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WO2025032195A1 - Forme cristalline h1 de l'hémihydrate de 5-((3r,55)-3-amino-5-trifluorométhyl-pipéridin-1-yl)-quinoléine-8-carbonitrile - Google Patents

Forme cristalline h1 de l'hémihydrate de 5-((3r,55)-3-amino-5-trifluorométhyl-pipéridin-1-yl)-quinoléine-8-carbonitrile Download PDF

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Publication number
WO2025032195A1
WO2025032195A1 PCT/EP2024/072511 EP2024072511W WO2025032195A1 WO 2025032195 A1 WO2025032195 A1 WO 2025032195A1 EP 2024072511 W EP2024072511 W EP 2024072511W WO 2025032195 A1 WO2025032195 A1 WO 2025032195A1
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WIPO (PCT)
Prior art keywords
peaks
crystalline polymorph
disease
degrees
expressed
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PCT/EP2024/072511
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English (en)
Inventor
Analia Ivanna CHAMORRO ORUE
Sven HAFERKAMP
Dominique Anna BOCK
Anna MELLOR
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of WO2025032195A1 publication Critical patent/WO2025032195A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • a crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate is provided herein. Processes for preparing the polymorph and pharmaceutical composition comprising the polymorph are also disclosed.
  • Enpatoran is a potent and selective dual toll-like receptor (TLR) 7/8 inhibitor in clinical development, including for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE).
  • TLR toll-like receptor
  • CLE/SLE systemic lupus erythematosus
  • the compound may be prepared according to the methods provided in WO 2017/106607.
  • Polymorphism refers to the occurrence of different crystalline forms of a single compound.
  • a single compound may give rise to a variety of polymorphic forms, each having different solid-state physical properties, such as different solubility, melting point, stability, dissolution rates and/or different X-ray diffraction peaks. Due to the possibility of variable solubility and/or stability of different polymorph, identifying the existence of polymorphs of pharmaceutical compounds is important for providing pharmaceutical products having predictable solubility profiles. It may be desirable to investigate solid state forms of a drug, including polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Unfortunately, the existence of particular polymorphic forms and their physical properties is unpredictable.
  • a crystalline form of a therapeutic agent like 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8- carbonitrile, or a salt or hydrate thereof, retains appropriate polymorphic and chemical stability, solubility, and other physicochemical properties over time and among various manufactured batches of the agent. If the physical or chemical properties vary with time and/or among batches, the administration of a therapeutically effective dose may become problematic and may lead to inconsistent dosages or to ineffective therapy. Therefore, it is important to choose a polymorphic form of the agent that is stable, is manufactured reproducibly, and has physicochemical properties favorable for its use as a therapeutic agent. [0006] However, the art remains unable to predict which crystalline form of an agent will have a combination of the desired properties and will be suitable for human administration, and how to make the agent in such a crystalline form.
  • the disclosure provides a crystalline polymorphic form of 5- ((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate, termed herein Form Hl.
  • the polymorphic form described herein is useful in the treatment of immune disorders, including TLR7/8-related diseases, such as cutaneous and systemic lupus erythematosus (CLE/SLE).
  • the disclosure provides a composition comprising 5-((3R,5S)-3- amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl.
  • An embodiment provides a pharmaceutical composition comprising Form Hl described herein, and one or more pharmaceutically acceptable carriers or excipients.
  • the disclosure provides methods of treating diseases responsive to the administration of a dual toll-like receptor (TLR) 7/8 inhibitor by the administration of a pharmaceutical dosage form comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl.
  • TLR dual toll-like receptor
  • Another aspect provides methods of treating a disease or disorder modulated by TLR 7/8, comprising administering to a mammal in need of such treatment an effective amount of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl.
  • the method may comprise the administration of a composition(s) comprising Form Hl alone or in combination with one or more additional polymorphs or compounds having inhibitory properties for TLR 7/8.
  • Another aspect provides the use of 5-((3R,5S)-3-amino-5-(trifluoromethyl)- piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl in the manufacture of a medicament for the treatment of an immune disorder.
  • Figure 1 shows the Powder X-ray diffractogram of Form Hl.
  • Figure 2 shows the single crystal structure of Form Hl.
  • Figure 3 shows the DSC scan of Form Hl (5 K/min).
  • Figure 4 shows the TGA scan of Form Hl form (5 K/min).
  • Figure 5 shows the Water Vapor Sorption Isotherm (25 °C) of Form Hl.
  • Figure 6 shows the SEM-Images of Form Hl (magnification: left: lOOx; middle:
  • polymorph or “polymorphic form” refer to a crystallographically distinct form of a substance.
  • the practical physical characteristics of a polymorphic form are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance.
  • Different polymorphs of the same compound may have different physical, chemical, biological and/or spectroscopic properties.
  • different polymorphic forms may have different stability properties.
  • a particular polymorphic form may be more sensitive to relative humidity, heat and/or light.
  • differences in stability result from changes in chemical reactivity, such as and without limitation, differential oxidation.
  • Such properties may provide for more suitable product qualities such as a dosage form that is more resistant to discoloration when comprised of a particular polymorph.
  • a particular polymorphic form may have a different dissolution rate thereby providing, for example, a more desirable bioavailability.
  • a particular polymorphic form may provide different compressibility and/or density properties, thereby providing more desirable characteristics for formulation and/or product manufacturing.
  • Mechanical characteristics may differ between polymorphs also. For example and without limitation, tablets having a higher ratio of a particular polymorph may be more resistant to crumbling on storage.
  • the different physical properties of polymorphs may affect their processing. For example, a particular polymorph may be more or less likely to form solvates or may be more difficult to filter and/or wash.
  • Polymorphs can be detected, identified, classified and characterized using well- known techniques such as, but not limited to, powder X-ray diffractometry (PXRD), single crystal X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetry (TGA), vibrational spectroscopy, solution calorimetry, solid state nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, Raman spectroscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography, quantitative analysis, solubility, and rate of dissolution.
  • PXRD powder X-ray diffractometry
  • DSC differential scanning calorimetry
  • TGA thermogravimetry
  • vibrational spectroscopy solution calorimetry
  • solid state nuclear magnetic resonance (NMR) infrared
  • IR infrared
  • Raman spectroscopy Raman spectroscopy
  • SEM scanning electron microscopy
  • peak refers a feature that one skilled in the art would recognize as not attributable to background noise.
  • the invention provides a crystalline polymorph of 5-((3R,5S)-3- amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl characterized by one or more peaks from the powder X-ray diffraction (PXRD) (Cu-Kai radiation), presented in degrees 29 ⁇ 0.2°, wherein the peaks comprise 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4 and 26.9. 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4 and 26.9.
  • PXRD powder X-ray diffraction
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, or each of the PXRD peaks 7.2, 9.7, 13.4, 14.3, 17.0, 17.8, 19.9, 20.6, 21.5, 21.9, 22.2, 22.6, 23.0, 23.5, 24.1, 25.1, 25.5, 25.8, 26.4 and 26.9. All PXRD peaks provided herein are measured with Cu-Kai radiation in degrees 29 and include ⁇ 0.2 degrees.
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by PXRD peaks comprising a peak at 13.4.
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by PXRD peaks comprising peaks at 9.7 and 13.4.
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by PXRD peaks comprising peaks at 7.2, 9.7 and 13.4.
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by PXRD peaks comprising peaks at 7.2, 9.7, 13.4 and 22.2.
  • the crystalline polymorph of 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl may be characterized by PXRD peaks comprising peaks at 7.2, 9.7, 13.4, 21.5 and 22.2.
  • compositions comprising 5-((3R,5S)-3-amino- 5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl.
  • the composition comprising Form Hl may compromise Form Hl alone or in combination with one or more additional polymorphs or compounds having inhibitory properties for TLR 7/8.
  • Enpatoran compositions comprising crystalline polymorph Form Hl may comprise Form Hl in any quantity. Compositions may comprise less than about 1 % Form Hl.
  • Compositions may comprise 1 % to 100% of Form Hl. Compositions may comprise 50 % to 100% of Form Hl. Compositions may comprise 80 % to 100% of Form Hl. Compositions may comprise 90 % to 100% of Form Hl. Compositions may comprise 5% to 99% of Form Hl. Compositions may comprise 10% to 95% Form Hl. Compositions may comprise 15% to 95% Form Hl. Compositions may comprise 1 % to 80% Form Hl. Compositions may comprise 1% to 75% Form Hl. Compositions may comprise 1 % to 70% Form Hl.
  • compositions may comprise 1% to 65% Form Hl. Compositions may comprise 1% to 60% Form Hl. Compositions may comprise 1 % to 55% Form Hl. Compositions may comprise 1 % to 50% Form Hl. Compositions may comprise 1 % to 25% Form Hl. Compositions may comprise 1 % to 20% Form Hl. Compositions may comprise 1 % to 15% Form Hl.
  • compositions may comprise 1 % to 10% Form Hl. Compositions may comprise 1% to 5% Form Hl.
  • compositions comprising Form Hl described herein, and one or more pharmaceutically acceptable carriers or excipients.
  • pharmaceutically acceptable carrier or excipient refers to a non-toxic carrier, adjuvant, excipient or vehicle that does not interfere with the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers or excipients that may be used in the pharmaceutical compositions of Form Hl include any such excipients known in the art.
  • compositions of this invention may be orally administered in any orally acceptable dosage form.
  • exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient may be combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents are optionally also added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound comprising Form Hl may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as,
  • Solid compositions of a similar type are also employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • the disclosure provides methods of treating diseases responsive to the administration of a dual toll-like receptor (TLR) 7/8 inhibitor by the administration to a patient in need thereof a pharmaceutical dosage form comprising 5-((3R,5S)-3-amino-5- (trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile hemihydrate Form Hl .
  • TLR dual toll-like receptor
  • patient or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • Another aspect provides methods of treating a disease or disorder modulated by TLR 7/8, comprising administering to a mammal in need of such treatment an effective amount of a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l- yl)quinoline-8-carbonitrile hemihydrate Form Hl.
  • the method may comprise the administration of a composition(s) comprising Form Hl alone or in combination with one or more additional polymorphs or compounds having inhibitory properties for TLR 7/8.
  • the present disclosure furthermore relates to a method for treating or preventing a disease or disorder in a subject, such as a TLR7/8 related disease or disorder, comprising administering to said subject an effective amount of a composition(s) comprising Form Hl.
  • a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8-carbonitrile
  • Form Hl may be an autoimmune disease, for instance, one characterized by joint pain, antinuclear antibody positivity, malar rash, or discoid rash.
  • the autoimmune disease is associated with the skin, muscle tissue, and/or connective tissue.
  • the autoimmune disease is not evidenced in the individual by skin, muscle tissue, and/or connective tissue symptoms.
  • the autoimmune disease is systemic.
  • Autoimmune diseases that may be treated or prevented by administering a composition comprising 5-((3R,5S)-3-amino-5-(trifluoromethyl)piperidin-l-yl)quinoline-8- carbonitrile Form Hl include, without limitation, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), lupus, such as systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, myositis, such as dermatomyo
  • RA
  • the autoimmune disease may also be, without limitation, polyangiitis overlap syndrome, Kawasaki's disease, sarcoidosis, glomerulonephritis, and cryopathies.
  • the autoimmune disease is selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic onset arthritis, and irritable bowel syndrome.
  • MCTD mixed connective tissue disease
  • APS antiphospholipid syndrome
  • systemic onset arthritis and irritable bowel syndrome.
  • the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis, and type I diabetes.
  • the autoimmune disease is rheumatoid arthritis.
  • the autoimmune disease is autoimmune pancreatitis (AIP).
  • the autoimmune disease is glomerulonephritis.
  • the autoimmune disease is pyelitis.
  • the autoimmune disease is sclerosing cholangitis.
  • the autoimmune disorder is psoriasis.
  • the autoimmune disease is a rheumatoid disease or disorder.
  • the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin disease, and multiple sclerosis.
  • SLE systemic lupus erythematosus
  • the autoimmune disease may be cutaneous and systemic lupus erythematosus (CLE/SLE).
  • CLE/SLE systemic lupus erythematosus
  • any of the above-mentioned autoimmune diseases is a TLR7/8-related autoimmune disease.
  • Form Hl is characterised by the following physical properties. Thermal behaviour shows dehydration ⁇ 100 °C, followed by melting of anhydrous form Al at -165 °C. TGA shows weight loss of -2.9 % (w/w) up to 130 °C which can be clearly assigned to degradation of 0.5 mol water. DSC and TGA profiles are displayed in Figures 3 and 4, respectively.
  • the DSC scan of Form Hl was acquired on a Mettler-Toledo DSC1 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.
  • the TGA scan of Form Hl was acquired on a Mettler-Toledo TGA 851 with a heating rate of 5 K/min, using nitrogen purge gas at 50 mL/min.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un polymorphe cristallin de l'hémihydrate de 5-((3R,5S)-3-amino-5-(trifluorométhyl)pipéridin-1-yl)quinoléine-8-carbonitrile. L'invention concerne également des procédés pour préparer le polymorphe et une composition pharmaceutique comprenant le polymorphe.
PCT/EP2024/072511 2023-08-09 2024-08-08 Forme cristalline h1 de l'hémihydrate de 5-((3r,55)-3-amino-5-trifluorométhyl-pipéridin-1-yl)-quinoléine-8-carbonitrile Pending WO2025032195A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23190665.2 2023-08-09
EP23190665 2023-08-09

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WO2025032195A1 true WO2025032195A1 (fr) 2025-02-13

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PCT/EP2024/072511 Pending WO2025032195A1 (fr) 2023-08-09 2024-08-08 Forme cristalline h1 de l'hémihydrate de 5-((3r,55)-3-amino-5-trifluorométhyl-pipéridin-1-yl)-quinoléine-8-carbonitrile

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106607A1 (fr) 2015-12-17 2017-06-22 Merck Patent Gmbh Antagonistes de tlr7/8 polycyliques et leur utilisation dans le traitement de maladies immunes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106607A1 (fr) 2015-12-17 2017-06-22 Merck Patent Gmbh Antagonistes de tlr7/8 polycyliques et leur utilisation dans le traitement de maladies immunes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"European Pharmacopeia"

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