Novel crystal morphology

Abstract

The present invention relates to a novel crystalline form of plitelivir and to pharmaceutical compositions containing same, methods for preparing same, the use of said crystalline form in medicine, and the use of said crystalline form for the treatment of herpes viruses.

Description

[Technical Field]

[0001] The present invention relates to a novel crystalline form of plitelivir and to pharmaceutical compositions containing same, methods for preparing same, the use of the crystalline form in medicine, and the use of the crystalline form for the treatment of herpes viruses. [Background technology]

[0002] Human herpesviruses are large, enveloped, double-stranded DNA viruses that share the common characteristic of causing lifelong infection in humans. This is achieved through their ability to exist within the host either as a dormant, asymptomatic latent infection or as a lytic infection with associated symptoms after activation. These viral infections are widespread worldwide, and it is notable that over 90% of all humans are chronically infected with one or more human herpesviruses.

[0003] Human herpesviruses are classified into three subfamilies (α, β, and γ) based on their biological characteristics, and each subfamily consists of eight members: herpes simplex virus subtypes 1 and 2 (HSV1, HSV2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus types 6-8 (HHV6-8).

[0004] HSV1 and HSV2 infections can cause disease in immunocompetent individuals. Both subtypes cause genital / anal and labial / nasal (herpes simplex) skin lesions, but HSV2 is more commonly associated with the former and HSV1 with the latter. Over 80% of genital infections are thought to be caused by HSV2. Worldwide, over 500 million people have genital herpes infections, and approximately 50–80% of the world's population has oral HSV infections, the primary cause of herpes simplex. HSV, particularly HSV1, can also cause lesions on the fingers (whitlows) and other skin sites.

[0005] The majority of individuals with HSV infection experience no noticeable symptoms. However, some experience recurrent (often severe) infections. In the United States, 20–40% of the population develops recurrent HSV lip lesions. Importantly, cold sores and whitlow provide a very easy route for the virus to spread to other individuals, which can lead to rarer, but more severe, HSV-associated conditions. For example, HSV-associated ocular keratitis is a leading cause of blindness, and HSV can also cause encephalitis in newborns, a life-threatening illness. Other disorders thought to be caused by HSV include herpes gladiatorum, Mollaret's meningitis, and possibly Bell's palsy.

[0006] Primary infection or reactivation of a pre-existing herpesvirus infection can be a major cause of disease in immunocompromised individuals. Primary risk populations include solid organ or stem cell transplant recipients, patients undergoing cancer treatment, individuals with HIV / AIDS, and ICU patients.

[0007] There is currently no cure for HSV, and although medications have been developed that may reduce outbreaks and / or shorten the duration of outbreaks to some extent, improved treatments are needed.

[0008] Currently, nucleoside analogs, such as acyclovir and its prodrugs, such as valacyclovir and famciclovir, are used as drugs against herpes viruses, such as HSV. To be effective, these nucleoside analogs must be phosphorylated by viral thymidine kinase (TK) and then converted by cellular kinases into nucleoside triphosphates that inhibit the activity of viral DNA polymerase. If the virus lacks functionally active TK, such as a resistant HHV1 mutant or a TK-negative virus, the nucleoside analogs cannot exert their effects.

[0009] Nucleoside analogues are administered clinically at very high doses, typically hundreds of milligrams to several grams per day. Even at these high doses, often administered over long treatment periods, these drugs do not completely prevent recurrence of HSV symptoms. Nucleoside analogues also do little to address the issue of viral shedding, leaving many individuals susceptible to asymptomatic HSV infection. Certain nucleoside analogues, especially when used at high doses, also raise safety concerns. For example, as documented for the nucleoside analog ganciclovir (Aoki, Chapter 45 in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition) 2015), these drugs have the potential to be incorporated into host genomic DNA via host DNA polymerases, raising concerns about their mutagenicity.

[0010] Given the inadequacies of existing treatments, there is an urgent need for the development of improved, well-tolerated antiherpes treatments. One class of compounds currently being investigated is helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex, which consists of a helicase, a primase, and a cofactor subunit and has essential functions for viral DNA replication. These agents are not nucleoside analogs and do not require phosphorylation by TK to inhibit HSV replication. Therefore, they may be active against TK-deficient HSV, which, as noted above, is a major mechanism of resistance to nucleoside analogs.

[0011] An example of a helicase-primase inhibitor is plitelivir, a thiazolylamide derivative with the chemical name N-methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide, which is disclosed in WO 2001 / 47904.

[0012] WO 2006 / 103011 generally mentions that pritelivir free base may exist in hydrated or solvated forms, but does not actually disclose experimental details regarding the preparation or characterization of these forms. WO 2013 / 045491 and WO 2013 / 045479 relate to pritelivir mesylate. Both mention the existence of polymorphic and solvated forms of the free base, but neither publication actually experimentally discloses these forms. WO 2013 / 045491 concludes that pritelivir free base is not suitable for long-term stable formulations, and that the low solubility of the free base is responsible for unfavorable drug release and resorption characteristics compared to the mesylate monohydrate, while WO 2013 / 045497 concludes that the free base has poor thermal and polymorphic stability and is not suitable for tableting. WO2013 / 045491 and WO2013 / 045479 disclose that the mesylate salt is particularly suitable for oral compositions.

[0013] WO 2018 / 096170 discloses a polymorph screening of pritelivir free base, noting that 14 different forms were observed, with additional forms observed during scale-up. The majority of these forms were solvated, with only three hydrated forms and one anhydrous form observed. The explicit focus of WO 2018 / 096170 is Form C (hemihydrate), which is the only form for which XRPD characterization data is provided. WO 2018 / 096170 states that the free base hemihydrate Form C was the only stable polymorph.

[0014] The present invention has been devised in consideration of the above points. Summary of the Invention

[0015] The present disclosure provides a novel crystalline solid form of pritelivir useful for pharmaceutical use. Pritelivir has the following structural formula: [ka] It has.

[0016] The present disclosure relates to certain novel solid forms of plitelivir that have promising and advantageous solid-state and / or biopharmaceutical properties.

[0017] In a first aspect, the present disclosure provides a crystalline form of plitelivir, wherein the crystalline form is Form 8 and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (λ=1.5406 Å) containing peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ; and b) DSC thermogram containing an endothermic event with an onset temperature of 224°C ± 2°C.

[0018] Form 8 is a nonsolvated anhydrous crystalline form of pritelivir free base and has a high melting point, which means that Form 8 can be handled at high temperatures without melting, for example, during size reduction procedures, i.e., micronization, and pharmaceutical manufacturing.

[0019] Advantageously, Form 8 possesses certain characteristics that make it particularly suitable for formulation and delivery via certain routes of administration: The solubility of Form 8 at room temperature in an aqueous medium containing 0.9% NaCl and 0.5% polysorbate 80 at 24 hours was determined to be approximately 70.7 μg / mL (see Example 2 of the present application).

[0020] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a crystalline form of plitelivir, the crystalline form being Form 8, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0021] In a further aspect, the present invention provides a method of treating a herpes virus (preferably HSV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of plitelivir, wherein the crystalline form is Form 8.

[0022] In a further aspect, the present invention provides a method for treating a herpes virus (conveniently, HSV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of plitelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8.

[0023] In another embodiment, there is provided a crystalline form of plitelivir which is Form 8 for use in the treatment of herpes virus (conveniently HSV) infection.

[0024] In another aspect, there is provided a pharmaceutical composition for use in treating herpes virus (conveniently, HSV) infection, comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Type 8.

[0025] In another aspect, there is provided the use of a crystalline form of plitelivir, or a pharmaceutical composition comprising plitelivir, for treating herpes virus (preferably HSV) infection, wherein the crystalline form is Form 8.

[0026] In another aspect, there is provided the use of a crystalline form of pritelivir or a pharmaceutical composition comprising a crystalline form of pritelivir, wherein the crystalline form is Form 8, in the manufacture of a medicament for treating herpes virus (preferably HSV) infection.

[0027] In another embodiment, a method for preparing a crystalline form of plitelivir, wherein the crystalline form is Form 8, is provided.

[0028] In another embodiment, there is provided a crystalline form of plitelivir obtained by the methods described herein, wherein the crystalline form is Form 8. [Brief explanation of the drawings]

[0029] Like the following detailed description, this abstract is better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the disclosed compositions and methods, the drawings show exemplary embodiments of the compositions and methods, but the compositions and methods are not limited to the particular embodiments disclosed. In the drawings [Figure 1] Figure 1: XRPD diffractogram of Form 8. [Figure 2] Figure 2: DSC and TGA thermograms of type 8. [Figure 3] Figure 3: XRPD diffractogram of Form C.

[0030] Detailed Description Next, the features and other details of the present disclosure will be described in more detail.Before further describing the present disclosure, certain terms used in the specification, examples, and appended claims will be summarized here.These definitions should be interpreted in the sense that those skilled in the art understand them in light of the remainder of the present disclosure.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0031] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated below.

[0032] As used herein, "pritelivir" means N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-2-(4-(pyridin-2-yl)phenyl)acetamide free base.

[0033] As used herein, "API" means an active pharmaceutical ingredient, such as plitelivir.

[0034] Unless the context otherwise requires, throughout this specification and claims, words like "comprise," "comprising," and the like are to be interpreted in an open and inclusive sense, and words like "a," "an," and the like are to be deemed to mean at least one, and not limited to one. Terms not specifically defined herein are to be given the meaning that would be given to them by one of ordinary skill in the art in light of this disclosure and the context.

[0035] When values ​​are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. Further, the term "about" means a ±10% variation from the nominal value, unless otherwise indicated or inferred.

[0036] The term "about" when used in reference to a numerical range, cutoff value, or specific value, indicates that the indicated value may vary by up to 10% from the listed value. Many of the numerical values ​​used herein are experimentally determined, so those skilled in the art should understand that such determinations may vary between different experiments and will vary widely. The numerical values ​​used herein should not be considered unduly limited by this inherent variation. Thus, the term "about" is used to encompass a variation of ±10% or less, ±5% or less, ±1% or less, ±0.5% or less, or ±0.1% or less from the specified value.

[0037] As used herein, when a composition is described as having, including, or comprising particular ingredients, or a process is described as having, including, or comprising particular process steps, it is contemplated that the compositions of the present teachings also consist essentially of or consist of the recited ingredients, and that the processes of the present teachings also consist essentially of or consist of the recited process steps.

[0038] The use of any examples or exemplary language herein, such as, "such as," "including," or "for example," is intended merely to better describe the present teachings and does not limit the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present teachings.

[0039] The terms "individual," "patient," or "subject" are used interchangeably and include any mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human. The compounds or pharmaceutical compositions of the present disclosure can be administered to mammals, such as humans, and can also be administered to other mammals, such as animals requiring veterinary treatment, for example, livestock animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, etc.). The mammal treated in the methods of the present disclosure is preferably a mammal for which treatment of an HSV infection is desired.

[0040] The term "modulation" includes antagonism (eg, inhibition), agonism, partial antagonism and / or partial agonism.

[0041] The term "pharmaceutically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human, as appropriate.

[0042] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any solvent, dispersion medium, coating agent, filler, etc., that is compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0043] As used herein, "pharmaceutical composition" means a composition comprising at least one compound disclosed herein formulated together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0044] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of a compound of interest that elicits the biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, physician, or other clinician. The compounds or pharmaceutical compositions of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve the desired therapeutic and / or prophylactic effect. A therapeutically effective dose may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the composition to elicit the desired response in a subject. Such results include, but are not limited to, reduction, remission, and / or regression of disease caused by or associated with HSV, or prevention of the progression of disease caused by or associated with HSV, as determined by any means suitable in the art.

[0045] "Treating" or "treatment" should be understood to include prevention as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or disease includes: (1) preventing or delaying the appearance of clinical symptoms of the developing condition, disorder, or disease in a person who is susceptible to or predisposed to the condition, disorder, or disease but who has not yet experienced or manifested clinical or subclinical symptoms of the condition, disorder, or disease; (2) inhibiting the condition, disorder, or disease, i.e., halting, reducing, or delaying the progression of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or disease, or at least one clinical or subclinical symptom thereof. As used herein, "treating" and similar terms can specifically include reducing the severity and / or frequency of HSV-induced symptoms, eliminating HSV-induced symptoms and / or the underlying cause of such symptoms, reducing the frequency or likelihood of HSV-induced symptoms and / or their underlying causes, slowing, preventing, and / or retarding the progression of HSV-induced disease, and ameliorating or repairing damage caused directly or indirectly by HSV infection.

[0046] The term "preventing" as used herein with respect to HSV infection or an HSV-related disorder means reducing the likelihood of HSV infection.

[0047] A reference to a particular value includes at least that particular value unless the context clearly indicates otherwise.

[0048] At various places herein, values ​​are disclosed in groups or ranges, and the description is specifically intended to include all individual subcombinations of the members of such groups and ranges, as well as any combination of the various endpoints of such groups or ranges. For example, integers in the range of 0 to 40 are specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and integers in the range of 1 to 20 are specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. All ranges are inclusive and combinable.

[0049] The use of any example or exemplary language herein, such as "such as," "including," or "for example," is intended merely to better illustrate the present teachings and does not limit the scope of the invention unless otherwise claimed.

[0050] A "crystalline form" is a solid material in which the components are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice that extends in all directions. Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms, and / or hydrated crystalline forms.

[0051] "Polymorphism" refers to the occurrence of a solid material in more than one crystalline form.

[0052] As used herein, the term "amorphous" refers to a solid material that does not have long-range order in the position of molecules. An amorphous solid is a substance in which molecules are randomly arranged, without a definite arrangement, e.g., molecular packing, and without long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions, and do not have a definite melting point. For example, an amorphous material is a solid material that does not have a sharp, characteristic crystalline peak in an X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in the XRPD pattern. Broad peaks are characteristic of amorphous solids.

[0053] A "hydrate" is a compound that exists in a solid composition with water molecules. The composition may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain a random amount of water. As used herein, the term "hydrate" refers to a compound in a solid form, i.e., in an aqueous solution, that may be in a hydrated form, but is not a hydrate as the term is used herein. A hydrate may be one in which both the compound and water form part of the crystal lattice.

[0054] A "solvate" has a similar composition to a hydrate, except that a solvent other than water is substituted for water. For example, methanol or ethanol can form an "alcoholate," which can also be stoichiometric or non-stoichiometric. As used herein, the term "solvate" refers to a compound in a solvent that may be in a solid form, i.e., a solvated form, but is not a solvate as the term is used herein. A solvate may be a crystal in which both the compound and the solvent form part of the crystal lattice.

[0055] "Anhydrous" means that the solid form of a compound does not incorporate water into its structure. For example, an anhydrous crystalline form does not have water forming part of the crystalline structure. Those skilled in the art will know techniques that can be used to quantify the amount of water associated with a solid. For example, water content can be determined by either Karl Fischer titration or thermogravimetric analysis (TGA). Preferably, the anhydrous solid form of a compound contains less than about 1.5% by weight of water, e.g., less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01% by weight.

[0056] "Unsolvated" or "non-solvated" means that the solid form of a compound does not have solvent incorporated into its structure. For example, an unsolvated crystalline form does not have solvent forming part of the crystalline structure. Those skilled in the art will know techniques that can quantify the amount of solvent associated with a solid. For example, solvent content can be determined by gas chromatography (GC). Suitably, an unsolvated or non-solvated solid form of a compound contains less than about 1.5% by weight of solvent, e.g., less than about 1.0%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01% by weight.

[0057] When a composition is identified herein as "consisting essentially of a specified component," the composition preferably comprises at least 70 wt% of the component, preferably at least 80 wt%, preferably at least 90 wt%, preferably at least 95 wt%, and most preferably at least 99 wt% of the component. Preferably, a composition identified as "consisting essentially of a specified component" consists of said component, except for one or more minor components.

[0058] The phrase "substantially as shown in the Figures" means an X-ray powder diffraction pattern or DSC thermogram having at least 50%, at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of its features appearing in the Figures.

[0059] Crystalline forms of pritelivir In one aspect, the present disclosure provides a novel crystalline form of plitelivir, described and characterized herein as Form 8.

[0060] The present disclosure also relates to pharmaceutical compositions comprising crystalline Form 8, and methods of preparing such forms.The present disclosure further relates to the use of crystalline Form 8 in the treatment or prevention of HSV infection.

[0061] There are many analytical methods that those skilled in the art of solid state chemistry can use to analyze solid forms.The term "analyze" as used herein means to obtain information about the solid structure of a solid form.For example, powder X-ray diffraction (PXRD / XRPD) is a suitable technique for distinguishing amorphous solid forms from crystalline solid forms, and for characterizing and identifying specific crystalline solid forms of a compound.

[0062] Due to differences in instrumentation, samples, and sample preparation, peak values ​​are often reported with the modifier "±0.2° 2θ." This is common practice in solid state chemistry due to the inherent variability in peak values. The variability in peak intensity is a result of how individual crystals are oriented in the sample container with respect to the external X-ray source (known as "preferred orientation"). This orientation effect does not provide structural information about the crystal.

[0063] Powder X-ray diffraction is only one of several analytical techniques that can be used to characterize and / or identify crystalline solid forms. Differential scanning calorimetry (DSC) can also be used to characterize and / or identify crystalline solid forms. Typical variations in values ​​related to the starting temperature of a differential scanning calorimetry measurement are on the order of plus or minus 2°C.

[0064] It should be noted that unless otherwise noted, the thermal data (DSC and TGA) presented herein were obtained at a heating rate of 10°C / min. Additionally, DSC data were obtained using an aluminum punch pan.

[0065] In a first aspect, a crystalline form of plitelivir is provided, wherein the crystalline form is Form 8 and is characterized by data selected from one or more of the following: a) an X-ray powder diffraction (XRPD) pattern measured using Cu Ka (λ=1.5406 Å) containing peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ; and b) DSC thermogram containing an endothermic event with an onset temperature of 224°C ± 2°C.

[0066] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided that includes peaks at 2θ values ​​of 10.5 and 24.7 °2θ ± 0.2 °2θ, and further includes at least one, two, three, or four specific peaks selected from peaks at 2θ values ​​of 17.4, 17.9, 23.0, and 23.3 °2θ ± 0.2 °2θ.

[0067] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided that includes peaks at 2θ values ​​of 10.5 and 24.7 °2θ±0.2 °2θ, and further includes peaks at 2θ values ​​of 17.4, 17.9, 23.0, and 23.3 °2θ±0.2 °2θ.

[0068] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided, which includes peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.1°2θ.

[0069] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided that includes peaks at 2θ values ​​of 10.5 and 24.7 °2θ±0.1 °2θ, and further includes at least one, two, three, or four specific peaks selected from peaks at 2θ values ​​of 17.4, 17.9, 23.0, and 23.3 °2θ±0.1 °2θ.

[0070] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided that includes peaks at 2θ values ​​of 10.5 and 24.7 °2θ±0.1 °2θ, and further includes peaks at 2θ values ​​of 17.4, 17.9, 23.0, and 23.3 °2θ±0.1 °2θ.

[0071] In one embodiment, an XRPD pattern measured using Cu Ka (λ=1.5406 Å) is provided, wherein Form 8 is unsolvated and anhydrous, and comprises peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ, preferably 10.5 and 24.7°2θ±0.1°2θ. Preferably, Form 8 comprises less than about 2% by weight of solvent and / or water, e.g., less than about 1.5%, less than about 1%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% by weight of solvent and / or water.

[0072] In an embodiment, there is provided a crystalline form of compound of Formula (I), wherein the crystalline form is Form 8, characterized by an XRPD pattern measured with Cu Ka (λ=1.5406 Å) comprising peaks at 2θ values ​​of 10.5 and 24.7 °2θ ± 0.2 °2θ, and further comprising at least 2, 5, 10, 15, 20, 25, 30 or 35 additional peaks selected from the group consisting of the peaks set forth in Table 1 at °2θ ± 0.2 °2θ. [Table 1]

[0073] In an embodiment, there is provided a crystalline form of compound of Formula (I), wherein the crystalline form is Form 8, characterized by an XRPD pattern measured using Cu Ka (λ=1.5406 Å) comprising peaks at 2θ values ​​of 10.5 and 24.7 °2θ ± 0.1 °2θ, and further comprising at least 2, 5, 10, 15, 20, 25, 30 or 35 peaks selected from the group consisting of the peaks set forth in Table 1 at °2θ ± 0.1 °2θ.

[0074] In one embodiment, a crystalline form of pritelivir is provided, which is Form 8, characterized by an XRPD pattern measured using Cu Ka (λ=1.5406 Å) radiation substantially identical to that shown in FIG.

[0075] In one embodiment, there is provided a crystalline form of plitelivir, which is Form 8, characterized by a DSC thermogram containing an endothermic event with an onset temperature of 224°C ± 2°C, preferably 224°C ± 1°C.

[0076] In one embodiment, a crystalline form of pritelivir is provided, wherein the crystalline form is Form 8, characterized by a DSC thermogram including an endothermic event with an onset temperature of 224°C±2°C, preferably 224°C±1°C, wherein Form 8 is anhydrous and non-solvated.

[0077] In one embodiment, a crystalline form of plitelivir is provided, wherein the crystalline form is Form 8, characterized by a DSC thermogram substantially identical to that shown in FIG.

[0078] In one embodiment, Form 8 is substantially pure.

[0079] In one embodiment, Form 8 contains less than about 2 wt.% solvent and / or water, e.g., less than about 1.5 wt.%, less than about 1 wt.%, less than about 0.5 wt.%, less than about 0.4 wt.%, less than about 0.3 wt.%, less than about 0.2 wt.%, or less than about 0.1 wt.% solvent and / or water. Those skilled in the art will be aware of suitable analytical techniques that can quantify the amount of solvent / water associated with the solid. For example, water content can be determined by Karl Fischer titration. Residual solvent can be determined by gas chromatography. Thermogravimetric analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with the solid (surface-bound or incorporated into the crystalline structure). Preferably, Form 8 is anhydrous and non-solvated.

[0080] When the present specification states that the present specification relates to a crystalline form of pritelivir, the crystallinity is advantageously greater than about 60%, more advantageously greater than about 80%, even more advantageously greater than about 90%, preferably greater than 95%, greater than 98% or greater than 99% by weight.

[0081] In one embodiment, Form 8 is pure or substantially pure. As used herein, the term "substantially pure" means that the solid form of pritelivir contains about 20% by weight or less, or about 15% by weight or less, or about 10% by weight or less, or about 5% by weight or less, or about 2% by weight or less, or about 1% by weight or less, or about 0.5% by weight or less of contaminants or other solid forms of pritelivir (including, for example, alternative crystalline forms, hydrates, solvates, or amorphous forms as measured by XRPD). Thus, substantially pure Form 8 described herein will be understood to contain more than about 80% by weight, more than 85% by weight, more than 90% by weight, more than 95% by weight, more than 98% by weight, more than 99% by weight, or more than 99.5% by weight of crystalline Form 8 of pritelivir. Preferably, Form 8 is provided in which no other solid forms (amorphous and / or other crystalline forms) are detected when analyzed by solid-state techniques such as X-ray powder diffraction. Preferably, there is provided a crystalline form of pritelivir consisting essentially of Form 8. Preferably, there is provided a crystalline form of pritelivir consisting essentially of Form 8.

[0082] Pharmaceutical Compositions and Kits In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline form of plitelivir disclosed herein in combination with one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the crystalline form is Form 8.

[0083] In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of pritelivir (wherein the crystalline form is Form 8) and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of pritelivir (wherein the crystalline form is pure or substantially pure Form 8) and a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, a pharmaceutical composition is provided comprising pritelivir consisting essentially of crystalline Form 8. In one embodiment, a pharmaceutical composition is provided comprising pritelivir consisting of crystalline Form 8.

[0084] When the present specification refers to crystalline forms of pritelivir, the crystallinity is advantageously greater than about 60% by weight, more advantageously greater than about 80% by weight, even more advantageously greater than about 90% by weight, preferably greater than 95%, greater than 98% or greater than 99% by weight.

[0085] These formulations include those suitable for oral, rectal, topical, buccal, parenteral, rectal, vaginal or aerosol administration, although the most suitable mode of administration in any given case will depend on the extent and severity of the disease being treated and the nature of the particular compound being used.

[0086] In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of pritelivir disclosed herein in combination with one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the crystalline form is Form 8, and the pharmaceutical composition is suitable for parenteral administration.

[0087] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid, or liquid form, which contain one or more compounds of the present disclosure as an active ingredient, mixed with an organic or inorganic carrier or excipient suitable for topical, enteral, or parenteral application. The active ingredient can be formulated, for example, with a non-toxic pharmaceutically acceptable carrier for any form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0088] Advantageously, the present disclosure also provides kits for use by consumers in need of treatment, for example, for HSV infection. Such kits include appropriate dosage forms, as described above, and instructions describing how to use such dosage forms to mediate, reduce, or prevent HSV infection. The instructions would instruct the consumer or healthcare professional to apply the dosage forms according to administration regimens known to those skilled in the art. Such kits can be packaged and sold in single or multiple kit units. Such kits can also include information, such as scientific references, package insert materials, clinical trial results and / or summaries thereof, demonstrating or demonstrating the activity and / or benefits of the compositions and / or describing dosing, administration, side effects, drug interactions, or other information useful to healthcare providers. Such information can be based on the results of various studies, such as studies using laboratory animals, including in vivo models, and studies based on human clinical trials. The kits described herein can be provided, marketed, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, prescribing personnel, and the like. In some embodiments, kits can also be sold directly to consumers.

[0089] It may be desirable to provide a memory aid on the kit, for example, in the form of numbers next to the tablets or capsules, which numbers correspond to the days in the regimen on which the designated tablets or capsules should be taken. Another example of such a memory aid is a calendar printed on a card, e.g., "First week, Monday, Tuesday, etc.... Second week, Monday, Tuesday, etc." Other variations of memory aids will become readily apparent. A "daily dose" may refer to one tablet or capsule or multiple tablets or capsules to be taken in a single day. Also, a daily dose of a first compound may consist of one tablet or capsule, while a daily dose of a second compound may consist of multiple tablets or capsules. The memory aid should reflect this.

[0090] Treatment method In one embodiment, there is provided crystalline pritelivir Type 8 for use as a pharmaceutical.

[0091] In one aspect, a pharmaceutical composition for use as a medicament is provided, comprising a crystalline form of plitelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8.

[0092] In one embodiment, crystalline plitelivir Form 8 for use in therapy is provided.

[0093] In one aspect, a pharmaceutical composition for use in therapy is provided, comprising a crystalline form of plitelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8.

[0094] In one embodiment, there is provided a method of treating a herpes virus (preferably HSV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of pritelivir, wherein the crystalline form is Form 8. In another embodiment, there is provided a method of treating a herpes virus (preferably HSV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8.

[0095] In one embodiment, provided is a method of inhibiting HSV replication in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of pritelivir, wherein the crystalline form is Form 8. In one embodiment, provided is a method of inhibiting HSV replication in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8.

[0096] In one embodiment, there is provided a method of reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of pritelivir, wherein the crystalline form is Form 8. In one embodiment, there is provided a method of reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8.

[0097] In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by or associated with an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of pritelivir, wherein the crystalline form is Form 8. In one embodiment, there is provided a method for inhibiting the development or progression of a disease or disorder caused by or associated with an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8.

[0098] In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by or associated with an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of pritelivir, wherein the crystalline form is Form 8. In one embodiment, there is provided a method for treating or preventing a disease or disorder caused by or associated with an HSV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8.

[0099] In certain embodiments, pritelivir type 8 according to the present invention, or a pharmaceutical composition according to the present invention, can shorten the time to healing (e.g., the time to complete recovery of the lesion) and the duration of symptoms of an HSV infection, such as herpes labialis or genital herpes, in a disease or disorder. The time to healing of the lesion can be defined as complete epithelialization of the mucocutaneous HSV lesion(s) within the treatment period and the absence of the appearance of new lesions, as assessed, for example, by a physician.

[0100] In one embodiment, pritelivir type 8 according to the present invention, or a pharmaceutical composition according to the present invention, can reduce pain or pain intensity (e.g., at the site of the lesion) caused as a result of an HSV infection in a disease or disorder, such as herpes labialis or genital herpes.

[0101] In another embodiment, there is provided a crystalline form of pritelivir for use in the treatment of herpes virus (conveniently HSV) infections, wherein the crystalline form is Form 8. In another embodiment, there is provided a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8, for use in the treatment of herpes virus (conveniently HSV) infections.

[0102] In one embodiment, there is provided a crystalline form of pritelivir for use in inhibiting HSV replication in a subject, wherein the crystalline form is Form 8. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8, for use in inhibiting HSV replication in a subject.

[0103] In one embodiment, there is provided a crystalline form of pritelivir for use in reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof, wherein the crystalline form is Form 8. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8, for use in reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof.

[0104] In one embodiment, there is provided a crystalline form of pritelivir for use in inhibiting the development or progression of a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 8. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is Form 8, for use in inhibiting the development or progression of a disease or disorder caused by or associated with HSV infection in a subject in need thereof.

[0105] In one embodiment, there is provided a crystalline form of pritelivir for use in the treatment or prevention of a disease or disorder caused by or associated with an HSV infection in a subject in need thereof, wherein the crystalline form is Form 8. In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of pritelivir and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form 8, for use in the treatment or prevention of a disease or disorder caused by or associated with an HSV infection in a subject in need thereof.

[0106] In another aspect, there is provided the use of a crystalline form of pritelivir, or a pharmaceutical composition comprising a crystalline form of pritelivir, wherein the crystalline form is Form 8, for treating herpes virus (preferably HSV) infection.

[0107] In one embodiment, there is provided a use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, wherein the crystalline form is Form 8, for inhibiting HSV replication in a subject.

[0108] In one embodiment, there is provided a pharmaceutical composition comprising a crystalline form of plitelivir, wherein the crystalline form is Form 8, for use in reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof.

[0109] In one embodiment, there is provided a use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, for use in inhibiting the development or progression of a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 8.

[0110] In one embodiment, there is provided a use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, wherein the crystalline form is Form 8, for use in the treatment or prevention of a disease or disorder caused by or associated with HSV infection.

[0111] In another aspect, there is provided the use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, in the manufacture of a medicament for treating herpes virus (preferably HSV) infection, wherein the crystalline form is Form 8.

[0112] In one embodiment, there is provided the use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, in the manufacture of a medicament for inhibiting HSV replication in a subject, wherein the crystalline form is Form 8.

[0113] In one embodiment, there is provided the use of a crystalline form of pritelivir, or a pharmaceutical composition comprising a crystalline form of pritelivir, wherein the crystalline form is Form 8, in the manufacture of a medicament for reducing the likelihood or severity of symptoms of HSV infection in a subject in need thereof.

[0114] In one embodiment, there is provided the use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, in the manufacture of a medicament for inhibiting the development or progression of a disease or disorder caused by or associated with HSV infection in a subject in need thereof, wherein the crystalline form is Form 8.

[0115] In one embodiment, there is provided the use of a crystalline form of plitelivir, or a pharmaceutical composition comprising a crystalline form of plitelivir, wherein the crystalline form is Form 8, in the manufacture of a medicament for treating or preventing a disease or disorder caused by or associated with HSV infection in a subject in need of such treatment or prevention.

[0116] In certain embodiments, the disease or disorder caused by or associated with HSV infection is selected from herpes labialis (e.g., cold sores or whitlow), genital herpes, HSV-associated ocular keratitis, HSV-associated encephalitis, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis, and Bell's palsy.

[0117] In certain embodiments, the disease or disorder caused by or related to HSV infection is selected from herpes labialis (for example, cold sore or whitlow) or genital herpes.In one embodiment, disease or disorder is recurrent herpes labialis or recurrent genital herpes.The individual who has a history of multiple recurrences of herpes labialis or recurrent genital herpes, for example, HSV that recurs 6 times or more every year, can be considered to have recurrent HSV.

[0118] In one embodiment, the herpes virus being treated is HSV 2. In a further embodiment, the herpes virus being treated is HSV 2 and the subject in need of treatment has HSV 2 recurrent genital herpes.

[0119] In one embodiment, the herpes virus being treated is HSV 1. In yet another embodiment, both herpes viruses HSV-1 and HSV-2 are treated.

[0120] In one embodiment, the herpes virus being treated or prevented is resistant to a nucleoside antiviral therapy, hi one embodiment, the nucleoside antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir, and valacyclovir.

[0121] In one embodiment, the herpes virus being treated is one that has become resistant to nucleoside-based antiviral therapy, such as an acyclovir-resistant mucocutaneous HSV infection. In a further embodiment, the HSV infection being treated is a mucocutaneous HSV infection that is resistant to antiviral therapy with a nucleoside analog, such as acyclovir, penciclovir, famciclovir, ganciclovir, or valacyclovir.

[0122] In certain embodiments, the subject in need of the methods disclosed herein is immunocompromised. The subject may be immunocompromised due to diseases including HIV infection, cancer, hematopoietic cell or solid organ transplantation, and chronic glucocorticoid use or genetic immunodeficiency.

[0123] In certain embodiments, the subject in need of the methods disclosed herein is a newborn or infant.

[0124] In certain embodiments, the subject is a herpes positive patient.

[0125] In certain embodiments, a subject in need of the methods disclosed herein has an acyclovir-resistant mucocutaneous HSV infection, which may have been diagnosed with the disease based on clinical failure, e.g., failure to improve after at least 7 days of oral or intravenous administration of approved doses of acyclovir.

[0126] In certain embodiments, the subject in need of the methods disclosed herein has a primary genital HSV-associated herpes infection. In one embodiment, the subject in need of the methods disclosed herein has a severe or progressive genital HSV-associated herpes infection.

[0127] When used in accordance with this embodiment, appropriate dosages will vary depending, for example, on the mode of administration, the nature and severity of the infection being treated, and the particular infection being treated, and are within the purview of the treating physician. Typically, the recommended dosage may be in the range of about 0.1 to about 1000 μg / kg body weight.

[0128] The compound of the present disclosure can be administered by any conventional route, particularly enterally, topically, orally, nasally, for example, in the form of tablets or capsules, via suppositories, or parenterally.Suitable formulations and pharmaceutical compositions include those that are formulated by conventional methods using one or more physiologically acceptable carriers or excipients, and those that are known, commercially available, and currently used in clinical practice.Therefore, the compound can be formulated for oral administration, buccal administration, topical administration, parenteral administration, rectal administration, or transdermal administration, or can be formulated in a form suitable for administration by inhalation or insufflation (either orally or nasally).

[0129] In addition to being useful for human treatment, the crystalline forms of the present invention may be useful for the veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. Advantageously, such animals include horses, dogs and cats.

[0130] combination Pritelavir Form 8 or a pharmaceutical composition comprising Pritelavir Form 8 of the present invention may be administered alone as a monotherapy or in addition to one or more other substances and / or treatments. Such combined treatments may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment.

[0131] Also contemplated herein are methods comprising administering a second active agent. For example, in addition to being infected with HSV, a subject or patient may also have HSV infection-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by HSV infection. Also contemplated herein are pharmaceutical compositions comprising the crystalline Form 8 of pritelivir of the present invention or the crystalline Form 8 of pritelivir of the present invention in combination with at least one other agent previously shown to treat these HSV infection-related diseases. Such joint treatment can be achieved independently (by simultaneous, sequential, or separate administration of the individual components of the treatment) and / or via a pharmaceutical composition of the present invention comprising a second active agent.

[0132] Thus, provided herein is a method for treating an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pritelivir type 8 according to the present invention or a pharmaceutical composition comprising pritelivir type 8 according to the present invention, and simultaneously administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0133] In one embodiment, the additional therapeutic agent is selected from one or more of the following agents: i. Nucleoside polymerase inhibitors, such as acyclovir, valacyclovir, famciclovir, penciclovir and ganciclovir; ii. Pyrophosphate polymerase inhibitors, such as foscarnet; iii. saturated fatty alcohols, such as docosanol; iv. Agents such as idoxuridine, trifluridine and vidarabine; v. Corticosteroids; and vi. Other helicase-primase inhibitors, such as amenamevir.

[0134] In some embodiments, pritelivir form 8 or a pharmaceutical composition comprising pritelivir form 8 may be administered as part of a combination therapy in combination with one or more antiviral agents, including nucleoside analogs such as acyclovir, foscarnet, ganciclovir, or penciciovir, or their respective prodrugs, vaiaciciovir or famciclovir.

[0135] In some embodiments, the first amount and the second amount together constitute a pharmaceutically effective amount.The first amount, the second amount, or both may be the same as, greater than, or less than the effective amount of each compound administered as a monotherapy.The disclosed compound and the therapeutically effective amount of antiviral agent may be administered to a subject in combination, i.e., simultaneously or separately, in any predetermined order, by the same or different administration route.In some instances, it may be advantageous to start administering pritelivir first, for example, one or more days or several weeks before starting administration of the antiviral agent.In addition, additional agents may be administered in combination with the above-mentioned combination therapy.

[0136] Method for preparing type 8 In one embodiment, a method for preparing a crystalline form of plitelivir, wherein the crystalline form is Form 8, is provided.

[0137] In one embodiment, the method for preparing Form 8 comprises the steps of: a) providing a solution of plitelivir in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture resulting from step b) for at least 1 hour; d) optionally isolating the solid formed from step c); and e) Optionally, drying the solid isolated from step d).

[0138] In one embodiment, the first solvent system comprises a solvent in which pritelivir has a solubility of at least 100 mg / mL at room temperature, for example, at least 200 mg / mL, 300 mg / mL, 400 mg / mL, or 500 mg / mL. Preferably, the first solvent system comprises DMSO. Preferably, the first solvent system consists essentially of DMF. Preferably, the first solvent system consists of DMF.

[0139] Preferably, step a) is carried out at room temperature.

[0140] Preferably, the second solvent system comprises a solvent in which pritelivir has a solubility of less than 20 mg / mL, for example, less than 10 mg / mL at room temperature. Preferably, the second solvent system comprises THF. Preferably, the second solvent system consists essentially of THF. Preferably, the second solvent system consists of THF.

[0141] Preferably, the first solvent system comprises DMSO and the second solvent system comprises THF.

[0142] Preferably, the second solvent system is an anti-solvent system.

[0143] Preferably, in step b), the second solvent system is added at room temperature.

[0144] Preferably, in step b) the second solvent system is added dropwise to the solution from step a).

[0145] Preferably, the addition of the second solvent system in step b) is carried out over a period of at least 10 minutes, such as at least 20 minutes, for example at least 25 minutes. Preferably, the addition of the second solvent system in step b) is carried out over a period of about 30 minutes.

[0146] Preferably, the stirring in step c) is carried out at room temperature.

[0147] Suitably, the stirring in step c) is carried out for at least 1 hour, such as at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours or at least 22 hours.

[0148] Suitably, step d) comprises isolating the solid by centrifugation.

[0149] Suitably, step e) comprises drying the solid at a temperature above room temperature, for example above 30° C. or above 40° C. Suitably, step e) comprises drying the solid at a temperature of about 50° C.

[0150] The invention is illustrated by the following non-limiting examples. [Example]

[0151] The following abbreviations are used herein: DMSO: dimethyl sulfoxide DSC: Differential scanning calorimetry PXRD: Powder X-ray diffraction RT: room temperature TGA: Thermogravimetric analysis THF: tetrahydrofuran XRPD: X-ray powder diffraction

[0152] Apparatus and method Polarized Light Microscope (PLM): Micrographs were collected using an Olympus BX53 polarized light microscope. The samples were dispersed on glass slides with methyl silicone oil.

[0153] Powder X-ray diffraction (PXRD): PXRD diffractograms were obtained on a Rigaku Smartlab SE diffractometer using Cu, Kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 radiation with a Kα2:Kα1 intensity ratio of 0.50. The X-ray tube settings were 40 kV, 15 mA, and scan mode -D. The scan range (2θ) was 3–40°, the step size (2θ) was 0.02°, and the scan rate (2θ) was 10° / min.

[0154] Differential scanning calorimetry (DSC): DSC was performed on a TA Instruments DSC2500 differential scanning calorimeter using a temperature gradient from room temperature to 300 °C (heating rate 10 °C / min). The purge gas was N2 (>99.999%). Punched aluminum pans were used.

[0155] Thermogravimetric analysis (TGA): TGA thermograms were obtained on a TA Instruments TGA500 thermogravimetric analyzer using a temperature gradient from room temperature to 300 °C (heating rate 10 °C / min). The purge gas was N2 (>99.999%). Open aluminum pans were used.

[0156] Example 1: Preparation and characterization of Form 8 Preparation of type 8 Pritellivir was charged into a 4 mL glass vial, and 2 volumes of DMSO were added. A clear solution was obtained with magnetic stirring at room temperature. The antisolvent THF was added dropwise to the DMSO solution, followed by gradual precipitation. The suspension was stirred at room temperature for 24 hours. The solid was isolated by centrifugation, dried at 50°C, and then analyzed by XRPD, DSC, and TGA.

[0157] Characterizing Type 8 Characterization data for type 8 are shown in Figures 1 and 2.

[0158] Form 8 was shown to be crystalline by XRPD (Figure 1). DSC showed two small endothermic events with onsets of approximately 31°C and 189°C, followed by a sharp endotherm with an onset of 224°C (Figure 2). TGA showed a gradual weight loss of 1.3% between 34 and 185°C.

[0159] Example 2: Determination of the solubility of Form 8 method Sample preparation: Excess Form 8 was added to a vehicle containing 0.9% NaCl and 0.5% polysorbate 80 to achieve an approximately 3 mg / mL suspension. The mixture was sonicated for 15 minutes and then stirred at 500 rpm at room temperature. At 24 hours, the mixture was filtered and the filtrate was analyzed by HPLC to determine solubility.

[0160] HPLC method: Equipment: Agilent 1260 Column: ACE Ultracore Super C18 (100mm x 4.6mm x 2.5μm) (P / N: CORE-25A-1046U) Wavelength: 234 nm Column temperature: 20℃ Column flow: 1.0 mL / min Collection time: 25 minutes Injection volume: 5 μL Holding time: Approximately 14 minutes Mobile phase A: 5 mM (NH4)2HPO4 and 5 mM NH4H2PO4 in H2O Mobile phase B: ACN [Table 2]

[0161] result: The solubility of Form 8 in 0.9% NaCl and 0.5% polysorbate 80 at RT for 24 hours was approximately 70.7 μg / mL.

[0162] Comparative solubility determination of Form C (hemihydrate) disclosed in WO 2018 / 096170 method The solubility of Form C (the hemihydrate disclosed in WO 2018 / 096170) was determined in the same medium used to determine the solubility of Form 8 as described above.

[0163] Form C was prepared as follows.

[0164] 2-(4-(pyridin-2-yl)phenyl)acetic acid (38.40 g, 80%, 180.074 mmol, 1.00 eq) was added to DMF (385 mL). HOBT (17.38 g, 128.624 mmol, 0.71 eq) was added at 20 °C, followed by stirring for 10 min. 2-Chloro-4-methylthiazole-5-sulfonamide (26.66 g, 128.624 mmol, 0.71 eq) and EDCI (27.12 g, 141.486 mmol, 0.79 eq) were added. The mixture was stirred for 36 h at 20 °C under N2. The mixture was added to water (780 mL) and stirred for 30 min. The solid was collected by filtration. The filter cake was washed twice with water (2×100 mL) and then dried under reduced pressure at 50° C. for 12 hours to give a white solid. Form C was obtained by slurrying the white solid in ethanol:water (v:v=1:1) and filtering at 50° C. Form C was confirmed to be crystalline by XRPD ( FIG. 3 ).

[0165] Sample preparation: Excess Form C was added to a vehicle containing 0.9% NaCl and 0.5% polysorbate 80. The mixture was sonicated for 15 minutes and then stirred at 500 rpm at room temperature. At 24 hours, the mixture was filtered and the filtrate was analyzed by HPLC to determine solubility.

[0166] HPLC method: Equipment: Agilent 1260 Column: ACE Ultracore Super C18 (100mm x 4.6mm x 2.5μm) (P / N: CORE-25A-1046U) Wavelength: 234nm Column temperature: 20℃ Column flow: 1.0 mL / min Collection time: 25 minutes Injection volume: 5 μL Holding time: Approximately 14 minutes Mobile phase A: 5 mM (NH4)2HPO4 and 5 mM NH4H2PO4 in H2O Mobile phase B: ACN [Table 3]

[0167] result The solubility of Form C in 0.9% NaCl and 0.5% polysorbate 80 at RT for 24 hours was approximately 8.4 μg / mL, which is lower than the value determined for Form 8 in the same medium.

Claims

1. Crystal morphology of pretellivir, which is of type 8 and characterized by data selected from one or more of the following: a) X-ray powder diffraction (XRPD) pattern measured using CuKa (λ = 1.5406 Å) including peaks at 2θ values ​​of 10.5 and 24.7°2θ ± 0.2°2θ; and b) A DSC thermogram including an endothermic event with a starting temperature of 224°C ± 2°C.

2. The crystalline morphology according to claim 1, characterized by an XRPD pattern measured using Cu Ka (λ=1.5406 Å), which includes peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ.

3. The crystalline morphology according to claim 1, characterized by an XRPD pattern measured using CuKa (λ=1.5406 Å) radiation, which includes peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ, and further includes at least one, two, three, or four specific peaks selected from peaks at 2θ values ​​of 17.4, 17.9, 23.0 and 23.3°2θ±0.2°2θ.

4. The crystal morphology according to claim 1, characterized by an XRPD pattern measured using CuKa (λ=1.5406Å) radiation, which includes peaks at 2θ values ​​of 10.5 and 24.7°2θ±0.2°2θ, and further includes peaks at 2θ values ​​of 17.4, 17.9, 23.0 and 23.3°2θ±0.2°2θ.

5. The crystal morphology according to claim 1, characterized by an XRPD pattern measured using CuKa (λ=1.5406 Å) radiation, which includes at least 2, 5, 10, 15, 20, 25, 30, or 35 further peaks selected from the group consisting of peaks listed in Table 1 at °2θ±0.2°2θ.

6. The crystal morphology according to claim 5, characterized by an XRPD pattern measured using substantially the same Cu Ka (λ=1.5406 Å) radiation as shown in Figure 1.

7. The crystal morphology according to claim 1, characterized by a DSC thermogram including an endothermic event with a starting temperature of 224°C ± 2°C.

8. The crystalline morphology according to claim 1, characterized by a DSC thermogram substantially identical to that shown in Figure 2.

9. The crystalline form according to claim 1, which is substantially pure.

10. The crystalline form according to claim 1, comprising less than 2% by weight of solvent and / or water.

11. A pharmaceutical composition comprising a crystalline form of pretellivir and a pharmaceutically acceptable carrier, diluent, or excipient, wherein the crystalline form is type 8 as described in any one of claims 1 to 10.

12. A composition comprising the crystalline form of pretellivir according to any one of claims 1 to 10, or a pharmaceutical composition comprising the crystalline form of pretellivir according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the composition or pharmaceutical composition is for treating herpesvirus (conveniently HSV) infection in a subject requiring treatment, characterized in that the composition or pharmaceutical composition is administered to the subject in a therapeutically effective amount of the crystalline form of pretellivir (where the crystalline form is type 8).

13. A composition or pharmaceutical composition for use in the treatment of herpesvirus (conveniently HSV) infection, comprising a crystalline form of pretellivir as described in any one of claims 1 to 10, or a pharmaceutical composition comprising a crystalline form of pretellivir as described in any one of claims 1 to 10 and a pharmaceutically acceptable carrier, diluent, or excipient.

14. A method for preparing the crystalline form of pretellivir, wherein the crystalline form is type 8, and the method The method includes the following steps: a. A step of providing a solution of pretellivir in a first solvent system; b. A step of adding a second solvent system to the solution obtained in step a); c. Stirring the mixture from step b) for at least 1 hour; d. Optionally, a step of isolating the solid formed from step c); and e. Optionally, a step of drying the solid isolated from step d).

15. A crystalline form of pretellivir obtained by the method described in claim 14.

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