Micronized crystalline hydrochloride of antiviral helicase primase inhibitor compounds

Abstract

The present invention provides a micronized solid crystalline form of the hydrochloride salt of a specific antiviral helicase primase inhibitor compound represented by formula (I), a composition thereof, a method for producing the same, and a method for using the same in the treatment or prevention of herpes simplex infection and diseases transmitted thereby. [Formula 1] TIFF2026524685000025.tif41169

Description

Summary of the Invention

[0001] The present invention provides a micronized solid crystalline form of a hydrochloride salt of a specific antiviral helicase primase inhibitor compound, a composition thereof, a method for producing the same, and a method for using the same in the treatment or prevention of herpes simplex infections and diseases mediated thereby.

Background Art

[0002] Pandemics of viral infections have plagued humanity since ancient times, causing mucocutaneous infections such as oral herpes and genital herpes. The disease symptoms often interfere with daily activities, and in some cases, infections with herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) are particularly life-threatening diseases (encephalitis) or vision-impairing diseases (keratitis) in immunocompromised patient populations such as neonates, the elderly, and transplant or cancer patients, or patients with hereditary immunodeficiency syndromes or diseases. After infection, alpha herpesvirus survives in a latent state in the host neurons, reactivates periodically, and often causes significant mental distress to patients. Currently, there is no effective treatment.

[0003] So far, small molecule drugs, vaccines, interleukins, interferons, therapeutic proteins, antibodies, and immunomodulatory drugs with specific or non-specific mechanisms of action lack either the effectiveness to replace nucleoside drugs such as acyclovir, valacyclovir, and famciclovir as the first choice for treatment or the required safety profile.

[0004] Known aminothiazoles (e.g., pritelivir, HN0037) are the most potent drugs developed today. These antiviral agents act by inhibiting the helicase primase of herpesvirus, have a lower resistance rate in vitro compared to nucleoside drugs, and show excellent efficacy in animal models, but their development is hindered by off-target carbonic anhydrase activity, reduced penetration into neuronal tissue and the brain, and abnormal pharmacokinetic profiles.

[0005] Herpesviruses are neurotrophic viruses that, after infection, invade and colonize neuronal tissue, remaining dormant in the host's neurons for life, thus providing a means of permanent exposure to neurons. Such permanent exposure to neurons by latent herpesviruses carries the risk of lifelong recurrence and periodic reactivation of herpes infections, often causing significant psychosocial distress to patients. Such exposure to neurons by herpesviruses can further cause herpesvirus encephalitis (or herpes simplex encephalitis; HSE), which is thought to be caused by the transmission of herpesviruses from peripheral facial sites after HSV-1 reactivation, or from neuronal tissue to the brain along nerve axons. The virus lies dormant in the ganglia or nerve tissue of the trigeminal nerve, invading the brain and causing HSE. Therefore, it is important to provide highly effective antiviral agents that can also treat and eliminate (dormant) herpesviruses in nerve tissue and neurons, thereby preventing recurrence and reactivation of herpes infections, or even serious effects such as HSE. For example, known antiviral drugs, such as known aminothiazoles, do not have sufficient potency to invade nerve tissue or cross the blood-brain barrier to enter the brain, and therefore cannot provide an effective and eradicative cure for latent or dormant herpesviruses, or even HSE.

[0006] A novel solid crystalline salt form of an antiviral helicase primase inhibitor compound represented by formula (A), also known as IM-250, and its deuterated analog are described in EP22151820 (filed January 17, 2022) and the subsequent international application WO2023 / 135303A1 (published July 20, 2023): [ka] Here, Y is selected from CH3 or CD3.

[0007] This application relates, in particular, to the hydrochloride (HCl salt) of the compound IM-250 represented by formula (I). [ka] Here, Y is selected from CH3 or CD3, and more specifically has the following formula: [ka]

[0008] WO2017 / 174640 describes the free base of the racemic mixture of IM-250, and WO2019 / 068817 describes both enantiomers of IM-250 and their pharmaceutically acceptable salts, respectively. WO2022 / 090409 describes the deuterated analog of IM-250 and its pharmaceutically acceptable salts. Some of the antiviral effects of IM-250 are described in Sci. Transl. Med. 2021;13:eabf8668 and Antivir. Res. 2021;195:105190.

[0009] The specific dosage or dosage form of the selected salt or crystalline form of IM-250 has not yet been described.

[0010] The scientific paper Serajuddin ATM, “Salt formation to improve drug solubility”, Adv. Drug Deliv. Rev. 2007; 59:603-616, discloses the relationship between salt formation of pharmacologically active substances and their effects on solubility, dissolution rate, and related factors from the perspective of pharmacobiological availability.

[0011] Kesisoglu et al. “Understanding the Effect of ApI Properties on Bioavailability Through Absorption Modeling”, The AAPS Journal, 2008; 10(4):516-525 describes how the solid-phase and physical properties of active pharmaceutical ingredients, as well as the particle size of pharmaceutical ingredients, affect their absorption properties and, consequently, the bioavailability of the drug.

[0012] Crystallization or salt formation can positively affect important drug properties such as solubility, dissolution rate, bioavailability, hygroscopicity, flavor, developability, and physical / chemical stability. The objective is to provide an optimized dosage or dosage form of the antiviral compound represented by formula (A) that exhibits optimized physicochemical and pharmaceutical properties without adversely affecting other important parameters such as the hygroscopicity and bioavailability of the active compound, ultimately leading to improvements in the manufacture, handling, storage, and pharmaceutical properties of the compound represented by formula (A).

[0013] [summary] The present invention relates to a novel selected crystalline form in a micronized form of the hydrochloride salt of the antiviral helicase primase inhibitor IM-250 represented by formula (I), or to a cocrystal, hydrate, or solvate thereof. [ka] Here, Y is selected from CH3 or CD3.

[0014] These newly selected micronized crystalline forms are useful, for example, in the treatment of human patients suffering from herpes simplex virus-mediated diseases. The novel micronized solid forms of this disclosure may be useful in the preparation of pharmaceuticals for the treatment or prevention of herpes simplex virus infections and diseases. The novel micronized solid forms of this disclosure may be used as helicase primase inhibitors. Surprisingly, the inventors of this invention have found that providing the selected crystalline hydrochloride form of IM-250 in a micronized form further improves its suitability for providing pharmaceuticals with optimized properties. Such advantages include, for example, improved bioavailability, which allows for administration at lower doses compared to the corresponding unmicronized drug. Thus, the inventors of this invention have for the first time combined the specific advantages shown for the selected IM-250 hydrochloride form and its deuterated analogs with the advantages of providing the drug in a micronized form, proposing a novel and improved drug dosage form or method of administration of IM-250. [Brief explanation of the drawing]

[0015] [Figure 1] The X-ray powder diffraction (XRPD) pattern of IM-250 hydrochloride is shown. [Figure 2] This shows the XRPD pattern of IM-250 hydrochloride crystallized from ethanol. [Figure 3] The XRPD pattern of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is shown. [Figure 4] Microscopic observation of IM-250 hydrochloride crystals under transmitted light and cross-polarized light for PSD evaluation (magnification x162). [Figure 5] Microscopic observation (magnification x162) of IM-250 hydrochloride crystals (same crystals as in Figure 4) under cross-polarized light. [Figure 6] Particle size distribution profile (cumulative particle size distribution) of IM-250 hydrochloride crystals. [Figure 7] Distribution histogram of PSD evaluation for IM-250 hydrochloride. [Figure 8] Particle size distribution of finely powdered IM-250 hydrochloride by laser diffraction. [Figure 9] Microscopic observation of finely powdered IM-250 hydrochloride. [Figure 10] Overlay XPRD profiles of an untreated IM-250 hydrochloride batch and the same batch after micronization. [Figure 11] Overlay DSC profiles of an untreated IM-250 hydrochloride batch and the same batch after micronization. [Figure 12] Microscopic observation of d3-IM-250 hydrochloride crystals under transmitted light and cross-polarized light for PSD evaluation (magnification x162). [Figure 13] Microscopic observation (magnification x162) of d3-IM-250 hydrochloride crystals (same crystals as in Figure 4) under cross-polarized light. [Figure 14] Particle size distribution profile (cumulative particle size distribution) of d3-IM-250 hydrochloride crystals. [Figure 15] Distribution histogram of PSD evaluation for d3-IM-250 hydrochloride. [Figure 16] Particle size distribution of finely powdered d3-IM-250 hydrochloride by laser diffraction. [Figure 17] Microscopic observation of finely powdered d3-IM-250 hydrochloride. [Figure 18] Particle size distribution and d90 value of IM-250 hydrochloride (GMP campaign) before micronization, as determined by laser diffraction. [Figure 19] Particle size distribution and d90 value of finely powdered IM-250 hydrochloride (GMP campaign) obtained by laser diffraction.

[0016] [Detailed explanation] The following description includes certain specific details to provide a complete understanding of the various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure can be implemented without these detailed descriptions. The following descriptions of some embodiments are based on the understanding that this disclosure should be construed as illustrative of the subject matter described in the claims and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this 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.

[0017] [Definition] Unless otherwise required by context, throughout this specification and the claims, variations thereof such as “comprise” and “comprising” shall be interpreted in an open and comprehensive sense, i.e., “including, but not limited to.”

[0018] Throughout this specification, any reference to “one embodiment” or “an embodiment” means that certain features, configurations, or characteristics described in relation to an embodiment are included in at least one embodiment of the present invention. Therefore, not all expressions “in one embodiment” or “in an embodiment” in this specification necessarily describe the same embodiment.

[0019] Furthermore, specific features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0020] Embodiments referred to as “crystalline form” throughout this specification include crystals, salts, cocrystals, hydrates, and / or solvates of formula (I) disclosed herein.

[0021] In the sense of this disclosure, “deuterated,” “deuterated,” “deuterated,” or “deuterated” means that one or more hydrogen atoms of the compound of formula (I) are deuterated (represented by “D”). 2 This means that it will be replaced by H).

[0022] In some compounds of formula (I), residue Y represents CD3. Surprisingly, such deuterated aminothiazole compounds, when administered to mammals, e.g., humans, have been found to exhibit increased resistance to metabolism compared to their respective non-deuterated compounds, and are therefore useful in increasing 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 means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium (see the Experiments section for details).

[0023] The deuterium-labeled or substituted therapeutic compounds of this disclosure have, surprisingly, been found to have improved DMPK (drug metabolism and pharmacokinetic) properties related to absorption, distribution, metabolism, and excretion (ADME). Deuterium substitution has been found to result in certain therapeutic benefits due to improved metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index.

[0024] The concentration of deuterium may be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable or radioactive isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its naturally occurring isotopic composition (about 99.98% hydrogen). Accordingly, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium having an isotopic purity of at least 50%, preferably at least 95%, and more preferably at least 99%.

[0025] The proportion of deuterium incorporation can be determined by quantitative analysis using numerous conventional methods such as mass spectroscopy (peak area), or by internal standards or other deuterated materials in the compound. 1 Compared to the signal from the H signal, the remaining specific deuterated site 1 This can be obtained by quantifying the H-NMR signal.

[0026] It will be recognized that, depending on the origin of the chemicals used in the synthesis, some variation in the natural isotopic abundances will occur in the synthesized compound. Therefore, preparations of non-deuterated analogs of the compounds of the present invention essentially contain small amounts of deuterated isotopologs. The concentrations of naturally abundant and stable hydrogen and carbon isotopes, despite this variation, are small and insignificant compared to the degree of stable isotopic substitution of the compounds of the present invention. See, for example, Comp. Biochem. Physiol. 1998;119A:725.

[0027] The term "isotope enrichment factor" at a particular position normally occupied by hydrogen refers to the ratio between the abundance of deuterium at that position and the natural abundance of deuterium at that position. For example, an isotope enrichment factor of 3500 means that the amount of deuterium at a particular position is 3500 times the natural abundance of deuterium, or that 52.5% of the compound has deuterium at a particular position (i.e., 52.5% deuterium incorporation at a given position). The abundance of deuterium in the Earth's oceans is approximately 1 atom out of 6500 hydrogen atoms (about 154 ppm). Thus, deuterium accounts for about 0.015% of all natural hydrogen atoms in the Earth's oceans (0.030% on a weight basis), and its abundance varies slightly from one type of natural water to another.

[0028] The deuterated compounds of the present disclosure are preferably characterized by an isotope enrichment factor of at least 6300, or by a degree of deuteration of at least 95%. More preferably, they are characterized by an isotope enrichment factor of at least 6500, or by a degree of deuteration of at least 98%.

[0029] Any formula or structure given herein is also intended to represent compounds further comprising additional isotopically labeled atoms. Additional isotopes that can be incorporated into the compounds of the present disclosure include, for example, isotopes of hydrogen, as well as isotopes of carbon, nitrogen, oxygen and fluorine ( 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F and 35 S, etc., but not limited to these). The present disclosure further 3 H, 13 C and 14This includes various isotope-labeled compounds incorporating radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), metabolic studies, or reaction kinetics studies, including drug or substrate tissue distribution assays or radiotherapy of patients. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and methods of preparation, by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents.

[0030] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, and / or emulsifiers, or any combination of the above approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other national counterparts as acceptable for use in humans or livestock.

[0031] "Pharmaceutical composition" means a formulation of the compounds of this disclosure (e.g., the compounds of formula (I)) and a medium (dosage form) commonly accepted in the art for the delivery of the biologically active compounds to a mammal, such as a human. Such a medium includes all pharmaceutically acceptable excipients therefor.

[0032] The term “effective dose” means an amount of a compound that, when administered, is sufficient to prevent or, to some extent, the onset of an infection or one or more symptoms of the disorder, disease, or condition being treated. The term “effective dose” also refers to an amount of a compound sufficient to elicit a biological or medical response in a cell, tissue, system, animal, or human, as determined by a researcher, veterinarian, physician, or clinician.

[0033] "Prevention," "prevention," or "preventive measures" means any treatment of an infection, disease, or condition that prevents the development of clinical symptoms of the disease or condition.

[0034] In some embodiments, 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 such conditions.

[0035] The "treatment" and "procedure" for a disease include the following: (1) To prevent or reduce the risk of developing a disease, that is, to prevent the development of clinical symptoms of a disease in subjects who are potentially exposed to a disease or have a predisposition to the disease but have not yet experienced or manifested symptoms of the disease. (2) To suppress the disease, that is, to prevent or reduce the onset of the disease or its clinical symptoms. (3) To alleviate (cure) the disease, that is, to reduce the disease or its clinical symptoms, and (4) To improve or alleviate symptoms or disorders caused by a disease.

[0036] The terms “subject” or “patient” refer to an animal, such as a mammal (including a human), that is the subject of treatment, observation, or experimentation. The methods described herein may be useful in the treatment and / or veterinary use of humans. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, a domestic animal (e.g., a dog or a cat), livestock (e.g., a cattle, a horse, a sheep, a goat, and a pig), and / or an experimental 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. “A human (or patient) who needs it” means a human who may or may be suspected of having an infectious disease or disease or condition that would benefit from a particular treatment, for example, being treated with a compound disclosed herein in accordance with this application.

[0037] In this specification, references to values ​​or parameters using "about" include (and describe) embodiments relating to the value or parameter itself. For example, a description referring to "about x" includes a description of "x." Also, the singular forms "a" and "the" include multiple references unless the context clearly indicates otherwise. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0038] "Pharmacologically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0039] The term “substantially represented” includes, for example, when referring to an XRPD pattern, DSC thermogram, or TGA thermogram, a pattern, thermogram, or spectrum that is not necessarily identical to those shown herein but, as considered by those skilled in the art, falls within the limits of experimental error or deviation.

[0040] Furthermore, the compounds of this disclosure may exist in solvates, e.g., solvated water, or pharmaceutically acceptable solvates, e.g., alcohols, particularly ethanol. “Solvates” are formed by the interaction of a solvent with a compound. When the solvent is water, the “solvate” is a “hydrate.” It is understood that salts of this disclosure may also include solvates.

[0041] Suitable solvents for forming salts and solvents of the compound represented by formula (I) as defined herein include acetonitrile, dichloromethane (DCM), alcohols such as methanol, ethanol, and 2-propanol (isopropanol), aldehydes, ketones such as acetone, ethers such as tetrahydrofuran (THF) or dioxane, esters such as ethyl acetate, or alkanes such as pentane, hexane, heptane, or cyclohexane, and water, as well as mixtures thereof.

[0042] Micronization is a method of reducing the average particle diameter of solid materials through friction or other means. Conventional micronization techniques focused on mechanical means such as crushing and grinding. Modern technology utilizes the properties of supercritical fluids to manipulate the principles of solubility. The term micronization usually refers to reducing the average particle size to the micrometer range and is used to enhance the effectiveness of solid materials, for example, by improving solubility and bioavailability. However, it can also have beneficial effects on other material properties such as fluidity and transport properties (in the case of bulk materials), reactivity, abrasiveness, extractability and reaction behavior, taste, and compressibility.

[0043] "d 90 The "value" refers to the percentile value, which indicates that 90% (by volume) of the particles are below this value. For example, d 90 A value of 20.0 μm means that 90% (by volume) of the particles are 20.0 μm or smaller. Similarly, d 90 A value of 10.0 μm indicates that 90% (by volume) of the particles are 10.0 μm or smaller. 90 The value can be derived from the evaluation of the particle size distribution (PSD) by laser diffraction (particle size analysis).

[0044] Similarly, "d 10 "d 25 "d 50 " and / or "d 75 Each of these terms defines particles that are less than or equal to that value as a percentage (volume ratio).

[0045] "d 90 The term "particle size distribution" refers to the size distribution of 90% of particles (by volume) expressed in μm units. 90 This means that the particle size is smaller than the value.

[0046] Similarly, "d 10 Particle size distribution”, “d 25 Particle size distribution”, “d 50 "particle size distribution" and / or "d 75 The term "particle size distribution" refers to the distribution where 10%, 25%, 50%, and / or 75% (by volume) of the particles are defined as d 10 d25 d 50 and / or d 75 This means that the value (in μm) is either above or below the specified value.

[0047] These d values ​​are particularly related to the cumulative particle volume in the particle distribution curve.

[0048] This patent application discloses a novel micronized crystalline form of antiviral aminothiazole compounds having a more appropriate pharmacokinetic and stability profile (for example, improved solubility and bioavailability can increase the rate of transfer of antiviral compounds into nerve tissue and the brain). Furthermore, antiviral aminothiazole compounds in the novel micronized crystalline form are more suitable for drug development and use as pharmaceuticals because they are characterized by improved stability and bioavailability of the compounds.

[0049] [Solid hydrochloride form of the compound of formula (I)] The micronized crystalline hydrochloride form of the compound 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 the present invention have discovered that IM-250 hydrochloride exhibits advantageous physical properties such as good physical and chemical stability, good water solubility, and good bioavailability, while being non-hygroscopic, for example. Variations in the crystalline structure of a pharmaceutical raw material or active ingredient can affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ability to consistently prepare doses at known strengths), and stability (e.g., thermal stability, shelf life, etc.) of a pharmaceutical formulation or active ingredient. Such variations can affect the preparation and formulation of pharmaceutical compositions in different dosage and dispensing forms, such as solutions or solid oral dosage forms including tablets and capsules. Compared to other forms such as amorphous or noncrystalline forms, certain crystalline forms may offer desirable or appropriate improvements in hygroscopicity, particle size control, dissolution rate, solubility, purity, physicochemical stability, manufacturability, yield, and / or process control. Therefore, the micronized crystalline hydrochloride form of the compound of formula (I) may offer additional advantages such as improved methods for producing the compound, stability or storability of the compound's formulation, stability or storability of the active pharmaceutical ingredient, and / or improved bioavailability and / or stability of the compound as an active ingredient.

[0050] In certain embodiments, novel pulverized solid forms, such as the crystalline form of the compound of formula (I), are disclosed.

[0051] The present invention relates particularly to the following embodiments: In preferred embodiments, combined with any of the embodiments described above or below, the micronized crystalline form is a compound represented by formula (I), or a cocrystal, hydrate, or solvate thereof. [ka] Here, Y is selected from CH3 and CD3.

[0052] In a more preferred embodiment, combined with any of the embodiments described above or below, the micronized crystalline form is a compound having the following structure, or a cocrystal, hydrate, or solvate thereof. [ka]

[0053] In a more preferred embodiment, combined with any of the embodiments described above or below, the micronized crystal morphology has the following structure. [ka]

[0054] In a more preferred embodiment, combined with any of the embodiments described above or below, the micronized crystalline form is a compound having the following structure, or a cocrystal, hydrate, or solvate thereof. [ka]

[0055] In a more preferred embodiment, combined with any of the embodiments described above or below, the micronized crystal morphology has the following structure. [ka]

[0056] [IM-250 hydrochloride] A further embodiment of the present invention relates to a finely powdered hydrochloride of compound IM-250, which is IM-250 hydrochloride and has the following structure. [ka]

[0057] In one embodiment of the present invention, such pulverized IM-250 hydrochloride is characterized by an XRPD pattern that includes (characteristic peaks) degree 2θ reflections (±0.3 degrees 2θ) at 13.7 degrees, 17.7 degrees, and 22.8 degrees.

[0058] In some embodiments, the micronized IM-250 hydrochloride is characterized by an XRPD pattern having degree 2θ reflections (±0.3 degrees 2θ) at 13.7 degrees, 17.7 degrees, and 22.8 degrees, and an XRPD pattern having one, two, or three degree 2θ reflections (±0.3 degrees 2θ) at 17.0 degrees, 19.8 degrees, and 21.8 degrees.

[0059] In some embodiments, the micronized IM-250 hydrochloride is characterized by an XRPD pattern having a degree 2θ reflectance (±0.3 degrees 2θ) at 13.7, 17.0, 17.7, 19.8, 21.8, and 22.8 degrees.

[0060] In some embodiments, the micronized IM-250 hydrochloride is characterized by an XRPD pattern containing at least four of the following peaks: 13.7, 17.0, 17.7, 19.8, 21.8, and 22.8 degrees 2θ (±0.3 degrees 2θ).

[0061] All values ​​were measured using a diffractometer with Cu-Kα emission at a wavelength of 1.54 Å.

[0062] In some embodiments, the micronized IM-250 hydrochloride has an XRPD pattern 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 20-degree reflectors with maximum intensity, similar to the XRPD pattern substantially shown in Figure 1.

[0063] In some embodiments, the pulverized IM-250 hydrochloride 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 20-degree reflectors with maximum intensity, similar to the XRPD pattern substantially shown in Figure 2.

[0064] In some embodiments, such finely powdered IM-250 hydrochloride exhibits an X-ray powder diffraction (XRPD) pattern, substantially as shown in Figure 1.

[0065] In some embodiments, such finely powdered IM-250 hydrochloride exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2.

[0066] In some embodiments, the micronized IM-250 hydrochloride has a thermogravimetric thermogram showing a mass loss of approximately 9.8% when heated at a start / end temperature of approximately 151 / 170°C.

[0067] In some embodiments, the micronized IM-250 hydrochloride has a thermogravimetric thermogram indicating a decomposition onset temperature of approximately 221°C.

[0068] In some embodiments, this specification provides a micronized IM-250 hydrochloride having the following structure. [ka] Here, the molar ratio of hydrochloride to (S)-2-(2',5'-difluoro[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide is 1:1 ± 0.2.

[0069] In some embodiments, IM-250 hydrochloride is d 90 The material is pulverized so that its particle size is approximately 20.0 μm or less, for example, in the range of approximately 1.0 to 20.0 μm, or in the range of approximately 2.0 to 12.0 μm.

[0070] In some embodiments, IM-250 hydrochloride is d 90 The material is pulverized so that its particle size is 20.0 μm or less, for example, in the range of 1.0 to 20.0 μm, or in the range of 2.0 to 12.0 μm.

[0071] In some embodiments, IM-250 hydrochloride is d 90 The values ​​fall within the range of approximately 1.0 μm to approximately 2.0 μm, greater than approximately 2.0 μm to approximately 3.0 μm, greater than approximately 3.0 μm to approximately 4.0 μm, greater than approximately 4.0 μm to approximately 6.0 μm, greater than approximately 6.0 μm to approximately 8.0 μm, greater than approximately 8.0 μm to approximately 10.0 μm, or greater than approximately 10.0 μm to approximately 12.0 μm.

[0072] In some embodiments, 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 3.0 μm, 3.5 μm, 3.9 μm, or 4.0 μm.

[0073] In some embodiments, d 90 The values ​​are 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.

[0074] In a preferred embodiment, d of IM-250 hydrochloride 90 The value is approximately 11.0 μm or less, or approximately 10.0 μm or less.

[0075] In a preferred embodiment, d of IM-250 hydrochloride 90 The value is 11.0 μm or less, or 10.0 μm or less.

[0076] In a more preferred embodiment, d of IM-250 hydrochloride 90 The value is approximately 6.0 μm or less.

[0077] In a more preferred embodiment, d of IM-250 hydrochloride 90The value is 6.0 μm or less.

[0078] In certain embodiments, d of IM-250 hydrochloride 90 The value is approximately 4.0 μm or less.

[0079] In a more specific embodiment, d of IM-250 hydrochloride 90 The value is 4.0 μm or less.

[0080] The micronized hydrochloride salt IM-250 hydrochloride was unexpectedly found to exhibit several advantages in terms of chemical and physical stability, hygroscopicity (lack of hygroscopicity), and improved bioavailability. On the other hand, as shown in the following examples, the other salts tested did not exhibit as many advantages. Therefore, micronized IM-250 hydrochloride is a particularly preferred embodiment of the present invention.

[0081] [Deuterated IM-250 hydrochloride-d3-IM-250 hydrochloride] Further embodiments of the present invention relate to a finely powdered deuterated compound of IM-250 hydrochloride (d3-IM-250 hydrochloride) having the following structure. [ka]

[0082] In one embodiment of the present invention, such pulverized d3-IM-250 hydrochloride is characterized by an XRPD pattern that includes (characteristic peaks) degree 2θ reflections (±0.3 degree 2θ) at 13.8 degrees, 17.8 degrees, and 21.8 degrees.

[0083] In some embodiments, the micronized d3-IM-250 hydrochloride is characterized by an XRPD pattern that includes one, two, three, four, or five degree 2θ reflections (±0.3 degree 2θ) at 13.8, 17.8, and 21.8 degrees, and one, two, three, four, or five degree 2θ reflections (±0.3 degree 2θ) at 11.3, 11.9, 19.8, 21.0, and 21.3 degrees.

[0084] In some embodiments, the micronized d3-IM-250 hydrochloride is characterized by an XRPD pattern including degree 2θ reflections (±0.3 degrees 2θ) at 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3, and 21.8 degrees.

[0085] In some embodiments, the micronized d3-IM-250 hydrochloride is characterized by an XRPD pattern containing at least four of the following peaks: 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3, and 21.8 degrees 2θ (±0.3 degrees 2θ).

[0086] All values ​​were measured using a diffractometer with Cu-Kα emission at a wavelength of 1.54 Å.

[0087] In some embodiments, the micronized d3-IM-250 hydrochloride 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 20-degree reflectors with maximum intensity, similar to the XRPD pattern substantially shown in Figure 3.

[0088] In some embodiments, the micronized d3-IM-250 hydrochloride has a thermogravimetric thermogram showing a mass loss of approximately 7.8% when heated at a start / end temperature of approximately 149 / 167°C.

[0089] In some embodiments, the micronized d3-IM-250 hydrochloride has a thermogravimetric thermogram indicating a decomposition onset temperature of approximately 225°C.

[0090] In some embodiments, the micronized d3-IM-250 hydrochloride has a differential scanning calorimetry thermogram that includes an endothermic reaction with an onset temperature of approximately 188°C.

[0091] Therefore, the finely powdered d3-IM-250 hydrochloride may also be characterized by a melting point of 188-194°C (±5°C).

[0092] In some embodiments, this specification provides a micronized d3-IM-250 hydrochloride having the following structure. [ka] Here, the hydrochloride salt and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide are present in a molar ratio of 1:1 ± 0.2.

[0093] In some embodiments, d3-IM-250 hydrochloride is d 90 The material is pulverized so that its particle size is approximately 20.0 μm or less, for example, in the range of approximately 1.0 to 20.0 μm, or in the range of approximately 2.0 to 12.0 μm.

[0094] In some embodiments, d3-IM-250 hydrochloride is d 90 The material is pulverized so that its particle size is 20.0 μm or less, for example, in the range of 1.0 to 20.0 μm, or in the range of 2.0 to 12.0 μm.

[0095] In some embodiments, d3-IM-250 hydrochloride is d 90 The values ​​fall within the range of approximately 1.0 μm to approximately 2.0 μm, greater than approximately 2.0 μm to approximately 3.0 μm, greater than approximately 3.0 μm to approximately 4.0 μm, greater than approximately 4.0 μm to approximately 6.0 μm, greater than approximately 6.0 μm to approximately 8.0 μm, greater than approximately 8.0 μm to approximately 10.0 μm, or greater than approximately 10.0 μm to approximately 12.0 μm.

[0096] In some embodiments, d3-IM-250 hydrochloride 90 The value is in the range of approximately 2.0 μm to approximately 5.0 μm, for example, d 90 The values ​​are 3.0 μm, 3.5 μm, 3.9 μm, or 4.0 μm.

[0097] In some embodiments, d3-IM-250 hydrochloride 90The values ​​are 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.

[0098] In a preferred embodiment, d3-IM-250 hydrochloride is d 90 The value is approximately 11.0 μm or less, or approximately 10.0 μm or less.

[0099] In a preferred embodiment, d3-IM-250 hydrochloride is d 90 The value is 11.0 μm or less, or 10.0 μm or less.

[0100] In a more preferred embodiment, d3-IM-250 hydrochloride d 90 The value is approximately 6.0 μm or less.

[0101] In a more preferred embodiment, d3-IM-250 hydrochloride d 90 The value is 6.0 μm or less.

[0102] In certain embodiments, d3-IM-250 hydrochloride 90 The value is approximately 4.0 μm or less.

[0103] In more specific embodiments, d3-IM-250 hydrochloride 90 The value is 4.0 μm or less.

[0104] The micronized deuterated hydrochloride, d3-IM-250 hydrochloride, was found to exhibit several surprising advantages with respect to chemical and physical stability, hygroscopicity (lack of hygroscopicity), and improved bioavailability. Other salts tested, on the other hand, did not exhibit as many advantages. Therefore, micronized crystalline deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) is a particularly preferred embodiment of the present invention.

[0105] [Dosage form and medical use of the powdered solid form of compound (I)] Further aspects of the present invention relate to pharmaceutical formulations comprising one or more compounds of any of the embodiments described above.

[0106] Further aspects of the present invention relate to any of the compounds of the above embodiments for use as pharmaceuticals.

[0107] In particular, the present invention relates to the compound described above for use in the treatment or prevention of diseases or disorders related to viral infections.

[0108] More specifically, the present invention relates to the use of the described compounds for the treatment or prevention of diseases or disorders associated with viral infections caused by herpes viruses, particularly herpes simplex virus, i.e., for the treatment or prevention of herpes infections such as herpes simplex virus infection.

[0109] In a further aspect, the present invention relates to the use of the described compounds for treating and eliminating latent (dormant) forms of herpesviruses in nerve tissue and nerves, preferably for avoiding or preventing recurrence and reactivation of herpes infections, or even serious associated effects such as herpes simplex encephalitis (HSE).

[0110] In a further embodiment, the present invention relates to the use of the described compounds in the treatment or prevention of neurodegenerative diseases caused by viruses, such as Alzheimer's disease, which is caused particularly by viruses, especially herpes simplex virus.

[0111] In a further embodiment, the present invention relates to the use of the above-mentioned compounds in the following patients: Patients with herpes infections, especially herpes simplex infections, oral herpes, 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; neonates and infants; herpes-positive patients, especially herpes simplex-positive patients, patients for relapse suppression (suppressive therapy); or patients resistant to nucleoside antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, especially herpes-positive patients, especially herpes simplex-positive patients.

[0112] The compounds according to the present invention are considered for use in the prevention and treatment of disorders and diseases in humans and animals, respectively.

[0113] Accordingly, the present invention relates to the use of the compounds described herein for the preparation of pharmaceuticals.

[0114] Furthermore, the present invention relates to methods for preventing or treating viral infection-related diseases or disorders, particularly those caused by herpesviruses such as herpes simplex virus, and to methods for treating and eliminating latent (dormant) forms of herpesviruses in nerve tissue and nerves, preferably to avoid or prevent recurrence and reactivation of herpes infection, or even serious effects associated with infections such as herpes simplex encephalitis (HSE), or to methods for preventing or treating viral neurodegenerative diseases, particularly Alzheimer's disease, wherein the method comprises administering an effective amount of the compound described herein or a composition containing the compound to a human or animal in need thereof.

[0115] In practical use, the compounds used in the present invention can be combined as active ingredients in a tight mixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier can take a wide variety of forms depending on the desired form of the preparation to be administered, for example, orally or parenterally (including intravenously). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycol, oil, alcohol, flavoring agents, preservatives, coloring agents, etc., in the case of oral liquid formulations such as suspensions, elixirs, and solutions; or, in the case of oral solid formulations such as powders, hard and soft capsules, and tablets, a carrier such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants, with solid oral formulations being preferred over liquid formulations.

[0116] For ease of administration, tablets and capsules offer the most advantageous oral dosage forms, in which case solid drug carriers are obviously used. If necessary, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations must contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, be varied and, conveniently, may range from about 2.0 percent to about 60.0 percent of the unit weight. The amount of the active compound in such therapeutically useful compositions is such that an effective dose is obtained. The active compound may also be administered intranasally, for example, as droplets or sprays, or as eye drops.

[0117] Tablets, pills, capsules, etc., may also contain binders such as tragacanth gum, acacia, 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. If the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the above types of materials.

[0118] Various other substances may be present, either as a coating or to modify the physical shape of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrups or elixirs may contain sucrose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavor.

[0119] The compounds used in this invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water appropriately mixed with a surfactant such as hydroxypropyl cellulose. Dispersants can also be prepared in a mixture of glycerin, liquid polyethylene glycol, and its oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0120] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for immediate preparation of sterile injection solutions or dispersions. In all cases, the forms must be sterile and liquid enough to be easily injected. They must be stable under manufacturing conditions and preserved against 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.

[0121] To provide an effective dose of the compound of the present invention to mammals, particularly humans, any suitable route of administration can be used. For example, it can be administered orally, rectally, topically, parenterally (including intravenously), orally, in the lungs, or nasally. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, gels, ointments, aerosols, and the like. Preferably, the compound of the present invention is administered orally or topically as eye drops, creams, or gels, and more preferably, the compound of the present invention is administered orally.

[0122] The effective dose of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be easily determined by those skilled in the art.

[0123] The compounds of the present invention may also be present in combination with further active ingredients, in particular one or more active ingredients that exhibit advantageous effects in the treatment of any of the disorders or diseases described herein. More particularly, the compounds of the present invention are present in a composition in combination with at least one further active substance that is effective in treating diseases or disorders associated with viral infection (antiviral active compound), preferably by herpesvirus, particularly herpes simplex virus, and thus diseases or disorders associated with so-called combination therapy. At least one further active substance (immunomodulator, e.g., glucocorticoid) is effective in treating diseases or disorders associated with viral infection, and more preferably, antiviral active compounds selected from the group consisting of nucleoside drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, as well as compounds such as foscarnet and cidofovir.

[0124] Accordingly, the present invention further relates to a pharmaceutical composition comprising one or more compounds in a micronized form as described herein that are effective in treating diseases or disorders associated with viral infection (antiviral active compounds), and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active substance.

[0125] A further aspect of the present invention relates to the use of the compounds described herein acting as helicase primase inhibitors in combination therapy with oncolytic viruses for the treatment of tumors, cancers, or neoplasms.

[0126] Further embodiments of this additional aspect of the present invention relate to a pharmaceutical composition for use as an antidote in combination therapy with oncolytic viruses for the treatment of cancer, comprising at least one helicase primemase inhibitor as defined in any embodiment described herein, which acts to control, modulate, inhibit or block the activity of oncolytic viruses sensitive to the inhibitor used in cancer treatment, and which may further comprise at least one further active substance such as at least one pharmaceutically acceptable carrier and / or excipient and / or antiviral activity or immunomodulatory compound, and which comprises a checkpoint inhibitor that is effective in treating diseases or disorders associated with oncolytic virus infection used in cancer treatment.

[0127] Further embodiments of this additional aspect of the present invention relate to helicase primemase inhibitor compounds or pharmaceutical compositions of the present 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 tumor, and preferably the cancerous disease is selected from liver cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, brain cancer, melanoma, and glioblastoma, among others.

[0128] Further embodiments of this additional aspect of the present invention relate to helicase primemase inhibitor compounds or pharmaceutical compositions of the present invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the oncolytic virus is an oncolytic herpesvirus.

[0129] Further embodiments of this additional aspect of the present invention relate to helicase primemase inhibitor compounds or pharmaceutical compositions of the present invention for use in combination therapy with oncolytic viruses as described in WO2020 / 109389, wherein the cancer therapy includes infusion, injection, intratumoral injection or topical or transdermal application of oncolytic viruses or oncolytic virus-infected cells and / or helicase primemase inhibitors or pharmaceutical compositions comprising the same.

[0130] Further embodiments of this additional aspect of the present invention relate to helicase primemase inhibitor compounds or pharmaceutical compositions of the present 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 isolate or experimental herpesvirus strain or genetically engineered or polymutated and optionally attenuated or booster-immunized oncolytic herpesvirus.

[0131] Further embodiments of this additional aspect of the present invention relate to a kit comprising at least one helicase primemase inhibitor compound or pharmaceutical composition of the present invention and at least one oncolytic virus selected from wild-type, laboratory strain, clinical isolate and genetically modified or polymutant oncolytic viruses, for use in combination therapy with oncolytic viruses as described in WO2020 / 109389.

[0132] Further embodiments of this additional aspect of the present invention relate to the kit for use in the treatment of cancer as defined herein.

[0133] The helicase primemase 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; patients with herpes-positive disease, especially those with oncolytic herpes simplex, to suppress recurrent or oncolytic viral shedding; patients resistant to nucleoside antiviral therapy such as acyclovir, penciclovir, famciclovir, ganciclovir, valacyclovir and / or foscarnet or cidofovir, especially those with herpes-positive disease, especially those with oncolytic herpes simplex.

[0134] [Preparation of the micronized hydrochloride of formula (I)] Further aspects of the present invention relate to the preparation of compounds of formula (I) and their cocrystals, hydrates, or solvates in a micronized form.

[0135] The hydrochloride compound (I) was prepared by the method described in the aforementioned European patent application EP22151820 and the subsequent international application PCT / EP2023 / 050883, and the resulting solid crystal form was then subjected to the desired d 90 value and / or d 90 It can be prepared by going through a process of pulverizing until a particle size distribution is obtained.

[0136] Suitable methods for fine grinding include grinding, abrasion, fine grinding using supercritical fluids, and fine grinding utilizing the principle of solubility. These methods may also include a sieving step. In principle, any known technique suitable for intentionally reducing the average particle size to the micrometer range can be used.

[0137] In a preferred embodiment of the present invention, micronization is performed by reducing the particle size to d as defined herein. 90 value and / or d 90 This includes reducing the particle size distribution.

[0138] Preferably, the fine grinding is performed on the particle size (d) of the crystalline form produced by synthesis and recrystallization. 90 value / d 90 This includes reducing the particle size distribution to about 1 / 10, preferably at least 1 / 15, more preferably at least 1 / 20, and even more preferably at least 1 / 25, compared to the non-micronized form obtained from synthesis and (re)crystallization.

[0139] Particle size distribution can be measured using sieving analysis, laser diffraction (international standard ISO 13320-1; for other laser diffraction analysis techniques, see, for example, http: / / pharmazie-lehrbuch.de / kapitel / 3-1.pdf), or other methods well known to those skilled in the art, such as electron sensing zones, light shielding, sedimentation, and microscopic observation. Sieving is one of the oldest methods for classifying powders by particle size distribution. Furthermore, there are also methods for measuring volume particle size distribution using TEM (e.g., see Clariant Analytical Services TECHNICAL SHEET 106 TEM-Partikelgrose). These methods are widely known and described in the technical field, such as in analytical chemistry textbooks and the United States Pharmacopeia (USP) publication USP-NF (2004-Chapter 786- (The United States Pharmacopeial Convention, Inc., Rockville, Md.)). The latter sets out the implementing standards of the United States Food and Drug Administration (FDA). The techniques used are described as good examples in, for example, "Pharmaceutical dosage forms: volume 2, 2nd edition, Ed.: HA Lieberman, L. Lachman, JB Schwartz" (page 187). The book also mentions additional methods such as electron sensing zones, light shielding, air permeation, and sedimentation in gases or liquids. The particle size distribution values ​​used in this invention are generally obtained by laser diffraction analysis (particle size analysis).

[0140] More specifically, the measurement of particle size distribution is based on the European Pharmacopoeia 2.9.31 and the United States Pharmacopoeia. <429> The analysis is performed using a laser diffraction method in accordance with [specific standards]. Measurements are performed in a suspension of water and Tween80(R) using a Beckman Coulter measurement system. Sample suspension is performed by sonication, and the particle size distribution is calculated using the Fraunhofer calculation model. These laser diffraction analysis techniques provide a volume-weighted distribution, where the contribution of each particle within the distribution is related to the volume of the particle (corresponding to mass if the density is uniform), i.e., the relative contribution is proportional to the particle size. More specifically, the particle size distribution (PSD) according to the present invention is analyzed using a laser particle size analyzer for salt forms under evaluation, ranging from 5 to 100 g of sample to a maximum of 2 kg of GMP sample. Details are shown in Examples 3, 5, and 7 below.

[0141] The micronized hydrochloride compound of formula (I) according to the present invention can be further processed and converted into a suitable pharmaceutical dosage form. For example, it can be filled into capsules, pouches, or other equivalent dosage forms, or the micronized particles can be compressed into a suitable tablet form, including uncoated tablets, coated tablets, delayed-release tablets, chewable tablets, and the like.

[0142] [Experimental Department] [X-ray Powder Diffraction (XRPD)] XRPD analysis was performed using a Bruker D2 phase diffractometer with a copper anticathode, a single-crystal silicone sample holder, and a position-sensitive detector (LynxExe). The powder sample was loaded onto a flat single-crystal silicone sample holder in a manner that avoided desirable orientation and sensed the flatness of the sample surface. The instrument's operating conditions were as follows: Ambient temperature and atmosphere, X-ray generator voltage 30kV and intensity 10mA, X-ray source: target copper; emitted radiation Kα1=0.15406nm, Kα2=0.15444nm, ratio Kα2 / Kα1=0.5, Kβ filter: emitted nickel, slit: divergence prevention 1nM, Soller slit 2.5°, goniometer: angle sector analyzed from 4° to 45° or 4° to 50° for 2θ, step size 0.07° for 2θ, sample holder rotation speed: 30rpm, detection: exposure time per step size of goniometer 1s.

[0143] [Differential Scanning Calorimeter (DSC)] DSC analysis was performed using a Q1000 TA Instruments analyzer. The samples to be analyzed were weighed in aluminum capsules, then crimped and placed in a calorimeter oven. The instrument operating conditions were as follows: heater lamp 10°C / min, final temperature 230°C or 240°C, carrier gas: nitrogen (Messer “qualite Azote 5.0”), flow rate 50 mL / min.

[0144] [Thermogravimetric analysis (TGA)] TGA analysis was performed using a TA Instruments TGA Hi-Res 2950. The samples were placed in an open aluminum basket and analyzed as follows: Mass assay 5 mg; heating lamp 10°C / min; final temperature 500°C; carrier gas: nitrogen (Messer “qualite Azote 5.0”) flow rate 95-105 mL / min.

[0145] [Laser diffraction particle size analysis] Laser diffraction analysis is performed according to European Pharmacopoeia 2.9.31 and United States Pharmacopoeia. <429> It was carried out according to the instructions.

[0146] [Optical microscopy observation and particle size distribution (PSD) evaluation] Optical microscopy analysis is performed using a LEICA DMIRB microscope equipped with a digital camera and motorized stage. Microscopic images are acquired using a Microvision Instruments image analysis station. A few milligrams of the test sample are placed on a microscope slide with silicone oil, covered with a coverslip, and then gently pressed to disperse the sample before analysis.

[0147] In PSD (particle size distribution) evaluation, approximately 1 milligram of the test sample is dispersed in soybean oil pre-saturated with the crystalline substance to be analyzed. Then, several microliters are dropped onto a microscope slide with a coverslip and analyzed. Image analysis (automated object detection) works in conjunction with statistical analysis of the detected particle surface to establish a particle size distribution profile.

[0148] The characteristic diameter value is d min d mean d max (expressed as a distribution value of particle numbers) and d x This is given as =Y. This means that x percent of the total measured surface area of ​​the observed sample (considered the population) consists of particles with a diameter of less than Y μm.

[0149] (Example 1: Synthesis of IM-250 hydrochloride) [(S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide hydrochloride] [ka] IM-250 free base (205 mg, 470 μmol) was prepared, for example, by the method described in Example 7(-) of WO2019 / 068817, or by the method described in international application PCT / EP2023 / 050883, and dissolved in acetone (5 mL) with stirring using a rotary evaporator at 50°C and atmospheric pressure. An amount of 1N hydrochloric acid corresponding to a 1:1 stoichiometric ratio was added. The solvent was then evaporated at 50°C to obtain a thin film. This thin film was resuspended in ethanol (4 mL) at room temperature and dissolved. The solvent was evaporated at 50°C to obtain a meringue-like substance. This thin film was resuspended in isopropanol (1 mL) at 50°C and dissolved. Partial separation occurred when held at room temperature (after about 30 minutes), and then it was heated again to 50°C to redissolve. Strong crystallization occurred immediately. An additional heating (50°C) and cooling (room temperature) cycle was performed once (20 minutes each), and the sample was then kept 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 colorless crystalline IM-250 hydrochloride.

[0150] XRPD analysis was performed. Figure 1 shows the XRPD pattern of IM-250 hydrochloride. The XRPD peaks were identified and included in Table 1 below.

[0151] [Table 1]

[0152] TGA and DSC analyses were performed. TGA analysis showed a 9.8% mass loss when heated at start / end temperatures of 151 / 170°C, before the primary pyrolysis was detected at a start temperature of 221°C. This 9.8% mass loss may be attributed to the leakage of the hydrochloric acid portion. DSC analysis did not reveal the true melting point. The undecomposed double endothermic event observed from 160°C is associated with the loss of the hydrochloric acid portion observed on the TGA profile.

[0153] [Alternative synthesis of IM-250 hydrochloride using ethanol] IM-250 free base (4.75 g), (preparable by the method described in Example 7(-) of WO2019 / 068817) was dissolved in acetone (150 mL) and stirred using a rotary evaporator at room temperature and atmospheric pressure. Then, 1N hydrochloric acid in a volume equivalent to a 1:1 stoichiometric ratio was added. This solvent was partially evaporated at 50°C (approximately 100 mL). To better capture the water introduced by the hydrochloric acid solution, ethanol (50 mL) was added to the solution, and further evaporation was carried out until a few milliliters of the remaining volume remained (syrupy liquid). The sample was then returned to room temperature to initiate crystallization. A further ethanol (50 mL) was then added to the sample (always to help better remove the water introduced with the hydrochloric acid solution), resulting in an unexpected increase in crystallization. XRPD analysis was performed. Figure 2 shows the XRPD pattern of IM-250 hydrochloride. The identified XRPD peaks were similar to those shown in Figure 1, indicating that the same hydrochloric acid polymorph was produced.

[0154] (Example 2: Synthesis of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride)) [(S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide hydrochloride] [ka] To a 50 mL solution of deuterated IM-250 free base (850 mg) (available by the method described in WO2022 / 090409 or international application PCT / EP2023 / 050883) in acetone (50 mL), an amount of 1N hydrochloric acid corresponding to a 1:1 stoichiometric ratio was added. After homogenizing the solution at 40°C, the solvent was removed under vacuum (50°C). Spontaneous crystallization of a white solid was induced when only a few mL remained in the flask. To completely remove the water produced by the addition of hydrochloric acid, ethanol (2 × 5 mL) was added to the flask and concentrated and dried at 50°C (only partial redissolution was observed during ethanol addition and stirring at 50°C). Further ethanol (5 mL) was added to the flask and the crystals were resuspended by stirring at 50°C and room temperature. The supernatant was removed from the solid and further dried under vacuum at 50-60°C for about 3 hours. White crystals of deuterated IM-250 hydrochloride (d3-IM-250 hydrochloride) were obtained in good yield.

[0155] XRPD analysis was performed. Figure 3 shows the XRPD pattern of IM-250 hydrochloride (d3-IM-250 hydrochloride). The XRPD peaks were identified and summarized in Table 2 below.

[0156] [Table 2]

[0157] TGA and DSC analyses were performed. TGA analysis showed a mass loss of 7.8% when heated at start / end temperatures of 149 / 167°C, prior to the start temperature of 225°C where the main thermal decomposition was detected. This 7.8% mass loss is thought to be due to the elimination of the HCl functional group. DSC analysis did not reveal a true melting point, but a broad endothermic peak was observed, starting at approximately 188°C and peaking at 194°C (transition enthalpy -15 J / g).

[0158] (Example 3: Evaluation of particle size distribution of IM-250 hydrochloride) The particle size distribution (PSD) of the IM-250 hydrochloride batch prepared using ethanol in Example 1 was evaluated by microscopic observation and image analysis. Microscopic images are shown in Figures 4 and 5. The PSD quantification results, particle size distribution profile, and distribution histogram are shown in Table 3, Figure 6, and Figure 7, respectively. The sample mainly contained large birefringent particles, with 90% of the particles having a particle size (d 90 ) It is approximately 203 μm or less.

[0159] [Table 3]

[0160] Regarding crude IM-250 hydrochloride from another batch obtained from a different experiment, the particle size (d 90 The size was measured to be approximately 193 μm or less.

[0161] (Example 4: Micronization of IM-250 hydrochloride) IM-250 hydrochloride was micronized at HOLOPHARM, with an average of d 90 A sample with a particle size of 6.1 μm was obtained. Figure 8 shows the particle size distribution of the pulverized sample, and Figure 9 is a micrograph. As shown in Figures 10 and 11, the pulverized sample showed the same diffraction peak position and DSC profile as the non-pulverized bulk, indicating that both samples have the same crystalline morphology. IM-250 hydrochloride showed no changes even after storage for at least 3 weeks under both conditions of 40°C / 75%RH and 60°C, confirming its chemical and physical stability as a bulk powder. By repeating this experiment, each of the following can be observed. 90 =3.3μm and d 90 A finely powdered material with a particle size of 3.9 μm was obtained.

[0162] (Example 5: Evaluation of particle size distribution of deuterated IM-250 hydrochloride) The particle size distribution (PSD) of a batch of d3-IM-250 hydrochloride was evaluated by microscopic observation and image analysis. Microscopic images are shown in Figures 12 and 13. The PSD quantification results, particle size distribution profile, and distribution histogram are shown in Table 4, Figure 14, and Figure 15, respectively. The sample mainly contained large birefringent particles, with 90% of the particles having a particle size of (d 90 ) It is approximately 156 μm or less.

[0163] [Table 4]

[0164] (Example 6: Micronization of deuterated IM-250 hydrochloride) d3-IM-250 hydrochloride was pulverized in a similar manner at HOLOPHARM, with an average of d 90 A sample with a particle size of 3.0 μm was obtained. Figure 16 shows the particle size distribution of the pulverized sample, and Figure 17 shows its micrograph. XRPD analysis showed no changes in the diffraction peak position or intensity of d3-IM-250 hydrochloride before and after pulverization. No changes in the crystalline phase were observed either.

[0165] (Example 7: Micronization and particle size distribution measurement of IM-250 hydrochloride (GMP campaign)) Fine grinding was performed using a Hosokawa-Alpine spiral jet mill 100. The raw material was 1.9 kg of IM-250 hydrochloride, which had the particle size distribution (PSD) shown in Figure 18, d 90 The value was 139.8 μm. Fine grinding was performed using nitrogen as the grinding medium at a pressure of 5 bar. The product was continuously fed to the mill via a twin-screw feeder, and after pulverization, it was collected in a fine filter bag and separated with a yield of 97%. The particle size distribution conforms to European Pharmacopoeia 2.9.31 and United States Pharmacopoeia. <429> The measurement was performed using laser diffraction in accordance with the standard, and measurements were carried out in water and Tween80(R) suspension using a Beckman Coulter measurement system. Sample suspension was performed by sonication, and the particle size distribution was calculated using the Fraunhofer calculation model. The average d of the pulverized material 90The value was 8.7 μm, and it showed the PSD distribution shown in Figure 19. Due to micronization, d 90 The value decreased to 1 / 16th of its original value.

[0166] (Example 8: Bioavailability of micronized IM-250 hydrochloride / d3-IM-250 hydrochloride and non-micronized control in male mice) The oral bioavailability of a suspension of micronized crystalline IM-250 hydrochloride (and d3-IM-250 hydrochloride) and a suspension of non-micronized crystalline IM-250 hydrochloride (and d3-IM-250 hydrochloride) was compared after a single oral administration to male C57bl / 6 mice (approximately 8 weeks old). Approximately 2 hours before administration of 10 mg / kg of the test substance, three animals from each group were defecated. The suspension was prepared by directly adding the powder to 0.5% HPMC in PBS, sonicated, and then administered orally at a dose of 5 mL / kg via enteral tube. Blood samples (20 μL) were collected from the tail vein using capillary microsampling in lithium heparin blood collection tubes at 0.5 hours, 1 hour, 2 hours, 5 hours, 12 hours, and 24 hours. The samples were frozen with dry ice within 1-2 minutes of collection and stored at -20°C until LC-MS / MS analysis by non-chiral LC-MS. Blood peak concentration (C max ), elimination half-life (t 1 / 2 ), area under the curve (AUC 0-24h The following data (Table 5) was obtained:

[0167] [Table 5]

[0168] Relative bioavailability in male mice with different salt morphologies In international application PCT / EP2023 / 050883, the relative bioavailability of various crystalline and salt forms of IM-250 suspension (derived from DMSO stock solution) was evaluated after a single oral administration to male C57bl / 6 mice. The area under the curve (AUC) was measured for IM-250 free base form I, IM-250 napadisylate, and IM-250 hydrochloride. 0-24hThe relative bioavailability of IM-250 hydrochloride (deuterated and undeuterated) and IM-250 suspension was calculated and compared. Furthermore, the effect of deuteration of IM-250 hydrochloride on PK parameters in male mice was evaluated. All IM-250 forms tested were un-micronized. In these comparative evaluations, the inventors have already demonstrated remarkable improvements achievable with hydrochloride (deuterated and undeuterated).

[0169] Herein, the pharmacokinetic properties of these selected salt forms can be further improved by the additional step of micronization, as shown herein.

[0170] [Conclusion] In both micronization test samples, C max and AUC 0-24h As is evident from the comparative analysis, improved bioavailability was achieved. This may allow for a reduction in the amount administered to patients compared to non-micronized materials.

Claims

1. A finely powdered crystalline form of a compound represented by formula (I), or its cocrystal, hydrate, or solvate, The pulverized crystal form has a particle size (d ９０ value / d ９０ A micronized crystalline form in which the particle size distribution is reduced to at least one-tenth compared to the non-micronized form. 【Chemistry 1】 (Here, Y is CH) ３ and CD ３ (Selected from)

2. The following structure 【Chemistry 2】 Having, or its cocrystal, hydrate, or solvate, The micronized crystalline form of the compound according to claim 1.

3. An X-ray powder diffractogram measured with a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å contains at least four of the following peaks (±0.2 degrees 2θ): 13.7, 17.0, 17.7, 19.8, 21.8, and 22.8 degrees. The micronized crystalline form of the compound according to claim 2.

4. Having an XRPD pattern substantially shown in Figure 1 or Figure 2, The pulverized crystal form according to any one of claims 2 and 3.

5. The hydrochloride salt and (S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide are present in a 1:1 molar ratio. The pulverized crystal form according to any one of claims 2 to 4.

6. d measured as defined in the specification ９０ The value is approximately 20.0 μm or less. The pulverized crystal form according to any one of claims 2 to 5.

7. d measured as defined in the specification ９０ The value is approximately 6.0 μm or less. The pulverized crystal form according to any one of claims 2 to 5.

8. The following structure: 【Transformation 3】 Having, or its cocrystal, hydrate, or solvate, The micronized crystalline form of the compound according to claim 1.

9. An X-ray powder diffractogram measured with a diffractometer using Cu-Kα radiation at a wavelength of 1.54 Å contains at least four of the following peaks (±0.2 degrees 2θ): 11.3, 11.9, 13.8, 17.8, 19.8, 21.0, 21.3, and 21.8 degrees. The micronized crystalline form of the compound according to claim 8.

10. The XRPD pattern substantially shown in Figure 3 is The pulverized crystal form according to any one of claims 8 and 9.

11. Hydrochloride and (S)-2-(2',5'-difluoro[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d ３ )-5-(S-methylsulfonimidoyl)thiazole-2-yl)acetamide is present in a 1:1 molar ratio. The pulverized crystal form according to any one of claims 8 to 10.

12. d measured as defined in the specification ９０ The value is approximately 20.0 μm or less. The pulverized crystal form according to any one of claims 8 to 11.

13. d measured as defined in the specification ９０ where the value is about 6.0 μm or less The pulverized crystal form according to any one of claims 8 to 12.

14. A therapeutically effective amount of the micronized crystalline form of formula (I) described in any one of claims 1 to 13, At least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active ingredient (antiviral compound) effective in treating a disease or disorder associated with a viral infection, A pharmaceutical composition containing [the specified ingredient].

15. This includes treatment or elimination of latent forms of herpesvirus in nerve tissue and nerves, and This includes the prevention and treatment of recurrent and reactivation of herpes infections, or serious associated effects such as herpes simplex encephalitis (HSE), Used for the prevention and treatment of herpes simplex infection or herpes-borne disorders, A micronized crystalline form according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14.

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