Micronized crystalline hydrochloride salts of antiviral helicase-primase inhibitor compounds

Abstract

The present invention provides micronized solid crystalline forms of a hydrochloride salt of a specific antiviral helicase-eliciting enzyme inhibitor compound according to Formula (I), compositions thereof, methods for their production, and methods of using the micronized solid crystalline forms in the treatment or prevention of herpes simplex infection and herpes simplex mediated diseases.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480047367.0 (22) Application Date 2024.07.16 (30) Priority Data 23185927.3 2023.07.17 EP (85) PCT International Application Entering National Phase Date 2026.01.15 (86) PCT International Application Application Data PCT / EP2024 / 070165 2024.07.16 (87) PCT International Application Publication Data WO2025 / 017032 EN 2025.01.23 (71) Applicant Innovative Molecule GmbH Address Munich, Germany (72) Inventor Gerard Kleiman Christine Geiger (74) Patent Agency Beijing Daokete Law Firm 16152 Patent Attorney Xie Yiting (51) Int.Cl. C07D 277 / 54 (2006.01) A61K 31 / 426 (2006.01) A61P 31 / 12 (2006.01) A61P 31 / 22 (2006.01) (54) Invention Title Micronized Crystalline Hydrochloride of Antiviral Helicase-Initiator Compound (57) Abstract This invention provides a micronized solid crystal form of a specific antiviral helicase-initiator compound hydrochloride according to formula (I), a composition thereof, a method of producing thereof, and a method of using the micronized solid crystal form to treat or prevent herpes simplex infection and herpes simplex-mediated diseases. Claims 2 pages, Description 20 pages, Drawings 12 pages, CN 121532378 A 2026.02.13 CN 1 21 53 23 78 A 1. A micronized crystalline form of a compound according to formula (I), wherein Y is selected from CH3 and CD3; or their eutectic, hydrate, or solvate, wherein the micronized crystalline form is characterized by a particle size reduction of at least 10 times (d90 value / d90 particle size distribution) compared to the non-micronized crystalline form. 2. The micronized crystalline form of the compound according to claim 1, having the following structure: , or its eutectic, hydrate, or solvate. 3. The micronized crystalline form of the compound according to claim 2, characterized by an X-ray powder diffraction pattern comprising at least four of the following peaks (±0.2 degrees 2θ): 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees, and 22.8 degrees, as determined by Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer. 4. The micronized crystalline form according to any one of claims 2 to 3, having an XRPD pattern substantially as shown in Figure 1 or Figure 2.5. The micronized crystalline form according to any one of claims 2 to 4, wherein the hydrochloride and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide are present in a 1:1 molar ratio. 6. The micronized crystalline form according to any one of claims 2 to 5, having a d90 value less than or equal to about 20.0 μm as defined in the specification. 7. The micronized crystalline form according to any one of claims 2 to 5, having a d90 value less than or equal to about 6.0 μm as defined in the specification. 8. The micronized crystalline form of the compound according to claim 1, having the following structure: , or a eutectic, hydrate, or solvate thereof. 9. The micronized crystalline form of the compound according to claim 8, characterized in that the micronized crystalline form comprises an X-ray powder diffraction pattern including at least four of the following peaks (±0.2 degrees 2θ): 11.3 degrees, 11.9 degrees, 13.8 degrees, 17.8 degrees, 19.8 degrees, 21.0 degrees, 21.3 degrees, and 21.8 degrees, as determined by Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer. 10. The micronized crystalline form according to any one of claims 8 to 9, having an XRPD pattern substantially as shown in FIG3. Claims 1 / 2 Page 2 CN 121532378 A 11. The micronized crystalline form according to any one of claims 8 to 10, wherein the hydrochloride and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide are present in a 1:1 molar ratio. 12. The micronized crystalline form according to any one of claims 8 to 11, having a d90 value of less than or equal to about 20.0 μm as defined in the specification. 13. The micronized crystalline form according to any one of claims 8 to 12, having a d90 value of less than or equal to about 6.0 μm as defined in the specification. 14. A pharmaceutical composition comprising a therapeutically effective amount of a micronized crystalline form of formula (I) according to any one of claims 1 to 13 and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one other active substance (antiviral active compound) that is effective in treating a disease or condition associated with a viral infection.15. The micronized crystal form according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14, for the prevention and treatment of herpes simplex infection or herpes simplex-mediated diseases, including treating or eliminating latent forms of herpesvirus in neuronal tissue and nerves, and including the prevention and treatment of recurrence and reactivation of herpes infection or serious effects associated therewith, such as herpes encephalitis (HSE). Claims 2 / 2 Page 3 CN 121532378 A Micronized Crystalline Hydrochloride of Antiviral Helicase-Initiator Compounds Summary of the Invention

[0001] The present invention provides micronized solid crystal forms of hydrochloride of specific antiviral helicase-initiator compounds, compositions thereof, methods of their production, and methods of using the micronized solid crystal form to treat or prevent herpes simplex infection and herpes simplex-mediated diseases. Background and Prior Art

[0002] Viral infections have plagued humans since ancient times, causing mucocutaneous and skin infections such as rashes and genital herpes. Disease symptoms often interfere with daily activities, and herpes simplex virus 1 and 2 (HSV-1 and HSV-2) infections are occasionally the cause of life-threatening illnesses (encephalitis) or vision-impairing diseases (keratitis), particularly in newborns, the elderly, and immunocompromised patients, such as transplant recipients, cancer patients, or patients with inherited immunodeficiency syndromes or diseases. Following infection, the alpha herpesvirus persists in a latent form in the host's neurons for life, reactivating periodically and often causing severe psychosocial distress in patients. There is currently no cure.

[0003] To date, vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators, and small molecule drugs with specific or non-specific modes of action lack alternatives to the efficacy or required safety profile of the nucleoside analogues acyclovir, valacyclovir, and famciclovir as the preferred treatment.

[0004] Aminothiazoles (e.g., prepirenylvir, HN0037) are known to be the most effective drugs currently under development. Compared to nucleoside drugs, these antiviral agents act by inhibiting the herpesvirus helicase-initiating enzyme, exhibiting low resistance rates in vitro and superior efficacy in animal models. However, off-target carbonic anhydrase activity, reduced neuronal tissue and brain penetration, and unusual pharmacokinetic characteristics have hindered their development.

[0005] Herpesviruses are neurotrophic viruses, meaning that after infection they enter and remain in neuronal tissue, causing the herpesvirus to persist in the host's neurons in a latent form for life, resulting in permanent neuronal exposure. This permanent neuronal exposure of herpesviruses in a latent form is a cause of the lifelong risk of recurrent and periodic reactivation of herpes infections, often causing severe psychosocial distress in patients.This type of neuronal herpesvirus exposure is a further cause of herpesvirus encephalitis (or herpes simplex encephalitis; HSE), which is believed to result from HSV-1 reactivation in the peripheral facial region or from neuronal tissue spreading along nerve axons into the brain. The virus remains dormant in the ganglia or neuronal tissue of the trigeminal nerve and causes HSE upon entering the brain. Therefore, it is important to provide highly active antiviral drugs that also allow for the treatment and elimination of (dormant) herpesvirus in neuronal tissue and nerves, thereby preventing recurrence and reactivation of herpes infection or even serious effects like HSE. Known antiviral drugs, such as known aminothiazoles, are not potent enough to enter neuronal tissue or cross the blood-brain barrier to reach the brain, and therefore cannot provide an effective and eradicative therapy for treating latent or dormant forms of herpesvirus or even HSE.

[0006] Novel solid crystalline salt forms of antiviral helicase initiator inhibitor compounds (also known as IM-250) according to formula (A) and their deuterated analogs have been described in EP patent application EP22151820 (filed: January 17, 2022) and subsequent international application WO2023 / 135303A1 (publication date: July 20, 2023): Specification 1 / 20 pages 4 CN 121532378 A Formula (A) Wherein Y is selected from CH3 or CD3.

[0007] This application particularly relates to the hydrochloride (HCl salt) of such compounds IM-250 according to formula (I): , Wherein Y is selected from CH3 or CD3, or more specifically has the following formula:

[0008] .

[0009] WO2017 / 174640 describes the free base of the racemic form of IM-250, and WO2019 / 068817 describes two enantiomers of IM-250 and their pharmaceutically acceptable salts, respectively. WO2022 / 090409 describes deuterated analogs of IM-250 and their pharmaceutically acceptable salts. Some antiviral results of IM-250 have been described in Sci. Transl. Med. 2021; 13:eabf8668 and Antivir. Res. 2021;195:105190.

[0010] Specific dosages or administration methods of selected salts or crystal forms of IM-250 have not been described.

[0011] The scientific publication Serajuddin A.T.M., “Salt formation to improve drug solubility”, Adv. Drug Deliv. Rev. 2007; 59:603-616, discloses the relationship between salt formation of active pharmaceutical ingredients and its influence on related factors in the context of solubility, dissolution rate and drug bioavailability.

[0012] Kesisoglu et al., “Understanding the Effect of ApI Properties on Bioavailability Through Absorption Modeling”, The AAPS Journal, 2008; 10(4):516-525, describe the solid-phase and physical properties of active pharmaceutical ingredients, and how the particle size of pharmaceutical ingredients can affect their absorption properties and ultimately the bioavailability of the drug.

[0013] Crystallization or salt formation can positively affect important pharmaceutical properties such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, developability, and physical / chemical stability. There is a need to provide optimized dosage forms or administration formats of antiviral compounds according to formula (A) that exhibit optimized physicochemical and pharmaceutical properties without adversely affecting other important parameters, such as the hygroscopicity or bioavailability of the active compound. The ultimate goal is to achieve improvements in the production, handling, storage, and pharmaceutical properties of the compound according to formula (A) 2 / 20 pages 5 CN 121532378 A.

[0014] Summary This invention relates to novel, selected crystal forms of the hydrochloride salt of the antiviral helicase-initiator inhibitor IM-250 having formula (I) in a micronized form: , wherein Y is selected from CH3 or CD3, or their cocrystals, hydrates or solvates.

[0015] These newly selected micronized crystal forms can be used, for example, to treat human patients suffering from herpes simplex-mediated diseases. The novel micronized solid forms of this disclosure can be used to prepare medicaments for the treatment or prevention of herpes simplex virus infection and disease. The novel micronized solid forms of this disclosure can be used as helicase-initiator inhibitors. The inventors of the present invention have surprisingly discovered that the selected crystalline hydrochloride forms of IM-250 providing a micronized form further improve their suitability for providing medicaments with optimized properties, such advantages including, for example, allowing administration at lower doses compared to non-micronized matching pairs due to improved bioavailability. Therefore, the inventors of this invention, for the first time, combine the specific advantages already shown by the selected IM-250 HCl salt form and its deuterated analogues with the advantages of providing a micronized form of the drug to provide new and improved dosage forms or administration methods for IM-250. Brief Description of the Drawings

[0016] Figure 1 depicts an X-ray powder diffraction (XRPD) pattern of the IM-250 HCl salt.

[0017] Figure 2 depicts an XRPD pattern of the IM-250 HCl salt when crystallized from EtOH.

[0018] Figure 3 depicts an XRPD pattern of the deuterated IM-250 HCl salt (d3-IM-250 HCl salt).

[0019] Figure 4: Microscopic observation results of IM-250 HCl salt crystals used for PSD evaluation in transmitted light and orthogonally polarized light – magnification × 162.

[0020] Figure 5: Microscopic observation results of IM-250 HCl salt crystals (same as the crystals in Figure 4) in orthogonally polarized light – magnification × 162.

[0021] Figure 6: Particle size distribution diagram (cumulative particle size distribution) of IM-250 HCl salt crystals.

[0022] Figure 7: Distribution histogram of IM-250 HCl salt PSD evaluation.

[0023] Figure 8: Particle size distribution of micronized IM-250 HCl salt determined by laser diffraction.

[0024] Figure 9: Microscopic observation results of micronized IM-250 HCl salt.

[0025] Figure 10: Overlapped XRPD diagrams of natural IM-250 HCl salt batches and the same batch after micronization.

[0026] Figure 11 Overlapping DSC plots of natural IM-250 HCl salt batches and the same batch after micronization.

[0027] Figure 12 Microscopic observation results of d3-IM-250 HCl salt crystals used for PSD evaluation in transmitted light and orthogonally polarized light – magnification ×162.

[0028] Figure 13 Microscopic observation results of d3-IM-250 HCl salt crystals (same as the crystals in Figure 4) in orthogonally polarized light – magnification ×162.

[0029] Figure 14 Particle size distribution diagram (cumulative particle size distribution) of d3-IM-250 HCl salt crystals.

[0030] Figure 15 Distribution histogram of d3-IM-250 HCl salt PSD evaluation.

[0031] Figure 16 Particle size distribution of micronized d3-IM-250 HCl salt determined by laser diffraction. Specification 3 / 20 pages 6 CN 121532378 A

[0032] Figure 17 Microscopic observation results of micronized d3-IM-250 HCl salt.

[0033] Figure 18 Particle size distribution and d90 value of IM-250 HCl salt (GMP production batch) before micronization, determined by laser diffraction.

[0034] Figure 19 Particle size distribution and d90 value of micronized IM-250 HCl salt (GMP production batch), determined by laser diffraction.

[0035] Detailed Description In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will understand that the present disclosure may be practiced without these details. The following description of several embodiments is made with the understanding that the present disclosure is considered to be exemplary of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. The headings used throughout the disclosure are provided for convenience only and should not be construed as limiting the claims in any way.The embodiments shown under any heading may be combined with the embodiments shown under any other heading.

[0036] Definitions Unless the context otherwise requires, throughout the specification and claims, the word “comprising” and its variations, such as “including” and “containing”, shall be interpreted as having an open, inclusive meaning, i.e., “including but not limited to”.

[0037] References to “one embodiment” or “implementation” throughout the specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of this disclosure. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout the specification do not necessarily all refer to the same embodiment.

[0038] Furthermore, a particular feature, structure, or characteristic may be combined in one or more embodiments in any suitable manner.

[0039] Embodiments referred to as “crystalline form” throughout the specification include crystals, salts, eutectics, hydrates, and / or solvates of formula (I) disclosed herein.

[0040] In the sense of this disclosure, “deuterated,” “deuterated,” “deuterated,” or “deuterated” means that one or more hydrogen atoms in a compound of formula (I) are replaced by deuterium (2H, represented by “D”).

[0041] In some compounds of formula (I), residue Y represents CD3. Surprisingly, when administered to mammals such as humans, such deuterated aminothiazole compounds exhibit increased resistance to metabolism compared to the corresponding undeuterated compounds, and thus can be used to increase the half-life of compounds of formula (I). See, for example, Foster in Trends Pharmacol. Sci. 1984:5; 524. Such deuterated aminothiazole compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium (details in the Experimental section).

[0042] The deuterium-labeled or substituted therapeutic compounds of this disclosure have surprisingly demonstrated improved DMPK (drug metabolism and pharmacokinetics) properties relating to absorption, distribution, metabolism, and excretion (ADME). Deuterium substitution has been shown to provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index.

[0043] The concentration of deuterium can be defined by an isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable or radioactive isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to have hydrogen at its natural abundance isotopic composition (about 99.98% hydrogen). Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium with an isotopic purity of at least 50%, preferably at least 95%, and more preferably at least 99%.

[0044] The percentage of deuterium doping can be obtained by quantitative analysis using many conventional methods, such as mass spectrometry (peak area) or by quantifying the residual 1H-NMR signal of a specific deuteration site by comparing it with a signal from an internal standard or other undeuterated 1H signals in the compound, as described on page 4 / 20 of the specification, CN 121532378 A.

[0045] It should be recognized that there are some variations in the natural isotopic abundance in the synthesized compounds, depending on the source of the chemical materials used in the synthesis. Therefore, the preparation of undeuterated analogues of the compounds of the present invention will inherently contain a small amount of deuterated isotopes. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Comp. Biochem. Physiol. 1998; 119A:725.

[0046] The term "isotope enrichment factor" at a particular location typically occupied by hydrogen refers to the ratio between the abundance of deuterium at that location and the natural abundance of deuterium at that location. For example, an isotope enrichment factor of 3500 means that the amount of deuterium at a particular location is 3500 times the natural abundance of deuterium, or that 52.5% of the compound has deuterium at that location (i.e., 52.5% deuterium incorporation at a given location). The abundance of deuterium in Earth's oceans is approximately one atom out of 6500 hydrogen atoms (approximately 154 parts per million (ppm)). Thus, deuterium accounts for approximately 0.015% (0.030% by weight) of all naturally occurring hydrogen atoms in Earth's oceans; the abundance varies slightly from one type of natural water to another.

[0047] The deuterated compounds of this disclosure are preferably characterized by an isotope enrichment factor of at least 6300 or a degree of deuteration of at least 95%. More preferably, the isotope enrichment factor is at least 6500, or the degree of deuteration is at least 98%.

[0048] Any formula or structure given herein is also intended to represent compounds that further include isotopically labeled atoms. Examples of other isotopes that may be incorporated into the compounds of this disclosure include other isotopes of hydrogen and isotopes of carbon, nitrogen, oxygen, and fluorine, such as, but not limited to, 3H (tritium), 11C, 13C, 14C, 15N, 18F, and 35S. This disclosure further includes various isotopically labeled compounds in which radioactive isotopes such as 3H, 13C, and 14C are incorporated. Such isotopically labeled compounds can be used 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 radiotherapy of patients. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the following schemes or examples and formulations, in which a non-isotope-labeled reagent is replaced with an readily available isotope-labeled reagent.

[0049] "Pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent and / or emulsifier, or a combination of one or more of the above, that has been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or by the corresponding agency in other countries for use in humans or livestock.

[0050] "Pharmaceutical composition" means a formulation of the compounds of this disclosure (e.g., compounds of formula (I)) and a medium (administration form) generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). Such mediums include all pharmaceutically acceptable excipients.

[0051] The term "effective amount" means an amount of compound that, when administered, is sufficient to prevent or, to a certain extent, alleviate the development of one or more symptoms of an infection or a disease, condition, or illness being treated. The term “effective amount” also refers to an amount of compound sufficient to elicit a biological or medical response in cells, tissues, systems, animals, or humans, as sought by researchers, veterinarians, physicians, or clinicians.

[0052] “Prevention” or “protection” means any treatment of an infection, disease, or condition that prevents the development of clinical symptoms of the disease or condition.

[0053] In some embodiments, the compound may be administered to subjects (including humans) who are at risk of an infection, disease, or condition or who have a family history of an infection, disease, or condition.

[0054] “Treatment” for a disease includes the following: (1) preventing or reducing the risk of developing a disease, i.e., preventing a subject who may be exposed to or susceptible to a disease but has not yet experienced or exhibited symptoms of the disease from developing clinical symptoms of the disease, (2) suppressing the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms, (3) alleviating (curing) the disease, i.e., causing the disease or its clinical symptoms to subside, and (4) improving or reducing symptoms or damage caused by the disease.

[0055] The terms “subject” or “patient” refer to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a domesticated animal (e.g., a dog and a cat), a farm animal (e.g., a cow, a horse, a sheep, a goat, and a pig), and / or a laboratory animal (e.g., a mouse, a rat, a hamster, a guinea pig, a pig, a rabbit, a dog, and a monkey). In some embodiments, the subject (or patient) is a human. “Person in need (or patient)” means a person who may have or is suspected of having an infection or disease or condition that would benefit from certain treatments; for example, treatment with compounds disclosed herein according to this application.

[0056] The term “about” as used herein includes (and describes) embodiments relating to that value or parameter itself. For example, a description relating to “about X” includes a description of “X”. Moreover, unless the context clearly indicates otherwise, the singular forms “an” and “the” include plural references. Thus, for example, a reference to “the compound” includes a variety of such compounds, and a reference to “the assay” includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0057] “Pharmaceutical acceptable” or “physiologically acceptable” means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0058] When referring to, for example, XRPD plots, DSC thermographs, or TGA thermographs, the term “substantially as described” includes plots, thermographs, or spectra that are not necessarily the same as those depicted herein, but which, when considered by those skilled in the art, fall within the range of experimental error or bias.

[0059] Furthermore, the compounds of this disclosure may exist in the form of solvates, such as those comprising water as a solvate, or pharmaceutically acceptable solvates, such as alcohols, particularly ethanol. A “solvent” is formed by the interaction of a solvent and a compound. When the solvent is water, a “solvent” is a “hydrate.” It should be understood that salts of this disclosure may also include solvates.

[0060] Suitable solvents for salt formation and solvent formation of compounds according to formula (I) as defined herein include: acetonitrile, dichloromethane (DCM), alcohols (e.g., particularly methanol, ethanol, 2-propanol (isopropanol)), aldehydes, ketones (particularly acetone), ethers (e.g., tetrahydrofuran (THF) or dioxane), esters (e.g., ethyl acetate) or alkanes (e.g., particularly pentane, hexane, heptane or cyclohexane) and water, and mixtures thereof.

[0061] Micronization is a process of reducing the average diameter of solid material particles, for example, by friction. Conventional micronization techniques focus on mechanical means, such as milling and grinding. Modern technology utilizes the properties of supercritical fluids and manipulates the principle of solubility. The term micronization generally refers to reducing the average particle size to the micrometer range and is used to increase the effectiveness of solid materials by, for example, improving solubility or bioavailability. However, it can also beneficially affect other material properties, such as flow and transport behavior (for bulk materials), reactivity, grindability, extraction and reaction behavior, taste, compressibility, etc.

[0062] The term "d90 value" is a percentile value, which means that 90% (by volume) of the particles have a size less than or equal to that value. For example, a d90 value of 20.0 μm means that 90% (by volume) of the particles have a size less than or equal to 20.0 μm; a d90 value of 10.0 μm means that 90% (by volume) of the particles have a size less than or equal to 10.0 μm.The “d90 value” can be obtained from the particle size distribution (PSD) by laser diffraction (particle size analysis).

[0063] Similarly, the terms “d10”, “d25”, “d50” and / or “d75” define the percentage (by volume) of particles with a size less than or equal to that value in the corresponding specification 6 / 20 page 9 CN 121532378 A.

[0064] The term “d90 particle size distribution” means that 90% (by volume) of the particles have a particle size lower than the d90 value, expressed in μm.

[0065] Similarly, the terms “d10 particle size distribution”, “d25 particle size distribution”, “d50 particle size distribution” and / or “d75 particle size distribution” refer to 10%, 25%, 50% and / or 75% (by volume) of the particles having a particle size higher than or lower than the d10, d25, d50 and / or d75 values, expressed in μm, respectively.

[0066] These d values ​​particularly relate to the cumulative particle volume in the particle distribution curve.

[0067] This patent application discloses novel micronized crystalline forms of antiviral aminothiazole compounds, which have more suitable pharmacokinetic and stability characteristics (e.g., allowing antiviral drug compounds to enter neuronal tissues and the brain at higher throughputs due to improved solubility and bioavailability). Furthermore, the novel micronized crystalline forms of antiviral aminothiazole compounds are characterized by improved compound stability and improved bioavailability, making them more suitable for drug development and use as pharmaceuticals.

[0068] Solid hydrochloride salt form of formula (I) The micronized crystalline HCl salt form of formula (I) compounds offers advantages in bioavailability and stability, making them suitable for use as active ingredients in pharmaceutical compositions. Surprisingly, the inventors of this invention have discovered, for example, that IM-250 HCl salts exhibit advantageous physical properties, such as good physical and chemical stability, good water solubility, and good bioavailability, while being non-hygroscopic. Changes in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, the ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.). Such changes can affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solutions or solid oral dosage forms, including tablets and capsules. Specific crystal forms may provide desired or suitable hygroscopicity, particle size control, improved dissolution rates, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control compared to other forms such as amorphous or non-crystalline forms.Therefore, the micronized crystalline hydrochloride form of the compound of formula (I) can provide advantages, such as improvements in: the method of manufacturing the compound, the stability or storability of the compound as a pharmaceutical product, the stability or storability of the pharmaceutical substance of the compound, and / or the bioavailability and / or stability of the compound as an active agent.

[0069] In certain embodiments, novel micronized solid forms of the compound of formula (I) are disclosed, such as micronized crystal forms.

[0070] The present invention particularly relates to the following embodiments: In a preferred embodiment in combination with any of the above or the following embodiments, the micronized crystal form is a compound according to formula (I)

[0071] wherein Y is selected from CH3 and CD3; or a eutectic, hydrate or solvate thereof.

[0072] In a more preferred embodiment in combination with any of the above or the following embodiments, the micronized crystal form is a compound having the following structure: (See specification 7 / 20 pages 10 CN 121532378 A), or a eutectic, hydrate or solvate thereof.

[0073] In a more preferred embodiment in combination with any of the above or below embodiments, the micronized crystal form has the following structure: .

[0074] In a more preferred embodiment in combination with any of the above or below embodiments, the micronized crystal form is a compound having the following structure: , or a eutectic, hydrate or solvate thereof.

[0075] In a more preferred embodiment in combination with any of the above or below embodiments, the micronized crystal form has the following structure: .

[0076] IM-250 HCl Salt Another embodiment of the present invention relates to a micronized HCl salt of compound IM-250, which is an IM-250 HCl salt having the following structure.

[0077] In one embodiment of the present invention, such a micronized IM-250 HCl salt is characterized by an XRPD plot including 2θ angular reflections (±0.3 degrees 2θ) at (characteristic peaks) at 13.7 degrees, 17.7 degrees and 22.8 degrees.

[0078] In some embodiments, the micronized IM-250 HCl salt is characterized by an XRPD plot that includes one, two, or three of the following: 2θ angular reflections (±0.3 degrees 2θ) at 13.7 degrees, 17.7 degrees, and 22.8 degrees, and 2θ angular reflections (±0.3 degrees 2θ) at 17.0 degrees, 19.8 degrees, and 21.8 degrees. Specification 8 / 20 pages 11 CN 121532378 A

[0079] In some embodiments, the micronized IM-250 HCl salt is characterized by an XRPD plot that includes 2θ angular reflections (±0.3 degrees 2θ) at 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees, and 22.8 degrees.

[0080] In some embodiments, the micronized IM-250 HCl salt is characterized by an XRPD plot that includes at least four of the following peaks: 2θ angles (±0.3 degrees 2θ) at 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees, and 22.8 degrees.

[0081] All values ​​were determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0082] In some embodiments, the micronized IM-250 HCl salt has an XRPD plot that shows 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 20-degree reflections with the highest intensity, as substantially as the XRPD plot shown in Figure 1.

[0083] In some embodiments, the micronized IM-250 HCl salt has an XRPD pattern showing 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 20-degree reflectances with maximum intensity, as shown substantially in Figure 2.

[0084] In some embodiments, such micronized IM-250 HCl salt exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

[0085] In some embodiments, such micronized IM-250 HCl salt exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2.

[0086] In some embodiments, the micronized IM-250 HCl salt has a thermogravimetric analysis pyrometry (TGA) chromatogram showing a mass loss of approximately 9.8% upon heating at an initial / final temperature of approximately 151 °C / 170 °C.

[0087] In some embodiments, the micronized IM-250 HCl salt has a thermogravimetric analysis pyrograph indicating that the decomposition initiation temperature is about 221°C.

[0088] In some embodiments, a micronized IM-250 HCl salt having the following structure is provided herein, wherein the molar ratio of the hydrochloride to (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide is 1 to 1 ± 0.2.

[0089] In some embodiments, the IM-250 HCl salt is micronized, wherein the d90 value is less than or equal to about 20.0 μm, for example in the range of about 1.0 μm to 20.0 μm, or in the range of about 2.0 μm to 12.0 μm.

[0090] In some embodiments, the IM-250 HCl salt is micronized, wherein the d90 value is less than or equal to 20.0 μm, for example in the range of 1.0 μm to 20.0 μm, or in the range of 2.0 μm to 12.0 μm.

[0091] In some embodiments, the IM-250 HCl salt is micronized to a d90 value in the range of about 1.0 μm to about 2.0 μm, greater than about 2.0 μm to about 3.0 μm, greater than about 3.0 μm to about 4.0 μm, greater than about 4.0 μm to about 6.0 μm, greater than about 6.0 μm to about 8.0 μm, greater than about 8.0 μm to about 10.0 μm, or greater than about 10.0 μm to about 12.0 μm.

[0092] In some embodiments, the d90 value of the IM-250 HCl salt is in the range of about 2.0 μm to about 5.0 μm, for example, d90 values ​​of 3.0 μm, 3.5 μm, 3.9 μm, or 4.0 μm.

[0093] In some embodiments, the d90 value of the IM-250 HCl salt is in the range of about 9.0 μm to about 12.0 μm, for example, the d90 value is 9.5 μm or 10.0 μm.

[0094] In a preferred embodiment, the d90 value of the IM-250 HCl salt is less than or equal to about 11.0 μm or less than or equal to about 10.0 μm.

[0095] In a preferred embodiment, the d90 value of the IM-250 HCl salt is less than or equal to 11.0 μm or less than or equal to 10.0 μm.

[0096] In a more preferred embodiment, the d90 value of the IM-250 HCl salt is less than or equal to about 6.0 μm.

[0097] In a more preferred embodiment, the d90 value of the IM-250 HCl salt is less than or equal to 6.0 μm.

[0098] In one specific embodiment, the d90 value of the IM-250 HCl salt is less than or equal to about 4.0 μm.

[0099] In a more specific embodiment, the d90 value of the IM-250 HCl salt is less than or equal to 4.0 μm.

[0100] Surprisingly, the micronized hydrochloride salt (IM-250 HCl salt) has several advantages in terms of chemical and physical stability, (lack of) hygroscopicity, and improved bioavailability, while other tested salts, as shown in the following examples, are less advantageous. Therefore, the micronized IM-250 HCl salt is a particularly preferred embodiment of the present invention.

[0101] Deuterated IM-250 HCl Salt – d3-IM-250 HCl Salt Another embodiment of the present invention relates to a micronized deuterated compound of an IM-250 HCl salt (d3-IM-250 HCl salt) having the following structure.

[0102] In one embodiment of the invention, such micronized d3-IM-250 HCl salt is characterized by an XRPD plot that includes 2θ angular reflectance (±0.3 degrees 2θ) at (characteristic peaks) at 13.8 degrees, 17.8 degrees and 21.8 degrees.

[0103] In some embodiments, the micronized d3-IM-250 HCl salt is characterized by an XRPD plot that includes one, two, three, four, or five of the following: 2θ angular reflections (±0.3 degrees 2θ) at 13.8 degrees, 17.8 degrees, and 21.8 degrees, and 2θ angular reflections (±0.3 degrees 2θ) at 11.3 degrees, 11.9 degrees, 19.8 degrees, 21.0 degrees, and 21.3 degrees.

[0104] In some embodiments, the micronized d3-IM-250 HCl salt is characterized by an XRPD plot that includes 2θ angular reflections (±0.3 degrees 2θ) at 11.3 degrees, 11.9 degrees, 13.8 degrees, 17.8 degrees, 19.8 degrees, 21.0 degrees, 21.3 degrees, and 21.8 degrees.

[0105] In some embodiments, the micronized d3-IM-250 HCl salt is characterized by an XRPD plot that includes at least four of the following peaks: 2θ (± 0.3 degrees 2θ) at 11.3 degrees, 11.9 degrees, 13.8 degrees, 17.8 degrees, 19.8 degrees, 21.0 degrees, 21.3 degrees, and 21.8 degrees.

[0106] All values ​​were determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

[0107] In some embodiments, the micronized d3-IM-250 HCl salt has an XRPD plot that shows 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 20-degree reflections with the greatest intensity, as substantially as the XRPD plot shown in Figure 3.

[0108] In some embodiments, the micronized d3-IM-250 HCl salt has a thermogravimetric analysis (TGA) pyrometry ...

[0112] In some embodiments, a micronized d3-IM-250 HCl salt having the following structure is provided herein, wherein the molar ratio of the hydrochloride to (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide is 1 to 1 ± 0.2.

[0113] In some embodiments, the d3-IM-250 HCl salt is micronized, wherein the d90 value is less than or equal to about 20.0 μm, for example in the range of about 1.0 μm to 20.0 μm, or in the range of about 2.0 μm to 12.0 μm.

[0114] In some embodiments, the d3-IM-250 HCl salt is micronized, wherein the d90 value is less than or equal to 20.0 μm, for example in the range of 1.0 μm to 20.0 μm, or in the range of 2.0 μm to 12.0 μm.

[0115] In some embodiments, the d3-IM-250 HCl salt is micronized to a d90 value in the range of about 1.0 μm to about 2.0 μm, greater than about 2.0 μm to about 3.0 μm, greater than about 3.0 μm to about 4.0 μm, greater than about 4.0 μm to about 6.0 μm, greater than about 6.0 μm to about 8.0 μm, greater than about 8.0 μm to about 10.0 μm, or greater than about 10.0 μm to about 12.0 μm.

[0116] In some embodiments, the d90 value of the d3-IM-250 HCl salt is in the range of about 2.0 μm to about 5.0 μm, for example, d90 values ​​of 3.0 μm, 3.5 μm, 3.9 μm, or 4.0 μm.

[0117] In some embodiments, the d90 value of the d3-IM-250 HCl salt is in the range of about 9.0 μm to about 12.0 μm, for example, the d90 value is 9.5 μm or 10.0 μm.

[0118] In a preferred embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to about 11.0 μm or less than or equal to about 10.0 μm.

[0119] In a preferred embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to 11.0 μm or less than or equal to 10.0 μm.

[0120] In a more preferred embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to about 6.0 μm.

[0121] In a more preferred embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to 6.0 μm.

[0122] In one specific embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to about 4.0 μm.

[0123] In a more specific embodiment, the d90 value of the d3-IM-250 HCl salt is less than or equal to 4.0 μm.

[0124] The micronized deuterated HCl salt (d3-IM-250 HCl salt) has surprisingly demonstrated several advantages in terms of chemical and physical stability, (lack of) hygroscopicity, and improved bioavailability, while other tested salts are less advantageous. Therefore, the micronized crystalline deuterated IM-250 HCl salt (d3-IM-250 HCl salt) is a particularly preferred embodiment of the present invention.

[0125] Application Form and Medical Use of Compounds of Formula (I) in Micronized Solid Form Another aspect of the present invention relates to a pharmaceutical preparation comprising one or more of the compounds in any of the above embodiments.

[0126] Another aspect of the present invention relates to compounds in any of the above embodiments used as a medicament.

[0127] In particular, the present invention relates to said compounds for the treatment or prevention of diseases or conditions associated with viral infections.

[0128] More particularly, the present invention relates to said compounds for the treatment or prevention of diseases or conditions associated with viral infections caused by herpesviruses, particularly herpes simplex virus (i.e., for the treatment or prevention of herpes infections, such as herpes simplex infection).

[0129] In another aspect, the present invention relates to said compounds for the treatment and elimination of latent (dormant) forms of herpesviruses in neuronal tissue and nerves (preferably for the avoidance or prevention of recurrence and reactivation of herpes infections or even the serious effects associated therewith, such as herpes simplex encephalitis (HSE)).

[0130] In another aspect, the present invention relates to the compounds for the treatment or prevention of neurodegenerative diseases caused by viruses (e.g., particularly Alzheimer's disease caused by viruses, especially herpes simplex virus).

[0131] In another aspect, the present invention relates to the compounds for the treatment and prevention of herpes infections (especially herpes simplex infection) in patients exhibiting cold sores, genital herpes and herpes-associated keratitis, Alzheimer's disease, encephalitis, pneumonia, hepatitis; patients with suppressed immune systems, such as AIDS patients, cancer patients, patients with genetic immunodeficiency, transplant patients; newborns and infants; herpes-positive patients, especially herpes simplex-positive patients, for the purpose of suppressing relapse (suppressive therapy); or for patients resistant to nucleoside antiviral therapies such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or phosphonoformic acid or cidofovir, especially herpes-positive patients, especially herpes simplex-positive patients.

[0132] The compounds according to the invention are considered for the prevention and treatment of corresponding symptoms and diseases in humans and animals.

[0133] Therefore, the present invention relates to the use of compounds as described herein in the preparation of pharmaceuticals.

[0134] Furthermore, the present invention relates to methods for preventing or treating diseases or conditions associated with viral infections (e.g., diseases or conditions associated with viral infections caused by herpesviruses, such as, in particular, herpes simplex virus), and methods for treating and eliminating latent (dormant) forms of herpesviruses in neuronal tissue and nerves (preferably for avoiding or preventing recurrence and reactivation of herpes infection or even serious effects associated therewith, such as herpes simplex encephalitis (HSE)), or methods for preventing or treating neurodegenerative diseases caused by viruses (e.g., in particular Alzheimer's disease), said methods comprising administering to a person or animal in need an effective amount of a compound as described herein or a composition comprising said compound.

[0135] In practical applications, the compounds used in the present invention may be tightly mixed as active ingredients with a drug carrier according to conventional pharmaceutical formulation techniques. The carrier may take various forms, depending on the desired formulation for administration, for example, orally or parenteral (including intravenously). In preparing compositions for oral dosage forms, any commonly used pharmaceutical medium, such as water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., may be used in the case of oral liquid formulations (e.g., suspensions, elixirs, and solutions); or in the case of oral solid formulations (e.g., powders, hard capsules, soft capsules, and tablets), a carrier, such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, disintegrant, etc., may be used, wherein solid oral formulations are preferred over liquid formulations.

[0136] Tablets and capsules represent the most advantageous form of oral dosage unit due to their ease of administration, in which case solid pharmaceutical carriers are obviously used. If desired, tablets may be coated using standard aqueous or non-aqueous techniques. Such compositions and formulations should contain at least 0.1% of the active compound. Of course, the percentage of the active compound in these compositions may vary and is conveniently between about 2.0% and about 60.0% by weight. The amount of the active compound in such therapeutically useful compositions is the amount that will yield an effective dose. The active compound can also be administered intranasally, for example, as a liquid drop or spray, or as an eye drop.

[0137] Tablets, pills, capsules, etc., may also contain binders, such as gum arabic, gum arabic, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, or alginic acid; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, it may contain a liquid carrier, such as fatty oil, in addition to the materials of the types described above. Specification 12 / 20 pages 15 CN 121532378 A

[0138] Various other materials may be present as coatings or used to change the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both.Syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetener, methylparaben and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavoring.

[0139] The compounds used in this invention may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water with a suitable surfactant such as hydroxypropyl cellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0140] Suitable forms of medicine for injection include sterile aqueous solutions or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. In all cases, the dosage form must be sterile and must be fluid to facilitate injection. It must be stable under manufacturing and storage conditions and must be preserved to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0141] The compounds of the present invention can be administered to mammals, particularly humans, via any suitable route of administration. For example, they can be administered orally, rectally, topically, parenterally (including intravenously), ocularly, pulmonaryly, nasally, etc. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, gels, ointments, aerosols, etc. Preferably, the compounds of the present invention are administered orally or topically as eye drops, creams, or gels, more preferably orally.

[0142] The effective dose of the active ingredient used may vary depending on the specific compound used, the method of administration, the condition being treated, and the severity of the condition being treated. Such doses can be readily determined by those skilled in the art.

[0143] The compounds of the present invention may also be present in combination with other active ingredients, particularly with one or more active ingredients that have shown advantageous effects in treating any of the conditions or diseases described herein. In particular, the compounds of the present invention are present in the composition in combination with at least one other active substance (antiviral active compound) that is effective in treating diseases or conditions associated with viral infections (preferably diseases or conditions associated with viral infections caused by herpesviruses, such as, in particular, herpes simplex virus), thus relating to so-called combination therapy. This at least one other active substance (immunomodulator, such as glucocorticoid) is effective in treating diseases or conditions associated with viral infections, or more preferably, is an antiviral active compound selected from nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir, and trifluorouridine, as well as compounds such as phosphonoformic acid and cidofovir.

[0144] Therefore, the present invention further relates to 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 other active substance (antiviral active compound) effective in treating a disease or condition associated with viral infection.

[0145] Another aspect of the invention relates to the use of the compounds described herein as helicase priming enzyme inhibitors in combination therapy with oncolytic viruses to treat tumors, cancers, or tumor formation.

[0146] Further embodiments of this additional aspect of the invention relate to pharmaceutical compositions used as antidotes in combination therapy with oncolytic viruses to treat cancer, the pharmaceutical composition comprising at least one helicase priming enzyme inhibitor as defined in any of the embodiments described herein, the inhibitor being used to control, modulate, inhibit, or shut down the activity of oncolytic viruses sensitive to said inhibitors used in cancer therapy, and the pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier and / or excipient and / or at least one other active substance effective in treating a disease or condition associated with oncolytic virus infection used in cancer treatment, such as an antiviral active compound or an immunomodulatory compound, including checkpoint inhibitors.

[0147] Further embodiments of this other aspect of the invention relate to helicase primase inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapy with oncolytic viruses as described in detail in WO2020 / 109389, wherein the cancer described in the specification 13 / 20 pages 16 CN 121532378 A is a solid cancer, preferably selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, and glioblastoma, etc.

[0148] Further embodiments of this other aspect of the invention relate to helicase primase inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the oncolytic virus is an oncolytic herpesvirus.

[0149] Further embodiments of this further aspect of the invention relate to helicase primase inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the cancer therapy comprises infusion, injection, intratumoral injection, or local or transdermal administration of oncolytic viruses or oncolytic virus-infected cells and / or helicase primase inhibitors or pharmaceutical compositions comprising them.

[0150] Further embodiments of this further aspect of the invention relate to helicase primase inhibitor compounds or pharmaceutical compositions of the invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the oncolytic virus or oncolytic virus-infected cells are selected from oncolytic wild-type, clinical isolates or laboratory herpesvirus strains or genetically engineered or multimutated optionally attenuated or enhanced oncolytic herpesviruses.

[0151] Further embodiments of this aspect of the invention relate to a kit comprising at least one of the helicase primase inhibitor compounds or pharmaceutical compositions of the invention for combination therapy with at least one oncolytic virus as described in WO2020 / 109389 and selected from wild-type, laboratory strains, clinical isolates, and genetically engineered or multimutant oncolytic viruses.

[0152] Further embodiments of this aspect of the invention relate to the kits described herein for treating cancers as defined herein.

[0153] The helicase primase inhibitor compounds, pharmaceutical compositions, or kits described herein for combination therapy with oncolytic viruses may be applied to one or more of the following patient groups: infants; herpes-positive patients, particularly oncolytic herpes simplex-positive patients, for suppressing relapse or shedding of oncolytic viruses; patients, particularly herpes-positive patients, particularly oncolytic herpes simplex-positive patients resistant to nucleoside antiviral therapies such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir, and / or foscarnet or cidofovir.

[0154] Preparation of Micronized HCl Salts of Formula (I) Another aspect of the present invention relates to the preparation of micronized forms of compounds of formula (I), including their eutectic, hydrated, or solvated forms.

[0155] HCl salt compounds (I) may be prepared as described in the aforementioned EP patent application EP22151820 and subsequent international application PCT / EP2023 / 050883, followed by a step of micronizing the resulting solid crystal form until the desired d90 value and / or d90 particle size distribution is obtained.

[0156] Suitable micronization measures include milling, grinding, micronization by using supercritical fluids, and micronization by manipulating solubility principles. The methods may also include a sieving step. In principle, any known technique suitable for achieving a desired reduction in average particle size to the micrometer range may be used.

[0157] In a preferred aspect of the invention, micronization includes reducing the particle size to a d90 value and / or d90 particle size distribution as defined herein.

[0158] Preferably, micronization includes reducing the particle size (d90 value / d90 particle size distribution) of the crystal form obtained by synthesis and recrystallization by about 10 times, preferably by at least 15 times, more preferably by at least 20 times, and even more preferably by at least 25 times, in each case compared to the unmicronized form that can be obtained by synthesis and (re)crystallization methods.

[0159] The particle size distribution can be determined using sieving analysis or laser diffraction (International Standard ISO 13320-1; for further details on laser diffraction, see, for example, http: / / pharmazie-lehrbuch.de / kapitel / 3-1.pdf), or by electronic sensing, light barrier, sedimentation, or microscopic examination, procedures well known to those skilled in the art.Sieving is one of the oldest methods for classifying powders by particle size distribution. Another method involves determining the volumetric particle size distribution by TEM (see, for example, Clariant Analytical Services TECHNICAL SHEET 106 TEM-Partikelgröße). These methods are well known in the art and are described in any analytical chemistry textbook or in the United States Pharmacopeia (USP) publication USP-NF (2004-Chapter 786-(United States Pharmacopeia Convention Corporation, Rockville, Md.)), which describes standards that can be implemented by the U.S. Food and Drug Administration (FDA). As a good example, the techniques used are described, for example, in Pharmaceutical dosage forms: Volume 2, 2nd edition, edited by H. A. Lieberman, L. Lachman, and J. B. Schwartz. It also mentions (page 187) other methods: electronic sensing zones, light barriers, air permeation, and gas or liquid sedimentation. The particle size distribution values ​​used in this invention are generally obtained by laser diffraction analysis (particle size analysis).

[0160] More specifically, according to European Pharmacopoeia 2.9.31 and USP <429> Particle size distribution was measured by laser diffraction. Measurements were performed in suspensions in water and Tween 80® using a measurement system from Beckman Coulter. Sample suspension was performed using sonication, and particle size distribution was calculated using a Fraunhofer computational model. These laser diffraction analysis techniques produce volume-weighted distributions. Here, the contribution of each particle in the distribution is related to the volume of that particle (or mass if the density is homogeneous), i.e., the relative contribution will be proportional to the size. More specifically, the particle size distribution (PSD) according to the invention was performed on samples from 5 g to 100 g up to 2 kg GMP samples in the salt form being evaluated, and analyzed using a laser particle size analyzer. Further details are shown in Examples 3, 5, and 7 below.

[0161] The micronized HCl salt compound of formula (I) according to the invention can then be further processed and converted into suitable pharmaceutical dosage forms, for example by filling into capsules, sacs, or other equivalent dosage forms, or by compressing the micronized particles into suitable tablet forms, including uncoated and coated tablets, delayed-release tablets, chewable tablets, etc.

[0162] Experimental Section X-ray Powder Diffraction (XRPD) XRPD analysis was performed on a Bruker D2 phase diffractometer using a copper countercathode, a single-crystal silicon sample holder, and a position-sensitive detector (LynxExe). The powder sample was mounted on a flat single-crystal silicon sample holder in a manner that avoided preferential orientation and ensured the planarity of the sample surface.The instrument operating conditions are as follows: ambient temperature and atmosphere; X-ray generator voltage 30kV, intensity 10mA; X-ray source: target copper; emitted radiation Kα1=0.15406nm, Kα2=0.15444nm, ratio Kα2 / Kα1=0.5, Kβ filtered radiation nickel; slit: anti-divergence 1nM, Soles slit 2.5°; goniometer: for angular sectors analyzed from 4° to 45° or 4° to 50°, the step size for 2θ is 0.07°; sample holder rotation speed: 30rpm; detection: exposure time per step of the goniometer is 1 second.

[0163] Differential scanning calorimetry (DSC) DSC analysis was performed on a Q1000 TA instrument analyzer. The sample to be analyzed was weighed in an aluminum box, then rolled up and placed in the calorimeter oven. The instrument operating conditions were as follows: heater heating at 10℃ / min; final temperature 230℃ or 240℃; carrier gas: nitrogen (Messer “qualité Azote 5.0”), flow rate 50mL / min.

[0164] Thermogravimetric analysis (TGA) was performed on a TA instrument TGA Hi-Res 2950. The sample was placed in an open aluminum basket and analyzed as follows: mass determination 5mg; heating at 10℃ / min; final temperature 500℃; carrier gas: nitrogen (Messer “qualité Azote 5.0”), flow rate 95 to 105mL / min.

[0165] Laser diffraction particle size analysis was performed according to European Pharmacopoeia 2.9.31 and USP. <429> Laser diffraction analysis was performed. Instruction manual, pages 15 / 20, 18 CN 121532378 A

[0166] Optical microscopy and particle size distribution (PSD) assessment were performed on a LEICA DMIRB microscope equipped with a digital camera and motorized stage. Microscopic patterns were acquired using a Microvision Instruments image analysis station. A few milligrams of test sample were placed on a microscope slide with silicone oil, covered with a coverslip, dispersed by applying soft pressure to the coverslip, and then analyzed.

[0167] For PSD assessment (particle size analysis), approximately 1 milligram of test sample was dispersed in soybean oil pre-saturated with a crystallizing material for analysis. A few microliters were then dropped onto a microscope slide covered with a coverslip and analyzed.

[0168] Image analysis (automated object detection) was correlated with statistical analysis of the detected particle surfaces to establish a particle size distribution map.

[0169] The characteristic diameter values ​​are given in the form of dmin, daverage, dmax (represented as particle number distribution values) and in the form of dx=Y, which means that the x percentage of the total measured surface in the observed sample (considered as a population) consists of particles with a diameter less than Y μm.

[0170] Example 1: Synthesis of IM-250 HCl Salt (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide hydrochloride

[0171] IM-250 free base (205 mg, 470 μmol) (which may be obtained as described in Example 7 of WO2019 / 068817 or as described in International Application PCT / EP2023 / 050883) was dissolved in acetone (5 mL) by stirring on a rotary evaporator at 50 °C and atmospheric pressure. A certain volume of 1N HCl corresponding to a 1:1 stoichiometric ratio was added. The solvent was then evaporated to dryness at 50 °C to form a thin film. The film was resuspended at room temperature and dissolved in EtOH (4 mL). The solvent was then evaporated to dryness at 50°C to form a meringue. The film was resuspended at 50°C and dissolved in isopropanol (1 mL), kept at room temperature, resulting in partial separation (after about 30 minutes), and then heated to 50°C again for redissolution. Strong crystallization occurred very rapidly. An additional heating (50°C) and cooling (room temperature) cycle was performed (20 minutes each time), and the sample was stored at room temperature for 2 days. The supernatant solvent was removed, and the powder was finally dried under dynamic vacuum (70°C, 40 minutes) to obtain IM-250 HCl salt as colorless crystals.

[0172] XRPD analysis was performed. Figure 1 shows the XRPD plot of IM-250 HCl salt. XRPD peaks were identified and included in Table 1 below.

[0173] Table 1: XRPD Peak Positions (°2) and Intensities (Pages 16 / 20, CN 121532378 A)

[0174]

[0175] TGA and DSC analyses were performed. TGA analysis showed a mass loss of 9.8% upon heating at starting / ending temperatures of 151°C / 170°C before major thermal decomposition was detectable at an initial temperature of 221°C. This 9.8% mass loss is likely attributable to the detachment of the HCl fraction. DSC analysis indicated no true melting point. An unresolved double endothermic event observed at 160°C occurred simultaneously with the loss of the HCl fraction observed on the TGA plot.

[0176] An alternative method for synthesizing IM-250 HCl salt using EtOH: 4.75 g of free IM-250 base (obtainable as described in Example 7(-) of WO2019 / 068817) was dissolved in acetone (150 mL) by stirring on a rotary evaporator at room temperature and atmospheric pressure. A volume of 1N HCl corresponding to a 1:1 stoichiometric ratio was then added. The solvent was partially evaporated (approximately 100 mL) at 50°C.To better capture the water from the HCl solution, 50 mL of EtOH was added to the solution, followed by further evaporation until the remaining volume was a few milliliters (a syrupy liquid). The sample was then brought to room temperature, causing crystallization to begin. An additional 50 mL of EtOH was then added to the sample (always to help remove the water from the HCl solution), resulting in an unexpected increase in crystallization. XRPD analysis was performed. Figure 2 shows the XRPD plot of the IM-250 HCl salt. The identified XRPD peaks are similar to those shown in Figure 1, indicating the formation of the same HCl polymorph.

[0177] Example 2: Synthesis of deuterated IM-250 HCl salt (d3-IM-250 HCl salt) (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonylimino)thiazolyl-2-yl)acetamide hydrochloride Specification 17 / 20 pages 20 CN 121532378 A

[0178] A certain amount of 1N HCl corresponding to a 1:1 stoichiometric ratio was added to a solution of 850 mg of deuterated IM-250 free base as described in WO2022 / 090409 or international application PCT / EP2023 / 050883 in acetone (50 mL). The solution was homogenized at 40°C, and then the solvent was removed under vacuum (50°C). When only a few mL remained in the flask, spontaneous crystallization of a white solid was triggered. To completely remove the water introduced by the addition of HCl, EtOH (2 × 5 mL) was added to the flask and concentrated to dryness at 50°C (only partial redissolution was observed during the addition of EtOH and stirring at 50°C). Then, more EtOH (5 mL) was added to the flask and stirred at 50°C and room temperature to resuspend the crystals. The supernatant was removed from the solid and then further dried under vacuum at 50–60°C for about 3 hours. White crystals of deuterated IM-250 HCl salt (d3-IM-250 HCl salt) with good yield were obtained.

[0179] XRPD analysis was performed. Figure 3 shows the XRPD plot of IM-250 HCl salt (d3-IM-250 HCl salt). XRPD peaks were identified and included in Table 2 below.

[0180] Table 2: XRPD peak positions (°2) and intensity. Specification 18 / 20 pages 21 CN 121532378 A

[0181] TGA and DSC analyses were performed. TGA analysis showed a mass loss of 7.8% upon heating at starting / ending temperatures of 149°C / 167°C before major thermal decomposition was detectable at an initial temperature of 225°C. This 7.8% mass loss is likely attributable to the removal of the HCl moiety.DSC analysis showed that there was no true melting point, but rather a broad endothermic period starting at about 188 °C and peaking at 194 °C (transition enthalpy – 15 J / g).

[0182] Example 3: Particle size distribution assessment of IM-250 HCl salt The particle size distribution (PSD) of the batches of IM-250 HCl salt prepared with EtOH in Example 1 was assessed by microscopy and image analysis. The micrographs are reported in Figures 4 and 5. The quantitative results of PSD, particle size distribution plots and distribution histograms are reported in Table 3, Figure 6 and Figure 7, respectively. The samples mainly contained large birefringent particles: 90% of the particles had a particle size (d90) of less than or equal to about 203 μm.

[0183] Table 3: Quantitative results of PSD assessment of IM-250 HCl salt

[0184] With another batch of crude IM-250 HCl salt from another experiment, a particle size (d90) of less than or equal to about 193 μm was measured.

[0185] Example 4: Micronization of IM-250 HCl Salt IM-250 HCl salt was micronized in HOLOPHARM to obtain samples with an average d90 value of 6.1 μm. Figure 8 shows the particle size distribution of the micronized samples, and Figure 9 is a micrograph. As shown in Figures 10 and 11, the micronized samples showed the same diffraction peak positions and the same DSC curves as the non-micronized bulk, indicating that the two samples contained the same crystal form. IM-250 HCl salt has shown chemical and physical stability as a bulk powder, as no changes were observed after storage at 40°C / 75% RH and 60°C for at least 3 weeks. By repeating the experiment, micronized materials with d90=3.3 μm and d90=3.9 μm were obtained, respectively.

[0186] Example 5: Particle Size Distribution Evaluation of Deuterated IM-250 HCl Salt The particle size distribution (PSD) of d3-IM-250 HCl salt batches was evaluated by microscopy and image analysis. Micrographs are reported in Figures 12 and 13. Quantitative PSD results, particle size distribution maps, and distribution histograms are reported in Table 4, Figure 14, and Figure 15, respectively. The samples mainly consist of large birefringent particles: 90% of the particles have a particle size (d90) less than or equal to about 156 μm.

[0187] Table 4: Quantitative results of PSD evaluation of deuterated IM-250 HCl salt

[0188] Example 6: Micronization of deuterated IM-250 HCl salt d3-IM-250 HCl salt was micronized in a similar manner at HOLOPHARM to obtain samples with an average d90 value of 3.0 μm. Figure 16 shows the particle size distribution of the micronized sample, and Figure 17 is a micrograph. XRPD analysis did not demonstrate any difference in the position and intensity of the diffraction peaks of d3-IM-250 HCl salt before and after micronization. No changes in the crystalline phase were observed.

[0189] Example 7: Micronization and PSD determination of IM-250 HCl salt (GMP production batch) Micronization was performed using a spiral jet mill 100 from Hosokawa-Alpine. The starting material was 1.9 kg of IM-250 HCl salt, which had a PSD distribution according to Figure 18, with a d90 value of 139.8 μm. Micronization was performed using nitrogen as the grinding medium at a pressure of 5 bar. The product was continuously transferred to the mill using a twin-screw feeder, and after micronization, it was collected in a fine filter bag and separated in 97% yield. According to European Pharmacopoeia 2.9.31 and USP <429> Particle size distribution was determined by laser diffraction. Measurements were performed in suspensions in water and Tween 80® using a measurement system from Beckman Coulter. Sample suspension was performed using sonication, and particle size distribution was calculated using the Fraunhofer computational model. The micronized material had an average d90 value of 8.7 μm and a PSD distribution according to Figure 19. Micronization reduced the d90 value by 16-fold.

[0190] Example 8: Bioavailability of micronized IM-250 HCl salt / d3-IM-250 HCl salt versus non-micronized matched pair in male mice The oral bioavailability of suspended micronized crystalline IM-250 HCl salt (and d3-IM-250 HCl salt) versus suspended non-micronized crystalline IM-250 HCl salt (and d3-IM-250 HCl salt) after a single oral dose was examined in male C57bl / 6 mice (approximately 8 weeks old). Animals (n=3 per group) were fasted approximately 2 hours prior to administration of the 10 mg / kg test substance. A suspension was prepared directly by adding the powder to a 0.5% HPMC solution in PBS, sonicated, and orally administered at a gavage volume of 5 mL / kg. Blood samples (20 μL) were collected via capillary microsampling at 0.5 h, 1 h, 2 h, 5 h, 12 h, and 24 h, collected from the tail vein into Li-heparin tubes. Samples were frozen on dry ice for 1 to 2 minutes after sampling and stored at –20 °C until LC-MS / MS analysis by non-chiral LC-MS. Peak plasma concentration (Cmax), elimination half-life (t1 / 2), and area under the curve (AUC0–24 h) were determined.The following data were obtained (Table 5): Table 5: Effect of micronized IM-250 HCl salt / d3-IM-250 HCl salt on PK parameters in male mice compared with non-micronized matched pairs

[0191] Relative bioavailability of different salt forms in male mice The relative bioavailability of IM-250 (derived from DMSO stock solution) in different crystalline and salt forms after single oral administration in male C57bl / 6 mice was evaluated in international application PCT / EP2023 / 050883. The area under the curve (AUC0-24h) and relative bioavailability of IM-250 suspensions were calculated and compared between IM-250 free base form I (IM-250 naphthalene disulfonate) and IM-250 HCl salt. In further tests, the effect of deuteration of IM-250 HCl salt on PK parameters in male mice was evaluated. All of the IM-250 forms tested were non-micronized. In those comparative evaluations, the inventors have demonstrated surprising improvements achievable with HCl salts (deuterated and undeuterated).

[0192] Now, with an additional micronization step, as shown herein, the pharmacokinetic properties of those selected salt forms can be further improved.

[0193] Conclusion: Improved bioavailability was obtained using both micronized test materials, as evident in this matched-pair comparison of Cmax and AUC0-24h. This allows for lower patient doses compared to the non-micronized material.Instruction manual 20 / 20 pages 23 CN 121532378 A Figure 1 Figure 2 Instruction manual Figure 1 / 12 pages 24 CN 121532378 A Figure 3 Instruction manual Figure 2 / 12 pages 25 CN 121532378 A Figure 4 Figure 5 Instruction manual Figure 3 / 12 pages 26 CN 121532378 A Figure 6 Figure 7 Instruction manual Figure 4 / 12 pages 27 CN 121532378 A Figure 8 Figure 9 Instruction manual Figure 5 / 12 pages 28 CN 121532378 A Figure 10 Figure 11 Instruction manual Figure 6 / 12 pages 29 CN 121532378 A Figure 12 Instruction manual Figure 7 / 12 pages 30 CN 121532378 A Figure 13 Instruction manual Figure 8 / 12 pages 31 CN 121532378 A Figure 14 Figure 15 Instruction manual Figure 9 / 12 pages 32 CN 121532378 A Figure 16 Figure 17 Appendix to the Instruction Manual Page 10 / 12 33 CN 121532378 A Figure 18 Appendix to the Instruction Manual Page 11 / 12 34 CN 121532378 A Figure 19 Appendix to the Instruction Manual Page 12 / 12 35 CN 121532378 A.

Claims

1. A micronized crystal form of a compound according to formula (I) Where Y is selected from CH3 and CD3; Or its eutectic, hydrate or solvate, wherein the micronized crystal form is characterized by a particle size reduction of at least 10 times compared to the non-micronized crystal form (d 90 value / d 90 Particle size distribution).

2. The micronized crystal form of the compound according to claim 1 has the following structure: ， Or its eutectic, hydrate or solvate.

3. The micronized crystal form of the compound according to claim 2, characterized in that the micronized crystal form comprises an X-ray powder diffraction pattern including at least four of the following peaks (±0.2 degrees 2θ): 13.7 degrees, 17.0 degrees, 17.7 degrees, 19.8 degrees, 21.8 degrees, and 22.8 degrees, as determined by Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

4. The micronized crystal form according to any one of claims 2 to 3, having an XRPD pattern substantially as shown in Figure 1 or Figure 2.

5. The micronized crystal form according to any one of claims 2 to 4, wherein the hydrochloride and ( S )-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)- N -methyl- N -(4-methyl-5-( S (-Methylsulfonylimide)thiazo-2-yl)acetamide exists in a 1:1 molar ratio.

6. The micronized crystal form according to any one of claims 2 to 5, having a dm less than or equal to about 20.0 μm as defined in the specification. 90 value.

7. The micronized crystal form according to any one of claims 2 to 5, having a dm less than or equal to about 6.0 μm as defined in the specification. 90 value.

8. The micronized crystal form of the compound according to claim 1, having the following structure: ， Or its eutectic, hydrate or solvate.

9. The micronized crystal form of the compound according to claim 8, characterized in that the X-ray powder diffraction pattern includes at least four of the following peaks (±0.2 degrees 2θ): 11.3 degrees, 11.9 degrees, 13.8 degrees, 17.8 degrees, 19.8 degrees, 21.0 degrees, 21.3 degrees and 21.8 degrees, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å.

10. The micronized crystal form according to any one of claims 8 to 9, having an XRPD pattern substantially as shown in FIG3.

11. The micronized crystal form according to any one of claims 8 to 10, wherein the hydrochloride and ( S )-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)- N -methyl- N -(4-(methyl- d 3)-5-( S (-Methylsulfonylimide)thiazo-2-yl)acetamide exists in a 1:1 molar ratio.

12. The micronized crystal form according to any one of claims 8 to 11, having a dm less than or equal to about 20.0 μm as defined in the specification. 90 value.

13. The micronized crystal form according to any one of claims 8 to 12, having a dm less than or equal to about 6.0 μm as defined in the specification. 90 value.

14. A pharmaceutical composition comprising a therapeutically effective amount of a micronized crystalline form of formula (I) according to any one of claims 1 to 13 and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one other active substance (antiviral active compound) that is effective in treating a disease or condition associated with a viral infection.

15. The micronized crystal form according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14, for the prevention and treatment of herpes simplex infection or herpes simplex-mediated conditions, including treating or eliminating latent forms of herpesvirus in neuronal tissue and nerves, and including the prevention and treatment of recurrence and reactivation of herpes infection or serious effects associated therewith, such as herpes encephalitis (HSE).

Images