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WO2023183852A1 - Phosphonate prodrugs and use thereof - Google Patents

Phosphonate prodrugs and use thereof Download PDF

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Publication number
WO2023183852A1
WO2023183852A1 PCT/US2023/064827 US2023064827W WO2023183852A1 WO 2023183852 A1 WO2023183852 A1 WO 2023183852A1 US 2023064827 W US2023064827 W US 2023064827W WO 2023183852 A1 WO2023183852 A1 WO 2023183852A1
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Prior art keywords
compound
nanoparticle
alkyl
certain embodiments
acid
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PCT/US2023/064827
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French (fr)
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WO2023183852A9 (en
Inventor
Howard E. Gendelman
Benson EDAGWA
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Board Of Regents Of The University Of Nebraska
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Publication of WO2023183852A1 publication Critical patent/WO2023183852A1/en
Publication of WO2023183852A9 publication Critical patent/WO2023183852A9/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • 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
    • 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
    • C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • Nucleoside compounds and their prodrug derivatives play important roles in medical applications, particularly, for the treatment of viral infections and cancers.
  • tenofovir and tenofovir alafenamide have been effectively used for the treatment and prevention of human immunodeficiency virus (HIV) infections.
  • HIV human immunodeficiency virus
  • nucleoside compounds require host or viral kinase mediated conversion into their therapeutically active triphosphate forms prior to incorporation into elongating DNA or RNA, causing chain termination. Further, catalytic phosphorylation efficiency of synthetic nucleosides is slow and inefficient. Moreover, conventional nucleoside administrations have certain limitations such as variable drug pharmacokinetic profiles, short drug half-lives, poor physicochemical properties that have limited their transformation into long acting medicines, limited cellular and tissue penetration, and systemic toxicities.
  • a prodrug of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof wherein said prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof
  • R 1 is a nucleoside, nucleotide, or nucleobase, or analog thereof;
  • R 2 is optionally substituted aryl
  • R 3 is halo, OH, CN, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C3-5 cycloalkyl, or C3-5 heterocycloalkyl;
  • R 4 is the alkyl chain of a fatty acid
  • R a , R a , R b , and R b each, independently, are one of H, halo, and C1-5 alkyl;
  • nanoparticle comprising a compound described above, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant.
  • the polymer or surfactant typically is an amphiphilic block copolymer, which can comprise at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).
  • An exemplary polymer or surfactant is P407.
  • the nanoparticle described above can have a diameter in the range of about 100 nm to 1 pm.
  • a pharmaceutical composition comprising a compound provided above or a nanoparticle comprising such compound, and a pharmaceutically acceptable carrier.
  • Still another aspect of this invention is a method of treating a medical condition in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound or a nanoparticle or a pharmaceutical composition featured in this disclosure.
  • the medical condition is a cancer, a viral infection, or a clotting disorder.
  • the medical condition is a viral infection selected from the group consisting of an HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, SARS-CoV, or Ebola infection.
  • the compound or nanoparticle or pharmaceutical composition is administered via injection, which can be administered one time in a 1 to 12 month period or longer.
  • Figure 1 depicts the 1 H NMR spectroscopy of a compound of formula I.
  • Figure 2 depicts the 13 C NMR spectroscopy of a compound of formula I.
  • Figure 3 depicts the 31 P NMR spectroscopy of a compound of formula I.
  • Figure 4 depicts the human and rat plasma stabilities of a compound of formula I.
  • Figure 5 depicts the cell viability of a compound of formula I and its nanoparticles.
  • Figure 6 depicts the intracellular drug uptake of a compound of formula I.
  • the present disclosure provides phosphonate prodrugs of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, nanoparticles and pharmaceutical compositions comprising the same, and their use for treating medical conditions such as viral infections, cancers, and clotting disorders.
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and 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.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • composition or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration.
  • salts of compounds may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NWf, wherein W is Ci-4 alkyl, and the like.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium and calcium
  • salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, stearyl sulfate, tetradecyl sulfate, vitamin E (alpha tocopherol) succinate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , K + , Ca 2+ , NH4 + , and NW4 + (where W can be a Ci-4 alkyl group), and the like.
  • salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • emulsions e.g., such as an oil/water or water/oil emulsions
  • lactated Ringer lactated Ringer’s
  • sucrose normal glucose
  • binders fillers
  • disintegrants e.g., such as an oil/water or water/oil e
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a nonhuman animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • administering means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, transmucosal (e.g., buccal, sublingual, nasal, or transdermal) administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject.
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).
  • terapéuticaally effective amount means an amount of a composition (e.g., a composition described herein), or a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective for producing some desired therapeutic effect in a subject.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; F may be in any isotopic form, including 18 F and 19 F; and the like.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • Ci-6 alkyl is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, Ci-5, C1 ⁇ , C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 30 carbon atoms (“C1-30 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”).
  • an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
  • heteroalkyl refers to an “alkyl” group in which at least one carbon atom has been replaced with an O, S, or N atom.
  • the heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a Ci-Ce alkylene-OH group.
  • the “heteroalkyl” may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen).
  • the heteroalkyl is an “alkyl” group in which 1-3 carbon atoms have been replaced with oxygen atoms.
  • One type of heteroalkyl group is an “alkoxy” group.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-30 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to
  • C2-3 alkenyl 3 carbon atoms
  • an alkenyl group has 2 carbon atoms (“C2 alkenyl”).
  • the one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl).
  • Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
  • C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon triple bonds (e.g, 1, 2, 3, or
  • alkynyl does not contain any double bonds.
  • an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”).
  • an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl).
  • C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like.
  • Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”).
  • an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene.
  • Particularly aryl groups include pheny
  • cycloalkyl refers to a monovalent cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C3- scycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.
  • cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.
  • heterocyclyl refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • alkylene As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
  • Alkylene, “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.
  • heteroalkylene refers to a divalent radical of a heteroalkyl group. When a range or number of carbons is provided for a particular “heteroalkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Heteroalkylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • cycloalkylene refers to a divalent radical of a cycloalkyl, cycloalkenyl, and heterocycloalkyl group repsectively.
  • cycloalkylene When a range or number of carbons is provided for a particular “cycloalkylene,” “cycloalkenylene,” or “heterocycloalkylene” group, it is understood that the range or number refers to the range or number of carbons in the cyclyl carbon divalent radical, “cycloalkylene,” “cycloalkenylene,” or “heterocycloalkylene” group may be substituted or unsubstituted with one or more substituents as described herein.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • halo or ’’halogen refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).
  • the halo group is either fluoro or chloro.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms.
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • the present disclosure covers a prodrug of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, wherein said prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof:
  • R 1 is a nucleoside, nucleotide, or nucleobase, or analog thereof;
  • R 2 is optionally substituted aryl
  • R 3 is halo, OH, CN, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C3-5 cycloalkyl, or C3-5 heterocycloalkyl;
  • R 4 is the alkyl chain of a fatty acid
  • R a , R a , R b , and R b each, independently, are one of H, halo, and C1-5 alkyl;
  • nucleosides, nucleotides, nucleobases, and analogs thereof include, but are not limited to, abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), tenofovir alafenamide (TAF), tenofovir disoproxil fumarate, didanosine, vidarabine, BCX4430, cytarabine, gemcitabine, zalcitabine, acyclovir, valacyclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, islatravir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS- 441524, GS-331007, cidofovir, adefovir, adefovir dipivoxil, laninamivir,
  • the nucleoside, nucleotide, or nucleobase, or analog thereof is a nucleoside-analog reverse transcriptase inhibitor.
  • nucleoside- analog reverse transcriptase inhibitors include, without limitation, abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), telbivudine, entecavir, zidovudine, adefovir dipivoxil, adefovir, stavudine, didanosine, emtricitabine, and zalcitabine.
  • the nucleoside-analog reverse transcriptase inhibitor is selected from the group consisting of abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), telbivudine, entecavir, and zidovudine.
  • the nucleoside or analog thereof is selected from the group consisting of abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), and tenofovir (TFV).
  • the nucleoside or analog thereof is selected from the group consisting of islatravir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS- 441524, GS-331007.
  • the nucleoside or analog thereof refers to a radical of the nucleoside or analog thereof or a radical of the nucleoside or analog thereof without its sugar moiety.
  • the nucleotide or analog thereof refers to a radical of the nucleotide or analog thereof or a radical of the nucleotide or analog thereof without its sugar and one or more phosphate moieties.
  • variable R 1 based on a nucleoside, nucleotide, or nucleobase, or analog thereof include, but are not limited to, the following:
  • R 1 is:
  • the compound of formula I features that R 2 is phenyl, which is optionally substituted. In certain embodiments, R 2 is phenyl.
  • the compound of formula I features that each of R a , R a , R b , and R b is H; and m is 2. In certain embodiments, each of R a , R a , R b , and R b is H; and m is 1. In certain embodiments, each of R a , R a , R b , and R b is H; and m is 3.
  • the compound of formula I features that n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. [0077] In various embodiments, the compound of formula I features that each of R a , R a , R b , and R b is H; m is 2; and n is 0. In certain embodiments, each of R a , R a , R b , and R b is H; m is 1; and n is 0. In certain embodiments, each of R a , R a , R b , and R b is H; m is 3; and n is 0.
  • the compound of formula I features that p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • the compound of formula I features that each of R a , R a , R b , and R b is H; m is 2; and each of n and p is 0. In certain embodiments, each of R a , R a , R b , and R b is H; m is 1; and each of n and p is 0. In certain embodiments, each of R a , R a , R b , and R b is H; m is 3; and each of n and p is 0.
  • the compound of formula I features that R 4 is the aliphatic chain of a fatty acid.
  • fatty acids include, without limitation, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.
  • R 4 is the alkyl chain of a fatty acid. VW
  • the compound of formula I features that R 4 is 3 , w being an integer of 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In certain embodiments, R 4 is , w being an integer of 4-10. In certain embodiments, R 4 is , w being an JCH3 integer of 5-10. In certain embodiments, R 4 is , w being an integer of 6-10. In certain embodiments, R 4 is , w being an integer of 7-9.
  • R 4 is , w being 6.
  • An exemplary compound of formula I features that R 4 is , w being 7.
  • An exemplary compound of formula I features that R 4 , W being 8.
  • An exemplary compound of formula I features that R 4 is w being 9.
  • An J CH 3 exemplary compound of formula I features that R 4 is , w being 10.
  • Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 heterocycloalkylene comprising O, or a combination thereof, wherein L 1 is optionally substituted with one or more halo, Ci-4 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl,
  • Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 heterocycloalkylene comprising O, or a combination thereof.
  • the compound of formula I features that Li is
  • the compound of formula I has the following structure: pharmaceutically acceptable salt thereof.
  • the compounds of formula I described above can be synthesized from the corresponding nucleoside, nucleotide, or nucleobase, or analogs thereof following procedures known in the field.
  • a method of chemically synthesizing an exemplary compound of this invention can reference relevant protocols as described in WO 2019/140365 Al, which is incorporated by reference in its entirety.
  • the pharmaceutically acceptable salt of the compound of formula I can be a salt of the compound of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • physiologically compatible mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid
  • organic acids such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
  • the compounds of formula I may be formed into nanocrystals or other crystalline forms.
  • the compounds may be complexed with a hydrophobic counterion, including but not limited to pamoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, napsylate, mandelic acid, tosylate, benzenesulfonate, benzoate, besylate, hydroxynaphthoate and isothionates used to form a crystalline and/or solid salt compound forms.
  • the pharmaceutically acceptable salt can be characterized by a ratio of drug to counterion of 1 : 1 or 2: 1.
  • the compound salt can be crystalline or an amorphous solid.
  • a nanoparticle comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant.
  • the compound including any crystalline or solid salt form of the compound
  • the compound: polymer (or surfactant) ratio (by weight) is about 10: 1, about 10:6 to about 1000:6, about 20:6 to about 500:6, about 50:6 to about 200:6, or about 100:6.
  • the nanoparticles are a submicron colloidal dispersion of nanosized compound crystals or solid salt forms of the compound stabilized by polymers (or surfactants) (e.g. polymer-coated compound crystals; a nanoformulation).
  • the compound of the nanoparticles may be crystalline or a solid salt form complexed with a hydrophobic counterion.
  • the nanoparticles containing the compound are crystalline.
  • the nanoparticles and/or the compound may be crystalline, amorphous, or are solid-state nanoparticles of the compound that is formed as crystal that combines the compound and polymer (or surfactant).
  • the term “crystalline” refers to an ordered state (i.e. non-amorphous) and/or a substance exhibiting long- range order in three dimensions.
  • the majority e.g., at least 50%, 60%, 70%, 80%, 90%, 95% or more
  • the compound and, optionally the hydrophobic portion of the polymer (or surfactant) are crystalline or a solid salt form complexed with a hydrophobic counterion.
  • the resultant nanoparticle is up to about 2 or 3 pm in diameter (e.g., zaverage diameter) or its longest dimension, particularly up to about 1 pm (e.g., about 100 nm to about 1 pm).
  • the diameter or longest dimension of the nanoparticle may be about 50 to about 800 nm.
  • the diameter or longest dimension of the nanoparticle is about 50 to about 750 nm, about 50 to about 500 nm, about 200 nm to about 500 nm, or about 200 nm to about 400 nm.
  • the nanoparticles may be, for example, rod shaped, elongated rods, irregular, or round shaped.
  • the nanoparticles of the instant invention may be neutral or charged.
  • the nano particles may be charged positively or negatively.
  • the methods generate nanoparticles comprising a compound (e.g., crystalline or amorphous) coated (either partially or completely) with a polymer (or surfactant).
  • synthesis methods include, without limitation, milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques.
  • milling e.g., wet milling
  • homogenization e.g., high pressure homogenization
  • PRINT nonwetting template
  • U.S. Patent Application Publication No. 2013/0236553 incorporated by reference herein, provides methods suitable for synthesizing nanoparticles of the instant invention.
  • the polymers (or surfactants) are firstly chemically modified with targeting ligands and then used directly or mixed with non-targeted polymers (or surfactants) in certain molar ratios to coat on the surface of drug suspensions - e.g., by using a nanoparticle synthesis process (e.g., a crystalline nanoparticle synthesis process) such as milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques, thereby preparing targeted nanoformulations.
  • the nanoparticles may be used with or without further purification, although the avoidance of further purification is desirable for quicker production of the nano particles.
  • the nanoparticles are synthesized using milling and/or homogenization.
  • the nanoparticles are synthesized by adding the compound to a polymer (or surfactant) (described below) solution and then generating the nanoparticles (e.g., by wet milling or high pressure homogenization).
  • the compound and polymer (or surfactant) solution may be agitated prior to wet milling or high pressure homogenization to form nanoparticles.
  • polymers include, without limitation, synthetic or natural phospholipids, PEGylated lipids (e.g., PEGylated phospholipid), lipid derivatives, polysorbates, amphiphilic copolymers, amphiphilic block copolymers, polyethylene glycol)-co-poly(lactide- co-glycolide) (PEG-PLGA), their derivatives, ligand-conjugated derivatives and combinations thereof.
  • PEG-PLGA polyethylene glycol)-co-poly(lactide- co-glycolide)
  • Other surfactants and their combinations that can form stable nanosuspensions and/or can chemically/physically bind to the targeting ligands of HIV infectable/infected CD4+ T cells, macrophages and dendritic cells can be used in the instant invention.
  • surfactants include, without limitation: 1) nonionic surfactants (e.g., pegylated and/or polysaccharide-conjugated polyesters and other hydrophobic polymeric blocks such as poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), other polyesters, polypropylene oxide), poly(l,2-butylene oxide), poly(n-butylene oxide), poly(tetrahydrofurane), and poly(styrene); glyceryl esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropyleneglycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, poloxamine
  • the polymer (or surfactant) of the instant invention may be charged or neutral.
  • the polymer (or surfactant) is neutral or negatively charged (e.g., poloxamers, polysorbates, phospholipids, and their derivatives).
  • the polymer (or surfactant) is an amphiphilic block copolymer or lipid derivative.
  • at least one polymer (or surfactant) of the nanoparticle is an amphiphilic block copolymer, particularly a copolymer comprising at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene).
  • the polymer (or surfactant) is a triblock amphiphilic block copolymer.
  • the polymer (or surfactant) is a triblock amphiphilic block copolymer comprising a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol.
  • amphiphilic block copolymer is a copolymer comprising at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).
  • poloxamers include, without limitation, Pluronic® L31, L35, F38, L42, L43, L44, L61, L62, L63, L64, P65, F68, L72, P75, F77, L81, P84, P85, F87, F88, L92, F98, L101, P1O3, P104, PIOS, F1O8, L121, L122, L123, F127,10RS, 1OR8, 12R3,17R1,17R2,17R4, 17R8,22R4,25R1,25R2,2SR4,25RS,2SR8,31R1, 31R2, and 31R4.
  • the polymer (or surfactant) is poloxamer 407 (Pluronic® F127).
  • the polymer (or surfactant) is present in the nano particle and/or surfactant solution to synthesize the nanoparticle (as described hereinabove) at a concentration ranging from about 0.0001% to about 10% or 15% by weight.
  • the concentration of the polymer (or surfactant) ranges from about 0.01% to about 15%, about 0.01% to about 10%, or about 0.1% to about 6% by weight.
  • the nanoparticle comprises at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or higher therapeutic agent by weight.
  • the compounds and nanoformulations thereof of the present invention may be used for the treatment and or prevention of drug and alcohol addiction, drug abuse, abstinence or overdose.
  • the compounds and/or nanoformulations thereof are used for the treatment of opioid use disorders such as opioid dependence/addiction.
  • the compounds and nanoformulations thereof of the present invention can also be used for treating diseases/disorders not related to drug addiction including but not limited to cancer, pain ⁇ including chronic pain, degenerative pain, inflammatory pain, visceral pain, neuropathic pain or trauma-related (broken bones, dental, bums, surgery) pain, fibromyalgia, arthritis and obesity.
  • the compounds may also be packaged with additional drugs or compounds into nanoparticles (or nanoformulations) or co-administered with other drugs.
  • a pharmaceutical composition comprising a compound of formula I or a nanoparticle comprising the same, and a pharmaceutically acceptable carrier.
  • the compounds and nanoformulations of the present invention may be conveniently formulated for administration with any pharmaceutically acceptable carrier(s).
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • oral (enteral) administration parenteral (by injection) administration
  • rectal administration transdermal administration
  • intradermal administration intrathecal administration
  • SC subcutaneous
  • IV intravenous
  • IM intramuscular
  • intranasal administration intranasal administration.
  • the pharmaceutical compositions disclosed herein are administered orally.
  • the pharmaceutical compositions disclosed herein are administered via injection, microarray patch or implantable device.
  • the pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life.
  • the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the pharmaceutical dosage forms described herein can be administered as a unit dose.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • compositions provided herein comprise the compound of formula I as the sole active agent, or in combination with other active agents.
  • compositions suitable for administration to humans are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005. Methods of Use and Treatment
  • kits for preventing, inhibiting, and/or treating a medical condition comprise administering a compound and/or nanoparticle and/or pharmaceutical composition of the instant invention to a subject (e.g., a human) in need thereof.
  • the medical condition is a microbial (e.g., viral) infection, cancer, or a blood clotting disorder (e.g., the compound or nanoparticle of the invention can be used as an antiplatelet drug to inhibit or prevent formation of a blood clot).
  • Microbial infections include, without limitation, viral, bacterial, fungal, mycobacterial and parasitic infections.
  • the disease or disorder is a viral infection. Examples of viral infections include, without limitation: HIV, Hepatitis B, Hepatitis C, Influenza A, Influenza B, Ebola, and Herpes Simplex.
  • the viral infection is a retroviral or lentiviral infection, particularly an HIV infection (e.g., HIV-1).
  • the cancer includes, but is not limited to, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia), lymphoma (e.g., Hodgkin lymphoma, Non-Hodgkin lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers (e.g., gliomas, meningiomas, and pituitary adenomas), lung cancer, ovarian cancer, stomach cancer, skin cancer (e.g., melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.
  • leukemia e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia
  • lymphoma
  • the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 2 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 3 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 4 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 5 month period.
  • the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 6 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 7 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 8 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 9 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 10 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 11 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 12 month period.
  • the compounds and/or nanoparticles and/or pharmaceutical composition of the instant invention can be administered to an animal, in particular a mammal, more particularly a human, in order to treat/inhibit/prevent the disease or disorder (e.g., an HIV infection).
  • the pharmaceutical compositions of the instant invention may also comprise at least one other therapeutic agent such as an antiviral agent, particularly at least one other anti-HIV compound/agent.
  • the additional anti-HIV compound may also be administered in a separate pharmaceutical composition from the compounds or compositions of the instant invention.
  • the pharmaceutical compositions may be administered at the same time or at different times (e.g., sequentially).
  • the dosage ranges for the administration of the compounds, nanoparticles, and/or compositions of the invention are those large enough to produce the desired effect (e.g., curing, relieving, treating, and/or preventing the disease or disorder (e.g., HIV infection), the symptoms of it (e.g., AIDS, ARC), or the predisposition towards it).
  • the pharmaceutical composition of the instant invention is administered to the subject at an amount from about 5 pg/kg to about 500 mg/kg.
  • the pharmaceutical composition of the instant invention is administered to the subject at an amount greater than about 5 pg/kg, greater than about 50 pg/kg, greater than about 0.1 mg/kg, greater than about 0.5 mg/kg, greater than about 1 mg/kg, or greater than about 5 mg/kg.
  • the pharmaceutical composition of the instant invention is administered to the subject at an amount from about 0.5 mg/kg to about 100 mg/kg, about 10 mg/kg to about 100 mg/kg, or about 15 mg/kg to about 50 mg/kg.
  • the dosage should not be so large as to cause significant adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • administering a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof comprises administering a composition having an amount of the compound as described herein, supra.
  • the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, as the sole active agent.
  • the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with another active agent (e.g., an antiviral agent or an anticancer agent).
  • another active agent e.g., an antiviral agent or an anticancer agent.
  • M4TFV product
  • Successful synthesis of the compounds was confirmed by ’H, 13 C, and 31 P NMR spectroscopy using a Bruker Avance-III HD operating at 500 MHz and a magnetic field strength of 11.7 T. See Figures 1-3.
  • Example 2 Nanoparticles Comprising a Compound of Formula I
  • Nanocrystals of M4TFV (“NM4TFV”) were manufactured by high-pressure homogenization in aqueous buffers stabilized by non-ionic surfactants. Specifically, M4TFV was dispersed in a P407 or Tween 20/ PEG 3350 solution in lOmM HEPES pH 5.5 and allowed to form a presuspension. The compound to P407 to PEG 3350 ratio was maintained at 2: ’A: ’A (w/w), and the suspension concentration was in the range 0.1-10% w/v for the drug/prodrug and 0.025-2.5% w/v for P407or Tween 20/PEG.
  • the presuspensions were homogenized on an Avestin EmulsiFlex-C3 high-pressure homogenizer at 15,000- 20,000 psi until the desired particle size of 250-350 nm was achieved.
  • Nanoparticles were characterized for particle size, PDI and zeta potential by dynamic light scattering using a Malvern Zetasizer Nano-ZS.
  • MTT assay Cell viability after treatment with M4TFV or compound nanoparticles (NM4TFV) was evaluated by MTT assay. Briefly, human monocyte derived macrophages (MDM) cultured on 96-well plates at a density of 0.08 * 10 6 cells per well were treated with various concentrations (0.2- 500 pM) of M4TFV or NMTFV formulations for 8 h. After drug treatment, cells were washed and incubated with 100 pL/well of MTT solution (5 mg/mL) for 45 min at 37 °C. After incubation MTT was removed, and 200 pL/well of DMSO was added and mixed thoroughly.
  • MDM human monocyte derived macrophages

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Abstract

Provided herein are prodrugs of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, wherein said prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof: (I). Further disclosed are nanoparticles comprising one of the compounds and methods of using the same for treating a medical condition, e.g., HIV infection.

Description

PHOSPHONATE PRODRUGS AND USE THEREOF
CROSS REFERENCE
[001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/269,831, filed March 23, 2022, the disclosure of which is incorporated by reference herein in its entirety.
STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
[002] This invention was made with government support under Grant Nos. DA028555, AG043540, NS034239, NS036126, MH064570, NS043985, and MH062261 awarded by the National Institutes of Health. The government has certain rights in this invention.
BACKGROUND
[003] Nucleoside compounds and their prodrug derivatives play important roles in medical applications, particularly, for the treatment of viral infections and cancers. For example, tenofovir and tenofovir alafenamide have been effectively used for the treatment and prevention of human immunodeficiency virus (HIV) infections.
[004] There are several issues associated with the use of nucleoside compounds. They require host or viral kinase mediated conversion into their therapeutically active triphosphate forms prior to incorporation into elongating DNA or RNA, causing chain termination. Further, catalytic phosphorylation efficiency of synthetic nucleosides is slow and inefficient. Moreover, conventional nucleoside administrations have certain limitations such as variable drug pharmacokinetic profiles, short drug half-lives, poor physicochemical properties that have limited their transformation into long acting medicines, limited cellular and tissue penetration, and systemic toxicities.
[005] Therefore, there is a high medical need to develop new drug delivery systems that improve intracellular delivery of pre-activated nucleosides.
SUMMARY
[006] In one aspect, provided herein is a prodrug of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, wherein said prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof
Figure imgf000004_0001
(I), wherein
R1 is a nucleoside, nucleotide, or nucleobase, or analog thereof;
R2 is optionally substituted aryl;
R3 is halo, OH, CN, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C3-5 cycloalkyl, or C3-5 heterocycloalkyl;
R4 is the alkyl chain of a fatty acid;
Ra, Ra , Rb, and Rb each, independently, are one of H, halo, and C1-5 alkyl;
Li is C1-5 alkylene, C1-5 heteroalkylene, C3-5 cycloalkylene, C3-5 cycloalkenylene, C3-5 heterocycloalkylene, or a combination thereof, wherein L1 is optionally substituted with one or more halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, or =CH2;
L2 is -(C=O)-X- or -X-(C=O)-, in which X is O, NRN, or S, RN being H or alkyl; and m, n, and p each, independently, are integers of 0-3.
[007] In another aspect, provided herein is a nanoparticle, comprising a compound described above, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant.
[008] The polymer or surfactant typically is an amphiphilic block copolymer, which can comprise at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene). An exemplary polymer or surfactant is P407.
[009] The nanoparticle described above can have a diameter in the range of about 100 nm to 1 pm.
[0010] In a further aspect, provided herein is a pharmaceutical composition, comprising a compound provided above or a nanoparticle comprising such compound, and a pharmaceutically acceptable carrier.
[0011] Still another aspect of this invention is a method of treating a medical condition in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound or a nanoparticle or a pharmaceutical composition featured in this disclosure. [0012] In various embodiments, the medical condition is a cancer, a viral infection, or a clotting disorder. In certain embodiments, the medical condition is a viral infection selected from the group consisting of an HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, SARS-CoV, or Ebola infection.
[0013] In certain embodiments, the compound or nanoparticle or pharmaceutical composition is administered via injection, which can be administered one time in a 1 to 12 month period or longer.
[0014] The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the drawings, description and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 depicts the 1 H NMR spectroscopy of a compound of formula I.
[0016] Figure 2 depicts the 13C NMR spectroscopy of a compound of formula I.
[0017] Figure 3 depicts the 31P NMR spectroscopy of a compound of formula I.
[0018] Figure 4 depicts the human and rat plasma stabilities of a compound of formula I.
[0019] Figure 5 depicts the cell viability of a compound of formula I and its nanoparticles.
[0020] Figure 6 depicts the intracellular drug uptake of a compound of formula I.
DETAILED DESCRIPTION
[0021] As generally described herein, the present disclosure provides phosphonate prodrugs of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, nanoparticles and pharmaceutical compositions comprising the same, and their use for treating medical conditions such as viral infections, cancers, and clotting disorders.
Definitions
[0022] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.
[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
[0024] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
[0025] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from the group consisting of two or more of the recited elements or components.
[0026] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.
[0027] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.
[0028] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.
[0029] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.
[0030] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. [0031] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context. For example, the term “about 10 mg” means 10 mg with a ±10% variation from 10 mg, i.e., an amount in the range of 9 mg to 11 mg.
[0032] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, 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, and 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.
[0033] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.
[0034] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
[0035] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient or a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
[0036] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0037] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration.
[0038] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.
[0039] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NWf, wherein W is Ci-4 alkyl, and the like.
[0040] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, stearyl sulfate, tetradecyl sulfate, vitamin E (alpha tocopherol) succinate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, xinafoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, K+, Ca2+, NH4+, and NW4+ (where W can be a Ci-4 alkyl group), and the like.
[0041] For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
[0042] As used herein, “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).
[0043] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a nonhuman animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.
[0044] As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, transmucosal (e.g., buccal, sublingual, nasal, or transdermal) administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
[0045] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).
[0046] The phrase "therapeutically effective amount" as used herein means an amount of a composition (e.g., a composition described herein), or a compound of formula I, or a pharmaceutically acceptable salt thereof, which is effective for producing some desired therapeutic effect in a subject.
[0047] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc. , New Y ork, 2001 ; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.
[0048] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
[0049] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
[0050] In the compounds provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.
[0051] Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D or deuterium), and 3H (T or tritium); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; F may be in any isotopic form, including 18F and 19F; and the like. [0052] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure. When describing the disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.
[0053] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-6, Ci-5, C1^, C1-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[0054] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 30 carbon atoms (“C1-30 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“Ci-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.
[0055] The term “heteroalkyl” as used herein refers to an “alkyl” group in which at least one carbon atom has been replaced with an O, S, or N atom. The heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a Ci-Ce alkylene-OH group. In certain embodiments, the “heteroalkyl” may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen). In certain embodiments, the heteroalkyl is an “alkyl” group in which 1-3 carbon atoms have been replaced with oxygen atoms. One type of heteroalkyl group is an “alkoxy” group.
[0056] As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-30 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to
3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.
[0057] As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 30 carbon atoms, one or more carbon-carbon triple bonds (e.g, 1, 2, 3, or
4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g, 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-30 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like.
[0058] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl .
[0059] The term “cycloalkyl” refers to a monovalent cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C3- scycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted.
[0060] As used herein, “heterocyclyl,” “heterocycloalkyl,” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
[0061] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0062] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.
“Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein. [0063] As used herein, “heteroalkylene” refers to a divalent radical of a heteroalkyl group. When a range or number of carbons is provided for a particular “heteroalkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Heteroalkylene” group may be substituted or unsubstituted with one or more substituents as described herein.
[0064] As used herein, “cycloalkylene,” “cycloalkenylene,” and “heterocycloalkylene” refer to a divalent radical of a cycloalkyl, cycloalkenyl, and heterocycloalkyl group repsectively. When a range or number of carbons is provided for a particular “cycloalkylene,” “cycloalkenylene,” or “heterocycloalkylene” group, it is understood that the range or number refers to the range or number of carbons in the cyclyl carbon divalent radical, “cycloalkylene,” “cycloalkenylene,” or “heterocycloalkylene” group may be substituted or unsubstituted with one or more substituents as described herein.
[0065] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
[0066] As used herein, “halo” or ’’halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.
[0067] As used herein, “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.
[0068] In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
Compounds [0069] Disclosed herein, in certain embodiments, are compounds of formula I that provide improved formulation solubility (e.g., in an aqueous solution), stability, and processability of nucleosides, nucleotides, and nucleobases, and analogs thereof.
[0070] As set forth in the SUMMARY section above, the present disclosure covers a prodrug of a nucleoside, a nucleotide, or a nucleobase, or an analog thereof, wherein said prodrug is a compound of formula I, or a pharmaceutically acceptable salt thereof:
Figure imgf000017_0001
(I), wherein
R1 is a nucleoside, nucleotide, or nucleobase, or analog thereof;
R2 is optionally substituted aryl;
R3 is halo, OH, CN, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C3-5 cycloalkyl, or C3-5 heterocycloalkyl;
R4 is the alkyl chain of a fatty acid;
Ra, Ra , Rb, and Rb each, independently, are one of H, halo, and C1-5 alkyl;
Li is C1-5 alkylene, C1-5 heteroalkylene, C3-5 cycloalkylene, C3-5 cycloalkenylene, C3-5 heterocycloalkylene, or a combination thereof, wherein L1 is optionally substituted with one or more halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, or =CH2;
L2 is -(C=O)-X- or -X-(C=O)-, in which X is O, NRN, or S, RN being H or alkyl; and m, n, and p each, independently, are integers of 0-3.
[0071] Examples of nucleosides, nucleotides, nucleobases, and analogs thereof include, but are not limited to, abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), tenofovir alafenamide (TAF), tenofovir disoproxil fumarate, didanosine, vidarabine, BCX4430, cytarabine, gemcitabine, zalcitabine, acyclovir, valacyclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, islatravir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS- 441524, GS-331007, cidofovir, adefovir, adefovir dipivoxil, laninamivir, stavudine, telbivudine, zidovudine, idoxuridine, trifluridine, ticagrelor, cangrelor, 5 -fluorouracil (5-FU), 5-bromo-2- deoxy-uridine, capecitabine, cladribine, capecitabine, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), and fludarabine. In certain embodiments, the nucleoside, nucleotide, or nucleobase, or analog thereof is a nucleoside-analog reverse transcriptase inhibitor. Examples of nucleoside- analog reverse transcriptase inhibitors include, without limitation, abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), telbivudine, entecavir, zidovudine, adefovir dipivoxil, adefovir, stavudine, didanosine, emtricitabine, and zalcitabine. In certain embodiments, the nucleoside-analog reverse transcriptase inhibitor is selected from the group consisting of abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV), telbivudine, entecavir, and zidovudine. In certain embodiments, the nucleoside or analog thereof is selected from the group consisting of abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), and tenofovir (TFV). In certain embodiments, the nucleoside or analog thereof is selected from the group consisting of islatravir, remdesivir, ribavirin, entecavir, sofosbuvir, brivudine, GS- 441524, GS-331007. Referring to formula I, in certain embodiments, the nucleoside or analog thereof refers to a radical of the nucleoside or analog thereof or a radical of the nucleoside or analog thereof without its sugar moiety. Referring to formula I, in certain embodiments, the nucleotide or analog thereof refers to a radical of the nucleotide or analog thereof or a radical of the nucleotide or analog thereof without its sugar and one or more phosphate moieties.
[0072] Referring back to formula I, examples of variable R1 based on a nucleoside, nucleotide, or nucleobase, or analog thereof include, but are not limited to, the following:
Figure imgf000018_0001
Figure imgf000019_0001
[0073] In certain embodiments, R1 is:
Figure imgf000019_0002
[0074] In various embodiments, the compound of formula I features that R2 is phenyl, which is optionally substituted. In certain embodiments, R2 is phenyl.
[0075] In various embodiments, the compound of formula I features that each of Ra, Ra , Rb, and Rb is H; and m is 2. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; and m is 1. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; and m is 3.
[0076] In various embodiments, the compound of formula I features that n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. [0077] In various embodiments, the compound of formula I features that each of Ra, Ra , Rb, and Rb is H; m is 2; and n is 0. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; m is 1; and n is 0. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; m is 3; and n is 0.
[0078] In various embodiments, the compound of formula I features that p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
[0079] In various embodiments, the compound of formula I features that each of Ra, Ra , Rb, and Rb is H; m is 2; and each of n and p is 0. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; m is 1; and each of n and p is 0. In certain embodiments, each of Ra, Ra , Rb, and Rb is H; m is 3; and each of n and p is 0.
[0080] In various embodiments, the compound of formula I features that R4 is the aliphatic chain of a fatty acid. Examples of fatty acids include, without limitation, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid. In certain embodiments, R4 is the alkyl chain of a fatty acid. VW
[0081] In various embodiments, the compound of formula I features that R4 is 3 , w being an integer of 2-10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In certain embodiments, R4 is
Figure imgf000020_0001
, w being an integer of 4-10. In certain embodiments, R4 is
Figure imgf000020_0002
, w being an JCH3 integer of 5-10. In certain embodiments, R4 is , w being an integer of 6-10. In certain embodiments, R4 is
Figure imgf000020_0003
, w being an integer of 7-9. An exemplary compound of formula
I features that R4 is
Figure imgf000020_0004
, w being 5. An exemplary compound of formula I features that
R4 is
Figure imgf000020_0005
, w being 6. An exemplary compound of formula I features that R4 is
Figure imgf000020_0006
, w being 7. An exemplary compound of formula I features that R4
Figure imgf000020_0007
, W being 8. An exemplary compound of formula I features that R4 is
Figure imgf000020_0008
w being 9. An JCH3 exemplary compound of formula I features that R4 is , w being 10. [0082] In various embodiments, the compound of formula I features that Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 cycloalkylene, C3-5 heterocycloalkylene comprising O, or a combination thereof, wherein L1 is optionally substituted with one or more halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, or =CH2. In certain embodiments, Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 heterocycloalkylene comprising O, or a combination thereof, wherein L1 is optionally substituted with one or more halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl,
OH, CN, or =CH2.
[0083] In various embodiments, the compound of formula I features that Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C5 cycloalkylene, C3-4 heterocycloalkylene comprising O, or a combination thereof, wherein L1 is optionally substituted with one, two, or three substituents selected from halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, and =CH2. In certain embodiments, Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-4 heterocycloalkylene comprising O, or a combination thereof, wherein L1 is optionally substituted with one, two, or three substituents selected from halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, and =CH2. [0084] In certain embodiments, Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 heterocycloalkylene comprising O, or a combination thereof.
[0085] In certain embodiments, the compound of formula I features that Li is
Figure imgf000021_0001
Figure imgf000021_0002
[0086] In various embodiments, the compound of formula I features that L2 is -X-(C=O)-, in which X is O or NH.
[0087] In various embodiments, the compound of formula I has the following structure:
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
pharmaceutically acceptable salt thereof.
[0088] The compounds of formula I described above can be synthesized from the corresponding nucleoside, nucleotide, or nucleobase, or analogs thereof following procedures known in the field. For example, a method of chemically synthesizing an exemplary compound of this invention can reference relevant protocols as described in WO 2019/140365 Al, which is incorporated by reference in its entirety.
[0089] In various embodiments, the pharmaceutically acceptable salt of the compound of formula I can be a salt of the compound of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids, such as methanesulphonic acid, p-toluenesulphonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.
[0090] It is further envisioned that the compounds of formula I may be formed into nanocrystals or other crystalline forms. In certain embodiments, the compounds may be complexed with a hydrophobic counterion, including but not limited to pamoic acid, myristic acid, palmitic acid, stearic acid, behenic acid, napsylate, mandelic acid, tosylate, benzenesulfonate, benzoate, besylate, hydroxynaphthoate and isothionates used to form a crystalline and/or solid salt compound forms.
[0091] The pharmaceutically acceptable salt can be characterized by a ratio of drug to counterion of 1 : 1 or 2: 1. The compound salt can be crystalline or an amorphous solid.
Nanoparticles
[0092] In one aspect, provided herein is a nanoparticle, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant. Typically, the compound (including any crystalline or solid salt form of the compound) maybe encapsulated by a polymer or surfactant coating to form nanoparticles (or nanoformulations). [0093] In certain embodiments, the compound: polymer (or surfactant) ratio (by weight) is about 10: 1, about 10:6 to about 1000:6, about 20:6 to about 500:6, about 50:6 to about 200:6, or about 100:6.
[0094] In a particular embodiment, the nanoparticles are a submicron colloidal dispersion of nanosized compound crystals or solid salt forms of the compound stabilized by polymers (or surfactants) (e.g. polymer-coated compound crystals; a nanoformulation). In a particular embodiment, the compound of the nanoparticles may be crystalline or a solid salt form complexed with a hydrophobic counterion. In certain embodiments, the nanoparticles containing the compound are crystalline. In certain embodiments, the nanoparticles and/or the compound may be crystalline, amorphous, or are solid-state nanoparticles of the compound that is formed as crystal that combines the compound and polymer (or surfactant). As used herein, the term “crystalline” refers to an ordered state (i.e. non-amorphous) and/or a substance exhibiting long- range order in three dimensions. In a particular embodiment, the majority (e.g., at least 50%, 60%, 70%, 80%, 90%, 95% or more) of the compound (and, optionally the hydrophobic portion of the polymer (or surfactant) are crystalline or a solid salt form complexed with a hydrophobic counterion.
[0095] In certain embodiments, the resultant nanoparticle is up to about 2 or 3 pm in diameter (e.g., zaverage diameter) or its longest dimension, particularly up to about 1 pm (e.g., about 100 nm to about 1 pm). For example, the diameter or longest dimension of the nanoparticle may be about 50 to about 800 nm. In a particular embodiment, the diameter or longest dimension of the nanoparticle is about 50 to about 750 nm, about 50 to about 500 nm, about 200 nm to about 500 nm, or about 200 nm to about 400 nm. The nanoparticles may be, for example, rod shaped, elongated rods, irregular, or round shaped. The nanoparticles of the instant invention may be neutral or charged. The nano particles may be charged positively or negatively.
[0096] Methods of synthesizing the nanoparticles of the instant invention are known in the art. In certain embodiment, the methods generate nanoparticles comprising a compound (e.g., crystalline or amorphous) coated (either partially or completely) with a polymer (or surfactant). Examples of synthesis methods include, without limitation, milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques. For example, U.S. Patent Application Publication No. 2013/0236553, incorporated by reference herein, provides methods suitable for synthesizing nanoparticles of the instant invention. In a particular embodiment, the polymers (or surfactants) are firstly chemically modified with targeting ligands and then used directly or mixed with non-targeted polymers (or surfactants) in certain molar ratios to coat on the surface of drug suspensions - e.g., by using a nanoparticle synthesis process (e.g., a crystalline nanoparticle synthesis process) such as milling (e.g., wet milling), homogenization (e.g., high pressure homogenization), particle replication in nonwetting template (PRINT) technology, and/or sonication techniques, thereby preparing targeted nanoformulations. The nanoparticles may be used with or without further purification, although the avoidance of further purification is desirable for quicker production of the nano particles. In a particular embodiment, the nanoparticles are synthesized using milling and/or homogenization.
[0097] In a particular embodiment, the nanoparticles are synthesized by adding the compound to a polymer (or surfactant) (described below) solution and then generating the nanoparticles (e.g., by wet milling or high pressure homogenization). The compound and polymer (or surfactant) solution may be agitated prior to wet milling or high pressure homogenization to form nanoparticles.
[0098] Examples of polymers (or surfactants) include, without limitation, synthetic or natural phospholipids, PEGylated lipids (e.g., PEGylated phospholipid), lipid derivatives, polysorbates, amphiphilic copolymers, amphiphilic block copolymers, polyethylene glycol)-co-poly(lactide- co-glycolide) (PEG-PLGA), their derivatives, ligand-conjugated derivatives and combinations thereof. Other surfactants and their combinations that can form stable nanosuspensions and/or can chemically/physically bind to the targeting ligands of HIV infectable/infected CD4+ T cells, macrophages and dendritic cells can be used in the instant invention. Further examples of surfactants include, without limitation: 1) nonionic surfactants (e.g., pegylated and/or polysaccharide-conjugated polyesters and other hydrophobic polymeric blocks such as poly(lactide-co-glycolide) (PLGA), polylactic acid (PLA), polycaprolactone (PCL), other polyesters, polypropylene oxide), poly(l,2-butylene oxide), poly(n-butylene oxide), poly(tetrahydrofurane), and poly(styrene); glyceryl esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, polypropyleneglycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers, poloxamines, cellulose, methylcellulose, hydroxylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polysaccharides, starch and their derivatives, hydroxy ethyl starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone, and their combination thereof); and 2) ionic surfactants (e.g., phospholipids, amphiphilic lipids, 1,2- dialkylglycero-3-alkylphophocholines, 1, 2- distearoyl-snglecro-3-phosphocholine (DSPC), 1,2- distearoyl-sn-glycero-3- phosphoethanolamine-N[carboxy(polyethylene glycol) (DSPE-PEG), dimethylaminoethanecarbamoyl cholesterol (DC-Chol), N-[l-(2,3-Dioleoyloxy)propyl]-N,N,N- trimethylammonium (DOTAP), alkyl pyridinium halides, quaternary ammonium compounds, lauryldimethylbenzylammonium, acyl carnitine hydrochlorides, dimethyldioctadecylammonium (DDAB), n-octylamines, oleylamines, benzalkonium, cetyltrimethylammonium, chitosan, chitosan salts, poly(ethylenimine) (PEI), poly(N-isopropyl acrylamide(PNIPAM), and poly(allylamine) (PAH), poly (dimethyldiallylammonium chloride) (PDDA), alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecyl sulfate, alkyl polyoxyethylene sulfates, alginic acid, alginic acid salts, hyaluronic acid, hyaluronic acid salts, gelatins, dioctyl sodium sulfosuccinate, sodium carboxymethylcellulose, cellulose sulfate, dextran sulfate and carboxymethylcellulose, chondroitin sulfate, heparin, synthetic poly(acrylic acid) (PAA), poly (methacrylic acid) (PMA), poly(vinyl sulfate) (PVS), poly(styrene sulfonate) (PSS), bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, derivatives thereof, and combinations thereof).
[0099] The polymer (or surfactant) of the instant invention may be charged or neutral. In a particular embodiment, the polymer (or surfactant) is neutral or negatively charged (e.g., poloxamers, polysorbates, phospholipids, and their derivatives).
[00100] In a particular embodiment, the polymer (or surfactant) is an amphiphilic block copolymer or lipid derivative. In a particular, embodiment, at least one polymer (or surfactant) of the nanoparticle is an amphiphilic block copolymer, particularly a copolymer comprising at least one block of poly(oxyethylene) and at least one block of poly(oxypropylene). In a particular embodiment, the polymer (or surfactant) is a triblock amphiphilic block copolymer. In a particular embodiment, the polymer (or surfactant) is a triblock amphiphilic block copolymer comprising a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol.
[00101] In a particular embodiment, the amphiphilic block copolymer is a copolymer comprising at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).
[00102] Examples of poloxamers include, without limitation, Pluronic® L31, L35, F38, L42, L43, L44, L61, L62, L63, L64, P65, F68, L72, P75, F77, L81, P84, P85, F87, F88, L92, F98, L101, P1O3, P104, PIOS, F1O8, L121, L122, L123, F127,10RS, 1OR8, 12R3,17R1,17R2,17R4, 17R8,22R4,25R1,25R2,2SR4,25RS,2SR8,31R1, 31R2, and 31R4.
[00103] In a particular embodiment, the polymer (or surfactant) is poloxamer 407 (Pluronic® F127).
[00104] In a particular embodiment of the invention, the polymer (or surfactant) is present in the nano particle and/or surfactant solution to synthesize the nanoparticle (as described hereinabove) at a concentration ranging from about 0.0001% to about 10% or 15% by weight. In a particular embodiment, the concentration of the polymer (or surfactant) ranges from about 0.01% to about 15%, about 0.01% to about 10%, or about 0.1% to about 6% by weight. In a particular embodiment, the nanoparticle comprises at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or higher therapeutic agent by weight.
[00105] The compounds and nanoformulations thereof of the present invention may be used for the treatment and or prevention of drug and alcohol addiction, drug abuse, abstinence or overdose. In one embodiment the compounds and/or nanoformulations thereof are used for the treatment of opioid use disorders such as opioid dependence/addiction. In addition, the compounds and nanoformulations thereof of the present invention can also be used for treating diseases/disorders not related to drug addiction including but not limited to cancer, pain {including chronic pain, degenerative pain, inflammatory pain, visceral pain, neuropathic pain or trauma-related (broken bones, dental, bums, surgery) pain, fibromyalgia, arthritis and obesity. [00106] The compounds may also be packaged with additional drugs or compounds into nanoparticles (or nanoformulations) or co-administered with other drugs.
Pharmaceutical Compositions
[00107] In one aspect, provided herein is a pharmaceutical composition, comprising a compound of formula I or a nanoparticle comprising the same, and a pharmaceutically acceptable carrier. The compounds and nanoformulations of the present invention may be conveniently formulated for administration with any pharmaceutically acceptable carrier(s).
[00108] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally. In certain embodiments, the pharmaceutical compositions disclosed herein are administered via injection, microarray patch or implantable device.
[00109] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time. [00110] The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein can be administered as a unit dose. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
[00111] In various embodiments, the pharmaceutical compositions provided herein comprise the compound of formula I as the sole active agent, or in combination with other active agents.
[00112] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005. Methods of Use and Treatment
[00113] In one aspect, provided herein are methods for preventing, inhibiting, and/or treating a medical condition (i.e., a disease or disorder). The methods comprise administering a compound and/or nanoparticle and/or pharmaceutical composition of the instant invention to a subject (e.g., a human) in need thereof.
[00114] In various embodiments, the medical condition is a microbial (e.g., viral) infection, cancer, or a blood clotting disorder (e.g., the compound or nanoparticle of the invention can be used as an antiplatelet drug to inhibit or prevent formation of a blood clot). Microbial infections include, without limitation, viral, bacterial, fungal, mycobacterial and parasitic infections. In a particular embodiment, the disease or disorder is a viral infection. Examples of viral infections include, without limitation: HIV, Hepatitis B, Hepatitis C, Influenza A, Influenza B, Ebola, and Herpes Simplex. In a particular embodiment, the viral infection is a retroviral or lentiviral infection, particularly an HIV infection (e.g., HIV-1). In a particular embodiment, the cancer includes, but is not limited to, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia), lymphoma (e.g., Hodgkin lymphoma, Non-Hodgkin lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers (e.g., gliomas, meningiomas, and pituitary adenomas), lung cancer, ovarian cancer, stomach cancer, skin cancer (e.g., melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer.
[00115] In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 1 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 2 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 3 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 4 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 5 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 6 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 7 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 8 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 9 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 10 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 11 month period. In certain embodiments, the compound, or nanoparticle, or pharmaceutical composition is administered one time in a 12 month period.
[00116] The compounds and/or nanoparticles and/or pharmaceutical composition of the instant invention can be administered to an animal, in particular a mammal, more particularly a human, in order to treat/inhibit/prevent the disease or disorder (e.g., an HIV infection). The pharmaceutical compositions of the instant invention may also comprise at least one other therapeutic agent such as an antiviral agent, particularly at least one other anti-HIV compound/agent. The additional anti-HIV compound may also be administered in a separate pharmaceutical composition from the compounds or compositions of the instant invention. The pharmaceutical compositions may be administered at the same time or at different times (e.g., sequentially). The dosage ranges for the administration of the compounds, nanoparticles, and/or compositions of the invention are those large enough to produce the desired effect (e.g., curing, relieving, treating, and/or preventing the disease or disorder (e.g., HIV infection), the symptoms of it (e.g., AIDS, ARC), or the predisposition towards it). In a particular embodiment, the pharmaceutical composition of the instant invention is administered to the subject at an amount from about 5 pg/kg to about 500 mg/kg. In a particular embodiment, the pharmaceutical composition of the instant invention is administered to the subject at an amount greater than about 5 pg/kg, greater than about 50 pg/kg, greater than about 0.1 mg/kg, greater than about 0.5 mg/kg, greater than about 1 mg/kg, or greater than about 5 mg/kg. In a particular embodiment, the pharmaceutical composition of the instant invention is administered to the subject at an amount from about 0.5 mg/kg to about 100 mg/kg, about 10 mg/kg to about 100 mg/kg, or about 15 mg/kg to about 50 mg/kg. The dosage should not be so large as to cause significant adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counter indications. [00117] In various embodiments, administering a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, comprises administering a composition having an amount of the compound as described herein, supra.
[00118] In various embodiments, the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, as the sole active agent.
[00119] In various embodiments, the composition comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with another active agent (e.g., an antiviral agent or an anticancer agent).
[00120] Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
EXAMPLES
[00121] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
Example 1: Synthesis and Characterization of a Compound of Formula I
[00122] Monophenyl tenofovir (2 g, 1 equiv) was dried from anhydrous benzene (15 mL), resuspended in anhydrous ACN (25 mL) and then cooled at -10 °C under an argon atmosphere. After the addition of 5 equivalents of SOChthe reaction was heated at 65°C for 2 h under protection from light. The mixture was then dried from of 15 ml anhydrous benzene by rotary evaporation. The chlorinated compound was then resuspended in mixture of anhydrous acetonitrile and tetrahydrofuran (15 mL each) and cooled to -10 °C. A solution of 2-(4-steroyl ester phenyl) ethanol (2.2g, 1 equiv) in anhydrous tetrahydrofuran (15 mL) was then added followed by dropwise addition of EtsN (4 equiv) at -10 °C. The reaction mixture was then warmed to room temperature, then heated at 45 °C for 24 h under protection from light. The mixture was then concentrated to remove solvents. The residue was purified by silica column flash chromatography, eluting with 95% then 92.5% DCM in methanol. The desired compound fractions from the columns were dried on a rotary evaporator further dried under high vacuum to obtain the product (“M4TFV”) as white powders, with chemical yields of >65% as a single isomer at the phosphorous chiral center. Successful synthesis of the compounds was confirmed by ’H, 13C, and 31P NMR spectroscopy using a Bruker Avance-III HD operating at 500 MHz and a magnetic field strength of 11.7 T. See Figures 1-3.
Compound plasma stability
[00123] To determine differences in rate of M4TFV stability in plasma across species, 100 pl rat and human plasma was incubated with 1 pM compound solution at 37 °C. At different time points (0, 30 min, 2 h, 6 h and 24 h), 0.9 ml of methanol (containing 0.1% formic A and 2.5 mM ammonium formate) was added to each sample and vortexed for 3 min. The samples were then centrifuged at 16,000 g for 10 min after which 10 pl of the supernatant was mixed with 80% methanol (containing 0.1% FA and 2.5 mM ammonium formate) containing an internal standard (IS) and analyzed by LC- MS/MS. For the time zero start time, a 100 pl of ice-cold blood was spiked with M4TFV and immediately 0.9 ml of methanol (containing 0.1% formic acid and 2.5 mM ammonium formate) was added. Results of the compound stability in human and rat plasma are shown in Figure 4.
Example 2: Nanoparticles Comprising a Compound of Formula I
[00124] Nanocrystals of M4TFV (“NM4TFV”) were manufactured by high-pressure homogenization in aqueous buffers stabilized by non-ionic surfactants. Specifically, M4TFV was dispersed in a P407 or Tween 20/ PEG 3350 solution in lOmM HEPES pH 5.5 and allowed to form a presuspension. The compound to P407 to PEG 3350 ratio was maintained at 2: ’A: ’A (w/w), and the suspension concentration was in the range 0.1-10% w/v for the drug/prodrug and 0.025-2.5% w/v for P407or Tween 20/PEG. The presuspensions were homogenized on an Avestin EmulsiFlex-C3 high-pressure homogenizer at 15,000- 20,000 psi until the desired particle size of 250-350 nm was achieved. Nanoparticles were characterized for particle size, PDI and zeta potential by dynamic light scattering using a Malvern Zetasizer Nano-ZS.
Example 3: In Vitro Evaluation of a Compound of Formula I
[00125] Cell viability after treatment with M4TFV or compound nanoparticles (NM4TFV) was evaluated by MTT assay. Briefly, human monocyte derived macrophages (MDM) cultured on 96-well plates at a density of 0.08 * 106 cells per well were treated with various concentrations (0.2- 500 pM) of M4TFV or NMTFV formulations for 8 h. After drug treatment, cells were washed and incubated with 100 pL/well of MTT solution (5 mg/mL) for 45 min at 37 °C. After incubation MTT was removed, and 200 pL/well of DMSO was added and mixed thoroughly. Absorbance was measured at 490 nm on a Molecular Devices SpectraMax M3 plate reader with SoftMax Pro 6.2 software (Sunnyvale, CA). Results of the cell viability are shown in Figure 5. [00126] Intracellular drug uptake studies were performed in human MDM using flat-bottom, 12- well plates at a density of 1.2 x 106 cells per well, with each treatment completed in triplicate. For cellular uptake studies, MDMs were treated with 50 pM NM4TFV. At 2, 4, and 8 h after treatment, the cells were collected, processed, and analyzed for drug content by UPLC-UV/vis. Results of the intracellular drug uptake are shown in Figure 6.
INCORPORATION BY REFERENCE
[00127] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
EQUIVALENTS
[00128] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I:
Figure imgf000035_0001
(I), or a pharmaceutically acceptable salt thereof, wherein
R1 is a nucleoside, nucleotide, or nucleobase, or analog thereof;
R2 is optionally substituted aryl;
R3 is halo, OH, CN, C1-5 alkyl, C1-5 haloalkyl, C1-5 alkoxy, C3-5 cycloalkyl, or C3-5 heterocycloalkyl;
R4 is the alkyl chain of a fatty acid;
Ra, Ra , Rb, and Rb each, independently, are one of H, halo, and C1-5 alkyl;
Li is C1-5 alkylene, C1-5 heteroalkylene, C3-5 cycloalkylene, C3-5 cycloalkenylene, C3-5 heterocycloalkylene, or a combination thereof, wherein L1 is optionally substituted with one or more halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, or =CH2;
L2 is -(C=O)-X- or -X-(C=O)-, in which X is O, NR1, or S, RN being H or alkyl; and m, n, and p each, independently, are integers of 0-3.
2. The compound of claim 1, wherein R1 is
Figure imgf000035_0002
Figure imgf000036_0001
3. The compound of claim 1 or 2, wherein R2 is phenyl.
4. The compound of any one of claims 1-3, wherein each of Ra, Ra , Rb, and Rb is H; m is 2; and each of n and p is 0.
5. The compound of any one of claims 1-4, wherein R4 is
Figure imgf000036_0002
, w being an integer of 2-10.
6. The compound of any one of claims 1-5, wherein Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, Cs cycloalkylene, C3-4 heterocycloalkylene comprising O, or a combination thereof, wherein L1 is optionally substituted with one, two, or three substituents selected from halo, Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, OH, CN, and =CH2.
7. The compound of any one of claims 1-5, wherein Li is C1-5 alkylene, C1-5 heteroalkylene comprising O, C3-5 heterocycloalkylene comprising O, or a combination thereof.
Figure imgf000037_0001
10. The compound of any one of claims 1-9, wherein L2 is -X-(C=O)-, in which X is
O or NH.
11. The compound of claim 1, having the following structure:
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
pharmaceutically acceptable salt thereof.
12. A nanoparticle, comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a polymer or surfactant.
13. The nanoparticle of claim 12, wherein said polymer or surfactant is an amphiphilic block copolymer.
14. The nanoparticle of claim 13, wherein said amphiphilic block copolymer comprises at least one block of poly(oxy ethylene) and at least one block of poly(oxypropylene).
15. The nanoparticle of claim 14, wherein said polymer or surfactant is P407.
16. The nanoparticle of any one of claim 12-15, wherein the diameter of the nanoparticle is about 100 nm to 1 pm.
17. A pharmaceutical composition, comprising a compound of any one of claims 1-11 or a nanoparticle of any one of claims 12-16, and a pharmaceutically acceptable carrier.
18. A method of treating a medical condition in a subject in need thereof, wherein said method comprises administering to said subject a therapeutically effective amount of a compound of any one of claims 1-11, a nanoparticle of any one of claims 12-16, or a pharmaceutical composition of claim 17.
19. The method of claim 18, wherein the medical condition is a cancer, a viral infection, or a clotting disorder.
20. The method of claim 18, wherein the medical condition is a viral infection selected from the group consisting of an HIV, hepatitis B, hepatitis C, influenza A, influenza B, herpes simplex, SARS-CoV, or Ebola infection.
21. The method of claim 18, wherein the compound, nanoparticle, or pharmaceutical composition is administered via injection, microarray patch or implantable device.
22. The method of any one of claims 18-21, wherein the compound, nanoparticle, or pharmaceutical composition is administered one time in a 1 to 12 month period or longer.
PCT/US2023/064827 2022-03-23 2023-03-22 Phosphonate prodrugs and use thereof WO2023183852A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180071323A1 (en) * 2013-03-15 2018-03-15 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US20200308214A1 (en) * 2016-12-23 2020-10-01 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Nucleoside phosphate compound and preparation method and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180071323A1 (en) * 2013-03-15 2018-03-15 The Regents Of The University Of California Acyclic nucleoside phosphonate diesters
US20200308214A1 (en) * 2016-12-23 2020-10-01 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Nucleoside phosphate compound and preparation method and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE ANONYMOUS : "(4-formamidophenyl) diphenyl phosphate", XP093096406, retrieved from PUBCHEM *

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