAsorp (HidenIsochema Ltd.) For isothermal tests, the chamber temperature was maintained at a constant 25.0 ± 1.0 °C water bath.

[0097] HPLC analysis The solubility of 9-ING-41 polymorphic forms in water or buffer was determined using HPLC under the following conditions: Equipment: Agilent 1260 Infinity Series Diluent: Acetonitrile Flow rate: 1.5mL / min Mobile phase: A: 0.05% TFA in water B: 0.05% TFA in acetonitrile Injection volume: 1μL Column: XDB-C18, 4.6*50mm, 1.8μm Column temperature: 40℃ Detection: 220nm Run time: 8 minutes (2 minute delay between injections) Gradient (T / B%): 0.0 / 70, 6.0 / 100, 8.0 / 100

[0098] The solubility of the 9-ING-41 polymorphic forms in 30% acetonitrile in water was determined using HPLC under the following conditions: Equipment: Agilent 1260 Infinity Series Diluent: 30% acetonitrile aqueous solution Flow rate: 1.5mL / min Mobile phase: A: 0.05% TFA in water B: 0.05% TFA in acetonitrile Injection volume: 5μL Column: XDB-C18, 4.6*50mm, 1.8μm Column temperature: 40℃ Detection: 220nm Run time: 8 minutes (2 minute delay between injections) Gradient (T / B%): 0.0 / 70, 6.0 / 100, 8.0 / 100

[0099] Example Example 1: Preparation of 9-ING-41 Crude 9-ING-41 can be obtained by the general methods described in U.S. Pat. No. 8,207,216 and in 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.

[0100] Example 2: Preparation of 9-ING-41 Crystalline Form I Crystalline Form I of 9-ING-41 can be prepared by: Synthesis of intermediate 1 [ka]

[0101] A 3 L four-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-nitro-2H-1,3-benzodioxole-5-carbaldehyde (200 g, 1.02 mol, 1.00 equiv.), ammonium acetate (200 g, 2.59 mol, 2.53 equiv.), acetic acid (2 L), and nitromethane (313 g, 5.13 mol, 5.00 equiv.). The solution was stirred at 100 °C for 12 h. The reaction was repeated three times. The solutions were combined and diluted with 20 L of water. The resulting solution was extracted with 3 × 10 L of ethyl acetate, and the organic layers were combined. The mixture was washed with 3 × 10 L of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This gave 450 g (crude) of 5-nitro-6-[(E)-2-nitroethenyl]-2H-1,3-benzodioxole (1) as a dark green solid. Synthesis of intermediate 2 [ka]

[0102] Iron (120 g, 2.14 mol, 17.01 equiv.) was slowly added to a suspension of 5-nitro-6-[(Z)-2-nitroethenyl]-2H-1,3-benzodioxole (30 g, 125.97 mmol, 1.00 equiv.), silica gel (120 g), toluene (200 mL), and cyclohexane (400 mL) in acetic acid (300 mL) at 80 °C under nitrogen. The resulting black mixture was stirred at 80 °C for 8 h. The reaction was repeated 10 times. The reaction mixture was combined. The solid was filtered off. The filtrate was concentrated in vacuo, and the residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 5). The collected fractions were combined and concentrated in vacuo to give 67.3 g (33%) of 2H,5H-[1,3]dioxolo[4,5-f]indole (2) as an off-white solid. Synthesis of intermediate 3 [ka]

[0103] Sodium hydride (19.9 g, 497.50 mmol, 1.18 equiv, 60%) was added portionwise to a solution of 2H,3H,5H-furo[2,3-f]indole (67.3 g, 422.78 mmol, 1.00 equiv) in N,N-dimethylformamide (1.3 L) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 1 h, and CHCl (70.9 g, 499.51 mmol, 1.18 equiv) was added dropwise. The resulting solution was stirred at room temperature for 3 h. The solution was quenched by adding 1 L of ice water. The resulting solution was extracted with 3 × 1 L of ethyl acetate, and the organic layers were combined. The mixture was washed with 3 × 1 L of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 10). The collected fractions were combined and concentrated in vacuo to give 71 g (97%) of 5-methyl-2H,3H,5H-furo[2,3-f]indole (3) as a pale yellow solid. Synthesis of intermediate 4 [ka]

[0104] Ethyl 2-chloro-2-oxoacetate (220 g, 1.61 mol, 3.96 equiv.) was added dropwise to a solution of 5-methyl-2H,3H,5H-furo[2,3-f]indole (70.4 g, 406.44 mmol, 1.00 equiv.) in ethyl ether (1.6 L) at 0 °C under nitrogen. The resulting solution was warmed to room temperature and stirred for 4 h. The reaction was slowly quenched by adding 2 L of ice water, and the pH of the resulting solution was adjusted to 9 with Na2CO3. The resulting mixture was extracted with 3 × 1.5 L of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 92.8 g (84%) of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (4) as a pale yellow solid.

[0105] 1H NMR (300 MHz, DMSO-d6): δ 8.28(s,4H),7.56(s,4H),7.27(s,4H),6.17(s,1H),6.08(s,8H),4.35(q,J=7.1 Hz,7H),3.85(s,11H),3.35(s,2H),1.35(t,J=7.1 Hz,11H),1.25(s,2H). Synthesis of intermediate 5 [ka]

[0106] A 10 L four-neck round-bottom flask was charged with 2-bromo-4-fluorophenol (500 g, 2.62 mol, 1.00 equiv.), N,N-dimethylformamide (5 L), potassium carbonate (1253 g, 9.07 mol, 3.46 equiv.), and ethyl (2E)-4-bromobut-2-enoate (1010 g, 5.23 mol, 2.00 equiv.). The resulting solution was stirred at room temperature for 12 hours. The solid was collected by filtration. The reaction was then quenched by adding 15 L of water and extracted with 3 × 10 L of ethyl acetate. The organic layers were combined and washed with 4 × 20 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 20). The collected fractions were combined and concentrated in vacuo to give 500 g (63%) of ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (5) as a white solid. Synthesis of intermediate 6 [ka]

[0107] A 2 L three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with ethyl (2E)-4-(2-bromo-4-fluorophenoxy)but-2-enoate (125 g, 412.37 mmol, 1.00 equiv.), benzyltriethylazanium chloride (99 g, 434.64 mmol, 1.05 equiv.), sodium formate dihydrate (45.1 g), Pd(OAc)2 (2.9 g, 12.92 mmol, 0.03 equiv.), sodium carbonate (92 g, 868.01 mmol, 2.10 equiv.), and N,N-dimethylformamide (1.25 L). The resulting solution was stirred at 80 °C for 12 hours. The reaction was repeated four times. The reaction mixture was combined, and the solid was filtered off. The filtrate was diluted with 10 L of brine and extracted with 3 × 5 L of ethyl acetate. The organic layers were combined and washed with 4 × 6 L of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 20). The collected fractions were combined and concentrated under vacuum. This gave 258 g (crude) of ethyl 2-(5-fluoro-1-benzofuran-3-yl)acetate (6) as a pale yellow oil. Synthesis of intermediate 7 [ka]

[0108] A 5 L round-bottom flask was charged with ethyl 2-(5-fluoro-1-benzofuran-3-yl)acetate (147 g, 661.53 mmol, 1.00 equiv.), methanol (1 L), tetrahydrofuran (1 L), water (1 L), and LiOH (47.7 g, 1.99 mol, 3.01 equiv.). The resulting solution was stirred at room temperature for 3 h. The reaction was repeated twice. The mixture was concentrated in vacuo and then extracted with 1 L of dichloromethane. The aqueous layer was collected, and the pH of the layer was adjusted to 1-3 with hydrogen chloride (1 mol / L). The resulting solution was extracted 3 times with 1 L of ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 160 g (62%) of 2-(5-fluoro-1-benzofuran-3-yl)acetic acid (7) as a white solid. Synthesis of intermediate 8 [ka]

[0109] A 10 L round-bottom flask was charged with 2-(5-fluoro-1-benzofuran-3-yl)acetic acid (160 g, 824.1 mmol, 1.00 equiv.), NHCl (436 g, 8.16 mol, 9.89 equiv.), N,N-dimethylformamide (6 L), DIEA (1064 g, 8.24 mol, 9.99 equiv.), and HATU (376 g, 988.88 mmol, 1.20 equiv.). The resulting solution was stirred at room temperature for 12 hours. The resulting solution was diluted with 10 L of water. The solid was collected by filtration to give 126 g (78%) of 2-(5-fluoro-1-benzofuran-3-yl)acetamide (8) as a white solid. Synthesis of 9-ING-41 in crystalline form I [ka]

[0110] t-BuOK (1200 mL, 1 mol / L in THF) was added dropwise to a solution of ethyl 2-[5-methyl-2H,3H,5H-furo[2,3-f]indol-7-yl]-2-oxoacetate (100 g, 365.9 mmol, 1.00 equiv.), 2-(5-fluoro-1-benzofuran-3-yl)acetamide (72 g, 372.7 mmol, 1.02 equiv.) in tetrahydrofuran (3 L) at 0 °C under nitrogen. The reaction was stirred at room temperature for 2 h. The reaction was cooled to 0 °C, poured into 2 L of NH4Cl (saturated solution in water), and extracted with 4 × 2 L of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column using ethyl acetate / dichloromethane / petroleum ether (1 / 1 / 5). The collected fractions were combined and concentrated under vacuum to give 107.9 g (74%) of 3-(5-fluoro-1-benzofuran-3-yl)-4-[5-methyl-2H,5H-[1,3]dioxolo[4,5-f]indol-7-yl]-2,5-dihydro-1H-pyrrole-2,5-dione as a red solid. This red solid is 9-ING-41 crystalline form I. MS-ESI: [M+H]=405.

[0111] Example 3: Preparation of 9-ING-41 Crystalline Form I Crystalline Form I of 9-ING-41 was also prepared by slow evaporation of a solution of 9-ING-41 as follows. Approximately 30–105 mg of 9-ING-41 solid was weighed into glass vials. Each vial was filled with 3 mL of a single solvent. The resulting 2 mL of drug solution or suspension was manually filtered into a clean glass vial using a plastic non-contaminating syringe equipped with a 0.22 μm nylon filter cartridge. The resulting filtrate was then either 1) covered with a film containing a pinhole and allowed to evaporate in a laboratory fume hood under ambient conditions, or 2) mixed in a binary mixture, each containing equal amounts of two different filtrates. The binary mixture was then covered with a film containing a pinhole and allowed to evaporate in a laboratory fume hood under ambient conditions, yielding solid 9-ING-41 crystalline Form I. This procedure was used to prepare 9-ING-41 crystalline Form I from the following solvents or solvent mixtures: Ethyl acetate 2-Propanol:Ethyl acetate 2-Methyl-1-propanol:Ethyl acetate 1-Butanol:Ethyl acetate 3-Methylbutanol: Tetrahydrofuran ("THF") 3-Methylbutanol:Ethyl acetate ·THF: water Acetonitrile:water Methyl t-butyl ether (MTBE): ethyl acetate Water:Ethyl acetate

[0112] Example 4: Preparation of 9-ING-41 solvate 6 9-ING-41 solvate 6 was prepared from ethanol:acetone and ethanol:ethyl acetate using the method described in Example 3 above.

[0113] 9-ING-41 solvate 6 was also prepared by slurrying 9-ING-41 Form I in ethanol for 3 days.

[0114] Example 5: Preparation of 9-ING-41 solvate 7 Using the method described in Example 3 above, 9-ING-41 solvate 7 was prepared from methanol / THF; methanol / acetonitrile; methanol / MTBE; methanol / acetone; and methanol / ethyl acetate.

[0115] 9-ING-41 solvate 7 was also prepared by slurrying 9-ING-41 Form I in methanol for 3 days.

[0116] Example 6: Preparation of 9-ING-41 solvate 8 9-ING-41 solvate 8 was prepared by slurrying 9-ING-41 Form I in ethyl acetate for 3 days.

[0117] Example 7: Preparation of 9-ING-41 solvate 9 9-ING-41 solvate 9 was prepared from acetonitrile / acetone; MTBE / acetone; acetone / water and pure acetone using the method described in Example 3 above.

[0118] 9-ING-41 solvate 9 was also prepared by slurrying 9-ING-41 Form I in acetone for 3 days.

[0119] Example 8: Preparation of 9-ING-41 solvate 3 Using the method described in Example 3 above, 9-ING-41 solvate 3 was prepared from 2-methyl-1-propanol / acetone; and 1-butanol / acetone.

[0120] Example 9: Preparation of 9-ING-41 solvates 1, 2, 4 and 5 Using the method described in Example 3 above, 9-ING-41 solvates 1, 2, 4 and 5 were prepared from the solvents shown below: Solvate 1: Acetone / Ethyl Acetate Solvate 2: Acetone / toluene Solvate 4: 2-propanol / THF Solvate 5:2-propanol / acetone

[0121] Example 10: Water solubility test 10–30 mg of 9-ING-41 Form I was added to 2 mL of water or buffer solution buffered to pH = 1.2, 4.5, or 6.8. The samples were shaken at 200 rpm on a shaker for 24 hours. Sample vials were visually inspected to confirm saturation. 1 mL of each suspension was filtered through a 0.22 μm nylon syringe filter into a separate clean, clear glass vial at 24 hours. The filtrate was analyzed using HPLC (accurately diluted if necessary), and the remaining solid was analyzed using XRPD.

[0122] Form I was poorly soluble in water or pH 1.2, 4.5, or 6.8 buffers. 9-ING-41 was not detectable in the filtrate by HPLC. Analysis of the remaining solids showed no change in crystalline form over the course of the experiment: the remaining solids in experiments in which Form I was used remained as Form I.

[0123] Example 11: Solubility of 30% acetonitrile in water Approximately 5 mg of 9-ING-41 Form I was added to 2 mL of 30% acetonitrile / 70% water (vol / vol). The sample was shaken on a shaker at 200 rpm for 24 hours. The vial was visually inspected to confirm saturation. 1 mL of the suspension was filtered through a 0.22 μm nylon syringe filter into separate clean, clear glass vials at 2 and 24 hours. The filtrate was analyzed using HPLC (accurately diluted if necessary), and the remaining solid was analyzed using XRPD.

[0124] The filtrate from experiments performed with 9-ING-41 Form I contained 0.046 mg / mL of 9-ING-41 after 2 hours and 0.048 mg / mL of 9-ING-41 after 24 hours, as determined by HPLC.

[0125] Analysis of the remaining solids showed no change in crystalline form over the course of the experiment: the remaining solids in experiments in which Form I was used remained as Form I.

[0126] Amorphous 9-ING-41 was determined to have a solubility of 0.057 mg / mL in 30% acetonitrile / 70% water (vol / vol) after 30 minutes.

[0127] Example 13: Mechanical and Pressure Effects 9.90 mg of 9-ING-41 Form I was weighed into a mortar and ground for 5 minutes. The remaining solid was collected and analyzed by XRPD, which showed that the crystalline form (i.e., Form I) was unchanged as a result of the grinding.

[0128] 9-ING-41 Form I was compressed into two tablets, weighing 38.9 mg and 36.2 mg, respectively. The tablets were then crushed into a powder and analyzed by XRPD, which showed that the crystalline form (i.e., Form I) of 9-ING-41 Form I was not changed as a result of compressing it into tablets.

[0129] Example 14: Heat Treatment - Preparation of Amorphous 9-ING-41 9-ING-41 Form I was heated by DSC at a rate of 10°C / min to a final temperature of 260°C. The molten product was immediately placed in an ice bath and held for 15 minutes. Analysis of the residue by XRPD showed that the material was amorphous.

[0130] 9-ING-41 Form I was heated at a rate of 10° C. / min to a final temperature of 260° C., then cooled to −40° C., reheated to 260° C. at the same heating rate, and then cooled to 40° C. Analysis of the residue by XRPD showed that the material was amorphous.

[0131] Example 15: Preparation of amorphous 9-ING-41 Amorphous 9-ING-41 was prepared from ethanol / acetonitrile; ethanol / toluene; 2-propanol / acetonitrile; 2-methyl-1-propanol / acetonitrile and MTBE / toluene using the method described in Example 3 above.

Claims

1. A solid form of crystalline form I of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione.

2. 2. The solid form of claim 1, characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

3. 10. The solid form of claim 1, characterized by an X-ray powder diffraction pattern with a peak at 5.5 degrees ±0.2 degrees 2-theta on the 2-theta scale at lambda = 1.54 Angstroms (Cu Kα).

4. 10. The solid form of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 20.4, 22.1, and 24.7 degrees ±0.2 degrees 2-theta on the 2-theta scale at lambda = 1.54 Angstroms (Cu Kα).

5. 10. The solid form of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 17.7, 18.4, 18.9, and 20.8 degrees ±0.2 degrees 2-theta on the 2-theta scale at lambda = 1.54 Angstroms (Cu Kα).

6. 10. The solid form of claim 1, characterized by an X-ray powder diffraction pattern having peaks at 5.5, 9.4, 11.8, 13.4, 15.3, 24.7, and 29.3 degrees ±0.2 degrees 2-theta on the 2-theta scale at lambda = 1.54 Angstroms (Cu Kα).

7. 10. The solid form of claim 1, characterized by an X-ray powder diffraction pattern having peaks at three or more of the following positions on the 2-theta scale at lambda = 1.54 Angstroms (Cu Kα): 5.5, 9.4, 11.8, 13.4, 15.3, 17.7, 18.4, 18.9, 20.4, 20.8, 22.1, 24.7, and 29.3 degrees ± 0.2 degrees 2-theta.

8. 8. The solid form of any one of claims 1 to 7, characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2 when heated at a rate of 10°C / min.

9. 8. The solid form of any one of claims 1 to 7, characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 228°C when heated at a rate of 10°C / min.

10. 10. The solid form of any one of claims 1 to 9, characterized by a thermogravimetric analysis profile substantially as shown in Figure 3 when heated at a rate of 10°C / min.

11. 11. The solid form of any one of claims 1 to 10, characterized by a dynamic vapor sorption (DVS) profile substantially as shown in Figure 4.

12. 12. A process for preparing the solid form of any one of claims 1 to 11, the process 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 solvent to form a solution; and (ii) concentrating the solution.

13. 13. The process of claim 12, wherein the solvent comprises: a mixture of ethyl acetate / dichloromethane / petroleum ether in a volume ratio of about 1:1:5; ethyl acetate; a mixture of 2-propanol / ethyl acetate in a volume ratio of about 1:1; a mixture of 2-methyl-1-propanol / ethyl acetate in a volume ratio of about 1:1; a mixture of 1-butanol / ethyl acetate in a volume ratio of about 1:1; a mixture of 3-methylbutanol / tetrahydrofuran (THF) in a volume ratio of about 1:1; a mixture of 3-methylbutanol / ethyl acetate in a volume ratio of about 1:1; A mixture of THF / water in a volume ratio of about 1:1; A mixture of acetonitrile / water in a volume ratio of about 1:1; a mixture of methyl t-butyl ether (MTBE) / ethyl acetate in a volume ratio of about 1:1; or A mixture of water and ethyl acetate in a volume ratio of approximately 1:1 A process that has

14. 12. A process for preparing the solid form of any one of claims 1 to 11, comprising heating one or more of 9-ING-41 solvates 1 to 9 at a sufficient temperature and for a sufficient time to produce the solid form of any one of claims 1 to 11.

15. A solid form of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione which is solvate 1, solvate 2, solvate 3, solvate 4, solvate 5, solvate 6, solvate 7, solvate 8 or solvate 9, or a mixture thereof.

16. A solid form of 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5-dione, which is amorphous.

17. A pharmaceutical composition comprising the solid form of any one of claims 1 to 11 or 15 and a pharmaceutically acceptable excipient.

18. 18. The pharmaceutical composition of claim 17, further comprising the solid form of claim 16.

19. 19. A process for preparing the pharmaceutical composition of claim 17 or 18, the process comprising dissolving the solid form in an aqueous solvent, a non-aqueous solvent, or a mixture of aqueous and / or non-aqueous solvents, or mixing the solid form with a pharmaceutically acceptable excipient.

20. 17. A method of treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a solid form of any one of claims 1 to 11, 15 or 16.

21. 21. The method of claim 20, wherein the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, or pancreatic cancer.

22. 17. A method of treating traumatic brain injury in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a solid form of any one of claims 1 to 11, 15 or 16.

23. 17. A solid form according to any one of claims 1 to 11, 15 or 16 for use in the treatment of cancer.

24. 27. The solid form of any one of claims 1 to 11, 15 or 16 for use according to claim 23, wherein the cancer is brain cancer, lung cancer, breast cancer, ovarian cancer, bladder cancer, neuroblastoma, kidney cancer, or pancreatic cancer.

25. 17. A solid form according to any one of claims 1 to 11, 15 or 16 for use in the treatment of traumatic brain injury.

Images