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WO2025128749A1 - Promédicaments de dihydrogénophosphate d'hydroxyméthyle de c-nucléosides - Google Patents

Promédicaments de dihydrogénophosphate d'hydroxyméthyle de c-nucléosides Download PDF

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Publication number
WO2025128749A1
WO2025128749A1 PCT/US2024/059655 US2024059655W WO2025128749A1 WO 2025128749 A1 WO2025128749 A1 WO 2025128749A1 US 2024059655 W US2024059655 W US 2024059655W WO 2025128749 A1 WO2025128749 A1 WO 2025128749A1
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formula
compound
c8alkyl
alkyl
mixture
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Eugene J. Eisenberg
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Promedy LLC
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Promedy LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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

Definitions

  • RNA viruses which are responsible for infections ranging from the common cold to life-threatening hemorrhagic fevers, are a leading cause of worldwide human infectious diseases. Despite the benefit of vaccinations for many RNA viral infections, RNA viruses are a major global threat. This is due in part to the high evolution rate and high capacity to spread from animals to humans (Woolhouse MEJ, et al., Emerging Infectious Diseases 2016, 22:2037–2044).
  • nucleosides and nucleotides are metabolized to a monophosphate derivative, which is highly polar and cannot diffuse across the cell membrane.
  • the monophosphate derivative is then converted stepwise to the triphosphate derivative.
  • One nucleoside in particular that has been widely investigated is GS-441524, a 1’-cyano 4-aza-7,9-dideazaadenosine C-nucleoside that has shown activity against a range of viruses, including Yellow Fever, Dengue Fever, Parainfluenza 3, MERS, SARS, SARS-CoV, Ebola 1 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • GS-441524 has poor oral bioavailability in several species, including non-human primates (Mackman, R. L. et al. J. Med. Chem. 2021, 64: 5001–5017; Li, Y. et al. J. Med. Chem., 2022, 65:2785-2793; Wei, D. et al. Bioorg. Med. Chem., 2001, 46, 116364). For this reason, various 5’-, 4’-, and 3’-prodrugs of GS-441524 have been studied and developed in an attempt to obtain higher exposures of GS-441524.
  • remdesivir had no significant effect on patients with COVID-19 who were already being ventilated (WHO Solidarity Trial Consortium, Lancet, 2022, 399:10339). [0009] In addition to its unclear benefit against COVID-19 in certain circumstances, remdesivir exhibits poor water solubility and must be administered as an intravenous solution. This is most beneficial for a hospital setting, but limits its outpatient use and broad patient access. While currently approved for outpatient settings where a healthcare provider has immediate access to medication to treat an allergic reaction (VEKLURY. Prescribing Information.
  • Obeldesivir was studied in a Phase III clinical trial for patients who had a high risk of developing severe COVID-19, but this study was terminated when it was determined that that there would not be a statistically significant treatment effect (NCT05603143).
  • a Phase II clinical trial is currently ongoing to study the effect of obeldesivir in nonhospitalized adults with acute respiratory syncytial virus (RSV) (NCT06585150). While obeldesivir is being developed as an oral pill, it is lipophilic, and often poorly water-soluble lipophilic molecules require additional excipients for consistent bioavailability and dissolution in the GI tract fluids at efficacious doses.
  • Described herein are hydroxymethyl dihydrogen prodrugs of C-nucleotides, including of GS-441524. It has been surprisingly discovered that in certain embodiments, the prodrugs described herein exhibit unexpected and advantageous properties, including enhanced oral bioavailability compared to GS-441524. As described in Example 2, Compound 1 and Compound 2, prodrugs of Formula I, were administered orally and intravenously to mice. Certain PK parameters were measured, and these results were compared to the parameters measured following GS-441524 administration.
  • the PK parameters were obtained using a saline dose without organic solvents, which is especially advantageous for therapy and formulation.
  • the prodrugs described herein potentially can be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route. This is especially advantageous over remdesivir, which is administrated with sulfobutylether- ⁇ -cyclodextrin as vehicle. Sulfobutylether- ⁇ -cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing additional toxicity. [0014] Due to the superior PK, tablets of the prodrugs described herein could potentially reduce tablet size over GS-441524.
  • enhanced solubility could potentially reduce the tablet size over obeldesivir because minimal excipients may be required for formulation. This could allow for lower pill burden, the potential for formulating combination products, and/or increased dose-range interrogation of the target.
  • the ability of the prodrugs described herein to be formulated for both oral and parenteral administration is advantageous.
  • An oral formulation, such as a pill can be widely distributed and administrated, while a parenteral 4 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 formulation, for example, an intravenous solution, is most beneficial for patients that are severely ill and must be treated in a hospital.
  • the prodrugs described herein exhibit superior bioavailability compared to GS-441524 and have the additional benefit of enhanced solubility, which potentially allows for advantageous formulations compared to formulations of remdesivir and obeldesivir.
  • R 1 and R 2 are each independently hydrogen, N(R a )2, N3, CN, NO2, S(O)nR 3a , halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl;
  • R 3 is hydrogen, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R 3a , halogen, C 1 -C 8 alkyl, C 3 - C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl
  • X 1 and X 2 are each independently CR 11 or N;
  • the prodrug of Formula I is a prodrug of Formula IA: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , X 1 , and X 2 are as defined herein.
  • the prodrug of Formula I is a prodrug of Formula IB: 6 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the prodrug of Formula I is a prodrug of Formula IC: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , X 2 , and X 4 are as defined herein.
  • the prodrug of Formula IC is a prodrug of Formula IC-1: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein.
  • the prodrug of Formula IC is a prodrug of Formula IC-2: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein. 7 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the prodrug of Formula I is a prodrug of Formula ID: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein.
  • compositions comprising a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • the pharmaceutical composition is in a dosage form suitable for parenteral administration. In other embodiments, the dosage form is suitable for oral administration.
  • Also provided herein is a method to treat an RNA viral infection in a host in need thereof comprising administering a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier.
  • the method is to treat an RNA viral infection in a host in need thereof.
  • the method is to prevent an RNA viral infection in a host in need thereof.
  • the RNA viral infection is a Coronaviridae viral infection, for example a betacoronavirus viral infection, such as COVID-19 caused by the SARS-CoV (severe acute respiratory syndrome coronavirus) virus or the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) virus.
  • FIG. 1A is a profile of GS-441524 in plasma after oral administration of GS-441524 (10 mg/kg), Compound 1 (94 mg-eq/kg), and Compound 2 (10 mg-eq/kg) as described in Example 2.
  • the dose for Compound 1 and Compound 2 is the mg-equivalent GS-441524/kg dose.
  • FIG. 1B is a profile of GS-441524 in plasma after intravenous administration of Compound 2 (10 mg-eq/kg) as described in Example 2.
  • DETAILED DESCRIPTION Definitions [0027] When referring to the prodrugs and compositions provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • Halogen or “halo” means fluoro, bromo, chloro, or iodo.
  • “Patient” or “subject” includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in other embodiments, the patient is human.
  • the terms “subject” and “patient” are used interchangeably.
  • the terms “subject” and “subjects” refer to an animal, such as a mammal including a non- primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee, and a human), and in certain embodiments, a human.
  • the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat).
  • the subject is a human.
  • a “pharmaceutically acceptable salt” of a prodrug means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent prodrug. It is 11 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 understood that the pharmaceutically acceptable salts are non-toxic.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the term “substantially free of” or “substantially in the absence of” stereoisomers with respect to a composition refers to a composition that includes at least 85% or 90% by weight, 12 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the total weight % constitutes the weight % of the designated stereoisomer plus the weight % of the undesignated stereoisomer in the composition based on weight of the designated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt) plus the weight of the undesignated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt).
  • the prodrugs are substantially free of stereoisomers.
  • Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms.
  • the atoms of the prodrugs recited herein are meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.
  • administering and variants thereof (e.g., in some embodiments, “administering” a compound) in reference to a prodrug described herein means introducing the prodrug as described herein into the system of the animal in need of treatment.
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the prodrug thereof and other agents.
  • “Therapeutically effective amount” is an amount of a prodrug or composition, that when administered to a patient, is sufficient to affect such treatment for the RNA viral infection, e.g., to ameliorate a symptom of the disease.
  • the amount of a prodrug described herein which 13 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 constitutes a “therapeutically effective amount” will vary depending on the prodrug, the RNA viral infection and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment of an RNA viral infection described herein or one or more symptoms thereof.
  • the term “therapeutic agent” includes a prodrug provided herein.
  • a therapeutic agent is an agent that is known to be useful for, or has been or is currently being used for the treatment or prevention of an RNA viral infection or one or more symptoms thereof.
  • “Treating” or “treatment” of an RNA viral infection described herein, as used herein, includes (i) preventing the RNA viral infection from occurring in a human, i.e., causing the clinical symptoms of the virus not to develop in an animal that may be exposed to or predisposed to the RNA viral infection, but does not yet experience or display symptoms of the RNA viral infection; (ii) inhibiting the RNA viral infection, i.e., arresting its development and/or its replication; and (iii) relieving the RNA viral infection, e.g., relieving or reducing a symptom thereof.
  • Treating” or “treatment” of any RNA viral infection refers, in certain embodiments, to ameliorating a RNA viral infection that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible in the subject, for example, viral load.
  • “treating” or “treatment” includes modulating the RNA viral infection, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the RNA viral infection. [0049] “Preventing” or “prevent” of the RNA viral infection, as used herein, includes the administration of a prodrug as described herein to reduce the likelihood of an occurrence or reoccurrence of the viral infection, or to minimize a new viral infection relative to a viral infection that would have occurred without such treatment.
  • prevention includes administering a prodrug as described herein to a host who has been exposed to and is thus at risk of contracting a viral infection. 14 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0050]
  • prodrug refers to any agent(s) which can be used in the prevention of a viral infection, or one or more symptoms thereof.
  • the term “prophylactic agent” includes a prodrug as provided herein. In certain other embodiments, the term “prophylactic agent” does not refer to a prodrug provided herein.
  • a prophylactic agent can be an agent that is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression, and/or severity of the RNA viral infection.
  • prophylactically effective amount refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with an RNA viral infection, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
  • the term “anomer” refers to a stereoisomer that differs in the configuration of the carbon bound to the base (the 2-position of the nucleoside).
  • a nucleoside can exist as either the ⁇ -anomer or the ⁇ -anomer.
  • the compounds described herein can exist as either the ⁇ -anomer, the ⁇ -anomer, or a mixture thereof. In a preferred embodiment, the compounds described herein are the ⁇ -anomers. In an alternative embodiment, the compounds described herein are the ⁇ -anomers.
  • the compound of Formula I is a compound of Formula I-1: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • the compound of Formula I is a compound of Formula I-2: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. 15 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the compound of Formula I is a compound of Formula I-3: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • Base is selected from .
  • Base is selected from [0057]
  • Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R 1 , R 2 , and R 3 are hydrogen.
  • Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R 1 , R 2 , and R 3 are independently selected from hydrogen and C1-C8alkyl.
  • Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID is hydrogen and R 1 and R 2 are independently selected from hydrogen and C1-C8alkyl.
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, N(R a )2, N3, CN, and NO2, S(O)nR 3a , and halogen.
  • R 4 is OR a , N(R a )2, N3, CN, NO2, halogen, or S(O)nR 3a .
  • Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID X 2 is CH, X 1 is CR 11 , and R 11 is -CN.
  • R 5 is NR 7 R 8 .
  • R 5 is NH2.
  • R 5 is N 3 , NO, NO 2 , CHO, or CN.
  • anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging includes, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. 35 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0116]
  • pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), 36 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • suspensions e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions
  • compositions suitable for parenteral administration to a subject may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the RNA viral infection.
  • compositions are supplied either separately or mixed together in unit dosage form, in certain embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
  • parenteral dosage forms are provided.
  • Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. 37 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0124] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and poly
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein.
  • compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. In certain embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and 38 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to 39 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, in certain embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, TX
  • CAB O SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier can be administered to a host in need thereof to treat an RNA viral infection.
  • the method is for inhibiting an RNA viral infection.
  • the method is for relieving an RNA viral infection.
  • the method is for the prevention of an RNA viral infection.
  • RNA viral infections include Coronaviridae, Flaviviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Picornaviridae.
  • the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection, Middle Eastern respiratory syndrome (MERS) coronavirus infection, severe acute respiratory coronavirus-2 (SARS-CoV- 2) infection, or another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS Middle Eastern respiratory syndrome coronavirus
  • SARS-CoV- 2 severe acute respiratory coronavirus-2
  • WIV1 human coronavirus
  • the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection.
  • the Coronaviridae infection is Middle Eastern respiratory syndrome (MERS) coronavirus infection.
  • the Coronaviridae infection is severe acute respiratory coronavirus-2 (SARS- CoV-2) infection.
  • the SARS-CoV-2 viral infection is caused by a variant of SARS- CoV-2, for example an Alpha, Beta, Gamma, Delta, Epsilon, Eta, Iota, Kappa, Mu, Omicron, or Zeta variant.
  • the SARS-CoV-2 viral infection is caused an Alpha variant (Pango Lineage B.1.1.7).
  • the SARS-CoV-2 viral infection is caused a Beta variant (Pango lineages: B.1.351, B.1.351.2, B.1.351.3). In some embodiments, the SARS-CoV-2 viral infection is caused a Gamma variant (Pango Lineages: P.1, P.1.1, P.1.2). In some embodiments, the SARS-CoV-2 viral infection is caused an Epsilon variant (Pango Lineages: B.1.427, B.1.429). In some embodiments, the SARS-CoV-2 viral infection is caused an Eta variant (Pango Lineage: B.1.525). In some embodiments, the SARS-CoV-2 viral infection is caused an Iota variant (Pango Lineage: B.1.526).
  • the SARS- CoV-2 viral infection is caused a Kappa variant (Pango Lineage: B.1.617.1). In some embodiments, the SARS-CoV-2 viral infection is caused a Mu variant (Pango Lineages: B.1.621, B.1.621.1). In some embodiments, the SARS-CoV-2 viral infection is caused an Omicron variant (Pango Lineages: B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5). In some embodiments, the SARS-CoV-2 viral infection is caused a Zeta variant (Pango Lineages: P.2).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Flaviviridae virus infection.
  • Flaviviridae viral infections include, 41 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 but are not limited to, Dengue fever, Yellow fever, West Nile fever, Zika fever, Japanese encephalitis virus, and Hepatitis C (HCV).
  • the Flaviviridae viral infection is selected from dengue fever, yellow fever, West Nile fever, Zika fever, and Japanese encephalitis virus.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat an Orthomyxoviridae infection, for example, an influenza viral infection.
  • the Orthomyxoviridae infection is influenza type A, influenza type B, or influenza type C.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Paramyxoviridae viral infection.
  • Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and human parainfluenza viruses (HPIVs).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Filoviridae viral infection.
  • No.127531.00009 (4) NS5B non-substrate inhibitor; (5) Interferon alfa-2a, which may be pegylated or otherwise modified, and/or ribavirin; (6) Non-substrate-based inhibitor; (7) Helicase inhibitor; (8) Antisense oligodeoxynucleotide (S-ODN); (9) Aptamer; (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus; (13) Viral antigen or partial antigen that induces a host antibody response; or (14) Nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor.
  • S-ODN Antisense oligodeoxynucleotide
  • Aptamer (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus; (13) Vi
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier can be administered with a steroid.
  • COVID- 19-associated systemic inflammation and hypoxemic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein 44 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 (CRP), D-dimer, and ferritin. It is thought that modulating IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19.
  • patients can be administered an IL-6- targeting monoclonal antibody, pharmaceutical inhibitor, or protein degrader, such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with Olumiant (baricitinib) or Actemra (tocilizumab).
  • immunosuppressant drugs used to treat the overreacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and, IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolate (CellCept, Myfortic)).
  • Additional antibodies and biologies include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta)).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor.
  • NSAID nonsteroidal anti-inflammatory drug
  • Non-limiting examples of a protein 45 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 pump inhibitor include famotidine (Pepcid and Zantac), omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), and dexlansoprazole (Dexilant), zegerid (omeprazole with sodium bicarbonate).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen without a protein pump inhibitor.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically 46 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen with a protein pump inhibitor.
  • 47 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 EXAMPLES [0155] Example 1.
  • Step 1 To a solution of compound 1-1 (3.0 g, 5.38 mmol, 1.0 eq), compound 1-2 (3.5 g, 13.45 mmol, 2.5 eq), K 2 CO 3 (2.2 g, 16.14 mmol, 3.0 eq) and KI (3.1 g, 18.84 mmol, 3.5 eq) in acetonitrile (60 mL, 20 ⁇ M) under nitrogen was stirred at 55 °C for 48h. LCMS showed the 48 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 reaction was completed.
  • Step 2 A solution of compounds 1-3A and 1-3B (5.21 g) in water (120 mL, 25 mM) and acetic acid (25 mL, 5 mM) was stirred at 60 o C overnight. LC-MS showed the reaction was complete. Then the mixture was cooled and extracted with ethyl acetate (100 mL x 2).
  • Step 3 To a solution of compounds 1-4A and 1-4B (250 mg, 0.37 mmol, 1.0 eq) in DCM (10 mL, 40 mM) under N2 at -68 o C was added BCl3 (1.9 mL, 1.9 mmol, 5.0 eq) dropwise and the temperature was controlled under -60 o C.
  • the reaction was stirred at -50 o C for 5h.
  • the solution was quenched with anhydrous methanol (20 mL).
  • the reaction mixture was concentrated to afford a crude product which was purified by reverse phase prep-HPLC to afford two compounds.
  • the two compounds were tentatively assigned.
  • the first eluting peak is tentatively Compound 1 and the second eluting peak is tentatively Compound 2 or the first eluting peak is tentatively one of the ⁇ -anomer and ⁇ - anomer of Compound 1 and the second eluting peak is the other of the ⁇ -anomer and ⁇ -anomer of Compound 1.
  • Compound 1 27 mg, 18%) and Compound 2 (42 mg, 28%) were off-white solids.
  • Plasma samples were collected into pre-chilled collection tubes containing K2EDTA and processed to plasma at 9 timepoints over a span of pre-dose to 49 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 24 h post-administration. Plasma samples were subjected to protein precipitation with a 12.5- fold volume of methanol, vortexed and centrifuged. [0161] An aliquot of 10 ⁇ L plasma samples or 10 ⁇ L working solutions mixed with 10 ⁇ L 100% ACN (100 ng/mL internal standard working solution) and 170 ⁇ L precipitant (40% methanol/40% acetonitrile/20% isopropyl alcohol (v/v/v)) were dispensed into a 96-well plate.
  • PK parameters Cmax, AUC(0-24h), and F%) for GS-441524 following oral administration of GS- 441524, Compound 1, or Compound 2 is shown in Table 1 below.
  • Table 2 provides the C max for the remaining prodrug in plasma following administration of Compound 1 or Compound 2.
  • Table 1 Pharmacokinetic Parameters for GS-441524 in Plasma Following Administration of GS-441524, Compound 1, and Compound 2 to Balb/C Mice 50 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 a Based on prodrug dose b Based on GS-441524 dose Table 2.
  • the C max of GS-441524 following oral and intravenous administration of Compound 2 was 3,947 nM and 27,738 nM, respectively. This compares to a Cmax of 2,049 of GS-441524 following oral administration of GS-441524.
  • the AUC(0-24h) of GS-441524 following oral administration of Compound 2 was 13,018 nM ⁇ h, which is approximately 3-fold higher than the AUC(0-24h) of GS-441524 following GS-441524 oral administration.
  • Table 2 provides the PK parameters for Compound 1 and Compound 2 following administration of Compound 1 and Compound 2, respectively.
  • FIG. 1B is a graph measuring the concentration of GS-441524 following intravenous administration of Compound 2, and as shown in the figure, Compound 2 fully converts into GS-441524 after approximately 4 hours and only a trace of Compound 2 was observed after administration.
  • GS-441524 and its current prodrugs are poorly water- soluble molecules that require additional excipients to be dissolved in GI tract fluids at efficacious doses. Because of this, the size requirement for solid preparations of these lipophilic prodrugs could limit their dose or result in a high pill burden, which may in turn reduce their efficacy and/or ability to be formulated in drug combinations for future development programs.
  • a conventional tablet of Compound 1 or Compound 2 could potentially require less excipients and effectively reduce tablet size over GS-441524 and its lipophilic prodrugs for efficacious target coverage.
  • Compound 2 could enable greater clinical target coverage to allow for increased dose-range interrogation of the target as well as the use of highly tolerable parenteral administrations when oral treatment is not viable, for example is severely ill patients.
  • Compound 1 and Compound 2 are expected to be readily converted to GS-441524 by ubiquitously distributed alkaline phosphatase, Compound 1 and Compound 2 can potentially be dosed via multiple parenteral as well as nasal and intratracheal routes in addition to the oral dosing.
  • administration of an organic-aqueous-based formulation via the intravenous route is challenging in outpatients and necessitates the use of large volumes of intravenous fluid to ensure safe drug delivery.
  • the enhanced solubility of Compound 1 and Compound 2 will potentially require less intravenous fluid.
  • Compound 1 and Compound 2 may also be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route, potentially with minimal site reaction.
  • GS-441524 prodrug remdesivir which is administrated with sulfobutylether- ⁇ -cyclodextrin as vehicle.
  • Sulfobutylether- ⁇ -cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing 52 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 additional toxicity.
  • Example 2 demonstrates, after an intravenous administration in mice of a 14 mg/kg 100% aqueous solution of Compound 2, the pharmacokinetics of GS-441524 in plasma were comparable to those of an organic-aqueous-based formulation of GS-441524 as reported in Wang, A.Q. et al.

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Abstract

L'invention concerne des promédicaments d'hydroxydiméthylphosphate et des compositions pharmaceutiques de ceux-ci pour le traitement d'infections virales à ARN, comprenant, mais sans y être limitées, des infections virales à coronaviridae.
PCT/US2024/059655 2023-12-11 2024-12-11 Promédicaments de dihydrogénophosphate d'hydroxyméthyle de c-nucléosides Pending WO2025128749A1 (fr)

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WO2023168194A1 (fr) * 2022-03-03 2023-09-07 Gilead Sciences, Inc. Composés antiviraux et leurs procédés de fabrication et d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2023168194A1 (fr) * 2022-03-03 2023-09-07 Gilead Sciences, Inc. Composés antiviraux et leurs procédés de fabrication et d'utilisation

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