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EP-3641771-B1 - COMPOSITIONS COMPRISING CRYSTALLINE RESIQUIMOD MONOSULFATE ANHYDRATE SALT OR OTHER RESIQUIMOD CRYSTALLINE SALTS OR OTHER CRYSTALLINE SALTS OF 1H-IMIDAZO-[4,5-C]-QUINOLINE DERIVATIVES FOR THE TREATMENT OF CANCER

EP3641771B1EP 3641771 B1EP3641771 B1EP 3641771B1EP-3641771-B1

Inventors

  • LI, LIXIN

Dates

Publication Date
20260513
Application Date
20170623

Claims (13)

  1. A crystal form of resiquimod in the form of a sulfate salt, wherein the sulfate salt is a monosulfate salt and an anhydrate, and the crystal form has an x-ray powder diffraction spectrum that comprises peaks at 7.6 ±0.2 degrees 2θ, 11.7 ±0.2 degrees 2θ, and 18.2 ±0.2 degrees 2θ.
  2. The crystal form of claim 1, which is thermodynamically stable at room temperature for at least about 2 days.
  3. The crystal form of claim 1, which is thermodynamically stable at room temperature for at least about 1 week.
  4. The crystal form of claim 1, having: a differential scanning calorimetry thermogram comprising an endothermic peak at about 217.1 °C; or a differential scanning calorimetry thermogram comprising an endothermic peak at about 105.3 °C, about 219.2 °C, or both.
  5. The crystal form of claim 1, having an x-ray powder diffraction spectrum that further comprises peaks at 15.5 ±0.2 degrees 2θ, 17.6 ±0.2 degrees 2θ, and 24.4 ±0.2 degrees 2θ.
  6. The crystal form of claim 5, having an x-ray powder diffraction spectrum that further comprises peaks at 9.6 ±0.2 degrees 2θ, 13.4 ±0.2 degrees 2θ, and 23.5 ±0.2 degrees 2θ.
  7. A composition comprising the crystal form of any one of claims 1-6.
  8. The composition of claim 7, wherein the composition is in the form of a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier.
  9. A solid dosage form, comprising the crystal form of any one of claims 1-6, or the composition of any one of claims 7-8.
  10. A method for preparing a composition comprising combining the crystal form of any one of claims 1-6 with a pharmaceutically acceptable carrier or excipient.
  11. The crystal form of any one of claims 1-6, the composition of claim 7 or 8, or the solid dosage form of claim 9, for use in a method of treating a cancer in a subject in need thereof, comprising administering the crystal form, composition, or solid dosage form to the subject in need thereof.
  12. The crystal form of any one of claims 1-6, the composition of claim 7 or 8, or the solid dosage form of claim 9, for use in a method of treating a tumor in a subject in need thereof, comprising administering the crystal form, composition, or solid dosage form to the subject in need thereof.
  13. The crystal form, composition or solid dosage form for use of claim 12, wherein the tumor is a carcinoma, a sarcoma, or a blastoma.

Description

TECHNICAL FIELD The present disclosure relates to crystal forms of pharmaceutical compounds, formulations including, methods of forming, and methods of using these crystal forms. DOCUMENTS CITED WO2011084726 has a coversheet showing a picture of the following compound: and has an abstract, which states: "A compound of formula: Pharmaceutical compositions containing the compound, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in an animal by administering an effective amount of the compound to the animal are also disclosed". US2003119861 has an abstract, which states: "1-substituted, 2-substituted 1H-imidazo[4,5-c]-quinolin-4-amines are disclosed. These compounds function as antiviral agents, they induce biosynthesis of interferon, and they inhibit tumor formation in animal models. This invention also provides intermediates for preparing such compounds, pharmaceutical compositions containing such compounds, and pharmacological methods of using such compounds". WO0134709 has an abstract, which states: "Dye labeled imidazonaphthyridine, imidazopyridine and imidazoquinoline compounds having immune response modulating activity are disclosed. The compounds are useful, inter alia, for determining the binding and/or receptor sites of the molecules". WO2009099650 has an abstract, which states: "The invention provides a method for the treatment of superficial bladder cancer and inflammatory diseases of the bladder which employs certain Toll-like Receptor (TLR)-agonists". WO2011084725 has a coversheet showing a picture of the following compound: and has an abstract, which states: "A compound of formula:[ I ] Pharmaceutical compositions containing the compound, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in an animal by administering an effective amount of the compound to the animal are also disclosed". Bioorg Med Chem Lett. 2009 Apr 15; 19(8): 2211-4 has an abstract, which states: "Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N(1)-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC(50) value of 7.5 microM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7". US4689338 has an abstract, which states: "1H-Imidazo[4,5-c]quinolin-4-amines which are antivirals. Pharmacological methods of using such compounds and pharmaceutical compositions containing such compounds are also described". SUMMARY According to an aspect defined in claim 1, described herein is a crystal form of resiquimod in the form of a sulfate salt, wherein the sulfate salt is a monosulfate salt and an anhydrate, and the crystal form has an x-ray powder diffraction spectrum that comprises peaks at 7.6 ±0.2 degrees 2θ, 11.7 ±0.2 degrees 2θ, and 18.2 ±0.2 degrees 2θ. In one embodiment, the crystal form is included in a pharmaceutical composition useful for treating a disease or condition. In one embodiment, the disease or condition is cancer. In some embodiments, pharmaceutical compositions are described including resiquimod in the form of a sulfate salt in crystal form A. The sulfate salt is a monosulfate salt and an anhydrate. This crystal form can be prepared in an appropriate dosage from. Also described herein, in implementations, is resiquimod in the form of a sulfate salt in crystal form A characterized by x-ray powder diffraction spectrum that comprises peaks at about 7 to about 8 degrees 2θ, about 13.5 to about 14.5 degrees 2θ, about 18 to about 19 degrees 2θ, and/or about 15 to about 16 degrees 2θ. The sulfate salt in crystal form A can be stable at room temperature for at least about 2 days or at least about 1 week. Also described herein, in implementations, are pharmaceutical compositions comprising a crystal form of a compound of Formula I: Formula I can be a compound having a formula 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinoline-2-methanol hemihydrate, 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]-quinoline-1-ethanol, 2-ethoxymethyl-1-(2-methylpro