[go: up one dir, main page]

WO2025017032A1 - Sels de chlorhydrate cristallins micronisés de composés antiviraux inhibiteurs d'hélicase-primase - Google Patents

Sels de chlorhydrate cristallins micronisés de composés antiviraux inhibiteurs d'hélicase-primase Download PDF

Info

Publication number
WO2025017032A1
WO2025017032A1 PCT/EP2024/070165 EP2024070165W WO2025017032A1 WO 2025017032 A1 WO2025017032 A1 WO 2025017032A1 EP 2024070165 W EP2024070165 W EP 2024070165W WO 2025017032 A1 WO2025017032 A1 WO 2025017032A1
Authority
WO
WIPO (PCT)
Prior art keywords
micronized
crystalline form
hci salt
compounds
dgo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/070165
Other languages
English (en)
Inventor
Gerald Kleymann
Christian Gege
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innovative Molecules GmbH
Original Assignee
Innovative Molecules GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Innovative Molecules GmbH filed Critical Innovative Molecules GmbH
Publication of WO2025017032A1 publication Critical patent/WO2025017032A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention provides micronized solid crystalline forms of the hydrochloride salt of specific antiviral helicase-primase inhibitor compounds, compositions thereof, methods of producing the same, and methods of using the same in the treatment or prophylaxis of herpes simplex infections and -mediated diseases.
  • herpes labialis and herpes genitalis The pandemic of viral infections has plagued civilization since ancient times, causing mucocutaneous infection such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally herpes simplex virus 1 and 2 (HSV-1 and HSV- 2) infections are the cause of life-threatening (encephalitis) or sight-impairing disease (keratitis), especially in neonates, elderly and the immunocompromised patient population such as transplant or cancer patients or patients with an inherited immunodeficiency syndrome or disease. After infection the alpha herpesviridae persist for life in neurons of the host in a latent form, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available.
  • vaccines interleukins, interferones, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or non-specific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir and famciclovir as the first choice of treatment.
  • the known aminothiazoles are the most potent drugs in development today. These antiviral agents act by inhibiting the herpesviral helicase primase, display low resistance rates in vitro and superior efficacy in animal models compared to nucleosidic drugs, however, development is hampered by off-target carbonic anhydrase activity, reduced neuronal tissue and brain penetration and an unusual pharmacokinetic profile.
  • Herpes viruses are neurotrophic viruses, which means that after infection they enter and settle in neuronal tissue leading to a persisting presence of herpes viruses for life in neurons of the host in a latent form and a permanent neuronal exposure. Such permanent neuronal exposure with latent forms of herpes viruses is the reason for life-long risk of recurrent and periodically reactivating herpes infections often resulting in significant psychosocial distress for the patient.
  • herpesvirus encephalitis or herpes simplex encephalitis; HSE
  • HSE herpes simplex encephalitis
  • the virus lies dormant in the ganglion of the trigeminal cranial nerve or in the neuronal tissue and gains access to the brain where it causes HSE. It is therefore important to provide highly active antiviral drugs allowing to treat and eliminate also (dormant) herpes viruses in neuronal tissue and nerves and therewith avoid recurrence and reactivation of herpes infections or even the severe implications like HSE.
  • Known antiviral drugs as e.g. the known aminothiazoles, having insufficient efficacy to enter neuronal tissue or to cross the blood brain barrier to enter the brain are not able to provide an effective and eradicative cure for treating also latent or dormant forms of herpes viruses or even HSE.
  • HCI salts hydrochloride salts of such compounds IM-250 according to the Formula (I): with Y selected from CH3 or CD3, or more specifically having the following formulas:
  • WO2017/174640 describes the free base of IM-250 in its racemic form
  • WO2019/068817 describes both enantiomers of IM-250 and pharmaceutically acceptable salts thereof, respectively.
  • W02022/090409 describes deuterated analogs of IM-250 and pharmaceutically acceptable salts thereof.
  • Crystallisation or salt formation may positively influence important drug properties, such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, developability and physical/chemical stability.
  • the present invention relates to novel, selected crystalline forms of the hydrochloride salt of the antiviral helicase-primase inhibitor IM-250 with Formula (I) in micronized form: wherein Y is selected from CH3 or CD3, or a co-crystal, hydrate or solvate thereof.
  • Figure 1 depicts a X-ray powder diffraction (XRPD) pattern of IM-250 HCI salt.
  • Figure 2 depicts a XRPD pattern of IM-250 HCI salt when crystallized from EtOH.
  • Figure 3 depicts a XRPD pattern of deuterated IM-250 HCI salt (d3-IM-250 HCI salt).
  • Figure 10 overlaid XRPD profiles for the native IM-250 HCI salt batch and the same batch after micronization.
  • Figure 11 overlaid DSC profiles for the native IM-250 HCI salt batch and the same batch after micronization.
  • Figure 14 granulometric profile of d3-IM-250 HCI salt crystals (cumulated particle size distribution).
  • Figure 15 distribution histogram of d3-IM-250 HCI salt PSD assessment.
  • Figure 16 particle size distribution by laser diffraction of micronized d3-IM-250 HCI salt.
  • Embodiments that reference throughout this specification to "a crystalline form” include the crystalline, salt, co-crystal, hydrate and/or solvate of Formula (I) disclosed herein.
  • Deuteration means that one or more hydrogen atom(s) of the compound of Formula (I) is/are replaced by deuterium ( 2 H, represented by “D”).
  • residue Y represents CD3. It has surprisingly been found, that such deuterated aminothiazole compounds exhibit increased resistance to metabolism and thus be useful for increasing the half-life of a compound of Formula (I), compared to a respective undeuterated compound, when administered to a mammal, e.g. a human. See, for example, Foster in Trends Pharmacol. Sci. 1984:5;524.
  • Such deuterated aminothiazole compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium (see Experimental Section for details).
  • Deuterium labelled or substituted therapeutic compounds of the disclosure surprisingly turned out to have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with deuterium turned out to afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • DMPK drug metabolism and pharmacokinetics
  • ADME absorption, distribution, metabolism and excretion
  • the concentration of deuterium may be defined by an isotopic enrichment factor.
  • any atom not specifically designated as a particular isotope is meant to represent any stable or radioactive isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition (about 99.98% hydrogen).
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium with an isotopic purity of at least 50%, preferably an isotopic purity of at least 95%, more preferably an isotopic purity of at least 99%.
  • the percentage of deuterium incorporation can be obtained by quantitative analysis using a number of conventional methods, such as mass spectroscopy (peak area) or by quantifying the remaining residual 1 H-NMR signals of the specific deuteration site compared to signals from internal standards or other, non-deuterated 1 H signals in the compound.
  • isotopic enrichment factor at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at the position and the natural abundance of deuterium at that position.
  • an isotopic enrichment factor of 3500 means that the amount of deuterium at the particular position is 3500-fold the natural abundance of deuterium, or that 52.5% of the compounds have deuterium at the particular position (i.e., 52.5% deuterium incorporation at the given position).
  • the abundance of deuterium in the oceans of Earth is approximately one atom in 6500 hydrogen atoms (about 154 parts per million (ppm)). Deuterium thus accounts for approximately 0.015 percent (on a weight basis, 0.030 percent) of all naturally occurring hydrogen atoms in the oceans on Earth; the abundance changes slightly from one kind of natural water to another.
  • the deuterated compounds of this disclosure are preferably characterized by an isotopic enrichment factor of at least 6300, or by a deuteration degree of at least 95%. More preferably by an isotopic enrichment factor of at least 6500, or by a deuteration degree of at least 98%.
  • any formula or structure given herein, is also intended to represent compounds comprising in addition further isotopically labeled atoms.
  • additional isotopes that can be incorporated into compounds of the disclosure include further isotopes of hydrogen, as well as isotopes of carbon, nitrogen, oxygen and fluorine, such as, but not limited to 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F and 35 S.
  • the disclosure further comprises various isotopically labeled compounds into which radioactive isotopes such as 3 H, 13 C and 14 C are incorporated.
  • Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or radioactive treatment of patients.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, and/or emulsifier, or a combination of one or more of the above which has been approved by the United States Food and Drug Administration (FDA), European Medicines Agency (EMA) or other national counterparts as being acceptable for use in humans or domestic animals.
  • FDA United States Food and Drug Administration
  • EMA European Medicines Agency
  • a “pharmaceutical composition” refers to a formulation of a compound of the disclosure (e.g. a compound of Formula (I)) and a medium (administration form) generally accepted in the art for the delivery of the biologically active compound to mammals, e.g. humans.
  • a medium includes all pharmaceutically acceptable excipients therefor.
  • an effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, an infection or one or more of the symptoms of a disorder, disease, or condition being treated.
  • the term “effective amount” also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • Prevention or “preventing” or “prophylaxis” means any treatment of an infection, disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of an infection, disease or condition.
  • Treating” and “treatment” of a disease include the following:
  • the terms “subject” or “patient” refer to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment.
  • the methods described herein may be useful in human therapy and/or veterinary applications.
  • the subject is a mammal (or the patient).
  • the subject (or the patient) is human, domestic animals (e.g. dogs and cats), farm animals (e.g. cattle, horses, sheep, goats, and pigs) and/or laboratory animals (e.g. mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys).
  • the subject (or the patient) is a human.
  • “Human (or patient) in need thereof’ refers to a human who may have or is suspect to have an infection or disease or conditions that would benefit from certain treatment; for example, being treated with the compounds disclosed herein according to the present application.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter perse. For example, description referring to “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g. reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • thermogram substantially as shown in
  • a DSC thermogram or a TGA thermogram includes a pattern, thermogram or spectrum that is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art.
  • solvates such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol.
  • a “solvate” is formed by the interaction of a solvent and a compound. When the solvent is water, the “solvate” is a “hydrate”. It is understood, that also a salt of the present disclosure can include a solvate.
  • Suitable solvents for salt- and solvent formation of the compounds according to Formula (I) as defined herein comprise: acetonitrile, dichloromethane (DCM), alcohols, such as especially methanol, ethanol, 2-propanol (iso-propanol), aldehydes, ketones, especially acetone, ethers, e.g. tetrahydrofuran (THF) or dioxane, esters, e.g. ethyl acetate, or alkanes, such as especially pentane, hexane, heptane or cyclohexane and water, and mixtures thereof.
  • DCM dichloromethane
  • alcohols such as especially methanol, ethanol, 2-propanol (iso-propanol)
  • ketones especially acetone
  • ethers e.g. tetrahydrofuran (THF) or dioxane
  • esters e.g. ethy
  • Micron ization is the process of reducing the average diameter of a solid material's particles, e.g. by friction.
  • Traditional techniques for micronization focus on mechanical means, such as milling and grinding. Modern techniques make use of the properties of supercritical fluids and manipulate the principles of solubility.
  • the term micronization usually refers to the reduction of average particle diameters to the micrometer range and is used to increase the efficacy of the solid material by e.g. improving solubility or bioavailability, however can beneficially influence other material properties like flow and conveying behaviour (for bulk materials), reactivity, abrasiveness, extraction and reaction behaviour, taste, compressibility, and many more.
  • dgo value is a percentile value, which refers to 90% (by volume) of the particles have a size that is less than or equal to the value.
  • dgo value of 20.0 pm means 90% (by volume) of the particles is less than or equal to 20.0 pm in size
  • a dgo value of 10.0 pm means 90% (by volume) of the particles is less than or equal to 10.0 pm in size.
  • the “dgo value” can be derived from a particle-size distribution (PSD) assessment by laser diffraction (granulometry analysis).
  • the terms “d 1 o”, “d25”, “dso” and/or “d/s” define the respective percentage (by volume) of the particles having a size that is less than or equal to the value.
  • dgo particle size distribution means that 90% (per volume) of the particles have a particle size lower than the dgo value expressed in pm.
  • d particle size distribution mean that 10%, 25%, 50% and/or 75% (per volume) of the particles have a particle size above or below the respectively defined dw, d25, dso and/or d?s value expressed in pm.
  • d-values relate in particular to the cumulative particle volume in the particle distribution curve.
  • This patent application discloses new micronized crystalline forms of antiviral aminothiazole compounds with a more suitable pharmacokinetic and stability profile (e.g. due to improved solubility and bioavailability allowing a higher passage of the antiviral drug compound into neuronal tissue and into the brain). Furthermore, the new micronized crystalline forms of antiviral aminothiazole compounds are characterized by improved compound stability and improved bioavailability, making them more suitable for pharmaceutical development and use as a medicament.
  • Micronized crystalline HCI salt forms of compounds of Formula (I) may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition.
  • IM-250 HCI salt for example, exhibits advantageous physical properties such as good physical and chemical stability, good aqueous solubility and good bioavailability, while being non-hygroscopic.
  • Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability etc.), manufacturability (e.g. ease of handling, ability to consistently prepare doses of known strength) and stability (e.g. thermal stability, shelf life etc.) of a pharmaceutical drug product or active ingredient.
  • micronized crystalline hydrochloride salt forms of the compound of Formula (I) may provide additional advantages such as improving: the manufacturing process of the compound, the stability or storability of a drug product form of the compound, the stability or storability of a drug substance of the compound and/or the bioavailability and/or stability of the compound as an active agent.
  • novel micronized solid forms such as micronized crystalline forms of compounds of Formula (I) are disclosed.
  • the micronized, crystalline form is a compound according to Formula (I) wherein Y is selected from CH3 and CD3; or a co-crystal, hydrate or solvate thereof.
  • the micronized, crystalline form is a compound with the following structure: or a co-crystal, hydrate or solvate thereof.
  • micronized, crystalline form is of the following structure:
  • the micronized, crystalline form is a compound with the following structure: or a co-crystal, hydrate or solvate thereof.
  • micronized, crystalline form is of the following structure:
  • a further embodiment of the invention relates to a micronized HCI salt of compound IM-250, which is IM-250 HCI salt with the structure
  • such micronized IM-250 HCI salt is characterized by an XRPD pattern comprising (characteristic peaks) degree 20-reflections ( ⁇ 0.3 degrees 20) at 13.7, 17.7 and 22.8 degrees.
  • micronized IM-250 HCI salt is characterized by an XRPD pattern comprising degree 20-reflections ( ⁇ 0.3 degrees 20) at 13.7, 17.7 and 22.8 degrees and one, two or three of the degree 20-reflections ( ⁇ 0.3 degrees 20) at 17.0, 19.8 and 21.8 degrees.
  • micronized IM-250 HCI salt is characterized by an XRPD pattern comprising degree 20-reflections ( ⁇ 0.3 degrees 20) at 13.7, 17.0, 17.7, 19.8, 21.8 and 22.8 degrees.
  • micronized IM-250 HCI salt is characterized by an XRPD pattern comprising at least 4 of the following peaks: 13.7, 17.0, 17.7, 19.8, 21.8 and 22.8 degrees 20 ( ⁇ 0.3 degrees 20).
  • micronized IM-250 HCI salt has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine of the degree 20-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 1.
  • micronized IM-250 HCI salt has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine of the degree 20-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 2.
  • such micronized IM-250 HCI salt exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 1.
  • such micronized IM-250 HCI salt exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 2.
  • XRPD X-ray powder diffraction
  • micronized IM-250 HCI salt has a thermogravimetric analysis thermogram revealing a mass loss of about 9.8% upon heating with an onset/endset temperature of about 151/170°C.
  • micronized IM-250 HCI salt has a thermogravimetric analysis thermogram revealing a onset temperature of decomposition of about 221 °C.
  • micronized IM-250 HCI salt with the structure wherein hydrochloride and (S)-2-(2',5'-difluoro-[1 ,1'-biphenyl]-4-yl)-/V-methyl-A/-(4-methyl-5-(S- methylsulfonimidoyl)thiazol-2-yl)acetamide are in a 1 to 1 ⁇ 0.2 molar ratio.
  • the IM-250 HCI salt is micronized with a dgo value of less than or equal to about 20.0 pm, such as ranging from about 1.0 to 20.0 pm, or ranging from about 2.0 to 12.0 pm.
  • the IM-250 HCI salt is micronized with a dgo value of less than or equal to 20.0 pm, such as ranging from 1.0 to 20.0 pm, or ranging from 2.0 to 12.0 pm.
  • the IM-250 HCI salt is micronized to a dgo value ranges from about 1 .0 to about 2.0 pm, from greater than about 2.0 to about 3.0 pm, from greater than about 3.0 to about 4.0 pm, from greater than about 4.0 to about 6.0 pm, from greater than about 6.0 to about 8.0 pm, from greater than about 8.0 to about 10.0 pm, or from greater than about 10.0 to about 12.0 pm.
  • the dgo value of the IM-250 HCI salt ranges from about 2.0 to about 5.0 pm, for example, the dgo value is 3.0, 3.5, 3.9 or 4.0 pm.
  • the dgo value of the IM-250 HCI salt ranges from about 9.0 to about 12.0 pm, for example, the dgo value is 9.5 or 10.0 pm. In a preferred embodiment, the dgo value of the IM-250 HCI salt is less than or equal to about 11 .0 pm or is less than or equal to about 10.0 pm.
  • the dgo value of the IM-250 HCI salt is less than or equal to 11 .0 pm or is less than or equal to 10.0 pm.
  • the dgo value of the IM-250 HCI salt is less than or equal to about 6.0 pm.
  • the dgo value of the IM-250 HCI salt is less than or equal to 6.0 pm.
  • the dgo value of the IM-250 HCI salt is less than or equal to about 4.0 pm.
  • the dgo value of the IM-250 HCI salt is less than or equal to 4.0 pm.
  • micronized hydrochloride salt IM-250 HCI salt
  • micronized IM-250 HCI salt is a particularly preferred embodiment of the present invention.
  • a further embodiment of the invention relates to a micronized deuterated compound of the IM- 250 HCI salt (dg-IM-250 HCI salt) with the structure
  • micronized d3-IM-250 HCI salt is characterized by an XRPD pattern comprising (characteristic peaks) degree 20-reflections ( ⁇ 0.3 degrees 20) at 13.8,
  • micronized d3-IM-250 HCI salt is characterized by an XRPD pattern comprising degree 20-reflections ( ⁇ 0.3 degrees 20) at 13.8, 17.8 and 21 .8 degrees and one, two, three, four or five of the degree 20-reflections ( ⁇ 0.3 degrees 20) at 11 .3, 11 .9, 19.8, 21.0 and 21 .3 degrees.
  • micronized d3-IM-250 HCI salt is characterized by an XRPD pattern comprising degree 20-reflections ( ⁇ 0.3 degrees 20) at 11 .3, 11 .9, 13.8, 17.8, 19.8, 21 .0, 21 .3 and
  • micronized da-IM-250 HCI salt is characterized by an XRPD pattern comprising at least 4 of the following peaks: 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3 and 21.8 degrees 20 ( ⁇ 0.3 degrees 20).
  • micronized d3-IM-250 HCI salt has an XRPD pattern displaying at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine of the degree 20-reflections with the greatest intensity as the XRPD pattern substantially as shown in FIG. 3.
  • micronized d3-IM-250 HCI salt has a thermogravimetric analysis thermogram revealing a mass loss of about 7.8% upon heating with an onset/endset temperature of about 149/167°C.
  • micronized d3-IM-250 HCI salt has a thermogravimetric analysis thermogram revealing a onset temperature of decomposition of about 225°C.
  • micronized d3-IM-250 HCI salt has a differential scanning calorimetry thermogram comprising an endotherm with an onset at about 188°C.
  • a micronized d3-IM-250 HCI salt may further be characterized by having a melting point of 188 to 194°C ( ⁇ 5°C).
  • micronized d3-IM-250 HCI salt with the structure wherein hydrochloride and (S)-2-(2',5'-difluoro-[1 ,1'-biphenyl]-4-yl)-/V-methyl-/ ⁇ /-(4-(methyl-d3)-5- (S-methylsulfonimidoyl)thiazol-2-yl)acetamide are in a 1 to 1 ⁇ 0.2 molar ratio.
  • the d3-IM-250 HCI salt is micronized with a dgo value of less than or equal to about 20.0 pm, such as ranging from about 1.0 to 20.0 pm, or ranging from about 2.0 to 12.0 pm.
  • the d3-IM-250 HCI salt is micronized with a dgo value of less than or equal to 20.0 pm, such as ranging from 1.0 to 20.0 pm, or ranging from 2.0 to 12.0 pm.
  • the d3-IM-250 HCI salt is micronized to a dgo value ranges from about 1 .0 to about 2.0 pm, from greater than about 2.0 to about 3.0 pm, from greater than about 3.0 to about 4.0 pm, from greater than about 4.0 to about 6.0 pm, from greater than about 6.0 to about 8.0 pm, from greater than about 8.0 to about 10.0 pm, or from greater than about 10.0 to about 12.0 pm.
  • the dgo value of the d3-IM-250 HCI salt ranges from about 2.0 to about 5.0 pm, for example, the dgo value is 3.0, 3.5, 3.9 or 4.0 pm. In some embodiments, the dgo value of the d3-IM-250 HCI salt ranges from about 9.0 to about 12.0 pm, for example, the dgo value is 9.5 or 10.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to about 11 .0 pm or is less than or equal to about 10.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to 11 .0 pm or is less than or equal to 10.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to about 6.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to 6.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to about 4.0 pm.
  • the dgo value of the d3-IM-250 HCI salt is less than or equal to 4.0 pm.
  • micronized deuterated HCI salt ds-IM-250 HCI salt
  • micronized crystalline deuterated IM-250 HCI salt d3-IM-250 HCI salt
  • a further aspect of the present invention relates to a pharmaceutical formulation, comprising one or more of the compounds of any of the above described embodiments.
  • a further aspect of the present invention relates to the compounds of any of the above described embodiments for the use as a medicament.
  • the invention relates to the described compounds for use in the treatment or prophylaxis of a disease or disorder associated with viral infections.
  • the invention relates to the described compounds for use in the treatment or prophylaxis of a disease or disorder, which is associated with viral infections caused by herpes viruses, such as in particular by Herpes simplex viruses, i.e. for the use in the treatment or prophylaxis of herpes infections, such as herpes simplex infections.
  • the invention relates to the described compounds for use in treating and eliminating latent (dormant) forms of herpes viruses in neuronal tissue and nerves, preferably for avoiding or preventing recurrence and reactivation of herpes infections or even severe implications associated therewith, such as herpes simplex encephalitis (HSE).
  • HSE herpes simplex encephalitis
  • the invention relates to the described compounds for use in the treatment or prophylaxis of neurodegenerative diseases caused by viruses, such as in particular Alzheimer's disease caused by viruses, in particular caused by Herpes simplex viruses.
  • the invention relates to the described compounds for the use in the treatment and prophylaxis of herpes infections, in particular Herpes simplex infections, in patients displaying Herpes labialis, Herpes genitalis and Herpes-related keratitis, Alzheimer's disease, encephalitis, pneumonia, hepatitis; in patients with a suppressed immune system, such as AIDS patients, cancer patients, patients having a genetic immunodeficiency, transplant patients; in new-born children and infants; in Herpes-positive patients, in particular Herpes-simplex-positive patients, in patients for suppressing recurrence (suppression therapy); or for use in patients, in particular in Herpes-positive patients, in particular Herpes-simplex-positive patients, who are resistant to nucleosidic antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and/or foscarnet or
  • the compounds according to the present invention are considered for the use in the prophylaxis and treatment of the respective disorders and diseases in humans as well as in animals.
  • the invention relates to the use of the compounds as described herein for the preparation of a medicament.
  • the invention relates to a method of preventing or treating a disease or disorder associated with viral infections, such as a disease or disorder, which is associated with viral infections caused by herpes viruses, such as in particular by Herpes simplex viruses as well as a method of treating and eliminating latent (dormant) forms of herpes viruses in neuronal tissue and nerves, preferably for avoiding or preventing recurrence and reactivation of herpes infections or even severe implications associated therewith, such as herpes simplex encephalitis (HSE) or a method of preventing or treating neurodegenerative diseases caused by viruses, such as in particular Alzheimer's disease, said methods comprising administering to a human or animal in need thereof an effective amount of a compound or of a composition comprising said compounds as described herein.
  • a disease or disorder associated with viral infections such as a disease or disorder, which is associated with viral infections caused by herpes viruses, such as in particular by Herpes simplex viruses as well as a method of treating and eliminating latent (dor
  • the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2.0 percent to about 60.0 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray or as eye drops.
  • the tablets, pills, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatine; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavouring such as cherry or orange flavour.
  • the compounds used in the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, gels, ointments, aerosols and the like.
  • compounds of the present invention are administered orally or topical as eye drops, creams or gels, more preferably the compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention may also be present in combination with further active ingredients, in particular with one or more active ingredients exhibiting advantageous effects in the treatment of any of the disorders or diseases as described herein.
  • Very particularly the compounds of the present invention are present in a composition in combination with at least one further active substance being effective in treating a disease or disorder associated with viral infections (antiviral active compounds), preferably a disease or disorder being associated with viral infections caused by herpes viruses, such as in particular by Herpes simplex viruses, thus relating to a so called combination therapy.
  • the at least one further active substance being effective in treating a disease or disorder associated with viral infections or more preferably antiviral active compounds selected from the group consisting of nucleosidic drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, as well as compounds such as foscarnet and cidofovir.
  • antiviral active compounds selected from the group consisting of nucleosidic drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, as well as compounds such as foscarnet and cidofovir.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the compounds in micronized form as described herein and at least one pharmaceutically acceptable carrier and/or excipient and/or at least one further active substance being effective in treating a disease or disorder associated with viral infections (antiviral active compounds).
  • a further aspect of the invention relates to the use of the compounds described herein, which act as helicase primase inhibitors, in a combination therapy with oncolytic viruses for treating tumors, cancer or neoplasia.
  • a further embodiment of this additional aspect of the invention relates to a pharmaceutical composition for the use as an antidote in a combination therapy with oncolytic viruses for treating cancer, which comprises at least one helicase primase inhibitor as defined in any embodiment described herein, which acts to control, modulate, inhibit or shut off the activity of oncolytic viruses sensitive to said inhibitors used in cancer therapy, and which may further comprise at least one pharmaceutically acceptable carrier and/or excipient and/or at least one further active substance, such as antiviral active or immune modulating compounds, including checkpoint inhibitors, being effective in treating a disease or disorder associated with oncolytic viral infections used in the treatment of cancer.
  • a further embodiment of this additional aspect of the invention relates to the helicase primase inhibitor compounds or the pharmaceutical compositions of the present invention for the use in a combination therapy with oncolytic viruses as described in detail in W02020/109389, wherein the cancer to be treated is solid cancer, preferably the cancer disease is selected from liver cancer, lung cancer, colon cancer, pancreas cancer, kidney cancer, brain cancer, melanoma and glioblastoma etc.
  • a further embodiment of this additional aspect of the invention relates to the helicase primase inhibitor compounds or the pharmaceutical compositions of the present invention for the use in a combination therapy with oncolytic viruses as described in W02020/109389, wherein the oncolytic viruses are oncolytic herpesviruses.
  • a further embodiment of this additional aspect of the invention relates to the helicase primase inhibitor compounds or the pharmaceutical compositions of the present invention for the use in a combination therapy with oncolytic viruses as described in W02020/109389, wherein the cancer therapy comprises infusion, injection, intratumoral injection or topical or transdermal application of the oncolytic viruses or oncolytic virus infected cells and/or of the helicase primase inhibitors or the pharmaceutical composition comprising the same.
  • a further embodiment of this additional aspect of the invention relates to the helicase primase inhibitor compounds or the pharmaceutical compositions of the present invention for the use in a combination therapy with oncolytic viruses as described in W02020/109389, wherein the oncolytic viruses or oncolytic viruses infected cells are selected from an oncolytic wildtype, a clinical isolate or a laboratory herpesvirus strain or a genetically engineered or multi-mutated optionally attenuated or boosted oncolytic herpesvirus.
  • a further embodiment of this additional aspect of the invention relates to a kit comprising at least one of the helicase primase inhibitor compounds or the pharmaceutical composition of the present invention for the use in a combination therapy with oncolytic viruses as described in W02020/109389, and at least one oncolytic virus selected from a wildtype, a laboratory strain, a clinical isolate and a genetically engineered or multi-mutated oncolytic virus.
  • a further embodiment of this additional aspect of the invention relates to said kit for the use in the treatment of cancer as defined herein.
  • the helicase primase inhibitor compounds, pharmaceutical compositions or kits for the use in a combination therapy with oncolytic viruses as described herein may be applied to one or more of the following patient groups: infants; herpes-positive patients, in particular oncolytic herpes- simplex-positive patients, for suppressing recurrence or oncolytic viral shedding; patients, in particular herpes-positive patients, in particular oncolytic herpes-simplex-positive patients, who are resistant to nucleosidic antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and/or foscarnet or cidofovir.
  • nucleosidic antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and/or foscarnet or cidofovir.
  • a further aspect of the present invention relates to the preparation of the compounds of the Formula (I) in micronized form, including their co-crystals, hydrates or solvates.
  • the HCI salt compounds (I) can be prepared as described in in the above mentioned EP patent application EP22151820 and in the subsequent international application PCT/EP2023/050883, followed by a step of micronizing the resulting solid crystal forms until the desired dgo value and/or dgo particle size distribution is obtained.
  • micronization comprises milling, grinding, micronization by using supercritical fluids and by manipulating the principles of solubility.
  • the methods may further comprise a step of sieving.
  • any known technique can be used which is suitable to achieve the intended reduction of average particle diameters to the micrometer range.
  • micronization comprises the reduction of the particle size to dgo values and/or a dgo particle size distribution as defined herein.
  • micronization comprises reducing the particle size (dgo value / dgo particle size distribution) of the crystalline forms resulting from synthesis and recrystallization by a factor of about 10, preferably by a factor of at least 15, more preferably by a factor of at least 20, even more preferably by a factor of at least 25, in each case compared to the non-micronized form obtainable from the synthesis and (re-)crystallization process.
  • Particle size distributions might be measured using sieve analysis, or laser diffraction (international standard ISO 13320-1 ; for further laser diffraction analytical technologies see for example http://pharmazie-lehrbuch.de/kapitel/3-1.pdf), or electronic sensing zone, light obstruction, sedimentation or microscopy which are procedures well known by the person skilled in the art.
  • Sieving is one of the oldest methods of classifying powders by particle size distribution.
  • a further method includes the determination of the volume particle size distribution by TEM (see e.g. Clariant Analytical Services TECHNICAL SHEET 106 TEM-PumblegroUe).
  • the measurement of the particle size distributions are performed by laser diffraction according to Ph.Eur. 2.9.31 and USP ⁇ 429>.
  • the measurement is performed in suspension in water and Tween 80® using a measurement system from Beckman Coulter.
  • the sample suspension is performed using sonification and calculation of the particle size distribution is performed using Fraunhofer calculation model.
  • These laser diffraction analytical technologies yield volume weighted distributions.
  • the contribution of each particle in the distribution relates to the volume of that particle (equivalent to mass if the density is uniform), i.e. the relative contribution will be proportional to size.
  • PSD particle size distribution
  • micronized HCI salt compounds of the Formula (I) according to the invention may then be further processed and transferred into suitable pharmaceutical dosage forms, e.g. by filling into capsules, sachets or other comparable dosage forms, or by compressing the micronized particles into an suitable tablet form, including non-coated and coated tablets, retarded release tablet forms, chewable tablets etc.
  • suitable pharmaceutical dosage forms e.g. by filling into capsules, sachets or other comparable dosage forms, or by compressing the micronized particles into an suitable tablet form, including non-coated and coated tablets, retarded release tablet forms, chewable tablets etc.
  • XRPD analysis was performed on a Broker D2 Phase diffractometer using a copper anti-cathode, a mono-crystalline silicone sample holder and a position sensitive detector (LynxExe). Powder sample was loaded on a flat mono-crystalline silicone sample holder in a way to avoid preferred orientation and to sensure planarity of the speciem surface.
  • DSC Differential scanning calorimeter
  • DSC analysis was performed on a Q1000 TA Instruments analyzer. The sample to be analyzed was weighed in an aluminium capsule, which was then crimped and put into the calorimeter oven. Instrument operation conditions were as follows: heater ramp 10°C/min; final temperature 230°C or 240°C; carrier gas: nitrogen (Messer "qualite Azote 5.0") with flow rate of 50 mL/min.
  • TGA analysis was performed on a TA Instruments TGA Hi-Res 2950.
  • the sample was placed in an opened aluminium basket and analysed as follows: mass assay 5 mg; heating ramp 10°C/min; final temperature 500°C; carrier gas: nitrogen (Messer "qualite Azote 5.0") with flow rate of 95- 105 mL/min.
  • Analysis by optical microscopy is performed on a LEICA DMIRB microscope equipped with a digital camera and a motorized stage. Acquisition of microscopy patterns is performed with a Microvision Instruments image analysis station. A few milligrams of the tested sample are put onto a microscope slide with silicon oil, covered with a coverslip, dispersed by a soft pressure applied onto the coverslide and then analyzed.
  • PSD assessment granulometry analysis
  • soybean oil previously saturated with the crystalline material to analyze.
  • a few microliters are then dropped onto a microscope slide with coverslip and analyzed.
  • Image analysis is associated to statistical analysis of the detected particles surfaces in order to establish a granulometric profile.
  • IM-250 free base (205 mg, 470 pmol), obtainable as described for example as Example 7(-) in WO2019/068817, or as described in in the international application PCT/EP2023/050883, was solubilized in acetone (5 mL) by stirring on a rotary evaporator at 50°C and atmospheric pressure. A volume of 1 N HCI corresponding to a 1 :1 stoichiometry was the added. The solvent was then evaporated to dryness at 50°C leading to a film. This film was resuspended and solubilized in EtOH (4 mL) at rt. The solvent was then evaporated to dryness at 50°C leading to a meringue.
  • This film was resuspended and solubilized in isopropanol (1 mL) at 50°C, kept at rt leading to a partial demixing (after approx. 30 min) and then warmed again to 50°C for resolubilization. Very quickly, a strong crystallization occurred.
  • One additional heating (50°C) and cooling (rt) cycle was performed (each 20 min) and the the sample was kept at rt for 2 days. The supernatant solvent was removed and the powder was finally dried under a dynamic vacuum (70°C for 40 min) to obtain IM-250 HCI salt as colorless crystals.
  • FIG. 1 shows a XRPD pattern of IM-250 HCI salt. XRPD peaks were identified and are included in Table 1 below.
  • TGA and DSC analysis were performed.
  • the TGA analysis showed a mass loss of 9.8% upon heating with an onset/endset temperature of 151/170°C before the main thermal decomposition can be detected with an onset temperature of 221 °C.
  • the 9.8% mass loss can be attributed to the departure of the HCI moiety.
  • the DSC analysis revealed no true melting point. The not resolved double endothermic events observed from 160°C are concomitant to the loss of the HCI moiety observed on the TGA profile.
  • IM-250 free base (4.75 g), obtainable as described as Example 7(-) in WO2019/068817, was solubilized in acetone (150 mL) by stirring on a rotary evaporator at rt and atmospheric pressure. A volume of 1 N HCI corresponding to a 1 :1 stoichiometry was then added. The solvent was partially evaporated (about 100 mL) at 50°C. To better trap the water brought by the HCI solution, EtOH (50 mL) was added to the solution before performing a new evaporation up to a remaining volume of a few milliliters (syrupy liquid). The sample was then brought back at rt, leading to a beginning of crystallization.
  • FIG. 2 shows a XRPD pattern of IM-250 HCI salt. The XRPD peaks identified were similar as shown in FIG. 1 , indicating that the same HCI polymorph was produced.
  • Example 2 Synthesis of deuterated IM-250 HCI salt (ds-IM-250 HCI salt)
  • FIG. 3 shows a XRPD pattern of IM-250 HCI salt (ds-IM-250 HCI salt). XRPD peaks were identified and are included in Table 2 below.
  • TGA and DSC analysis were performed.
  • the TGA analysis showed a mass loss of 7.8% upon heating with an onset/endset temperature of 149/167°C before the main thermal decomposition can be detected with an onset temperature of 225°C.
  • the 7.8% mass loss can be attributed to the departure of the HCI moiety.
  • the DSC analysis revealed no true melting point, rather a wide endotherm with onset at about 188°C and peak at 194°C (transition enthalphy -15 J/g).
  • Example 3 Particle size distribution assessment of IM-250 HCI salt
  • PSD particle size distribution
  • IM-250 HCI salt was micronized at HOLOPHARM, leading to sample with a mean dgo value of
  • Figure 8 shows the particle size distribution of the micronized sample and Figure 9 a microscopy picture.
  • the micronized sample shows the same diffraction peak positions and the same DSC profile as the non-micronized bulk, indicating both samples comprise the same crystal form.
  • Example 5 Particle size distribution assessment of deuterated IM-250 HCI salt
  • PSD particle size distribution
  • Example 6 Micronization of deuterated IM-250 HCI salt ds-IM-250 HCI salt was micronized at HOLOPHARM in a similar manner, leading to sample with a mean dgo value of 3.0 pm.
  • Figure 16 shows the particle size distribution of the micronized sample and Figure 17 a microscopy picture. XRPD analyses did not evidence any differences in the diffraction peak positions and intensities of d3-IM-250 HCI salt before and after micronization. No change in the crystalline phase was observed.
  • Example 7 Micronization and PSD determination of IM-250 HCI salt (GMP-campaign)
  • the micronization was performed using spiral jet mill 100 from Hosokawa-Alpine.
  • Starting material was 1 .9 kg of IM-250 HCI salt with a PSD distribution according to Figure 18 with a dgo value of 139.8 pm.
  • the micronization was performed using nitrogen as milling as with a pressure of 5 bar.
  • the product is constantly transferred using a double screw feeder into the mill and collected in a fine filter bag after micronization and was isolated in 97% yield.
  • the particle size distribution is performed by laser diffraction according to Ph.Eur. 2.9.31 and USP ⁇ 429>.
  • the measurement is performed in suspension in water and Tween 80® using a measurement system from Beckman Coulter.
  • Example 8 Bioavailability of micronized IM-250 HCI salt/da-IM-250 HCI salt versus non- micronized matched pairs in male mice
  • Table 5 Effect of micronization for micronized IM-250 HCI salt/d3-IM-250 HCI salt in male mice on PK parameters compared to non-micronized matched pair

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formes cristallines solides micronisées du sel de chlorhydrate de composés inhibiteurs d'hélicase-primase antiviraux spécifiques selon Formule (I), des compositions de celles-ci, des procédés de production de celles-ci, et des procédés d'utilisation de celles-ci dans le traitement ou la prophylaxie d'infections et de maladies à médiation par herpès simplex.
PCT/EP2024/070165 2023-07-17 2024-07-16 Sels de chlorhydrate cristallins micronisés de composés antiviraux inhibiteurs d'hélicase-primase Pending WO2025017032A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23185927 2023-07-17
EP23185927.3 2023-07-17

Publications (1)

Publication Number Publication Date
WO2025017032A1 true WO2025017032A1 (fr) 2025-01-23

Family

ID=87378110

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/070165 Pending WO2025017032A1 (fr) 2023-07-17 2024-07-16 Sels de chlorhydrate cristallins micronisés de composés antiviraux inhibiteurs d'hélicase-primase

Country Status (1)

Country Link
WO (1) WO2025017032A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017174640A1 (fr) 2016-04-06 2017-10-12 Innovatives Molecules Gmbh Dérivés d'aminothiazole utiles en tant qu'agents antiviraux
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
WO2020109389A1 (fr) 2018-11-28 2020-06-04 Innovative Molecules Gmbh Inhibiteurs d'hélicase-primase pour le traitement du cancer au cours d'une polythérapie comprenant des virus oncolytiques
WO2022090409A1 (fr) 2020-10-29 2022-05-05 Innovative Molecules Gmbh Composés d'aminothiazole deutérés en tant que composés antiviraux
WO2023135303A1 (fr) 2022-01-17 2023-07-20 Innovative Molecules Gmbh Formes cristallines solides d'inhibiteurs d'hélicase-primase et leur procédé de préparation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017174640A1 (fr) 2016-04-06 2017-10-12 Innovatives Molecules Gmbh Dérivés d'aminothiazole utiles en tant qu'agents antiviraux
WO2019068817A1 (fr) 2017-10-05 2019-04-11 Innovative Molecules Gmbh Énantiomères de thiazoles substitués utilisés comme composés antiviraux
WO2020109389A1 (fr) 2018-11-28 2020-06-04 Innovative Molecules Gmbh Inhibiteurs d'hélicase-primase pour le traitement du cancer au cours d'une polythérapie comprenant des virus oncolytiques
WO2022090409A1 (fr) 2020-10-29 2022-05-05 Innovative Molecules Gmbh Composés d'aminothiazole deutérés en tant que composés antiviraux
WO2023135303A1 (fr) 2022-01-17 2023-07-20 Innovative Molecules Gmbh Formes cristallines solides d'inhibiteurs d'hélicase-primase et leur procédé de préparation

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical dosage forms", vol. 2
COMP. BIOCHEM. PHYSIOL., vol. 119A, 1998, pages 725
KESISOGLOU FILIPPOS ET AL: "Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling", THE AAPS JOURNAL, vol. 10, no. 4, 6 December 2008 (2008-12-06), pages 516 - 525, XP093092976, ISSN: 1554-2726, DOI: 10.1208/s12248-008-9061-4 *
KESISOGLU ET AL.: "Understanding the Effect of ApI Properties on Bioavailability Through Absorption Modeling", THE AAPS JOURNAL, vol. 10, no. 4, 2008, pages 516 - 525
SERAJUDDIN A. T. M: "Salt formation to improve drug solubility", ADV. DRUG DELIV. REV., vol. 59, 2007, pages 603 - 616, XP022211982, DOI: 10.1016/j.addr.2007.05.010
SERAJUDDIN ET AL: "Salt formation to improve drug solubility", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM , NL, vol. 59, no. 7, 24 August 2007 (2007-08-24), pages 603 - 616, XP022211982, ISSN: 0169-409X, DOI: 10.1016/J.ADDR.2007.05.010 *

Similar Documents

Publication Publication Date Title
US12384758B2 (en) Crystalline form of LNP023
EP3845221B1 (fr) Formes à l'état solide de sofosbuvir
JP2024161449A (ja) ヤヌスキナーゼ阻害剤の結晶形
US20250115565A1 (en) Solid crystalline forms of helicase-primase inhibitors and process of preparation thereof
US20240425463A1 (en) Process for manufacturing a diphenylphrazine derivative
WO2025017032A1 (fr) Sels de chlorhydrate cristallins micronisés de composés antiviraux inhibiteurs d'hélicase-primase
UA125938C2 (uk) Кристалічна форма n-бутилдеоксигалактоноджириміцину
US10513500B2 (en) Crystalline forms of Lesinurad
CN106316964A (zh) 苯基氨基嘧啶化合物或其盐的多晶型物
US10501450B2 (en) Anhydrate-free polymorphically pure micronized crystalline brexpiprazole di-hydrate for use in intramuscular injectable sustained release formulations
US12415807B2 (en) PKC inhibitor solid state forms
US12129238B2 (en) Crystalline form of propoxazepam, the method of its making and use as medicinal agent
US12378227B2 (en) Therapeutic cocrystals of 3-{[5-(azetidine-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy)-N-(5-methylpyrazin-2-yl)benzamide
CN107474057B (zh) (5-(2-腈基苄基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基)乙酸酯盐酸盐的晶型及其制备方法和用途
CN112543634A (zh) Ebna1抑制剂晶体形式及其制备和使用方法
WO2025032197A1 (fr) Forme cristalline de 5-((3r,5s)-3-amino-5-trifluorométhyl-pipéridin-1-yl)-quinoléine-8-carbonitrile
AU2023385491A1 (en) Crystalline forms of 5-[(2,4-dinitrophenoxy)methyl]-1-methyl-2-nitro-1h-imidazole
HK40050819A (en) Ebna1 inhibitor crystalline forms, and methods of preparing and using same
HK40052085B (en) Pharmaceutical compound, the method of its making and use as medicinal agent
HK40052085A (en) Pharmaceutical compound, the method of its making and use as medicinal agent
EA046462B1 (ru) Кристаллическая форма n-бутилдеоксигалактоноджиримицина

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24740481

Country of ref document: EP

Kind code of ref document: A1