WO2024102477A1 - Crystalline forms of eltanexor and process for preparing same - Google Patents

Crystalline forms of eltanexor and process for preparing same Download PDF

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Publication number
WO2024102477A1
WO2024102477A1 PCT/US2023/037156 US2023037156W WO2024102477A1 WO 2024102477 A1 WO2024102477 A1 WO 2024102477A1 US 2023037156 W US2023037156 W US 2023037156W WO 2024102477 A1 WO2024102477 A1 WO 2024102477A1
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crystalline form
ray powder
powder diffraction
structural formula
diffraction peaks
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PCT/US2023/037156
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French (fr)
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Brian C. Austad
Evan Hecker
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Karyopharm Therapeutics Inc.
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Publication of WO2024102477A1 publication Critical patent/WO2024102477A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RNAs are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus. Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters.
  • NLS nuclear import/localization
  • NES export
  • One of major exportins is Chromosomal Region Maintenance 1 (CRM1), which is also called exportin- 1 or Xpol.
  • the solid form of a compound can be important in the formulation of pharmaceutical compositions.
  • different crystalline forms of a compound can have different physical properties (e.g., stability, dissolution rate, density, etc.) rotating to their suitability for use in pharmaceutical compositions.
  • the present invention relates to crystalline forms of the compound represented by Structural Formula 1, designated crystalline Forms I-XIV, and compositions comprising the crystalline form.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form n characterized by X-ray powder diffraction peaks at 2 ⁇ angles 21.7°, 22.0°, 22.7°, and 25.1°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form in characterized by X-ray powder diffraction peaks at 2 ⁇ angles 6.5°, 17.5°, 21.2°, and 21.9°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form IV characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.5°, and 24.7°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form V characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.2°, and 24.7°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form VII characterized by X-ray powder diffraction peaks at 2 ⁇ angles 16.0°, 21.4°, 22.6°, and 29.5°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form VIII characterized by X-ray powder diffraction peaks at 2 ⁇ angles 18.7°, 19.8°, 22.4°, and 26.0°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form IX characterized by X-ray powder diffraction peaks at 2 ⁇ angles 8.1°, 18.5°, 20.8°, and 22.5°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form X characterized by X-ray powder diffraction peaks at 2 ⁇ angles 5.6°, 16.8°, 23.2°, and 28.3°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form XI characterized by X-ray powder diffraction peaks at 2 ⁇ angles 7.7°, 16.2°, 20.2°, and 27.2°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form XIII characterized by X-ray powder diffraction peaks at 2 ⁇ angles 4.9°, 14.7°, 19.6°, and 24.5°.
  • the present invention is a crystalline form of the compound represented by Structural Formula 1 : wherein the crystalline form is Form XIV characterized by X-ray powder diffraction peaks at 2 ⁇ angles 6.4°, 8.1°, 19.8°, and 20.4°.
  • the present invention is a composition, comprising particles of one or more crystalline forms of the compound represented by Structural Formula 1: wherein the one or more crystalline forms are selected from: crystalline Form n characterized by x-ray powder diffraction peaks at 2 ⁇ angles 21.7°, 22.0°, 22.7°, and 25.1°; crystalline Form III characterized by x-ray powder diffraction peaks at 2 ⁇ angles 6.5°, 17.5°, 21.2°, and 21.9°; crystalline Form IV characterized by x-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.5°, and 24.7°; crystalline Form V characterized by x-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.2°, and 24.7°; crystalline Form VII characterized by x-ray powder diffraction peaks at 2 ⁇ angles 16.0°, 21.4°, 22.6°, and 29.5°; crystalline Form VIII characterized by x-ray powder
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the compound represented by Structural Formula (I), as described herein, and a pharmaceutically acceptable carrier.
  • the present invention relates to a method for treating or preventing a CRM1 -associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the cornpound represented by Structural Formula (I), as described herein.
  • the present invention relates to a method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the compound represented by Structural Formula (I), as described herein.
  • FIG. 1 is an x-ray powder diffraction (XRPD) pattern of the crystalline Form I of the compound represented by Structural Formula 1.
  • FIG. 2 is a graph depicting a differential scanning calorimetry (DSC) thermogram of the crystalline Form I of the compound represented by Structural Formula 1.
  • FIG. 3 is a graph depicting a thermogravimetric analysis (TGA) thermogram of the crystalline Form I of the compound represented by Structural Formula 1.
  • FIG. 4 is a dynamic vapor sorption (DVS) pattern of the crystalline Form I of the compound represented by Structural Formula 1.
  • FIG. 5 is an XRPD pattern of the crystalline Form II of the compound represented by Structural Formula 1.
  • FIG. 6 is an XRPD pattern of the crystalline Form III of the compound represented by Structural Formula 1.
  • FIG. 7 is a graph depicting a DSC thermogram of the crystalline Form III of the compound represented by Structural Formula 1.
  • FIG. 8 is a graph depicting a TGA thermogram of the crystalline Form III of the compound represented by Structural Formula 1.
  • FIG. 9 is an XRPD pattern of the crystalline Form IV of the compound represented by Structural Formula 1.
  • FIG. 10 is a graph depicting a DSC thermogram of the crystalline Form IV of the compound represented by Structural Formula 1.
  • FIG. 11 is a graph depicting a TGA thermogram of the crystalline Form IV of the compound represented by Structural Formula 1.
  • FIG. 12 is an XRPD pattern of the crystalline Form V of the compound represented by Structural Formula 1.
  • FIG. 13 is a graph depicting a DSC thermogram of the crystalline Form V of the compound represented by Structural Formula 1.
  • FIG. 14 is a graph depicting a TGA thermogram of the crystalline Form V of the cornpound represented by Structural Formula 1.
  • FIG. 15 is an XRPD pattern of the crystalline Form VI of the compound represented by Structural Formula 1.
  • FIG. 16 is a graph depicting a DSC thermogram of the crystalline Form VI of the compound represented by Structural Formula 1.
  • FIG. 17 is a graph depicting a TGA thermogram of the crystalline Form VI of the compound represented by Structural Formula 1.
  • FIG. 18 is an XRPD pattern of the crystalline Form VII of the compound represented by Structural Formula 1.
  • FIG. 19 is a graph depicting a DSC thermogram of the crystalline Form VII of the compound represented by Structural Formula 1.
  • FIG. 20 is a graph depicting a TGA thermogram of the crystalline Form VII of the compound represented by Structural Formula 1.
  • FIG. 21 is an XRPD pattern of the crystalline Form VIII of the compound represented by Structural Formula 1.
  • FIG. 22 is an XRPD pattern of the crystalline Form IX of the compound represented by Structural Formula 1.
  • FIG. 23 is a graph depicting a DSC thermogram of the crystalline Form IX of the compound represented by Structural Formula 1.
  • FIG. 24 is a graph depicting a TGA thermogram of the crystalline Form IX of the compound represented by Structural Formula 1.
  • FIG. 25 is an XRPD pattern of the crystalline Form X of the coirpound represented by Structural Formula 1.
  • FIG. 26 is a graph depicting a DSC thermogram of the crystalline Form X of the compound represented by Structural Formula 1.
  • FIG. 27 is a graph depicting a TGA thermogram of the crystalline Form X of the compound represented by Structural Formula 1.
  • FIG. 28 is an XRPD pattern of the crystalline Form XI of the compound represented by Structural Formula 1.
  • FIG. 29 is a graph depicting a TGA thermogram of the crystalline Form XI of the compound represented by Structural Formula 1.
  • FIG. 30 is a graph depicting a DSC thermogram of the crystalline Form XII of the compound represented by Structural Formula 1.
  • FIG. 31 is a graph depicting a TGA thermogram ofthe crystalline Form XII of the coinpound represented by Structural Formula 1.
  • FIG. 32 is an XRPD pattern of the crystalline Form XIII of the compound represented by Structural Formula 1.
  • FIG. 33 is a graph depicting a DSC thermogram of the crystalline Form XIII of the compound represented by Structural Formula 1.
  • FIG. 34 is a graph depicting a TGA thermogram of the crystalline Form XIII of the compound represented by Structural Formula 1.
  • FIG. 35 is an XRPD pattern of the crystalline Form XIV of the compound represented by Structural Formula 1.
  • FIG. 36 is a graph depicting a DSC thermogram of the crystalline Form XIV of the compound represented by Structural Formula 1.
  • FIG. 37 is a graph depicting a TGA thermogram of the crystalline Form XIV of the compound represented by Structural Formula 1.
  • FIG. 38 is a diagram schematically depicting the relationship between crystalline Forms I-XIV.
  • crystalline forms of the compound of Structural Formula 1 designated ciystalline Forms I-XIV.
  • Crystal refers to a homogeneous solid formed by a repeating, three-dimensional pattern of atoms, ions or molecules (e.g., an anhydrous molecule or a salt thereof solvate thereof, or combination of the foregoing) having fixed distances between constituent parts.
  • the unit cell is the simplest repeating unit in this pattern.
  • the ciystalline forms provided herein can be identified on the basis of characteristic peaks in an x-ray powder diffraction (XRPD) analysis.
  • XRPD a scientific technique that measures the x-rays, neutrons or electrons scattered by a powder or microcrystalline material as a function of scattering angle.
  • XRPD can be used to identify and characterize crystalline solids, as the diffraction pattern produced by a particular solid is typically distinctive to that solid and can be used as a “fingerprint” to identify that solid.
  • an XRPD pattern or diffiactogram e.g., a pattern or diffiactogram produced by a sample, such as an unknown sample
  • a reference XRPD pattern or diffiactogram can be used to determine the identity between the sample material and the reference material. Both the position and the relative intensity of the peaks in an XRPD diffiactogram are indicative of the particular phase and identity of a material.
  • a crystalline form provided herein can be a sole crystalline form or can comprise a mixture of two or more different crystalline forms.
  • crystalline Form I of the compound represented by Structural Formula 1 is provided as a sole crystalline form.
  • a crystalline form can comprise a mixture of two or more crystalline forms of the compound represented by Structural Formula 1, e.g., a mixture of crystalline Form I with one or more of crystalline forms, e.g., Forms II- XIV, of the compound represented by Structural Formula 1.
  • Single crystalline form refers to a single crystal of a crystalline solid or a plurality of crystals of a crystalline solid wherein each of the plurality of crystals has the same crystal form.
  • FIGs. 1, 5, 6, 9, 12, 15, 18, 21, 22, 25, 28, 32, and 35 show XRPD patterns of the crystalline Forms I-XIV described herein.
  • An XRPD pattern that is “substantially in accordance” with one or more figures herein showing an XRPD pattern or diffiactogram is an XRPD pattern that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the XRPD pattern of one or more figures provided herein.
  • an XRPD pattern that is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures.
  • An XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffiaction pattern presented herein and/or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data.
  • a person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern of the sample and the corresponding XRPD pattern disclosed herein.
  • any 2 ⁇ angle specified herein means the specified value ⁇ 0.2°.
  • a 2 ⁇ of 4.4° this is to be understood to mean 4.4° ⁇ 0.2°, that is, a 2 ⁇ angle of from 4.2° to 4.6°.
  • the crystalline forms I, III- VII, IX, X, and XII-XIV provided herein can also be identified on the basis of differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA).
  • DSC is a thennoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature.
  • DSC can be used to detect physical transformations, such as phase transitions, of a sample.
  • DSC can be used to detect the temperature(s) at which a sample undergoes crystallization, melting or glass transition.
  • TGA is a method of thermal gravimetric analysis in which changes in physical and chemical properties of a material are measured as a function of increasing temperature (with constant heating rate) or as a function of time (with constant temperature and/or constant mass loss). TGA can provide information about physical phenomena, such as second-order phase transitions, or about chemical phenomena, such as desolvation and/or decomposition.
  • FIGs. 2, 7, 10, 13, 16, 19, 23, 26, 30, 33, and 36 show DSC thermograms of the crystalline Forms I, III-VII, IX, X, and XII-XIV described herein. For example, FIG.
  • FIG. 7 shows a differential scanning calorimetry thermogram of crystalline Form III comprising a broad endothermic peak at about 70 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting.
  • FIG. 8 shows a thermogravimetric thermogram of crystalline Form in, demonstrating weight loss of about 8% starting at about 70 °C, consistent with desolvation, and in agreement with the DSC data shown in FIG. 7.
  • a DSC or TGA thermogram that is “substantially in accordance” with one or more figures herein showing a DSC or TGA thermogram is a DSC or TGA thermogram that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the DSC or TGA thermogram of one or more figures provided herein.
  • any temperature associated with DSC or TGA specified herein means the specified value ⁇ 5 °C or less.
  • a DSC or TGA temperature is the specified value ⁇ 3 °C, in more preferred embodiments, ⁇ 2 °C.
  • the crystalline Form I can be additionally characterized by dynamic vapor sorption (DVS), wherein a sample is subjected to varying conditions of humidity and temperature, and the response of the sample is measured gravimetrically.
  • DVS dynamic vapor sorption
  • the result of a DVS analysis particularly can be a dual curve providing sample weight percent as a function of relative humidity (RH) overtime, a dual curve providing sample water content as a function of RH overtime, a curve providing weight percent in relation to RH, or a curve providing water content in relation to RH.
  • Equipment useful for measuring such data is known in the art, and any such equipment can be used to measure the compounds according to the present disclosure.
  • DVS analysis can be carried out by scanning at a series of specific RH values.
  • specific polymorphs according to the disclosure may be identified and described in relation to the representative graph and/or the approximate peaks obtained in DVS analysis, particularly scanning from 0% to 95% RH with a step interval of 5% or 10% RH.
  • FIG. 4 shows a DVS pattern of the crystalline Form I described herein.
  • a DVS pattern that is “substantially in accordance” with one or more figures herein showing a DVS patterns is a DVS pattern that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the DVS pattern of one or more figures provided herein.
  • crystalline forms provided herein may be crystalline forms of the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • Solvate refers to a chemical compound formed by the interaction of a solute (e.g., a compound of Structural Formula 1) and one or more solvents (e.g., methanol, ethanol, water).
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvents e.g., methanol, ethanol, water
  • solvate includes solvates containing a single type of solvent molecule and solvates containing more than one type of solvent
  • a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form I, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 4.6°, 22.8°, 23.2°, and 24.4°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 4.6°, 20.0°, 22.8°, 23.2°, and 24.4°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 4.6°, 19.0°, 20.0°, 22.8°, 23.2°, 23.7°, 24.4°, and 27.9°.
  • crystalline Form I is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1.
  • Crystalline Form I may be further characterized by a differential scanning calorimetry thermogram comprising a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 2.
  • the TGA thermogram is substantially in accordance with that in FIG. 3.
  • Crystalline Form I can be additionally characterized by dynamic vapor sorption pattern demonstrating reversible 0.12 % w/w water adsorption from 0 to 90 % RH.
  • the DVS pattern is substantially in accordance with the one found in FIG. 4.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form II, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 21.7°, 22.0°, 22.7°, and 25.1°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 8.0°, 21.7°, 22.0°, 22.7°, and 25.1 °; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected from 8.0°, 16.2°, 21.7°, 22.0°, 22.7°, 24.1°, 25.1°, and 27.6°.
  • crystalline Form II is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 5.
  • Crystalline Form II may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a nitromethane solvate.
  • a crystalline form of the compound represented by the compound represented by Structural Formula 1 wherein the crystalline form is Form III, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 6.5°, 17.5°, 21.2°, and 21.9°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 6.5°, 17.5°, 21.2°, 21.9°, and 22.1°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 6.5°, 10.6°, 17.5°, 20.6°, 21.2°, 21.9°, and 22.1°, 23.0°.
  • crystalline Form III is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.
  • Crystalline Form m may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 70 °C, consistent with solvate melting and desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 7.
  • the TGA thermogram is substantially in accordance with that in FIG. 8.
  • Crystalline Form in may be a crystalline form of the compound represented by the cornpound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a dimethoxyethane solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form IV, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 7.4°, 23.0°, 24.5°, and 24.7°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 7.4°, 18.4°, 23.0°, 24.5°, and 24.7°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 7.4°, 18.4°, 20.5°, 23.0°, 23.7°, 24.5°, 24.7°, and 27.7°.
  • crystalline Form IV is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 9.
  • Crystalline Form IV may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 99 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 10.
  • the TGA thermogram is substantially in accordance with that in FIG. 11.
  • Crystalline Form IV may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a 2 -propanol solvate.
  • a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form V, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 7.4°, 23.0°, 24.2°, and 24.7°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 7.4°, 18.4°, 23.0°, 24.5°, and 24.7°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 7.4°, 10.3°, 18.2°, 18.6°, 23.0°, 24.5°, 24.7°, and 27.4°.
  • crystalline Form V is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 12.
  • Crystalline Form V may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 128 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 13.
  • the TGA thermogram is substantially in accordance with that in FIG. 14.
  • Crystalline Form V may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is an ethanol solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form VI, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 9.9°, 19.2°, 22.4°, and 24.4°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 9.9°, 19.2°, 22.4°, 23.5°, and 24.4°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 9.9°, 19.2°, 21.3°, 21.9°, 22.4°, 23.5°, 24.4°, and 29.2°.
  • crystalline Form VI is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 15.
  • Crystalline Form VI may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 112 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 16.
  • the TGA thermogram is substantially in accordance with that in FIG. 17.
  • Crystalline Form VI may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a methanol solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form VII, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 16.0°, 21.4°, 22.6°, and 29.5°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 11.7°, 16.0°, 21.4°, 22.6°, and 29.5°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 8.1°, 11.7°, 16.0°, 17.6°, 21.4°, 22.6°, 25.8°, and 29.5°.
  • crystalline Form VII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 18.
  • Crystalline Form VII may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 138 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 19.
  • the TGA thermogram is substantially in accordance with that in FIG. 20.
  • Crystalline Form VII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is an acetonitrile solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form VIII, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 18.7°, 19.8°, 22.4°, and 26.0°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 18.7°, 19.8°, 20.3°, 22.4°, and 26.0°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 18.7°, 19.8°, 20.3°, 21.7°, 22.4°, 23.2°, 26.0°, and 29.1°.
  • crystalline Form VIII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 21.
  • Crystalline Form VIII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a dichloromethane solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form IX, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 8.1°, 18.5°, 20.8°, and 22.5°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 8.1°, 18.5°, 20.0°, 20.8°, and 22.5°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 8.1°, 18.5°, 20.0°, 20.8°, 22.5°, 22.8°, 23.0°, and 26.4°.
  • crystalline Form IX is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 22.
  • Crystalline Form IX may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 69 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 23.
  • the TGA thermogram is substantially in accordance with that in FIG. 24.
  • Crystalline Form IX may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a 2 -methyltetrahydrofuran solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form X, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 5.6°, 16.8°, 23.2°, and 28.3°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 5.6°, 16.8°, 23.2°, 24.9°, and 28.3°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 4.6°, 5.6°, 11.2°, 16.8°, 23.2°, 24.9°, 27.9°, and 28.3°.
  • crystalline Form X is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 25.
  • Crystalline Form X may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 136 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 26.
  • the TGA thermogram is substantially in accordance with that in FIG. 27.
  • Crystalline Form X may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is an acetic acid solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form XI, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 7.7°, 16.2°, 20.2°, and 27.2°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 5.4°, 7.7°, 16.2°, 20.2°, and 27.2°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 5.4°, 7.7°, 16.2°, 20.2°, 23.8°, 24.2°, 25.5°, and 27.2°.
  • crystalline Form XI is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 28.
  • Crystalline Form XI may be further characterized by a TGA thermogram substantially in accordance with that in FIG. 29.
  • Crystalline Form XI may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a dimethyl sulfoxide solvate.
  • a crystalline form XII is provided.
  • Crystalline Form XII may be characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 136 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 30.
  • the TGA thermogram is substantially in accordance with that in FIG. 31.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form XIII, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 4.9°, 14.7°, 19.6°, and 24.5°; by at least four x-ray powder diffraction peaks at 29 angles selected from 4.9°, 14.7°, 19.6°, 19.9°, and 24.5°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 4.9°, 14.2°, 14.7°, 19.6°, 19.9°, 24.5°, 25.5°, and 25.8°.
  • crystalline Form XIII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 32.
  • Crystalline Form XIII may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 129 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 33.
  • the TGA thermogram is substantially in accordance with that in FIG. 34.
  • Crystalline Form XIII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is an acetone solvate.
  • a crystalline form of the compound represented by Structural Formula 1 wherein the crystalline form is Form XIV, and is characterized by x-ray powder diffraction peaks at 2 ⁇ angles of 6.4°, 8.1 °, 19.8°, and 20.4°; by at least four x-ray powder diffraction peaks at 2 ⁇ angles selected from 6.4°, 8.1°, 19.8°, 20.4°, and 27.3°; or by at least five x-ray powder diffraction peaks at 2 ⁇ angles selected 6.4°, 8.1°, 16.2°, 19.8°, 20.4°, 24.4°, 24.8°, and 27.3°.
  • crystalline Form XIV is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 35.
  • Crystalline Form XIV may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 86 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting.
  • the DSC thermogram is substantially in accordance with that in FIG. 36.
  • the TGA thermogram is substantially in accordance with that in FIG. 37.
  • Crystalline Form XIV may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate.
  • the compound of Structural Formula 1 is a tert-butanol solvate.
  • composition comprising particles of one or more crystalline forms of the compound represented by Structural Formula 1: wherein the one or more crystalline forms are selected from the crystalline forms of any one of the aspects of the first through the fourteenth embodiments described above.
  • the one or more crystalline forms are selected from: crystalline Form n characterized by x-ray powder diffraction peaks at 2 ⁇ angles 21.7°, 22.0°, 22.7°, and 25.1°; crystalline Form III characterized by x-ray powder diffraction peaks at 2 ⁇ angles 6.5°, 17.5°, 21.2°, and 21.9°; crystalline Form IV characterized by x-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.5°, and 24.7°; crystalline Form V characterized by x-ray powder diffraction peaks at 2 ⁇ angles 7.4°, 23.0°, 24.2°, and 24.7°; crystalline Form VII characterized by x-ray powder diffraction peaks at 2 ⁇ angles 16.0°, 21.4°, 22.6°, and 29.5°; crystalline Form VIII characterized by x-ray powder diffraction peaks at 2 ⁇ angles 18.7°, 19.8°, 22.4°, and 26.0°; crystalline Form I
  • the disclosure relates to a pharmaceutical composition, comprising a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above or a composition of any one of the aspects of the fifteenth embodiment described above and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises crystalline Form I of the compound represented by Structural Formula 1, characterized by x-ray powder diffraction peaks at 2 ⁇ angles 4.6°, 22.8°, 23.2°, and 24.4°, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit formation of a pharmaceutical composition, i.e., a dosage form capable of being administered to a subject.
  • a “pharmaceutically acceptable carrier” should not destroy the activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers are well known in the art.
  • compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfete, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat [00121] Pharmaceutical compositions of the disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal
  • parenteral includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions are administered orally, subcutaneously, intraperitoneally or intravenously.
  • Sterile injectable forms of the pharmaceutical compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • Pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • a provided oral formulation is formulated for immediate release or sustained/delayed release.
  • the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles.
  • a provided compound can also be in micro-encapsulated form.
  • Specific pharmaceutically acceptable carriers suitable for use in an oral formulation such as a tablet or capsule include, but are not limited to, microcrystalline cellulose (Avicel PH101), croscarmellose Sodium (Ac-Di-Sol), kollidon 30 powder (polyvinylpyrrolidone, povidone), colloidal silicon dioxide M5-P, magnesium stearate, microcrystalline cellulose (Avcel PH102), sodium lauryl sulfete (Kolliphor SLS Fine) and Colloidal Silicon Dioxide M5-P.
  • microcrystalline cellulose Avicel PH101
  • croscarmellose Sodium Ac-Di-Sol
  • kollidon 30 powder polyvinylpyrrolidone, povidone
  • colloidal silicon dioxide M5-P colloidal silicon dioxide
  • magnesium stearate magnesium stearate
  • microcrystalline cellulose Avcel PH102
  • sodium lauryl sulfete Kolliphor SLS Fine
  • compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • the amount of the crystalline form of the compound represented by the compound represented by Structural Formula 1 in pharmaceutical compositions of this disclosure is such that is effective to measurably treat or prevent in the treatment of disorders associated with CRM1 activity in a subject.
  • a pharmaceutical composition of this disclosure is formulated for administration to a subject in need of such pharmaceutical composition.
  • the term “subject,” as used herein, can be a human subject or an animal.
  • the amount of the crystalline form of the compound of Structural Formula 1 that can be combined with the pharmaceutically acceptable carrier materials to produce a pharmaceutical composition in a single dosage form will vary depending upon the host treated and/or the particular mode of administration.
  • the pharmaceutical compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound of Structural Formula 1 can be administered to a patient receiving these compositions.
  • the dosage is from about 0.5 to about 100 mg/kg of body weight, or between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day. Exemplary doses, include but are not limited to, 1.0 mg/kg twice a day for about 4-14 days and 1.5 mg/kg once a day for 5 to 10 days.
  • the pharmaceutical composition of crystalline form of the compound of Structural Formula 1 can be formulated to deliver to the subject the dosage of the compound represented by Structural Formula (I) of 80 mg (45 mg/m 2 BS A), delivered, for example, twice weekly.
  • the pharmaceutical composition of the crystalline form can be formulated to deliver to the subject the dosage of the compound represented by Structural Formula (I) of 100 mg, delivered, for example, once per day on selected days of a treatment cycle.
  • a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • a maintenance dose of a pharmaceutical composition of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • Crystalline forms of the compound represented by Structural Formula I disclosed herein, such as crystalline Form I, and pharmaceutical compositions comprising same are generally useful for the inhibition of CRM1 and are, therefore, useful for treating one or more disorders associated with activity of CRM1.
  • the present disclosure provides a method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of the compound of Structural Formula 1 or a pharmaceutical composition described herein.
  • the crystalline formsand pharmaceutical composition comprising same can also be administered to cells in culture, e.g., in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described hereinbelow.
  • the activity of crystalline Form I and a pharmaceutical composition comprising same as an inhibitor of CRM1 may be assayed in vitro, in vivo or in a cell line.
  • Detailed conditions for assaying an inhibitor of CRM1, such as crystalline Form I of the compound represented by Structural Formula I are set forth in International Publication No. WO 14/205389.
  • treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms, either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • CRM1 -mediated disorder or condition or disorder associated with CRM1 activity means any disease or other deleterious condition in which CRM1 is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which CRM1 is known to play a role.
  • the present disclosure provides methods of treating a disease associated with expression or activity of p53, p73, p21, pRB, p27, INB, NFNB, c- Abl, FOXO proteins, COX-2, or an HDAC (histone deacetylases) in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.
  • the present disclosure relates to a method of treating or lessening the severity of a disease or condition selected from a proliferative disorder (e.g., cancer), an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder or a neurodegenerative disorder wherein said method comprises administering to a patient in need thereof a compound or composition according to the present disclosure.
  • a proliferative disorder e.g., cancer
  • an inflammatory disorder e.g., an autoimmune disorder, a viral infection, an ophthalmological disorder or a neurodegenerative disorder
  • terapéuticaally effective amount means an amount of a crystal form of the compound represented by Structural Formula 1 that is effective in treating or lessening the severity of one or more symptoms of a disorder or condition. In the case of promoting wound healing, a therapeutically effective amount is an amount that promotes healing of a wound.
  • prophylaxis or “prophylactic” refer to measures taken to preventing or increasing resistance to a disease prior to its onset as well as to measures that ameliorate the symptoms of a disease when taken prior to its onset Prophylaxis also includes measures taken to prevent the recurrence of a disease.
  • prophylactically effective amount means an amount of a crystal form of the compound represented by Structural Formula 1 that is effective for prophylaxis of a condition treatable by such compound.
  • promoting wound healing means treating a subject with a wound and achieving healing, either partially or fully, of the wound. Promoting wound healing can mean, e.g., one or more of the following: promoting epidermal closure; promoting migration of the dermis; promoting dermal closure in the dermis; reducing wound healing complications, e.g., hyperplasia of the epidermis and adhesions; reducing wound dehiscence; and promoting proper scab formation.
  • the present disclosure relates to a method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline form of the compound represented by Structural Formula 1 or a pharmaceutical composition described herein.
  • Cancers treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, hematologic malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic and myeloproliferative syndromes) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteosarcomas, and stromal tumors).
  • Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC.
  • breast cancer can include invasive or non- invasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple.
  • the cancer is multiple myeloma.
  • Inflammatory disorders treatable by a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel), atherosclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, sepsis, psoriasis and other dermatological inflammatory disorders (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and dermatosis with acute inflammatory components, pemphigus, pemphigoid, allergic dermatitis), and urticarial syndromes.
  • multiple sclerosis rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, va
  • Viral diseases treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma,
  • Viral diseases treatable by the compounds of this disclosure also include chronic viral infections, including hepatitis B and hepatitis C. Additionally, viral diseases treatable by the compounds of this disclosure include infections caused by a coronavirus, e.g., SARS, MERS, and SARS-CoV-2.
  • a coronavirus e.g., SARS, MERS, and SARS-CoV-2.
  • Exemplary ophthalmology disorders include, but are not limited to, macular edema (diabetic and nondiabetic macular edema), aged related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, ulceris, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, comeal ulcer, conjunctival ulcer, chronic nummular
  • Neurodegenerative diseases treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, Parkinson’s, Alzheimer’s, and Huntington’s, and Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease).
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystic kidney disorder (PKD) and other renal disorders.
  • disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystic kidney disorder (PKD) and other renal disorders.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders related to food intake such as obesity and hyperphagia.
  • crystalline forms of the compound represented by Structural Formula lor pharmaceutical cornpositions described herein may be used to treat or prevent allergies and respiratory disorders, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
  • allergies and respiratory disorders including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the disorder or condition associated with CRM1 activity is beta-thalassemia, muscular dystrophy, arthritis, for example, osteoarthritis and rheumatoid arthritis, ankylosing spondilitis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren’s syndrome, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, gut diseases, peritoneal
  • the disorder or condition associated with CRM1 activity is head injury, uveitis, inflammatory pain, allergen induced asthma, non-allergen induced asthma, glomerular nephritis, ulcerative colitis, necrotizing enterocolitis, hyperimmunogtobulinemia D with recurrent fever (HIDS), TNF receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes, Muckle- Wells syndrome (urticaria deafness amyloidosis), familial cold urticaria, neonatal onset multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome, pyogenic sterile arthritis, pyoderma gangrenosum acne (PAPA), deficiency of the interleukin- 1 -receptor antagonist (DIRA), subarachnoid hemorrhage, polycystic kidney disease,
  • DIRA interleukin
  • the present disclosure relates to a use of a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of a disorder associated with
  • the present disclosure also relates to crystalline form I or pharmaceutical compositions described herein for use in treating a disorder associated with CRM1 activity. Specific examples of disorders associated with CRM1 activity are as set forth in detail herein. [00152] In yet further aspects, the present disclosure relates to a use of a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of a disease associated with expression or activity of p53, p73, p21, pRB, p27, INB, NFNB, c-Abl, FOXO proteins, COX- 2 or an HDAC in a subject.
  • the present disclosure relates to a use of a crystalline form or pharmaceutical compositions described herein in the manufacture of a medicament for the treatment of any of cancer and/or neoplastic disorders, angiogenesis, autoimmune disorders, inflammatory disorders and/or diseases, epigenetics, hormonal disorders and/or diseases, viral diseases, neurodegenerative disorders and/or diseases, wounds, and ophthalmologic disorders.
  • the present disclosure relates to a method for inhibiting CRM1 in a biological sample comprising contacting the biological sample with, or administering to the patient, a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat a neoplastic disorder.
  • a “neoplastic disorder” is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth.
  • Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e.g., tumors arising from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors.
  • Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others. Crystalline forms or pharmaceutical compositions described herein are also useful in treating non-solid cancers.
  • Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary.
  • malignancies e.g., sarcomas, adenocarcinomas, and carcinomas
  • gastrointestinal e.g., colon
  • genitourinary e.g., renal, urothelial, or testicular tumors
  • Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
  • Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependy
  • Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Yet further exemplary cancers include endocervical cancer, flcell ALL, T-cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • endocervical cancer flcell ALL, T-cell ALL, B- or T-cell lymphoma
  • mast cell cancer glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
  • Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing’s sarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma and chondroblastic osteosarcoma.
  • Further exemplary cancer that can be treated by a crystalline form of the compound of Structural Formula (1) or pharmaceutical compositions described herein are penile cancer and nasopharyngeal cancer.
  • Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
  • the disclosure relates to a method for treating or preventing a CRM1 -associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above, a composition of any one of the aspects of the fifteenth embodiment described above or a pharmaceutical composition of any one of the aspects of the sixteenth embodiment described above.
  • the method comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline formof the compound represented by Structural Formula 1, or a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a crystalline formof the compound represented by Structural Formula 1, and a pharmaceutically acceptable carrier.
  • the disorder is a proliferative disorder, cancer, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, an allergic disorder, or a respiratory disorder.
  • the disorder is cancer.
  • the cancer is multiple myeloma, relapsed or refractory multiple myeloma, penta-refractoiy multiple myeloma, acute myeloid leukemia, relapsed or refractory acute myeloid leukemia, secondary acute myeloid leukemia, diffuse large B-cell lymphoma, relapsed or refractory diffuse large B-cell lymphoma, recurrent or refractory B-cell non-Hodgkin lymphoma, recurrent or refractory extranodal marginal zone lymphoma, recurrent follicular lymphoma, recurrent or refractory indolent adult non-Hodgkin lymphoma, recurrent or refractory mantle cell lymphoma, recurrent or refractory marginal zone lymphoma, recurrent or refractory small lymphocytic lymphoma, recurrent Walden
  • crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from leukemia, lymphoma or a sold cancer, wherein the leukemia is selected from: hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and chronic lymphocytic leukemia; the lymphoma is selected from: cutaneous T-Cell lymphoma; diffuse large B-cell lymphoma; mantle cell lymphoma; and follicular lymphoma; the solid cancer is selected from: prostate cancer; breast cancer; liver cancer; colon cancer; pancreatic cancer; renal cancer; and ovarian cancer.
  • the leukemia is selected from: hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and chronic lymphocytic leukemia
  • the lymphoma is selected from: cutaneous T-Cell lymphom
  • crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from a lymphoma, selected from non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, follicular lymphoma and mantle cell lymphoma; a leukemia selected from hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and chronic lymphocytic leukemia; or a solid tumor selected from prostate, breast, liver, colorectal, pancreatic, renal, osteosarcoma, lung, cervical and ovarian cancers.
  • a lymphoma selected from non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, folli
  • crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from a colorectal cancer, a prostate cancer, a myelodysplastic syndrome, an inflammatory bowel disease, a nasopharyngeal cancer, and a penile cancer.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered together with an additional “second” therapeutic agent or treatment.
  • second therapeutic agent may be made from any agent that is typically used in a monotherapy to treat the indicated disease or condition.
  • the term “administered together” and related terms refers to the simultaneous or sequential administration of therapeutic agents to a subject in need thereof to treat any one or more indications described herein.
  • crystalline forms or pharmaceutical compositions described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure relates to a single unit dosage form comprising crystalline form I or pharmaceutical compositions described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the effective amount of crystalline forms of the compound represented by Structural Formula 1 is less than its effective amount would have been if the second therapeutic agent were not administered.
  • the effective amount of the second therapeutic agent is less than its effective amount would have been if crystalline forms of the compound represented by Structural Formula 1 were not administered. In this way, undesired side effects associated with high doses of either agent may be minimized.
  • Other potential advantages including without limitation improved dosing regimens and/or reduced drug cost
  • the additional agents may be administered separately from crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein, as part of a multiple dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with crystalline forms or pharmaceutical compositions described herein.
  • crystalline forms of the compound represented by Structural Formula lor pharmaceutical compositions described herein may be administered alone or in combination with other compounds useful for treating or preventing inflammation.
  • exemplary anti-inflammatory agents include, for example, steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e.g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide).
  • steroids e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethas
  • the other therapeutic agent is an antibiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxycycline or streptomycin).
  • the other therapeutic agent is a PDE4 inhibitor (e.g., roflumilast or rolipram).
  • the other therapeutic agent is an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine).
  • the other therapeutic agent is an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine).
  • the other compound is drotrecogin alfa.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with dexamethasone.
  • anti-inflammatory agents include, for example, aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4- hydroxybutyric acid, 2-amino-4- picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antrafenine, apazone, beclomethasone, bendazac, benory
  • a crystalline form of the cornpound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered with a selective COX-2 inhibitor for treating or preventing inflammation.
  • selective COX-2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with an anthracycline or a Topo n inhibitor.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical cornpositions described herein are administered in combination with Doxorubicin (Dox).
  • Dox Doxorubicin
  • a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with bortezomib (and more broadly including carfilzomib).
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered together with an additional cancer treatment.
  • additional cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, and hormonal therapy, epigenetic therapy, proteosome inhibitors, and anti- angiogenic therapies. Examples of each of these treatments are provided below.
  • the term “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • crystalline forms of the compound represented by Structural Formula 1 can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising file crystalline forms of the compound represented by Structural Formula 1, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of crystalline forms of the compound represented by Structural Formula 1 can be administered.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are co-administered with a chemotherapy.
  • Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
  • chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others).
  • antimetabolites e.g., folic acid, purine, and pyrimidine derivatives
  • alkylating agents e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others.
  • agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carfilzomib, Carmofur, Carmustine, Celecoxib, Cetuximab , Chlorambucil, Chlormethine, CHOEP-21, CHOP, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine or ara-C, dacarbazine, Dactinomycin, DA EPOCH, Daratumumab , Daunorubicin,
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used in combination with or as a part of a targeted therapy.
  • Targeted therapy constitutes the use of agents specific for the target of interest (e.g., a deregulated protein) in cancer cells.
  • Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell.
  • Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin- dependent kinase inhibitors such as Alvocidib and Seliciclib.
  • Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells.
  • Examples include the anti-HER2/neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies.
  • Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
  • Exemplary fusion proteins include Aflibercept and Denileukin diflitox.
  • the targeted therapy can be used in combination with a pharmaceutical composition described herein, e.g., Gleevec (Vignari and Wang 2001).
  • Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor.
  • Radionuclides which are attached to these peptides eventually kill the cancer cell if the nuclide decays in the vicinity of the cell.
  • RGDs Radionuclides which are attached to these peptides
  • An example of such therapy includes BEXXAR®.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with angiogenesis.
  • Diseases associated with angiogenesis include cancer, cardiovascular disease and macular degeneration.
  • Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one. Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature.
  • VEGF Vascular endothelial growth factor
  • Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g., VEGF).
  • growth factors e.g., bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.
  • Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.
  • VEGF vascular endothelial growth factor
  • VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis.
  • VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision.
  • Anti-angiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sunitinib, sorafenib, or monoclonal antibodies or receptor“decoys” to VEGF or VEGF receptor including bevacizumab or VEGF-Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non- VEGF angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin or endostatin.
  • VEGF vascular endothelial growth factor
  • FGF fibroblast growth factor
  • angiopoietins angiostatin or endostatin.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with epigenetics.
  • Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence.
  • epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.
  • Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
  • Exemplary diseases associated with epigenetics include ATR-syndrome, fragile X- syndrome, ICF syndrome, Angelman’s syndrome, Prader- Wills syndrome, BWS, Rett syndrome, D-thalassaemia, cancer, leukemia, Rubinstein-Taybi syndrome and Coffin-Lowry syndrome.
  • DNA methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals.
  • CpG islands stretches of DNA near promoter regions that have higher concentrations of CpG sites (known as CpG islands) that are free of methylation in normal cells.
  • CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off.
  • This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer. Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more common in human cancer than DNA sequence mutations.
  • Microsatellites are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH1 can make a microsatellite unstable and lengthen or shorten it Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.
  • Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “autistic-like” behavior.
  • Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMRI (fragile X mental retardation 1) gene. People who do not have fragile X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMRI gene. However, individuals with over 200 repeats have a full mutation, and they usually show symptoms of the syndrome.
  • FMRI fragment X mental retardation 1
  • Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi, Coffin- Lowry, Prader-Willi, Angelman, Beckwith- Wiedemann, ATR-X, and Rett syndromes.
  • Epigenetic therapies include inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, which have shown promising anti-tumorigenic effects for some malignancies, as well as antisense oligonucleotides and siRNA.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered with an immunotherapy.
  • Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patients own immune system to fight the tumor. Conte rary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, prostate cancer vaccine Provenge, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.
  • Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor’s immune cells will often attack the tumor in a graft-versus- tumor effect.
  • the immunotherapy agent(s) can be used in combination with crystalline forms or pharmaceutical compositions described herein.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered with a hormonal therapy.
  • the growth of some cancers can be inhibited by providing or blocking certain hormones.
  • hormone-sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which respond to certain retinoids/retinoic acids. Removing or blocking estrogen or testosterone is often an important additional treatment.
  • administration of hormone agonists, such as progestogens may be therapeutically beneficial.
  • the hormonal therapy agents can be used in combination with a pharmaceutical composition described herein.
  • Hormonal therapy agents include the administration of hormone agonists or hormone antagonists and include retinoids/retinoic acid, compounds that inhibit estrogen or testosterone, as well as administration of progestogens.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with inflammation, particularly in humans and other mammals. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered prior to the onset of, at, or after the initiation of inflammation. When used prophylactically, the pharmaceutical compositions are preferably provided in advance of any inflammatory response or symptom. Administration can prevent or attenuate inflammatory responses or symptoms.
  • Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondouloarthropathies, other seronegative inflammatory arthridities, polymyalgia rheumatica, various vasculidities (e.g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis, systemic lupus erythematosus, juvenile arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis,
  • Exemplary inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory components.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
  • Crystalline form I or pharmaceutical compositions described herein may be used to treat chronic hepatitis infection, including hepatitis B and hepatitis C.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases, such as organ-tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and Grave's disease.
  • organ-tissue autoimmune diseases e.g., Raynaud's syndrome
  • scleroderma myasthenia gravis
  • transplant rejection transplant rejection
  • endotoxin shock sepsis
  • psoriasis psoriasis
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat multiple sclerosis.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with a viral infection, particularly in humans and other mammals. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered prior to the onset of at, or after the initiation of viral infection. When used prophylactically, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered in advance of any viral infection or symptom thereof.
  • Exemplary viral diseases include acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfect
  • Exemplary viral influenza A strains include H1N1, H3N2, H5N1, H7N3, H7N9.
  • a compound described herein can also be used to treat or prevent influenza B.
  • Exemplary viral pathogens include Adenovirus, Coxsackievirus, Dengue virus, Encephalitis Virus, Epstein-Barr virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Herpes simplex virus type 1, Herpes simplex virus type 2, cytomegalovirus, Human herpesvirus type 8, Human immunodeficiency virus, Influenza virus, measles virus, Mumps virus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabies virus, Respiratory syncytial virus, Rubella virus, Varicella-zoster virus, West Nile virus, Dungee, SARS, MERS, SARS-CoV-2, and Yellow fever virus. Viral pathogens may also include viruses that cause resistant viral infections.
  • Antiviral drugs are a class of medications used specifically for treating viral infections. Antiviral action generally falls into one of three mechanisms: interference with the ability of a virus to infiltrate a target cell (e.g., amantadine, rimantadine and pleconaril), inhibition of the synthesis of virus (e.g., nucleoside analogues, e.g., acyclovir and zidovudine (ACT), and inhibition of the release of virus (e.g., zanamivir and oseltamivir).
  • a target cell e.g., amantadine, rimantadine and pleconaril
  • inhibition of the synthesis of virus e.g., nucleoside analogues, e.g., acyclovir and zidovudine (ACT)
  • ACT acyclovir and zidovudine
  • inhibition of the release of virus e.g., zanamivir and oseltamivir
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent an ophthamology disorder.
  • ophthamology disorders include macular edema (diabetic and nondiabetic macular edema), age related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, ulceris, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis
  • ophthalmology disorders treatable using crystalline form or pharmaceutical compositions described herein include proliferative vitreoretinopathy and chronic retinal detachment.
  • Inflammatory eye diseases are also treatable using crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a neurodegenerative disease.
  • Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons.
  • Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes.
  • many similarities appear which relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously.
  • There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death.
  • Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
  • Huntington’s disease causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices.
  • the striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder.
  • Exemplary treatments for Huntington’s disease include tetrabenazine, neuroleptics, benzodiazepines, amantadine, remacemide, valproic acid, selective serotonin reuptake inhibitors (SSRIs), mirtazapine and antipsychotics.
  • SSRIs selective serotonin reuptake inhibitors
  • the mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells.
  • the alpha-synuclein-ubiquitin complex cannot be directed to the proteosome.
  • This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies.
  • the latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles - the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rabi may reverse this defect caused by alpha-synuclein in animal models.
  • Parkinson’s disease therapies include levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors, MAO-B inhibitors such as selegilene and rasagilene, anticholinergics and amantadine.
  • dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride
  • dopa decarboxylate inhibitors such as selegilene and rasagilene
  • anticholinergics and amantadine include levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorph
  • Amyotrophic lateral sclerosis is a disease in which motor neurons are selectively targeted for degeneration.
  • exemplary ALS therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline.
  • exemplary neurodegenerative therapeutics includes antisense oligonucleotides and stem cells.
  • Wounds are a type of condition characterized by cell or tissue damage. Wound healing is a dynamic pathway that optimally leads to restoration of tissue integrity and function.
  • the wound healing process consists of three overlapping phases.
  • the first phase is an inflammatory phase, which is characterized by homeostasis, platelet aggregation and degranulation. Platelets as the first response, release multiple growth factors to recruit immune cells, epithelial cells, and endothelial cells.
  • the inflammatory phase typically occurs over days 0-5.
  • the second stage of wound healing is the proliferative phase during which macrophages and granulocytes invade the wound. Infiltrating fibroblasts begin to produce collagen.
  • the principle characteristics of this phase are epithelialization, angiogenesis, granulation tissue formation and collagen production.
  • the proliferative phase typically occurs over days 3-14.
  • the third phase is the remodeling phase where matrix formation occurs.
  • the fibroblasts, epithelial cells, and endothelial cells continue to produce collagen and collagenase as well as matrix metalloproteases (MMPs) for remodeling. Collagen crosslinking takes place and the wound undergoes contraction.
  • MMPs matrix metalloproteases
  • the remodeling phase typically occurs from day 7 to one year.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used for promoting wound healing (e.g., promoting or accelerating wound closure and/or wound healing, mitigating scar fibrosis of the tissue of and/or around the wound, inhibiting apoptosis of cells surrounding or proximate to the wound).
  • the present disclosure relates to a method for promoting wound healing in a subject, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above, a composition of any one of the aspects of the fifteenth embodiment described above, or a pharmaceutical composition of any one of the aspects of the sixteenth embodiment described above.
  • the method need not achieve complete healing or closure of the wound; it is sufficient for the method to promote any degree of wound closure. In this respect ⁇ the method can be employed alone or as an adjunct to other methods for healing wounded tissue.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat wounds during the inflammatory (or early) phase, during the proliferative (or middle) wound healing phase, and/or during the remodeling (or late) wound healing phase.
  • the subject in need of wound healing is a human or an animal, for example, a dog, a cat, a horse, a pig, or a rodent, such as a mouse.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered topically, for example, proximate to the wound site, or systemically.
  • a therapeutically effective amount of crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered (optionally in combination with other agents) to the wound site by coating the wound or applying a bandage, packing material, stitches, etc., that are coated or treated with the compound or composition described herein.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be formulated for topical administration to treat surface wounds.
  • Topical formulations include those for delivery via the mouth (buccal) and to the skin such that a layer of skin (i.e., the epidermis, dermis, and/or subcutaneous layer) is contacted with the pharmaceutical composition described herein.
  • Topical delivery systems may be used to administer topical formulations of the compounds and compositions described herein.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered at or near the wound site by, for example, injection of a solution, injection of an extended release formulation, or introduction of a biodegradable implant comprising the compound or composition described herein.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat acute wounds or chronic wounds.
  • a chronic wound results when the normal reparative process is interrupted.
  • Chronic wounds can develop from acute injuries as a result of unrecognized persistent infections or inadequate primary treatment In most cases however, chronic lesions are the end stage of progressive tissue breakdown owing to venous, arterial, or metabolic vascular disease, pressure sores, radiation damage, or tumors.
  • Chronic wounds include, but are not limited to the following: chronic ischemic skin lesions; scleroderma ulcers; arterial ulcers; diabetic foot ulcers; pressure ulcers; venous ulcers; non-healing lower extremity wounds; ulcers due to inflammatory conditions; and/or long-standing wounds.
  • Other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, and arterial insufficiencies, and pressure wounds and cold and warm bums.
  • Yet other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, arterial insufficiencies, and pressure wounds.
  • Acute wounds include, but are not limited to, post-surgical wounds, lacerations, hemorrhoids and fissures.
  • crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used for diabetic wound healing or accelerating healing of leg and foot ulcers secondary to diabetes or ischemia in a subject
  • the wound is a surface wound.
  • the wound is a surgical wound (e.g., abdominal or gastrointestinal surgical wound).
  • the wound is a bum.
  • the wound is the result of radiation exposure.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can also be used for diabetic wound healing, gastrointestinal wound healing, or healing of an adhesion due, for example, to an operation.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can also be used to heal wounds that are secondary to another disease.
  • inflammatory skin diseases such as psoriasis and dermatitis
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to heal wounds that are secondary to these diseases, for example, inflammatory skin diseases, such as psoriasis and dermatitis.
  • the wound is an internal wound.
  • the internal wound is a chronic wound.
  • the wound is a vascular wound.
  • the internal wound is an ulcer.
  • Examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, Crohn’s disease, ulcerative colitis, internal surgical sutures and skeletal fixation.
  • Other examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, internal surgical sutures and skeletal fixation.
  • wounds include, but are not limited to, abrasions, avulsions, blowing wounds (i.e., open pneumothorax), bum wounds, contusions, gunshot wounds, incised wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, sfiton wounds, stab wounds, surgical wounds, subcutaneous wounds, diabetic lesions, or tangential wounds.
  • blowing wounds i.e., open pneumothorax
  • bum wounds i.e., contusions, gunshot wounds, incised wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, sfiton wounds, stab wounds, surgical wounds, subcutaneous wounds, diabetic lesions, or tangential wounds.
  • wounds that can be treated by the pharmaceutical compositions described herein include acute conditions or wounds, such as thermal bums, chemical bums, radiation bums, bums caused by excess exposure to ultraviolet radiation (e.g., sunbum); damage to bodily tissues, such as the perineum as a result of labor and childbirth; injuries sustained during medical procedures, such as episiotomies; trauma- induced injuries including cuts, incisions, excoriations; injuries sustained from accidents; post-surgical injuries, as well as chronic conditions, such as pressure sores, bedsores, conditions related to diabetes and poor circulation, and all types of acne.
  • acute conditions or wounds such as thermal bums, chemical bums, radiation bums, bums caused by excess exposure to ultraviolet radiation (e.g., sunbum); damage to bodily tissues, such as the perineum as a result of labor and childbirth; injuries sustained during medical procedures, such as episiotomies; trauma- induced injuries including cuts, incisions, excoriations; injuries sustained from accidents
  • the wound can include dermatitis, such as impetigo, intertrigo, folliculitis and eczema, wounds following dental surgery; periodontal disease; wounds following trauma; and tumor- associated wounds.
  • dermatitis such as impetigo, intertrigo, folliculitis and eczema
  • wounds following dental surgery periodontal disease
  • wounds following trauma and tumor- associated wounds.
  • wounds include animal bites, arterial disease, insect stings and bites, bone infections, compromised skin/muscle grafts, gangrene, skin tears or lacerations, skin aging, surgical incisions, including slow or non-healing surgical wounds, intracerebral hemorrhage, aneurysm, dermal asthenia, and post-operation infections.
  • the wound is selected from the group consisting of a bum wound, an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a thermal bum, a chemical bum, a radiation bum, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation.
  • the wound is selected from the group consisting of an incised wound, an open wound, a surgical or post- surgical wound, a diabetic lesion, a pressure sore, a bedsore, and a condition or wound related to diabetes or poor circulation.
  • the wound is selected from the group consisting of a nonradiation bum wound, an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a thermal bum, a chemical bum, a pressure sore, a bedsore, and a condition rotated to diabetes or poor circulation.
  • the wound is selected from the group consisting of an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation.
  • the present disclosure also relates to methods for reducing scar formation during wound healing in a subject.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered directly to the wound or to cells proximate the wound at an amount effective to reduce scar formation in and/or around the wound.
  • a method of reducing scar formation during wound healing in a subject comprising administering to the subject a therapeutically effective amount of crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein.
  • the wound can include any injury to any portion of the body of a subject
  • the present disclosure relates to methods for ameliorating, reducing, or decreasing the formation of scars in a subject that has suffered a bum injury. In other embodiments, the present disclosure relates to methods for treating, reducing the occurrence of, or reducing the probability of developing hypertrophic scars in a subject that has suffered an acute or chronic wound or injury.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders.
  • Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are useful as radiosensitizers. Therefore, pharmaceutical compositions described herein can be administered in combination with radiation therapy.
  • Radiation therapy is the medical use of high-energy radiation (e.g., X-rays, gamma rays, charged particles) to shrink tumors and kill malignant cells, and is generally used as part of cancer treatment. Radiation therapy kills malignant cells by damaging their DNA.
  • Radiation therapy can be delivered to a patient in several ways.
  • radiation can be delivered from an external source, such as a machine outside the patient’s body, as in external beam radiation therapy.
  • External beam radiation therapy for the treatment of cancer uses a radiation source that is external to the patient, typically either a radioisotope, such as 60 Co, 137 Cs, or a high energy X-ray source, such as a linear accelerator.
  • the external source produces a collimated beam directed into the patient to the tumor site.
  • External-source radiation therapy avoids some of the problems of internal-source radiation therapy, but it undesirably and necessarily irradiates a significant volume of non-tumorous or healthy tissue in the path of the radiation beam along with the tumorous tissue.
  • the adverse effect of irradiating of healthy tissue can be reduced, while maintaining a given dose of radiation in the tumorous tissue, by projecting the external radiation beam into the patient at a variety of “gantry” angles with the beams converging on the tumor site.
  • the particular volume elements of healthy tissue, along the path of the radiation beam, change, reducing the total dose to each such element of healthy tissue during the entire treatment
  • the irradiation of healthy tissue also can be reduced by tightly collimating the radiation beam to the general cross section of the tumor taken perpendicular to the axis of the radiation beam.
  • Numerous systems exist for producing such a circumferential collimation some of which use multiple sliding shutters which, piecewise, can generate a radio-opaque mask of arbitrary outline.
  • the amount can be at least about 1 Gray (Gy) fractions at least once every other day to a treatment volume.
  • the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume.
  • the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume for five consecutive days per week
  • radiation is administered in 10 Gy fractions every other day, three times per week to a treatment volume.
  • a total of at least about 20 Gy is administered to a patient in need thereof.
  • at least about 30 Gy is administered to a patient in need thereof.
  • at least about 40 Gy is administered to a patient in need thereof.
  • the patient receives external beam therapy four or five times a week.
  • An entire course of treatment usually lasts from one to seven weeks depending on the type of cancer and the goal of treatment For example, a patient can receive a dose of 2 Gy/day over 30 days.
  • Internal radiation therapy is localized radiation therapy, meaning the radiation source is placed at the site of the tumor or affected area.
  • Internal radiation therapy can be delivered by placing a radiation source inside or next to the area requiring treatment.
  • Internal radiation therapy is also called brachytherapy.
  • Brachytherapy includes intracavitary treatment and interstitial treatment.
  • intracavitary treatment containers that hold radioactive sources are put in or near the tumor. The sources are put into the body cavities.
  • interstitial treatment the radioactive sources alone are put into the tumor. These radioactive sources can stay in the patient permanently. Typically, the radioactive sources are removed from the patient after several days. The radioactive sources are in containers.
  • the radiopharmaceutical agent can be administered by targeted delivery or by systemic delivery of targeted radioactive conjugates, such as a radiolabeled antibody, a radiolabeled peptide and a liposome delivery system.
  • targeted delivery the radiolabelled pharmaceutical agent can be a radiolabelled antibody. See, for example, Ballangrud A. M., et al. Cancer Res., 2001; 61 :2008-2014 and Goldenber, D.M. J. Nucl. Med., 2002; 43(5):693-713, the contents of which are incorporated by reference herein.
  • the radiopharmaceutical agent can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. See, for example, Emfietzoglou D, Kostarelos K, Sgouros G. An analytical dosimetry study for the use of radionuclide-liposome conjugates in internal radiotherapy. J Nucl Med 2001; 42:499-504, the contents of which are incorporated by reference herein.
  • the radiolabeled pharmaceutical agent can be a radiolabeled peptide.
  • a radiolabeled peptide See, for example, Weiner RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases, Appl Radiat Isot 2002 Nov;57(5):749-63, the contents of which are incorporated by reference herein.
  • brachytherapy can be used to deliver the radiopharmaceutical agent to the target site.
  • Brachytherapy is a technique that puts the radiation sources as close as possible to the tumor site. Often the source is inserted directly into the tumor.
  • the radioactive sources can be in the form of wires, seeds or rods. Generally, cesium, iridium or iodine are used.
  • Systemic radiation therapy is another type of radiation therapy and involves the use of radioactive substances in the blood.
  • Systemic radiation therapy is a form of targeted therapy.
  • a patient typically ingests or receives an injection of a radioactive substance, such as radioactive iodine or a radioactive substance bound to a monoclonal antibody.
  • a “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases.
  • the radiolabelled pharmaceutical agent for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source.
  • RI radioisotope
  • the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents.
  • the radioisotope is a metallic radioisotope
  • a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule.
  • the radioisotope is a non-metallic radioisotope
  • flie non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.
  • a “metallic radioisotope” is any suitable metallic radioisotope useful in a therapeutic or diagnostic procedure in vivo or in vitro.
  • Suitable metallic radioisotopes include, but are not limited to: Actinium-225, Antimony- 124, Antimony- 125, Arsenic-74, Barium- 103, Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Bismuth212, Bismuth213, Cadmium-109, Cadmium- 115m, Calcium-45, Cerium- 139, Cerium-141, Cerium-144, Cesium- 137, Chromium-51, Cobalt-55, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-60, Copper-62, Copper-64, Copper-67, Erbium- 169, Europium-152, Gallium-64, Gallium-67, Gallium-68, Gadolin
  • a “non-metallic radioisotope” is any suitable nonmetallic radioisotope (non-metallic radioisotope) usefill in a therapeutic or diagnostic procedure in vivo or in vitro.
  • Suitable non- metallic radioisotopes include, but are not limited to: Iodine- 131, Iodine-125, Iodine-123, Phosphorus-32, Astatine-211, Fluorine- 18, Cafbon-11, Oxygen- 15, Bromine-76, and Nitrogen-13.
  • Identifying the most appropriate isotope for radiotherapy requires weighing a variety of factors. These include tumor uptake and retention, blood clearance, rate of radiation delivery, half-life and specific activity of the radioisotope, and the feasibility of large-scale production of the radioisotope in an economical fashion.
  • the key point for a therapeutic radiopharmaceutical is to deliver the requisite amount of radiation dose to the tumor cells and to achieve a cytotoxic or tumoricidal effect while not causing unmanageable side-effects.
  • the physical half-life of the therapeutic radioisotope can be similar to the biological half-life of the radiopharmaceutical at the tumor site. For example, if the half-life of the radioisotope is too short, much of the decay will have occurred before the radiopharmaceutical has reached maximum target/background ratio. On the other hand, too long a half-life could cause unnecessary radiation dose to normal tissues. Ideally, the radioisotope should have a long enough half-life to attain a minimum dose rate and to irradiate all the cells during the most radiation sensitive phases of the cell cycle. In addition, the half-life of a radioisotope has to be long enough to allow adequate time for manufacturing, release, and transportation.
  • the target receptor sites in tumors are typically limited in number. As such, it is preferred that the radioisotope have high specific activity. The specific activity depends primarily on the production method. Trace metal contaminants can be minimized as they often compete with the radioisotope for the chelator and their metal complexes compete for receptor binding with the radiolabeled chelated agent.
  • the type of radiation that is suitable for use in the methods of the present disclosure can vary. For example, radiation can be electromagnetic or particulate in nature. Electromagnetic radiation usefill in the practice of this disclosure includes, but is not limited to, X-rays and gamma rays.
  • Particulate radiation useful in the practice of this disclosure includes, but is not limited to, electron beams (beta particles), protons beams, neutron beams, alpha particles, and negative pi mesons.
  • the radiation can be delivered using conventional radiological treatment apparatus and methods, and by intraoperative and stereotactic methods. Additional discussion regarding radiation treatments suitable for use in the practice of this disclosure can be found throughout Steven A. Leibel et al., Textbook of Radiation Oncology (1998) (publ. W. B. Saunders Company), and particularly in Chapters 13 and 14. Radiation can also be delivered by other methods such as targeted delivery, for example by radioactive “seeds,” or by systemic delivery of targeted radioactive conjugates. J.
  • D and E-particle emitters For tumor therapy, both D and E-particle emitters have been investigated. Alpha particles are particularly good cytotoxic agents because they dissipate a large amount of energy within one or two cell diameters.
  • the E-particle emitters have relatively long penetration range (2-12 mm in the tissue) depending on the energy level. The long-range penetration is particularly important for solid tumors that have heterogeneous blood flow and/or receptor expression. The E-particle emitters yield a more homogeneous dose distribution even when they are heterogeneously distributed within the target tissue.
  • therapeutically effective amounts of crystalline form or pharmaceutical compositions described herein are administered in combination with a therapeutically effective amount of radiation therapy to treat cancer (e.g., lung cancer, such as non-small cell lung cancer).
  • cancer e.g., lung cancer, such as non-small cell lung cancer.
  • the amount of radiation necessary can be determined by one of kill in the art based on known doses for a particular type of cancer. See, for example, Cancer Medicine 5 th ed., Edited by R.C. Bast et al., July 2000, BC Decker.
  • compound of Structural Formula 1 is the compound represented by the following structural formula
  • Prominent Peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.
  • assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO.
  • the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks.” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.
  • “Characteristic peaks,” to the extent they exist, are a subset of Representative Peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ⁇ 0.2° 2 ⁇ . Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
  • X-Ray Powder Diffraction patterns were collected on a Broker AXS C2 GADDS diffractometer using Cu K ⁇ radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector.
  • X-ray optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm. A weekly performance check is carried out using a certified standard NIST 1976 Corundum (flat plate).
  • the beam divergence i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm
  • a ⁇ - ⁇ continuous scan mode was employed with a sampledetector distance of 20 cm which gives an effective 2 ⁇ range of 3.2°-29.7°.
  • the sample was exposed to the X-ray beam for 120 seconds.
  • the software used for data collection was GADDS for XP/20004.1.43 and the data were analyzed and presented using Diffrac Plus EVA v15.0.0.0.
  • Non-ambient conditions Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at 20 °C/min and subsequently held isothermally for 1 minute before data collection was initiated.
  • X-ray Powder Diffraction patterns were collected on a Broker D8 diffractometer using Cu K ⁇ radiation (40 kV, 40 mA), 0-2 ⁇ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector.
  • the instrument was performance checked using a certified Corundum standard (NIST 1976).
  • the software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analyzed and presented using Diffrac Plus EVA vlS.0.0.0.
  • Angular range 2 to 42° 2 ⁇ ;
  • Step size 0.05° 2 ⁇
  • TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto- sampler. The instrument was temperature calibrated using certified Alumel and Nickel. Typically 5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample.
  • the instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium. Typically 0.5- 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 280 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software vl.0.1.2 ( or v 1.0.1.3).
  • the sample temperature was maintained at 25 °C by the instrument controls.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min.
  • the relative humidity (RH) was measured by a calibrated Rotronic probe (dynamic range of 1.0 -100 % RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy ⁇ 0.005 mg).
  • NMR spectra were collected on a Broker 400MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin vl.3 using the standard Broker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone. Samples were prepared in DMSO-d 6 , unless otherwise stated. Off-line analysis was carried out using ACD Spectres Processor 2012.
  • the compound of Structural Formula (1) can be synthesized according to the procedure described in the International Application PCT/US22/30294, filed on May 20, 2022, the teachings of which are incorporated herewith in their entirety. Briefly, the compound of Formula (1) can be synthesized by the following sequence of reactions:
  • the crude material (a compound of Structural Formula (1)) was dissolved in hot methyl isobutyl ketone (MIBK) (with a possible treatment with SiliaMetS® DMT, the silica-bound 2,4,6 - trimercaptotriazine (trithiocyanuric acid, TMT)), filtered and then concentrated to precipitate out the product, which was then filtered off and dried to provide the crystalline Form I. From 20 to 40 parts of MIBK per one part of the solid can be used to dissolve the starting material. Isolation can be accomplished at temperatures from 0-5 °C to room temperature.
  • MIBK methyl isobutyl ketone
  • crude compound of Structural Formula (1) was charged to a reactor followed by 25 weights of methylisobutylketone (MIBK).
  • MIBK methylisobutylketone
  • the compound of Formula (1) was dissolved by heating to 65-70°C.
  • a slurry of SiliaBond® DMT (Si-DMT) (the silica-bound equivalent of 2,4,6- trimercaptotriazine (trithiocyanuric acid)) was charged.
  • the slurry was mixed at 65-70°C for 4 hours.
  • the slurry was polish filtered to remove the scavenger.
  • the scavenger cake was washed with MIBK pre-heated to 65-70°C.
  • Step 1 involves the preparation of the acrylamide represented by the chemical structure referenced as KPT-9508/MB3 in the scheme reproduced below.
  • Isobutylchloroformate is used to generate the mixed anhydrides that are then quenched in ammonium hydroxide to provide MB3/KPT-9508.
  • the details of the reaction scheme are as follows:
  • ammonium hydroxide 29.653 kg 26% w/w aqueous solution
  • ammonium hydroxide 29.653 kg 26% w/w aqueous solution
  • the solution temperature adjusted to 0-5 °C (internal temperature 8.4 °C to 3.0 °C for 11 hours 36 minutes).
  • a separate 206 L glass lined vessel, inerted under nitrogen was charged with 2- MeTHF (24.0 kg) which was heated at reflux for 30 minutes to dry the glass vessel and condenser assembly.
  • the vessel and contents were adjusted to ⁇ 30 °C, then the 2-MeTHF sampled for IPC (the first sample showed residual water of 0.2% w/v with a target of ⁇ 0.1 % w/v so the reflux was repeated with additional 2-MeTHF).
  • the vessel was drained and then dried under vacuum.
  • the batch was transferred to the first vessel containing ammonium hydroxide with vigorous agitation, while maintaining a temperature of 0-10 °C in the receiving vessel (temperature range of 0.1 °C to 9 .1 °C over a range of 40 minutes).
  • the reaction mixture from the second vessel was rinsed into the first vessel with 2-MeTHF (13.1 kg), agitated for 30 minutes at 4.3 °C, and then sampled for IPC (Residual KG1+KG5 wrt MB3+MC8 was 2% a/a with target of NMT 2% a/a).
  • the batch was then adjusted to a temperature of 20-25 °C (53 minutes, internal temperature 1.7 °C to 20.4 °C). Agitation was stopped for 49 minutes to allow for phase separation and the lower aqueous phase was drained and discarded (separation time 58 minutes, interface with organic layer, upper organic phase 140 L, lower aqueous phase 20 L). Water (77.5 kg) was charged while maintaining a temperature of 20-25 °C (temperature range 22.2 °C to 24.3 °C for 40 minutes), and agitated for 20 minutes. Agitation was then stopped for 45 minutes to allow for phase separation and the lower aqueous phase was drained and discarded (separation time 35 minutes, interface with aqueous layer, upper organic phase 144 L, lower aqueous phase 86 L).
  • the batch was isolated by filtration through 20 cfin polyester filter cloth with cotton backing cloth (filtration time of 2 hours 20 minutes held at 22.5 °C on SRF filter), then the filtrate was returned to the vessel and re-filtered over 1 hour and 24 minutes at 22.2 °C to rinse forward the remaining solids.
  • the filter cake was washed with n-heptane (21.2 kg in two portions - filtration times of 15, and 17 minutes), then de-liquored (2 hours) and dried under a stream of nitrogen (58 hours, ambient temperature).
  • IPC analysis showed the LOD to be 1.4% w/w at 58 hours with a limit of NMT 5% w/w, and the product was packaged to provide 12.4 kg, 80% yield of KPT-9508.
  • the isolated product conformed to the HPLC standard for this compound.
  • HPLC conditions were as follows:
  • Step 2 consists of two telescoped conversions to form the dibrominated mixture of isomers ME2/KPT-9515 + ME3/KPT-9506 (Step 2a below) which is then dehydrobrominated to form the intermediate mixture of isomers MB5/KPT-7538 + MB9/KPT-9507 (Step 2b).
  • the batch was charged with 275 mL of 10% w/v sodium bisulfite solution over a minimum period of 30 minutes while maintaining an internal temperature of 20-30 °C.
  • the batch was charge with 275 mL of water over a period of 5 minutes while maintaining an internal temperature of 20-30 °C.
  • the batch was further agitated at 20-30 °C for a minimum period of 60 minutes.
  • An aliquot of the batch in removed and observed for the presence of residual bromine. The complete reduction of bromine was observed by the presence of a white to off-white suspension.
  • a 500 mL three neck round bottom flask was equipped with a thermometer, overhead stirrer and nitrogen inlet. The flask was charged with 25 g of ME2 (49 mmol; 1.0 eq.) and 140 mL of ACN (8 parts with respect (wrt) to MB3) and 70 mL of water (4 parts with respect to MB3). To a separate 100 mL round-bottom flask was charged 8.6 mL of DIPEA (49 mmol, 1.0 eq. wrt MB3) and 52 mL of ACN (3 parts wrt MB3). The mixture was agitated for 20-30 minutes.
  • the DIPEA solution was added portion wise to the suspension of ME2 over a period of 1.0 to 1.5 hours.
  • the addition assembly was rinsed forward with 9 mL of ACN (0.5 parts wrt MB3).
  • the batch was agitated for 2-3 hours at 20-25 °C. IPC testing was performed and the IPC target was met (target: residual ME2 wrt MB5 is no more than (NMT) 0.3% a/a).
  • the resulting suspension was filtered using filter paper.
  • the filter cake was washed with 34 mL of 8:2 ACN/H 2 O mixture (2 parts wrt MB3).
  • the filter cake was washed with 34 mL of ACN (2 parts wrt MB3).
  • the filter cake was dried by nitrogen purge with aspirator suction for 20 hours.
  • the isolated product was a white solid and the purity was assessed by HPLC under the following protocol:
  • UPLC column Agilent Zorbax SB-CN, 3.0 x 100 mm, 1.8 ⁇ m 2.
  • Detector 260 nm
  • Needle Wash 50% ACN : 50% H 2 O
  • Trifluoroacetic Acid (TFA), reagent grade or equivalent.
  • ME2 impurity standard 1389-NN-130-1 or equivalent
  • KF9 (KPT-452) impurity standard use current reference standard
  • the reaction mixture is filtered and the filter cake washed with dioxane:water about 7: 1 v/v (at about 40-45 °C, about 3 parts wrt MB5).
  • the resulting filtrate is subjected to vacuum distillation and is distilled to a target volume of about 4.5-5.5 parts wrt MB5.
  • the resulting suspension is adjusted to an internal temperature of about 50-55 °C.
  • the reaction mixture is then charged with MeOH (about 20 parts wrt MB5) portionwise. The suspension is then agitated at about 50-55 °C for about 60-70 min.
  • the reaction mixture is then cooled to about 20-25 °C and then further cooled to about 0-5 °C over about 2-2.5 hours and is maintained at that temperature for a period of about 2-2.5 hours.
  • the resulting suspension is then filtered and the filter cake washed with MeOH (about 10 parts wrt MB5). The cake is then dried.
  • the dried filter cake from General Procedure 1 is then transferred to a flask equipped with an overhead stirrer, thermometer and nitrogen inlet and Si DMT (about 5 eq. wrt MB5) is charged to the flask. MIBK is then charged to the flask (about 25 parts wrt MB5).
  • the reaction mix is then heated to an internal temperature of about 65-70 °C and maintained at that temperature for about 1-1.5 hours if no scavenger used and about 4-5 hours if scavenger is used.
  • the reaction mixture is then filtered hot at about 65-70 °C into a clean flask equipped with an overhead stirrer, thermometer and nitrogen inlet
  • the filter is washed with MIBK (at about 65-70 °C, about 1.0 part wrt MB5).
  • MIBK at about 65-70 °C, about 1.0 part wrt MB5
  • the filtrate is slowly cooled to about 20-30 °C over about 3-3.5 hours, and then distilled under vacuum to a target volume of about 3-4 parts wrt MB5.
  • the batch temperature is adjusted to about 55-60 °C and the reaction mixture is agitated at 55-60 °C for about 2-2.5 hours.
  • the suspension is cooled to about 0-5 °C over about 2-2.5 hours and is stirred at this temperature for a minimum of about 1 hour.
  • the reactions mixture is then filtered and the resulting cake is washed with MIBK (about 1.0 part wrt MB5 at about 0-5 °C).
  • a 500 mL four neck round bottom flask was equipped with an overhead stirrer, a thermometer, reflux condenser and N 2 bubbler. The flask was flushed with nitrogen for a minimum of 30 minutes. Under a N 2 flow, to the flask was charged with 15.5 g of compound 4 (MB5) (36.1 mmol, 1.0 eq.), 8.95 g of MB7 (72.2 mmol., 2.0 eq. wrt MB5), 5.88 g of Cs 2 CO 3 (18.0 mmol., 0.5 eq. wrt MB5) and 0.415 g of Pd catalyst PT4 (Strem Amphos Palladacycle Gen. 2, cat.
  • reaction mixture was then further degassed by bubbling nitrogen through it for a period of 60-70 minutes.
  • the reaction mixture was then heated to an internal temperature of 55-60 °C, and was maintained at that temperature for a period of 7-7.5 hours.
  • the reaction temperature was adjusted to 40-45 °C, and an IPC sample was taken.
  • the reaction mixture was adjusted to 40-45 °C, followed by charging a slurry of 7.75 g of celite (0.5 parts wrt MB5) and 39 mL of dioxane: water 7:1 v/v (2.5 parts wrt MB5).
  • the resulting suspension was agitated at 40-45 °C for 15-20 minutes.
  • the reaction mixture was filtered and the filter cake was washed with 46.5 mL of pre-warmed dioxane:water 7:1 v/v (40-45 °C, 3 parts wrt MB5).
  • the resulting filtrate was subjected to vacuum distillation and was distilled to a target volume of 70-85 mL (4.5-5.5 parts wrt MB5).
  • the resulting thick suspension was adjusted to an internal temperature of 50-55 °C.
  • To the reaction mixture at 50-55 °C was then charged 310 mL of MeOH (20 parts wrt MB5) portionwise. The suspension was then agitated at 50-55 °C for a period of 60-70 minutes.
  • the reaction mixture was then cooled to 20-25 °C and then further cooled to 0-5 °C over 2-2.5 hours and was maintained at that temperature for a period of 2-2.5 hours.
  • the resulting suspension was then filtered through a Buchner funnel using a Whatmann filter paper and the filter cake was washed with 155 mL of MeOH (10 parts wrt MB5).
  • the cake was then dried under vacuum at 45-50 °C for about 4.5 hours. Crystalline Form VI (the methanolate) was obtained in 89% yield. Purity of the product was very good (HPLC purity was 99.3% to 99.4 area % with acceptable levels of Pd and boronic acid.
  • the dried filter cake was then transferred to a 500 mL three-necked round bottom flask equipped with an overhead stirrer, a thermometer and a nitrogen inlet, followed by charging 0.25 g of SiDMT (5 eq. wrt MB5 (230 ppm of residual Pd). [The following calculation can be used to determine, based on residual palladium level, how much DMT silica to charge.
  • MIBK 4-methyl-2-pentanone
  • the reaction mixture was then filtered hot at 65-70 °C through a Buchner funnel (with a Whatmann filter paper) into a new 500 mL three-necked round bottom flask equipped with an overhead stirrer, a thermometer and a nitrogen inlet.
  • the filter paper was then washed with 15 mL of prewarmed MIBK (65-70 °C, 1 part wrt MB5). With agitation the filtrate was slowly cooled to 20-30 °C over 3-3.5 hours, and then distilled under vacuum to a target volume of 50-55 mL (3-4 parts wrt MB5).
  • the bath temperature was adjusted to 55-60 °C and the reaction mixture was agitated at 55-60 °C for 3-3.5 hours.
  • the suspension was cooled to 0-5 °C over 2-2.5 hours and was stirred at the temperature for a minimum of 1.0 hour.
  • the reaction mixture was then filtered through a Buchner funnel using a Whatmann filter paper.
  • the cake was then washed with 15.5 mL of pre-cooled MIBK (1.0 part wrt MB5) at 0-5 °C.
  • the filter cake was then dried in a vacuum oven at 48-53 °C for 1-2 hours to provide the product (crystalline Form I) as a solid.
  • the overall yield was 81-86%, HPLC purity was 100.0 % a/a with acceptable level of Pd and boronic acid.
  • the solution/slurry is polish filtered hot to a clean reactor while maintaining a temperature of about 80-85 °C.
  • 2 volumes of MIBK is then charged to the original reactor and heated to about 80-85 °C.
  • the solvent is transferred to the batch via the polish filtration apparatus as a rinse of the reactor/filtration system.
  • the solution is then cooled slightly to induce nucleation during a hold period.
  • the solids are crystallized via a controlled cooling crystallization with a final temperature of 0-5 °C.
  • the slurry is held at this temperature for an appropriate time to complete crystallization and then the solids are isolated via filtration.
  • About 2 volumes of MIBK are polish filtered to the reactor and cooled to about 0-5 °C. Once at temperature the wash is charged to the cake in two portions and pulled through the cake with suction. Following completion of the wash, the solids are dried and packaged.
  • the reaction mixture was then filtered hot at about 80-85°C through a Buchner funnel (with a Whatmann filter paper) into a 500 mL erlenmeyer flask.
  • the filter paper/SiDMT/Cs 2 CO 3 was then washed with about 34 mL of pre-warmed 4-methyl-2-pentanone/MIBK (about 80-85 °C; about 2 V wrt MB6 as the methanolate Form VI).
  • the easy max vessel was cleaned and the contents of the Erlenmeyer containing the filtrate and wash was warmed to about 80-85°C and put back in the easy max vessel.
  • the batch temperature was adjusted to about 80-85 °C and the reaction mixture was agitated for about 30 min to reach dissolution.
  • crystalline Form I of the compound represented by Structural Formula 1 can be prepared as described above.
  • the XRPD pattern of Form I of the compound represented by Structural Formula 1 is depicted in FIG. 1, and the peaks are tabulated in Table 2.
  • the TGA trace of crystalline Form I is depicted in FIG. 3. No weight change is observed from ambient temperature up to about 250 °C, followed by sample degradation. [00330] The DSC trace of crystalline Form I is depicted in FIG. 3. The DSC thermogram displays a sharp endothermic peak observed at approximately 225 °C, which corresponds to melting.
  • the DVS pattern of crystalline Form I is depicted in FIG. 4. Two DVS cycles have been recorded. The DVS pattern displays a weight gain of about 0.12% at 90% RH and gradual reversible uptake over 0-90% RH range.
  • XRPD pattern of crystalline Form I after the DVS cycle is identical to the XRPD of crystalline Form I prior to the DVS cycle.
  • crystalline Form I exposed stored for one week at 97% RH at 25 °C and at 75% RH at 4025 °C. In both cases the XRPD patterns of crystalline Form I after the exposure were identical to the XRPD patterns of crystalline Form I before the exposure.
  • Example 2 Preparation and characterization of crystalline Forms II-XIV of the compound represented by Structural Formula 1
  • Crystalline Forms II-XIV of the compound represented by Structural Formula 1 were obtained from crystalline Form I by maturation of suspensions of crystalline Form I in various solvents, as well as cooling, slow evaporation, or addition of antisolvents to solutions obtained in maturation and solubility studies of crystalline Form I according to the following protocols:
  • Crystalline Form I was treated with increasing volumes of different solvents until either the material fully dissolved or 100 volumes of solvent had been added. After each addition, the systems were shaken at 50 °C for 5 minutes. Samples obtained as suspensions were matured and samples obtained as clear solutions were cooled and, if no solid was produced, allowed to slowly evaporate as reported below.
  • Maturation RT-50 °C suspensions obtained at 25 °C after the solubility assessment were shaken in the maturation chamber between 25 °C - 50 °C for 72 hours (8 hour cycles), then allowed to stand at room temperature for 10 min. The solids were recovered from the vial and analyzed by XRPD (see Table 3).
  • Cooling clear solutions obtained after the solubility assessment or maturation were placed at 5 °C for 24 hours and then at -20 °C for 24 hours. Solids obtained were recovered from the vial and analyzed by XRPD (see Table 3).
  • Antisolvent addition stock solutions of crystalline Form I were prepared in 16 mL of THF and ethyl acetate by dissolving the sample at 50 °C. The solutions were filtered (0.45 ⁇ m PTFE) and dispensed into 4 mL vials, 1600 ⁇ L each vial (40 mg of crystalline Form I in
  • Crystalline Forms II-XIV convert back to crystalline Form I either by exposure to 40 °C / 75 % RH for 1 week or by heating via DSC or variable temperature XRPD.
  • Thermal analysis of crystalline Forms III- VII, IX, X, XIII, and XIV shows defined solvent loss step by TGA and an endothermic event by DSC associated with the solvent loss and conversion to crystalline Form I, which followed by the melting of crystalline Form I at 225-226 °C.
  • Crystalline Forms II-XI, XIII, and XVII comprise various solvates of the coinpound of Structural Formula 1, while Crystalline Form XII is a metastable solvent-free form which showed a limited stability at ambient conditions and easily converted to crystalline Form I.
  • Table 5 summarizes characterization data for Crystalline Forms II-IX.

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Abstract

The invention relates to a crystalline form of the compound represented by Structural Formula 1, and pharmaceutical compositions comprising the crystalline form of the compound represented by Structural Formula 1 described herein. The crystalline form of the compound of Structural Formula 1 and compositions comprising the crystalline form of the compound represented by Structural Formula 1 provided herein, can be incorporated into pharmaceutical compositions, which can be used to treat various disorders. Also described herein are methods for preparing the crystalline form of the compound represented by Structural Formula 1.

Description

CRYSTALLINE FORMS OF ELTANEXOR AND PROCESS FOR
PREPARING SAME
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/424,534, filed November 11, 2022, the contents of which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0001] Cells from most major human solid and hematologic malignancies exhibit abnormal cellular localization of a variety of oncogenic proteins, tumor suppressor proteins, and cell cycle regulators (Crenshaw et al, 2004, Falini et al 2006). For example, certain abnormalities lead to localization of important cellular regulator molecules in the cytoplasm rather than in the nucleus. Restoration of appropriate nuclear localization of cellular regulators can normalize some properties of neoplastic cells can restore sensitivity of cancer cells to DNA damaging agents and can lead to regression of established tumors.
[0002] Specific proteins and RNAs are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus. Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. One of major exportins is Chromosomal Region Maintenance 1 (CRM1), which is also called exportin- 1 or Xpol.
[0003] International Publication No. WO2014205389 describes compounds having inhibitory activity against CRM1, useful in the treatment of disorders associated with CRM1 activity, such as cancer. (E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-l-yl)-2- (pyrimidin-5-yl)acrylamide (also referred to as Eltanexor) is one of the compounds disclosed in International Publication No. WO 14/205389, which is incorporated herein by reference in its entirety. Eltanexor has the chemical structure shown in Structural Formula 1 :
Figure imgf000003_0001
[0004] The solid form of a compound can be important in the formulation of pharmaceutical compositions. For example, different crystalline forms of a compound can have different physical properties (e.g., stability, dissolution rate, density, etc.) rotating to their suitability for use in pharmaceutical compositions.
[0005] There is a need for crystalline forms of the compound of Structural Formula 1 that are thermodynamically stable and suitable for use in pharmaceutical compositions (e.g., are readily dissolvable, exhibit low hygroscopicity, good flow properties and/or good chemical and thermal stability). There is a further need for crystalline forms of the compound of Structural Formula 1 having physical properties that enable the manufacture of the compound of Structural Formula 1 and its pharmaceutical compositions in high yield and high purity with long shelflife.
SUMMARY OF THE INVENTION
[0006] The present invention relates to crystalline forms of the compound represented by Structural Formula 1, designated crystalline Forms I-XIV, and compositions comprising the crystalline form.
[0007] In one embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000003_0002
wherein the crystalline form is Form n characterized by X-ray powder diffraction peaks at 2θ angles 21.7°, 22.0°, 22.7°, and 25.1°. [0008] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000004_0003
wherein the crystalline form is Form in characterized by X-ray powder diffraction peaks at 2θ angles 6.5°, 17.5°, 21.2°, and 21.9°.
[0009] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000004_0001
wherein the crystalline form is Form IV characterized by X-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.5°, and 24.7°.
[0010] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000004_0002
wherein the crystalline form is Form V characterized by X-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.2°, and 24.7°.
[0011] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000005_0001
wherein the crystalline form is Form VII characterized by X-ray powder diffraction peaks at 2θ angles 16.0°, 21.4°, 22.6°, and 29.5°.
[0012] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000005_0002
wherein the crystalline form is Form VIII characterized by X-ray powder diffraction peaks at 2θ angles 18.7°, 19.8°, 22.4°, and 26.0°.
[0013] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000005_0003
wherein the crystalline form is Form IX characterized by X-ray powder diffraction peaks at 2θ angles 8.1°, 18.5°, 20.8°, and 22.5°.
[0014] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000006_0001
wherein the crystalline form is Form X characterized by X-ray powder diffraction peaks at 2θ angles 5.6°, 16.8°, 23.2°, and 28.3°.
[0015] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000006_0002
wherein the crystalline form is Form XI characterized by X-ray powder diffraction peaks at 2θ angles 7.7°, 16.2°, 20.2°, and 27.2°.
[0016] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000006_0003
wherein the crystalline form is Form XIII characterized by X-ray powder diffraction peaks at 2θ angles 4.9°, 14.7°, 19.6°, and 24.5°.
[0017] In another embodiment, the present invention is a crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000007_0001
wherein the crystalline form is Form XIV characterized by X-ray powder diffraction peaks at 2θ angles 6.4°, 8.1°, 19.8°, and 20.4°.
[0018] In another embodiment, the present invention is a composition, comprising particles of one or more crystalline forms of the compound represented by Structural Formula 1:
Figure imgf000007_0002
wherein the one or more crystalline forms are selected from: crystalline Form n characterized by x-ray powder diffraction peaks at 2θ angles 21.7°, 22.0°, 22.7°, and 25.1°; crystalline Form III characterized by x-ray powder diffraction peaks at 2θ angles 6.5°, 17.5°, 21.2°, and 21.9°; crystalline Form IV characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.5°, and 24.7°; crystalline Form V characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.2°, and 24.7°; crystalline Form VII characterized by x-ray powder diffraction peaks at 2θ angles 16.0°, 21.4°, 22.6°, and 29.5°; crystalline Form VIII characterized by x-ray powder diffraction peaks at 2θ angles 18.7°, 19.8°, 22.4°, and 26.0°; crystalline Form IX characterized by x-ray powder diffraction peaks at 2θ angles 8.1°, 18.5°, 20.8°, and 22.5°; crystalline Form X characterized by x-ray powder diffraction peaks at 2θ angles 5.6°, 16.8°, 23.2°, and 28.3°; crystalline Form XI characterized by x-ray powder diffraction peaks at 2θ angles 7.7°, 16.2°, 20.2°, and 27.2°; crystalline Form XIII characterized by x-ray powder diffraction peaks at 2θ angles 4.9°, 14.7°, 19.6°, and 24.5°; and crystalline Form XIV characterized by x-ray powder diffraction peaks at 2θ angles 6.4°, 8.1°, 19.8°, and 20.4°.
[0019] In another embodiment, the present invention relates to a pharmaceutical composition comprising a crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the compound represented by Structural Formula (I), as described herein, and a pharmaceutically acceptable carrier.
[0020] In another embodiment, the present invention relates to a method for treating or preventing a CRM1 -associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the cornpound represented by Structural Formula (I), as described herein.
[0021] In another embodiment, the present invention relates to a method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline form of the compound represented by Structural Formula (I) or a composition comprising one or more crystalline forms of the compound represented by Structural Formula (I), as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] The foregoing will be apparent from the following more particular description of example embodiments of the invention.
[0023] FIG. 1 is an x-ray powder diffraction (XRPD) pattern of the crystalline Form I of the compound represented by Structural Formula 1.
[0024] FIG. 2 is a graph depicting a differential scanning calorimetry (DSC) thermogram of the crystalline Form I of the compound represented by Structural Formula 1. [0025] FIG. 3 is a graph depicting a thermogravimetric analysis (TGA) thermogram of the crystalline Form I of the compound represented by Structural Formula 1.
[0026] FIG. 4 is a dynamic vapor sorption (DVS) pattern of the crystalline Form I of the compound represented by Structural Formula 1.
[0027] FIG. 5 is an XRPD pattern of the crystalline Form II of the compound represented by Structural Formula 1.
[0028] FIG. 6 is an XRPD pattern of the crystalline Form III of the compound represented by Structural Formula 1.
[0029] FIG. 7 is a graph depicting a DSC thermogram of the crystalline Form III of the compound represented by Structural Formula 1.
[0030] FIG. 8 is a graph depicting a TGA thermogram of the crystalline Form III of the compound represented by Structural Formula 1.
[0031] FIG. 9 is an XRPD pattern of the crystalline Form IV of the compound represented by Structural Formula 1.
[0032] FIG. 10 is a graph depicting a DSC thermogram of the crystalline Form IV of the compound represented by Structural Formula 1.
[0033] FIG. 11 is a graph depicting a TGA thermogram of the crystalline Form IV of the compound represented by Structural Formula 1.
[0034] FIG. 12 is an XRPD pattern of the crystalline Form V of the compound represented by Structural Formula 1.
[0035] FIG. 13 is a graph depicting a DSC thermogram of the crystalline Form V of the compound represented by Structural Formula 1.
[0036] FIG. 14 is a graph depicting a TGA thermogram of the crystalline Form V of the cornpound represented by Structural Formula 1.
[0037] FIG. 15 is an XRPD pattern of the crystalline Form VI of the compound represented by Structural Formula 1.
[0038] FIG. 16 is a graph depicting a DSC thermogram of the crystalline Form VI of the compound represented by Structural Formula 1.
[0039] FIG. 17 is a graph depicting a TGA thermogram of the crystalline Form VI of the compound represented by Structural Formula 1.
[0040] FIG. 18 is an XRPD pattern of the crystalline Form VII of the compound represented by Structural Formula 1.
[0041] FIG. 19 is a graph depicting a DSC thermogram of the crystalline Form VII of the compound represented by Structural Formula 1. [0042] FIG. 20 is a graph depicting a TGA thermogram of the crystalline Form VII of the compound represented by Structural Formula 1.
[0043] FIG. 21 is an XRPD pattern of the crystalline Form VIII of the compound represented by Structural Formula 1.
[0044] FIG. 22 is an XRPD pattern of the crystalline Form IX of the compound represented by Structural Formula 1.
[0045] FIG. 23 is a graph depicting a DSC thermogram of the crystalline Form IX of the compound represented by Structural Formula 1.
[0046] FIG. 24 is a graph depicting a TGA thermogram of the crystalline Form IX of the compound represented by Structural Formula 1.
[0047] FIG. 25 is an XRPD pattern of the crystalline Form X of the coirpound represented by Structural Formula 1.
[0048] FIG. 26 is a graph depicting a DSC thermogram of the crystalline Form X of the compound represented by Structural Formula 1.
[0049] FIG. 27 is a graph depicting a TGA thermogram of the crystalline Form X of the compound represented by Structural Formula 1.
[0050] FIG. 28 is an XRPD pattern of the crystalline Form XI of the compound represented by Structural Formula 1.
[0051] FIG. 29 is a graph depicting a TGA thermogram of the crystalline Form XI of the compound represented by Structural Formula 1.
[0052] FIG. 30 is a graph depicting a DSC thermogram of the crystalline Form XII of the compound represented by Structural Formula 1.
[0053] FIG. 31 is a graph depicting a TGA thermogram ofthe crystalline Form XII of the coinpound represented by Structural Formula 1.
[0054] FIG. 32 is an XRPD pattern of the crystalline Form XIII of the compound represented by Structural Formula 1.
[0055] FIG. 33 is a graph depicting a DSC thermogram of the crystalline Form XIII of the compound represented by Structural Formula 1.
[0056] FIG. 34 is a graph depicting a TGA thermogram of the crystalline Form XIII of the compound represented by Structural Formula 1.
[0057] FIG. 35 is an XRPD pattern of the crystalline Form XIV of the compound represented by Structural Formula 1.
[0058] FIG. 36 is a graph depicting a DSC thermogram of the crystalline Form XIV of the compound represented by Structural Formula 1. [0059] FIG. 37 is a graph depicting a TGA thermogram of the crystalline Form XIV of the compound represented by Structural Formula 1.
[0060] FIG. 38 is a diagram schematically depicting the relationship between crystalline Forms I-XIV.
DETAILED DESCRIPTION OF THE INVENTION
[0061] A description of example embodiments of the invention follows.
Crystalline Forms of the Compound of Structural Formula 1
[0062] It is to be understood that the term “about”, when referring to a numerical value for temperature, means that the numerical value has a range ±5 °C of the recited numerical value, unless specified otherwise. For example, when a described embodiment or a claim recites a temperature of “about 20 °C”, this is to be understood to mean 20 °C ± 5 °C, that is, a temperature from 15 °C to 25 °C.
[0063] It is to be understood that the term
“about”, when referring to a numerical value for time, means that the numerical value has a range ±5 minutes of the recited numerical value, unless specified otherwise. For example, when a described embodiment or a claim recites a period of time of “about 60 minutes”, this is to be understood to mean 60 minutes ± 5 minutes, that is, a period of time from 55 minutes to 65 minutes.
[0064] It is to be understood that the term “about”, when referring to a numerical value for an alcohol-to-water volume ratio, means that the numerical value for x has a range ± 5% of the recited numerical value, unless specified otherwise. For example, when a described embodiment or a claim recites an alcohol-to-water volume ratio of “about 70/30”, this is to be understood to mean an alcohol-to-water volume ratio from 75/25 to 65/35.
[0065] Provided herein are crystalline forms of the compound of Structural Formula 1, designated ciystalline Forms I-XIV.
[0066] “Crystalline” or “crystal,” as used herein, refers to a homogeneous solid formed by a repeating, three-dimensional pattern of atoms, ions or molecules (e.g., an anhydrous molecule or a salt thereof solvate thereof, or combination of the foregoing) having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern. [0067] The ciystalline forms provided herein can be identified on the basis of characteristic peaks in an x-ray powder diffraction (XRPD) analysis. XRPD is a scientific technique that measures the x-rays, neutrons or electrons scattered by a powder or microcrystalline material as a function of scattering angle. XRPD can be used to identify and characterize crystalline solids, as the diffraction pattern produced by a particular solid is typically distinctive to that solid and can be used as a “fingerprint” to identify that solid. For example, an XRPD pattern or diffiactogram (e.g., a pattern or diffiactogram produced by a sample, such as an unknown sample) that is substantially in accordance with a reference XRPD pattern or diffiactogram can be used to determine the identity between the sample material and the reference material. Both the position and the relative intensity of the peaks in an XRPD diffiactogram are indicative of the particular phase and identity of a material.
[0068] A crystalline form provided herein can be a sole crystalline form or can comprise a mixture of two or more different crystalline forms. For example, in some embodiments, crystalline Form I of the compound represented by Structural Formula 1 is provided as a sole crystalline form. Alternatively, in other embodiments, a crystalline form can comprise a mixture of two or more crystalline forms of the compound represented by Structural Formula 1, e.g., a mixture of crystalline Form I with one or more of crystalline forms, e.g., Forms II- XIV, of the compound represented by Structural Formula 1.
[0069] “Single crystalline form,” as used herein, refers to a single crystal of a crystalline solid or a plurality of crystals of a crystalline solid wherein each of the plurality of crystals has the same crystal form.
[0070] FIGs. 1, 5, 6, 9, 12, 15, 18, 21, 22, 25, 28, 32, and 35show XRPD patterns of the crystalline Forms I-XIV described herein. An XRPD pattern that is “substantially in accordance” with one or more figures herein showing an XRPD pattern or diffiactogram is an XRPD pattern that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the XRPD pattern of one or more figures provided herein. Thus, an XRPD pattern that is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures. An XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffiaction pattern presented herein and/or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern of the sample and the corresponding XRPD pattern disclosed herein.
[0071] It is to be understood that any 2θ angle specified herein means the specified value ± 0.2°. For example, when a described embodiment or a claim specifies a 2θ of 4.4°, this is to be understood to mean 4.4° ± 0.2°, that is, a 2θ angle of from 4.2° to 4.6°.
[0072] The crystalline forms I, III- VII, IX, X, and XII-XIV provided herein can also be identified on the basis of differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA). DSC is a thennoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample is measured as a function of temperature. DSC can be used to detect physical transformations, such as phase transitions, of a sample. For example, DSC can be used to detect the temperature(s) at which a sample undergoes crystallization, melting or glass transition.
[0073] TGA is a method of thermal gravimetric analysis in which changes in physical and chemical properties of a material are measured as a function of increasing temperature (with constant heating rate) or as a function of time (with constant temperature and/or constant mass loss). TGA can provide information about physical phenomena, such as second-order phase transitions, or about chemical phenomena, such as desolvation and/or decomposition. [0074] FIGs. 2, 7, 10, 13, 16, 19, 23, 26, 30, 33, and 36 show DSC thermograms of the crystalline Forms I, III-VII, IX, X, and XII-XIV described herein. For example, FIG. 7 shows a differential scanning calorimetry thermogram of crystalline Form III comprising a broad endothermic peak at about 70 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting. FIG. 8 shows a thermogravimetric thermogram of crystalline Form in, demonstrating weight loss of about 8% starting at about 70 °C, consistent with desolvation, and in agreement with the DSC data shown in FIG. 7. A DSC or TGA thermogram that is “substantially in accordance” with one or more figures herein showing a DSC or TGA thermogram is a DSC or TGA thermogram that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the DSC or TGA thermogram of one or more figures provided herein.
[0075] It is to be understood that any temperature associated with DSC or TGA specified herein means the specified value ± 5 °C or less. For example, when an embodiment or a claim specifies an endothermic peak at about 184 °C, this is to be understood to mean 184 °C ± 5 °C or less, that is a temperature of from 179 °C to 189 °C. In preferred embodiments, a DSC or TGA temperature is the specified value ± 3 °C, in more preferred embodiments, ± 2 °C.
[0076] The crystalline Form I can be additionally characterized by dynamic vapor sorption (DVS), wherein a sample is subjected to varying conditions of humidity and temperature, and the response of the sample is measured gravimetrically. The result of a DVS analysis particularly can be a dual curve providing sample weight percent as a function of relative humidity (RH) overtime, a dual curve providing sample water content as a function of RH overtime, a curve providing weight percent in relation to RH, or a curve providing water content in relation to RH. Equipment useful for measuring such data is known in the art, and any such equipment can be used to measure the compounds according to the present disclosure. In certain embodiments, DVS analysis can be carried out by scanning at a series of specific RH values. Thus, specific polymorphs according to the disclosure may be identified and described in relation to the representative graph and/or the approximate peaks obtained in DVS analysis, particularly scanning from 0% to 95% RH with a step interval of 5% or 10% RH.
[0077] FIG. 4 shows a DVS pattern of the crystalline Form I described herein. A DVS pattern that is “substantially in accordance” with one or more figures herein showing a DVS patterns is a DVS pattern that would be considered by one skilled in the art to represent the same crystalline form of the compound represented by Structural Formula 1 as the sample of the compound represented by Structural Formula 1 that provided the DVS pattern of one or more figures provided herein.
[0078] In some embodiments, crystalline forms provided herein may be crystalline forms of the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. “Solvate,” as used herein, refers to a chemical compound formed by the interaction of a solute (e.g., a compound of Structural Formula 1) and one or more solvents (e.g., methanol, ethanol, water). Thus, “solvate” includes solvates containing a single type of solvent molecule and solvates containing more than one type of solvent molecule (mixed solvates or co-solvates). Typically, the one or more solvents in solvates described herein is an organic solvent or a combination of organic solvents, although water can also form solvates, called hydrates.
FORM I [0079] In a first embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form I, and is characterized by x-ray powder diffraction peaks at 2θ angles of 4.6°, 22.8°, 23.2°, and 24.4°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 4.6°, 20.0°, 22.8°, 23.2°, and 24.4°; or by at least five x-ray powder diffraction peaks at 2θ angles selected from 4.6°, 19.0°, 20.0°, 22.8°, 23.2°, 23.7°, 24.4°, and 27.9°. In some aspects of the first embodiment, crystalline Form I is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 1.
[0080] Crystalline Form I may be further characterized by a differential scanning calorimetry thermogram comprising a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the first embodiment, the DSC thermogram is substantially in accordance with that in FIG. 2. In some aspects of the first embodiment, the TGA thermogram is substantially in accordance with that in FIG. 3.
[0081] Crystalline Form I can be additionally characterized by dynamic vapor sorption pattern demonstrating reversible 0.12 % w/w water adsorption from 0 to 90 % RH. In some aspects of the first embodiment, the DVS pattern is substantially in accordance with the one found in FIG. 4.
FORM II
[0082] In a second embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form II, and is characterized by x-ray powder diffraction peaks at 2θ angles of 21.7°, 22.0°, 22.7°, and 25.1°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 8.0°, 21.7°, 22.0°, 22.7°, and 25.1 °; or by at least five x-ray powder diffraction peaks at 2θ angles selected from 8.0°, 16.2°, 21.7°, 22.0°, 22.7°, 24.1°, 25.1°, and 27.6°. In some aspects of the second embodiment, crystalline Form II is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 5.
[0083] Crystalline Form II may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a nitromethane solvate.
FORM III
[0084] In a third embodiment, a crystalline form of the compound represented by the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form III, and is characterized by x-ray powder diffraction peaks at 2θ angles of 6.5°, 17.5°, 21.2°, and 21.9°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 6.5°, 17.5°, 21.2°, 21.9°, and 22.1°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 6.5°, 10.6°, 17.5°, 20.6°, 21.2°, 21.9°, and 22.1°, 23.0°. In some aspects of the third embodiment, crystalline Form III is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.
[0085] Crystalline Form m may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 70 °C, consistent with solvate melting and desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting. In some aspects of the third embodiment, the DSC thermogram is substantially in accordance with that in FIG. 7. In some aspects of the third embodiment, the TGA thermogram is substantially in accordance with that in FIG. 8.
[0086] Crystalline Form in may be a crystalline form of the compound represented by the cornpound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a dimethoxyethane solvate. FORM IV
[0087] In a fourth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form IV, and is characterized by x-ray powder diffraction peaks at 2θ angles of 7.4°, 23.0°, 24.5°, and 24.7°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 18.4°, 23.0°, 24.5°, and 24.7°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 7.4°, 18.4°, 20.5°, 23.0°, 23.7°, 24.5°, 24.7°, and 27.7°. In some aspects of the fourth embodiment, crystalline Form IV is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 9.
[0088] Crystalline Form IV may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 99 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the fourth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 10. In some aspects of the fourth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 11.
[0089] Crystalline Form IV may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a 2 -propanol solvate.
FORM V [0090] In a fifth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form V, and is characterized by x-ray powder diffraction peaks at 2θ angles of 7.4°, 23.0°, 24.2°, and 24.7°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 18.4°, 23.0°, 24.5°, and 24.7°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 7.4°, 10.3°, 18.2°, 18.6°, 23.0°, 24.5°, 24.7°, and 27.4°. In some aspects of the fifth embodiment, crystalline Form V is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 12.
[0091] Crystalline Form V may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 128 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the fifth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 13. In some aspects of the fifth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 14.
[0092] Crystalline Form V may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is an ethanol solvate.
FORM VI
[0093] In a sixth embodiment; a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form VI, and is characterized by x-ray powder diffraction peaks at 2θ angles of 9.9°, 19.2°, 22.4°, and 24.4°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 9.9°, 19.2°, 22.4°, 23.5°, and 24.4°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 9.9°, 19.2°, 21.3°, 21.9°, 22.4°, 23.5°, 24.4°, and 29.2°. In some aspects of the sixth embodiment, crystalline Form VI is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 15.
[0094] Crystalline Form VI may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 112 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the sixth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 16. In some aspects of the sixth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 17. [0095] Crystalline Form VI may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a methanol solvate.
FORM VII
[0096] In a seventh embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form VII, and is characterized by x-ray powder diffraction peaks at 2θ angles of 16.0°, 21.4°, 22.6°, and 29.5°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 11.7°, 16.0°, 21.4°, 22.6°, and 29.5°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 8.1°, 11.7°, 16.0°, 17.6°, 21.4°, 22.6°, 25.8°, and 29.5°. In some aspects of the seventh embodiment, crystalline Form VII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 18.
[0097] Crystalline Form VII may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 138 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the seventh embodiment, the DSC thermogram is substantially in accordance with that in FIG. 19. In some aspects of the seventh embodiment, the TGA thermogram is substantially in accordance with that in FIG. 20.
[0098] Crystalline Form VII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is an acetonitrile solvate.
FORM VIII
[0099] In a eighth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form VIII, and is characterized by x-ray powder diffraction peaks at 2θ angles of 18.7°, 19.8°, 22.4°, and 26.0°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 18.7°, 19.8°, 20.3°, 22.4°, and 26.0°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 18.7°, 19.8°, 20.3°, 21.7°, 22.4°, 23.2°, 26.0°, and 29.1°. In some aspects of the eighth embodiment, crystalline Form VIII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 21.
[00100] Crystalline Form VIII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a dichloromethane solvate. FORM IX
[00101] In a ninth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form IX, and is characterized by x-ray powder diffraction peaks at 2θ angles of 8.1°, 18.5°, 20.8°, and 22.5°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 8.1°, 18.5°, 20.0°, 20.8°, and 22.5°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 8.1°, 18.5°, 20.0°, 20.8°, 22.5°, 22.8°, 23.0°, and 26.4°. In some aspects of the ninth embodiment, crystalline Form IX is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 22.
[00102] Crystalline Form IX may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 69 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting. In some aspects of the ninth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 23. In some aspects of the ninth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 24.
[00103] Crystalline Form IX may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a 2 -methyltetrahydrofuran solvate.
FORM X
[00104] In a tenth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form X, and is characterized by x-ray powder diffraction peaks at 2θ angles of 5.6°, 16.8°, 23.2°, and 28.3°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 5.6°, 16.8°, 23.2°, 24.9°, and 28.3°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 4.6°, 5.6°, 11.2°, 16.8°, 23.2°, 24.9°, 27.9°, and 28.3°. In some aspects of the tenth embodiment, crystalline Form X is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 25.
[00105] Crystalline Form X may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 136 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the tenth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 26. In some aspects of the tenth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 27.
[00106] Crystalline Form X may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is an acetic acid solvate.
FORM XI
[00107] In an eleventh embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form XI, and is characterized by x-ray powder diffraction peaks at 2θ angles of 7.7°, 16.2°, 20.2°, and 27.2°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 5.4°, 7.7°, 16.2°, 20.2°, and 27.2°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 5.4°, 7.7°, 16.2°, 20.2°, 23.8°, 24.2°, 25.5°, and 27.2°. In some aspects of the eleventh embodiment, crystalline Form XI is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 28.
[00108] Crystalline Form XI may be further characterized by a TGA thermogram substantially in accordance with that in FIG. 29.
[00109] Crystalline Form XI may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a dimethyl sulfoxide solvate. FORM XII
[00110] In a twelfth embodiment, a crystalline form XII is provided. Crystalline Form XII may be characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 136 °C, consistent with desolvation, and a sharp endothermic peak at about 225 °C, consistent with melting. In some aspects of the twelfth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 30. In some aspects of the twelfth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 31.
FORM XIII
[00111] In a thirteenth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form XIII, and is characterized by x-ray powder diffraction peaks at 2θ angles of 4.9°, 14.7°, 19.6°, and 24.5°; by at least four x-ray powder diffraction peaks at 29 angles selected from 4.9°, 14.7°, 19.6°, 19.9°, and 24.5°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 4.9°, 14.2°, 14.7°, 19.6°, 19.9°, 24.5°, 25.5°, and 25.8°. In some aspects of the thirteenth embodiment, crystalline Form XIII is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 32.
[00112] Crystalline Form XIII may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 129 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting. In some aspects of the thirteenth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 33. In some aspects of the thirteenth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 34.
[00113] Crystalline Form XIII may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is an acetone solvate.
FORM XIV
[00114] In a fourteenth embodiment, a crystalline form of the compound represented by Structural Formula 1 is provided, wherein the crystalline form is Form XIV, and is characterized by x-ray powder diffraction peaks at 2θ angles of 6.4°, 8.1 °, 19.8°, and 20.4°; by at least four x-ray powder diffraction peaks at 2θ angles selected from 6.4°, 8.1°, 19.8°, 20.4°, and 27.3°; or by at least five x-ray powder diffraction peaks at 2θ angles selected 6.4°, 8.1°, 16.2°, 19.8°, 20.4°, 24.4°, 24.8°, and 27.3°. In some aspects of the fourteenth embodiment, crystalline Form XIV is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 35.
[00115] Crystalline Form XIV may be further characterized by a differential scanning calorimetry thermogram comprising a broad endothermic peak at about 86 °C, consistent with desolvation, and a sharp endothermic peak at about 226 °C, consistent with melting. In some aspects of the fourteenth embodiment, the DSC thermogram is substantially in accordance with that in FIG. 36. bi some aspects of the fourteenth embodiment, the TGA thermogram is substantially in accordance with that in FIG. 37.
[00116] Crystalline Form XIV may be a crystalline form of the compound represented by the compound represented by Structural Formula 1, wherein the compound is in the form of a solvate. For example, the compound of Structural Formula 1 is a tert-butanol solvate.
[00117] In a fifteenth embodiment, the disclosure relates to composition, comprising particles of one or more crystalline forms of the compound represented by Structural Formula 1:
Figure imgf000022_0001
wherein the one or more crystalline forms are selected from the crystalline forms of any one of the aspects of the first through the fourteenth embodiments described above. For example, the one or more crystalline forms are selected from: crystalline Form n characterized by x-ray powder diffraction peaks at 2θ angles 21.7°, 22.0°, 22.7°, and 25.1°; crystalline Form III characterized by x-ray powder diffraction peaks at 2θ angles 6.5°, 17.5°, 21.2°, and 21.9°; crystalline Form IV characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.5°, and 24.7°; crystalline Form V characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.2°, and 24.7°; crystalline Form VII characterized by x-ray powder diffraction peaks at 2θ angles 16.0°, 21.4°, 22.6°, and 29.5°; crystalline Form VIII characterized by x-ray powder diffraction peaks at 2θ angles 18.7°, 19.8°, 22.4°, and 26.0°; crystalline Form IX characterized by x-ray powder diffraction peaks at 2θ angles 8.1°, 18.5°, 20.8°, and 22.5°; crystalline Form X characterized by x-ray powder diffraction peaks at 2θ angles 5.6°, 16.8°, 23.2°, and 28.3°; crystalline Form XI characterized by x-ray powder diffraction peaks at 2θ angles 7.7°, 16.2°, 20.2°, and 27.2°; crystalline Form XIII characterized by x-ray powder diffraction peaks at 2θ angles 4.9°, 14.7°, 19.6°, and 24.5°; and crystalline Form XIV characterized by x-ray powder diffraction peaks at 2θ angles 6.4°, 8.1°, 19.8°, and 20.4°. Pharmaceutical Compositions
[00118] In a sixteenth embodiment, the disclosure relates to a pharmaceutical composition, comprising a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above or a composition of any one of the aspects of the fifteenth embodiment described above and a pharmaceutically acceptable carrier. For example, the pharmaceutical composition comprises crystalline Form I of the compound represented by Structural Formula 1, characterized by x-ray powder diffraction peaks at 2θ angles 4.6°, 22.8°, 23.2°, and 24.4°, and a pharmaceutically acceptable carrier.
[00119] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit formation of a pharmaceutical composition, i.e., a dosage form capable of being administered to a subject. A “pharmaceutically acceptable carrier” should not destroy the activity of the compound with which it is formulated. Pharmaceutically acceptable carriers are well known in the art.
[00120] Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfete, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat [00121] Pharmaceutical compositions of the disclosure may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided pharmaceutical compositions are administrable intravenously and/or intraperitoneally.
[00122] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the pharmaceutical compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [00123] Pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained/delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro-encapsulated form.
[00124] Specific pharmaceutically acceptable carriers suitable for use in an oral formulation such as a tablet or capsule include, but are not limited to, microcrystalline cellulose (Avicel PH101), croscarmellose Sodium (Ac-Di-Sol), kollidon 30 powder (polyvinylpyrrolidone, povidone), colloidal silicon dioxide M5-P, magnesium stearate, microcrystalline cellulose (Avcel PH102), sodium lauryl sulfete (Kolliphor SLS Fine) and Colloidal Silicon Dioxide M5-P. Each of the above listed carriers can be used in an oral formulation either alone or in any combination.
[00125] Further pharmaceutically acceptable carriers suitable for use in an oral formulation such as a tablet or capsule include, but are not limited to, microcrystalline cellulose (Avicel PHI 12), crospovidone (polyplasdone XL- 10), colloidal silicone dioxide (Cab-O-Sil M-5P), Talc, starch and calcium stearate. In a particular aspect, the crystalline form I is present in the oral formulation from about 25-45% by weight. For ophthalmic use, provided pharmaceutical compositions may be formulated as micronized suspensions or in an ointment such as petrolatum. [00126] Pharmaceutical compositions of this disclosure may also be administered by nasal aerosol or inhalation.
[00127] The amount of the crystalline form of the compound represented by the compound represented by Structural Formula 1 in pharmaceutical compositions of this disclosure is such that is effective to measurably treat or prevent in the treatment of disorders associated with CRM1 activity in a subject. In certain embodiments, a pharmaceutical composition of this disclosure is formulated for administration to a subject in need of such pharmaceutical composition. The term “subject,” as used herein, can be a human subject or an animal. [00128] The amount of the crystalline form of the compound of Structural Formula 1 that can be combined with the pharmaceutically acceptable carrier materials to produce a pharmaceutical composition in a single dosage form will vary depending upon the host treated and/or the particular mode of administration. In one embodiment, the pharmaceutical compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound of Structural Formula 1 can be administered to a patient receiving these compositions. In another embodiment, the dosage is from about 0.5 to about 100 mg/kg of body weight, or between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 6 times per day. Exemplary doses, include but are not limited to, 1.0 mg/kg twice a day for about 4-14 days and 1.5 mg/kg once a day for 5 to 10 days.
[00129] In certain embodiments, the pharmaceutical composition of crystalline form of the compound of Structural Formula 1 can be formulated to deliver to the subject the dosage of the compound represented by Structural Formula (I) of 80 mg (45 mg/m2 BS A), delivered, for example, twice weekly. In alternative embodiments, the pharmaceutical composition of the crystalline form can be formulated to deliver to the subject the dosage of the compound represented by Structural Formula (I) of 100 mg, delivered, for example, once per day on selected days of a treatment cycle.
[00130] It should also be understood that a specific dosage and treatment regimen for any particular subject (e.g., patient) will depend upon a variety of factors, including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
[00131] Upon improvement of a subject’s condition, a maintenance dose of a pharmaceutical composition of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
Methods of Treatment and Uses for Crystalline Forms and Pharmaceutical Compositions
Comorisina Same
[00132] Crystalline forms of the compound represented by Structural Formula I disclosed herein, such as crystalline Form I, and pharmaceutical compositions comprising same are generally useful for the inhibition of CRM1 and are, therefore, useful for treating one or more disorders associated with activity of CRM1. Thus, in certain embodiments, the present disclosure provides a method for treating a disorder associated with CRM1 activity, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form of the compound of Structural Formula 1 or a pharmaceutical composition described herein. The crystalline formsand pharmaceutical composition comprising same can also be administered to cells in culture, e.g., in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described hereinbelow. [00133] The activity of crystalline Form I and a pharmaceutical composition comprising same as an inhibitor of CRM1 may be assayed in vitro, in vivo or in a cell line. Detailed conditions for assaying an inhibitor of CRM1, such as crystalline Form I of the compound represented by Structural Formula I, are set forth in International Publication No. WO 14/205389.
[00134] The term “treat” or “treating" means to alleviate symptoms, eliminate the causation of the symptoms, either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
[00135] The term “CRM1 -mediated” disorder or condition or “disorder associated with CRM1 activity,” as used herein, means any disease or other deleterious condition in which CRM1 is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which CRM1 is known to play a role. In some embodiments, the present disclosure provides methods of treating a disease associated with expression or activity of p53, p73, p21, pRB, p27, INB, NFNB, c- Abl, FOXO proteins, COX-2, or an HDAC (histone deacetylases) in a subject comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. In another embodiment, the present disclosure relates to a method of treating or lessening the severity of a disease or condition selected from a proliferative disorder (e.g., cancer), an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder or a neurodegenerative disorder wherein said method comprises administering to a patient in need thereof a compound or composition according to the present disclosure. In a more specific embodiment, the present disclosure relates to a method of treating or lessening the severity of cancer. Specific examples of the above disorders are set forth in detail below.
[00136] The term “therapeutically effective amount” means an amount of a crystal form of the compound represented by Structural Formula 1 that is effective in treating or lessening the severity of one or more symptoms of a disorder or condition. In the case of promoting wound healing, a therapeutically effective amount is an amount that promotes healing of a wound.
[00137] As used herein, the term “prophylaxis” or “prophylactic” refer to measures taken to preventing or increasing resistance to a disease prior to its onset as well as to measures that ameliorate the symptoms of a disease when taken prior to its onset Prophylaxis also includes measures taken to prevent the recurrence of a disease.
[00138] The term “prophylactically effective amount” means an amount of a crystal form of the compound represented by Structural Formula 1 that is effective for prophylaxis of a condition treatable by such compound.
[00139] As used herein, “promoting wound healing” means treating a subject with a wound and achieving healing, either partially or fully, of the wound. Promoting wound healing can mean, e.g., one or more of the following: promoting epidermal closure; promoting migration of the dermis; promoting dermal closure in the dermis; reducing wound healing complications, e.g., hyperplasia of the epidermis and adhesions; reducing wound dehiscence; and promoting proper scab formation.
[00140] In some embodiments, the present disclosure relates to a method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline form of the compound represented by Structural Formula 1 or a pharmaceutical composition described herein.
[00141] Cancers treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, hematologic malignancies (leukemias, lymphomas, myelomas including multiple myeloma, myelodysplastic and myeloproliferative syndromes) and solid tumors (carcinomas such as prostate, breast, lung, colon, pancreatic, renal, ovarian as well as soft tissue and osteosarcomas, and stromal tumors). Breast cancer (BC) can include basal-like breast cancer (BLBC), triple negative breast cancer (TNBC) and breast cancer that is both BLBC and TNBC. In addition, breast cancer can include invasive or non- invasive ductal or lobular carcinoma, tubular, medullary, mucinous, papillary, cribriform carcinoma of the breast, male breast cancer, recurrent or metastatic breast cancer, phyllodes tumor of the breast and Paget’s disease of the nipple. In one embodiment, the cancer is multiple myeloma.
[00142] Inflammatory disorders treatable by a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein include, but are not limited to, multiple sclerosis, rheumatoid arthritis, degenerative joint disease, systemic lupus, systemic sclerosis, vasculitis syndromes (small, medium and large vessel), atherosclerosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, sepsis, psoriasis and other dermatological inflammatory disorders (such as eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, and dermatosis with acute inflammatory components, pemphigus, pemphigoid, allergic dermatitis), and urticarial syndromes.
[00143] Viral diseases treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster. Viral diseases treatable by the compounds of this disclosure also include chronic viral infections, including hepatitis B and hepatitis C. Additionally, viral diseases treatable by the compounds of this disclosure include infections caused by a coronavirus, e.g., SARS, MERS, and SARS-CoV-2.
[00144] Exemplary ophthalmology disorders include, but are not limited to, macular edema (diabetic and nondiabetic macular edema), aged related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epitheliitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, comeal ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats' disease, familial exudative vitreoretinopathy, pulseless disease (Takayasu's disease), Eales disease, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon- associated retinopathy, hypertensive retinopathy, radiation retinopathy, comeal epithelial stem cell deficiency or cataract.
[00145] Neurodegenerative diseases treatable by a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein include, but are not limited to, Parkinson’s, Alzheimer’s, and Huntington’s, and Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease).
[00146] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, polycystic kidney disorder (PKD) and other renal disorders.
[00147] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders related to food intake such as obesity and hyperphagia.
[00148] In another embodiment, crystalline forms of the compound represented by Structural Formula lor pharmaceutical cornpositions described herein may be used to treat or prevent allergies and respiratory disorders, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD).
[00149] In some embodiments, the disorder or condition associated with CRM1 activity is beta-thalassemia, muscular dystrophy, arthritis, for example, osteoarthritis and rheumatoid arthritis, ankylosing spondilitis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospirosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren’s syndrome, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, gut diseases, peritoneal endometriosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia-ID, Behcet’s disease, incontinentia pigmenti, tuberculosis, asthma, Crohn’s disease, colitis, ocular allergy, appendicitis, Paget’s disease, pancreatitis, periodonitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica- induced diseases, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary periodic fever syndrome, psychosocial stress diseases, neurppathological diseases, familial amyloidotic polyneuropathy, inflammatory neuropathy, Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, amyotropic lateral sclerosis, Huntington’s disease, cataracts, or hearing loss.
[00150] In other embodiments, the disorder or condition associated with CRM1 activity is head injury, uveitis, inflammatory pain, allergen induced asthma, non-allergen induced asthma, glomerular nephritis, ulcerative colitis, necrotizing enterocolitis, hyperimmunogtobulinemia D with recurrent fever (HIDS), TNF receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes, Muckle- Wells syndrome (urticaria deafness amyloidosis), familial cold urticaria, neonatal onset multisystem inflammatory disease (NOMID), periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA syndrome), Blau syndrome, pyogenic sterile arthritis, pyoderma gangrenosum acne (PAPA), deficiency of the interleukin- 1 -receptor antagonist (DIRA), subarachnoid hemorrhage, polycystic kidney disease, transplant, organ transplant, tissue transplant, myelodysplastic syndrome, irritant-induced inflammation, plant irritant-induced inflammation, poison ivy/ urushiol oil-induced inflammation, chemical irritant-induced inflammation, bee sting-induced inflammation, insect bite-induced inflammation, sunburn, bums, dermatitis, endotoxemia, lung injury, acute respiratory distress syndrome, alcoholic hepatitis, or kidney injury caused by parasitic infections.
[00151] In further aspects, the present disclosure relates to a use of a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of a disorder associated with
CRM1 activity. The present disclosure also relates to crystalline form I or pharmaceutical compositions described herein for use in treating a disorder associated with CRM1 activity. Specific examples of disorders associated with CRM1 activity are as set forth in detail herein. [00152] In yet further aspects, the present disclosure relates to a use of a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of a disease associated with expression or activity of p53, p73, p21, pRB, p27, INB, NFNB, c-Abl, FOXO proteins, COX- 2 or an HDAC in a subject. In some embodiments, the present disclosure relates to a use of a crystalline form or pharmaceutical compositions described herein in the manufacture of a medicament for the treatment of any of cancer and/or neoplastic disorders, angiogenesis, autoimmune disorders, inflammatory disorders and/or diseases, epigenetics, hormonal disorders and/or diseases, viral diseases, neurodegenerative disorders and/or diseases, wounds, and ophthalmologic disorders.
[00153] In some embodiments, the present disclosure relates to a method for inhibiting CRM1 in a biological sample comprising contacting the biological sample with, or administering to the patient, a crystalline form of the compound represented by Structural Formula lor pharmaceutical compositions described herein.
Neoplastic Disorders
[00154] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat a neoplastic disorder. A “neoplastic disorder" is a disease or disorder characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. Exemplary neoplastic disorders include: carcinoma, sarcoma, metastatic disorders, e.g., tumors arising from prostate, brain, bone, colon, lung, breast, ovarian, and liver origin, hematopoietic neoplastic disorders, e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders, and metastatic tumors. Prevalent cancers include: breast, prostate, colon, lung, liver, and pancreatic cancers. Treatment with the compound can be in an amount effective to ameliorate at least one symptom of the neoplastic disorder, e.g., reduced cell proliferation, reduced tumor mass, etc.
[00155] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are useful in the prevention and treatment of cancer, including for example, solid tumors, soft tissue tumors, and metastases thereof, as well as in familial cancer syndromes such as Li Fraumeni Syndrome, Familial Breast-Ovarian Cancer (BRCA1 or BRAC2 mutations) Syndromes, and others. Crystalline forms or pharmaceutical compositions described herein are also useful in treating non-solid cancers. Exemplary solid tumors include malignancies (e.g., sarcomas, adenocarcinomas, and carcinomas) of the various organ systems, such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon), and genitourinary (e.g., renal, urothelial, or testicular tumors) tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancers, renal-cell carcinoma, liver cancer, non-small cell carcinoma of the lung, and cancer of the small intestine.
[00156] Exemplary cancers described by the National Cancer Institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer;
Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS- Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non- Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor.
[00157] Further exemplary cancers include diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Yet further exemplary cancers include endocervical cancer, flcell ALL, T-cell ALL, B- or T-cell lymphoma, mast cell cancer, glioblastoma, neuroblastoma, follicular lymphoma and Richter’s syndrome.
[00158] Exemplary sarcomas include fibrosarcoma, alveolar soft part sarcoma (ASPS), liposarcoma, leiomyosarcoma, chondrosarcoma, synovial sarcoma, chordoma, spindle cell sarcoma, histiocytoma, rhabdomyosarcoma, Ewing’s sarcoma, neuroectodermal sarcoma, phyllodes/osteogenic sarcoma and chondroblastic osteosarcoma.
[00159] Further exemplary cancer that can be treated by a crystalline form of the compound of Structural Formula (1) or pharmaceutical compositions described herein are penile cancer and nasopharyngeal cancer.
[00160] Metastases of the aforementioned cancers can also be treated or prevented in accordance with the methods described herein.
[00161] In the seventeenth embodiment, the disclosure relates to a method for treating or preventing a CRM1 -associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above, a composition of any one of the aspects of the fifteenth embodiment described above or a pharmaceutical composition of any one of the aspects of the sixteenth embodiment described above. For example, the method comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline formof the compound represented by Structural Formula 1, or a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a crystalline formof the compound represented by Structural Formula 1, and a pharmaceutically acceptable carrier.
[00162] In certain aspects of the seventeenth embodiment, the disorder is a proliferative disorder, cancer, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, an allergic disorder, or a respiratory disorder. For example, the disorder is cancer.
[00163] In certain aspects of the seventeenth embodiment, the cancer is multiple myeloma, relapsed or refractory multiple myeloma, penta-refractoiy multiple myeloma, acute myeloid leukemia, relapsed or refractory acute myeloid leukemia, secondary acute myeloid leukemia, diffuse large B-cell lymphoma, relapsed or refractory diffuse large B-cell lymphoma, recurrent or refractory B-cell non-Hodgkin lymphoma, recurrent or refractory extranodal marginal zone lymphoma, recurrent follicular lymphoma, recurrent or refractory indolent adult non-Hodgkin lymphoma, recurrent or refractory mantle cell lymphoma, recurrent or refractory marginal zone lymphoma, recurrent or refractory small lymphocytic lymphoma, recurrent Waldenstrom macroglobulinemia, non-Hodgkin lymphoma, transformed recurrent non-Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, neuroendocrine carcinoma, non-small cell lung cancer, liposarcoma, dedifferentiated liposarcoma, malignant peripheral nerve sheath tumors, alveolar soft part sarcoma, Ewing sarcoma, soft tissue sarcoma, breast cancer, ovarian cancer, ovarian carcinoma, endometrial cancer, endometrial carcinoma, cervical carcinoma, glioblastoma, glioma, malignant glioma, recurrent brain neoplasm, recurrent childhood central nervous system neoplasm, recurrent childhood glioblastoma, refractory central nervous system neoplasm, multiple myeloma, refractory multiple myeloma, thymoma, advanced thymic epithelial tumor, de novo myelodysplastic syndrome, myelodysplastic syndrome, secondary myelodysplastic syndrome, esophageal cancer, gastric cancer, hormone-resistant prostate cancer, metastatic prostate carcinoma in the soft tissue, prostate adenocarcinoma, recurrent melanoma, leukemia, relapsed acute lymphoblastic leukemia (ALL), refractory ALL, relapsed acute myelogenous leukemia (AML), refractory AML, prolymphocytic leukemia, relapsed mixed lineage leukemia, refractory mixed lineage leukemia, relapsed biphenotypic leukemia, refractory biphenotypic leukemia, chronic myelogenous leukemia (CML) in blast crisis, refractory chronic lymphocytic leukemia, mixed phenotype acute leukemia, squamous cell carcinoma, recurrent small cell lung carcinoma, recurrent squamous cell lung carcinoma, colorectal neoplasm, acinar cell adenocarcinoma of the pancreas, duct cell adenocarcinoma of the pancreas, pancreatic cancer, or salivary gland cancer. For example, the cancer is refractory multiple myeloma, such as penta-refractory multiple myeloma.
[00164] In various example embodiments, crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from leukemia, lymphoma or a sold cancer, wherein the leukemia is selected from: hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and chronic lymphocytic leukemia; the lymphoma is selected from: cutaneous T-Cell lymphoma; diffuse large B-cell lymphoma; mantle cell lymphoma; and follicular lymphoma; the solid cancer is selected from: prostate cancer; breast cancer; liver cancer; colon cancer; pancreatic cancer; renal cancer; and ovarian cancer. [00165] In various example embodiments, crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from a lymphoma, selected from non-Hodgkin's B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, follicular lymphoma and mantle cell lymphoma; a leukemia selected from hairy cell leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, acute myeloid leukemia and chronic lymphocytic leukemia; or a solid tumor selected from prostate, breast, liver, colorectal, pancreatic, renal, osteosarcoma, lung, cervical and ovarian cancers.
[00166] In various example embodiments, crystalline forms of the compound represented by Structural Formula 1, or pharmaceutical compositions described herein can be used for treating a disorder selected from a colorectal cancer, a prostate cancer, a myelodysplastic syndrome, an inflammatory bowel disease, a nasopharyngeal cancer, and a penile cancer.
Combination therapies
[00167] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered together with an additional “second” therapeutic agent or treatment. The choice of second therapeutic agent may be made from any agent that is typically used in a monotherapy to treat the indicated disease or condition. As used herein, the term “administered together” and related terms refers to the simultaneous or sequential administration of therapeutic agents to a subject in need thereof to treat any one or more indications described herein. For example, crystalline forms or pharmaceutical compositions described herein may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure relates to a single unit dosage form comprising crystalline form I or pharmaceutical compositions described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
[00168] In one embodiment of the disclosure, where a second therapeutic agent is administered to a subject, the effective amount of crystalline forms of the compound represented by Structural Formula 1 is less than its effective amount would have been if the second therapeutic agent were not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would have been if crystalline forms of the compound represented by Structural Formula 1 were not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art. The additional agents may be administered separately from crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein, as part of a multiple dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with crystalline forms or pharmaceutical compositions described herein.
[00169] In certain embodiments, crystalline forms of the compound represented by Structural Formula lor pharmaceutical compositions described herein may be administered alone or in combination with other compounds useful for treating or preventing inflammation. Exemplary anti-inflammatory agents include, for example, steroids (e.g., Cortisol, cortisone, fludrocortisone, prednisone, 6[alpha]-methylprednisone, triamcinolone, betamethasone or dexamethasone), nonsteroidal antiinflammatory drugs (NSAIDS (e.g., aspirin, acetaminophen, tolmetin, ibuprofen, mefenamic acid, piroxicam, nabumetone, rofecoxib, celecoxib, etodolac or nimesulide). In another embodiment, the other therapeutic agent is an antibiotic (e.g., vancomycin, penicillin, amoxicillin, ampicillin, cefotaxime, ceftriaxone, cefixime, rifampinmetronidazole, doxycycline or streptomycin). In another embodiment, the other therapeutic agent is a PDE4 inhibitor (e.g., roflumilast or rolipram). In another embodiment, the other therapeutic agent is an antihistamine (e.g., cyclizine, hydroxyzine, promethazine or diphenhydramine). In another embodiment, the other therapeutic agent is an anti-malarial (e.g., artemisinin, artemether, artsunate, chloroquine phosphate, mefloquine hydrochloride, doxycycline hyclate, proguanil hydrochloride, atovaquone or halofantrine). In one embodiment, the other compound is drotrecogin alfa. In a specific embodiment, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with dexamethasone.
[00170] Further examples of anti-inflammatory agents include, for example, aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algestone, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4- hydroxybutyric acid, 2-amino-4- picoline, aminopropylon, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine, antrafenine, apazone, beclomethasone, bendazac, benorylate, benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen, betamethasone, betamethasone- 17-valerate, bezitramide, [alpha]-bisabolol, bromfenac, p- bromoacetanilide, 5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid, bucolome, budesonide, bufexamac, bumadizon, buprenorphine, butacetin, butibufen, butorphanol, carbamazepine, carbiphene, caiprofen, carsalam, chlorobutanol, chloroprednisone, chlorthenoxazin, choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac, clobetasol, clocortolone, clometacin, clonitazene, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort, dehydrotestosterone, desomorphine, desonide, desoximetasone, dexamethasone, dexamethasone-21- isonicotinate, dexoxadrol, dextromoramide, dextropropoxyphene, deoxycorticosterone, dezocine, diampromide, diamorphone, diclofenac, difenamizole, difenpiramide, diflorasone, diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, enoxolone, epirizole, eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, fluazacort, flucloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoxaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin butyl, fluocoitolone, fluoresone, fluoromethoIone, fluperolone, flupirtine, fluprednidene, fluprednisolone, fluproquazone, flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfosal, gentisic acid, glafenine, glucametacin, glycol salicylate, guaiazulene, halcinonide, halobetasol, halometasone, haloprednone, heroin, hydrocodone, hydro cortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone cypionate, hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p- lactophenetide, lefetamine, levallorphan, levorphanol, levophenacyl-morphan, lofentanil, lonazolac, lomoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrysone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mesalamine, metazocine, methadone, methotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate, metiazinic acid, metofoline, metopon, mofebutazone, mofezolac, mometasone, morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine, nabumetone, nalbuphine, nalorphine, 1 -naphthyl salicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'- propoxyacetanilide, norlevorphanol, normethadone, normorphine, norpipanone, olsalazine, opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, paranyline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenomorphan, phenyl acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol, piketoprofen, piminodine, pipebuzone, piperylone, pirazolac, piritramide, piroxicam, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone, prednival, prednylidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o- acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverine, simetride, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine, tinoridine, tixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, triamcinolone acetonide, tropesin, viminol, xenbucin, ximoprofen, zaltoprofen and zomepirac.
[00171] In one embodiments, a crystalline form of the cornpound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered with a selective COX-2 inhibitor for treating or preventing inflammation. Exemplary selective COX-2 inhibitors include, for example, deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, and lumiracoxib.
[00172] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with an anthracycline or a Topo n inhibitor. In certain embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical cornpositions described herein are administered in combination with Doxorubicin (Dox). In certain embodiments, a crystalline form of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered in combination with bortezomib (and more broadly including carfilzomib).
Cancer Combination Therapies
[00173] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein, are administered together with an additional cancer treatment. Exemplary additional cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, kinase inhibitors, immunotherapy, and hormonal therapy, epigenetic therapy, proteosome inhibitors, and anti- angiogenic therapies. Examples of each of these treatments are provided below. As used herein, the term “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, crystalline forms of the compound represented by Structural Formula 1 can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising file crystalline forms of the compound represented by Structural Formula 1, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
[00174] The amount of both crystalline forms of the compound represented by Structural Formula 1 and additional therapeutic agent (in those pharmaceutical compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, pharmaceutical compositions of this disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of crystalline forms of the compound represented by Structural Formula 1 can be administered.
Chemotherapy
[00175] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are co-administered with a chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. “Chemotherapy” usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.
[00176] Examples of chemotherapeutic agents used in cancer therapy include, for example, antimetabolites (e.g., folic acid, purine, and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle poison, cytotoxic agents, topoisomerase inhibitors and others). Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan, Belotecan, Bexarotene, Bendamustine, Bleomycin, Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin, Carboquone, Carfilzomib, Carmofur, Carmustine, Celecoxib, Cetuximab , Chlorambucil, Chlormethine, CHOEP-21, CHOP, Cisplatin, Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine or ara-C, Dacarbazine, Dactinomycin, DA EPOCH, Daratumumab , Daunorubicin, Decitabine, Demecolcine, Dexamethasone , Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin, Eribulin, Estramustine, Etoglucid, Etoposide, FLAG (Flu + Cyt), Floxuridine, Fludarabine, Fluorouracil (5FU), FOLFOX, Fotemustme, Gemcitabine, gemcitabine-oxaliplatin (GemOx), Gliadel implants, Hydroxycarbamide, Hydroxyurea, Ibrutinib , Idarubicin, Ifosfamide, Irinotecan, Irofulven, Ixabepilone, Ixazomib, Larotaxel, Lenalidomide , Leucovorin, Liposomal doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nab-paclitaxel , Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatm, Pirarubicin, Pixantrone, PLD (pegylated liposomal doxorubicin), Plicamycin, Pomalidomide , Porfimer sodium, Prednimustine, Procarbazine, Raltitrexed, Ranimustine, R-CHOP, r-dhaox, r-dhap, Rituximab , Romidepsin Rubitecan, Sapacitabine, Semustine, Sitimagene ceradenovec, Sorafonib , Strataplatin, Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine, Tioguanine, Tipifamib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Tretinoin, Treosulfan, Trofosfiunide, Uramustine, Valrubicin, Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxic agents described herein.
Targeted therapy
[00177] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used in combination with or as a part of a targeted therapy. Targeted therapy constitutes the use of agents specific for the target of interest (e.g., a deregulated protein) in cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and also cyclin- dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include the anti-HER2/neu antibody trastuzumab (Herceptin®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include Aflibercept and Denileukin diflitox. In some embodiments, the targeted therapy can be used in combination with a pharmaceutical composition described herein, e.g., Gleevec (Vignari and Wang 2001).
[00178] Targeted therapy can also involve small peptides as “homing devices” which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor.
[00179] Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®.
Angiogenesis
[00180] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with angiogenesis. Diseases associated with angiogenesis include cancer, cardiovascular disease and macular degeneration.
[00181] Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in granulation tissue. However, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one. Angiogenesis may be a target for combating diseases characterized by either poor vascularization or abnormal vasculature.
[00182] Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds, are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair. Other diseases, such as age-related macular degeneration, may be created by a local expansion of blood vessels, interfering with normal physiological processes.
[00183] Vascular endothelial growth factor (VEGF) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries.
[00184] Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g., VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.
[00185] Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.
[00186] Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision.
[00187] Anti-angiogenic therapy can include kinase inhibitors targeting vascular endothelial growth factor (VEGF) such as sunitinib, sorafenib, or monoclonal antibodies or receptor“decoys” to VEGF or VEGF receptor including bevacizumab or VEGF-Trap, or thalidomide or its analogs (lenalidomide, pomalidomide), or agents targeting non- VEGF angiogenic targets such as fibroblast growth factor (FGF), angiopoietins, or angiostatin or endostatin.
Epigenetics
[00188] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with epigenetics. Epigenetics is the study of heritable changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. One example of epigenetic changes in eukaryotic biology is the process of cellular differentiation. During morphogenesis, stem cells become the various cell lines of the embryo which in turn become fully differentiated cells. In other words, a single fertilized egg cell changes into the many cell types including neurons, muscle cells, epithelium, blood vessels etc. as it continues to divide. It does so by activating some genes while inhibiting others.
[00189] Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if a mutation in the DNA has been caused in sperm or egg cell that results in fertilization, then some epigenetic changes are inherited from one generation to the next. Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
[00190] Exemplary diseases associated with epigenetics include ATR-syndrome, fragile X- syndrome, ICF syndrome, Angelman’s syndrome, Prader- Wills syndrome, BWS, Rett syndrome, D-thalassaemia, cancer, leukemia, Rubinstein-Taybi syndrome and Coffin-Lowry syndrome.
[00191] The first human disease to be linked to epigenetics was cancer. Researchers found that diseased tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same patients. Because methylated genes are typically tamed off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chromatin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes.
[00192] DNA methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals. However, there are stretches of DNA near promoter regions that have higher concentrations of CpG sites (known as CpG islands) that are free of methylation in normal cells. These CpG islands become excessively methylated in cancer cells, thereby causing genes that should not be silenced to turn off. This abnormality is the trademark epigenetic change that occurs in tumors and happens early in the development of cancer. Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more common in human cancer than DNA sequence mutations.
[00193] Furthermore, although epigenetic changes do not alter the sequence of DNA, they can cause mutations. About half of the genes that cause familial or inherited forms of cancer are turned off by methylation. Most of these genes normally suppress tumor formation and help repair DNA, including O6-methylguanine-DNA methyltransferase (MGMT), MLH1 cyclin-dependent kinase inhibitor 2B (CDKN2B), and RASSF1 A. For example, hypermethylation of the promoter of MGMT causes the number of G-to-A mutations to increase.
[00194] Hypermethylation can also lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they usually consist of repeats of the dinucleotide CA. Too much methylation of the promoter of the DNA repair gene MLH1 can make a microsatellite unstable and lengthen or shorten it Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers.
[00195] Fragile X syndrome is the most frequently inherited mental disability, particularly in males. Both sexes can be affected by this condition, but because males only have one X chromosome, one fragile X will impact them more severely. Indeed, fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “autistic-like” behavior.
[00196] Fragile X syndrome gets its name from the way the part of the X chromosome that contains the gene abnormality looks under a microscope; it usually appears as if it is hanging by a thread and easily breakable. The syndrome is caused by an abnormality in the FMRI (fragile X mental retardation 1) gene. People who do not have fragile X syndrome have 6 to 50 repeats of the trinucleotide CGG in their FMRI gene. However, individuals with over 200 repeats have a full mutation, and they usually show symptoms of the syndrome. Too many CGGs cause the CpG islands at the promoter region of the FMRI gene to become methylated; normally, they are not This methylation turns the gene off, stopping the FMRI gene from producing an important protein called fragile X mental retardation protein. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile X, the epigenetic change associated with FMRI methylation is the real syndrome culprit.
[00197] Fragile X syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi, Coffin- Lowry, Prader-Willi, Angelman, Beckwith- Wiedemann, ATR-X, and Rett syndromes.
[00198] Epigenetic therapies include inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases and histone deacetylases, which have shown promising anti-tumorigenic effects for some malignancies, as well as antisense oligonucleotides and siRNA.
Immunotherapy
[00199] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered with an immunotherapy. Cancer immunotherapy refers to a diverse set of therapeutic strategies designed to induce the patients own immune system to fight the tumor. Conte
Figure imgf000047_0001
rary methods for generating an immune response against tumors include intravesicular BCG immunotherapy for superficial bladder cancer, prostate cancer vaccine Provenge, and use of interferons and other cytokines to induce an immune response in renal cell carcinoma and melanoma patients.
[00200] Allogeneic hematopoietic stem cell transplantation can be considered a form of immunotherapy, since the donor’s immune cells will often attack the tumor in a graft-versus- tumor effect. In some embodiments, the immunotherapy agent(s) can be used in combination with crystalline forms or pharmaceutical compositions described herein.
Hormonal therapy
[00201] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered with a hormonal therapy. The growth of some cancers can be inhibited by providing or blocking certain hormones. Common examples of hormone-sensitive tumors include certain types of breast and prostate cancers, as well as certain types of leukemia which respond to certain retinoids/retinoic acids. Removing or blocking estrogen or testosterone is often an important additional treatment. In certain cancers, administration of hormone agonists, such as progestogens may be therapeutically beneficial. In some embodiments, the hormonal therapy agents can be used in combination with a pharmaceutical composition described herein.
[00202] Hormonal therapy agents include the administration of hormone agonists or hormone antagonists and include retinoids/retinoic acid, compounds that inhibit estrogen or testosterone, as well as administration of progestogens.
Inflammation and Autoimmune Disease
[00203] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with inflammation, particularly in humans and other mammals. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered prior to the onset of, at, or after the initiation of inflammation. When used prophylactically, the pharmaceutical compositions are preferably provided in advance of any inflammatory response or symptom. Administration can prevent or attenuate inflammatory responses or symptoms. Exemplary inflammatory conditions include, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, spondouloarthropathies, other seronegative inflammatory arthridities, polymyalgia rheumatica, various vasculidities (e.g., giant cell arteritis, ANCA+ vasculitis), gouty arthritis, systemic lupus erythematosus, juvenile arthritis, juvenile rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (e.g., insulin dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis (acute or chronic), multiple organ injury syndrome (e.g., secondary to septicemia or trauma), myocardial infarction, atherosclerosis, stroke, reperfusion injury (e.g., due to cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, thermal injury (i.e., sunburn), necrotizing enterocolitis, granulocyte transfusion associated syndrome, and/or Sjogren's syndrome. Exemplary inflammatory conditions of the skin include, for example, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, and dermatosis with acute inflammatory components.
[00204] In another embodiment, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent allergies and respiratory conditions, including asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, and any chronic obstructive pulmonary disease (COPD). Crystalline form I or pharmaceutical compositions described herein may be used to treat chronic hepatitis infection, including hepatitis B and hepatitis C.
[00205] Additionally, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat autoimmune diseases and/or inflammation associated with autoimmune diseases, such as organ-tissue autoimmune diseases (e.g., Raynaud's syndrome), scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, sepsis, psoriasis, eczema, dermatitis, multiple sclerosis, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), and Grave's disease.
[00206] In a particular embodiment, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat multiple sclerosis.
Viral infections
[00207] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a disease or disorder associated with a viral infection, particularly in humans and other mammals. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be administered prior to the onset of at, or after the initiation of viral infection. When used prophylactically, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered in advance of any viral infection or symptom thereof.
[00208] Exemplary viral diseases include acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi’s sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, influenza-like syndrome, severe bronchiolitis with pneumonia, COVID-19, German measles, congenital rubella, Varicella, and herpes zoster.
[00209] Exemplary viral influenza A strains include H1N1, H3N2, H5N1, H7N3, H7N9. A compound described herein can also be used to treat or prevent influenza B.
[00210] Exemplary viral pathogens include Adenovirus, Coxsackievirus, Dengue virus, Encephalitis Virus, Epstein-Barr virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Herpes simplex virus type 1, Herpes simplex virus type 2, cytomegalovirus, Human herpesvirus type 8, Human immunodeficiency virus, Influenza virus, measles virus, Mumps virus, Human papillomavirus, Parainfluenza virus, Poliovirus, Rabies virus, Respiratory syncytial virus, Rubella virus, Varicella-zoster virus, West Nile virus, Dungee, SARS, MERS, SARS-CoV-2, and Yellow fever virus. Viral pathogens may also include viruses that cause resistant viral infections.
[00211] Antiviral drugs are a class of medications used specifically for treating viral infections. Antiviral action generally falls into one of three mechanisms: interference with the ability of a virus to infiltrate a target cell (e.g., amantadine, rimantadine and pleconaril), inhibition of the synthesis of virus (e.g., nucleoside analogues, e.g., acyclovir and zidovudine (ACT), and inhibition of the release of virus (e.g., zanamivir and oseltamivir).
Ophthalmology
[00212] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent an ophthamology disorder. Exemplary ophthamology disorders include macular edema (diabetic and nondiabetic macular edema), age related macular degeneration wet and dry forms, aged disciform macular degeneration, cystoid macular edema, palpebral edema, retina edema, diabetic retinopathy, chorioretinopathy, neovascular maculopathy, neovascular glaucoma, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, choroiditis, retinal pigment epithelitis, conjunctivitis, cyclitis, scleritis, episcleritis, optic neuritis, retrobulbar optic neuritis, keratitis, blepharitis, exudative retinal detachment, comeal ulcer, conjunctival ulcer, chronic nummular keratitis, ophthalmic disease associated with hypoxia or ischemia, retinopathy of prematurity, proliferative diabetic retinopathy, polypoidal choroidal vasculopathy, retinal angiomatous proliferation, retinal artery occlusion, retinal vein occlusion, Coats’ disease, familial exudative vitreoretinopathy, pulseless disease (Takayasu’s disease), Eales disease, antiphospholipid antibody syndrome, leukemic retinopathy, blood hyperviscosity syndrome, macroglobulinemia, interferon- associated retinopathy, hypertensive retinopathy, radiation retinopathy, corneal epithelial stem cell deficiency and cataract
[00213] Other ophthalmology disorders treatable using crystalline form or pharmaceutical compositions described herein include proliferative vitreoretinopathy and chronic retinal detachment.
[00214] Inflammatory eye diseases are also treatable using crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein.
Neurodegenerative disease
[00215] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may be used to treat or prevent a neurodegenerative disease. Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many similarities appear which relate these diseases to one another on a sub-cellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate many diseases simultaneously. There are many parallels between different neurodegenerative disorders including atypical protein assemblies as well as induced cell death.
[00216] Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
[00217] Huntington’s disease causes astrogliosis and loss of medium spiny neurons. Areas of the brain are affected according to their structure and the types of neurons they contain, reducing in size as they cumulatively lose cells. The areas affected are mainly in the striatum, but also the frontal and temporal cortices. The striatum's subthalamic nuclei send control signals to the globus pallidus, which initiates and modulates motion. The weaker signals from subthalamic nuclei thus cause reduced initiation and modulation of movement, resulting in the characteristic movements of the disorder. Exemplary treatments for Huntington’s disease include tetrabenazine, neuroleptics, benzodiazepines, amantadine, remacemide, valproic acid, selective serotonin reuptake inhibitors (SSRIs), mirtazapine and antipsychotics.
[00218] The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies. The latest research on pathogenesis of disease has shown that the death of dopaminergic neurons by alpha-synuclein is due to a defect in the machinery that transports proteins between two major cellular organelles - the endoplasmic reticulum (ER) and the Golgi apparatus. Certain proteins like Rabi may reverse this defect caused by alpha-synuclein in animal models. Exemplary Parkinson’s disease therapies include levodopa, dopamine agonists such as include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride, dopa decarboxylate inhibitors, MAO-B inhibitors such as selegilene and rasagilene, anticholinergics and amantadine.
[00219] Amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease) is a disease in which motor neurons are selectively targeted for degeneration. Exemplary ALS therapies include riluzole, baclofen, diazepam, trihexyphenidyl and amitriptyline.
[00220] Other exemplary neurodegenerative therapeutics includes antisense oligonucleotides and stem cells.
Wound Healing
[00221] Wounds are a type of condition characterized by cell or tissue damage. Wound healing is a dynamic pathway that optimally leads to restoration of tissue integrity and function. The wound healing process consists of three overlapping phases. The first phase is an inflammatory phase, which is characterized by homeostasis, platelet aggregation and degranulation. Platelets as the first response, release multiple growth factors to recruit immune cells, epithelial cells, and endothelial cells. The inflammatory phase typically occurs over days 0-5. The second stage of wound healing is the proliferative phase during which macrophages and granulocytes invade the wound. Infiltrating fibroblasts begin to produce collagen. The principle characteristics of this phase are epithelialization, angiogenesis, granulation tissue formation and collagen production. The proliferative phase typically occurs over days 3-14. The third phase is the remodeling phase where matrix formation occurs. The fibroblasts, epithelial cells, and endothelial cells continue to produce collagen and collagenase as well as matrix metalloproteases (MMPs) for remodeling. Collagen crosslinking takes place and the wound undergoes contraction. The remodeling phase typically occurs from day 7 to one year.
[00222] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used for promoting wound healing (e.g., promoting or accelerating wound closure and/or wound healing, mitigating scar fibrosis of the tissue of and/or around the wound, inhibiting apoptosis of cells surrounding or proximate to the wound). Thus, in an eighteenth embodiment, the present disclosure relates to a method for promoting wound healing in a subject, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a crystalline form of the compound represented by Structural Formula 1 according to any one of the aspects of the first through the fourteenth embodiments described above, a composition of any one of the aspects of the fifteenth embodiment described above, or a pharmaceutical composition of any one of the aspects of the sixteenth embodiment described above. [00223] The method need not achieve complete healing or closure of the wound; it is sufficient for the method to promote any degree of wound closure. In this respect^ the method can be employed alone or as an adjunct to other methods for healing wounded tissue.
[00224] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat wounds during the inflammatory (or early) phase, during the proliferative (or middle) wound healing phase, and/or during the remodeling (or late) wound healing phase.
[00225] In some embodiments, the subject in need of wound healing is a human or an animal, for example, a dog, a cat, a horse, a pig, or a rodent, such as a mouse.
[00226] In some embodiments, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are administered topically, for example, proximate to the wound site, or systemically.
[00227] More specifically, a therapeutically effective amount of crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered (optionally in combination with other agents) to the wound site by coating the wound or applying a bandage, packing material, stitches, etc., that are coated or treated with the compound or composition described herein. As such, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be formulated for topical administration to treat surface wounds. Topical formulations include those for delivery via the mouth (buccal) and to the skin such that a layer of skin (i.e., the epidermis, dermis, and/or subcutaneous layer) is contacted with the pharmaceutical composition described herein. Topical delivery systems may be used to administer topical formulations of the compounds and compositions described herein.
[00228] Alternatively, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered at or near the wound site by, for example, injection of a solution, injection of an extended release formulation, or introduction of a biodegradable implant comprising the compound or composition described herein.
[00229] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to treat acute wounds or chronic wounds. A chronic wound results when the normal reparative process is interrupted. Chronic wounds can develop from acute injuries as a result of unrecognized persistent infections or inadequate primary treatment In most cases however, chronic lesions are the end stage of progressive tissue breakdown owing to venous, arterial, or metabolic vascular disease, pressure sores, radiation damage, or tumors.
[00230] In chronic wounds, healing does not occur for a variety of reasons, including improper circulation in diabetic ulcers, significant necrosis, such as in bums, and infections. In these chronic wounds, viability or the recovery phase is often the rate-limiting step. The cells are no longer viable and, thus, initial recovery phase is prolonged by unfavorable wound bed environment.
[00231] Chronic wounds include, but are not limited to the following: chronic ischemic skin lesions; scleroderma ulcers; arterial ulcers; diabetic foot ulcers; pressure ulcers; venous ulcers; non-healing lower extremity wounds; ulcers due to inflammatory conditions; and/or long-standing wounds. Other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, and arterial insufficiencies, and pressure wounds and cold and warm bums. Yet other examples of chronic wounds include chronic ulcers, diabetic wounds, wounds caused by diabetic neuropathy, venous insufficiencies, arterial insufficiencies, and pressure wounds.
[00232] Acute wounds include, but are not limited to, post-surgical wounds, lacerations, hemorrhoids and fissures.
[00233] In a particular embodiment, crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used for diabetic wound healing or accelerating healing of leg and foot ulcers secondary to diabetes or ischemia in a subject
[00234] In one embodiment, the wound is a surface wound. In another embodiment, the wound is a surgical wound (e.g., abdominal or gastrointestinal surgical wound). In a further embodiment, the wound is a bum. In yet another embodiment, the wound is the result of radiation exposure.
[00235] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can also be used for diabetic wound healing, gastrointestinal wound healing, or healing of an adhesion due, for example, to an operation.
[00236] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can also be used to heal wounds that are secondary to another disease. For example, in inflammatory skin diseases, such as psoriasis and dermatitis, there are numerous incidents of skin lesions that are secondary to the disease, and are caused by deep cracking of the skin, or scratching of the skin. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be used to heal wounds that are secondary to these diseases, for example, inflammatory skin diseases, such as psoriasis and dermatitis.
[00237] In a further embodiment, the wound is an internal wound. In a specific aspect, the internal wound is a chronic wound. In another specific aspect, the wound is a vascular wound. In yet another specific aspect, the internal wound is an ulcer. Examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, Crohn’s disease, ulcerative colitis, internal surgical sutures and skeletal fixation. Other examples of internal wounds include, but are not limited to, fistulas and internal wounds associated with cosmetic surgery, internal indications, internal surgical sutures and skeletal fixation.
[00238] Examples of wounds include, but are not limited to, abrasions, avulsions, blowing wounds (i.e., open pneumothorax), bum wounds, contusions, gunshot wounds, incised wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, sfiton wounds, stab wounds, surgical wounds, subcutaneous wounds, diabetic lesions, or tangential wounds. Additional examples of wounds that can be treated by the pharmaceutical compositions described herein include acute conditions or wounds, such as thermal bums, chemical bums, radiation bums, bums caused by excess exposure to ultraviolet radiation (e.g., sunbum); damage to bodily tissues, such as the perineum as a result of labor and childbirth; injuries sustained during medical procedures, such as episiotomies; trauma- induced injuries including cuts, incisions, excoriations; injuries sustained from accidents; post-surgical injuries, as well as chronic conditions, such as pressure sores, bedsores, conditions related to diabetes and poor circulation, and all types of acne. In addition, the wound can include dermatitis, such as impetigo, intertrigo, folliculitis and eczema, wounds following dental surgery; periodontal disease; wounds following trauma; and tumor- associated wounds. Yet other examples of wounds include animal bites, arterial disease, insect stings and bites, bone infections, compromised skin/muscle grafts, gangrene, skin tears or lacerations, skin aging, surgical incisions, including slow or non-healing surgical wounds, intracerebral hemorrhage, aneurysm, dermal asthenia, and post-operation infections.
[00239] In certain embodiments, the wound is selected from the group consisting of a bum wound, an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a thermal bum, a chemical bum, a radiation bum, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation. In more preferred embodiments, the wound is selected from the group consisting of an incised wound, an open wound, a surgical or post- surgical wound, a diabetic lesion, a pressure sore, a bedsore, and a condition or wound related to diabetes or poor circulation.
[00240] In some embodiments, the wound is selected from the group consisting of a nonradiation bum wound, an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a thermal bum, a chemical bum, a pressure sore, a bedsore, and a condition rotated to diabetes or poor circulation. In some embodiments, the wound is selected from the group consisting of an incised wound, an open wound, a surgical or post-surgical wound, a diabetic lesion, a pressure sore, a bedsore, and a condition related to diabetes or poor circulation.
[00241] The present disclosure also relates to methods for reducing scar formation during wound healing in a subject. Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein can be administered directly to the wound or to cells proximate the wound at an amount effective to reduce scar formation in and/or around the wound. Thus, in some embodiments, a method of reducing scar formation during wound healing in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein.
[00242] The wound can include any injury to any portion of the body of a subject
[00243] In certain embodiments, the present disclosure relates to methods for ameliorating, reducing, or decreasing the formation of scars in a subject that has suffered a bum injury. In other embodiments, the present disclosure relates to methods for treating, reducing the occurrence of, or reducing the probability of developing hypertrophic scars in a subject that has suffered an acute or chronic wound or injury.
Other disorders
[00244] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein may also be used to treat disorders of abnormal tissue growth and fibrosis including dilative cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary fibrosis, hepatic fibrosis, glomerulonephritis, and other renal disorders.
Combination Radiation Therapy
[00245] Crystalline forms of the compound represented by Structural Formula 1 or pharmaceutical compositions described herein are useful as radiosensitizers. Therefore, pharmaceutical compositions described herein can be administered in combination with radiation therapy. Radiation therapy is the medical use of high-energy radiation (e.g., X-rays, gamma rays, charged particles) to shrink tumors and kill malignant cells, and is generally used as part of cancer treatment. Radiation therapy kills malignant cells by damaging their DNA.
[00246] Radiation therapy can be delivered to a patient in several ways. For example, radiation can be delivered from an external source, such as a machine outside the patient’s body, as in external beam radiation therapy. External beam radiation therapy for the treatment of cancer uses a radiation source that is external to the patient, typically either a radioisotope, such as 60Co, 137Cs, or a high energy X-ray source, such as a linear accelerator. The external source produces a collimated beam directed into the patient to the tumor site. External-source radiation therapy avoids some of the problems of internal-source radiation therapy, but it undesirably and necessarily irradiates a significant volume of non-tumorous or healthy tissue in the path of the radiation beam along with the tumorous tissue.
[00247] The adverse effect of irradiating of healthy tissue can be reduced, while maintaining a given dose of radiation in the tumorous tissue, by projecting the external radiation beam into the patient at a variety of “gantry” angles with the beams converging on the tumor site. The particular volume elements of healthy tissue, along the path of the radiation beam, change, reducing the total dose to each such element of healthy tissue during the entire treatment
[00248] The irradiation of healthy tissue also can be reduced by tightly collimating the radiation beam to the general cross section of the tumor taken perpendicular to the axis of the radiation beam. Numerous systems exist for producing such a circumferential collimation, some of which use multiple sliding shutters which, piecewise, can generate a radio-opaque mask of arbitrary outline.
[00249] For administration of external beam radiation, the amount can be at least about 1 Gray (Gy) fractions at least once every other day to a treatment volume. In a particular embodiment, the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume. Ln another particular embodiment, the radiation is administered in at least about 2 Gray (Gy) fractions at least once per day to a treatment volume for five consecutive days per week In another particular embodiment, radiation is administered in 10 Gy fractions every other day, three times per week to a treatment volume. In another particular embodiment, a total of at least about 20 Gy is administered to a patient in need thereof. In another particular embodiment, at least about 30 Gy is administered to a patient in need thereof. In another particular embodiment, at least about 40 Gy is administered to a patient in need thereof.
[00250] Typically, the patient receives external beam therapy four or five times a week. An entire course of treatment usually lasts from one to seven weeks depending on the type of cancer and the goal of treatment For example, a patient can receive a dose of 2 Gy/day over 30 days.
[00251] Internal radiation therapy is localized radiation therapy, meaning the radiation source is placed at the site of the tumor or affected area. Internal radiation therapy can be delivered by placing a radiation source inside or next to the area requiring treatment. Internal radiation therapy is also called brachytherapy. Brachytherapy includes intracavitary treatment and interstitial treatment. In intracavitary treatment, containers that hold radioactive sources are put in or near the tumor. The sources are put into the body cavities. In interstitial treatment, the radioactive sources alone are put into the tumor. These radioactive sources can stay in the patient permanently. Typically, the radioactive sources are removed from the patient after several days. The radioactive sources are in containers.
[00252] There are a number of methods for administration of a radiopharmaceutical agent For example, the radiopharmaceutical agent can be administered by targeted delivery or by systemic delivery of targeted radioactive conjugates, such as a radiolabeled antibody, a radiolabeled peptide and a liposome delivery system. In one particular embodiment of targeted delivery, the radiolabelled pharmaceutical agent can be a radiolabelled antibody. See, for example, Ballangrud A. M., et al. Cancer Res., 2001; 61 :2008-2014 and Goldenber, D.M. J. Nucl. Med., 2002; 43(5):693-713, the contents of which are incorporated by reference herein.
[00253] In another particular embodiment of targeted delivery, the radiopharmaceutical agent can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. See, for example, Emfietzoglou D, Kostarelos K, Sgouros G. An analytical dosimetry study for the use of radionuclide-liposome conjugates in internal radiotherapy. J Nucl Med 2001; 42:499-504, the contents of which are incorporated by reference herein.
[00254] In yet another particular embodiment of targeted delivery, the radiolabeled pharmaceutical agent can be a radiolabeled peptide. See, for example, Weiner RE, Thakur ML. Radiolabeled peptides in the diagnosis and therapy of oncological diseases, Appl Radiat Isot 2002 Nov;57(5):749-63, the contents of which are incorporated by reference herein.
[00255] In addition to targeted delivery, brachytherapy can be used to deliver the radiopharmaceutical agent to the target site. Brachytherapy is a technique that puts the radiation sources as close as possible to the tumor site. Often the source is inserted directly into the tumor. The radioactive sources can be in the form of wires, seeds or rods. Generally, cesium, iridium or iodine are used.
[00256] Systemic radiation therapy is another type of radiation therapy and involves the use of radioactive substances in the blood. Systemic radiation therapy is a form of targeted therapy. In systemic radiation therapy, a patient typically ingests or receives an injection of a radioactive substance, such as radioactive iodine or a radioactive substance bound to a monoclonal antibody.
[00257] A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, flie non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.
[00258] As used herein, a “metallic radioisotope” is any suitable metallic radioisotope useful in a therapeutic or diagnostic procedure in vivo or in vitro. Suitable metallic radioisotopes include, but are not limited to: Actinium-225, Antimony- 124, Antimony- 125, Arsenic-74, Barium- 103, Barium-140, Beryllium-7, Bismuth-206, Bismuth-207, Bismuth212, Bismuth213, Cadmium-109, Cadmium- 115m, Calcium-45, Cerium- 139, Cerium-141, Cerium-144, Cesium- 137, Chromium-51, Cobalt-55, Cobalt-56, Cobalt-57, Cobalt-58, Cobalt-60, Cobalt-64, Copper-60, Copper-62, Copper-64, Copper-67, Erbium- 169, Europium-152, Gallium-64, Gallium-67, Gallium-68, Gadoliniuml53, Gadolinium- 157 Gold-195, Gold-199, Hafnium-175, Hafnium-175-181, Holmium- 166, Indium-110, Indium- Ill, Iridium- 192, Iron 55, Iron-59, Krypton85, Lead-203, Lead-210, Lutetium-177, Manganese-54, Mercury-197, Mercury203, Molybdenum-99, Neodymium- 147, Neptunium- 237, Nickel-63, Niobium95, Osmium- 185+191, Palladium-103, Palladium- 109, Platinum- 195m, Praseodymium-143, Promethium-147, Promethium-149, Protactinium-233, Radium- 226, Rhenium- 186, Rhenium- 188, Rubidium-86, Ruthenium-97, Ruthenium-103, Ruthenium- 105, Ruthenium-106, Samarium-153, Scandium-44, Scandium-46, Scandium-47, Selenium-75, Silver- 110m, Silver-111, Sodium-22, Strontium-85, Strontium-89, Strontium- 90, Sulfur-35, Tantalum-182, Technetium-99m, Tellurium-125, Tellurium- 132, Thallium- 204, Thorium-228, Thorium-232, Thallium- 170, Tin-113, Tin-114, Tin-117m, Titanium-44, Tungsten-185, Vanadium-48, Vanadium-49, Ytterbium- 169, Yttrium-86, Yttrium-88, Yttrium-90, Yttrium-91, Zinc-65, Zirconium-89, and Zirconium-95. [00210] As used herein, a “non-metallic radioisotope” is any suitable nonmetallic radioisotope (non-metallic radioisotope) usefill in a therapeutic or diagnostic procedure in vivo or in vitro. Suitable non- metallic radioisotopes include, but are not limited to: Iodine- 131, Iodine-125, Iodine-123, Phosphorus-32, Astatine-211, Fluorine- 18, Cafbon-11, Oxygen- 15, Bromine-76, and Nitrogen-13.
[00259] Identifying the most appropriate isotope for radiotherapy requires weighing a variety of factors. These include tumor uptake and retention, blood clearance, rate of radiation delivery, half-life and specific activity of the radioisotope, and the feasibility of large-scale production of the radioisotope in an economical fashion. The key point for a therapeutic radiopharmaceutical is to deliver the requisite amount of radiation dose to the tumor cells and to achieve a cytotoxic or tumoricidal effect while not causing unmanageable side-effects.
[00260] The physical half-life of the therapeutic radioisotope can be similar to the biological half-life of the radiopharmaceutical at the tumor site. For example, if the half-life of the radioisotope is too short, much of the decay will have occurred before the radiopharmaceutical has reached maximum target/background ratio. On the other hand, too long a half-life could cause unnecessary radiation dose to normal tissues. Ideally, the radioisotope should have a long enough half-life to attain a minimum dose rate and to irradiate all the cells during the most radiation sensitive phases of the cell cycle. In addition, the half-life of a radioisotope has to be long enough to allow adequate time for manufacturing, release, and transportation.
[00261] Other practical considerations in selecting a radioisotope for a given application in tumor therapy are availability and quality. The purity has to be sufficient and reproducible, as trace amounts of impurities can affect the radiolabeling and radiochemical purity of the radiopharmaceutical.
[00262] The target receptor sites in tumors are typically limited in number. As such, it is preferred that the radioisotope have high specific activity. The specific activity depends primarily on the production method. Trace metal contaminants can be minimized as they often compete with the radioisotope for the chelator and their metal complexes compete for receptor binding with the radiolabeled chelated agent. The type of radiation that is suitable for use in the methods of the present disclosure can vary. For example, radiation can be electromagnetic or particulate in nature. Electromagnetic radiation usefill in the practice of this disclosure includes, but is not limited to, X-rays and gamma rays. Particulate radiation useful in the practice of this disclosure includes, but is not limited to, electron beams (beta particles), protons beams, neutron beams, alpha particles, and negative pi mesons. The radiation can be delivered using conventional radiological treatment apparatus and methods, and by intraoperative and stereotactic methods. Additional discussion regarding radiation treatments suitable for use in the practice of this disclosure can be found throughout Steven A. Leibel et al., Textbook of Radiation Oncology (1998) (publ. W. B. Saunders Company), and particularly in Chapters 13 and 14. Radiation can also be delivered by other methods such as targeted delivery, for example by radioactive “seeds,” or by systemic delivery of targeted radioactive conjugates. J. Padawer et al., Combined Treatment with Radioestradiol lucanthone in Mouse C3HBA Mammary Adenocarcinoma and with Estradiol lucanthone in an Estrogen Bioassay, Int. J. Radiat. Oncol. Biol. Phys. 7:347-357 (1981). Other radiation delivery methods can be used in the practice of this disclosure.
[00263] For tumor therapy, both D and E-particle emitters have been investigated. Alpha particles are particularly good cytotoxic agents because they dissipate a large amount of energy within one or two cell diameters. The E-particle emitters have relatively long penetration range (2-12 mm in the tissue) depending on the energy level. The long-range penetration is particularly important for solid tumors that have heterogeneous blood flow and/or receptor expression. The E-particle emitters yield a more homogeneous dose distribution even when they are heterogeneously distributed within the target tissue.
[00264] In a particular embodiment, therapeutically effective amounts of crystalline form or pharmaceutical compositions described herein are administered in combination with a therapeutically effective amount of radiation therapy to treat cancer (e.g., lung cancer, such as non-small cell lung cancer). The amount of radiation necessary can be determined by one of kill in the art based on known doses for a particular type of cancer. See, for example, Cancer Medicine 5th ed., Edited by R.C. Bast et al., July 2000, BC Decker.
Synthetic Methods
[00265] Also provided herein are synthetic methods for preparing the compound represented by Structural Formula 1 and its crystal forms:
[00266]
Figure imgf000063_0001
EXEMPLIFICATION
General Materials and Methods
[00267] As used herein, compound of Structural Formula 1 is the compound represented by the following structural formula
Figure imgf000064_0001
XRPD
[00268] “Prominent Peaks” are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.
[00269] If multiple diffraction patterns are available, then assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks.” In general, the more data collected to determine Representative Peaks, the more confident one can be of the classification of those peaks.
[00270] “Characteristic peaks,” to the extent they exist, are a subset of Representative Peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ±0.2° 2θ. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
[00271] X-Ray Powder Diffraction patterns were collected on a Broker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm. A weekly performance check is carried out using a certified standard NIST 1976 Corundum (flat plate).
[00272] The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm A θ-θ continuous scan mode was employed with a sampledetector distance of 20 cm which gives an effective 2θ range of 3.2°-29.7°. Typically the sample was exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP/20004.1.43 and the data were analyzed and presented using Diffrac Plus EVA v15.0.0.0.
[00273] Ambient conditions: Samples were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
[00274] Non-ambient conditions: Samples run under non-ambient conditions were mounted on a silicon wafer with heat-conducting compound. The sample was then heated to the appropriate temperature at 20 °C/min and subsequently held isothermally for 1 minute before data collection was initiated.
[00275] Additionally, X-ray Powder Diffraction patterns were collected on a Broker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA), 0-2θ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The instrument was performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analyzed and presented using Diffrac Plus EVA vlS.0.0.0.
[00276] Samples were run under ambient conditions as flat plate specimens using powder as received. The sample was gently packed into a cavity cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are:
Angular range: 2 to 42° 2θ;
Step size: 0.05° 2θ;
Collection time: 0.5 s/step.
TGA
[00277] TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto- sampler. The instrument was temperature calibrated using certified Alumel and Nickel. Typically 5-10 mg of each sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample.
[00278] The instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3 and the data were analyzed using Universal Analysis v4.5A.
DSC
[00279] DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium. Typically 0.5- 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 280 °C. A purge of dry nitrogen at 50 ml/min was maintained over the sample.
[00280] The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3 and the data were analysed using Universal Analysis v4.5A.
DVS
[00281] Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by DVS Intrinsic Control software vl.0.1.2 ( or v 1.0.1.3). The sample temperature was maintained at 25 °C by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min. The relative humidity (RH) was measured by a calibrated Rotronic probe (dynamic range of 1.0 -100 % RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by the microbalance (accuracy ±0.005 mg). [00282] Typically 5 - 20 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25 °C (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans giving 1 complete cycle). The standard isotherm was performed at 25 °C at 10% RH intervals over a 0-90% RH range. Data analysis was carried out using Microsoft Excel using DVS Analysis Suite v6.2 (or 6.1 or 6.0).
[00283] Table 1. Method for SMS DVS Intrinsic experiments
Figure imgf000066_0001
Figure imgf000067_0002
[00284] The sample was recovered after completion of the isotherm and re-analyzed by XRPD.
1HNMR
[00285] NMR spectra were collected on a Broker 400MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running with Topspin vl.3 using the standard Broker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone. Samples were prepared in DMSO-d6, unless otherwise stated. Off-line analysis was carried out using ACD Spectres Processor 2012.
[00286] Example 1 - Preparation and characterization of crystalline Form I of the compound represented by Structural Formula 1
[00287] The compound of Structural Formula (1) can be synthesized according to the procedure described in the International Application PCT/US22/30294, filed on May 20, 2022, the teachings of which are incorporated herewith in their entirety. Briefly, the compound of Formula (1) can be synthesized by the following sequence of reactions:
Figure imgf000067_0001
Figure imgf000068_0001
[00288] Once the compound of Structural Formula (1) is prepared and isolated as a solid, its crystalline forms can be obtained as follows.
[00289] In one example embodiment, the crude material (a compound of Structural Formula (1)) was dissolved in hot methyl isobutyl ketone (MIBK) (with a possible treatment with SiliaMetS® DMT, the silica-bound 2,4,6 - trimercaptotriazine (trithiocyanuric acid, TMT)), filtered and then concentrated to precipitate out the product, which was then filtered off and dried to provide the crystalline Form I. From 20 to 40 parts of MIBK per one part of the solid can be used to dissolve the starting material. Isolation can be accomplished at temperatures from 0-5 °C to room temperature.
[00290] In another example embodiment, crude compound of Structural Formula (1) was charged to a reactor followed by 25 weights of methylisobutylketone (MIBK). The compound of Formula (1) was dissolved by heating to 65-70°C. Upon verification of a solution, a slurry of SiliaBond® DMT (Si-DMT) (the silica-bound equivalent of 2,4,6- trimercaptotriazine (trithiocyanuric acid)) was charged. The slurry was mixed at 65-70°C for 4 hours. Following completion, the slurry was polish filtered to remove the scavenger. The scavenger cake was washed with MIBK pre-heated to 65-70°C. The solution was then cooled to 20-30°C and distilled to 4-5 volumes. The slurry was heated to 55-60°C, held for 2 hours, and then slowly cooled to 0-5°C over at least 2 hours. After a hold of at least 1 hour at 0-5°C the crystalline Form I of the compound of Structural Form (1) was isolated by filtration. [00291] The synthetic procedure of the International Application PCT/US22/30294 can be carried out as follows.
[00292] Step 1
[00291] Step 1 involves the preparation of the acrylamide represented by the chemical structure referenced as KPT-9508/MB3 in the scheme reproduced below.
Isobutylchloroformate is used to generate the mixed anhydrides that are then quenched in ammonium hydroxide to provide MB3/KPT-9508. The details of the reaction scheme are as follows:
Figure imgf000069_0001
[00294] To a 558 L glass lined conical bottom vessel equipped with sulfuric acid scrubber and inerted under nitrogen was charged ammonium hydroxide (29.653 kg 26% w/w aqueous solution) and the solution temperature adjusted to 0-5 °C (internal temperature 8.4 °C to 3.0 °C for 11 hours 36 minutes).
[00295] A separate 206 L glass lined vessel, inerted under nitrogen was charged with 2- MeTHF (24.0 kg) which was heated at reflux for 30 minutes to dry the glass vessel and condenser assembly. The vessel and contents were adjusted to < 30 °C, then the 2-MeTHF sampled for IPC (the first sample showed residual water of 0.2% w/v with a target of <0.1 % w/v so the reflux was repeated with additional 2-MeTHF). The vessel was drained and then dried under vacuum. [00296] To the 206L vessel was charged KG1 (KPT-454, 15.5 kg), and 2-MeTHF (77.1 kg), then the batch was agitated and adjusted to 0-5 °C (internal temperature 15.5 °C to 0.7 °C over 15 minutes) to form a solution. The subsequent additions of isobutyl chloroformate and N-methyl morpholine followed by quenching in ammonium hydroxide required completion within a maximum of 4 hours (actual time 3 hours 5 minutes). Isobutyl chloroformate (12.1 kg) was charged while maintaining a temperature of 0-5 °C (temperature range of 0.0 °C to 1.0 °C for 25 minutes) and the addition equipment rinsed forward with 2-MeTHF (8.1 kg). N-methyl morpholine (8.9 kg, pre-cooled to 4-8 °C) was charged while maintaining a temperature of 0-5 °C (temperature range 0.4 °C to 5.6 °C over 25 minutes) and the addition equipment rinsed forward with 2-MeTHF (5.4 kg). The batch was agitated for a period of 30-45 minutes (35 minutes, internal temperature 1.8 °C to 0.5 °C).
[00297] While maintaining a temperature of 0-5 °C, the batch was transferred to the first vessel containing ammonium hydroxide with vigorous agitation, while maintaining a temperature of 0-10 °C in the receiving vessel (temperature range of 0.1 °C to 9 .1 °C over a range of 40 minutes). The reaction mixture from the second vessel was rinsed into the first vessel with 2-MeTHF (13.1 kg), agitated for 30 minutes at 4.3 °C, and then sampled for IPC (Residual KG1+KG5 wrt MB3+MC8 was 2% a/a with target of NMT 2% a/a). The batch was then adjusted to a temperature of 20-25 °C (53 minutes, internal temperature 1.7 °C to 20.4 °C). Agitation was stopped for 49 minutes to allow for phase separation and the lower aqueous phase was drained and discarded (separation time 58 minutes, interface with organic layer, upper organic phase 140 L, lower aqueous phase 20 L). Water (77.5 kg) was charged while maintaining a temperature of 20-25 °C (temperature range 22.2 °C to 24.3 °C for 40 minutes), and agitated for 20 minutes. Agitation was then stopped for 45 minutes to allow for phase separation and the lower aqueous phase was drained and discarded (separation time 35 minutes, interface with aqueous layer, upper organic phase 144 L, lower aqueous phase 86 L).
[00298] The batch was cooled to 0-5 °C (from 22.5 °C to 3.3 °C for 65 minutes) and placed under vacuum, then gradually warmed to a temperature of 17.3 °C and distilled to a target volume of 57-62 L (visual volume 61 L, dip volume measured at 57 L) over 3 hours 10 minutes. N-heptane (10.5 kg) was charged over 30 minutes at a temperature of 20.7 °C to 21.7 °C, then agitated for 1 hour to crystallize the product. The presence of solids was verified visually, then further n-heptanes (94.9 kg) was charged in 1 hour over a temperature range of 22.2 °C to 22.5 °C. [00299] The batch was isolated by filtration through 20 cfin polyester filter cloth with cotton backing cloth (filtration time of 2 hours 20 minutes held at 22.5 °C on SRF filter), then the filtrate was returned to the vessel and re-filtered over 1 hour and 24 minutes at 22.2 °C to rinse forward the remaining solids. The filter cake was washed with n-heptane (21.2 kg in two portions - filtration times of 15, and 17 minutes), then de-liquored (2 hours) and dried under a stream of nitrogen (58 hours, ambient temperature). IPC analysis showed the LOD to be 1.4% w/w at 58 hours with a limit of NMT 5% w/w, and the product was packaged to provide 12.4 kg, 80% yield of KPT-9508. The isolated product conformed to the HPLC standard for this compound.
[00300] The HPLC conditions were as follows:
Apparatus:
1. UPLC column: Agilent Zorbax SB-CN, 3.0 x 100 mm. 1.8 μm
2. Detector: 260 nm
3. Column temp: 50 °C
4. Mobile phase: A: 0.1% TFA in H20
B: 50% ACN : 45% MeOH : 5%H20
5. Flow rate: 0.5 ml/min
6. Injection volume: 5 μL
7. Run time: 32 minutes
8. Gradient: Time (min) %A %B
0.0 75 25
5.0 75 25
21.0 55 45
22.0 30 70
28.0 30 70
28.1 75 25
32.0 75 25
9. Dissolution Solvent (DS): 75% ACN: 25% H2O + 0.1% TFA
10. Purge solvent: 50% ACN: 50% H2O
11. Needle Wash: 50% ACN: 50% H2O
12. Thermo Scientific 'Targer' all-plastic disposable Luer-Lok syringe, 3 ml or equivalent (must be compatible with ACN/H2O DS)
13. 0.2 μm PTFE filter
14. BECTON DICKINSON & CO. (8-D) prepackaged needle or equivalent Reagents and Standards:
1. Acetonitrile (ACN), Methanol (MeOH), Water (H2O), HPLC grade or equivalent
2. Trifluoroacetic Acid (TFA), reagent grade or equivalent
3. MB3 Resolution Standard: 1393-ES-038-1(Contain Unk-1=0.04%, MC8=10%, KG1=0.4%, KG5:0.4%) or equivalent
[00301] Step 2
[00302] Step 2 consists of two telescoped conversions to form the dibrominated mixture of isomers ME2/KPT-9515 + ME3/KPT-9506 (Step 2a below) which is then dehydrobrominated to form the intermediate mixture of isomers MB5/KPT-7538 + MB9/KPT-9507 (Step 2b).
[00303] Step 2a Scheme
Figure imgf000072_0001
[00304] In a 2 L three-neck round bottom flask fitted with overhead agitation, thermometer, addition funnel and nitrogen bubbler was charged 14.69 g of NaBr and 110 mL of acetic acid. The contents of the batch were agitated at ambient temperature. The batch was charged with 45.6 g of bromine. The addition funnel was rinsed forward with 110 mL of acetic acid. In a separate 500 mL three-neck flask was charged 55 g of MB3 and 220 mL of acetic acid. The contents of the 500 mL flask were agitated at ambient temperature to form a solution.
[00305] The contents of the 500 mL vessel were charged via addition funnel into the 2L vessel over a period of 1 hour while maintaining the internal temperature in the range of 20- 30 °C. The addition funnel was rinsed forward with 110 mL of acetic acid. The batch was further agitated at 20-30 °C for a minimum period of 16 hours.
[00306] The batch was charged with 275 mL of 10% w/v sodium bisulfite solution over a minimum period of 30 minutes while maintaining an internal temperature of 20-30 °C. The batch was charge with 275 mL of water over a period of 5 minutes while maintaining an internal temperature of 20-30 °C. The batch was further agitated at 20-30 °C for a minimum period of 60 minutes. An aliquot of the batch in removed and observed for the presence of residual bromine. The complete reduction of bromine was observed by the presence of a white to off-white suspension.
[00307] The contents of the batch were then filtered through Whatmann paper (70 mm) on a Buchner funnel under reduced pressure. The filter cake was washed with 220 mL of water in two approximately equal portions. The collected cake was maintained under reduced pressure for a minimum period of 15 minutes at 20-30 °C. The intermediate ME2 product was obtained with a crude mass of 102.13 g and HPLC purity against developed standards of ME2: 86.0% a/a and ME3: 9.5% a/a.
[00308] Step 2b Scheme
Figure imgf000073_0001
[00309] A 500 mL three neck round bottom flask was equipped with a thermometer, overhead stirrer and nitrogen inlet. The flask was charged with 25 g of ME2 (49 mmol; 1.0 eq.) and 140 mL of ACN (8 parts with respect (wrt) to MB3) and 70 mL of water (4 parts with respect to MB3). To a separate 100 mL round-bottom flask was charged 8.6 mL of DIPEA (49 mmol, 1.0 eq. wrt MB3) and 52 mL of ACN (3 parts wrt MB3). The mixture was agitated for 20-30 minutes. With vigorous agitation, the DIPEA solution was added portion wise to the suspension of ME2 over a period of 1.0 to 1.5 hours. The addition assembly was rinsed forward with 9 mL of ACN (0.5 parts wrt MB3). The batch was agitated for 2-3 hours at 20-25 °C. IPC testing was performed and the IPC target was met (target: residual ME2 wrt MB5 is no more than (NMT) 0.3% a/a).
[00310] The resulting suspension was filtered using filter paper. The filter cake was washed with 34 mL of 8:2 ACN/H2O mixture (2 parts wrt MB3). The filter cake was washed with 34 mL of ACN (2 parts wrt MB3). The filter cake was dried by nitrogen purge with aspirator suction for 20 hours. The isolated product was a white solid and the purity was assessed by HPLC under the following protocol:
Apparatus:
1. UPLC column: Agilent Zorbax SB-CN, 3.0 x 100 mm, 1.8 μm 2. Detector: 260 nm
3. Column temp: 50 °C
4. Mobile phase: A: 0.1% TFA in H2O
B: 50% ACN: 45% MeOH: 5%HiO
5. Flow rate: 0.5 ml/ min
6. Injection volume: 4 μL
7. Run time: 35 minutes
8. Gradient: Time (min) %A %B 0.0 75 25
5.0 75 25
21.0 55 45
25.0 30 70
30.0 30 70
31.0 75 25
35.0 75 25
9. Dissolution Solvent (DS): DMSO
10. Purge solvent: 50% ACN : 50% H2O
11. Needle Wash: 50% ACN : 50% H2O
12. Thermo Scientific 'Targer' all-plastic disposable Luer-Lok syringe, 3 ml or equivalent (must be compatible with ACN/H2O DS)
13. 0.2 μm PTFE filter
14. BECTON DICKINSON & CO. (B-D) prepackaged needle or equivalent
Reagents and Standards:
1. Acetonitrile (ACN), Dimethylsulfoxide (DMSO), Methanol (MeOH), Water (H2O), HPLC grade or equivalent
2. Trifluoroacetic Acid (TFA), reagent grade or equivalent.
3. KG1 impurity standard: 03-STD-061 or equivalent
4. KG5 impurity standard: 1267-0-101-1 or equivalent.
5. MB3 impurity standard: 1393-ES-038-1 or equivalent
6. ME2 impurity standard: 1389-NN-130-1 or equivalent
7. ME3 impurity standard: KP9506-C-1-A or equivalent
8. MB5 Resolution Standard: 1389-NN-174-1(ContainUnk-1=0.14%, MC8=0.13%, MB9=3.4%) or equivalent. Duplicate runs resulted in isolated yields of 86.0% and 90.7% having 99.2% a/a and 99.2% a/a respectively. [00311] Step 3
Figure imgf000075_0001
[00312] The following is a description of a scalable process for the manufacture of compound 5, (E)-3-(3-(3,5- bis(trifluoromethyl)phenyl)-1H- 1 ,2,4-triazol-1 -yl)-2-(pyrimidin-5-yl)acrylamide (MB6/KPT-
8602). [00313] The following HPLC protocol can be used.
Apparatus:
1. UPLC column: Agilent Zorbax SB-CN, 3.0 x 100 mm. 1.8 μm
2. Detector: 260 nm
3. Column temp: 50°C
4. Mobile phase: A: 0.1% TFA in H2O B: 50% ACN: 45% MeOH: 5% H2O
5. Flow rate: .05 mL/min
6. Injection volume: 4 μL Run time: 35 minutes
8. Gradient: Time (min) %A %B 0.0 75 25 5.0 75 25 21.0 55 45 25.0 30 70 30.0 30 70 31.0 75 25 35.0 75 25
9. Dissolution Solvent (DS): (75% ACN: 25% H2O) + 0.1% TFA
10. Purge solvent: 50% ACN: 50% H2O
11. Needle Wash: 50% ACN: 50% H2O
12. Thermo Scientific ‘Targer’ all-plastic disposable Luer-Lok syringe, 3 mL or equivalent (must be compatible with ACN/ H2O DS)
13. 0.2 μm PTFE filter
14. BECTON DICKINSON & CO. (B-D) prepackaged needle or equivalent
Reagents and Standards:
1. Acetonitrile (ACN), Methanol (MeOH), Water (H2O), HPLC grade or equivalent
2. Trifluoroacetic acid (TFA), reagent grade or equivalent
3. MB3 (KPT-9508) impurity standard: use current reference standard
4. MC8 (KPT-9505) impurity standard: use current reference standard
5. KG1 (KPT-454) impurity standard: use current reference standard
6. KF9 (KPT-452) impurity standard: use current reference standard
MC0 (KPT-8781) impurity standard: use current reference standard
8. MB6 (KPT-8602) reference standard: use current reference standard
[00314] In another embodiment, instead of palladium tetrakistriphenylphosphine, a more robust and selective Pd catalyst (i.e. Strem amphos palladacycle gen. 2 (Cat #46-0342)) was used.
[00315] The process has been carried out at 15.5 g scale in demonstration experiments and successfully generated 81-86% overall yields of compound 5 (MB6 (KPT-8602) as represented by Structural Formula (VII)) as crystalline Form I. Purity of the product was very good (HPLC purity was 100% a/a) with acceptable levels of Pd and boronic acid MB7. [00316] GENERAL REACTION CONDITIONS STEP 3: The following reaction conditions were used: about 1.0 eq. MB5, about 2.0 eq. MB7, about 0.5 eq. Cs2CO3, about 24 parts of degassed dioxane:H2O 7: 1 v/v, 2 mol% Strem amphos palladacycle gen. 2 (Cat #46- 0342), 7-7.5 hours at 55-60 °C. All eq. are with respect to (wrt) MB5.
[00317] ISOLATION OF METHANOLATE (FORM VI)-GENERAL PROCEDURE 1:A general isolation procedure for Form VI (methanolate precursor to the final Form I) is as follows: After the 7-7.5 hour reaction time at 55-60 °C (see general reaction conditions above), the reaction mixture is adjusted to about 40-45 °C followed by charging of a slurry of celite (about 0.5 parts wrt MB5) and dioxane:water at about 7: 1 v/v (about 2.5 parts wrt MB5). The resulting suspension is agitated at about 40-45 °C for about 15-20 min. The reaction mixture is filtered and the filter cake washed with dioxane:water about 7: 1 v/v (at about 40-45 °C, about 3 parts wrt MB5). The resulting filtrate is subjected to vacuum distillation and is distilled to a target volume of about 4.5-5.5 parts wrt MB5. The resulting suspension is adjusted to an internal temperature of about 50-55 °C. The reaction mixture is then charged with MeOH (about 20 parts wrt MB5) portionwise. The suspension is then agitated at about 50-55 °C for about 60-70 min. The reaction mixture is then cooled to about 20-25 °C and then further cooled to about 0-5 °C over about 2-2.5 hours and is maintained at that temperature for a period of about 2-2.5 hours. The resulting suspension is then filtered and the filter cake washed with MeOH (about 10 parts wrt MB5). The cake is then dried.
[00318] ISOLATION OF FORM I- GENERAL PROCEDURE 2:
The dried filter cake from General Procedure 1 is then transferred to a flask equipped with an overhead stirrer, thermometer and nitrogen inlet and Si DMT (about 5 eq. wrt MB5) is charged to the flask. MIBK is then charged to the flask (about 25 parts wrt MB5). The reaction mix is then heated to an internal temperature of about 65-70 °C and maintained at that temperature for about 1-1.5 hours if no scavenger used and about 4-5 hours if scavenger is used. The reaction mixture is then filtered hot at about 65-70 °C into a clean flask equipped with an overhead stirrer, thermometer and nitrogen inlet The filter is washed with MIBK (at about 65-70 °C, about 1.0 part wrt MB5). With agitation, the filtrate is slowly cooled to about 20-30 °C over about 3-3.5 hours, and then distilled under vacuum to a target volume of about 3-4 parts wrt MB5. The batch temperature is adjusted to about 55-60 °C and the reaction mixture is agitated at 55-60 °C for about 2-2.5 hours. Then the suspension is cooled to about 0-5 °C over about 2-2.5 hours and is stirred at this temperature for a minimum of about 1 hour. The reactions mixture is then filtered and the resulting cake is washed with MIBK (about 1.0 part wrt MB5 at about 0-5 °C).
[00319] The general procedures above were followed on a 153g scale. Variations in the procedure (amounts used, temperatures, time, etc.) can occur while still obtaining a good yield and purity. Additional examples of isolation (General Procedure 1) and recrystallization conditions (General Procedure 2) are also provided below.
15.5 g SCALE OF GENERAL PROCEDURES 1 AND 2
[00320] A 500 mL four neck round bottom flask was equipped with an overhead stirrer, a thermometer, reflux condenser and N2 bubbler. The flask was flushed with nitrogen for a minimum of 30 minutes. Under a N2 flow, to the flask was charged with 15.5 g of compound 4 (MB5) (36.1 mmol, 1.0 eq.), 8.95 g of MB7 (72.2 mmol., 2.0 eq. wrt MB5), 5.88 g of Cs2CO3 (18.0 mmol., 0.5 eq. wrt MB5) and 0.415 g of Pd catalyst PT4 (Strem Amphos Palladacycle Gen. 2, cat. #46-0342, 0.72 mmol., 0.02 eq. wrt MB5), followed by charging 326 mL of degassed 1,4-dioxane (21 parts wrt MB5) and 47 mL of degassed water (3 parts wrt MB5).
With moderate agitation, the reaction mixture was then further degassed by bubbling nitrogen through it for a period of 60-70 minutes. The reaction mixture was then heated to an internal temperature of 55-60 °C, and was maintained at that temperature for a period of 7-7.5 hours. The reaction temperature was adjusted to 40-45 °C, and an IPC sample was taken. Upon completion, the reaction mixture was adjusted to 40-45 °C, followed by charging a slurry of 7.75 g of celite (0.5 parts wrt MB5) and 39 mL of dioxane: water 7:1 v/v (2.5 parts wrt MB5). The resulting suspension was agitated at 40-45 °C for 15-20 minutes. The reaction mixture was filtered and the filter cake was washed with 46.5 mL of pre-warmed dioxane:water 7:1 v/v (40-45 °C, 3 parts wrt MB5). The resulting filtrate was subjected to vacuum distillation and was distilled to a target volume of 70-85 mL (4.5-5.5 parts wrt MB5). The resulting thick suspension was adjusted to an internal temperature of 50-55 °C. To the reaction mixture at 50-55 °C was then charged 310 mL of MeOH (20 parts wrt MB5) portionwise. The suspension was then agitated at 50-55 °C for a period of 60-70 minutes. The reaction mixture was then cooled to 20-25 °C and then further cooled to 0-5 °C over 2-2.5 hours and was maintained at that temperature for a period of 2-2.5 hours. The resulting suspension was then filtered through a Buchner funnel using a Whatmann filter paper and the filter cake was washed with 155 mL of MeOH (10 parts wrt MB5). The cake was then dried under vacuum at 45-50 °C for about 4.5 hours. Crystalline Form VI (the methanolate) was obtained in 89% yield. Purity of the product was very good (HPLC purity was 99.3% to 99.4 area % with acceptable levels of Pd and boronic acid.
[00321] The dried filter cake was then transferred to a 500 mL three-necked round bottom flask equipped with an overhead stirrer, a thermometer and a nitrogen inlet, followed by charging 0.25 g of SiDMT (5 eq. wrt MB5 (230 ppm of residual Pd). [The following calculation can be used to determine, based on residual palladium level, how much DMT silica to charge. To calculate mm Pd in the product: Mmol Pd =ppm Pd x g product/106.42 x 100 and Scavenger Charge = mmol Pd x 4 eq./Scavenger loading (mmol/g).] To the solids was then charged 390 mL of 4-methyl-2-pentanone, also referred to herein as MIBK (25 parts wrt MB5). The reaction mixture was then heated to an internal temperature of 65-70 °C and maintained at that temperature for a period of 4-5 hours when scavenger treatment is conducted (if no scavenger treatment then 1-1.5 hours is sufficient). The reaction mixture was then filtered hot at 65-70 °C through a Buchner funnel (with a Whatmann filter paper) into a new 500 mL three-necked round bottom flask equipped with an overhead stirrer, a thermometer and a nitrogen inlet. The filter paper was then washed with 15 mL of prewarmed MIBK (65-70 °C, 1 part wrt MB5). With agitation the filtrate was slowly cooled to 20-30 °C over 3-3.5 hours, and then distilled under vacuum to a target volume of 50-55 mL (3-4 parts wrt MB5). The bath temperature was adjusted to 55-60 °C and the reaction mixture was agitated at 55-60 °C for 3-3.5 hours. The suspension was cooled to 0-5 °C over 2-2.5 hours and was stirred at the temperature for a minimum of 1.0 hour. The reaction mixture was then filtered through a Buchner funnel using a Whatmann filter paper. The cake was then washed with 15.5 mL of pre-cooled MIBK (1.0 part wrt MB5) at 0-5 °C. The filter cake was then dried in a vacuum oven at 48-53 °C for 1-2 hours to provide the product (crystalline Form I) as a solid. The overall yield was 81-86%, HPLC purity was 100.0 % a/a with acceptable level of Pd and boronic acid.
[00322] ISOLATION OF FORM I-GENERAL PROCEDURE 2A:
[00323] Crude MB6 methanolate Form VI is charged to a reactor followed by about 18 volumes of MIBK. The slurry is heated to about 80-85 °C to generate a solution. At this point, SiliaMetS®DMT (also referred to herein as SiDMT and being a silica-bound 2,4,6- trimercaptotriazme (trithiocyanuric, TMT) scavenger in about 1 volume of MIBK can be charged to the reactor for the removal of Pd. The use of this scavenger is optional. The solution (no scavenger) or slurry (with scavenger) is then mixed for a period of time. Once that time is complete, the solution/slurry is polish filtered hot to a clean reactor while maintaining a temperature of about 80-85 °C. 2 volumes of MIBK is then charged to the original reactor and heated to about 80-85 °C. Once at temperature the solvent is transferred to the batch via the polish filtration apparatus as a rinse of the reactor/filtration system. The solution is then cooled slightly to induce nucleation during a hold period. Following confirmed nucleation, the solids are crystallized via a controlled cooling crystallization with a final temperature of 0-5 °C. The slurry is held at this temperature for an appropriate time to complete crystallization and then the solids are isolated via filtration. About 2 volumes of MIBK are polish filtered to the reactor and cooled to about 0-5 °C. Once at temperature the wash is charged to the cake in two portions and pulled through the cake with suction. Following completion of the wash, the solids are dried and packaged.
17g SCALE OF GENERAL PROCEDURE 2A:
[00324] 17 g of crude MB6 (methanol solvate Form VI) was weighed into a 400 ml Easy max vessel. About 306 mL of 4-methyl-2-pentanone (MIBK; 18 V wrt MB6 methanolate) was added. The mixture was stirred moderately and warmed to about 80-85 °C to dissolve the solid. About 0.51 g of Si DMT (3%. wrt MB6 (methanolate Form VI) was charged to the vessel. About 18 mL of MIBK (2V X 0.51 g + IV rinse) was charged to the vessel. The mixture was stirred moderately for about 4.5 h at about 80-85°C. The reaction mixture was then filtered hot at about 80-85°C through a Buchner funnel (with a Whatmann filter paper) into a 500 mL erlenmeyer flask. The filter paper/SiDMT/Cs2CO3 was then washed with about 34 mL of pre-warmed 4-methyl-2-pentanone/MIBK (about 80-85 °C; about 2 V wrt MB6 as the methanolate Form VI). The easy max vessel was cleaned and the contents of the Erlenmeyer containing the filtrate and wash was warmed to about 80-85°C and put back in the easy max vessel. The batch temperature was adjusted to about 80-85 °C and the reaction mixture was agitated for about 30 min to reach dissolution. Then the solution was cooled to about 20-25 °C over a minimum of 3 hours. Then the suspension was cooled to about 0-5 °C over about 2-2.5 hours and was stirred at this temperature for a minimum of about 1.0 hour. The reaction mixture was then filtered through a Buchner funnel using a Whatmann filter paper.
[00325] The cake was then washed with about 34 mL of pre-cooled 4-methyl-2- pentanone/MIBK (about 2 vol wrt MB6 methanolate Form VI; at about 0-5 °C). The filter cake was then dried in a vacuum oven at about 25-30 °C for about 3 hours to provide the product as a white solid (% Yield 75%, Purity = 99.98% a/a). [00326] In some embodiments, crystalline Form I of the compound represented by Structural Formula 1 can be prepared as described above. The XRPD pattern of Form I of the compound represented by Structural Formula 1 is depicted in FIG. 1, and the peaks are tabulated in Table 2.
[00327] Table 2
Figure imgf000081_0001
[00328] Variable temperature XRPD studies were performed while heating crystalline Form I up to the melting point Upon cooling melt re-crystallized to form crystalline Form I with an identical XRPD pattern.
[00329] The TGA trace of crystalline Form I is depicted in FIG. 3. No weight change is observed from ambient temperature up to about 250 °C, followed by sample degradation. [00330] The DSC trace of crystalline Form I is depicted in FIG. 3. The DSC thermogram displays a sharp endothermic peak observed at approximately 225 °C, which corresponds to melting.
[00331] Lack of weight change observed upon heating of crystalline Form I to 250 °C, as well as absence of phase transitions and relatively high melting point demonstrated in the DSC experiment indicate favorable thermodynamic stability of Form I for pharmaceutical applications. Specifically, it is likely to be robust under heating due to compression forces of tablet manufacturing, and it is likely to have good thermal stability in tablet form, leading to long product shelf life.
[00332] The DVS pattern of crystalline Form I is depicted in FIG. 4. Two DVS cycles have been recorded. The DVS pattern displays a weight gain of about 0.12% at 90% RH and gradual reversible uptake over 0-90% RH range. XRPD pattern of crystalline Form I after the DVS cycle is identical to the XRPD of crystalline Form I prior to the DVS cycle.
[00333] Additionally, crystalline Form I exposed stored for one week at 97% RH at 25 °C and at 75% RH at 4025 °C. In both cases the XRPD patterns of crystalline Form I after the exposure were identical to the XRPD patterns of crystalline Form I before the exposure.
[00334] The minimal and reversible moisture uptake demonstrated by crystalline Form I, as well as stability upon storage at high relative humidity, is a physical property desirable in crystalline forms utilized in pharmaceutical compositions.
[00335] Example 2 - Preparation and characterization of crystalline Forms II-XIV of the compound represented by Structural Formula 1
[00336] Crystalline Forms II-XIV of the compound represented by Structural Formula 1 were obtained from crystalline Form I by maturation of suspensions of crystalline Form I in various solvents, as well as cooling, slow evaporation, or addition of antisolvents to solutions obtained in maturation and solubility studies of crystalline Form I according to the following protocols:
[00337] Crystalline Form I was treated with increasing volumes of different solvents until either the material fully dissolved or 100 volumes of solvent had been added. After each addition, the systems were shaken at 50 °C for 5 minutes. Samples obtained as suspensions were matured and samples obtained as clear solutions were cooled and, if no solid was produced, allowed to slowly evaporate as reported below.
[00338] Maturation RT-50 °C: suspensions obtained at 25 °C after the solubility assessment were shaken in the maturation chamber between 25 °C - 50 °C for 72 hours (8 hour cycles), then allowed to stand at room temperature for 10 min. The solids were recovered from the vial and analyzed by XRPD (see Table 3).
[00339] Cooling: clear solutions obtained after the solubility assessment or maturation were placed at 5 °C for 24 hours and then at -20 °C for 24 hours. Solids obtained were recovered from the vial and analyzed by XRPD (see Table 3).
[00340] Slow Evaporation: clear solutions were placed in vials for slow evaporation, a needle was inserted through the septum cap of the vials and the solvents were allowed to slowly evaporate under ambient conditions, either to dryness or until a solid appeared. The solids were recovered from the vial and analyzed by XRPD (see Table 3). Experiments using high-boiling solvents were uncapped to allow faster evaporation.
[00341] Antisolvent addition: stock solutions of crystalline Form I were prepared in 16 mL of THF and ethyl acetate by dissolving the sample at 50 °C. The solutions were filtered (0.45 μm PTFE) and dispensed into 4 mL vials, 1600 μL each vial (40 mg of crystalline Form I in
40 volumes). The systems were then treated with selected antisolvent and placed at 5 °C for
18 hours, followed by -20 °C for 18 hours. All the solids produced were analyzed by XRPD
(experiments details are summarized in Table 4).
Table 3.
Figure imgf000083_0001
Table 4.
Figure imgf000084_0001
[00342] The relationship between crystalline Forms II-XIV and crystalline Form I is shown in FIG. 38. Crystalline Forms II-XIV convert back to crystalline Form I either by exposure to 40 °C / 75 % RH for 1 week or by heating via DSC or variable temperature XRPD. Thermal analysis of crystalline Forms III- VII, IX, X, XIII, and XIV shows defined solvent loss step by TGA and an endothermic event by DSC associated with the solvent loss and conversion to crystalline Form I, which followed by the melting of crystalline Form I at 225-226 °C.
[00343] Crystalline Forms II-XI, XIII, and XVII comprise various solvates of the coinpound of Structural Formula 1, while Crystalline Form XII is a metastable solvent-free form which showed a limited stability at ambient conditions and easily converted to crystalline Form I. [00344] Table 5 summarizes characterization data for Crystalline Forms II-IX.
Table 5.
Figure imgf000084_0002
Figure imgf000085_0001
*All events recorded in the DSC thermograms are endothermic events; the indicated temperatures correspond to the maximum heat absorption on the thermogram.
XRPD peak listings for crystalline Forms II-XL XIII and XIV.
[00345] Crystalline Form II
Figure imgf000086_0001
[00346] Crystalline Form in
Figure imgf000086_0002
[00347] Crystalline Form IV
Figure imgf000087_0001
[00348] Crystalline Form V
Figure imgf000087_0002
[00349] Crystalline Form VI.
Figure imgf000087_0003
Figure imgf000088_0001
[00350] Crystalline Form VII.
Figure imgf000088_0002
[00351] Crystalline Form VIII.
Figure imgf000088_0003
[00352] Crystalline Form IX.
Figure imgf000088_0004
Figure imgf000089_0001
[00353] Crystalline Form X.
Figure imgf000089_0002
[00354] Crystalline Form XI.
Figure imgf000089_0003
Figure imgf000090_0001
[00355] Crystalline Form XIII.
Figure imgf000090_0002
[00356] Crystalline Form XIV.
Figure imgf000090_0003
INCORPORATION BY REFERENCE
[00357] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS
[00358] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS What is claimed is:
1. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000092_0001
wherein the crystalline form is Form II characterized by x-ray powder diffraction peaks at 2θ angles 21.7°, 22.0°, 22.7°, and 25.1°.
2. The crystalline form of claim 1, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 8.0°, 21.7°, 22.0°, 22.7°, and 25.1°.
3. The crystalline form of claim 1 or 2, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 8.0°, 16.2°, 21.7°, 22.0°, 22.7°, 24.1°, 25.1°, and 27.6°.
4. The crystalline form of any one of claims 1-3, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 5.
5. The crystalline form of any one of claims 1-4, wherein the compound of Structural Formula 1 is in the form of a solvate.
6. The crystalline form of claim 5, wherein the compound of Structural Formula 1 is a nitromethane solvate.
7. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000093_0001
wherein the crystalline form is Form III characterized by x-ray powder diffraction peaks at 2θ angles 6.5°, 17.5°, 21.2°, and 21.9°.
8. The crystalline form of claim 7, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 6.5°, 17.5°, 21.2°, 21.9°, and 22.1°.
9. The crystalline form of claim 7 or 8, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 6.5°, 10.6°, 17.5°, 20.6°, 21.2°, 21.9°, and 22.1°, 23.0°.
10. The crystalline form of any one of claims 7-9, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 6.
11. The crystalline form of any one of claims 7-10, wherein the crystalline form is characterized by a DSC thermogram having endothermic events at about 70 °C and at about 226 °C.
12. The crystalline form of any one of claims 7-11, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 7.
13. The crystalline form of any one of claims 7-12, wherein the compound of Structural Formula 1 is in the form of a solvate.
14. The crystalline form of claim 13, wherein the compound of Structural Formula 1 is a dimethoxyethane solvate.
15. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000094_0001
wherein the crystalline form is Form IV characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.5°, and 24.7°.
16. The crystalline form of claim 15, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 18.4°, 23.0°, 24.5°, and 24.7°.
17. The crystalline form of claim 15 or 16, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 18.4°, 20.5°, 23.0°, 23.7°, 24.5°, 24.7°, and 27.7°.
18. The crystalline form of any one of claims 15-17, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 9.
19. The crystalline form of any one of claims 15-18, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 99 °C and at about 225 °C.
20. The crystalline form of any one of claims 15-19, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 10.
21. The crystalline form of any one of claims 15-20, wherein the compound of Structural Formula 1 is in the form of a solvate.
22. The crystalline form of claim 21, wherein the compound of Structural Formula 1 is an 2 -propanol solvate.
23. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000095_0001
wherein the crystalline form is Form V characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.2°, and 24.7°.
24. The crystalline form of claim 23, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 23.0°, 24.5°, 24.7°, and 27.4°.
25. The crystalline form of claim 23 or 24, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 7.4°, 10.3°, 18.2°, 18.6°, 23.0°, 24.5°, 24.7°, and 27.4°.
26. The crystalline form of any one of claims 23-25, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 12.
27. The crystalline form of any one of claims 23-26, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 128 °C and at about 225 °C.
28. The crystalline form of any one of claims 23-27, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 13.
29. The crystalline form of any one of claims 23-28, wherein the compound of Structural Formula 1 is in the form of a solvate.
30. The crystalline form of claim 29, wherein the compound of Structural Formula 1 is an ethanol solvate.
31. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000096_0001
wherein the crystalline form is Form VII characterized by x-ray powder diffraction peaks at 2θ angles 16.0°, 21.4°, 22.6°, and 29.5°.
32. The crystalline form of claim 31, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 11.7°, 16.0°, 21.4°, 22.6°, and 29.5°.
33. The crystalline form of claim 31 or 32, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 8.1 °, 11.7°, 16.0°, 17.6°, 21.4°, 22.6°, 25.8°, and 29.5°.
34. The crystalline form of any one of claims 31-33, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 18.
35. The crystalline form of any one of claims 31-34, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 138 °C and at about 225 °C.
36. The crystalline form of any one of claims 31-35, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 19.
37. The crystalline form of any one of claims 31-36, wherein the compound of Structural Formula 1 is in the form of a solvate.
38. The crystalline form of claim 37, wherein the compound of Structural Formula 1 is an acetonitrile solvate.
39. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000097_0001
wherein the crystalline form is Form VIII characterized by x-ray powder diffraction peaks at 2θ angles 18.7°, 19.8°, 22.4°, and 26.0°.
40. The crystalline form of claim 39, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 18.7°, 19.8°, 20.3°, 22.4°, and 26.0°.
41. The crystalline form of claim 39 or 40, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 18.7°, 19.8°, 20.3°, 21.7°, 22.4°, 23.2°, 26.0°, and 29.1°.
42. The ciystalline form of any one of claims 39-41, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 21.
43. The ciystalline form of any one of claims 39-42, wherein the compound of Structural Formula 1 is in the form of a solvate.
44. The ciystalline form of claim 43, wherein the compound of Structural Formula 1 is a dichloromethane solvate.
45. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000098_0001
wherein the crystalline form is Form IX characterized by x-ray powder diffraction peaks at 2θ angles 8.1°, 18.5°, 20.8°, and 22.5°.
46. The crystalline form of claim 45, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 8.1°, 18.5°, 20.0°, 20.8°, and 22.5°.
47. The crystalline form of claim 45 or 46, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 8.1 °, 18.5°, 20.0°, 20.8°, 22.5°, 22.8°, 23.0°, and 26.4°.
48. The crystalline form of any one of claims 45-47, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 22.
49. The crystalline form of any one of claims 45-48, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 69 °C and at about 226 °C.
50. The crystalline form of any one of claims 45-49, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 23.
51. The crystalline form of any one of claims 45-50, wherein the compound of Structural Formula 1 is in the form of a solvate.
52. The crystalline form of claim 51, wherein the compound of Structural Formula 1 is a 2 -methyltetrahydrofuran solvate.
53. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000099_0001
wherein the crystalline form is Form X characterized by x-ray powder diffraction peaks at 2θ angles 5.6°, 16.8°, 23.2°, and 28.3°.
54. The crystalline form of claim 53, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 5.6°, 16.8°, 23.2°, 24.9°, and 28.3°.
55. The crystalline form of claim 53 or 54, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 4.6°, 5.6°, 11.2°, 16.8°, 23.2°, 24.9°, 27.9°, and 28.3°.
56. The crystalline form of any one of claims 53-55, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 25.
57. The crystalline form of any one of claims 53-56, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 136 °C and at about 225 °C.
58. The crystalline form of any one of claims 53-57, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 26.
59. The crystalline form of any one of claims 53-58, wherein the compound of Structural Formula 1 is in the form of a solvate.
60. The crystalline form of claim 59, wherein the compound of Structural Formula 1 is an acetic acid solvate.
61. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000100_0001
wherein the crystalline form is Form XI characterized by x-ray powder diffraction peaks at 2θ angles 7.7°, 16.2°, 20.2°, and 27.2°.
62. The crystalline form of claim 61, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 5.4°, 7.7°, 16.2°, 20.2°, and 27.2°.
63. The crystalline form of claim 61 or 62, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 5.4°, 7.7°, 16.2°, 20.2°, 23.8°, 24.2°, 25.5°, and 27.2°.
64. The crystalline form of any one of claims 61-63, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 28.
65. The crystalline form of any one of claims 61-64, wherein the compound of Structural Formula 1 is in the form of a solvate.
66. The crystalline form of claim 65, wherein the compound of Structural Formula 1 is a dimethyl sulfoxide solvate.
67. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000101_0001
wherein the crystalline form is Form XIII characterized by x-ray powder diffraction peaks at 2θ angles 4.9°, 14.7°, 19.6°, and 24.5°.
68. The crystalline form of claim 67, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 4.9°, 14.7°, 19.6°, 19.9°, and 24.5°.
69. The crystalline form of claim 67 or 68, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 4.9°, 14.2°, 14.7°, 19.6°, 19.9°, 24.5°, 25.5°, and 25.8°.
70. The crystalline form of any one of claims 67-69, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 32.
71. The crystalline form of any one of claims 67-70, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 129 °C and at about 226 °C.
72. The crystalline form of any one of claims 67-71, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 33.
73. The crystalline form of any one of claims 67-72, wherein the compound of Structural Formula 1 is in the form of a solvate.
74. The crystalline form of claim 73, wherein the compound of Structural Formula 1 is an acetone solvate.
75. A crystalline form of the compound represented by Structural Formula 1 :
Figure imgf000102_0001
wherein the crystalline form is Form XIV characterized by x-ray powder diffraction peaks at 2θ angles 6.4°, 8.1°, 19.8°, and 20.4°.
76. The crystalline form of claim 75, wherein the crystalline form is by at least four x-ray powder diffraction peaks at 2θ angles selected from 6.4°, 8.1°, 19.8°, 20.4°, and 27.3°.
77. The crystalline form of claim 75 or 76, wherein the crystalline form is characterized by at least five x-ray powder diffraction peaks at 2θ angles selected from 6.4°, 8.1°, 16.2°, 19.8°, 20.4°, 24.4°, 24.8°, and 27.3°.
78. The crystalline form of any one of claims 75-77, wherein the crystalline form is characterized by an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 35.
79. The crystalline form of any one of claims 75-78, wherein the crystalline form is characterized by a DSC thermogram having two endothermic events at about 86 °C and at about 226 °C.
80. The crystalline form of any one of claims 75-79, wherein the crystalline form is characterized by a DSC thermogram substantially in accordance with that depicted in FIG. 36.
81. The crystalline form of any one of claims 75-80, wherein the compound of Structural Formula 1 is in the form of a solvate.
82. The crystalline form of claim 81, wherein the compound of Structural Formula 1 is a tert-butanol solvate.
83. A composition, comprising particles of one or more crystalline forms of the compound represented by Structural Formula 1 :
Figure imgf000104_0001
wherein the one or more crystalline forms are selected from: crystalline Form II characterized by x-ray powder diffraction peaks at 2θ angles 21.7°, 22.0°, 22.7°, and 25.1°; crystalline Form in characterized by x-ray powder diffraction peaks at 2θ angles 6.5°, 17.5°, 21.2°, and 21.9°; crystalline Form IV characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.5°, and 24.7°; crystalline Form V characterized by x-ray powder diffraction peaks at 2θ angles 7.4°, 23.0°, 24.2°, and 24.7°; crystalline Form VII characterized by x-ray powder diffraction peaks at 2θ angles 16.0°, 21.4°, 22.6°, and 29.5°; crystalline Form VIII characterized by x-ray powder diffraction peaks at 2θ angles 18.7°, 19.8°, 22.4°, and 26.0°; crystalline Form IX characterized by x-ray powder diffraction peaks at 2θ angles 8.1°, 18.5°, 20.8°, and 22.5°; crystalline Form X characterized by x-ray powder diffraction peaks at 2θ angles 5.6°, 16.8°, 23.2°, and 28.3°; crystalline Form XI characterized by x-ray powder diffraction peaks at 2θ angles 7.7°, 16.2°, 20.2°, and 27.2°; crystalline Form XIII characterized by x-ray powder diffraction peaks at 2θ angles 4.9°, 14.7°, 19.6°, and 24.5°; and crystalline Form XIV characterized by x-ray powder diffraction peaks at 2θ angles 6.4°, 8.1°, 19.8°, and 20.4°.
84. A pharmaceutical composition, comprising the crystalline form of any one of claims 1-82 or a composition of claim 83 and a pharmaceutically acceptable carrier.
85. A method for treating or preventing a CRM 1 -associated disease or disorder, the method comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the crystalline form of any one of claims 1-82, a composition of claim 83, or a pharmaceutical composition of claim 84.
86. The method of claim 85, wherein the disorder is a proliferative disorder, cancer, an inflammatory disorder, an autoimmune disorder, a viral infection, an ophthalmological disorder, a neurodegenerative disorder, a disorder of abnormal tissue growth, a disorder related to food intake, an allergic disorder, or a respiratory disorder.
87. The method of claim 86, wherein the disorder is cancer.
88. The method of claim 87, wherein the cancer is selected from colorectal cancer, prostate cancer, myelodysplasia syndrome, naopharyngeal cancer and penile cancer..
89. The method of claim 88, wherein the cancer is myelopdysplastic syndrome.
90. The method of claim 89, wherein the myelodysplastic syndrome is recurrent/refractory.
91. The method of claim 88, wherein the cancer is penile cancer.
92. The method of claim 88, wherein the cancer is nasopharyngeal cancer.
93. A method for promoting wound healing in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1-82, a composition of claim 83, or a pharmaceutical composition of claim 84.
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