WO2024030429A1 - Ribonucléosides modifiés par une base en tant que promédicaments contre des infections virales et bactériennes - Google Patents

Ribonucléosides modifiés par une base en tant que promédicaments contre des infections virales et bactériennes Download PDF

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WO2024030429A1
WO2024030429A1 PCT/US2023/029214 US2023029214W WO2024030429A1 WO 2024030429 A1 WO2024030429 A1 WO 2024030429A1 US 2023029214 W US2023029214 W US 2023029214W WO 2024030429 A1 WO2024030429 A1 WO 2024030429A1
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mhz
nmr
phenyl
tert
diastereomers
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Vladislav A. Litosh
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The United States Government, As Represented By The Secretary Of The Army
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • nucleoside analogs also called antimetabolites
  • nucleoside transporters where they are metabolized into 5'-phosphates, the active species which interfere with a large variety of intracellular targets or viruses infiltrating the cells.
  • the most active clinically approved antimetabolite anticancer drugs such as gemcitabine or 5-fluorouracil, can exhibit fatal side effects, as they also affect rapidly proliferating normal human cells, lymphocytes, and sometimes even non-dividing cells, such as neurons, which substantially lowers their safety index.
  • Dolutegravir an integrase strand transfer inhibitor that is widely used to treat HIV, is implicated in neuropsychiatric side effects, while tenofovir disoproxil fumarate (TDF), an agent for treatment of chronic hepatitis B, appears to adversely affect renal function.
  • TDF tenofovir disoproxil fumarate
  • the design of efficient nanocarriers purposed to reduce the off-target effects of antiviral agents still remains in the early stages of development.
  • Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in the fight against cancer and infectious diseases for more than six decades. However, many of these agents are associated with significant and potentially lethal off-target intracellular effects that limit their use.
  • N4-hydroxycytidine having Structure I, exhibits promising activity against the New World alphaviruses, e.g, Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively), Ebola, Marburg, norovirus, as well as respiratory infections, most notably, SARS-CoV-2 and COVID-19.
  • New World alphaviruses e.g, Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively), Ebola, Marburg, norovirus, as well as respiratory infections, most notably, SARS-CoV-2 and COVID-19.
  • mutagenic properties of NHC substantially limit its potential to become a drug.
  • Figure 1 is an example according to various embodiments, illustrating the bioactivity of a compound having Structure IV (RIID1271) and control (NHC) compounds.
  • Figure 2 is an example according to various embodiments, illustrating the cytotoxicity a compound having Structure IV (RIID1271) and control (NHC) compounds.
  • a support includes a plurality of supports. Particularly when a single countable noun is listed as an element in a claim, this specification will generally use a phrase such as “a single.” For example, “a single support.”
  • a single support In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.
  • the term “standard temperature and pressure” generally refers to 25°C and 1 atmosphere. Standard temperature and pressure may also be referred to as “ambient conditions.” Unless indicated otherwise, parts are by weight, temperature is in °C, and pressure is at or near atmospheric.
  • elevated temperatures or “high-temperatures” generally refer to temperatures of at least 100°C.
  • all percentages indicating the amount of a component in a composition represent a percent by weight of the component based on the total weight of the composition.
  • mol percent or “mole percent” generally refers to the percentage that the moles of a particular component are of the total moles that are in a mixture. The sum of the mole fractions for each component in a solution is equal to 1.
  • a wavy bond line in a structure representing a cyclic structure indicates a bond that is shared with the main structure, or the point at which the cyclic structure is fused to the main structure to form a polycyclic structure.
  • Various subscripts are also used. Each R-group has a numeric subscript which distinguishes it from other R-groups.
  • R-groups and lettered rings may also include a lowercase alphabetical subscript, indicating that different embodiments, may have differing numbers of that moiety. If a lowercase alphabetical subscript may be 0, it means that, in some embodiments, the moiety may not be present.
  • a dashed line in a cyclic structure indicates that in various embodiments one or more double-bounds may be present.
  • a compound may include more than one instance of a moiety, for example a moiety represented by an R-group, and that moiety is described as being “independently selected” from a list of options, each instance may be selected from the complete list without respect to any prior selections from the list; in other words, the instances may be the same or different and the same list item may be selected for multiple instances.
  • Some R-group substitutions indicate a range, such as C1 – C6 alkyl. Such a range indicates that the R-group may be a C1 alkyl, a C2 alkyl, a C3 alkyl, a C4 alkyl, a C5 alkyl, or a C6 alkyl.
  • treatment means to administer a composition to a subject or a system with an undesired condition.
  • the condition can include a disease (including infection) or disorder.
  • prevention means to administer a composition to a subject or a system at risk for the condition, and therefore includes preventing disease progression in symptomatic or asymptomatic subjects.
  • the condition can include a predisposition to a disease or disorder.
  • the effect of the administration of the composition to the subject can be, but is not limited to, the cessation of one or more symptoms of the condition, a reduction or prevention of one or more symptoms of the condition, a reduction in the severity of the condition, the complete ablation of the condition, a stabilization or delay of the development or progression of a particular event or characteristic, or minimization of the chances that a particular event or characteristic will occur.
  • the term “therapeutically effective amount” refers to an amount of a composition of the disclosure that when administered to a human subject in need thereof, is sufficient to effect treatment or prophylaxis for virus infection.
  • a therapeutically effective amount will depend upon the patient's size and gender, the stage and severity of the infection and the result sought. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations per day for successive days. For a given patient and condition, a therapeutically effective amount can be determined by methods known to those of skill in the art. For example, in reference to the treatment of a viral infection (e.g.
  • a therapeutically effective amount refers to that amount of the composition which has the effect of (1) reducing the shedding of the virus, (2) reducing the duration of the infection, (3) reducing infectivity and/or, (4) reducing the severity (or, preferably, eliminating) one or more other symptoms associated with the infection such as, for example, fever, headache, fatigue, dry cough, sore throat, respiratory distress, muscle aches, conjunctivitis, runny and/or stuffy nose.
  • Such an effective dose will generally depend on the factors described above.
  • a prophylactically effective dose is one that reduces the likelihood of contracting a virus infection.
  • the term "subject" refers to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and most preferably a human.
  • the subject is a non-human animal such as a farm animal (e.g., a horse, pig, or cow) or a pet (e.g., a dog or cat).
  • the subject is an elderly human.
  • the subject is a human adult.
  • the subject is a human child.
  • the subject is a human infant.
  • Treating refers to providing any type of medical management to a subject. Treating includes, but is not limited to, administering a composition comprising one or more active agents to a subject using any known method. for purposes such as curing, reversing, alleviating, reducing the severity of, inhibiting the progression of, or reducing the likelihood of a disease, disorder, or condition or one or more symptoms or manifestations of a disease, disorder or condition.
  • the administration of the drug can be oral, nasal, parental, topical, ophthalmic, or transdermal administration or delivery in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms.
  • the dosage forms include tablets, capsules, troches, powders, solutions, suspensions, suppositories, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the active ingredient of the biochemical composition, which are not otherwise undesirable.
  • Pharmaceutically acceptable salts include, but are not limited to, salts formed after combination of the amine compound with inorganic acids like hydrochloric acid, or organic carboxylic acids such as oxalic acid or acetic acid to form oxalate or acetate salts, respectively.
  • the pharmaceutically acceptable carrier may include pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the compositions of the invention from one organ, or portion of the body, to another organ, or portion of the body without affecting its biological effect.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the compositions of the invention from one organ, or portion of the body, to another organ, or portion of the body without affecting its biological effect.
  • Each carrier should be “acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • the novel bioactive nucleosides disclosed herein can be provided as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the compositions of the invention from one organ, or portion of the body, to another organ, or portion of the body without affecting its biological effect.
  • Each carrier should be “acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
  • Novel bioactive nucleosides disclosed herein can be combined with a pharmaceutically acceptable carrier to form a more facile administrable composition.
  • Various embodiments may provide novel, highly efficient, and selective anti-viral agents capable of protecting against diseases, including the emerging threat of biological warfare. Without being bound by theory, it is hypothesized that the attachment of a modifying moiety at the 5-carbon of NHC may make it less recognizable to cellular targets, which will reduce incidence of the off-target effects, while keeping the 4-hydroxylamimne moiety will retain the antiviral activity shown by NHC. Identification of the new lead compound with the activity similar to that of NHC but without its mutagenicity may allow moving forward with definitive in vivo tests in mouse models, to eventually develop drugs that will protect against diseases and emerging bioweapon threats.
  • Various embodiments relate to the synthesis of novel bioactive nucleosides and assaying their antiviral activity and cytotoxicity. Without being bound by theory, it is hypothesized that the novel base-modified nucleosides undergo cellular uptake followed by stepwise 5'-phosphorylation into active 5'-triphosphates that may interfere with viral RNA synthesis, while not affecting the host cellular targets. [0033] Further improvement of the initial hit compounds to a lead compound is also contemplated and is within the scope of the present disclosure.
  • Various embodiments may provide an NHC-based drug candidate that will retain the potency of the parent compound, but will be lacking its side effects, including cytotoxicity and mutagenicity. This result is expected to have an important positive impact by providing strong justification for continued drug development to protect against emerging bioweapon threats, particularly encephalitis viruses, as well as commonly transmitted infectious diseases, such as SARS-CoV-2 and COVID-19.
  • anomer is a type of geometric variation found at certain atoms in carbohydrate molecules.
  • An epimer is a stereoisomer that differs in configuration at any single stereogenic center.
  • An anomer is an epimer at the hemiacetal/hemiketal carbon in a cyclic saccharide, an atom called the anomeric carbon.
  • the anomeric carbon is the carbon derived from the carbonyl carbon compound (the ketone or aldehyde functional group) of the open-chain form of the carbohydrate molecule.
  • Two anomers are designated alpha ( ⁇ ) or beta ( ⁇ ), according to the configurational relationship between the anomeric center and the anomeric reference atom, hence they are relative stereodescriptors.
  • Structure IV may be synthesized via ⁇ - D-ribofuranose ( ⁇ -D-Rb) or ⁇ -D-ribofuranose ( ⁇ -D-Rb). [0037] It is to be appreciated that variations of Structure IV are contemplated and included in this disclosure.
  • Structure V provides a more generalized structure.
  • R1 may be any substituted or unsubstituted aryl moiety.
  • R1 may be a substituted or unsubstituted phenyl moiety.
  • the substituted aryl moiety may comprise one or more linear, branched, or cylic C1-C6 alkanes, alkenes, or alkynes. Additionally or alternatively, the substituted aryl moiety may comprise one or more halides.
  • R1 may be a tert-butyl substituent.
  • R2 may be a hydrogen, or a linear, branched, or cyclic C1-C6 alkane, alkene, or alkyne.
  • R3 may be oxygen, nitrogen, an amine, or an imine, such as an oxime.
  • R4 may be may be nitrogen or an imine.
  • R5 may be hydrogen, or an ⁇ -D-ribofuranose ( ⁇ -D-Rb) or ⁇ -D-ribofuranose ( ⁇ -D-Rb) moiety.
  • nucleobase modifications for anti-viral drug development.
  • the status quo pertaining to the current most effective nucleoside and nucleobase chemotherapeutic drugs is that these agents closely resemble natural analogs. Such resemblance gives these antimetabolites the desired anticancer or antiviral activity, but also leads to off-targeting due to metabolic and catabolic enzymatic recognition.
  • various embodiments utilize a modifying moiety that will minimize off-targeting while allowing chemotherapeutic action presumably consisting in interfering of the 5′-phosphorylated prodrug nucleosides with nucleic acid producing enzymes in viruses.
  • the nucleoside compounds of the present disclosure may be used alone or in combination with other agents effective against viral infection. They may be administered separately during the course of treatment, or may be administered in combination with an additional antiviral agent, for example, in a single dosage form such as a tablet, intravenous solution or capsule.
  • the other agents effective against viral infections include viral growth inhibitors.
  • Viral growth inhibitors preferably used in combination with the antiviral knockdown agent of the present disclosure are reverse transcriptase inhibitors.
  • the viral growth inhibitor used in combination with the novel nucleoside compounds of the present disclosure is an HBV growth inhibitor, including in particular, interferon, peginterferon, lamivudine, adefovir, entecavir, tenofovir, telbivudine, and clevudine, among which entecavir is preferred.
  • a nucleoside compound of the present disclosure can be administered simultaneously or sequentially with another agent, such as an antiviral, an antibiotic, an anti- inflammatory, or another agent.
  • a nucleoside compound can be administered simultaneously with another agent, such as a known antiviral, an antibiotic or an anti-inflammatory.
  • Simultaneous administration can occur through administration of separate compositions, each containing one or more of an nucleoside compound, a known antiviral, an antibiotic, an anti-inflammatory, or another agent. Simultaneous administration can occur through administration of one composition containing two or more of a nucleoside compound, an antiviral, an antibiotic, an anti-inflammatory, or another agent.
  • a nucleoside compound can be administered sequentially with an antiviral, an antibiotic, an anti- inflammatory, or another agent.
  • an nucleoside compound can be administered before or after administration of an antiviral, an antibiotic, an anti- inflammatory, or another agent.
  • the present invention also includes pharmaceutical compositions and formulations of antiviral nucleosides.
  • compositions comprise therapeutically effective amounts of at least one antiviral nucleoside, which amounts treat or prevent viral infection in a subject.
  • Pharmaceutical compositions for use in the present methods include therapeutically effective amounts of one or more antiviral nucleosides, i.e., an amount sufficient to prevent or treat the diseases described herein in a subject, formulated for local or systemic administration. There may be instances where two antiviral nucleosides of different structure are combined as one therapy in order to reach specific compartments within the subject for better therapeutic outcomes.
  • the subject is preferably a human but can be non-human as well.
  • a suitable subject can be an individual who is suspected of having, has been diagnosed as having, or is at risk of developing a viral infection.
  • the duration of treatment can extend over several days or longer, depending on the condition, with the treatment continuing until the viral infection is sufficiently reduced or eliminated.
  • Antiviral nucleosides for therapeutic administration are preferably low in toxicity. The progress of this therapy is easily monitored by conventional techniques and assays that may be used to adjust dosage to achieve a desired therapeutic effect.
  • a composition of the antiviral nucleosides can also include a pharmaceutically acceptable carrier.
  • Antiviral nucleosides containing compositions may contain, for example, such normally employed additives as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers, buffers and excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions typically contain 1%-95% of active ingredient, preferably 2%-70% active ingredient.
  • the antiviral nucleoside can also be mixed with diluents or excipients which are compatible and physiologically tolerable as selected in accordance with the route of administration and standard pharmaceutical practice.
  • Suitable diluents and excipients are, for example water saline dextrose glycerol or the like and combinations thereof.
  • the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents.
  • the formulations may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. Synthesis of novel bioactive nucleosides and assaying their antiviral activity and cytotoxicity.
  • the substituents vary with the size and the character, e.g., alkyl versus aryl, as well as substituted aryl versus non-substituted. Additionally, there is also a control compound with the missing alkyl substituent (i.e., 5-hydroxymethyl NHC).
  • the proposed variation in sizes and the character of the substitution patterns is meant to attenuate the activity versus side effects, particularly cytotoxicity and mutagenicity.
  • VEEV Venezuelan equine encephalitis virus
  • VEEV Venezuelan Equine Encephalitis Virus
  • 1CSH3 strain Venezuelan Equine Encephalitis Virus
  • DPBS Dulbecco’s phosphate buffered saline
  • E2 VEEV envelope 2
  • the cells were stained with Hoechst nuclear dye 1:10,000, Invitrogen H3570, 1 ⁇ g/ml in PBS) and CellMask Deep Red dye (1:10,000, Invitrogen H32721, 5 ⁇ g/ml in PBS) for host cell cytoplasmic staining.
  • the automated image acquisition was performed using an Opera QEHS confocal system (Perkin Elmer) and images analyzed using Acapella software. A compound that exhibits a ⁇ 50% inhibition/reduction in virus infections and ⁇ 20% loss in cell number in all 4 replicates is considered a hit.
  • Figure 1 is an example according to various embodiments, illustrating the bioactivity of a compound having Structure IV (RIID1271) and control (NHC) compounds.
  • Figure 2 is an example according to various embodiments, illustrating the cytotoxicity a compound having Structure IV (RIID1271) and control (NHC) compounds.
  • the anti-infection activity of the 5-modified nucleobases was diminutive, as was that of nucleoside derivatives with substituents of a smaller size. Nucleosides with larger R1 and R2 inhibited the infection at a higher rate, but the only compound with outstanding activity was RIID#1271 that showed almost complete suppression of the VEEV infection in the living cells.
  • Example 1 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]uracil
  • VAL-1-75 – RIID1255 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]uracil (VAL-1-75 – RIID1255) was prepared by the following procedure and with the following results: Treatment of 5- chloromethyluracil (322 mg, 2.000 mmol) with 2,2-dimethyl-1-phenyl-1-propanol (1.32 g, 8.000 mmol) at 135 oC for 3 hours afforded after purification 476 mg of product (83%).
  • Example 2 5-[1-(2-methyl)phenyl-2,2-(dimethyl)propoxymethyl]uracil [0073] 5-[1-(2-methyl)phenyl-2,2-(dimethyl)propoxymethyl]uracil (SKR-1-28 – VAL-1-90F1 – RIID1167) was prepared by the following procedure and with the following results: Treatment of 5-chloromethyluracil (110 mg, 0.680 mmol) with 2,2- dimethyl-1-(2-methylphenyl)-1-propanol (487 mg, 2.730 mmol) at 120 oC for 5 hours afforded after purification 150 mg of product (73%).
  • Example 4 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]uracil [0075] 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]uracil (SKR-1-1 – SSS-1-3 – RIID1127 was prepared by the following procedure and with the following results: Treatment of 5-chloromethyluracil (153 mg, 0.951 mmol) with 1-(phenyl)cyclohexanol (724 mg, 3.805 mmol) at 126 oC for 2.5 hours afforded after purification 182 mg of product (61%).
  • Example 5 5-[1-(phenyl)heptoxymethyl]uracil [0076] 5-[1-(phenyl)heptoxymethyl]uracil (SKR-1-32 – RIID1134 was prepared by the following procedure and with the following results: Treatment of 5-chloromethyluracil (75 mg, 0.460 mmol) with 1-phenyl-1-heptanol (199 mg, 1.860 mmol) at 135 oC for 3 hours afforded after purification 24 mg of product (16%).
  • Example 6 5-[1-(phenyl)ethoxymethyl]uracil [0077] 5-[1-(phenyl)ethoxymethyl]uracil (VAL-1-142 – VAL-1-149 – RIID1129) Treatment of 5-chloromethyluracil (505 mg, 3.145 mmol) with 1-phenyl-1-ethanol (1537 mg, 12.581 mmol) at 120 oC for 4 hours afforded after purification 551 mg of product (71%).
  • Example 7 5-[1-(phenyl)propoxymethyl]uracil [0078] 5-[1-(phenyl)propoxymethyl]uracil (VAL-2-3 – RIID1361 was prepared by the following procedure and with the following results: Treatment of 5-chloromethyluracil (522 mg, 3.251 mmol) with 1-phenyl-1-propanol (3542 mg, 26.009 mmol) at 125 oC for 16 hours afforded after purification 657 mg of product (78%).
  • Example 11 5-[methoxymethyl]uracil [0082] 5-[methoxymethyl]uracil (VAL-2-46 - RIID1385) was prepared exactly as described previously.3 1 H NMR (400 MHz, Methanol-d4) ⁇ 7.42 (s, 1 H), 4.14 (s, 2 H), 3.36 (s, 3 H). 13 C NMR (100 MHz, CD3OD) ⁇ 166.14 (C), 153.43 (C), 141.96 (CH), 111.22 (C), 67.67 (CH2), 58.40 (CH3).
  • Example 12 5-[hydroxymethyl]uracil [0083] 5-[hydroxymethyl]uracil (RIID1301) was purchased from Sigma-Aldrich (catalog #852589).
  • the reaction mixture was heated at reflux under nitrogen atmosphere for the period from 1 to 3 h, until a clear solution formed, then cooled down, and the excess of hexamethyldisilazane was removed under reduced pressure.
  • the residue was dissolved in anhydrous dichloromethane to the concentration of about 25 mM followed by addition of ⁇ -D- ribofuranose-1,2,3,5-tetraacetate (1.1 eq.).
  • the solution was immersed into ice-water bath and stirred for 10 min followed by addition of tin(IV) chloride (1.1 eq.).
  • reaction mixture was stirred at the temperature ranging from 0 to +5 oC for the period from 3 to 6 h, then poured into an equal volume of saturated aqueous solution of NaHCO3.
  • the organic layer was separated, and the aqueous layer was extracted thrice with an equal amount of dichloromethane. Combined organic extracts were washed with equal volume of water, brine, and dried over anhydrous Na2SO4.
  • Example 13 [0086] 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]uridine (VAL-1-77 – RIID1256 was prepared by the following procedure and with the following results: Treatment of 5- [1-phenyl-2,2-(dimethyl)propoxymethyl] uracil (444 mg, 1.540 mmol) afforded after two steps 241 mg of product (65%).
  • Example 5-[1-(2-methyl)phenyl-2,2-(dimethyl)propoxymethyl]uridine (SKR- 1-31 – VAL-1-90F2 – VAL-1-92F2 – RIID1168 was prepared by the following procedure and with the following results: Treatment of 5-[1-(2-methyl)phenyl-2,2- (dimethyl)propoxymethyl]uracil (112 mg, 0.372 mmol) afforded after two steps 45 mg of product (28%).
  • Example 18 [0091] 5-[1-(phenyl)propoxymethyl]uridine (VAL-2-6F1 – VAL-2-11 – RIID1375 was prepared by the following procedure and with the following results: Treatment of 5- [1-(phenyl)propoxymethyl] uracil (648 mg, 2.488 mmol) afforded after two steps 298 mg of product (41%).
  • Example 23 [0096] 5-[(hydroxy)methyl]uridine (RIID1292) was available from Combi-Blocks (catalog #QV-7894).
  • Examples 24 – 38 Synthesis of 5-modified-2′,3′,5′-tris-O-(tert-butyldimethylsilyl) uridines [0097] General procedure for the synthesis of 5-modified-2′,3′,5′-tris-O-(tert- butyldimethylsilyl) uridines. A 5-modified uridine was dissolved in anhydrous dichloromethane under nitrogen atmosphere to achieve concentration ranging from 35 to 140 mM.
  • Example 24 [0098] 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (VAL-1-78 was prepared by the following procedure and with the following results: Treatment of 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]uridine (236 mg, 0.561 mmol) afforded 492 mg of product (100%).
  • Example 26 [0100] 5-[1-(2-chloro)phenyl-2,2-(dimethyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (VAL-1-104 was prepared by the following procedure and with the following results: Treatment of 5-[1-(2-chloro)phenyl-2,2- (dimethyl)propoxymethyl]uridine (61 mg, 0.134 mmol) afforded 77 mg of product (72%).
  • Example 28 [0102] 5-[(1-phenyl)ethoxymethyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-1-145F1 – VAL-1-152F1 was prepared by the following procedure and with the following results: Treatment of 5-[(1-phenyl)ethoxymethyl]uridine (309 mg, 0.817 mmol) afforded 548 mg of product (93%).
  • Example 29 [0103] 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[(1- phenyl)ethoxymethyl]uracil (VAL-1-145F2 – VAL-1-152F2 – VAL-2-5 was prepared by the following procedure and with the following results: Treatment of 1- ⁇ -D-ribofuranosyl- 5-[(1-phenyl)propoxymethyl]uracil (62 mg, 0.163 mmol) afforded 105 mg of product (89%).
  • Example 30 [0104] 5-[(1-phenyl)propoxymethyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-2-8 – VAL-2-9F2 was prepared by the following procedure and with the following results: Treatment of 5-[(1-phenyl)propoxymethyl]uridine (212 mg, 0.541 mmol) afforded 322 mg of product (81%).
  • Example 31 [0105] 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[(1- phenyl)propoxymethyl]uracil (VAL-2-8F2 – VAL-2-10 was prepared by the following procedure and with the following results: Treatment of 1- ⁇ -D-ribofuranosyl-5-[(1- phenyl)propoxymethyl]uracil (78 mg, 0.199 mmol) afforded 90 mg of product (62%).
  • Example 32 [0106] 5-[(1-phenyl-2-methyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (VAL-2-36 – VAL-2-37F2 was prepared by the following procedure and with the following results: Treatment of 5-[(1-phenyl-2- methyl)propoxymethyl]uridine (226 mg, 0.557 mmol) afforded 208 mg of product (50%).
  • Example 33 [0107] 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[(1-phenyl-2- methyl)propoxymethyl]uracil (VAL-2-38 was prepared by the following procedure and with the following results: Treatment of 1- ⁇ -D-ribofuranosyl-5-[(1-phenyl-2- phenyl)propoxymethyl]uracil (51 mg, 0.126 mmol) afforded 53 mg of product (56%).
  • Example 35 [0109] 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5- [(benzyloxy)methyl]uracil (VAL-1-113F2 – VAL-1-119F2 was prepared by the following procedure and with the following results: Treatment of 1- ⁇ -D-ribofuranosyl-5- [(benzyloxy)methyl]uracil (18 mg, 0.048 mmol) afforded 10 mg of product (29%).
  • Example 36 [0110] 5-[( ⁇ 2-chloro ⁇ benzyloxy)methyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-2-22F2 was prepared by the following procedure and with the following results: Treatment of 5-[( ⁇ 2-chloro ⁇ benzyloxy)methyl]uridine (160 mg, 0.401 mmol) afforded 48 mg of product (41%).
  • Example 37 [0111] 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[( ⁇ 2- chloro ⁇ benzyloxy)methyl]uracil (VAL-2-24 was prepared by the following procedure and with the following results: Treatment of 1- ⁇ -D-ribofuranosyl-5-[( ⁇ 2- chloro ⁇ benzyloxy)methyl]uracil (138 mg, 0.348 mmol) afforded 122 mg of product (47%).
  • Example 38 [0112] 5-[(tert-butyldimethylsilyloxy)methyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (VAL-1-136 was prepared by the following procedure and with the following results: Treatment of 5-[(tert-butyldimethylsilyloxy)methyl]uridine (233 mg, 0.850 mmol) afforded 400 mg of product (64%).
  • Examples 39 – 52 sulfonylation of 5-modified-2′,3′,5′-tris-(tert-butyldimethylsilyl) uridines
  • [0113] General procedure for the sulfonylation of 5-modified-2′,3′,5′-tris-(tert- butyldimethylsilyl) uridines.
  • a 5-modified- 2′,3′,5′-tris-(tert-butyldimethylsilyl)uridine was dissolved in anhydrous dichloromethane under nitrogen atmosphere to achieve concentration ranging from 45 to 120 mM. 4-N,N-dimethylaminopyridine (0.2 eq) and imidazole (10 eq) were added.
  • Example 39 [0114] 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-1-79 - VAL-1-82 was prepared by the following procedure and with the following results: Treatment of 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (267 mg, 0.350 mmol) afforded 225 mg of product (62%).
  • Example 42 [0117] 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-1-85 was prepared by the following procedure and with the following results: Treatment of 5-[1- phenyl-1-(cyclohexyl)methoxymethyl]- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (109 mg, 0.138 mmol) afforded 97 mg of product (67%).
  • Example 43 [0118] 5-[1-(phenyl)ethoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′- tris-O-(tert-butyldimethylsilyl)uridine (VAL-1-153 was prepared by the following procedure and with the following results: Treatment of 5-[1-(phenyl)ethoxymethyl]- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (107 mg, 0.149 mmol) afforded 30 mg of product (20%).
  • Example 45 [0120] 5-[1-(phenyl)propoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-2-13F1 was prepared by the following procedure and with the following results: Treatment of 5-[1-(phenyl)propoxymethyl]- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (314 mg, 0.427 mmol) afforded 138 mg of product (32%).
  • Example 47 [0122] 5-[1-(phenyl-2-methyl)propoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-2-41 was prepared by the following procedure and with the following results: Treatment of 5-[1- (phenyl-2-methyl)propoxymethyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (208 mg, 0.278 mmol) afforded 106 mg of product (38%).
  • Example 48 [0123] 3-N-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[1-(phenyl-2-methyl)propoxymethyl]uracil (VAL- 2-37F1 was prepared by the following procedure and with the following results: Treatment of 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[1-(phenyl-2- methyl)propoxymethyl]uracil (173 mg, 0.234 mmol) afforded 162 mg of product (69%).
  • Example 49 [0124] 5-[(benzyloxy)methyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris- O-(tert-butyldimethylsilyl)uridine (VAL-1-121F1a – VAL-1-126 was prepared by the following procedure and with the following results: Treatment of 5-[(benzyloxy)methyl]- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (16 mg, 0.023 mmol) afforded 10 mg of product (56%).
  • Example 51 [0126] 3-N-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)-1- ⁇ -D-ribofuranosyl-5-[ ⁇ 2-chloro(benzyloxy) ⁇ methyl]uracil (VAL-2- 22F1 was prepared by the following procedure and with the following results: Treatment of 5-[(benzyloxy)methyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (144 mg, 0.165 mmol) afforded 151 mg of product (91%).
  • Example 52 [0127] 5-[(tert-butyldimethylsilyloxy)methyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (VAL-1-137 was prepared by the following procedure and with the following results: Treatment of 5- [(tert-butyldimethylsilyloxy)methyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (195 mg, 0.267 mmol) afforded 120 mg of product (45%).
  • Examples 53 – 61 synthesis of 5-modified-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosines
  • General procedure for the synthesis of 5-modified-4-N-hydroxy-2′,3′,5′-tris- O-(tert-butyldimethylsilyl)cytosines A 5-modified-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-(tert-butyldimethylsilyl)uridine was dissolved in anhydrous acetonitrile under nitrogen atmosphere to achieve concentration ranging from 20 to 100 mM.
  • Example 54 [0130] 5-[1-(2-methyl)phenyl-2,2-(dimethyl)propoxymethyl]-4-N-hydroxy-2′,3′,5′- tris-O-(tert-butyldimethylsilyl)cytosine (VAL-1-95 was prepared by the following procedure and with the following results: Treatment of 5-[1-(2-methyl)phenyl-2,2- (dimethyl)propoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (47 mg, 0.045 mmol) afforded 35 mg of product (98%).
  • Example 55 [0131] 5-[1-(2-chloro)phenyl-2,2-(dimethyl)propoxymethyl]-4-N-hydroxy-2′,3′,5′- tris-O-(tert-butyldimethylsilyl)cytosine (VAL-1-105 was prepared by the following procedure and with the following results: Treatment of 5-[1-(2-chloro)phenyl-2,2- (dimethyl)propoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (21 mg, 0.020 mmol) afforded 17 mg of product (100%).
  • Example 56 [0132] 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-86 was prepared by the following procedure and with the following results: Treatment of 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]-4-O- (2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (59 mg, 0.056 mmol) afforded 14 mg of product (30%).
  • Example 57 [0133] 5-[1-(phenyl)ethoxymethyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-155 was prepared by the following procedure and with the following results: Treatment of 5-[1-(phenyl)ethoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (29 mg, 0.029 mmol) afforded 14 mg of product (20%).
  • Example 58 [0134] 5-[(1-phenyl)propoxymethyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-2-15 was prepared by the following procedure and with the following results: Treatment of 5-[(1-phenyl)propoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (75 mg, 0.075 mmol) afforded 49 mg of product (88%).
  • Example 59 [0135] 5-[(1-phenyl-2-methyl)propoxymethyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-2-43) was prepared by the following procedure and with the following results: Treatment of 5-[(1-phenyl-2-methyl)propoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (53 mg, 0.052 mmol) afforded 20 mg of product (50%).
  • Example 60 5-[(benzyloxy)methyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-129) was prepared by the following procedure and with the following results: Treatment of 5-[(benzyloxy)methyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (22 mg, 0.023 mmol) afforded 17 mg of product (100%).
  • Example 61 [0137] 5-[(tert-butyldimethylsilyloxy)methyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-138 was prepared by the following procedure and with the following results: Treatment of 5-[(tert-butyldimethylsilyloxy)methyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (144 mg, 0.145 mmol) afforded 108 mg of product (100%).
  • Examples 62 – 68 synthesis of 5-modified-2′,3′,5′-tris-(tert-butyldimethylsilyl)cytosines [0138] General procedure for the synthesis of 5-modified-2′,3′,5′-tris-(tert- butyldimethylsilyl)cytosines.
  • a 5-modified-4-O-(2,4,6-triisopropylbenzenesulfonyl)- 2′,3′,5′-tris-(tert-butyldimethylsilyl)uridine was dissolved in anhydrous 1,4-dioxane under nitrogen atmosphere to achieve concentration ranging from 20 to 70 mM.
  • Example 62 [0139] 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-83 was prepared by the following procedure and with the following results: Treatment of 5-[1-phenyl-2,2-(dimethyl)propoxymethyl]-4-O-(2,4,6- triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (219 mg, 0.213 mmol) afforded 130 mg of product (80%).
  • Example 64 [0141] 5-[1-(2-chloro)phenyl-2,2-(dimethyl)propoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-107 was prepared by the following procedure and with the following results: Treatment of 5-[1-(2-chloro)phenyl-2,2- (dimethyl)propoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)uridine (22 mg, 0.021 mmol) afforded 17 mg of product (100%).
  • Example 65 [0142] 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (VAL-1-87 was prepared by the following procedure and with the following results: Treatment of 5-[1-phenyl-1-(cyclohexyl)methoxymethyl]-4-O- (2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)uridine (61 mg, 0.057 mmol) afforded 17 mg of product (38%).
  • Example 66 [0143] 5-[1-(phenyl)ethoxymethyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)cytosine (VAL-1-154 was prepared by the following procedure and with the following results: Treatment of 5-[1-(phenyl)ethoxymethyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′- tris-O-(tert-butyldimethylsilyl)uridine (51 mg, 0.052 mmol) afforded 24 mg of product (64%).
  • Example 68 [0146] 5-[(benzyloxy)methyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)cytosine (VAL- 1-127 was prepared by the following procedure and with the following results: Treatment of 5-[(benzyloxy)methyl]-4-O-(2,4,6-triisopropylbenzenesulfonyl)-2′,3′,5′-tris- O-(tert-butyldimethylsilyl)uridine (10 mg, 0.011 mmol) afforded 7 mg of product (91%).
  • Example 84 [0163] 5-[(benzyloxy)methyl]cytidine (VAL-1-132 – RIID1291 was prepared by the following procedure and with the following results: Treatment of 5-[(benzyloxy)methyl]- 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)cytosine (7 mg, 0.010 mmol) afforded 2 mg of product (58%).
  • Example 85 [0164] 5-[ ⁇ 2-chloro(benzyloxy) ⁇ methyl]-4-N-(hydroxy)cytidine (VAL-2-30 - RIID1382 was prepared by the following procedure and with the following results: Treatment of 5-[ ⁇ 2-chloro(benzyloxy) ⁇ methyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert- butyldimethylsilyl)cytosine (6 mg, 0.008 mmol) afforded 3 mg of product (95%).
  • Example 86 [0165] 5-[ ⁇ 2-chloro(benzyloxy) ⁇ methyl]cytidine (VAL-2-31 – RIID1383 was prepared by the following procedure and with the following results: Treatment of 5-[ ⁇ 2- chloro(benzyloxy) ⁇ methyl]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)cytosine (6 mg, 0.008 mmol) afforded 2 mg of product (58%).
  • Example 87 [0166] 5-[(hydroxy)methyl]-4-N-(hydroxy)cytidine (VAL-1-139 - RIID1294 was prepared by the following procedure and with the following results: Treatment of 5-[(tert- butyldimethylsilyloxy)methyl]-4-N-hydroxy-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)cytosine (108 mg, 0.145 mmol) followed by purification by column chromatography (SiO2, Dichloromethane/Methanol eluting from 20:1 to 10:1 afforded 10 mg of product (24%).
  • Example 88 [0167] 5-[methoxymethyl]uracil (VAL-2-46 - RIID1385) was prepared exactly as described previously.i ii 1 H NMR (400 MHz, Methanol-d4) ⁇ 7.42 (s, 1 H), 4.14 (s, 2 H), 3.36 (s, 3 H). 13 C NMR (100 MHz, CD3OD) ⁇ 166.14 (C), 153.43 (C), 141.96 (CH), 111.22 (C), 67.67 (CH2), 58.40 (CH3).
  • Example 89 [0168] 5-[(hydroxy)methyl]cytidine (RIID1293) was available from Toronto Research (catalog #H947090). REFERENCES 1.
  • Borland KM Wolfkiel PR, Burke MP, Lawson SM, Stockman CA, Bercz AP, Tolstolutskaya JN, Litosh, VA. Base-modified thymidine and thymine analogs with low cytotoxicity effectively obstruct DNA replication in papovaviridae. Bio Chem. Comp. 2016;4:3. doi: 10.7243/2052-9341-4-3 18.
  • Siegel R Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: A Cancer J. Clin.2021;71(1):7-33. doi: 10.3322/caac.21654. 19. Zhang J, Visser F, King KM, Baldwin SA, Young JD, Cass CE.

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Abstract

Divers nouveaux analogues de nucléosides décrits ici devraient permettre d'obtenir une efficacité supérieure contre une variété d'infections virales, y compris celles qui sont dangereuses pour les voies respiratoires, telles que le SARS-CoV-2 et la COVID-19, ainsi qu'une incidence inférieure et une gravité réduite d'effets secondaires.
PCT/US2023/029214 2022-08-01 2023-08-01 Ribonucléosides modifiés par une base en tant que promédicaments contre des infections virales et bactériennes WO2024030429A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20030119764A1 (en) * 1996-10-28 2003-06-26 Loeb Lawrence A Induction of viral mutation by incorporation of miscoding ribonucleoside analogs into viral RNA
US20060183706A1 (en) * 2002-01-17 2006-08-17 An Haoyun 2-Beta-modified-6-substituted adenosine analogs and their use as antiviral agents
US20130324709A1 (en) * 2012-05-29 2013-12-05 Hoffmann-La Roche Inc. Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030119764A1 (en) * 1996-10-28 2003-06-26 Loeb Lawrence A Induction of viral mutation by incorporation of miscoding ribonucleoside analogs into viral RNA
US20060183706A1 (en) * 2002-01-17 2006-08-17 An Haoyun 2-Beta-modified-6-substituted adenosine analogs and their use as antiviral agents
US20130324709A1 (en) * 2012-05-29 2013-12-05 Hoffmann-La Roche Inc. Process for the preparation of 2-deoxy-2-fluoro-2-methyl-d-ribofuranosyl nucleoside compounds

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DATABASE PUBCHEM COMPOUND 17 February 2021 (2021-02-17), ANONYMOUS : "CHEMBL487700", XP093137242, retrieved from PUBCHEM Database accession no. 103654247 *

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