Micronized crystalline hydrochloride salt of antiviral helicase-priming enzyme inhibitor compound

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

Invention Overview

[0001] The present invention provides a micronized solid crystal form of hydrochloride of a specific antiviral helicase-initiator inhibitor compound, a composition thereof, a method for producing the thereof, and a method for treating or preventing herpes simplex infection and herpes simplex-mediated diseases using the micronized solid crystal form. Background and Existing Technology

[0002] Viral infections have plagued humanity since ancient times, causing mucosal and skin infections such as rashes and genital herpes. Symptoms often disrupt 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 impairment (keratitis), particularly in newborns, the elderly, and immunocompromised individuals, such as transplant recipients, cancer patients, or those with inherited immunodeficiency syndromes or diseases. Following infection, the alpha herpesvirus persists in a latent form in the host's neurons for life, periodically reactivating and often causing severe psychosocial distress. Currently, there is 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 the efficacy or required safety to replace the nucleoside analogues acyclovir, valacyclovir, and famciclovir as the first-line treatment.

[0004] Aminothiazoles (e.g., prepirenylvir, HN0037) are among the most potent 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 virus to persist in the host's neurons in a latent form for life, resulting in permanent neuronal exposure. This permanent neuronal exposure to 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 neuronal herpesvirus exposure is a further cause of herpesvirus encephalitis (or herpes simplex encephalitis; HSE), which is believed to be caused by reactivation of HSV-1 in the peripheral facial region or by its spread along nerve axons from neuronal tissue to the brain. The virus remains dormant in the ganglia or neuronal tissue of the trigeminal cranial 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) herpesviruses in neuronal tissue and nerves, thereby preventing recurrence and reactivation of herpes infections or even severe effects like HSE. Known antiviral drugs, such as known aminothiazoles, are not effective enough to enter neuronal tissue or cross the blood-brain barrier to enter the brain, and therefore cannot provide an effective and eradicative treatment for latent or dormant forms of herpesvirus or even HSE.

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

[0007] This application specifically relates to the hydrochloride (HCl salt) of such compound IM-250 according to formula (I): , Where 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. WO2022 / 090409 describes deuterated analogs of IM-250 and their pharmaceutically acceptable salts. Some antiviral results of IM-250 have been described in [document name missing]. Sci.Transl.Med.2021;13:eabf8668 and Antivir.Res 2021;195:105190.

[0010] The specific dosage or administration method of the selected salt or crystal form of IM-250 has not been described.

[0011] Scientific publications Serajuddin ATM, "Salt formation to improve drug solubility", Adv. Drug Deliv. Rev. 2007; 59:603-616 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 was disclosed.

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

[0013] Crystallization or salt formation can positively influence important drug properties such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, discoverability, and physical / chemical stability. There is a need to provide optimized dosage forms or administration methods for 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 compounds according to formula (A).

[0014] Overview This invention relates to novel, selective crystalline forms of the micronized hydrochloride of the antiviral helicase-primase inhibitor IM-250 of formula (I): , Y is selected from CH3 or CD3, or their eutectic, hydrate or solvate.

[0015] These newly selected micronized crystal forms can be used, for example, to treat human patients suffering from herpes simplex-mediated conditions. 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 this invention have surprisingly discovered that the selected crystalline hydrochloride forms of IM-250 providing micronized forms further improve their suitability for providing medicaments with optimized properties, such advantages including, for example, allowing for lower dosage administration 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 forms and their deuterated analogues with the advantages of providing medicaments in micronized forms to provide new and improved dosage forms or administration methods for IM-250. Attached Figure Description

[0016] Figure 1 The X-ray powder diffraction (XRPD) pattern of IM-250 HCl salt is depicted.

[0017] Figure 2 XRPD plot of IM-250 HCl salt as crystallized from EtOH was depicted.

[0018] Figure 3 XRPD plots of deuterated IM-250 HCl salt (d3-IM-250 HCl salt) were depicted.

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

[0020] Figure 5 In orthogonally polarized light, IM-250 HCl salt crystals (and) Figure 4 Microscopic observation results (same as the crystal in the image) – 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 assessment.

[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 Overlapping XRPD images of natural IM-250 HCl salt batches and the same batches after micronization.

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

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

[0028] Figure 13 d3-IM-250 HCl salt crystals (with) Figure 4 Microscopic observation results of the crystals in orthogonally polarized light (same as those in the original crystal) – 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 assessment.

[0031] Figure 16 Particle size distribution of micronized d3-IM-250 HCl salt determined by laser diffraction.

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

[0033] Figure 18 Particle size distribution and dp of IM-250 HCl salt (GMP production batch) before micronization, determined by laser diffraction. 90 value.

[0034] Figure 19 Particle size distribution and dp of micronized IM-250 HCl salt (GMP production batch) determined by laser diffraction 90 value.

[0035] Detailed description In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure may be practiced without these details. The following description of several embodiments is made with the understanding that this disclosure is considered exemplary of the subject matter to be protected, 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. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

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

[0037] Throughout the specification, references to "an embodiment" or "an embodiment" 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, specific features, structures, or properties can be combined in any suitable manner in one or more implementations.

[0039] Embodiments in which “crystal form” is mentioned 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 of a compound of formula (I) are deuterated ( 2 H is replaced by "D".

[0041] In some compounds of formula (I), residue Y represents CD3. Surprisingly, when administered to mammals such as humans, these deuterated aminothiazole compounds exhibit increased resistance to metabolism compared to the corresponding undeuterated compounds, and could therefore 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 (see Experimental Section for details).

[0042] The deuterium-labeled or substituted therapeutic compounds disclosed herein have surprisingly demonstrated improved DMPK (drug metabolism and pharmacokinetics) properties involving 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 the isotope enrichment factor. In the compounds disclosed herein, 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 (approximately 99.98% hydrogen). Therefore, in the compounds disclosed herein, 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 analyzing the remaining residue at specific deuteration sites. 1 H-NMR signals differ from signals from internal standards or other undeuterated compounds. 1 The H signal is obtained by quantization.

[0045] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are variations in the natural isotopic abundance in the synthesized compounds. Therefore, the preparation of non-deuterated analogs of the compounds of the present invention will inherently contain small amounts 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" in the context of a particular location typically occupied by hydrogen refers to the ratio between the abundance of deuterium at that location and its natural abundance at that location. For example, an isotope enrichment factor of 3500 means that the amount of deuterium at a particular location is 3500 times its natural abundance, or that 52.5% of a compound contains 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)). Therefore, 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 disclosed herein are preferably characterized by an isotope enrichment factor of at least 6300 or a deuteration degree of at least 95%. More preferably, the isotope enrichment factor is at least 6500, or the deuteration degree 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 additional 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, others. 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F and 35 S. This disclosure further includes various isotope-labeled compounds, wherein radioactive isotopes are incorporated, for example 3 H, 13 C and 14 C. 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 isotopically 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 readily available isotopically labeled reagents are substituted for non-isotopically labeled reagents.

[0049] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, gliding agents, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents and / or emulsifiers, or combinations thereof, that have been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or by the corresponding agencies in other countries for use in humans or livestock.

[0050] "Pharmaceutical composition" refers to formulations of compounds of this disclosure (e.g., compounds of formula (I)) and media (administration forms) generally accepted in the art for the delivery of biologically active compounds to mammals (e.g., humans). Such media include all pharmaceutically acceptable excipients.

[0051] The term "effective amount" means an amount of a compound that, when applied, is sufficient to prevent or, to a certain extent, alleviate the development of one or more symptoms of an infection or the condition, disease, or illness being treated. The term "effective amount" also refers to an amount of a 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 implementations, the compound may be administered to subjects (including humans) who are at risk of infection, disease, or condition, or who have a family history of infection, disease, or condition.

[0054] The “treatment” for a disease includes the following: (1) To prevent or reduce the risk of developing the disease, i.e., to prevent subjects who may be exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease from developing clinical symptoms of the disease. (2) Suppressing disease, that is, preventing or reducing the development of disease or its clinical symptoms. (3) Alleviate (cure) the disease, that is, reduce or eliminate the disease or its clinical symptoms, and (4) Improve or alleviate symptoms or damage caused by 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 or cat), a farm animal (e.g., a cow, a horse, a sheep, a goat, or a pig), and / or a laboratory animal (e.g., a mouse, a rat, a hamster, a guinea pig, a pig, a rabbit, a dog, or 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". Furthermore, unless the context clearly indicates otherwise, the singular forms "an" and "the" include plural references. Thus, for example, a reference to "the compound" includes multiple 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 a compound, salt, composition, dosage form, or other material 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 one of ordinary skill 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 “solvate” is formed through the interaction of a solvent and a compound. When the solvent is water, a “solvate” is a “hydrate.” It should be understood that the 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., in particular methanol, ethanol, 2-propanol (isopropanol)), aldehydes, ketones (in particular acetone), ethers (e.g., tetrahydrofuran (THF) or dioxane), esters (e.g., ethyl acetate) or alkanes (e.g., in particular pentane, hexane, heptane or cyclohexane) and water, and mixtures thereof.

[0061] Micronization is a process that reduces the average diameter of solid material particles, for example, through friction. Traditional micronization techniques focus on mechanical means, such as milling and grinding. Modern techniques utilize the properties of supercritical fluids and manipulate 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 efficacy 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 "d" 90 The "value" is a percentile value, which refers to the size of 90% (by volume) of particles that is smaller than or equal to that value. For example, a d0.0 value of 20.0 μm. 90 The value means that 90% (by volume) of the particles are less than or equal to 20.0 μm in size; d0.0 is the minimum particle size. 90 The value means that 90% (by volume) of the particles are less than or equal to 10.0 μm in size. 90 The "value" can be obtained from the particle size distribution (PSD) by laser diffraction (particle size analysis).

[0063] Similarly, the term "d" 10 “d” 25 “d” 50 "and / or "d 75 Define the corresponding percentage (by volume) of particles whose size is less than or equal to this value.

[0064] The term "d" 90 "Particle size distribution" means that 90% (by volume) of the particles have a particle size distribution below d, expressed in μm. 90 Granularity of the value.

[0065] Similarly, the term "d" 10 Particle size distribution, d 25 Particle size distribution, d 50 "Particle size distribution" and / or "d" 75 "Particle size distribution" refers to the percentages of particles (by volume) that have a particle size distribution above or below the respective defined d (in μm) values. 10 d 25 d 50 and / or d 75 Granularity of the value.

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

[0067] This patent application discloses novel micronized crystalline forms of antiviral aminothiazole compounds, which possess more suitable pharmacokinetic and stability characteristics (e.g., allowing antiviral drug compounds to enter neuronal tissue and the brain at higher throughput 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] The solid hydrochloride form of compound (I) The micronized crystalline HCl salt form of compounds of formula (I) offers advantages in bioavailability and stability, making it suitable for use as an active ingredient 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. Variations in the crystal structure of a pharmaceutical substance or active ingredient can affect the dissolution rate of the pharmaceutical product or active ingredient (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 variations 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 can 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 in the form of 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 compounds of formula (I) are disclosed, such as micronized crystal forms.

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

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

[0072] In a more preferred embodiment, in combination with any of the above or following embodiments, the micronized crystal form is a compound having the following structure: , Or its eutectic, hydrate or solvate.

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

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

[0075] In a more preferred embodiment, in combination with any of the above or following 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 invention, such micronized IM-250 HCl salt is characterized by an XRPD plot that includes 2θ angular reflectance (±0.3 degrees 2θ) at (characteristic peaks) of 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.

[0079] In some embodiments, the micronized IM-250 HCl salt is characterized by an XRPD plot that includes 2θ angle 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 using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0082] In some embodiments, the micronized IM-250 HCl salt has an XRPD plot 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 substantially as Figure 1 The XRPD diagram shown.

[0083] In some embodiments, the micronized IM-250 HCl salt has an XRPD plot 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 substantially as Figure 2 The XRPD diagram shown.

[0084] In some implementations, such micronized IM-250 HCl salts exhibit essentially the same characteristics as... Figure 1 The X-ray powder diffraction (XRPD) pattern shown.

[0085] In some implementations, such micronized IM-250 HCl salts exhibit essentially the same characteristics as... Figure 2 The X-ray powder diffraction (XRPD) pattern shown.

[0086] In some implementations, the micronized IM-250 HCl salt has a thermogravimetric analysis pyrograph, which shows a mass loss of about 9.8% when heated at an initial / final temperature of about 151°C / 170°C.

[0087] In some implementations, the micronized IM-250 HCl salt has a thermogravimetric analysis pyrograph, which indicates that the decomposition begins at a temperature of approximately 221°C.

[0088] In some embodiments, this document provides micronized IM-250 HCl salt having the following structure. , Among them, hydrochloride and ( S )-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)- N -methyl- N -(4-methyl-5-( S The molar ratio of (-methylsulfonylimide)thiazolyl-2-yl)acetamide is 1 to 1 ± 0.2.

[0089] In some implementations, IM-250 HCl salt is micronized, wherein d 90 The 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 implementations, IM-250 HCl salt is micronized, wherein d 90 The 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 implementations, IM-250 HCl salt is micronized to d90 The value is 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 implementations, the d of IM-250 HCl salt 90 The value is in the range of approximately 2.0 μm to approximately 5.0 μm, for example, d 90 The values ​​are 3.0μm, 3.5μm, 3.9μm or 4.0μm.

[0093] In some implementations, the d of IM-250 HCl salt 90 The value is in the range of approximately 9.0 μm to approximately 12.0 μm, for example, d 90 The value is 9.5 μm or 10.0 μm.

[0094] In a preferred embodiment, the d of IM-250 HCl salt 90 The value 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 d of IM-250 HCl salt 90 The value 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 d of IM-250 HCl salt 90 The value is less than or equal to approximately 6.0 μm.

[0097] In a more preferred embodiment, the d of IM-250 HCl salt 90 The value is less than or equal to 6.0 μm.

[0098] In one specific implementation, the d of IM-250 HCl salt 90 The value is less than or equal to approximately 4.0 μm.

[0099] In a more specific implementation, the d of IM-250 HCl salt 90 The value 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 examples below, 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 having the following structure: IM-250 HCl salt (d3-IM-250 HCl salt). .

[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) of 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 angle 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 using Cu-Kα radiation at a wavelength of 1.54 Å on a diffractometer.

[0107] In some embodiments, the micronized d3-IM-250 HCl salt has an XRPD plot 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 substantially as Figure 3The XRPD diagram shown.

[0108] In some implementations, the micronized d3-IM-250 HCl salt has a thermogravimetric analysis pyrograph, which shows a mass loss of about 7.8% when heated at an initial / final temperature of about 149°C / 167°C.

[0109] In some implementations, the micronized d3-IM-250 HCl salt has a thermogravimetric analysis pyrograph, which indicates that the decomposition begins at a temperature of approximately 225°C.

[0110] In some embodiments, the micronized d3-IM-250 HCl salt has a differential scanning calorimetry (DSC) thermogram, which includes an endothermic start at approximately 188 °C.

[0111] Therefore, the micronized d3-IM-250 HCl salt is also characterized by having a melting point of 188°C to 194°C (±5°C).

[0112] In some embodiments, this document provides micronized d3-IM-250 HCl salts having the following structure. , Among them, hydrochloride and ( S )-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)- N -methyl- N -(4-(methyl-d3)-5-( S The molar ratio of (-methylsulfonylimide)thiazolyl-2-yl)acetamide is 1 to 1 ± 0.2.

[0113] In some implementations, d3-IM-250 HCl salt is micronized, wherein d 90 The 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 implementations, d3-IM-250 HCl salt is micronized, wherein d 90 The 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 implementations, d3-IM-250 HCl salt is micronized to d 90The value is 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 implementations, the d3-IM-250 HCl salt has a d 90 The value is in the range of approximately 2.0 μm to approximately 5.0 μm, for example, d 90 The values ​​are 3.0μm, 3.5μm, 3.9μm or 4.0μm.

[0117] In some implementations, the d3-IM-250 HCl salt has a d 90 The value is in the range of approximately 9.0 μm to approximately 12.0 μm, for example, d 90 The value is 9.5 μm or 10.0 μm.

[0118] In a preferred embodiment, the d3-IM-250 HCl salt of d 90 The value 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 d3-IM-250 HCl salt of d 90 The value 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 d3-IM-250 HCl salt of d 90 The value is less than or equal to approximately 6.0 μm.

[0121] In a more preferred embodiment, the d3-IM-250 HCl salt of d 90 The value is less than or equal to 6.0 μm.

[0122] In one specific implementation, the d3-IM-250 HCl salt of d 90 The value is less than or equal to approximately 4.0 μm.

[0123] In a more specific implementation, the d3-IM-250 HCl salt of d 90 The value is less than or equal to 4.0 μm.

[0124] 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 showed less advantage. Therefore, 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 uses of the micronized solid form of compound (I) 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 invention relates to compounds in any of the above-described embodiments used as pharmaceuticals.

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

[0128] More particularly, the present invention relates to the compounds used for the treatment or prevention of diseases or conditions associated with viral infections caused by herpesviruses, such as, in particular, 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 the compounds used for treating and eliminating latent (dormant) forms of herpesviruses in neuronal tissues and nerves (preferably for avoiding or preventing recurrence and reactivation of herpes infection or even the serious effects associated therewith, such as herpes simplex encephalitis (HSE)).

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

[0131] In another aspect, the present invention relates to the compounds for the treatment and prevention of herpes infections (particularly 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, particularly herpes simplex-positive patients, for the purpose of suppressing relapses (suppressive therapy); or for patients resistant to nucleoside antiviral therapies such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, particularly herpes-positive patients, especially herpes simplex-positive patients.

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

[0133] Therefore, this 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 an effective amount of a compound as described herein or a composition containing said compound to a person or animal in need.

[0135] In practical applications, the compounds used in this invention can be tightly mixed with a drug carrier as the active ingredient according to conventional pharmaceutical formulation techniques. The carrier can take various forms, depending on the desired formulation for administration, such as oral or parenteral (including intravenous) administration. In preparing oral dosage forms, any commonly used pharmaceutical medium, such as water, ethylene glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., can 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, diluents, granulating agents, lubricants, binders, disintegrants, etc., can be used, with solid oral formulations being 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 a solid drug carrier is obviously used. Tablets may be coated using standard aqueous or non-aqueous techniques if desired. 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 can vary and is conveniently between about 2.0% and about 60.0% by weight. The amount of active compound in compositions useful for such treatment is the amount that will yield an effective dose. The active compound may also be administered intranasally, for example, as liquid drops or sprays, or as eye drops.

[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 alginate; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit is in capsule form, in addition to the materials of the types mentioned above, it may contain a liquid carrier such as fatty oil.

[0138] Various other materials may be present as coatings or used to change the physical form of dosage units. 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 can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water with a suitable surfactant, such as hydroxypropyl cellulose. Dispersions can 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 drug forms 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 a 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 can 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, or nasally. 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, the compounds of the present invention are administered orally.

[0142] The effective dosage of the active ingredient used can vary depending on the specific compound used, the method of administration, the condition being treated, and the severity of the condition. Such dosages 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. More specifically, 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) that is effective in treating a disease or condition associated with a viral infection.

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

[0146] Other embodiments of this further 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 initiator 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 for 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 diseases or conditions associated with oncolytic virus infection for cancer treatment, such as antiviral active compounds or immunomodulatory compounds, including checkpoint inhibitors.

[0147] Other embodiments of this further aspect of the invention relate to helicase initiator 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 to be treated is a solid cancer, preferably selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, and glioblastoma, etc.

[0148] Other embodiments of this further aspect of the invention relate to helicase initiator 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] Other embodiments of this further aspect of the invention relate to helicase priming enzyme 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 includes infusion, injection, intratumoral injection or local or transdermal administration of oncolytic viruses or oncolytic virus-infected cells and / or helicase priming enzyme inhibitors or pharmaceutical compositions comprising them.

[0150] Other embodiments of this further aspect of the invention relate to helicase initiator 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 the cells infected by the oncolytic virus are selected from oncolytic wild-type, clinical isolates or laboratory herpesvirus strains or genetically engineered or multimutated optionally attenuated or enhanced oncolytic herpesviruses.

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

[0152] Other embodiments of this further aspect of the invention relate to the kit for treating cancers as defined herein.

[0153] The helicase initiator inhibitor compounds, pharmaceutical compositions, or kits described herein for use in 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, to suppress relapse or shedding of oncolytic viruses; and patients, particularly herpes-positive patients, especially 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 (I) HCl salts Another aspect of the invention relates to the preparation of micronized forms of compounds of formula (I), including their cocrystals, hydrates or solvates.

[0155] HCl salt compound (I) can be prepared as described in the aforementioned EP patent application EP22151820 and the subsequent international application PCT / EP2023 / 050883, followed by a micronization step to obtain the solid crystal form until the desired d is obtained. 90 value and / or d 90 Particle size distribution.

[0156] Suitable micronization methods include milling, grinding, micronization 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 can be used.

[0157] In a preferred aspect of the invention, micronization includes reducing the particle size to d as defined herein. 90 value and / or d 90 Particle size distribution.

[0158] Preferably, micronization includes reducing the particle size (d) of the crystal form obtained from synthesis and recrystallization. 90 value / d 90 The particle size distribution is reduced 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] Particle size distribution can be determined using sieving analysis or laser diffraction (International Standard ISO 13320-1; for further laser diffraction analysis techniques, see, for example, http: / / pharmazie-lehrbuch.de / kapitel / 3-1.pdf), or by electronic sensing, light barrier, sedimentation, or microscopy, 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 instance, in *Pharmaceutical Dosage Forms: Volume 2, 2nd Edition*, edited by HA Lieberman, L. Lachman, and JBSchwartz. 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 typically obtained through laser diffraction analysis (particle size analysis).

[0160] More specifically, according to the European Pharmacopoeia 2.9.31 and USP <429> Particle size distribution was measured using laser diffraction. A measurement system from Beckman Coulter was used in water and Tween 80. ® Measurements were performed in a suspension. Samples were suspended using ultrasonication, and particle size distribution was calculated using the 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, if the density is homogeneous, the mass), i.e., the relative contribution will be proportional to the size. More specifically, the particle size distribution (PSD) according to the invention is 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 a suitable pharmaceutical dosage form, for example by filling it into capsules, pouches or other equivalent dosage forms, or by compressing the micronized particles into a suitable tablet form, 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 reverse cathode, 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. Instrument operating conditions were as follows: ambient temperature and atmosphere; X-ray generator voltage 30 kV, intensity 10 mA; X-ray source: copper target; emitted radiation Kα1 = 0.15406 nm, Kα2 = 0.15444 nm, ratio Kα2 / Kα1 = 0.5, Kβ filtered radiation nickel; slit: anti-divergence 1 nM, Soles slit 2.5°; goniometer: 0.07° step size for 2θ analysis of angular sectors from 4° to 45° or 4° to 50°; sample holder rotation speed: 30 rpm; detection: exposure time of 1 second per goniometer step.

[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 rate 10℃ / min; final temperature 230℃ or 240℃; carrier gas: nitrogen (Messer “qualité Azote 5.0”), flow rate 50 mL / min.

[0164] Thermogravimetric analysis (TGA) TGA analysis 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 5 mg; temperature increase 10 °C / min; final temperature 500 °C; carrier gas: nitrogen (Messer “qualité Azote 5.0”), flow rate 95 to 105 mL / min.

[0165] Laser diffraction particle size analysis According to European Pharmacopoeia 2.9.31 and USP <429> Perform laser diffraction analysis.

[0166] Optical microscopy and particle size distribution (PSD) assessment Optical microscopy analysis was performed on a LEICA DMIRB microscope equipped with a digital camera and a 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 coated 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 mg of the test sample was dispersed in soybean oil pre-saturated with a crystallizing material for analysis. Several microliters were then dropped onto a microscope slide covered with a coverslip and analyzed.

[0168] Image analysis (automated object detection) is linked to statistical analysis of the detected particle surfaces to create particle size distribution maps.

[0169] Characteristic diameter value in d 最小 d 平均 d 最大 (Given as particle number distribution values) and in d x The expression is given in the form of =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 -Methylsulfonyl (amino)thiazolyl-2-yl)acetamide hydrochloride

[0171] IM-250 free base (205 mg, 470 μmol) was stirred on a rotary evaporator at 50 °C and atmospheric pressure (as in Example 7 of WO2019 / 068817, for example). The sample (as described in or obtained as in international application PCT / EP2023 / 050883) was dissolved in acetone (5 mL). A volume of 1N HCl corresponding to a 1:1 stoichiometry 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 reheated to 50 °C 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 finally the powder was dried under dynamic vacuum (70 °C, 40 minutes) to obtain IM-250 HCl salt as colorless crystals.

[0172] Perform XRPD analysis. Figure 1 The XRPD chromatogram of IM-250 HCl salt is shown. The XRPD peaks were identified and are included in Table 1 below.

[0173] Table 1: XRPD peak positions (°2) ) and intensity

[0174]

[0175] TGA and DSC analyses were performed. TGA analysis showed a 9.8% mass loss upon heating at initial / final 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 release of the HCl fraction. DSC analysis indicated no true melting point. An unresolved dual endothermic event observed at 160°C occurred simultaneously with the loss of the HCl fraction observed on the TGA plot.

[0176] Alternative methods for synthesizing IM-250 HCl salt using EtOH: IM-250 free base (4.75 g) (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 water from the HCl solution, EtOH (50 mL) was added to the solution, followed by further evaporation until a few milliliters remained (a syrupy liquid). The sample was then brought to room temperature, resulting in the initiation of crystallization. An additional 50 mL of EtOH was then added to the sample (always to further remove water from the HCl solution), resulting in an unexpected increase in crystallization. XRPD analysis was performed. Figure 2 The XRPD plot of IM-250 HCl salt is shown. The identified XRPD peaks are... Figure 1 The similarity shown indicates that the same HCl polymorph was produced.

[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- d 3)-5-( S -Methylsulfonium (imide)thiazolyl-2-yl)acetamide hydrochloride

[0178] A 1:1 stoichiometric amount of 1N HCl was added to a 50 mL solution of 850 mg of deuterated IM-250 free base as described in WO2022 / 090409 or international application PCT / EP2023 / 050883 in acetone. 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 it was 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) were obtained with good yield.

[0179] Perform XRPD analysis. Figure 3 The XRPD plot of IM-250 HCl salt (d3-IM-250 HCl salt) is shown. XRPD peaks were identified and included in Table 2 below.

[0180] Table 2: XRPD peak positions (°2) ) and intensity

[0181] TGA and DSC analyses were performed. TGA analysis showed a 7.8% mass loss upon heating at initial / final 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 indicated no true melting point, but rather a broad endothermic transition (enthalpy of change –15 J / g) starting at approximately 188°C and peaking at 194°C.

[0182] Example 3: Particle size distribution assessment of IM-250 HCl salt The particle size distribution (PSD) of the IM-250 HCl salt batches prepared with EtOH in Example 1 was evaluated by microscopy and image analysis. Micrographs are reported in [year missing]. Figure 4 and Figure 5 The PSD quantitative results, particle size distribution map, and distribution histogram are reported in Table 3. Figure 6 and Figure 7 The sample mainly consists of large birefringent particles: 90% of the particles have a particle size of less than or equal to approximately 203 μm (d). 90 ).

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

[0184] Using another batch of crude IM-250 HCl salt from another experiment, particle sizes less than or equal to approximately 193 μm were measured (d 90 ).

[0185] Example 4: Micronization of IM-250 HCl Salt IM-250 HCl salt was micronized in HOLOPHARM to obtain an average d 90 The sample with a value of 6.1 μm. Figure 8 The particle size distribution of the micronized sample is shown, and Figure 9 It is a photomicrograph. For example... Figure 10 and Figure 11 As shown, the micronized sample exhibited the same diffraction peak positions and DSC curves as the non-micronized bulk sample, indicating that both samples contained the same crystal form. IM-250 HCl salt, as a bulk powder, has shown chemical and physical stability, as no changes were observed after storage at 40°C / 75% RH and 60°C for at least 3 weeks. By repeating this experiment, samples with d... 90 =3.3μm and d 90 Micronized material with a particle size of 3.9 μm.

[0186] Example 5: Particle size distribution assessment of deuterated IM-250 HCl salt Particle size distribution (PSD) of d3-IM-250 HCl salt batches was assessed using microscopy and image analysis. Micrographs are reported on [date missing]. Figure 12 and Figure 13 The PSD quantitative results, particle size distribution map, and distribution histogram are reported in Table 4. Figure 14 and Figure 15 The sample mainly consists of large birefringent particles: 90% of the particles have a particle size of less than or equal to approximately 156 μm (d). 90 ).

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

[0188] Example 6: Micronization of deuterated IM-250 HCl salt d3-IM-250 HCl salt was micronized in HOLOPHARM in a similar manner to obtain an average d 90 The sample with a value of 3.0 μm. Figure 16 The particle size distribution of the micronized sample is shown, and Figure 17These are micrographs. XRPD analysis did not demonstrate any difference in the position and intensity of the diffraction peaks of the 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 has the following properties: Figure 18 The PSD distribution, where d 90 The particle size was 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 collected in a fine filter bag after micronization, achieving a separation yield of 97%. According to European Pharmacopoeia 2.9.31 and USP... <429> Particle size distribution was determined by laser diffraction. A measurement system from Beckman Coulter was used in water and Tween 80. ® Measurements were performed in a suspension. Samples were suspended using ultrasonication, and particle size distribution was calculated using the Fraunhofer computational model. The micronized material had an average dm of 8.7 μm. 90 Value and According to Figure 19 The PSD distribution. Micronization makes d 90 The value decreased by a factor of 16.

[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) following a single oral dose in male C57bl / 6 mice (approximately 8 weeks of age) was examined. Animals (n=3 per group) were fasted approximately 2 hours prior to administration of 10 mg / kg of the test substance. Suspensions were prepared directly by adding the powder to a 0.5% HPMC solution in PBS, sonicated, and administered orally 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 measurement. Determination of peak plasma concentration (C max Elimination half-life (t) 1 / 2 ) and area under the curve (AUC)0-24h The following data was obtained (Table 5): Table 5: Effect of micronized IM-250 HCl salt / d3-IM-250 HCl salt on PK parameters in male mice compared to non-micronized matched pairs.

[0191] Relative bioavailability of different salt forms in male mice In international application PCT / EP2023 / 050883, the relative bioavailability of IM-250 (derived from DMSO stock solution) in different crystalline and salt forms after a single oral dose in male C57bl / 6 mice was evaluated. The area under the curve (AUC) of the IM-250 suspension was calculated. 0-24h The relative bioavailability of IM-250 was measured and compared between 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 these IM-250 forms tested were non-micronized. In those comparative evaluations, the inventors have demonstrated surprising improvements achievable with HCl salt (deuterated and undeuterated).

[0192] Now, by adding an additional micronization step, as shown in this paper, the pharmacokinetic properties of those selected salt forms can be further improved.

[0193] Conclusion: Improved bioavailability was achieved using two micronized test materials, such as at C max and AUC 0-24h This is evident in the comparison of the matched pairs. Compared to non-micronized materials, this allows for lower patient doses.

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).

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