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WO2025137437A1 - Formes solides d'un modulateur du récepteur gabaa et leurs procédés d'utilisation - Google Patents

Formes solides d'un modulateur du récepteur gabaa et leurs procédés d'utilisation Download PDF

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Publication number
WO2025137437A1
WO2025137437A1 PCT/US2024/061265 US2024061265W WO2025137437A1 WO 2025137437 A1 WO2025137437 A1 WO 2025137437A1 US 2024061265 W US2024061265 W US 2024061265W WO 2025137437 A1 WO2025137437 A1 WO 2025137437A1
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Prior art keywords
compound
crystalline form
xrpd pattern
approximately
peaks
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Inventor
Andrew Hills
Shawn LACASSE
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • GABA Gamma-aminobutyric acid
  • (I) comprises the free base of Compound (I).
  • the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 13.9, 14.5, 16.9, 19.9, 20.1, and 25.0° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least one peak selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least two peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least three peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least four peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern comprising peaks at approximately 14.5, 16.9, and 19.9° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by NAI-1538907928v1 2 Jones Day Docket No.13371-344-228 an XRPD pattern that further comprises peaks at approximately 12.8, 13.9, and 20.1° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern that further comprises a peak selected from the group consisting of approximately 15.6, 22.0, and 23.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is designated as “Form 1” and is characterized by an XRPD pattern essentially as shown in FIG.1.
  • the crystalline form of Compound (I) exhibits a thermal event with an onset temperature of about 186 °C as characterized by DSC.
  • the crystalline form of Compound (I) exhibits a weight loss of about 0.21% upon heating from about 25 °C to about 200 °C.
  • the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks at approximately 8.5, 9.1, 11.5, 17.0, 18.2, 21.5, 23.6, and 24.0° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least one peak selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least two peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least three peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, further comprising at least four peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern comprising peaks at approximately 8.5, 9.1, and 17.0° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is designated as NAI-1538907928v1 3 Jones Day Docket No.13371-344-228 “Form 2” and is characterized by an XRPD pattern further comprises peaks at approximately 11.5, 11.8, and 18.2° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern further comprises a peak selected from the group consisting of approximately 14.2, 15.5, 21.5 and 22.4° 2 ⁇ ⁇ 0.2 °2 ⁇ . [0013] In one embodiment, the crystalline form of Compound (I) is designated as “Form 2” and is characterized by an XRPD pattern essentially as shown in FIG.2. [0014] In one embodiment, the crystalline form of Compound (I) comprises a sulfate salt of Compound (I).
  • the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least four peaks, each at a 2 ⁇ angle selected from the group consisting of approximately 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern comprising peaks at approximately 7.6, 13.2, and 24.3° 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the crystalline form of Compound (I) is characterized by an XRPD pattern further comprising peaks at approximately 17.5, 17.9, and 19.9° 2 ⁇ ⁇ 0.2 °2 ⁇ . In one embodiment, the crystalline form of Compound (I) is characterized by an XRPD pattern further comprising a peak selected from the group consisting of approximately 21.0, 21.4, 26.5, 26.7, and 27.7° 2 ⁇ ⁇ 0.2 °2 ⁇ . [0016] In one embodiment, the crystalline form of Compound (I) is a sulfate salt designated as “Form 3” and is characterized by an XRPD pattern essentially as shown in FIG.6.
  • the crystalline form of Compound (I) exhibits, as characterized by DSC, a thermal event with an onset temperature of about 209 °C. In one embodiment, the crystalline form of Compound (I) exhibits a weight loss of about 1.6% upon heating from about 50 °C to about 200 °C. In one embodiment, the crystalline form of Compound (I) exhibits a further weight loss of about 4% upon heating from about 200 °C to about 300 °C. [0017] In one embodiment, the crystalline form of Compound (I) is is anhydrous.
  • the present disclosure provides a composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3), wherein the chemical purity of the composition is at least about 98%. In one embodiment, the composition comprises not more than about 0.2% by weight of any single impurity.
  • the present disclosure provides a pharmaceutical composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) a composition comprising any crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprising carbamazepine.
  • the pharmaceutical composition is a solid intended for reconstitution prior to use.
  • the pharmaceutical composition is an oral dosage form.
  • the pharmaceutical composition is an oral tablet.
  • the present disclosure provides a method of treating a disorder for which a GABAA positive allosteric modulator is indicated in a subject comprising administering therapeutically effective amount of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof (or prepared therefrom) to the subject.
  • the present disclosure provides a method of treating pain in a subject comprising administering a therapeutically effective amount of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof (or prepared therefrom) to the subject.
  • the present disclosure provides a method of treating a panic disorder in a subject comprising administering a therapeutically effective of a crystalline form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) or a pharmaceutical composition thereof to the subject.
  • the pharmaceutical composition does not comprise carbamazepine and the method further comprising administering a therapeutically effective amount of carbamazepine to the subject.
  • the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in acetonitrile; (b) exchanging the acetonitrile for ethyl acetate; and (c) crystallizing Form 1 of Compound (I) from the ethyl acetate.
  • the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in acetonitrile; and (b) crystallizing Form 1 of Compound (I) from the acetonitrile.
  • the present disclosure provides a method for preparing the crystalline Form 1 of Compound (I), the method comprising: (a) dissolving Compound (I) in ethanol; and (b) crystallizing Form 1 of Compound (I) from the ethanol.
  • the present disclosure provides a method for preparing the crystalline Form 2 of Compound (I), the method comprising: (a) dissolving a Compound (I) in a 90:10 mixture of THF and water; and (b) rapidly evaporating the mixture of THF and water to form the crystalline form of the Compound (I).
  • FIG.1 is a representative X-ray powder diffraction (XRPD) pattern of Form 1 of Compound (I).
  • FIG.2 is a representative thermogravimetric analysis (TGA) thermogram of Form 1 of Compound (I).
  • FIG.3 is a representative differential scanning calorimetry (DSC) thermogram of Form 1 of Compound (I).
  • FIG.4 is an overlay of the 1 H NMR spectra of Form 1 of Compound (I) and Form 2 of Compound (I).
  • FIG.5 is a representative XRPD pattern of Form 2 of Compound (I).
  • FIG.6 is a representative XRPD pattern of Form 3 of Compound (I), which is a sulfate salt.
  • FIG.7 is a calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure of Form 1 of Compound (I).
  • FIG.8 is a representative DSC thermogram of Form 3 of Compound (I).
  • FIG.9 is a representative TGA thermogram of Form 3 of Compound (I).
  • DETAILED DESCRIPTION Provided herein are solid forms of Compound (I): N N , or a pharmaceutically the solid form is a crystalline form of the free .
  • the solid form is a crystalline form of a sulfate salt of Compound (I).
  • compositions comprising the same, methods of using it, use of it in combination with other therapeutic agents, methods of synthesizing the compound, and any data collected using Compound (I).
  • the solid forms of Compound (I) as disclosed herein may be any solid form, such as disclosed in Section 5.1. Such solid forms may be prepared as described in Section 5.2.
  • Compositions and pharmaceutical compositions as described in Section 5.3 may comprise a solid form of Compound (I) as described in any embodiment in Section 5.1.
  • compositions comprising the same may be used to treat a disease, disorder, or condition, such as pain or a panic disorder, in subject as described in Section 5.4 and in Section 5.5.
  • a disease, disorder, or condition such as pain or a panic disorder
  • the following terms used in this application, including the specification and claims, have the definitions given below.
  • All publications, patents and patent applications cited herein, whether supra or infra, are incorporated by reference in their entirety.
  • NAI-1538907928v1 7 Jones Day Docket No.13371-344-228 [0039]
  • chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.
  • Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art.
  • the data obtained by analyzing a sample of a solid via these techniques may be used to identify a particular solid form, because different solid forms, such as different crystal forms, will provide different diffraction patterns when analyzed by XRPD, the particular methods of which are described in greater detail in Section 6 (Examples), and in many cases will also provide different results when analyzed by DSC or TGA.
  • XRPD diffraction pattern
  • values of degrees 2 ⁇ derived from XRPD should therefore be understood as encompassing those deviations from the presented values that would be considered to be within experimental error.
  • the value of XRPD peak position may vary by up to ⁇ 0.5 degrees 2 ⁇ while still describing the particular XRPD peak, due to, for example, experimental error.
  • the value of XRPD peak position may vary by up to ⁇ 0.2 degrees 2 ⁇ while still describing the particular XRPD peak due to, for example, experimental error.
  • the value of XRPD peak position may vary by up to ⁇ 0.1 degrees 2 ⁇ due to, for example, experimental error.
  • the value of XRPD peak position may vary by up to ⁇ 0.05 degrees 2 ⁇ due to, for example, experimental error.
  • NAI-1538907928v1 8 Jones Day Docket No.13371-344-228 [0043] Unless otherwise indicated, the methods disclosed in the examples were used to characterize the various solid forms disclosed herein. [0044] The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.
  • Solid forms of Compound (I) which has a chemical name of 7-ethyl-4-(4'- (ethylsulfonyl)-6-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)-7H-imidazo[4,5-c]pyridazine, include crystalline solids and amorphous solids. Solid forms may be crystalline, amorphous, or mixtures of crystalline and amorphous forms. The crystal forms described herein, therefore, may have varying degrees of crystallinity or lattice order.
  • the solid forms described herein are not limited to any particular degree of crystallinity or lattice order and may be 0 – 100% crystalline. Methods of determining the degree of crystallinity are known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, N.J., 1995, pp.187 – 199, which is incorporated herein by reference in its entirety. [0046]
  • the solid forms provided herein may be used as active pharmaceutical ingredients in the preparation of pharmaceutical compositions for use in animals or humans. Thus, embodiments herein encompass the use of these solid forms as a final drug product.
  • Crystal refers to a solid formed by a repeating, three- dimensional pattern of atoms, ions or molecules having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern. Notwithstanding the homogenous nature of an ideal crystal, a perfect crystal rarely, if ever, exists. “Crystalline,” as used herein, encompasses crystalline forms that include crystalline defects, for example, crystalline defects commonly formed by manipulating (e.g., preparing, purifying) the crystalline forms described herein. A person skilled in the art is capable of determining whether a sample of a compound is crystalline notwithstanding the presence of such defects.
  • Crystalline forms can be characterized by analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR), single crystal x-ray diffraction, Raman spectroscopy, Fourier transform NAI-1538907928v1 9 Jones Day Docket No.13371-344-228 infrared spectroscopy (FTIR) and/or any other suitable analytical techniques.
  • analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR), single crystal x-ray diffraction, Raman spectroscopy, Fourier transform NAI-1538907928v1 9 Jones Day Docket No.13371-344-228 infrared spectroscopy (FTIR) and/or any other suitable analytical techniques.
  • XRPD x-ray powder diffraction
  • the term “substantially pure” with respect to any solid form e.g., a single crystalline form as disclosed herein (e.g., Form 1, 2, or 3), means no detectable amount of another crystalline form as determined by observing no detectable significant differences in an XRPD and/or DSC pattern between the single crystalline form and a crystalline composition of Compound (I).
  • a “substantially pure” solid form can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.
  • substantially pure refers to a purity of at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least 99.8%.
  • Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data provided by these techniques may be used to identify a particular solid form.
  • an XRPD pattern, DSC thermogram or TGA thermal curve that “matches” or, interchangeably, is “essentially as shown” with one or more figures herein showing an XRPD pattern or DSC thermogram or TGA thermal curve, respectively, is one that would be considered by one skilled in the art to represent the same single crystalline form of the compound as the sample of the compound that provided the pattern or thermogram or thermal curve of one or more figures provided herein.
  • an XRPD pattern or DSC thermogram or TGA thermal curve that matches or 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 diffraction 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 or DSC thermogram or TGA thermal curve of the sample NAI-1538907928v1 10 Jones Day Docket No.13371-344-228 and the corresponding XRPD pattern or DSC thermogram or TGA thermal curve disclosed herein.
  • the present disclosure provides a solid form of 7-ethyl-4-(4'- (ethylsulfonyl)-6-fluoro-2'-methoxy-[1,1'-biphenyl]-3-yl)-7H-imidazo[4,5-c]pyridazine (Compound (I)) or a pharmaceutically acceptable solvate thereof: N N .
  • the solid form comprising Compound (I) can be a crystalline form, a partially crystalline form, or a mixture of crystalline form(s), or amorphous form(s).
  • provided herein is a solid form comprising a crystalline form of Compound (I).
  • the solid form is substantially pure.
  • the solid form is anhydrous.
  • the solid form comprises less than 1% water by weight.
  • Compound (I) is described in International Patent Application No. PCT/IB2013/060631, which published as WO 2014/091368 A1, the entirety of which is incorporated herein by reference.
  • the various solid forms of Compound (I) may be characterized by, inter alia, XRPD, TGA, DSC, amongst others. 6.1.1 Form 1 of Compound (I)
  • provided herein is Form 1 of Compound (I).
  • Form 1 of Compound (I) may be characterized by an XRPD pattern essentially as shown in FIG.1.
  • NAI-1538907928v1 11 Jones Day Docket No.13371-344-228 [0058]
  • a solid form (e.g., Form 1) of Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu K ⁇ radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 peaks, each of which is located at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.0, 13.9, 14.5, 15.6, 16.9, 19.9, 20.1, 21.0, 21.6, 22.0, 23.4, and 25.0° 2 ⁇ .
  • the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (11) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 13) of the identified peaks.
  • the solid form (e.g., Form 1) of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks (e.g., 3, 4, 5, or 6 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 13.9, 14.5, 16.9, 19.9, 20.1, and 25.0° 2 ⁇ .
  • the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, or 7 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ .
  • the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ .
  • the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ .
  • the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.0, 15.6, 21.0, 21.6, 22.0, and 23.4° 2 ⁇ .
  • the solid form is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 14.5, 16.9, and 19.9° 2 ⁇ .
  • the XRPD pattern further comprises comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 12.8, 13.9, and 20.1° 2 ⁇ .
  • the XRPD pattern NAI-1538907928v1 12 Jones Day Docket No.13371-344-228 further comprises comprising at least one peak (e.g., 1, 2, or 3 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 15.6, 22.0, and 23.4° 2 ⁇ .
  • at least one peak e.g., 1, 2, or 3 peaks
  • a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 15.6, 22.0, and 23.4° 2 ⁇ .
  • the solid form undergoes a weight loss of about 0.21% upon heating from about 25 °C to about 200 °C when analyzed by TGA.
  • the solid form is characterized by TGA by heating a sample of the solid form from 0 °C to 350 °C at a rate of 10 °C/min.
  • the solid form is characterized by a TGA thermogram essentially as shown in FIG.2. [0063] In one embodiment, the solid form undergoes a thermal event at about 186 °C when characterized by DSC. In one embodiment, the solid form has a melting point of about 186 °C. In one embodiment, the solid form is characterized by DSC by heating a sample of the solid form from -30 °C to 250 °C at a rate of 10 °C/min. In one embodiment, the solid form is characterized by a DSC thermogram essentially as shown in FIG.3.
  • a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.1.
  • the XRPD pattern is measured by XRPD using Cu K ⁇ radiation having a wavelength of 1.5406 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.1 °2 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.05 °2 ⁇ .
  • a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 1) of free base of Compound (I).
  • the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I).
  • the solid form is substantially free of Form 2 of Compound (I).
  • the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I).
  • the solid form is NAI-1538907928v1 13 Jones Day Docket No.13371-344-228 substantially free of salts of Compound (I).
  • the solid form is provided as substantially pure.
  • the solid form is substantially chemically pure (e.g., at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure.
  • the solid form is substantially physically pure. [0068] All of the combinations of the above embodiments are encompassed by this application. 6.1.2 Form 2 of Compound (I) [0069] In one embodiment, provided herein is Form 2 of Compound (I).
  • Form 2 may be characterized by an XRPD pattern essentially as shown in FIG.5.
  • a solid form e.g., Form 2
  • Compound (I) comprising a free base of Compound (I), characterized an XRPD pattern, collected when measured using Cu K ⁇ radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks, each of which is located at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 8.5, 9.1, 11.5, 11.8, 13.0, 14.2, 15.3, 15.5, 17.0, 18.2, 21.5, 22.2, 22.4, 23.6, and 24.0° 2 ⁇ .
  • the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least eleven (11) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least thirteen (13) of the peaks.
  • the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 15) of the identified peaks.
  • the solid form (e.g., Form 2) of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks (e.g., 3, 4, 5, 6, 7, or 8 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 8.5, 9.1, 11.5, 17.0, 18.2, 21.5, 23.6, and 24.0° 2 ⁇ .
  • the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, or 7 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 11.8, 13.0, 14.2, 15.3, 15.5, NAI-1538907928v1 14 Jones Day Docket No.13371-344-228 22.2, and 22.4° 2 ⁇ .
  • the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ .
  • the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ .
  • the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, or 7 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 11.8, 13.0, 14.2, 15.3, 15.5, 22.2, and 22.4° 2 ⁇ .
  • the solid form is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 8.5, 9.1, and 17.0° 2 ⁇ .
  • the XRPD pattern further comprises comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 11.5, 11.8, and 18.2° 2 ⁇ .
  • the XRPD pattern further comprises comprising at least one peak (e.g., 1, 2, 3, or 4 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 14.2, 15.5, 21.5 and 22.4° 2 ⁇ .
  • a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.5.
  • the XRPD pattern is measured by XRPD using Cu K ⁇ radiation having a wavelength of 1.5406 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.1 °2 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.05 °2 ⁇ .
  • a solid form comprising a free base of Compound (I), which is a crystalline anhydrate (Form 2) of free base of Compound (I).
  • the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I).
  • the solid form is a mixture of Form 1 of Compound (I), as described herein, and Form 2 of Compound (I).
  • the solid form is substantially free of Form 1 of Compound (I). In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I). In some NAI-1538907928v1 15 Jones Day Docket No.13371-344-228 embodiments, the solid form is substantially free of salts of Compound (I). In some embodiments, the solid form is provided as substantially pure. In some embodiments, the solid form is substantially chemically pure. In some embodiments, the solid form is substantially physically pure. [0078] All of the combinations of the above embodiments are encompassed by this application. 6.1.3 Form 3 of Compound (I) [0079] In one embodiment, provided herein is Form 3 of Compound (I).
  • Form 3 may be characterized by an XRPD pattern essentially as shown in FIG.6.
  • a solid form e.g., Form 3 of Compound (I) comprising a sulfate salt of Compound (I), characterized an XRPD pattern, collected when measured using Cu K ⁇ radiation, comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks, each of which is located at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 7.6, 13.2, 17.5, 17.9, 19.9, 21.0, 21.4, 24.3, 26.5, 26.7, and 27.7 °2 ⁇ .
  • the solid form of Compound (I) is characterized by an XRPD pattern comprising at least five (5) of the peaks. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least seven (7) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising at least nine (9) of the peaks. In one embodiment, the solid form of Compound (I) is characterized by an XRPD pattern comprising all (e.g., 12) of the identified peaks.
  • the solid form (e.g., Form 3) of Compound (I) is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising at least three peaks (e.g., 3, 4, or 5 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 7.6, 13.2, 17.5, 21, and 24.3° 2 ⁇ .
  • the XRPD pattern further comprises at least one peak (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2 ⁇ .
  • a peak e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks
  • a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2 ⁇ .
  • the XRPD pattern further comprises at least two peaks (e.g., 2, 3, 4, 5, 6, 78, 9, 10, 11, or 12 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, NAI-1538907928v1 16 Jones Day Docket No.13371-344-228 21.4, 23.2, 23.3, and 27.7° 2 ⁇ .
  • peaks e.g., 2, 3, 4, 5, 6, 78, 9, 10, 11, or 12 peaks
  • the XRPD pattern further comprises at least three peaks (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2 ⁇ .
  • peaks e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks
  • the XRPD pattern further comprises at least four peaks (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks), each at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 6.5, 10.0, 12.1, 13.8, 15.1, 17.9, 19.1, 20.2, 21.4, 23.2, 23.3, and 27.7° 2 ⁇ .
  • the solid form is characterized by an XRPD pattern, when measured using Cu K ⁇ radiation, comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 7.6, 13.2, and 24.3° 2 ⁇ .
  • the XRPD pattern further comprises comprising peaks at approximately (e.g., ⁇ 0.2 °2 ⁇ ) 17.5, 17.9, and 19.9° 2 ⁇ . In one embodiment, the XRPD pattern further comprises comprising at least one peak (e.g., 1, 2, 3, 4, or 5 peaks) at a 2 ⁇ angle selected from the group consisting of approximately (e.g., ⁇ 0.2 °2 ⁇ ) 21.0, 21.4, 26.5, 26.7, and 27.7° 2 ⁇ . [0084] In one embodiment, provided herein is a solid form comprising a free base of Compound (I), characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG.6.
  • the XRPD pattern is measured by XRPD using Cu K ⁇ radiation having a wavelength of 1.5406 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.1 °2 ⁇ .
  • the solid form is characterized by an XRPD pattern according to any of the above embodiments, wherein the identified peak location has an error of (e.g., may vary by) ⁇ 0.05 °2 ⁇ .
  • a solid form comprising a sulfate salt of Compound (I), which is a crystalline anhydrate (Form 3) of a sulfate salt of Compound (I).
  • the solid form is substantially free non-crystalline forms (e.g., amorphous) of Compound (I).
  • the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound (I).
  • the solid form is substantially free of a free base of Compound (I).
  • the solid form is provided as substantially pure.
  • the solid form is substantially chemically pure.
  • the solid form is substantially physically pure.
  • a 1 of Compound (I) comprises: (a) dissolving Compound (I) in acetonitrile (ACN) to form a solution; (b) exchanging the ACN for ethyl acetate (EtOAc) to form a solvent-exchanged solution; and (c) subjecting the solvent-exchanged solution to conditions effective to crystallize Compound (I).
  • dissolving Compound (I) in ACN to form a solution is carried out at a temperature of about 80 °C.
  • the crystallizing comprises cooling the solvent-exchanged solution to crystallize Compound (I).
  • the obtained crystalline form of Compound (I) is purified by dissolving in EtOAc and recrystallizing.
  • crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane).
  • solvent evaporation slow or fast, via any known evaporation method
  • cooling e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C
  • an antisolvent e.g., heptane, isopropyl alcohol, chlorhexidine
  • vapor diffusion e.g., with heptane
  • a method for preparing Form 1 of Compound (I) comprises: (a) dissolving Compound (I) in ACN to form a solution; NAI-1538907928v1 18 Jones Day Docket No.13371-344-228 (b) subjecting the solution to conditions effective to crystalline Compound (I).
  • crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane).
  • the conditions effective to crystalline Compound (I) comprise cooling the solution.
  • the solution is filtered, e.g., through diatomaceous earth, prior to crystallizing Compound (I).
  • a method for preparing Form 1 of Compound (I) comprises: (a) dissolving Compound (I) in ethanol (EtOH) to form a solution; (b) subjecting the solution to conditions effective to crystalline Compound (I). [0095] In one embodiment, charcoal is also added to the solution. In one embodiment, the solution of Compound (I) in EtOH, and optionally charcoal, is heated.
  • crystallizing comprises one or more of solvent evaporation (slow or fast, via any known evaporation method), cooling (e.g., crash cooling to -80°C, freezer cooling to -15 to -25 °C, or refrigerator cooling to 2 to 8 °C), addition of an antisolvent (e.g., heptane, isopropyl alcohol, chlorhexidine), or vapor diffusion (e.g., with heptane).
  • the conditions effective to crystalline Compound (I) comprise cooling the solution.
  • a method for preparing Form 1 of Compound (I) may also comprise, in any embodiment, any method in Section 7 (Examples) indicated as resulting in Form 1 of Compound (I).
  • 2 of Compound (I) comprises: (a) dissolving a a of tetrahydrofuran (THF) and water to form a solution; and (b) evaporating the mixture of THF and water to form solid Form 2 of Compound (I).
  • evaporating the mixture of THF and water comprises maintaining the solution in a vessel without a lid at ambient temperature and allowing the mixture to evaporate over time.
  • crystallizing Compound (I), which may be in any form (e.g., crude Compound (I) or amorphous Compound (I)), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially chemically pure (e.g., comprising not more than 2% by weight of one or more compounds other than Compound (I)).
  • a composition of Form 1 of Compound (I) comprises not more than 1% by weight of one or more compounds other than Compound (I).
  • a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of one or more compounds other than Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight, such as not more than 0.03% by weight, of any single compound other than Compound (I). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% pure, at least about 99% pure, at least about 99.5% pure, or at least about 99.7% pure.
  • the one or more compounds other than Compound (I) that may be present as an impurity comprise an intermediate or a reagent used in the synthesis of NAI-1538907928v1 20 Jones Day Docket No.13371-344-228 Compound (I), such as disclosed in the Examples, or a side product generated in the synthesis of Compound (I).
  • an intermediate or a reagent used in the synthesis of NAI-1538907928v1 20 Jones Day Docket No.13371-344-228 Compound (I) such as disclosed in the Examples
  • a side product generated in the synthesis of Compound (I) One of skill in the art would recognize the various side products that could be generated in the synthesis of Compound (I) as disclosed in the Examples.
  • crystallizing Compound (I), e.g., crude Compound (I), by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially crystalline (e.g., comprising not more than 2% by weight of amorphous material).
  • a composition of Form 1 of Compound (I) comprises not more than 1% by weight of amorphous material.
  • a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of amorphous material.
  • a composition of Form 1 of Compound (I) may be at least about 98% crystalline, at least about 99% crystalline, at least about 99.5% crystalline, or 100% crystalline (e.g., no detectable amorphous content).
  • crystallizing Compound (I), e.g., crude Compound (I) by a method disclosed herein to generate Form 1 of Compound (I) generates a composition of Form 1 of Compound (I) that is substantially physically pure (e.g., comprising not more than 2% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I)).
  • a composition of Form 1 of Compound (I) comprises not more than 1% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). In certain embodiments, a composition of Form 1 of Compound (I) comprises not more than 0.05% by weight of another solid form of Compound (I), such as Form 2 or amorphous Compound (I). Said differently, in certain embodiments, a composition of Form 1 of Compound (I) may be at least about 98% by weight of Form 1 of Compound (I), at least about 99% by weight of Form 1 of Compound (I), or at least about 99.5% by weight of Form 1 of Compound (I).
  • the present disclosure provides a composition comprising Form 1 of Compound (I) and not more than about 5% by weight (e.g., 0% to 5%) of Form 2 of Compound (I).
  • a composition comprises Form 1 of Compound (I) and not more than about 4% by weight (e.g., 0% to 4%) of Form 2 of Compound (I).
  • a composition comprises Form 1 of Compound (I) and not more than about 3% by weight (e.g., 0% to 2%) of Form 2 of Compound (I).
  • a composition NAI-1538907928v1 21 Jones Day Docket No.13371-344-228 comprises Form 1 of Compound (I) and not more than about 4% by weight (e.g., 0% to 2%) of Form 2 of Compound (I).
  • a composition comprises Form 1 of Compound (I) and not more than about 1% by weight (e.g., 0% to 1%) of Form 2 of Compound (I).
  • compositions such as pharmaceutical compositions, formulated from a solid form of Compound (I) (e.g., Form 1, 2, or 3) and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprises a composition comprising a solid form of Compound (I) (e.g., Form 1, 2, or 3).
  • a solid form of Compound (I) e.g., Form 1, 2 or 3
  • a pharmaceutical composition comprises Form 1 of Compound (I) and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprises or is prepared from solid Form 2 of Compound (I) and one or more pharmaceutically acceptable excipients. In one embodiment, a pharmaceutical composition comprises or is prepared from solid Form 3 of Compound (I) and one or more pharmaceutically acceptable excipients.
  • Suitable modes of administration for a solid form of Compound (I), as disclosed herein, include oral, parenteral, topical, inhaled, intranasal, rectal/intravaginal, and ocular/aural administration.
  • Pharmaceutical compositions suitable for the aforementioned modes of administration may be formulated, e.g., to be immediate and/or modified release. Modified release dosage forms include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Pharmaceutical compositions suitable for oral administration include NAI-1538907928v1 22 Jones Day Docket No.13371-344-228 solid dosage forms, liquids, powders, lozenges (including liquid-filled), chewable dosage forms, multi- and nano-particulates, gels, solid solutions, liposomal dosage forms, films, ovules, sprays, and buccal/mucoadhesive patches.
  • Non-limiting examples of liquid oral dosage forms include suspensions, solutions, syrups, and elixirs.
  • Non-limiting examples of solid oral dosage forms include tablets, capsules, and the like.
  • a pharmaceutical composition e.g., tablet
  • a pharmaceutical composition e.g., tablet, may comprise about 5 wt.% to 60 wt.% of a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3).
  • a pharmaceutical composition e.g., tablet or capsule
  • a pharmaceutical composition is formulated for immediate release and comprises about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg of Compound (I) in a solid form disclosed here (e.g., Form 1, 2, or 3).
  • a pharmaceutical composition is formulated for modified release and comprises about 20 mg, about 22.5 mg, about 25 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 35 mg, about 40 mg, or about 50 mg of Compound (I) in a solid form disclosed here (e.g., Form 1, 2, or 3).
  • a pharmaceutical composition may contain one or more disintegrants.
  • disintegrants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • a pharmaceutical composition e.g., tablet
  • NAI-1538907928v1 23 Jones Day Docket No.13371-344-228 [00110]
  • a pharmaceutical composition e.g., tablet, may contain one or more binders. Binders are generally used to impart cohesive qualities to a formulated pharmaceutical composition.
  • binders that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • a pharmaceutical composition e.g., tablet, may contain one or more diluents.
  • diluents that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • a pharmaceutical composition e.g., tablet, may contain one or more surface active agents (“surfactants”).
  • surfactants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to, sodium lauryl sulfate and polysorbate 80.
  • a pharmaceutical composition may comprise about 0.2 wt.% to about 5 wt.% of one or more surfactants.
  • a pharmaceutical composition e.g., tablet, may contain one or more glidants, such as silicon dioxide and/or talc.
  • a pharmaceutical composition may comprise about 0.2 wt.% to about 1 wt.% of one or more glidants.
  • a pharmaceutical composition may contain one or more lubricants.
  • lubricants that may be used in a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) include, but are not limited to magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • a pharmaceutical composition may comprise about 0.25 wt.% to 10 wt.%, such as about 0.5 wt.% to 3 wt.% of a lubricant.
  • a pharmaceutical composition may further comprise one or more additional ingredients, including, but not limited to, antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents.
  • additional ingredients including, but not limited to, antioxidants, colorants, flavoring agents, preservatives, and taste-masking agents.
  • NAI-1538907928v1 24 Jones Day Docket No.13371-344-228 [00114]
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) may be formulated in a pharmaceutical composition for administration directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.
  • a pharmaceutical composition intended for parenteral administration may be prepared prior to use, e.g., by reconstituting a solid composition comprising a solid form of Compound (I) (e.g., Form 1, 2, or 3) with a liquid, such as sterile water (e.g., water for injection).
  • a solid composition may also comprise one or more excipients, such as a carbohydrate and/or buffering agent.
  • the preparation of pharmaceutical compositions intended for parenteral administration under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • a solid form of Compound (I) may be formulated in a pharmaceutical composition for administration topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical pharmaceutical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated.
  • a solid form of Compound (I) may be formulated in a pharmaceutical composition for administration intranasally or by inhalation.
  • a pharmaceutical composition comprising a solid form of Compound (I) may be in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine), e.g., for use in a dry powder inhaler, or as an aerosol spray for use with a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • a powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • a pressurized container, pump, spray, atomizer, or nebulizer may comprise a solution or suspension prepared from a solid form of Compound (I) (e.g., Form NAI-1538907928v1 25 Jones Day Docket No.13371-344-228 1, 2, or 3) for example, in ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • Compound (I) e.g., Form NAI-1538907928v1 25 Jones Day Docket No.13371-344-228 1, 2, or 3
  • a propellant(s) as solvent
  • an optional surfactant such as sorbitan trioleate
  • a solid form of Compound (I) prior to use in a dry powder or suspension, may be micronized to a size suitable for delivery by inhalation (e.g., less than 5 microns).
  • Capsules which may be made, for example, from gelatin or hydroxypropyl methylcellulose, blisters and cartridges for use in an inhaler or insufflator may be formulated from a solid form of Compound (I) (e.g., Form 1, 2, or 3) to contain a powder mix of Compound (I), a suitable powder base such as lactose or starch and a performance modifier such as I-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • a suitable solution for use in an atomizer using electrohydrodynamics to produce a fine mist may be prepared from a solid form of Compound (I) (e.g., Form 1, 2, or 3) to contain from 1 ⁇ g to 20 mg of Compound (I) per actuation.
  • Actuation volume may vary from 1 ⁇ L to 100 ⁇ L.
  • a solid form of Compound (I) may be formulated in a pharmaceutical composition for administration directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other pharmaceutical compositions suitable for ocular and aural administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such compositions may also be delivered by iontophoresis.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste- masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • the cyclodextrin may be used as an auxiliary additive, i.e., as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518, and WO 98/55148.
  • a kit comprising a pharmaceutical composition comprising a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient.
  • Such a kit may further comprise means for separately retaining said pharmaceutical composition in discreet dosage amounts, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet such as a blister pack, such as is commonly employed for the packaging of tablets, capsules, and the like.
  • Such a kit may be suitable for administering different dosage forms, such as, oral, and parenteral, for administering the pharmaceutical composition at a prescribed dosage interval.
  • Such a kit may further comprise directions for administration and may be provided.
  • Compound (I) including the solid forms thereof disclosed herein are useful because Compound (I) exhibits pharmacological activity as a GABAA channel modulator, more particularly, as a positive allosteric modulator of the GABA A channel.
  • Compound (I) and solid forms thereof may therefore be used in the treatment of diseases, disorders, or conditions in animals, such as humans, for which a GABAA positive allosteric modulator is indicated.
  • the present disclosure provides a method for treating a disease, disorder, or condition for which a GABA A positive allosteric modulator is indicated in a subject, such as a human subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a solid form of Compound (I), as disclosed herein (e.g., Form 1, 2, or 3) to the subject.
  • a method for treating a disease, disorder, or condition for which a GABA A positive allosteric modulator is indicated in a subject comprises administering a therapeutically effective amount of a pharmaceutical composition prepared from a solid form of Compound (I) (e.g., reconstituting a solid form of Compound (I)), to the subject.
  • a pharmaceutical composition prepared from a solid form of Compound (I) e.g., reconstituting a solid form of Compound (I)
  • the term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, rats, mice, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and/or turkeys.
  • humans i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other
  • the subject is a human.
  • a human subject to which administration of a therapeutic e.g., a compound as described herein
  • administration of a therapeutic e.g., a compound as described herein
  • patient also called a “patient.”
  • treatment and “treating” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, disorder, or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • a “therapeutically effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3
  • a subject e.g., a human subject.
  • a subject e.g, a human subject.
  • a solid form of Compound (I) may be used to treat a disease, disorder, or condition for which a GABAA positive allosteric modulator, NAI-1538907928v1 28 Jones Day Docket No.13371-344-228 such as a ⁇ 2/3/5 subunit ⁇ selective positive allosteric modulator, in a subject in need thereof, in a total daily dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 75 mg, or about 100 mg.
  • a GABAA positive allosteric modulator e.g., Form 1, 2, or 3
  • the solid form of Compound (I) may be administered once daily or multiples times daily (e.g., two or more times a daily).
  • a solid form of Compound (I) e.g., Form 1, 2, or 3
  • the aforementioned amounts of Compound (I) may be administered in a pharmaceutical composition (e.g., liquid pharmaceutical composition) prepared from (e.g., reconstituted from) a solid form of Compound (I).
  • the method of treatment involves a dosing titration period of about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, or about 21 days. In some embodiments the method of treatment does not require of a dose titration period.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be used as an analgesic and e.g., be administered to a subject as part of a method of treating pain, including acute pain, chronic pain, neuropathic pain, nociceptive (including inflammatory) pain, somatic pain, visceral pain, and dysfunctional pain.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be used as an as anticonvulsant and e.g., be administered to a subject as part of a method of treating epilepsy and/or epilepsy associated disorders, including Lennox-Gastaut syndrome, Dravet's disease, and generalized epilepsy with febrile seizures plus (GEFS+).
  • epilepsy and/or epilepsy associated disorders including Lennox-Gastaut syndrome, Dravet's disease, and generalized epilepsy with febrile seizures plus (GEFS+).
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an anxiolytic agent and e.g., be administered to a subject as part of a method of treating panic disorder, generalized anxiety disorder, a stress disorder (such as post-traumatic stress disorder, acute stress disorder NAI-1538907928v1 29 Jones Day Docket No.13371-344-228 and/or substance-induced stress disorder), a phobia (such as agoraphobia, social phobia and animal phobias), and/or obsessive-compulsive disorder.
  • a stress disorder such as post-traumatic stress disorder, acute stress disorder NAI-1538907928v1 29 Jones Day Docket No.13371-344-228 and/or substance-induced stress disorder
  • a phobia such as agoraphobia, social phobia and animal phobias
  • obsessive-compulsive disorder e.g., obsessive-compulsive
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as a muscle relaxant and e.g., be administered to a subject as part of a method of treating muscle spasm, dystonia, spasticity (including generalized and focal spasticity), and/or essential tremor.
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an antipsychotic agent and e.g., be administered to a subject as part of a method of treating schizophrenia.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be administered to a subject as part of a method of treating autism.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be used as an as an antidepressant agent and e.g., be administered to a subject as part of a method of treating a depressive disorder, bipolar disorder, and/or cyclothymia.
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as an antiemetic agent and e.g., be administered to a subject as part of a method of treating chemotherapy- or radiation- induced emesis, post-operative nausea and vomiting, and/or motion sickness.
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used as an as a cognition-enhancing agent and e.g., be administered to a subject as part of a method of treating a neurodegenerative disorder, such as Alzheimer's disease or cerebral ischemia.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be used as an as a sleep improving agent and e.g., be administered to a subject as part of a method of treating a sleep disorder, such as insomnia, and/or a circadian rhythm disorder, such as jetlag.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be used as a premedication prior to anesthesia or endoscopy.
  • a solid form of Compound (I) e.g., Form 1, 2, or 3
  • a pharmaceutical composition prepared therefrom may be used and administered to a subject as part of a method of treating an addiction phenotype, such as alcoholism.
  • a solid form of Compound (I) (e.g., Form 1, 2, or 3) or a pharmaceutical composition prepared therefrom may be used and administered to a subject as part of a method of treating Angelman syndrome, attention deficit hyperactivity disorder, bladder urgency, bowel abnormalities, an eating disorder, such as anorexia nervosa or bulimia nervosa, Fragile X syndrome, a hearing disorder, such as tinnitus and age-related hearing impairment, multiple sclerosis, a neurosis, overactive bladder with sensory disturbance, premenstrual syndrome, restless legs syndrome, and/or urinary incontinence.
  • Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurons and is activated by noxious stimuli via peripheral transducing mechanisms (see, e.g., Meyer et al., 2006, Wall and Melzack’s Textbook of Pain (5th Ed), Chapter 1).
  • These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction velocities, of which there are two main types, A- delta fibers (myelinated) and C fibers (non-myelinated).
  • Nociceptors encode the intensity, duration, and quality of noxious stimulus and by virtue of their topographically organized projection to the spinal cord, the location of the stimulus.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually, although not always, associated with a specific cause such as a defined injury, is often sharp and severe and can result from numerous origins such as surgery, dental work, a strain, or a sprain. Acute pain does not generally result in any persistent psychological response.
  • nociceptor activation When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation may be altered such that there is sensitization in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a heightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviors which may better enable repair processes to NAI-1538907928v1 31 Jones Day Docket No.13371-344-228 take place. The normal expectation would be that sensitivity returns to normal once the injury has healed.
  • Chronic pain are neuropathic pain (e.g., painful diabetic neuropathy or postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain, but may include any chronic painful condition affecting any system, such as those described by the International Association for the Study of Pain (Classification of Chronic Pain, a publication freely available for download at http://www.iasp-pain.org).
  • neuropathic pain e.g., painful diabetic neuropathy or postherpetic neuralgia
  • carpal tunnel syndrome back pain
  • headache cancer pain
  • arthritic pain chronic post-surgical pain
  • Such symptoms can include: 1) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia) (Meyer et al., 2006, Wall and Melzack's Textbook of 15 Pain (5th Ed), Chapter 1).
  • patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies.
  • pain can also be broadly categorized into nociceptive pain, affecting either the somatic or visceral systems, which can be inflammatory in nature (associated with tissue damage and the infiltration of immune cells), or neuropathic pain.
  • Nociceptive pain can be defined as the process by which intense thermal, mechanical, or chemical stimuli are detected by a subpopulation of peripheral nerve fibers, called nociceptors, and can be induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 2006, Wall and Melzack's Textbook of Pain (5 th Ed), Chapter 1).
  • Myelinated A-delta fibers transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibers transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a NAI-1538907928v1 32 Jones Day Docket No.13371-344-228 prominent feature of pain from strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, pain associated with gout, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumor related pain (e.g., bone pain, headache, facial pain, or visceral pain) or pain associated with cancer therapy (e.g., in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy).
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but, in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Nociceptive pain can also be related to inflammatory states.
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (McMahon et al., 2006, Wall and Melzack's Textbook of Pain (5th Ed), Chapter 3).
  • a common inflammatory condition associated with pain is arthritis. It has been estimated that almost 27 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease (Lawrence et al., 2008, Arthritis Rheum, 58, 15-35); most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life.
  • visceral pain refers to pain associated with conditions of such organs, such as painful bladder syndrome, interstitial cystitis, prostatitis, ulcerative colitis, Crohn's disease, renal colic, irritable bowel syndrome, endometriosis and dysmenorrheal (Classification of Chronic Pain, available at http://www.iasp-pain.org).
  • Neuropathic pain is currently defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many 5 disorders with diverse etiologies.
  • peripheral neuropathy include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency.
  • Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Dworkin, 2009, Am J Med, 122, S 1-S2; Geber et al., 2009, Am J Med, 122, S3-S12; Haanpaa et al., 2009, Am J Med, 122, S13-S21).
  • spontaneous pain which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • Such conditions include in particular fibromyalgia and chronic regional pain syndrome, which are often described as dysfunctional pain states e.g., fibromyalgia or complex regional pain syndrome (Woolf, 2010, J Clin Invest, 120, 3742-3744), but which are included in classifications of chronic pain states (Classification of Chronic Pain, available at http://www.iasp-pain.org).
  • a solid form of Compound (I) or a pharmaceutical composition prepared therefrom is used in a method of treating pain, as described in any embodiment herein, in a subject.
  • the solid form of Compound (I) is Form 1 as characterized NAI-1538907928v1 34 Jones Day Docket No.13371-344-228 according to any embodiment disclosed herein.
  • the pain is acute.
  • the pain is chronic.
  • the pain may be central and/or peripheral origin.
  • the pain may be of a neuropathic, nociceptive, and/or inflammatory nature, such as pain affecting either the somatic or visceral systems, as well as dysfunctional pain affecting multiple systems.
  • a solid form of Compound (I) as disclosed herein e.g., Form 1, 2, or 3 or a pharmaceutical composition prepared therefrom may be administered in combination with one or more additional therapeutic agents to treat a disease, disorder, or condition in a subject.
  • a solid form of Compound (I) as disclosed herein may be administered to a subject, e.g., to treat pain in that subject, in combination with one or more agents selected from the group consisting of: • an anticonvulsant, e.g., carbamazepine; • a selective Nav1.3 channel modulator, such as a compound disclosed in WO2008/118758; • a selective Nav1.7 channel modulator, such as a compound disclosed in WO2010/079443, e.g., 4-[2-(5-amino-1 H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2- fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide or 4-[2-(3-amino-1 H-pyrazol-4-yl)-4- (trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1, 3-thiazol
  • a solid form of Compound (I) as disclosed herein e.g., Form 1, 2, or 3
  • a pharmaceutical composition prepared therefrom to a subject together with one or more additional therapeutic agents that slow down the rate of metabolism of NAI-1538907928v1 38 Jones Day Docket No.13371-344-228 Compound (I), thereby leading to increased exposure in the subject.
  • an inhibitor of at least one isoform of CYP450 enzyme or an inhibitor of CYP3A4 may be administered to slow down the metabolism of Compound (I) and increase the exposure in the subject.
  • Non-limiting examples of isoforms of CYP450 include CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2- ⁇ [(4- methoxypyridin-3-yl)amino]sulfonyl ⁇ benzamide and N-(1-(2-(5-(4-fluorobenzyl)-3-(pyridin-4- yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide.
  • a solid form of Compound (I) as disclosed herein may be administered to a subject in combination with an anticonvulsant, e.g., to treat panic disorder.
  • an anticonvulsant e.g., to treat panic disorder.
  • the anticonvulsant is carbamazepine.
  • the additional therapeutic agent or agents may be administered to the subject together or separately, both physically (e.g., in the same pharmaceutical composition or in separate pharmaceutical compositions) or in time (e.g., at least 30 minutes, 1 hour, 2 hours, 12 hours, or 24 hours apart).
  • a pharmaceutical composition comprising or prepared from a solid form of Compound (I) and a pharmaceutically acceptable excipient may further comprise one or more additional therapeutic agents as described according to any embodiment herein.
  • a kit comprising two or more pharmaceutical compositions, at least one of which comprises or is prepared from a solid form of Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and a pharmaceutically acceptable excipient.
  • the additional pharmaceutical composition(s) may comprise the one or more additional therapeutic agents, as disclosed herein.
  • Such a kit may further comprise means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • kits such as are commonly employed for the packaging of tablets, capsules, and the like.
  • a kit may be suitable for administering different dosage forms, such as, oral, and parenteral, for administering each pharmaceutical composition at different dosage intervals, or for titrating the separate compositions against one another.
  • Such a kit may further comprise directions for administration and may be provided.
  • the present disclosure provides a pharmaceutical product (such as a dosage form or kit) comprising pharmaceutical composition comprising a solid form of NAI-1538907928v1 39 Jones Day Docket No.13371-344-228 Compound (I) as disclosed herein (e.g., Form 1, 2, or 3) and one or more additional therapeutically active agents for simultaneous, separate, or sequential administration to a subject for the treatment of a disorder for which a Na v 1.8 modulator is indicated. 7.
  • Compound (I) may be prepared as disclosed in International Patent Publication No. WO 2014/091368 A1, which is incorporated herein by reference in its entirety.
  • MS Mass spectra
  • ESI electrospray ionization
  • APCI atmospheric pressure chemical ionization
  • High pressure liquid chromatography (“HPLC”) was run under the following conditions: Column: Gemini NX C18, 5 ⁇ m, 21.2 x 100 mm Temperature: Ambient Detection: Evaporative Light Scattering Detector-Mass Spectrometry Mobile Phase A: 0.1 % diethylamine in water Mobile Phase B: 0.1 % diethylamine in ACN Gradient: 100-95% A over 1 min, 95-2% A over 6 min, 2 min hold, 2-95% A over 0.1 min, 9.9 min hold Flow rate: 18 mL/min Injection volume: 1000 ⁇ L NAI-1538907928v1 40 Jones Day Docket No.13371-344-228 [00157] Liquid chromatography-mass spectrometry (“LCMS”) indicates liquid chromatography mass spectrometry.
  • LCMS Liquid chromatography-mass spectrometry
  • reaction mixture was diluted with water (500 mL) and extracted 3 times with CH 2 Cl 2 (250 mL). The combined organic layers were washed twice with brine (300 mL), dried over Na2SO4, filtered, and reduced to dryness to give a yellow oil.
  • the crude was absorbed onto silica and purified (using silica gel column chromatography eluting with cyclohexane:EtOAc 8:2 to give the title compound as yellow solid in 64% yield, 31.70 g.
  • the reaction was heated at 100 °C for 12 hours and then allowed to cool to room temperature.
  • the reaction mixture was diluted with water (750 mL) and the aqueous layer was extracted twice with CH2Cl2 (250 mL).
  • the combined organic layers were washed with brine (300 mL), dried over Na 2 SO 4 , filtered, and reduced to dryness to give a solid.
  • the crude was purified by silica gel column chromatography eluting with a cyclohexane:EtOAc gradient from 95:5 to 8:2 to afford the title compound as colorless solid in 75% yield, 27.32 g.
  • Step 2 To a room temperature solution of 1-bromo-4-fluoro-2-methoxybenzene (5.00 g, 24.39 mmol) in N,N-dimethylformamide (15 mL) was added sodium ethanethiolate (2.66 g, 31.71 mmol) and the resulting reaction mixture was stirred for 72 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was further extracted 3 times with EtOAc (50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 3 To a room temperature solution of 1-bromo-4-ethylthio-2-methoxybenzene (1.00 g, 4.05 mmol) in acetic acid (60 mL) was added sodium perborate monohydrate (889 mg, 8.91 mmol) and the resulting reaction mixture was stirred for 16 hours. The reaction was concentrated in vacuo and the resulting crude was partitioned between water (20 mL) and CH 2 Cl 2 (50 mL). The organic layer was separated, washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated to afford the title product as a colorless liquid in 88% yield, 900 mg.
  • the reaction was stirred at 100 °C for 18 hours.
  • the reaction was cooled to room temperature, filtered through celite, and washed with EtOAc (50 mL). Water (75 mL) was added, the product extracted twice with EtOAc (50 mL), dried over Na 2 SO 4 , filtered, and concentrated under vacuum.
  • the residue was purified using silica gel column chromatography eluting with 15-65% methyl tert-butyl ether in heptanes to afford the title compound as a colorless solid in 42% yield, 985 mg.
  • Preparation 10 Synthesis of Compound (I) [00175] c]pyridazine (Preparation 6, 100 mg, 0.27 mmol), 2-(4-ethylsulfonyl-2-methoxyphenyl)-4,4,5,5-tetramethyl- NAI-1538907928v1 47 Jones Day Docket No.13371-344-228 [1,3,2]dioxaborolane (Preparation 9, 88 mg, 0.27 mmol) and cesium carbonate (177 mg, 0.54 mmol) in dioxane (5 mL) and water (1 mL) was degassed with argon for 10 minutes followed by the addition of 1,1'-bis(di-tert-butylphosphino) ferrocene palladium dichloride (4.4 mg, 0.005 mmol).
  • Example 3 Purity of Form 1 of Compound (I) [00179] Compound (I) as crystallized according to process B in Example 2 was assayed for purity using reverse-phase HPLC via one of two methods as described below: Method 1: Column: Waters Aquity BEH C18 Detection: UV Absorbance at 210 nm Mobile Phase A: 10 mM aqueous ammonium bicarbonate Mobile Phase B: ACN NAI-1538907928v1 48 Jones Day Docket No.13371-344-228 Run time: 21 minutes [00180] Quantification of impurities is achieved by area percent.
  • An elliptically graded multilayer mirror was used to focus Cu K ⁇ X-rays through the specimen and onto the detector.
  • a silicon specimen NIST SRM 640d
  • a specimen of the sample was sandwiched between 3- ⁇ m-thick films and analyzed in transmission geometry.
  • a beam-stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize the background generated by air.
  • Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position- sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b.
  • thermogram Differential Scanning Calorimetry (DSC) was performed using a TA Instrument Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed into an aluminum Tzero DSC pan, covered with NAI-1538907928v1 50 Jones Day Docket No.13371-344-228 a lid, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The data acquisition parameters and pan configuration are displayed on the thermogram. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate, e.g., (-30)-250-10 means "from -30 °C to 250 °C, at 10 °C/min".
  • thermogram The abbreviation of "T0C” on the thermogram means "Tzero pan and lid crimped”.
  • Thermogravimetric analysis (TGA) was performed using a TA Instruments 2950 IR thermogravimetric analyzer. Sample was placed in an aluminum sample pan and inserted into the TG furnace. The data acquisition and processing parameters are displayed on each thermogram. Nickel and AlumelTM were used as the calibration standards.
  • the method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate, e.g., 00-350-10 means "from 0 °C to 350 °C, at 10 °C/min".
  • the XRPD pattern indicates Form 1 is crystalline and is shown in FIG.1.
  • the DSC thermogram shown in FIG.2, shows a sharp endotherm with peak maximum at 187 °C.
  • TGA shown in FIG.3, indicates no weight loss from NAI-1538907928v1 51 Jones Day Docket No.13371-344-228 ambient temperature up to 150 °C and a 0.7% weight loss between 150 and 200 °C that is on the same order as the amount of EtOAc found by 1 H NMR.
  • the 1 H NMR spectrum shown as the bottom red trace in FIG.4, is consistent with the structure of Compound (I).
  • a small amount of EtOAc (0.53 wt. %; 0.027 mol/mol API) and other possible impurities were observed.
  • Form 1 of Compound (I) has an aqueous solubility of about 15 ⁇ g/mL at pH 2 and about 2 ⁇ g /mL at pH 7.
  • the single crystal structure of Form 1 of Compound (I) was determined by single crystal X-ray diffraction. Single crystals suitable for X-ray data collection were isolated from a crash cool experiment ( ⁇ 80 °C) of the filtrate that was obtained from a 2-week ambient trituration of Compound (I) in acetone. A colorless plate of C 22 H 21 FN 4 O 3 S having approximate dimensions of 0.84 mm ⁇ 0.66 mm ⁇ 0.48 mm, was mounted on a fiber in random orientation.
  • the space group was determined to be P ⁇ 1.
  • a calculated XRPD pattern was generated for Cu radiation using PowderCell 2.3 and the atomic coordinates, space group, and unit cell parameters from the single crystal structure.
  • FIG. 7 shows a calculated XRPD pattern of Form 1 of Compound (I), generated from the single crystal structure. All peaks in the experimental pattern of Form 1 of Compound (I) are represented in the calculated XRPD pattern, indicating that the prepared Form 1 is likely a single phase of Form 1.
  • Example 5 Solubility [00205] Form 1 of Compound (I) was dissolved in thirteen (13) different organic solvents including acetone, ACN, chloroform, p-dioxane, EtOH, EtOAc, n-heptane, MeOH, t-butyl methyl ether (TBME), isopropyl alcohol (IPA), THF, toluene, and n-hexane, in water, and in seven aqueous binary mixtures with water activity above approximately 0.8, including 78:22 v/v, acetone:water, 90:10 v/v acetone:water, 88:12 v/v ACN:water, 52:48 v/v EtOH:water, 39:61 v/v MeOH:water, 95:5 v/v THF:water, and 90:10 v/v THF:water.
  • organic solvents including acetone, ACN, chloroform, p-dioxane, EtOH, EtOAc
  • Table 3 provides the results of the equilibrium solubilities in each system tested.
  • Table 3 Equilibrium Solubilities of Compound (I) in various Solvent Systems Solvent Temperature Solubility XRPD Result NAI-1538907928v1 55 Jones Day Docket No.13371-344-228 acetone 40 °C 33 mg/mL Form 1 EtOAc 40 °C 9 mg/mL Form 1 ° s u s an a y e same an cons s en w orm .
  • Example 7 Limited Polymorph Screen
  • Fast Evaporation Sample solutions, consisting of API and solvent(s), were evaporated in 2-mL, 20-mL, or 40-mL HPLC vials in a fume hood at ambient temperature.
  • Solvent-Antisolvent Addition Either n-heptane ( ⁇ 2:1 to 3:1 v/v), IPA ( ⁇ 5:1 to 7:1 v/v), or chlorhexidine ( ⁇ 2:1 v/v) was added to aliquots of the mother liquors from the equilibrium solubility study of the stable form screen in an effort to precipitate kinetic forms. Recovered solids were submitted for XRPD analysis at ambient temperature. [00212] Cooling: Cooling experiments were conducted in either a refrigerator at 2 to 8 °C or in a freezer at -15 to -25 °C.
  • Crash Cooling A sealed 2-mL HPLC vial containing an aliquot of mother liquor filtrate from the equilibrium solubility study was placed inside a parafilmed 20-mL scintillation vial, then transferred to a -80 °C freezer for 1 day. The resulting mixture was manually pressure- filtered on a 0.22- ⁇ m nylon membrane to isolate the solid.
  • Precipitation Some solids formed as in situ precipitates in the mother liquor filtrates and were isolated.
  • Vapor Diffusion A centrifuge tube containing the THF mother liquor filtrate for Compound (I) was placed uncovered into a 20 mL glass scintillation vial containing a few milliliters of n-heptane antisolvent. The outer vial was sealed with parafilm, and the sample was left at ambient temperature for ⁇ 8 days before isolating the solid. [00216] Results are shown in Table 4 below. In Table 4, “RT” refers to room or ambient temperature.
  • Example 8 Competitive Slurry [00218] A competitive slurry was conducted in anhydrous acetone pre-saturated with of Compound (I) Form 1 at ambient temperature. The mixture with Form 1 and Form 2 were added and stirred/vortexed for five days. The slurry was centrifuge-filtered, and the wet cake was allowed to dry in air. The XRPD pattern of the resulting solid was consistent with Form 1.
  • Example 9 Attempted Scale-Up of Form 2 [00219] Attempt 1: Compound (I) (105.8 mg) was dissolved in 90:10 v/v THF:water (2.0 mL). Solvent was rapidly evaporated.
  • Form 1 Three unique XRPD patterns of the free base of Compound (I) were identified during the course of the screen: Form 1, Form 2 (from a fast evaporation in 90:10 THF:water) and Pattern B (Material B by SSCI annotation, from a fast evaporation in MeOH, mix of Form 1 and another pattern). Additionally, a sulfate salt of Compound (I) (“Form 3”) was also generated. Single crystals of Form 1 were isolated during the screen, the single crystal structure was solved, and a calculated powder pattern was generated. This calculated powder pattern was consistent with patterns of Form 1. Producing Form 2 in larger quantities was inefficient. Solution NMR on Form 2 did not show the presence of any residual solvents.
  • NAI-1538907928v1 Jones Day Docket No.13371-344-228 modifications could be made without departing from the spirit of the disclosed subject matter. Many variations will become apparent to those skilled in the art upon review of this specification. NAI-1538907928v1 62

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Abstract

L'invention concerne des formes cristallines solides de 7-éthyl-4-(4'-(éthylsulfonyl)-6-fluoro-2'-méthoxy-[l,I'-biphény l]-3-yl)-7 H-imidazo[4,5-c]pyridazine modulateur du récepteur GABA A, ainsi que leurs procédés de fabrication et d'utilisation. Formule (I).
PCT/US2024/061265 2023-12-21 2024-12-20 Formes solides d'un modulateur du récepteur gabaa et leurs procédés d'utilisation Pending WO2025137437A1 (fr)

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WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
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WO2019226820A1 (fr) * 2018-05-22 2019-11-28 Neurocycle Therapeutics, Inc. Composés modulateurs allostériques positifs gabaa pour le traitement du prurit et/ou de la dermatite
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WO1991011172A1 (fr) 1990-01-23 1991-08-08 The University Of Kansas Derives de cyclodextrines presentant une solubilite aqueuse amelioree et utilisation de ceux-ci
WO1994002518A1 (fr) 1992-07-27 1994-02-03 The University Of Kansas Derives de cyclodextrines ayant une meilleure solubilite aqueuse et leur utilisation
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WO2019226820A1 (fr) * 2018-05-22 2019-11-28 Neurocycle Therapeutics, Inc. Composés modulateurs allostériques positifs gabaa pour le traitement du prurit et/ou de la dermatite
CN117069724A (zh) * 2022-05-10 2023-11-17 上海赛默罗德生物科技有限公司 稠环化合物、药物组合物和应用

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