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WO2025046457A1 - Nouvelle forme cristalline de 2-(3-(2,,5'-difluoro-[1,1'-biphényl]-4-yl)-2-oxotetrahydropyrimidin-1(2h)-yl)-4-méthylthiazole-5-sulfonamide - Google Patents

Nouvelle forme cristalline de 2-(3-(2,,5'-difluoro-[1,1'-biphényl]-4-yl)-2-oxotetrahydropyrimidin-1(2h)-yl)-4-méthylthiazole-5-sulfonamide Download PDF

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WO2025046457A1
WO2025046457A1 PCT/IB2024/058310 IB2024058310W WO2025046457A1 WO 2025046457 A1 WO2025046457 A1 WO 2025046457A1 IB 2024058310 W IB2024058310 W IB 2024058310W WO 2025046457 A1 WO2025046457 A1 WO 2025046457A1
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crystalline form
compound
pharmaceutical composition
hsv
crystalline
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Zhixin ZONG
Yi Wu
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Assembly Biosciences Inc
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Assembly Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present disclosure relates to a novel crystalline form of a certain compound, which is useful in treating and/or inhibiting the development or progression of diseases or disorders caused by, or associated with, herpes virus infection.
  • Human herpes viruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing life-long infections in humans. This is accomplished by their ability to exist in the host either as a symptom free latent infection, where the virus lies dormant or, following activation, as a lytic infection with associated symptoms. These viral infections have widespread, worldwide prevalence and it is notable that over 90% of all humans are chronically infected with more than one human herpes virus.
  • HSV1 , HSV2 Herpes Simplex Virus subtype type 1 and 2
  • VZV Varicella Zoster Virus
  • EBV Epstein-Barr virus
  • CMV Cytomegalovirus
  • HHV 6-8 Human Herpes Viruses 6-8
  • HSV1 and 2 infections can cause disease in immune competent individuals. Both subtypes cause cutaneous genital/anal and oro-labial/nasal cavity (cold sore) lesions, although HSV2 is more commonly associated with the former and HSV1 the latter. It is believed that >80% of genital infections are caused by HSV2. Globally, over 500 million people have genital herpes infections and approximately 50 to 80% of the world’s population have oro-labial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1 , can also cause lesions on the fingers (Whitlows) and other areas of the skin.
  • HSV-related ocular keratitis is a major cause of blindness and HSV can also cause encephalitis in neonates, which is a life-threatening condition.
  • Other disorders believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis and possibly Bell's palsy.
  • nucleoside analogues such as acyclovir and its prodrugs, e.g., valacyclovir and famciclovir
  • these nucleoside analogues must be phosphorylated by viral thymidine kinase (TK) and subsequently converted by cellular kinases to the nucleoside triphosphate, which inhibits the activity of the viral DNA polymerase. If the virus has no functionally active TK, as is the case, for example, with resistant HHV1 mutants or with TK-negative viruses, the nucleoside analogues are unable to exert their effects.
  • TK viral thymidine kinase
  • Nucleoside analogues are clinically administered at very high doses, e.g., doses as high as several hundred milligrams to several grams are typically administered per day. Even at these high doses, which are often administered over long treatment durations, these drugs are unable to completely prevent recurrent outbreaks of symptoms from HSV infection. Nucleoside analogues also do little to address the issue of viral shedding, which can asymptomatically facilitate the transmission of HSV to more individuals. Certain nucleoside analogues, particularly when used at high doses, also give rise to safety concerns.
  • Helicase-primase inhibitors are antiviral agents with a novel mechanism of action. They inhibit the viral heterotrimeric complex consisting of helicase, primase, and cofactor subunits, which have functions that are essential for viral DNA replication. These agents are not nucleoside analogues and do not require phosphorylation by TK to inhibit HSV replication and they are therefore potentially active against TK-deficient HSV, which as described above, is a major mechanism of resistance to nucleoside analogues.
  • helicase-primase inhibitors Two examples are BILS-179 BS (Crute et al., (2002) Nature Medicine 8, p. 386-391) and amenamevir (Katsumata et al. (2016) Biochem Pharm 158 p. 201-206). [0013] Bl LS- 179 BS has been dosed orally to humans but was suspended in early clinical trials due to adverse events (Ruebsamen et al., (2019) Med. Chem. Commun., DOI: 10.1039/C9MD00233B).
  • a helicase-primase inhibitor is pritelivir, 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.
  • the compound has been disclosed in WO 2001/47904.
  • the effect of pritelivir on suppression of genital herpes following oral dosing was studied in 156 individuals (Wald et al., (2014) New England Journal of Medicine 370, p. 201-210).
  • the results of a subsequent phase II clinical study in subjects with recurrent genital HSV-2 were reported in Wald et al., (2016) (J. Am. Med. Assoc. 316(23), p. 2495-2503).
  • the present disclosure relates to a novel crystalline form of a certain compound, which is a potent helicase-primase inhibitor.
  • the compound is 2-(3-(2',5'-difluoro-[1 , 1 '-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide and is referred to herein also as ‘Compound T.
  • Compound 1 has the following structure:
  • the compound shown above is 2-(3-(2',5'-difluoro-[1 , 1 '-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide (also referred to herein as ‘Compound T) and is a potent helicase-primase inhibitor.
  • the present disclosure relates to a certain novel solid form of Compound 1 , which possesses promising and advantageous solid-state and/or biopharmaceutical properties.
  • the present disclosure is also directed to pharmaceutical compositions comprising the crystalline form, and to methods for preparing such form.
  • the present disclosure is further directed to the use of the crystalline form in the treatment of HSV infections.
  • the present disclosure provides a crystalline form of Compound 1 , wherein the crystalline form is Form C.
  • Form C can also be characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ⁇ 3°C.
  • Form C is a non-solvated and anhydrous crystalline form of Compound 1 and has a high melting point.
  • a high melting point means that Form C can be handled at high temperatures without it melting, for example, during size reduction procedures, e.g., micronization and/or the manufacturing of a pharmaceutical dosage form.
  • Form C is non-hygroscopic which is particularly advantageous when handling and storing Form C and pharmaceutical compositions comprising Form C at different humidities.
  • Form C has certain characteristics that make it particularly suited to formulation and delivery via certain routes of administration. It is a thermodynamically stable form and provides excellent Compound 1 stability, both chemically and physically, even when subjected to extreme temperature, humidity and light storage conditions. Furthermore, Form C possesses very good resistance to mechanical stress.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , wherein the crystalline form is Form C, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method of treating a herpes virus (conveniently a HSV) infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 , wherein the crystalline form is Form C.
  • a herpes virus conventionally a HSV
  • the method comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 , wherein the crystalline form is Form C.
  • the present invention provides a method of treating a herpes virus (conveniently a 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a herpes virus conventionally a HSV
  • a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 for use in the treatment of a herpes virus (conveniently a HSV) infection wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising Compound 1 for the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or a pharmaceutical composition comprising a crystalline form of Compound 1 in the manufacture of a medicament for treating a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • FIG. 1 is an overlay XRPD diffractogram of Forms A-G of Compound 1.
  • FIG. 2 is an XRPD diffractogram of Form C of the present disclosure.
  • FIG. 3 shows a DSC thermogram of Form C.
  • the DSC exhibited a sharp endotherm at an onset of 271.7 °C and a peak of 272.4 °C.
  • FIG. 4 shows a TGA thermogram of Form C.
  • the TGA data indicated a weight loss of 0.44% up to 200 °C.
  • FIG. 5 shows a DVS of Form C.
  • FIG. 6 shows a PLM image of Form C crystals.
  • Compound 1 refers to 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2- oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-sulfonamide.
  • API refers to an active pharmaceutical ingredient, e.g., Compound 1.
  • the terms “individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals ⁇ e.g., dogs, cats, and the like), farm animals e.g., cows, sheep, pigs, horses, and the like) and laboratory animals ⁇ e.g., rats, mice, guinea pigs, dogs, primates, and the like).
  • the mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HBV infection is desired.
  • modulation includes antagonism ⁇ e.g., inhibition), agonism, partial antagonism and/or partial agonism.
  • compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • terapéuticaally effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a therapeutically effective amount of Compound 1 is the quantity required to achieve a desired therapeutic and/or prophylactic effect.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • references to “treat”, “treating” or “treatment” includes: (1) delaying or reducing the likelihood of the appearance of clinical symptoms of the disease or disorder developing in a subject that may be afflicted with the disease or disorder but does not yet experience or display clinical or subclinical symptoms of the disease or disorder, (2) inhibiting the disease or disorder, i.e., arresting, reducing or delaying the progression of the disease or disorder or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease or disorder, i.e., causing regression of the disease, disorder or condition or at least one of its clinical or subclinical symptoms.
  • treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in improvement of the disease (e.g., via binding to the viral heterotrimeric complex and inhibiting the helicase and primase activity of the virus).
  • values are disclosed in groups or in ranges. It is specifically intended that the description include all individual sub-combination of the members of such groups and ranges and any combination of the various endpoints of such groups or ranges.
  • an integer in the range of 0 to 40 is 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
  • an integer in the range of 1 to 20 is 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.
  • a "crystalline form” is a solid material wherein the constituents of the solid material are arranged in a highly ordered microscopic structure, thereby forming a crystal lattice which extends in all directions.
  • Crystalline forms can include anhydrous crystalline forms, solvated crystalline forms and/or hydrated crystalline forms.
  • Polymorphism is when a solid material can exist in more than one crystalline form.
  • amorphous refers to a solid material having no long-range order in the position of its molecules.
  • Amorphous solids are substances in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long-range order.
  • Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD).
  • XRPD X-ray power diffraction
  • a "hydrate” is a compound that exists in a solid composition with water molecules.
  • the composition can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e. , a Compound 1 in water solution, while it may be hydrated, is not a hydrate as the term is used herein. Hydrates may be crystalline, wherein both the compound and water form part of the crystal lattice.
  • a “solvate” is a similar composition to a hydrate except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form, i.e., a Compound 1 in solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • Solvates may be crystalline, wherein both the compound and solvent form part of the crystal lattice.
  • anhydrous solid form of the compound does not have water incorporated into its structure.
  • an anhydrous crystalline form does not have water forming part of the crystal structure.
  • water content can be determined by either Karl Fischer Titration or Thermogravimetric Analysis (TGA).
  • an anhydrous solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 , about 0.05, or about 0.01 % by weight of water.
  • un-solvated or non-solvated means the solid form of the compound does not have solvent(s) incorporated into its structure.
  • an un-solvated crystalline form does not have solvent(s) forming part of the crystal structure.
  • solvent content can be determined by Gas Chromatography (GC).
  • GC Gas Chromatography
  • an un-solvated or nonsolvated solid form of the compound comprises less than about 2% by weight, such as less than about 1.5%, less than about 1%, such as less than about 0.5, about 0.4, about 0.3, about 0.2, about 0.1 , about 0.05, or about 0.01 % by weight of solvent.
  • composition where a composition is said to "consist essentially of" a particular component, said composition suitably comprises at least 70 wt% of said component, suitably at least 80 wt% thereof, suitably at least 90 wt% thereof, suitably at least 95 wt% thereof, most suitably at least 99 wt% thereof.
  • a composition said to "consist essentially of" a particular component consists of said component save for one or more trace components.
  • the phrase "substantially as shown in figure” refers to an X-ray powder diffraction pattern or DSC thermogram with at least 50%, or 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 figure.
  • the term “relative volumes” refers to the volume of a liquid (in mL) used relative to the mass of Compound 1 (in g). For example, 10 relative volumes of solvent equates to 10 mL for every gram of Compound 1 .
  • Compound 1 is 2-(3-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-oxotetrahydropyrimidin-1 (2H)- yl)-4-methylthiazole-5-sulfonamide shown below.
  • Compound 1 is a potent helicase-primase inhibitor and has an in-vitro EC50 value of approximately 0.019 iM against HSV-1 and 0.011 iM against HSV-2.
  • the in-vitro EC50 value against HSV-1 and/or HSV-2 can be determined in accordance with methods known to the skilled person, such as those disclosed in Field et al. (2013, Antiviral Res. 100, p. 297-299).
  • the in-vitro EC50 value can also be determined in accordance with the assays described in the Examples section of the present application.
  • Compound 1 can be prepared, isolated or obtained by any method apparent to those of skill in the art. An exemplary method of preparation is described in Example 1 below.
  • the present disclosure provides a crystalline form of Compound 1. Specifically, there is provided a novel crystalline form of Compound 1 described and characterized herein as Form C.
  • the present disclosure is also directed to pharmaceutical compositions comprising the crystalline Form C, and to methods for preparing such form.
  • the present disclosure is further directed to the use of Form C in the treatment or prevention of HSV infections.
  • X-ray powder diffraction is just one of several analytical techniques one may use to characterize and/or identify crystalline solid forms.
  • Differential scanning calorimetry may be used to characterize and/or identity crystalline solid forms.
  • a typical variability for a value associated with a differential scanning calorimetry onset temperature is of the order of ⁇ 3°C, or more preferably ⁇ 2°C.
  • thermal data (DSC and TGA) presented herein were acquired using a heating rate of 10°C/min. Furthermore, DSC data was acquired using aluminum punched pans.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • 1.5406 A comprising peaks at 15.1 , 25.3 and 30.5 °20 ⁇ 0.2 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ⁇ 0.2 °20.
  • 1.5406 A comprising peaks at 15.1 , 25.3 and 30.5 °20 ⁇ 0.2 °20 and further comprising peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ⁇ 0.2 °20.
  • 1.5406 A comprising peaks at 15.1 , 25.3 and 30.5 °20 ⁇ 0.1 °20 and further comprising at least one, two, three, four, or five specific peaks selected from peaks at 7.3, 8.5, 21.8, 36.7 and 37.0 °20 ⁇ O.1 °20.
  • Form C comprises less than about 2% by weight solvent and/or water, such as less than about 1.5% by weight, 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.
  • Form C comprises less than about 2% by weight water, such as less than about 1.5% by weight, less than about 1 %, less than about 0.5, less than about 0.4, less than about 0.3, or less than about 0.2 % by weight water.
  • suitable analytical techniques which can quantify the amount of solvent/water associated with a solid. For example, water content can be determined by Karl Fischer Titration. Residual solvents can be determined by Gas Chromatography. Thermogravimetric Analysis (TGA) can also quantify the amount of volatile material (i.e., solvent and water) associated with a solid (either surface bound or incorporated into the crystal structure).
  • Form C is anhydrous.
  • Form C is anhydrous and un-solvated.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by an XRPD pattern measured using Cu Ka (1.5406 A) radiation substantially the same as shown in Figure 2.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 269 °C ⁇ 3°C.
  • the DSC thermogram comprises no thermal events between 50 and 100 °C and an endothermic event with an onset temperature of 269 °C ⁇ 3°C.
  • the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 269 °C ⁇ 2°C
  • the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 260 °C ⁇ 2°C.
  • the DSC thermogram comprises no thermal events between 50 and 200 °C and an endothermic event with an onset temperature of 269 °C ⁇ 3°C.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 268 °C ⁇ 2°C, 269 °C ⁇ 2°C, or 270 °C ⁇ 2°C.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by a DSC thermogram comprising an endothermic event with an onset temperature of 272 °C ⁇ 2°C.
  • a crystalline form of Compound 1 wherein the crystalline form is Form C characterized by a DSC thermogram substantially the same as depicted in Figure 3.
  • Form C is substantially pure.
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight.
  • Form C is pure or substantially pure.
  • substantially pure means that the solid state form of Compound 1 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 any impurities or other solid forms of Compound 1 , including alternative crystalline forms, hydrates, solvates or amorphous forms, for example as measured by XRPD.
  • substantially pure Form C as described herein would be understood to contain greater than about 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 95% by weight, greater than 98% by weight, greater than 99% by weight, or greater than 99.5% by weight of crystalline Form C of Compound 1 .
  • Form C wherein when Form C is characterized by a solid-state technique, such as by X-Ray Powder diffraction, no other solid forms (amorphous and/or other crystalline forms) are detected.
  • a crystalline form of Compound 1 essentially consisting of Form C.
  • a crystalline form of Compound 1 consisting of Form C there is provided.
  • compositions comprising a crystalline form of Compound 1 as disclosed herein formulated together with one or more pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 wherein the crystalline form is Form C; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 wherein the crystalline form is pure or substantially pure Form C; and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition comprising Compound 1 wherein Compound 1 consists essentially of crystalline Form C.
  • a pharmaceutical composition comprising Compound 1 , wherein Compound 1 consists of crystalline Form C.
  • the pharmaceutical composition relates to a crystalline form of Compound 1
  • the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, yet more conveniently greater than about 90% and preferably greater than 95%, 98% or 99% by weight of Form C.
  • the pharmaceutical composition of the present invention include those suitable for oral, rectal, topical, buccal, parenteral, rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.
  • Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semi-solid or liquid form, which contains Compound 1 in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • Compound 1 may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • Compound 1 is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the progress or condition of the disease (e.g. HSV infection).
  • a pharmaceutical composition comprising an aqueous suspension of Compound 1 Form C.
  • the pharmaceutical composition is suitable for administration via injection (such as via subcutaneous or intramuscular injection).
  • an injectable pharmaceutical composition comprising an aqueous based suspension of Compound 1 Form C.
  • a solid dosage form e.g. a tablet for oral administration.
  • kits for use by e.g., a consumer in need of HSV infection treatment include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent HSV infection.
  • the instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art.
  • kits could advantageously be packaged and sold in single or multiple kit units.
  • An example of such a kit is a so-called blister pack.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material.
  • the packaging process recesses are formed in the plastic foil.
  • the recesses have the size and shape of the tablets or capsules to be packed.
  • the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are sealed in the recesses between the plastic foil and the sheet.
  • the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
  • a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested.
  • a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . “ etc.
  • a “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day.
  • a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.
  • the memory aid should reflect this.
  • crystalline Compound 1 Form C for use as a medicament.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, for use as a medicament.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, for use in therapy.
  • a method for treating a herpes virus (conveniently a HSV) infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • a method for treating a herpes virus (conveniently a 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a method for inhibiting HSV replication in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • a method for 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a method for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • a method for reducing the likelihood or severity of symptoms of a HSV infection in the subject in need thereof comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • a method for inhibiting the development or progression of a disease or disorder caused by, or associated with, 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • a method for treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 wherein the crystalline form is Form C.
  • a method for treating or preventing a disease or disorder caused by, or associated with, 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C.
  • Compound 1 Form C according to the present invention, or the pharmaceutical compositions according to the present invention can reduce time to healing of lesions (e.g., time to full recovery of lesions) and duration of symptoms resulting from HSV infections in diseases or disorders, such as herpes labialis or genital herpes.
  • the time to lesion healing may be defined as complete epithelization of mucocutaneous HSV lesion(s) within the treatment period and no appearance of new lesions, e.g., as assessed by a physician.
  • Compound 1 Form C according to the present invention, or the pharmaceutical compositions according to the present invention can reduce pain or pain intensity (for example, at a lesion site) caused as a consequence of HSV infections in diseases or disorders, such as herpes labialis or genital herpes.
  • a crystalline form of Compound 1 for use in the treatment of a herpes virus (conveniently a HSV) infection wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 for use in the inhibition of HSV replication in a subject wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of HSV replication in a subject, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 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 C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient 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 C.
  • a crystalline form of Compound 1 for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.
  • a pharmaceutical composition comprising a crystalline form of Compound 1 , and a pharmaceutically acceptable carrier, diluent or excipient for use in treating or preventing a disease or disorder caused by, or associated with, HSV infection, in a subject in need thereof, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for the treatment of a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • a herpes virus conveniently a HSV
  • the use of a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for the inhibition of HSV replication in a subject, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , 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 C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in treating or preventing a disease or disorder caused by, or associated with, HSV infection, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for treating a herpes virus (conveniently a HSV) infection, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for inhibiting HSV replication in a subject, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , in the manufacture of a medicament for reducing the likelihood or severity of symptoms of a HSV infection in a subject in need thereof, wherein the crystalline form is Form C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , 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 C.
  • a crystalline form of Compound 1 or the use of a pharmaceutical composition comprising a crystalline form of Compound 1 , 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 thereof, wherein the crystalline form is Form C.
  • the disease or disorder caused by, or associated with, HSV infection is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s), genital herpes, HSV-related ocular keratitis, HSV-related encephalitis, herpes gladiatorum, primary HSV gingivostomatitis, Mollaret's meningitis and Bell's palsy.
  • herpes labialis e.g., oro-labial cold sores or Whitlow’s
  • genital herpes genital herpes
  • HSV-related ocular keratitis e.g., HSV-related encephalitis
  • herpes gladiatorum e.g., primary HSV gingivostomatitis, Mollaret's meningitis and Bell's palsy.
  • the disease or disorder caused by, or associated with, HSV infection is selected from herpes labialis (e.g., oro-labial cold sores or Whitlow’s) or genital herpes.
  • the disease or disorder is recurrent herpes labialis or recurrent genital herpes. Individuals with a history of multiple recurrences of herpes labialis or recurrent genital herpes, e.g., HSV which recurs six times or more annually, may be regarded as having recurrent HSV.
  • the herpes virus being treated is HSV2. In a further embodiment, the herpes virus being treated is HSV2 and the subject in need of the treatment has HSV2 recurrent genital herpes.
  • the herpes virus being treated is HSV1. In yet a further embodiment, both herpes virus HSV-1 and HSV-2 are being treated.
  • the herpes virus being treated or prevented is resistant to nucleosidic anti-viral therapy.
  • the nucleosidic antiviral therapy is selected from therapy with the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir.
  • the herpes virus being treated is resistant to nucleosidic antiviral therapy, e.g., acyclovir-resistant mucocutaneous HSV infection.
  • the HSV infection being treated is a mucocutaneous HSV infection resistant to therapy with antiviral therapy with nucleoside analogues, such as acyclovir, penciclovir, famciclovir, ganciclovir or valacyclovir.
  • the subject in need of the methods disclosed herein is immunocompromised.
  • the subject may be immunocompromised due to conditions including HIV infection, cancer, hematopoietic cell or solid organ transplantation and chronic glucocorticoid use or a genetic immunodeficiency.
  • the subject in need of the methods disclosed herein is a neonate or an infant.
  • the subject is a herpes-positive patient.
  • the subject in need of the methods disclosed herein has acyclovir-resistant mucocutaneous HSV infection. This subject may have been diagnosed with condition on the basis of clinical failure, e.g., no improvement after oral or iv doses for at least 7 days with approved doses of acyclovir.
  • the subject in need of the methods disclosed herein has a primary genital HSV-related herpes infection.
  • the subject in need of the methods disclosed herein has severe or progressive genital HSV-related herpes infection.
  • the appropriate dosage is expected to vary depending on, for example, the mode of administration, and the nature and severity of the infection to be treated as well as the specific infection to be treated and is within the purview of the treating physician.
  • an indicated administration dose may be in the range between about 0.1 to about 1000 pg/kg body weight.
  • the crystalline form of the present invention, or a pharmaceutical composition comprising the crystalline form of the present invention is administered to a subject in need thereof once a week, twice a month, once a month, once every two months, once every three months, once every six months, or once every year.
  • the crystalline form of the present invention or a pharmaceutical composition comprising the crystalline form of the present invention, is administered to a subject in need thereof once every three months, once every six months, or once every year.
  • the crystalline form of the present invention, or a pharmaceutical composition comprising the crystalline form of the present invention is administered orally, or via injection.
  • the pharmaceutical composition is a solid dosage form administered orally.
  • a pharmaceutical composition of the present invention may suitably be an aqueous based suspension of Compound 1 Form C to be administered by intramuscular or subcutaneous injection.
  • the pharmaceutical composition is administered by subcutaneous injection.
  • the pharmaceutical composition is administered by intramuscular injection.
  • the subject being treated in a human.
  • the crystalline form of the present invention may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Conveniently, such animals include horses, dogs and cats.
  • compositions of the present invention may be administered alone as a sole therapy, or can be administered in addition with one or more other substances and or treatments. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.
  • a subject or patient can further have HSV infection-related co-morbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HSV.
  • HSV infection-related co-morbidities i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being infected with HSV.
  • Contemplated herein are also disclosed pharmaceutical compositions in combination with at least one other agent that has previously been shown to treat these HSV-infection-related conditions. Such conjoint treatment may be achieved independently (by way of simultaneous, sequential or separate administration of the individual components of the treatment) and/or via pharmaceutical compositions of the present invention that include a second active agent.
  • a method for treating or preventing HSV infection in a subject in need thereof comprising administering a therapeutically effective amount of a crystalline form of Compound 1 , and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent, wherein the crystalline form is Form C.
  • a method for treating or preventing 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 Compound 1 and a pharmaceutically acceptable carrier, diluent or excipient, wherein the crystalline form is Form C, and co-administering to the subject a therapeutically effective amount of an additional therapeutic agent.
  • 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 aliphatic alcohols, such as docosanol; iv. agents such as idoxuridine, trifluridine and vidarabine; v. a corticosteroid; and vi. other helicase-primase inhibitors, such as amenamevir.
  • nucleoside polymerase inhibitors such as acyclovir, valacyclovir, famciclovir, penciclovir and ganciclovir
  • pyrophosphate polymerase inhibitors such as foscarnet
  • iii. saturated aliphatic alcohols such as docosanol
  • agents such as
  • a crystalline form of Compound 1 according to the first aspect of the invention may be administered in a first amount as part of a combination therapy in conjunction with one or more antivirals, including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir or the respective prodrugs valacyclovir or famciclovir, which antiviral agents may be administered in a second amount.
  • one or more antivirals including nucleoside analogues such as acyclovir, foscarnet, ganciclovir or penciclovir or the respective prodrugs valacyclovir or famciclovir, which antiviral agents may be administered in a second amount.
  • the first and second amounts together comprise a pharmaceutically effective amount.
  • the first amount, the second amount, or both may be the same, more, or less than effective amounts of each compound administered as monotherapies.
  • Therapeutically effective amounts of a disclosed compound and antiviral may be co-administered to the subject, i.e. , administered to the subject simultaneously or separately, in any given order and by the same or different routes of administration.
  • additional drugs may be given in conjunction with the above combination therapy.
  • the crystalline form of Compound (I) is Form C.
  • the process to prepare Form C comprises the steps of: a) providing a solution of Compound 1 in a first solvent system; b) adding a second solvent system to the solution from step a); c) stirring the mixture obtained from step b), optionally for at least 1 hour; d) optionally, isolating the solids formed from step c); and e) optionally, drying the solids isolated from step d).
  • the first solvent system comprises a solvent wherein Compound 1 has a solubility of at least 25 mg/mL at room temperature, such as at least 50, 75, or 100 mg/mL.
  • the first solvent system comprises DMSO or DMF.
  • the first solvent system comprises DMSO.
  • the first solvent system consists essentially of DMSO.
  • the first solvent system consists of DMSO.
  • Compound 1 is dissolved in 1-10 relative volumes of the first solvent system, such as 1-5 relative volumes.
  • Compound 1 is dissolved in 1- 10 relative volumes of DMSO, such as 1-5, or 2-4 relative volumes of DMSO.
  • step a) is performed at 50 to 100 °C.
  • step a) is performed at 60 to 90 °C, such as 65 to 85 °C, 75 to 85 °C or 70 to 80 °C.
  • Compound 1 is dissolved in 1-5 relative volumes of DMSO (such as 2-4 relative volumes of DMSO) at a temperature of 60 to 90 °C (such as 70 to 80 °C).
  • the second solvent system comprises a solvent wherein Compound 1 has a solubility of less than 50 mg/mL at room temperature, such as less than 20, or less than 10 mg/mL.
  • the second solvent system comprises ethanol.
  • the second solvent system consists essentially of ethanol.
  • the second solvent system consists of ethanol.
  • 5-40 relative volumes of the second solvent system are added to the solution from step a), such as 5-20, 10-18, or 12-16 relative volumes.
  • 5-40 relative volumes of ethanol are added to the solution from step a), such as 5-20, 10-18, or 12-16 relative volumes of ethanol.
  • the first solvent system comprises DMSO and the second solvent system comprises ethanol.
  • the second solvent system is an anti-solvent system.
  • step b) the second solvent system is added at 40 to 90 °C, such as 40 to 80 °C, 55 to 80 °C, or 40 to 70 °C.
  • step b) the second solvent system is added at 50 to 65 °C, such as 50 to 60°C, 55 to 60 °C or 60 °C.
  • the second solvent system in step b) is added dropwise to the solution from step a).
  • the addition of the second solvent system in step b) is over a time period of at least 1 hour, such as at least 2 hours, such as at least 5 hours or such as at least 8 hours.
  • the addition of the second solvent in step b) is over a time period of about 5 hours.
  • the addition of the second solvent in step b) is over a time period of about 7 hours.
  • the addition of the second solvent in step b) is over a time period of about 8 hours.
  • the addition of the second solvent in step b) is over a time period of 8 to 10 hours.
  • the addition of the second solvent system in step b) is carried out in two portions.
  • 0.5-2 relatives volumes, such as 1-2 relative volumes, of the second solvent system (e.g. ethanol) are added in the first portion and 10-20 relative volumes, such as 10-15 relative volumes, of the second solvent system (e.g. ethanol) are added in the second portion.
  • the first portion of the second solvent system is added over 30 to 60 minutes.
  • the first portion of the second solvent system is added to the mixture being stirred at 40 to 90 °C, such as 40 to 80 °C, 40 to 70 °C, 65 to 85 °C, 70 to 80 °C, 50 to 60 °C, or 50 to 55 °C.
  • the first portion of the second solvent system is added to the mixture being stirred at the same temperature step a) was performed.
  • the second portion of the second solvent system is added to the mixture being stirred at 50 to 65 °C, such as 55 to 60 °C, 57 to 62 °C, or about 60 °C.
  • the mixture is stirred at 57 to 62 °C for 1-2 hours.
  • the mixture is stirred at 55 to 60 °C for 1-2 hours.
  • step b) further comprises an additional step (step b2)) of adding a seed of Compound 1 Form C to the solution.
  • a seed of Compound 1 Form C Suitably, 0.01 to 10% by weight of the seed relative to the amount of Compound 1 present in the solution in step a) is added.
  • 0.1 to 5% by weight of seed is added, such as about 2% by weight.
  • step b2) is carried out after the first portion of the second solvent system is added to the mixture.
  • step b2) is carried out before the second portion of the second solvent system is added to the mixture.
  • the stirring in step c) is performed at room temperature.
  • the stirring in step c) is performed at 18 to 22 °C.
  • the stirring in step c) is performed 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, at least 22 hours, or at least 24 hours.
  • the stirring in step c) is performed for at least 1 hour.
  • step d) comprises isolating the solids by filtration.
  • step e) comprises drying the solids at a temperature greater than room temperature, such as greater than 30°C, or greater than 40°C.
  • step e) comprises drying the solids at a temperature of about 50 °C.
  • NMP N-Methyl Pyrrolidone PLM: Polarized light microscopy
  • PLM Polarized-Light Microscopy
  • X-Ray Powder Diffraction (XRPD): XRPD diffractograms were acquired on Rigaku Smartlab MiniFlex 600C diffractometer using Cu, Ka, Ka 1(A): 1.540598, Ka2(A): 1.544426 radiation with a Ka2:Ka1 intensity ratio of 0.50.
  • X-Ray tube setting was 40 kV, 15 mA, Scan Mode 1D.
  • the scan range (2 theta) was 3-40°, step size (2 theta) of 0.02° with scan speed (2 theta) of 107min.
  • TGA Thermogravimetric Analysis
  • Karl Fischer (KF) water content KF was collected on 915 KF Ti-Touch Metrohm titrator using the volumetric method. 100 mg samples were used with 1:1 NMP:MeOH as diluent.
  • HPLC method The HPLC method conditions used for measuring stability samples are summarized in Table 1.
  • Step 1 Synthesis of 1-(4-methylthiazol-2-yl)tetrahydropyrimidin-2(1H)-one (Intermediate 1- 1)
  • Step 1A Synthesis of 4'-bromo-2,5-difluoro-1,1 '-biphenyl (Intermediate 1-2)
  • Step 2 Synthesis of 1-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-3-(4-methylthiazol-2-yl) tetrahydropyrimidin-2(1H)-one (Intermediate 1-3)
  • Step 3 Synthesis of 2-(3-(2',5'-difluoro-[1,1 , -biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonic acid (Intermediate 1-4)
  • Step 4 Synthesis of 2-(3-(2',5'-difluoro-[1,T-biphenyl]-4-yl)-2-oxotetrahydropyrimidin- 1(2H)-yl)-4-methylthiazole-5-sulfonamide (Compound 1)
  • Vero cells were cultured in Dulbecco’s Modified Eagle Medium (DM EM) supplemented with 10% foetal bovine serum and 100 units/mL penicillin and streptomycin. The cells were passaged 2-3 times per week to maintain sub-confluent densities.
  • DM EM Modified Eagle Medium
  • Vero cells were seeded into 96-well plates at a density of 2.5 * 10 3 cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 .L of infection medium (DMEM supplemented with 2% foetal bovine serum and 100 units/mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 iL of infection medium containing 80 TCID50 HSV-1 was added to the cells and incubated at 37°C for 4 days.
  • DMEM fetal bovine serum
  • a Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments.
  • 50 iL of infection medium containing 80 TCID50 HSV-1 was added to the cells and incubated at 37°C for 4 days.
  • Vero cells were seeded into 96-well plates at a density of 1.0 x 10 4 cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 iL of infection medium (DMEM supplemented with 2% foetal bovine serum and 100 units/mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 iL of infection medium containing 160 TCID50 HSV-2 G strain was added to the cells and incubated at 37°C for 5 days.
  • DMEM fetal bovine serum
  • a Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments.
  • 50 iL of infection medium containing 160 TCID50 HSV-2 G strain was added to the cells and incubated at 37
  • Figure 1 shows an overlay of the XRPD diffractograms for Forms A to G.
  • Table 3 provides a summary of the results of a competitive slurry experiment of Forms A, B and C mixed in a 1 : 1 : 1 ratio in three different solvent mixtures at both 25°C or 50°C. After 24 or 72 hour slurrying a sample was taken, filtered and analysed by XRPD.
  • Form C was determined to be an anhydrous crystalline form of Compound 1.
  • DSC shows a sharp melting endothermic with an onset temperature of 271.7 °C (see Figure 3), while TGA shows a weight loss of 0.44% up to 200° C (see Figure 4).
  • DVS analysis showed water update of 0.02% at 90% P/Po ( Figure 5) indicating Form C is non-hygroscopic. No change in crystalline form was observed post DVS experiment.
  • PLM shows plate-like birefringent crystals of Form C ( Figure 6).
  • Samples of Form C were subjected to stability testing under conditions of high temperature (60 °C), high humidity (90% RH at 25 °C), or illumination (4,500 Lux) for 11 days. Samples were taken after 5 days and 11 days and subjected to visual analysis, HPLC for Compound 1 purity, and XRPD for solid state analysis. The results are summarised in Table 5.
  • Compression testing was carried out for 5 mins at 10 tons pressure; XRPD testing showed the sample was still Form C.
  • Granulation testing was carried out for 3 mins, with neat grinding and ethanol-assisted grinding; in both cases XRPD testing showed the samples were still Form C after the tests.
  • the internal batch temperature was decreased to 55 to 60 °C (cooling rate 8-12 °C per hour), crystal seed (2 wt%) was added to the reactor, and the mixture was stirred at 55-60°C for 2-3 hours.
  • Ethanol (15 rel. vol.) was then added slowly over a period of 8-10 hr. The contents were stirred at 55 to 60 °C for 1 to 2 hours and then cooled at a cooling rate of 3-7°C per hour to give a final batch temperature of 18-22°C.

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Abstract

L'invention concerne une nouvelle forme cristalline d'un composé inhibiteur d'hélicase-primase, ainsi que des compositions pharmaceutiques la comprenant, des procédés pour sa production, l'utilisation de la forme cristalline dans un médicament et pour le traitement d'infections par le virus de l'herpès.
PCT/IB2024/058310 2023-08-28 2024-08-27 Nouvelle forme cristalline de 2-(3-(2,,5'-difluoro-[1,1'-biphényl]-4-yl)-2-oxotetrahydropyrimidin-1(2h)-yl)-4-méthylthiazole-5-sulfonamide Pending WO2025046457A1 (fr)

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