WO2023049727A1 - Virucidal compositions and use thereof - Google Patents

Virucidal compositions and use thereof Download PDF

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Publication number
WO2023049727A1
WO2023049727A1 PCT/US2022/076753 US2022076753W WO2023049727A1 WO 2023049727 A1 WO2023049727 A1 WO 2023049727A1 US 2022076753 W US2022076753 W US 2022076753W WO 2023049727 A1 WO2023049727 A1 WO 2023049727A1
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ligand
pharmaceutically acceptable
alkyl
optionally substituted
compound
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PCT/US2022/076753
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French (fr)
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Francesco Stellacci
Paulo Henrique Jacob SILVA
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Ecole Polytechnique Federale De Lausanne (Epfl)
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D5/00—Coating compositions, e.g. paints, varnishes or lacquers, characterised by their physical nature or the effects produced; Filling pastes
    • C09D5/14—Paints containing biocides, e.g. fungicides, insecticides or pesticides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
    • A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • 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
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to substituted cyclodextrin (CD) compounds having C9 to C25 alkyl linker groups, which irreversibly inhibit heparane sulfate proteoglycan-seeking viruses and are useful in the treatment of viral infections such as COVID-19.
  • CD substituted cyclodextrin
  • Vaccines are preventive drugs composed of modified or attenuated pathogens that are meant to stimulate an immunological bio-response prior to exposure to a live virus.
  • vaccines represent the most effective approach to preventing viral infections.
  • the durability of protection following vaccination is not 100%.
  • Vaccines are not always available, particularly in underdeveloped countries, and existing vaccines are highly unlikely to be effective against a virus that has not yet emerged. Thus, there remains a large unmet medical need for therapeutic interventions that can help at-risk and infected individuals.
  • Antivirals are drugs designed to fight against viruses and viral infections directly.
  • the life cycle of a virus is composed of multiple steps: 1 ) attachment, 2) entry, 3) uncoating, 4) biosynthesis, and 5) assembly and release.
  • the typical mechanism of action of existing antivirals involves inhibiting a step of the viral life cycle, thereby stopping replication.
  • Most antivirals target one or more of steps 2-5, requiring each antiviral to be specific for the manner in which such step is carried out by a particular virus.
  • viruses are often known to mutate and develop resistance to antivirals.
  • the first step of the viral life cycle is attachment.
  • the virus recognizes a host cell using receptors on viral attachment ligands (VALs) that recognize and bind to specific proteins present on host cell membranes.
  • VALs viral attachment ligands
  • HSPG heparane sulfate proteoglycans
  • SA sialic acid
  • binding inhibitors are reversible events, particularly when the environment (e.g., the bloodstream) surrounding a compound that is bound to a virus causes dissociation of the virus-compound complex, separating the virus from the compound that prevented binding and leaving the virus free to bind again.
  • dilution is a common event, especially in vivo.
  • virustatic Such temporary blocking of viral attachment and/or replication is referred to as virustatic.
  • virucidal The irreversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition is referred to as virucidal.
  • the present invention provides improved compositions and methods that can be used to treat viral diseases.
  • the invention provides a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I: wherein: each R, independently, is OH, SH, an -O-(C 9 to C 2 5)-optionally substituted alkyl- based ligand or a -S-(C 9 to C 25 )-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate (“SO 4 ") or a sulfonate (“SO 3 ”) moiety; each R’, independently, is H, -(CH 2 ) y -COOH, -(CH 2 ) y -SO 3 , a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
  • no more than 1 R group can be OH or SH and each of the remaining R groups have a sulfate or a sulfonate moiety.
  • each R group is an -O-(C 9 to C 25 )-optionally substituted alkyl-based ligand or a -S-(C 9 to C 25 )- optionally substituted alkyl-based ligand having a sulfate ("SO 4 ") or a sulfonate (“SO 3 ”) moiety.
  • the compounds of Formula I are useful as active agents in practice of the methods of treatment and in manufacture of the pharmaceutical formulations of the invention, and as intermediates in the synthesis of such active agents.
  • Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount of the one or more compounds of the invention and at least one pharmaceutically acceptable excipient, carrier and/or diluent.
  • Another aspect of the present invention provides the compounds of the invention for use in treating and/or preventing viral infections and/or diseases associated with viruses, particularly HSPG-seeking viruses.
  • Another aspect of the present invention provides a virucidal composition
  • a virucidal composition comprising an effective amount of one or more compounds of the invention and at least one suitable carrier or aerosol carrier.
  • Another aspect of the present invention provides a device comprising the virucidal composition of the invention or one or more compounds of the invention and means for applying and/or dispensing thereof.
  • Another aspect of the present invention provides a method of disinfection and/or sterilization of non-living surfaces using one or more compounds of the invention or a virucidal composition of the invention.
  • Another aspect of the present invention provides a use of one or more compounds of the invention or a virucidal composition of the invention for sterilization and/or for disinfection of human or animal skin and/or hair.
  • Another aspect of the present invention provides a use of one or more compounds of the invention or a virucidal composition of the invention for manufacturing virucidal surfaces.
  • Another aspect of the present invention provides a device comprising a surface coated with one or more compounds of the invention or with a virucidal composition of the invention.
  • Figure 1 illustrates the structures of the products described in Example 1 N.
  • Figure 2 provides the EC 5 o assay results from the study reported in Example 3B.
  • Figure 3 provides the virucidal assay results from the study reported in Example 3C.
  • alkene or “alkenyl” refers to a monoradical branched or unbranched, unsaturated or polyunsaturated hydrocarbon chain, having from about 2 to 30 carbon atoms, more preferably about 5 to 30 carbon atoms and still more preferably about 7 to about 15 carbon atoms. This term is exemplified by groups such as ethenyl, but- 2-enyl, hex-2, 5-dienyl, (2E,6E)-5-methyl-9Z. 3 -nona-2,6-diene, (3E,7E)-5-methyl-1Z. 3 - unacdeca-3,7-diene and the like.
  • alkenyl when recited to specify a group linking to another moiety [such as sulfonyl or -(C9 to C25 alkenej-SC ] refers to a diradical branched or unbranched, unsaturated or polyunsaturated hydrocarbon chain, a terminal hydrogen of which is substituted by such other moiety. This term is exemplified by groups such as: (2E,6E)-5-methyl-1Z. 3 ,9Z. 3 -nona-2,6-diene, (3E,7E)-5-methyl-1Z.
  • Alkenyl moieties can be substituted wherein 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain containing from 1 to 50 carbon atoms, preferably 5 to 30 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms.
  • alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and 6-isopropyl-3-methyl-10X 3 - decane.
  • alkyl when recited to specify a group linking to another moiety (such as sulfonylalkyl) refers to a diradical branched or unbranched saturated hydrocarbon chain derived from an alkyl monoradical, a terminal hydrogen of which is substituted by such other moiety; exemplified by groups such as methylene, ethylene, n- propylene, i-propylene, 1 X 3 ,9X 3 -nonane, 1X 3 ,11X 3 -undecane, 5-(4X 3 -butyl)-11X 3 -undecane, 1X 3 ,13X 3 -tridecane, 3-methyl-1X 3 ,13Z, 3 -tridecane, 1X 3 ,16X 3 -hexadecane, 2-(X 3 -methyl)-5- methyl-16X 3 -hexadecane, 1X 3 ,20X 3 -icosane, 1 X 3
  • substituted alkyl refers to an alkyl group in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent selected from the group comprising: alkenyl, alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkylamidoalkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsul
  • Preferred substiituents for "substituted alkyl” are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
  • alkyl-based ligand refers to a diradical branched or unbranched saturated or unsaturated hydrocarbon chain derived from an alkyl or alkenyl monoradical, a terminal hydrogen of which is substituted by another moiety, such as a sulfate or a sulfonate moiety.
  • the alkyl-based ligands of the invention can have 1 to 50 carbon atoms, preferably 9 to 25 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms.
  • substituted alkyl-based ligand refers to an alkyl-based ligand in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl.
  • Preferred substiituents for "substituted alkyl-based ligand" are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
  • alkyl ligand refers to a diradical branched or unbranched saturated hydrocarbon chain derived from an alkyl monoradical, a terminal hydrogen of which is substituted by another moiety, such as a sulfate or a sulfonate moiety.
  • the alkyl ligands of the invention can have 1 to 50 carbon atoms, preferably 9 to 25 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms.
  • substituted alkyl ligand refers to an alkyl ligand in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl.
  • Preferred substiituents for "substituted alkyl ligand" are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
  • the term “at least one” used in a phrase such as “at least one C atom” refers to “one C atom” or “two C atoms” or “more than two C atoms”.
  • Cyclodextrins are naturally occurring cyclic glucose derivatives consisting of alpha(14)-linked glucopyranoside units. Their cyclic structure creates a truncated cone shape with the primary hydroxyls of the glucose units on the narrow face and the secondary hydroxyls on the wider face. Each face can be readily and independently functionalised.
  • the most commonly used natural CDs have 6, 7, and 8 glucopyranoside units, and are referred to as alpha, beta and gamma cyclodextrin, respectively.
  • the preferred cyclodextrin is beta. Because of the cyclic structure of CDs, they have a cavity capable of forming supramolecular inclusion complexes with guest molecules.
  • CDs are naturally occurring, readily functionalised, have a cavity for guest inclusion and are biocompatible, they have found use in many commercial applications including drug delivery, air fresheners, etc.
  • the difference in reactivity of each face of CDs has been used for the synthesis of a wide range of modified cyclodextrins.
  • the primary face of CDs is more readily modified, with control over the degree and location of substitution being possible.
  • CD derivatives that bear a good leaving group, such as halogenated CDs are important intermediates in CD functionalisation. For example, replacing all of the primary hydroxyl units of CDs with iodo-units gives an intermediate that allows for complete functionalisation of the primary face, whilst leaving the secondary hydroxyls and the rigid truncated cone shape intact.
  • mammal refers to any animal classified as a mammal, including humans, domestic and farm animals or pet animals, such as dogs, horses, cats, cows, monkeys etc. Preferably, the mammal is human.
  • optionally substituted alkyl means either “alkyl” or “substituted alkyl,” as defined. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl including optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible.
  • esters of the compounds of the present invention refers to esters of the compounds of the present invention, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, morpholinoethyl esters and the like.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the compounds the invention and includes pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of Formula I may be prepared from an inorganic acid or from an organic acid, or can be prepared in situ during the final isolation and purification of the compounds of the invention. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of Formula I include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995.
  • the pharmaceutically acceptable salt of the compounds of the invention is a sodium salt.
  • the terms “subject” or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human, and other, e.g., avian animals, such as a chicken.
  • the terms “subject” or “patient” refer to a human and animals, such as dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, chicken.
  • the subject is a subject in need of treatment, or a subject being infected by a virus.
  • a subject can be an animal infected by a virus, such as a chicken.
  • the subject can be a healthy subject or a subject who has already undergone treatment.
  • the term does not denote a particular age or sex. Thus, adult, children and newborn subjects, whether male or female, are intended to be covered.
  • the term “therapeutically effective amount” refers to an amount of a compound of the invention effective to alter a virus, and to render it inert, in a recipient subject, and/or if its presence results in a detectable change in the physiology of a recipient subject, for example ameliorates at least one symptom associated with a viral infection, prevents or reduces the rate transmission of at least one viral agent.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures.
  • Those in need of treatment include those already being infected by a virus, as well as those in which the viral infection is to be prevented or those who are likely to come into contact with a virus.
  • the mammal, preferably human, to be treated herein may have been diagnosed as being infected by a virus, or may be predisposed or susceptible to be infected by a virus.
  • Treatment includes ameliorating at least one symptom of, curing and/or preventing the development of a disease or condition due to the viral infection. Preventing is meant attenuating or reducing the ability of a virus to cause infection or disease, for example by affecting a post-entry viral event.
  • the term “virucidal” refers to a characterization of antiviral efficacy determined by in vitro testing demonstrating irreversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition. Even following termination of the interaction (for example, by dilution) and absent any added materials or conditions promoting viral reconstitution, it is essentially impossible for the virus to resume infectivity. Interaction with antiviral compound or composition alters the virus, rendering it inert, and thereby prevents further infections.
  • virustatic refers to a characterization of antiviral efficacy determined by in vitro testing demonstrating reversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition. Once the interaction terminates (for example, by dilution) and absent any added materials or conditions promoting viral reconstitution, it is possible for the virus to resume infectivity.
  • water solubilizing moiety refers to a group appended to the parent molecular moiety, which increases the aqueous solubility of the overall composition; if replaced by a hydrogen the overall composition will be less soluble at micromolar concentrations.
  • Water soluble moieties include ketones, alcohols, aldehydes, ethylene glycols and charged groups such as amines, carboxylates, phosphates, sulfates and sulfonates.
  • the present invention provides improved compositions and methods that can be used to treat viral diseases.
  • the invention provides a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I: wherein: each R, independently, is OH, SH, an -O-(C 9 to C25)-optionally substituted alkyl- based ligand or a -S-(C 9 to C 25 )-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate ("SO4") or a sulfonate (“SO3”) moiety; each R’, independently, is H, -(CH 2 ) y -COOH, -(CH 2 ) y -SO’ 8 , a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
  • each R independently, is OH, SH, an -O-(C 9 to C25)-optionally substituted alkyl- based ligand or a
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 25 )-optionally substituted alkyl-based ligand or a -S-(Ci 2 to C 25 )-optionally substituted alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 20 )-optionally substituted alkyl-based ligand or a -S-(Ci 2 to C 20 )-optionally substituted alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 25 )-alkyl-based ligand or a -S-(Ci 2 to C 25 )-alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 2 o)-alkyl-based ligand or a -S-(Ci 2 to C 20 )- alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O- (Ci 2 to C 25 )-unbranched alkyl-based ligand or a -S-(Ci 2 to C 25 )-unbranched alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 20 )-unbranched alkyl-based ligand or a -S-(Ci 2 to C 20 )-unbranched alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O- (Ci 2 to C 25 )-alkyl ligand or a -S-(Ci 2 to C 25 )-alkyl ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 2 o)-alkyl ligand or a -S-(Ci 2 to C 29 )- alkyl ligand
  • the ligand of R in the compounds of Formula I is an -O- (Ci 2 to C 25 )-unbranched alkyl ligand or a -S-(Ci 2 to C 25 )-unbranched alkyl ligand.
  • the ligand of R in the compounds of Formula I is an -O-(Ci 2 to C 29 )- unbranched alkyl ligand or a -S-(Ci 2 to C 20 )-unbranched alkyl ligand.
  • R has a sulfate moiety and an -O-(C 9 to C 25 )-optionally substituted alkyl-based ligand or a -S-(C 9 to C 25 )-optionally substituted alkyl-based ligand, where no more than 1 R group can be OH or SH.
  • R has a sulfonate moiety and an -O-(Ci3 to Ci 8 )-optionally substituted alkyl-based ligand or a -S-(Ci 3 to Ci 8 )-optionally substituted alkyl-based ligand, where no more than 1 R group can be OH or SH.
  • R is an -O-(Ci 2 to Ci 8 )-optionally substituted alkyl-based ligand or a -S-(Ci 2 to Ci 8 )-optionally substituted alkyl-based ligand, or • R is an -O-(Ci 2 to Ci 8 )-alkyl-based ligand or a -S-(Ci 2 to Ci 8 )-alkyl-based ligand,
  • R is an -O-(Ci 2 to Ci 8 )-unbranched alkyl-based ligand or a -S-(Ci 2 to Ci 8 )- unbranched alkyl-based ligand,
  • R is an -O-(Ci 2 to Ci 8 )-optionally substituted alkyl ligand or a -S-(Ci 2 to Ci 8 )- optionally substituted alkyl ligand, or
  • R is an -O-(Ci 2 to Ci 8 )-alkyl ligand or a -S-(Ci 2 to Ci 8 )-alkyl ligand
  • R is an -O-(Ci 2 to Ci 8 )-unbranched alkyl ligand or a -S-(Ci 2 to Ci 8 )-unbranched alkyl ligand, where no more than 1 R group can be OH or SH.
  • the compounds useful as active agents in practice of the methods of treatment uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C 9 to C 25 )-optionally substituted alkyl-based ligand or a -S-(C 9 to C 25 )-optionally substituted alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Cw to C 29 )-optionally substituted alkyl-based ligand or a -S-(Cw to C 20 )-optionally substituted alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci 3 to Ci 8 )-optionally substituted alkyl-based ligand or a -S-(Ci 3 to Ci 8 )-optionally substituted alkyl-based ligand.
  • the compounds useful as active agents in practice of the methods of treatment uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C 9 to C 25 )-alkyl-based ligand or a -S-(C 9 to C 25 )-alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Cw to C 20 )-alkyl-based ligand or a -S-(Ci 0 to C 20 )-alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci 3 to Ci 8 )-alkyl-based ligand or a -S-(Ci 3 to Ci 8 )-alkyl-based ligand.
  • the compounds useful as active agents in practice of the methods of treatment uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C 9 to C 25 )-unbranched alkyl-based ligand or a -S-(C 9 to C 25 )- unbranched alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci 0 to C 20 )-unbranched alkyl-based ligand or a -S-(Ci 0 to C 20 )- unbranched alkyl-based ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci3 to Ci 8 )-unbranched alkyl-based ligand or a -S-(Ci3 to Ci 8 )- unbranched alkyl-based ligand.
  • the compounds useful as active agents in practice of the methods of treatment uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C 9 to C 25 )-alkyl ligand or a -S-(C 9 to C 25 )-alkyl ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci 0 to C 20 )-alkyl ligand or a -S-(Cio to C 20 )-alkyl ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci3 to Cis)-alkyl ligand or a -S-(Ci3 to Cis)-alkyl ligand.
  • the compounds useful as active agents in practice of the methods of treatment uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C 9 to C 2 s)-unbranched alkyl ligand or a -S-(C 9 to C 2 s)-unbranched alkyl ligand.
  • the ligand of R in the compounds useful as such is an -O- (Cio to C 20 )-unbranched alkyl ligand or a -S-(Ci 0 to C 20 )-unbranched alkyl ligand.
  • the ligand of R in the compounds useful as such is an -O-(Ci 3 to Ci 8 )- unbranched alkyl ligand or a -S-(Ci3 to Cis)-unbranched alkyl ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted C 9 -alkyl-based ligand, an -O- or -S-optionally substituted Cw-alkyl- based ligand, an -O- or -S-optionally substituted Cn-alkyl-based ligand, an -O- or -S- optionally substituted Ci 2 -alkyl-based ligand, an -O- or -S-optionally substituted Ci 3 -alkyl- based ligand, an -O- or -S-optionally substituted Cu-alkyl-based ligand, an -O- or -S- optionally substituted Ci 5 -alkyl-based ligand, an -O- or -S-optionally substituted Ci 6 -alkyl- based ligand, an -O- or -S-optionally substituted C -alkyl-based ligand,
  • the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted Ci 2 -alkyl-based ligand, an -O- or -S-optionally substituted Ci 3 -alkyl- based ligand, an -O- or -S-optionally substituted Cu-alkyl-based ligand, an -O- or -S- optionally substituted Ci 5 -alkyl-based ligand, an -O- or -S-optionally substituted Ci 6 -alkyl- based ligand, an -O- or -S-optionally substituted Cv-alkyl-based ligand, or an -O- or -S- optionally substituted Ci 8 -alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- Ci 2 -alkyl-based ligand, an -O- or -S- Ci 3 -alkyl-based ligand, an -O- or -S- Cu-alkyl-based ligand, an -O- or -S- Cis-alkyl-based ligand, an -O- or -S- Ci6-alkyl-based ligand, an -O- or - S- C 17-alkyl-based ligand, or an -O- or -S- Ci 8 -alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-unbranched alkyl-based ligand, an -O- or -S- C13- unbranched alkyl-based ligand, an - O- or -S- C14- unbranched alkyl-based ligand, an -O- or -S- C15- unbranched alkyl-based ligand, an -O- or -S- C - unbranched alkyl-based ligand, an -O- or -S- C17- unbranched alkyl-based ligand, or an -O- or -S- Ci 8 - unbranched alkyl-based ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted Ci 2 -alkyl ligand, an -O- or -S-optionally substituted Ci 3 -alkyl ligand, an -O- or -S-optionally substituted Ci4-alkyl ligand, an -O- or -S-optionally substituted Cisalkyl ligand, an -O- or -S-optionally substituted Ci 6 -alkyl ligand, an -O- or -S-optionally substituted C -alkyl ligand, or an -O- or -S-optionally substituted Ci 8 -alkyl ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-alkyl ligand, an -O- or -S- Ci 3 -alkyl ligand, an -O- or -S- Ci 4 -alkyl ligand, an -O- or -S- Cis-alkyl ligand, an -O- or -S- C -alkyl ligand, an -O- or -S- C -alkyl ligand, or an -O- or -S- Ci 8 -alkyl ligand.
  • the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-unbranched alkyl ligand, an -O- or -S- Ci 3 - unbranched alkyl ligand, an -O- or -S- Cu- unbranched alkyl ligand, an -O- or -S- C15- unbranched alkyl ligand, an -O- or -S- C - unbranched alkyl ligand, an -O- or -S- C17- unbranched alkyl ligand, or an -O- or -S- Ci 8 - unbranched alkyl ligand.
  • Still other aspects of the invention include a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I where:
  • R is an -O-(Ci 2 to C 2 o)-optionally substituted alkyl-based ligand or a -S-(Ci 2 to C 2 o)-optionally substituted alkyl-based ligand,
  • R is an -O-(Ci 2 to C 2 o)-optionally substituted alkyl ligand or a -S-(Ci 2 to C 20 )- optionally substituted alkyl ligand,
  • R is an -O-(Ci2 to Ci 8 )-optionally substituted alkyl ligand or a -S-(Ci2 to Ci 8 )- optionally substituted alkyl ligand,
  • R is an -O-(Ci2 to Ci 8 )-unbranched alkyl ligand or a -S-(Ci2 to Ci 8 )-unbranched alkyl ligand
  • the compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester is for use in treating a viral infection or a disease associated with an HSPG- seeking virus
  • the virus is HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV-A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H or HCV D168A,
  • the compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester is part of a virucidal composition including a suitable carrier,
  • the compound, pharmaceutically acceptable salt, pharmaceutically acceptable ester or virucidal composition is used in a method of disinfection and/or sterilization of non-living surfaces
  • the compound, pharmaceutically acceptable salt, pharmaceutically acceptable ester or virucidal composition is used in a surface coating for device.
  • Cyclodextrins are composed of alpha-(1 ->4)-linked D-glucopyranose units.
  • C# is the number of carbon atoms counting the shortest chain directly linking the ether to the sulfonate or sulfate
  • R' identifies any substitutions on the secondary face, or is absent where R' is H.
  • the compound PCD-SCI 2 SO 3 ' is a compound of Formula I where each R is -S-(CH 2 )I 2 SO 3 ‘, R' is H, and x is 7.
  • the compound is also named CD-M12S in Figure 1 F.
  • the compound yCD-OCio-(7-Et)-S0 4 _ is a compound of Formula I where each R is -O-(CH 2 ) 6 -C(CH 2 -CH 3 )-(CH 2 ) 3 -SO 4 -, R' is H, and x is 8.
  • the compound CD-SCi2SO3 -(R' -(CH 2 ) 4 -COOH) is a compound of Formula I where each R is -S-(CH 2 )I 2 SO 3 ‘, R' is -(CH 2 ) y -COOH, x is 7 and y is 4.
  • solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like].
  • solvents used in the reactions of the present invention are inert organic solvents. Reactions take place at room temperature and 1 atmosphere of pressure unless otherwise indicated.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
  • a mercapto-cyclodextrin (103) is contacted with a 1.5 to 2 times molar excess (per thiol group) of a sodium alkene sulfonate (102), optionally with a photoinitiator (such as 2,2- dimethoxy-2-phenylacetophenone), in a suitable solvent.
  • a photoinitiator such as 2,2- dimethoxy-2-phenylacetophenone
  • the compounds of Formula I can be synthesized using alternative synthetic routes.
  • a cyclodextrin (alpha, beta or gamma) halogenated on its primary face, preferably using bromine or iodine can be reacted with a thiolated optionally substituted alkyl-based ligand-sulfonate or -sulfate [i.e., HS-(optionally substituted alkyl- based ligand)-SO 3 ‘ or HS-(optionally substituted alkyl-based ligand)-SO 4 ] in a suitable solvent (preferably a dry, polar aprotic solvent such as DMF) in the presence of a base.
  • a suitable solvent preferably a dry, polar aprotic solvent such as DMF
  • the compounds of Formula I can also be prepared by reacting a cyclodextrin (alpha, beta or gamma) halogenated on its primary face, preferably using bromine or iodine, with a thiolated optionally substituted alkyl-based hydroxy ligand [i.e., HS-(optionally substituted alkyl-based ligand)-OH], followed by halogenation of the hydroxy moiety that can then be sulfonated.
  • a cyclodextrin alpha, beta or gamma
  • a thiolated optionally substituted alkyl-based hydroxy ligand i.e., HS-(optionally substituted alkyl-based ligand)-OH
  • the same can be done to sulfate this terminal hydroxy moiety by using a weaker sulfating agent to avoid sulfation of the hydroxy groups on the cyclodextrin's secondary face.
  • the compounds of Formula I where R is an -O-(C 9 to C 25 )-optionally substituted alkyl-based ligand can be synthesized by contacting a CD that is halogenated on the primary face (I or Br) with an co-hydroxy sulfonate or sulfate reactant corresponding to (102) or (105), under dry, basic conditions.
  • a compound of Formula I is prepared by a thiol-ene click reaction by contacting a cyclodextrin that is thiolated on its primary face with an optionally substituted alkyl-based ligand-(sulfonate or -sulfate)-1 -ene in the presence of UV light.
  • a cyclodextrin, halogenated on its primary face, is contacted with a thiolated optionally substituted alkyl-based ligand-sulfonate or -sulfate in the presence of a base.
  • a cyclodextrin having halogenated, optionally substituted alkyl-based ligands on its primary face is contacted with a sulfonating or a sulfating agent.
  • a compound of Formula I is contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt.
  • a pharmaceutically acceptable acid addition salt of Formula I is contacted with a base to form the corresponding free base of Formula I.
  • Formula I is a composition of matter where R' is H. o
  • the ligand of R is an -O-(Ci 2 to C 25 )-optionally substituted alkyl-based ligand or a -S-(Ci 2 to C 25 )-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to C 20 )-optionally substituted alkyl- based ligand or a -S-(Ci 2 to C 20 )-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-optionally substituted alkyl-based ligand or a -S-(Ci 2 to Ci 8 )-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci2 to C25)-alkyl-based ligand or a -S-(Ci2 to C25)- alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to C 20 )-alkyl-based ligand or a -S-(Ci 2 to C 20 )-alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-alkyl-based ligand or a -S-(Ci2 to Ci 8 )-alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to C 25 )-unbranched alkyl-based ligand or a - S-(Ci2 to C2s)-alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to C 2 o)-unbranched alkyl-based ligand or a -S-(Ci2 to C 2 o)-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(Ci2 to Ci 8 )-unbranched alkyl-based ligand or a -S-(Ci 2 to Ci 8 )-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to C 25 )-alkyl ligand or a -S-(Ci 2 to C 25 )-alkyl ligand.
  • the ligand of R is an -O-(Ci2 to C2o)-alkyl ligand or a -S-(Ci2 to C20)- alkyl ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-alkyl ligand or a -S-(Ci 2 to Ci 8 )-alkyl ligand.
  • the ligand of R is an -O-(Ci 2 to C 25 )-unbranched alkyl ligand or a -S-(Ci 2 to C 25 )-unbranched alkyl ligand.
  • the ligand of R is an -O-(Ci 2 to C 2 o)-unbranched alkyl ligand or a - S-(Ci2 to C2o)-unbranched alkyl ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-unbranched alkyl ligand or a -S-(Ci2 to Ci 8 )-unbranched alkyl ligand.
  • Formula I is a compound useful as an active agent in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents where R' is H.
  • the ligand of R is an -O-(C 9 to C 25 )-optionally substituted alkyl-based ligand or a -S-(C 9 to C 25 )-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci 0 to C 2 o)-optionally substituted alkyl- based ligand or a -S-(Ci 0 to C 2 o)-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-optionally substituted alkyl-based ligand or a -S-(Ci2 to Ci 8 )-optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(Ci3 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci 3 to Ci 8 )- optionally substituted alkyl-based ligand.
  • the ligand of R is an -O-(C 9 to C 25 )-alkyl-based ligand or a -S-(C 9 to C 25 )- alkyl-based ligand.
  • the ligand of R is an -O-(Cw to C 29 )-alkyl-based ligand or a -S-(Cw to C 20 )-alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-alkyl-based ligand or a -S-(Ci 2 to Ci 8 )-alkyl-based ligand.
  • the ligand of R is an -O-(Ci 3 to Ci 8 )-alkyl-based ligand or a -S-(Ci 3 to Ci 8 )-alkyl-based ligand.
  • the ligand of R is an -O-(C 9 to C 25 )-unbranched alkyl-based ligand or a -S- (C 9 to C 2 s)-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(Ci 0 to C 20 )-unbranched alkyl-based ligand or a -S-(Cio to C 20 )-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-unbranched alkyl- based ligand or a -S-(Ci 2 to Ci 8 )-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(Ci 3 to Ci 8 )-unbranched alkyl-based ligand or a -S-(Ci 3 to Ci 8 )-unbranched alkyl-based ligand.
  • the ligand of R is an -O-(C 9 to C 25 )-unbranched alkyl ligand or a -S-(C 9 to C 25 )-unbranched alkyl ligand.
  • the ligand of R is an -O-(Cw to C 29 )-unbranched alkyl ligand or a - S-(Cio to C 20 )-unbranched alkyl ligand.
  • the ligand of R is an -O-(Ci 2 to Ci 8 )-unbranched alkyl ligand or a -S-(Ci 2 to Ci 8 )-unbranched alkyl ligand.
  • the ligand of R is an -O-(Ci 3 to Ci 8 )-unbranched alkyl ligand or a -S-(Ci 3 to Ci 8 )-unbranched alkyl ligand.
  • Particularly preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention are the following: pCD-SCioS0 3 ‘, [BCD- SC11SO3; pCD-SCi 2 SO 3 ’, pCD-SCi 3 SO 3 ’,
  • More preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention is the following: pCD-SCi 2 SO 3 _ , 0CD- SCi 3 SO 3 ', pCD-SCuSOs", pCD-SCi5SO 3 ‘, pCD-SCi6SO 3 ', pCD-SCvSOs', pCD-SCi 3 SO 3 ' and pCD-SCnSCV
  • compositions of the invention find use in a variety of applications. As will be appreciated by those in the art, the compositions are antiviral and have demonstrated virucidal activity against HSV-2.
  • compositions of the invention are also useful as antivirals against, and in the treatment of diseases associated with HSPG-seeking viruses including, without limitation, HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV-A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H and HCV D168A.
  • diseases associated with HSPG-seeking viruses including, without limitation, HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV-A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H and HCV D168A.
  • Another aspect of the invention provides a method of disinfection and/or sterilization of surfaces using one or more compounds of the invention or the virucidal composition of the invention or the pharmaceutical composition of the invention.
  • the disinfection and/or sterilization is preferably done on living surfaces or non-living surfaces.
  • the living surfaces are human or animal skin and/or hair.
  • the non-living surface are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas.
  • the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • the method of disinfection and/or sterilization of surfaces comprises the steps of (i) providing at least one compound of the invention or a virucidal composition of the invention, or pharmaceutical composition of the invention, (ii) contacting a virus-contaminated surface or a surface suspected to be contaminated by a virus with the at least one compound of the invention or a virucidal composition of the invention or pharmaceutical composition of the invention for a time sufficient to obtain virucidal effect.
  • the virus-contaminated surface is human or animal skin and/or hair. In other embodiments, the virus-contaminated surface is a non-living surface.
  • the non-living surface is, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas.
  • the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • Another aspect of the invention provides a use of a compound of the invention or a virucidal composition of the invention or a pharmaceutical composition of the invention for sterilization and/or for disinfection.
  • sterilization and disinfection is for virus-contaminated surfaces or surfaces suspected to be contaminated by a virus.
  • the surfaces are human or animal skin and/or hair.
  • the invention provides a use of a compound of the invention or a virucidal composition of the invention or a pharmaceutical composition of the invention for sterilization and/or for disinfection of human or animal skin and/or hair.
  • the surfaces are non-living surfaces.
  • the non-living surfaces are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas.
  • the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • the virucidal composition of the invention or the pharmaceutical composition of the invention is used as virucidal hand disinfectant for frequent use.
  • the virucidal composition of the invention or the pharmaceutical composition of the invention is applied by spraying.
  • the virucidal composition of the invention of the pharmaceutical composition of the invention is applied on a protective mask.
  • Another aspect of the invention provides a use of the compounds of the invention or the virucidal composition of the invention for manufacturing (producing) virucidal surfaces (i.e. able to inactivate viruses).
  • Such surfaces are, but not limited to, textile, clothing, masks, touch screens, medical equipment, furniture.
  • the surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • the surfaces can be modified with the one or more compounds of the invention either through chemical modification or physical coating known in the art. Examples of physical coating are spraying or dipping the surface in a solution comprising the one or more compounds of the invention.
  • Another aspect of the invention provides a method for manufacturing (producing) a virucidal surface, wherein the method comprises coating the surface with the one or more compounds of the invention or the virucidal composition of the invention.
  • the surface is, but not limited to, textile, clothing, masks, touch screens, medical equipment, furniture.
  • the surface is fabric surface (masks, gloves, doctor coats, curtains, bed sheet), metal surface (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surface (furniture, floors, partition panels), concrete surface (hospitals, clinics and isolation wards and walls), and plastic surface (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • the coating can be done either through chemical modification or physical coating known in the art.
  • Another aspect of the invention provides a virucidal surface coating composition comprising the one or more compounds of the invention or the virucidal composition of the invention.
  • the virucidal surface coating composition of the invention can be sprayed or painted on surfaces.
  • the surfaces are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas.
  • the surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
  • Another aspect of the invention provides a device comprising a surface coated with one or more compounds of the invention or with the virucidal composition of the invention.
  • Such an antiviral coated device can be, but is not limited to, clothing, a mask, a glove, a touch screen, medical equipment, furniture, etc....
  • the device is a mask, clothing or medical equipment.
  • the device is a medical device.
  • Cytotoxicity is determined by exposing Vero cells to varying concentrations of test drug and measuring the percentage of cells surviving such exposure.
  • Antiviral activity is determined by plaque reduction assays on infected Vero cells, measuring the number of plaques that form in wells exposed to a mixture of a fixed concentration of the virus and varying concentrations of test drug.
  • Virucidal activity is determined by exposing Vero cells to different dilutions of a prep-incubated mixture of virus and an effective amount of test drug. After incubation, the solution is removed and the cells are incubated again, measuring the plaques that form, evaluating the viral titer. The decrease of viral titer with respect to an untreated control is an indication of virucidal activity.
  • the compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described.
  • Administration of the compounds of the invention or the pharmaceutically acceptable salts or esters thereof can be via any of the accepted modes of administration for agents that serve similar utilities.
  • a daily dose is from about 0.001 to 2.0 mg/kg of body weight/day, preferably about 0.005 to 0.75 mg/kg of body weight/day, and most preferably about 0.01 to 0.5 mg/kg of body weight.
  • the dosage range would be about 0.07 to 140 mg per day, preferably about 0.35 to 52.5 mg per day, and most preferably about 0.7 to 35 mg per day.
  • Administration can be as a single daily dose or divided into 2 or more doses per day, over a period of treatment lasting from about 1 to about 7 days.
  • the amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
  • compositions can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers, excipients and/or diluents, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • administration of the compounds can be achieved in various ways, including oral, buccal, inhalation (pulmonary, nasal), rectal, parenteral, intraperitoneal, intradermal, topical, transdermal, intracranial and/or intratracheal administration.
  • the compounds can be administered in a local rather than systemic manner, e.g., in a topical cream or gel, a depot or a sustained release formulation.
  • the compounds can be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes.
  • the compounds can be administered alone, in combination with each other, or they can be used in combination with other known compounds including oither antiviral agents.
  • Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th ed.), which is incorporated herein by reference.
  • for a brief review of methods for drug delivery see, Langer, Science (1990) 249:1527-1533, which is incorporated herein by reference.
  • Acceptable carriers, excipients or diluents include those that are acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable carrier, excipient and/or diluent" as used in the specification and claims includes both one and more than one such carrier, excipient and/or diluent.
  • Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the invention, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and [gamma] ethyl-L-glutamate non-degradable ethylene-vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT(TM) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3- hydroxybutyric acid.
  • the compounds of the invention can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • a compound of the invention (and optionally another active agent) can be formulated into preparations by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives.
  • the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the compounds of the invention in water-soluble form.
  • suspensions of the compounds of the invention can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds of the invention to allow for the preparation of highly concentrated solutions.
  • the amount of a compound of the invention that can be combined with a carrier material to produce a single dosage form will vary depending upon the viral disease treated, the mammalian species, and the particular mode of administration. It will be also understood, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular viral disease undergoing therapy, as is well understood by those of skill in the area.
  • a virucidal composition comprising an effective amount of one or more compounds of the invention and optionally at least one suitable carrier or aerosol carrier.
  • “An effective amount” refers to the amount sufficient for irreversibly inhibiting viruses; i.e. sufficient for obtaining virucidal effect.
  • the suitable carrier is selected from the group comprising stabilisers, fragrance, colorants, emulsifiers, thickeners, wetting agents, or mixtures thereof.
  • the virucidal composition can be in the form of a liquid, a gel, a foam, a spray or an emulsion.
  • the virucidal composition can be an air freshener, a sterilizing solution or a disinfecting solution.
  • Another aspect of the invention provides a device (or a product) comprising the virucidal composition of the invention or one or more compounds of the invention and means for applying and/or dispensing thereof (i.e. the compounds of the invention or the virucidal composition).
  • the means comprise a dispenser, a spray applicator or a solid support soaked with the compounds of the invention.
  • the support is a woven or non-woven fabric, a textile, a paper towel, cotton wool, an absorbent polymer sheet, or a sponge.
  • Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
  • Formulations of the active compound or a salt may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
  • MS Mass spectrometry
  • ESI electrospray ionization
  • MS2 mass/charge ratio
  • the suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium octa-7-enesulfonate white solid was collected, weighed (-5 g) was recrystallised in MilliQ water (100mL) yielding 3.1g of a white solid (yield 55.3%).
  • the suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the white solid was collected, weighed ( ⁇ 5 g) dissolved in 120mL of MilliQ water inside a 500 mL round bottom flask (a heat gun was used to help solubilize). The solution was kept overnight at 4°C. Thin white crystals formed and the viscous solution was decanted.
  • the wet white suspension was further collected using 45 mL Falcon tubes and centrifugation at 5500 rpm.
  • the suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid (insoluble Na 2 SO 3 , NaBr and other inorganics) on the filter.
  • the clear filtrate was evaporated using a rotary evaporator and the white residue was dried overnight under high vacuum.
  • the white solid was collected, weighed ( ⁇ 5 g) dissolved in 150mL of MilliQ water inside a 500 mL round bottom flask (a heat gun was used to help solubilize). The solution was kept overnight at 4°C when white thin crystals formed forming a viscous solution. This solution was decanted and further collected using 45 mL Falcon tubes and centrifugation at 5500 rpm.
  • the suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium dodeca-11-enesulfonate white solid was collected, weighed ( ⁇ 4.5 g) was recrystallised in MilliQ water (250mL) yielding 3 g of a white solid (yield 55 %).
  • the suspension was filtered into a clean 1 L round bottom flask and additional hot methanol and ethanol were used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium trideca-12-enesulfonate white solid was collected, weighed ( ⁇ 1 .4 g) was recrystallised in MilliQ water (100mL) yielding 0.7 g of a white solid (yield 64.7 %).
  • the powder was added to 250 mL of methanol and 250mL of ethanol under magnetic stirring at 80°C.
  • the suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na2SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium tetradeca- 13-enesulfonate white solid was collected, weighed ( ⁇ 1.6 g) was recrystallised in MilliQ water (150 mL) yielding 0.85 g of a white solid (yield 79.4%).
  • the white solid was extracted with a mixture of hot methanol, ethanol and isopropanol.
  • the powder was added to a mixture of 125 mL of methanol and 125 mL of ethanol and 125 mL of isopropanol under magnetic stirring at 80°C.
  • the suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • MS Mass spectrometry
  • ESI electrospray ionization
  • MS2 mass/charge ratio
  • 16-Bromo-1 -hexadecene (1 g, 3.3mmol) and Na 2 SO 3 (2.1 g, 16.5 mmol) were added into a mixture of methanol (70 mL) and MilliQ Water (130 mL). The mixture was refluxed for 7 days at 105°C. Thin layer chromatography (TLC) was used to monitor the reaction. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 2.7 g of a white solid.
  • TLC Thin layer chromatography
  • the white solid was extracted with a mixture of hot methanol, ethanol and isopropanol.
  • the powder was added to a mixture of 125 mL of methanol and 125 mL of ethanol and 125 mL of isopropanol under magnetic stirring at 80°C.
  • the suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • MS Mass spectrometry
  • ESI electrospray ionization
  • MS2 mass/charge ratio
  • 17-Bromo-1 -hexadecene (2g, 6.3mmol) and Na 2 SO 3 (3 g, 23.8 mmol) were added to 70 mL of MilliQ Water.
  • the mixture was placed inside an autoclave and the reaction was conducted at 200°C for 12h.
  • the resulting white slurry was transferred to two 45mL falcon tubed with the aid of additional MilliQ water, frozen with liquid nitrogen and lyophilised.
  • a white powder was collected after 48h from high vacuum and was washed vigorously for 16h with diethyl ether using magnetic stirring.
  • the white suspension was filtered and dried under high vacuum yielding 4.5 g of a white solid.
  • the white solid was extracted on the filter with hot ethanol and isopropanol into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium heptadeca-16-enesulfonate white solid was collected, weighed (-1.5 g) was recrystallised in a mixture of 20% ethanol in water (100mL) 1.1 g of crystalline needles that form a white powder once dried (yield 52.8%).
  • the white solid was extracted on the filter with hot ethanol and isopropanol into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid off the filter (insoluble Na 2 SO 3 , NaBr and other inorganics).
  • the filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum.
  • the resulting sodium octadeca-17-enesulfonate white solid was collected, weighed ( ⁇ 1.3 g) was recrystallised in a mixture of 20% ethanol in water (100mL) 0.8 g of crystalline needles that form a white powder once dried (yield 40.4%).
  • Chlorosulfonic acid (5.2 g, 0.03 mol) was added dropwise using an addition funnel into an ice-cooled three-neck round bottom flask with 40 mL of pyridine. While this solution equilibrated, undec-10-ene-1 -ol (6.5 g, 0.038 mol) was dissolved in 10 mL of pyridine, transferred to an addition funnel and connected to a free neck in the round bottom flask. The solution of undec-10-ene-1 -ol was added dropwise over 20 minutes, forming a grey mixture. The ice bath was switched to an oil bath and the temperature brought to 60°C and left stirring at this temperature for 16h. A saturated solution of NaHCO 3 was prepared, cooled in an ice bath.
  • the reaction crude was slowly added to the cold NaHCO 3 solution while it stirred. A clear solution formed and was allowed to stir for 12h at room temperature.
  • This solution was extracted with 100mL of 1 -butanol three times.
  • the 1 -butanol extracts were combined and washed with 250 mL of brine in a 1 L separatory funnel, collected, dried over MgSO 4 and the solvent was removed using a rotary evaporator.
  • the white solid on the walls of the round bottom flask was washed with 300mL of diethyl ether, filtered. The solid on the filter was further washed with 300mL of acetone. The solid was collected and dried under high vacuum.
  • Example 1A-1 L By following the procedures of Example 1A-1 L (as appropriate for chain length) and substituting the starting ®-bromoalk-1 -ene reactant with: a) 9-bromo-7-ethylnon-1-ene, b) 9-bromo-6,7-diethylnon-1 -ene, c) 7-(3-bromopropyl)undec-1 -ene, d) 11 ,12-dibromododec-1 -ene, e) 15-bromo-12-methylhexadec-1 -ene, f) 3-(4-bromobutyl)heptadec-16-enenitrile, g) 1 ,19-dibromo-10-vinylnonadecane, h) 22-bromodocos-1 -ene, i) (3E,7E)-9-bromo-5-methylnona-1 ,3,7-triene,
  • Ci I 9 H 2 I 7O49S14 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M] 7- calculated for C98H175O49S14- 369.1042; found 369.38781 .
  • HRMS High-resolution mass spectrometry
  • the product, pCD-SCwSOs' was purified by dialysis against Milli-Q H 2 O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-220 mg).
  • the product, pCD-SCi 3 SO 3 ' was purified by dialysis against Milli-Q H 2 O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-200 mg).
  • the product, pCD-SC SOa' was purified by dialysis against Milli-Q H 2 O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-200 mg).
  • the product, pCD-SCisSOs' was purified by dialysis against Milli-Q H 2 O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-270 mg).
  • the product, pCD-SCieSOs' was purified by dialysis against Milli-Q H 2 O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-275 mg).
  • the crude product, pCD-SCi 7 SO 3 ' was purified directly by dialysis, first against a 7:3 EtOH/H 2 O mixture, moving to 30/70 and finally two volumes of pure Milli-Q H 2 O for 4 days, (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-230 mg).
  • the crude product, pCD-SCi 8 SO 3 ' was purified directly by dialysis, first against a EtOH/H 2 O at rations of 80/20, 50/50, 30/70 then finally two volumes of pure Milli- Q H 2 O for 4 days, (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-290 mg).
  • Example 2A-2L By following the procedures of Example 2A-2L (as appropriate for chain length) and substituting the starting co-ene sulfonate reactant with: a) ((3-ethylnon-8-en-1 -yl)sulfonyl)-X 1 -oxidane, b) ((3,4-diethylnon-8-en-1 -yl)sulfonyl)-X 1 -oxidane, c) ((4-butyldec-9-en-1 -yl)sulfonyl)-X 1 -oxidane, d) (dodec-11 -ene-1 , 2-diyldisulfonyl)bis(X 1 -oxy) , e) ((5-methylhexadec-15-en-2-yl)sulfonyl)-X 1 -oxidane, f) 3-(4((X 1 -oxidanyle)dioxo-
  • Example 2A-2N By following the procedures of Example 2A-2N (as appropriate for chain length) and substituting the starting heptakis-(6-deoxy-6-mercapto)-[3-CD reactant with hexakis-(6- deoxy-6-mercapto)-a-CD or octakis-(6-deoxy-6-mercapto)-Y-CD, the corresponding a-CD and y-CD products are obtained.
  • A. Toxicity assay on Vero Cells Cytotoxicity of the compounds is tested on mammalian cells. Vero cells are plated 24h before the experiment in 96-well plates in order to have a confluent layer. Cells are then incubated with different concentrations of the compound being tested at 37°C for 24 h in DM EM w2% FBS. The solution is then removed and the cells washed with DMEM w2%FBS. 100 ul of DMEM w2% FBS is added in each well with 20 ul of MTS (CellTiter 96® AQueous One Solution Cell Proliferation Assay).
  • the EC 5 o data show notable increases of potency for C 9 and above, particularly C13 and above.
  • the corresponding dose-response graphs are presented in Figure 2, where the identification above each graph is another form of the compound name as shown in the upper left corner.
  • C. Virucidal assay against HSV-2 The virucidal activity of compounds of Formula I against HSV-2 is tested by virucidal assay. Vero cells are plated 24h before the experiment in 96-well plates in order to have a confluent layer. An effective amount of the compound of interest (100-300-500 pg/ml) is incubated with a fixed amount of viruses (10 5 - 10 6 pfu/ml) for 1 hour at 37 °C in DMEM - 2%FBS. A serial dilution of this solution is added in each well and incubated for 1 hour at 37°C.
  • the solution is removed and the cells incubated for 24 h in DMEM - 2% FBS with 0.45w% Methyl-Cellulose. The cells are then stained with crystal violet and the plaques counted. The viral titer is evaluated and compared against a reference with no compound.
  • polyethylene 1450 and 300 are melted at 50° C with stirring.
  • the pCD-SCnSOf, 2-deoxy-D-glucose, silica gel and stevioside are triturated together.
  • the triturated powders are slowly sifted into the melted PEGs with stirring.
  • the flavoring is added, followed by thorough mixing.
  • the mixture is poured into applicator tubes and allowed to cool to room temperature.
  • Example 5 Aqueous Cream Formulation
  • a part of the PCD-SCBSOS is dissolved in water with the 2-deoxy-D-glucose and propylene glycol at ambient temperature to produce an aqueous solution.
  • the paraffins and emulsifiers (cetostearyl alcohol and sodium lauryl sulphate) are mixed together, heated to 60° C, and emulsified with the aqueous solution, also at 60° C.
  • the remaining PCD-SCBSOS’ is added, the mixture dispersed, allowed to cool, and filled into lacquered aluminum tubes.
  • a nebuliser for example, as disclosed in US 9,364,618 B2 or EP 3,517,117 A1 is provided comprising the following pharmaceutical composition in its fluid reservoir: 14.0 mg PCD-SCBSOS’, 0.9% w/v NaCI dissolved in sterile deionised water.
  • the nebuliser is used to deliver the composition by inhalation as an aerosol to the lower respiratory tract of a patient suffering from influenza.

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Abstract

The invention relates to substituted cyclodextrin (CD) compounds having C9 to C25 optionally substituted alkyl-based linker groups, which irreversibly inhibit viruses and are useful in the treatment of viral infections. While the compounds of the invention show virus inhibition in the nanomolar range they show no in-vitro toxicity in the same range of concentration.

Description

VIRUCIDAL COMPOSITIONS AND USE THEREOF
[001] This application claims the benefit of priority of United States Provisional Patent Application Serial No. 63/246,967 filed September 22, 2021 , and Japanese Patent Application No. 2022-148837, filed September 20, 2022, the disclosure of which is incorporated by reference in its entirety for all purposes.
FIELD OF THE INVENTION
[002] This invention relates to substituted cyclodextrin (CD) compounds having C9 to C25 alkyl linker groups, which irreversibly inhibit heparane sulfate proteoglycan-seeking viruses and are useful in the treatment of viral infections such as COVID-19.
BACKGROUND OF THE INVENTION
[003] The recent emergence of SARS-CoV-2 resulted in a global pandemic (COVID- 19), threatening the health of the world’s population and causing dramatic socio-economic damage. It is known that new viruses can emerge or re-emerge every 3-4 years, as previously shown by H1 N1 , Ebola, H5N1 , Zika, etc., all episodes that revealed how our society is unprepared to respond to novel viruses. Indeed, even the percentages of people infected by known viruses such as HSV, HIV, and influenza evidence the urgency of developing novel strategies in fighting viral diseases.
[004] At present, there are two primary weapons against viruses: vaccines and antivirals. Vaccines are preventive drugs composed of modified or attenuated pathogens that are meant to stimulate an immunological bio-response prior to exposure to a live virus. At the moment, vaccines represent the most effective approach to preventing viral infections. However, the durability of protection following vaccination is not 100%. Vaccines are not always available, particularly in underdeveloped countries, and existing vaccines are highly unlikely to be effective against a virus that has not yet emerged. Thus, there remains a large unmet medical need for therapeutic interventions that can help at-risk and infected individuals. Antivirals are drugs designed to fight against viruses and viral infections directly.
[005] The life cycle of a virus is composed of multiple steps: 1 ) attachment, 2) entry, 3) uncoating, 4) biosynthesis, and 5) assembly and release. The typical mechanism of action of existing antivirals involves inhibiting a step of the viral life cycle, thereby stopping replication. Most antivirals target one or more of steps 2-5, requiring each antiviral to be specific for the manner in which such step is carried out by a particular virus. Given the error-prone nature of viral replication, viruses are often known to mutate and develop resistance to antivirals.
[006] The first step of the viral life cycle is attachment. In this step the virus recognizes a host cell using receptors on viral attachment ligands (VALs) that recognize and bind to specific proteins present on host cell membranes. It is known that the VALs of a significant percentage of all viruses target either heparane sulfate proteoglycans (HSPG) or sialic acid (SA) terminal moieties of proteins present on cell membranes. This facilitates a different approach to designing antivirals by mimicking HSPG or SA with a molecule (ranging from polymers to dendrimers, oligomers, nanoparticles, liposomes, monoclonal antibodies, and small molecules) that will bind to a virus and block viral entry. Many of these compounds have shown broad-spectrum activity and limited toxicity, yet none has been translated into a successful drug. The main limitation of such binding inhibitors lies in their mechanism itself. Binding is a reversible event, particularly when the environment (e.g., the bloodstream) surrounding a compound that is bound to a virus causes dissociation of the virus-compound complex, separating the virus from the compound that prevented binding and leaving the virus free to bind again. Unfortunately, dilution is a common event, especially in vivo. Such temporary blocking of viral attachment and/or replication is referred to as virustatic.
[007] The irreversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition is referred to as virucidal. Many known compounds, ranging from strong surfactants to alcohol, can irreversibly inhibit the infectivity of viruses. Most of these compounds, however, have not translated into acceptable drugs due to issues such as toxicity. Viruses are made of components similkar to those of the host, so a drug that damages or interferes with such common components in a virus or an infected cell will also damage (i.e., be toxic to) the host. Only a few compounds have demonstrated virucidal properties together with low toxicity, such as certain reported peptides, but these have been virus-specific, not broad spectrum.
[008] Therefore, there is still a need for virucidal agents that have low toxicity, excellent virucidal potency and broad-spectrum action.
[009] Prior, co-pending application PCT/EP2017/068291 , filed 17 July 2017, discloses substituted cyclodextrin compounds having alkyl linker groups bearing sulfate ("SO4") and sulfonate ("SO3") moieties that lure/target the attachment of a broad spectrum of viruses. These compounds have been demonstrated to have virucidal activity. It has recently been discovered that certain linker group lengths can significantly improve the efficacy of such compounds. SUMMARY OF THE INVENTION
[010] In accordance with the objects outlined above, the present invention provides improved compositions and methods that can be used to treat viral diseases.
[011] In one aspect, the invention provides a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I:
Figure imgf000004_0001
wherein: each R, independently, is OH, SH, an -O-(C9 to C25)-optionally substituted alkyl- based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate ("SO4") or a sulfonate ("SO3") moiety; each R’, independently, is H, -(CH2)y-COOH, -(CH2)y-SO 3, a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
[012] In another aspect, no more than 1 R group can be OH or SH and each of the remaining R groups have a sulfate or a sulfonate moiety. In yet another aspect, each R group is an -O-(C9 to C25)-optionally substituted alkyl-based ligand or a -S-(C9 to C25)- optionally substituted alkyl-based ligand having a sulfate ("SO4") or a sulfonate ("SO3") moiety.
[013] The compounds of Formula I are useful as active agents in practice of the methods of treatment and in manufacture of the pharmaceutical formulations of the invention, and as intermediates in the synthesis of such active agents. [014] Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount of the one or more compounds of the invention and at least one pharmaceutically acceptable excipient, carrier and/or diluent.
[015] Another aspect of the present invention provides the compounds of the invention for use in treating and/or preventing viral infections and/or diseases associated with viruses, particularly HSPG-seeking viruses.
[016] Another aspect of the present invention provides a virucidal composition comprising an effective amount of one or more compounds of the invention and at least one suitable carrier or aerosol carrier.
[017] Another aspect of the present invention provides a device comprising the virucidal composition of the invention or one or more compounds of the invention and means for applying and/or dispensing thereof.
[018] Another aspect of the present invention provides a method of disinfection and/or sterilization of non-living surfaces using one or more compounds of the invention or a virucidal composition of the invention.
[019] Another aspect of the present invention provides a use of one or more compounds of the invention or a virucidal composition of the invention for sterilization and/or for disinfection of human or animal skin and/or hair.
[020] Another aspect of the present invention provides a use of one or more compounds of the invention or a virucidal composition of the invention for manufacturing virucidal surfaces.
[021] Another aspect of the present invention provides a device comprising a surface coated with one or more compounds of the invention or with a virucidal composition of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[022] Figure 1 illustrates the structures of the products described in Example 1 N.
[023] Figure 2 provides the EC5o assay results from the study reported in Example 3B.
[024] Figure 3 provides the virucidal assay results from the study reported in Example 3C.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[025] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following abbreviations and definitions are supplied in order to facilitate the understanding of the present invention.
[026] As used in the specification and claims, the singular form "a", "an" and "the" includes plural references unless the context clearly dictates otherwise.
[027] The term “about” as used in conjunction with a number or a range of numbers, indicates that such number/range will be understood to be approximate. Thus, “about 2” encompasses the integers 1 , 2, 3 and 4. The term “about 9 to 25” should be read as "about 9 to about 25" and encompasses, e.g., ranges from 8 to 27, 10 to 28, 12 to 27 and 10 to 23.
[028] As used herein the term "alkene" or “alkenyl” refers to a monoradical branched or unbranched, unsaturated or polyunsaturated hydrocarbon chain, having from about 2 to 30 carbon atoms, more preferably about 5 to 30 carbon atoms and still more preferably about 7 to about 15 carbon atoms. This term is exemplified by groups such as ethenyl, but- 2-enyl, hex-2, 5-dienyl, (2E,6E)-5-methyl-9Z.3-nona-2,6-diene, (3E,7E)-5-methyl-1Z.3- unacdeca-3,7-diene and the like. The term “alkenyl” when recited to specify a group linking to another moiety [such as sulfonyl or -(C9 to C25 alkenej-SC ] refers to a diradical branched or unbranched, unsaturated or polyunsaturated hydrocarbon chain, a terminal hydrogen of which is substituted by such other moiety. This term is exemplified by groups such as: (2E,6E)-5-methyl-1Z.3,9Z.3-nona-2,6-diene, (3E,7E)-5-methyl-1Z.3,11X3-undeca-3,7- diene, (5E,9E)-1X3,14X3-tetradeca-5,9-diene, and (5E,9E,14E)-1X3,22X3-docosa-5,9,14- triene. Alkenyl moieties can be substituted wherein 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl.
[029] As used herein, the term “alkyl” refers to a monoradical branched or unbranched saturated hydrocarbon chain containing from 1 to 50 carbon atoms, preferably 5 to 30 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms. Representative examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and 6-isopropyl-3-methyl-10X3- decane. The term "alkyl" when recited to specify a group linking to another moiety (such as sulfonylalkyl) refers to a diradical branched or unbranched saturated hydrocarbon chain derived from an alkyl monoradical, a terminal hydrogen of which is substituted by such other moiety; exemplified by groups such as methylene, ethylene, n- propylene, i-propylene, 1 X3,9X3-nonane, 1X3,11X3-undecane, 5-(4X3-butyl)-11X3-undecane, 1X3,13X3-tridecane, 3-methyl-1X3,13Z,3-tridecane, 1X3,16X3-hexadecane, 2-(X3-methyl)-5- methyl-16X3-hexadecane, 1X3,20X3-icosane, 1 X3,23X3-tricosane and the like. The term “substituted alkyl” refers to an alkyl group in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent selected from the group comprising: alkenyl, alkenylthio, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxycarbonylalkyl, alkoxysulfonyl, alkylamidoalkyl, alkylcarbonyl, alkylcarbonylalkoxy, alkylcarbonylalkyl, alkylcarbonylalkylthio, alkylcarbonyloxy, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthio alkyl, alkylthioalkoxy, alkynyl, alkynyloxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, carboxyalkoxy, cyano, cyanoalkoxy, cyanoalkyl, cyanoalkylthio, 1 ,3-dioxolanyl, dioxanyl, dithianyl, ethylenedioxy, formyl, formylalkoxy, formylalkyl, haloalkenyl, haloalkenyloxy, haloalkoxy, haloalkyl, haloalkynyl, haloalkynyloxy, halogen, heterocycle, heterocyclocarbonyl, heterocycloxy, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, mercapto alkyl, methylenedioxy, nitro, sulfinyl and sulfonyl. Preferred substiituents for "substituted alkyl" are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
[030] As used herein, the term "alkyl-based ligand" refers to a diradical branched or unbranched saturated or unsaturated hydrocarbon chain derived from an alkyl or alkenyl monoradical, a terminal hydrogen of which is substituted by another moiety, such as a sulfate or a sulfonate moiety. The alkyl-based ligands of the invention can have 1 to 50 carbon atoms, preferably 9 to 25 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms.
[031] The term “substituted alkyl-based ligand” refers to an alkyl-based ligand in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl. Preferred substiituents for "substituted alkyl-based ligand" are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
[032] As used herein, the term "alkyl ligand" refers to a diradical branched or unbranched saturated hydrocarbon chain derived from an alkyl monoradical, a terminal hydrogen of which is substituted by another moiety, such as a sulfate or a sulfonate moiety. The alkyl ligands of the invention can have 1 to 50 carbon atoms, preferably 9 to 25 carbon atoms more preferably about 10 to 20 carbon atoms and still more preferably about 13 to about 18 carbon atoms.
[033] The term “substituted alkyl ligand” refers to an alkyl ligand in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is/are independently replaced by a substituent as described in the definition of substituted alkyl. Preferred substiituents for "substituted alkyl ligand" are selected from the group comprising: alkenyl, alkenylthio, alkoxysulfonyl, alkylcarbonylthio, alkylsulfinyl, alkylsulfinylalkyl, alkyl sulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkoxy, alkynylthio, aryl, arylcarbonyl, aryloxy, arylsulfonyl, cyanoalkylthio, dithianyl, heterocyclosulfonyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, mercapto, mercapto alkoxy, and mercapto alkyl.
[034] As used herein, the term “and/or” used in a phrase such as “A and/or B” herein is intended to include “A and B”, “A or B”, “A”, and “B”.
[035] As used in the specification and claims, the term “at least one” used in a phrase such as “at least one C atom” refers to “one C atom” or “two C atoms” or "more than two C atoms".
[036] The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. Also as used in the specification and claims, the language “comprising” can include analogous embodiments, as contrasted with the terms “consisting of” which includes only the embodiment recited and “consisting essentially of” which includes analogous embodiments to the extent that they do not materially affect the basic and novel characteristics of the claimed invention.
[037] Cyclodextrins ("CDs") are naturally occurring cyclic glucose derivatives consisting of alpha(14)-linked glucopyranoside units. Their cyclic structure creates a truncated cone shape with the primary hydroxyls of the glucose units on the narrow face and the secondary hydroxyls on the wider face. Each face can be readily and independently functionalised. The most commonly used natural CDs have 6, 7, and 8 glucopyranoside units, and are referred to as alpha, beta and gamma cyclodextrin, respectively. The preferred cyclodextrin is beta. Because of the cyclic structure of CDs, they have a cavity capable of forming supramolecular inclusion complexes with guest molecules. As CDs are naturally occurring, readily functionalised, have a cavity for guest inclusion and are biocompatible, they have found use in many commercial applications including drug delivery, air fresheners, etc. The difference in reactivity of each face of CDs has been used for the synthesis of a wide range of modified cyclodextrins. The primary face of CDs is more readily modified, with control over the degree and location of substitution being possible. CD derivatives that bear a good leaving group, such as halogenated CDs, are important intermediates in CD functionalisation. For example, replacing all of the primary hydroxyl units of CDs with iodo-units gives an intermediate that allows for complete functionalisation of the primary face, whilst leaving the secondary hydroxyls and the rigid truncated cone shape intact.
[038] As used herein, the term “mammal” (for purposes of treatment) refers to any animal classified as a mammal, including humans, domestic and farm animals or pet animals, such as dogs, horses, cats, cows, monkeys etc. Preferably, the mammal is human.
[039] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl,” as defined. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl including optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible.
[040] The term "pharmaceutically acceptable ester" refers to esters of the compounds of the present invention, which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, morpholinoethyl esters and the like.
[041] The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the desired biological activity of the compounds the invention and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of Formula I may be prepared from an inorganic acid or from an organic acid, or can be prepared in situ during the final isolation and purification of the compounds of the invention. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula I include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine. Other examples of organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In an embodiment, the pharmaceutically acceptable salt of the compounds of the invention is a sodium salt.
[042] As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human, and other, e.g., avian animals, such as a chicken. In preferred embodiments, the terms "subject" or "patient" refer to a human and animals, such as dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, chicken. In some embodiments, the subject is a subject in need of treatment, or a subject being infected by a virus. In other embodiment, a subject can be an animal infected by a virus, such as a chicken. However, in other embodiments, the subject can be a healthy subject or a subject who has already undergone treatment. The term does not denote a particular age or sex. Thus, adult, children and newborn subjects, whether male or female, are intended to be covered.
[043] As used herein, the term “therapeutically effective amount” refers to an amount of a compound of the invention effective to alter a virus, and to render it inert, in a recipient subject, and/or if its presence results in a detectable change in the physiology of a recipient subject, for example ameliorates at least one symptom associated with a viral infection, prevents or reduces the rate transmission of at least one viral agent.
[044] As used herein, the term “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already being infected by a virus, as well as those in which the viral infection is to be prevented or those who are likely to come into contact with a virus. Hence, the mammal, preferably human, to be treated herein may have been diagnosed as being infected by a virus, or may be predisposed or susceptible to be infected by a virus. Treatment includes ameliorating at least one symptom of, curing and/or preventing the development of a disease or condition due to the viral infection. Preventing is meant attenuating or reducing the ability of a virus to cause infection or disease, for example by affecting a post-entry viral event.
[045] As used herein, the term “virucidal” refers to a characterization of antiviral efficacy determined by in vitro testing demonstrating irreversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition. Even following termination of the interaction (for example, by dilution) and absent any added materials or conditions promoting viral reconstitution, it is essentially impossible for the virus to resume infectivity. Interaction with antiviral compound or composition alters the virus, rendering it inert, and thereby prevents further infections. [046] As used herein, the term “virustatic” refers to a characterization of antiviral efficacy determined by in vitro testing demonstrating reversible inhibition of the infectivity of a virus following interaction with an antiviral compound or composition. Once the interaction terminates (for example, by dilution) and absent any added materials or conditions promoting viral reconstitution, it is possible for the virus to resume infectivity.
[047] The term “water solubilizing moiety” refers to a group appended to the parent molecular moiety, which increases the aqueous solubility of the overall composition; if replaced by a hydrogen the overall composition will be less soluble at micromolar concentrations. Water soluble moieties include ketones, alcohols, aldehydes, ethylene glycols and charged groups such as amines, carboxylates, phosphates, sulfates and sulfonates.
Compounds of the Present Invention
[048] The present invention provides improved compositions and methods that can be used to treat viral diseases.
[049] In one aspect, the invention provides a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I:
Figure imgf000011_0001
wherein: each R, independently, is OH, SH, an -O-(C9 to C25)-optionally substituted alkyl- based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate ("SO4") or a sulfonate ("SO3") moiety; each R’, independently, is H, -(CH2)y-COOH, -(CH2)y-SO’8, a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
[050] In another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C25)-optionally substituted alkyl-based ligand or a -S-(Ci2 to C25)-optionally substituted alkyl-based ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C20)-optionally substituted alkyl-based ligand or a -S-(Ci2 to C20)-optionally substituted alkyl-based ligand.
[051] In another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C25)-alkyl-based ligand or a -S-(Ci2 to C25)-alkyl-based ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C2o)-alkyl-based ligand or a -S-(Ci2 to C20)- alkyl-based ligand.
[052] In still another aspect, the ligand of R in the compounds of Formula I is an -O- (Ci2 to C25)-unbranched alkyl-based ligand or a -S-(Ci2 to C25)-unbranched alkyl-based ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C20)-unbranched alkyl-based ligand or a -S-(Ci2 to C20)-unbranched alkyl-based ligand.
[053] In yet another aspect, the ligand of R in the compounds of Formula I is an -O- (Ci2 to C25)-alkyl ligand or a -S-(Ci2 to C25)-alkyl ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C2o)-alkyl ligand or a -S-(Ci2 to C29)- alkyl ligand
[054] In yet another aspect, the ligand of R in the compounds of Formula I is an -O- (Ci2 to C25)-unbranched alkyl ligand or a -S-(Ci2 to C25)-unbranched alkyl ligand. In yet another aspect, the ligand of R in the compounds of Formula I is an -O-(Ci2 to C29)- unbranched alkyl ligand or a -S-(Ci2 to C20)-unbranched alkyl ligand.
[055] In another aspect, R has a sulfate moiety and an -O-(C9 to C25)-optionally substituted alkyl-based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand, where no more than 1 R group can be OH or SH.
[056] In another aspect, R has a sulfonate moiety and an -O-(Ci3 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci3 to Ci8)-optionally substituted alkyl-based ligand, where no more than 1 R group can be OH or SH.
[057] In still another aspect,
• R is an -O-(Ci2 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci2 to Ci8)-optionally substituted alkyl-based ligand, or • R is an -O-(Ci2 to Ci8)-alkyl-based ligand or a -S-(Ci2 to Ci8)-alkyl-based ligand,
• R is an -O-(Ci2 to Ci8)-unbranched alkyl-based ligand or a -S-(Ci2 to Ci8)- unbranched alkyl-based ligand,
• R is an -O-(Ci2 to Ci8)-optionally substituted alkyl ligand or a -S-(Ci2 to Ci8)- optionally substituted alkyl ligand, or
• R is an -O-(Ci2 to Ci8)-alkyl ligand or a -S-(Ci2 to Ci8)-alkyl ligand,
• R is an -O-(Ci2 to Ci8)-unbranched alkyl ligand or a -S-(Ci2 to Ci8)-unbranched alkyl ligand, where no more than 1 R group can be OH or SH.
[058] The compounds useful as active agents in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C9 to C25)-optionally substituted alkyl-based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand. In another aspect, the ligand of R in the compounds useful as such is an -O-(Cw to C29)-optionally substituted alkyl-based ligand or a -S-(Cw to C20)-optionally substituted alkyl-based ligand. In still another aspect, the ligand of R in the compounds useful as such is an -O-(Ci3 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci3 to Ci8)-optionally substituted alkyl-based ligand.
[059] More particularly, the compounds useful as active agents in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C9 to C25)-alkyl-based ligand or a -S-(C9 to C25)-alkyl-based ligand. In another aspect, the ligand of R in the compounds useful as such is an -O-(Cw to C20)-alkyl-based ligand or a -S-(Ci0 to C20)-alkyl-based ligand. In still another aspect, the ligand of R in the compounds useful as such is an -O-(Ci3 to Ci8)-alkyl-based ligand or a -S-(Ci3 to Ci8)-alkyl-based ligand.
[060] Stilll more particularly, the compounds useful as active agents in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C9 to C25)-unbranched alkyl-based ligand or a -S-(C9 to C25)- unbranched alkyl-based ligand. In another aspect, the ligand of R in the compounds useful as such is an -O-(Ci0 to C20)-unbranched alkyl-based ligand or a -S-(Ci0 to C20)- unbranched alkyl-based ligand. In still another aspect, the ligand of R in the compounds useful as such is an -O-(Ci3 to Ci8)-unbranched alkyl-based ligand or a -S-(Ci3 to Ci8)- unbranched alkyl-based ligand.
[061] Even more particularly, the compounds useful as active agents in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C9 to C25)-alkyl ligand or a -S-(C9 to C25)-alkyl ligand. In another aspect, the ligand of R in the compounds useful as such is an -O-(Ci0 to C20)-alkyl ligand or a -S-(Cio to C20)-alkyl ligand. In still another aspect, the ligand of R in the compounds useful as such is an -O-(Ci3 to Cis)-alkyl ligand or a -S-(Ci3 to Cis)-alkyl ligand.
[062] Most particularly, the compounds useful as active agents in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents include those where the ligand of R is an -O-(C9 to C2s)-unbranched alkyl ligand or a -S-(C9 to C2s)-unbranched alkyl ligand. In another aspect, the ligand of R in the compounds useful as such is an -O- (Cio to C20)-unbranched alkyl ligand or a -S-(Ci0 to C20)-unbranched alkyl ligand. In still another aspect, the ligand of R in the compounds useful as such is an -O-(Ci3 to Ci8)- unbranched alkyl ligand or a -S-(Ci3 to Cis)-unbranched alkyl ligand.
[063] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted C9-alkyl-based ligand, an -O- or -S-optionally substituted Cw-alkyl- based ligand, an -O- or -S-optionally substituted Cn-alkyl-based ligand, an -O- or -S- optionally substituted Ci2-alkyl-based ligand, an -O- or -S-optionally substituted Ci3-alkyl- based ligand, an -O- or -S-optionally substituted Cu-alkyl-based ligand, an -O- or -S- optionally substituted Ci5-alkyl-based ligand, an -O- or -S-optionally substituted Ci6-alkyl- based ligand, an -O- or -S-optionally substituted C -alkyl-based ligand, an -O- or -S- optionally substituted Ci8-alkyl-based ligand, an -O- or -S-optionally substituted Cig-alkyl- based ligand, or an -O- or -S-optionally substituted C29-alkyl-based ligand.
[064] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted Ci2-alkyl-based ligand, an -O- or -S-optionally substituted Ci3-alkyl- based ligand, an -O- or -S-optionally substituted Cu-alkyl-based ligand, an -O- or -S- optionally substituted Ci5-alkyl-based ligand, an -O- or -S-optionally substituted Ci6-alkyl- based ligand, an -O- or -S-optionally substituted Cv-alkyl-based ligand, or an -O- or -S- optionally substituted Ci8-alkyl-based ligand.
[065] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-alkyl-based ligand, an -O- or -S- Ci3-alkyl-based ligand, an -O- or -S- Cu-alkyl-based ligand, an -O- or -S- Cis-alkyl-based ligand, an -O- or -S- Ci6-alkyl-based ligand, an -O- or - S- C 17-alkyl-based ligand, or an -O- or -S- Ci8-alkyl-based ligand.
[066] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-unbranched alkyl-based ligand, an -O- or -S- C13- unbranched alkyl-based ligand, an - O- or -S- C14- unbranched alkyl-based ligand, an -O- or -S- C15- unbranched alkyl-based ligand, an -O- or -S- C - unbranched alkyl-based ligand, an -O- or -S- C17- unbranched alkyl-based ligand, or an -O- or -S- Ci8- unbranched alkyl-based ligand.
[067] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- optionally substituted Ci2-alkyl ligand, an -O- or -S-optionally substituted Ci3-alkyl ligand, an -O- or -S-optionally substituted Ci4-alkyl ligand, an -O- or -S-optionally substituted Cisalkyl ligand, an -O- or -S-optionally substituted Ci6-alkyl ligand, an -O- or -S-optionally substituted C -alkyl ligand, or an -O- or -S-optionally substituted Ci8-alkyl ligand.
[068] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-alkyl ligand, an -O- or -S- Ci3-alkyl ligand, an -O- or -S- Ci4-alkyl ligand, an -O- or -S- Cis-alkyl ligand, an -O- or -S- C -alkyl ligand, an -O- or -S- C -alkyl ligand, or an -O- or -S- Ci8-alkyl ligand.
[069] In another aspect, the ligand of R in the compounds of Formula I is an -O- or -S- Ci2-unbranched alkyl ligand, an -O- or -S- Ci3- unbranched alkyl ligand, an -O- or -S- Cu- unbranched alkyl ligand, an -O- or -S- C15- unbranched alkyl ligand, an -O- or -S- C - unbranched alkyl ligand, an -O- or -S- C17- unbranched alkyl ligand, or an -O- or -S- Ci8- unbranched alkyl ligand.
[070] Still other aspects of the invention include a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I where:
• R' is H,
• x is 7,
• for R, no more than 1 can be OH or SH and each of the remaining R groups has a sulfate ("SO4") or a sulfonate ("SO3") moiety,
• R is an -O-(Ci2 to C2o)-optionally substituted alkyl-based ligand or a -S-(Ci2 to C2o)-optionally substituted alkyl-based ligand,
• R is an -O-(Ci2 to C2o)-optionally substituted alkyl ligand or a -S-(Ci2 to C20)- optionally substituted alkyl ligand,
• R is an -O-(Ci2 to Ci8)-optionally substituted alkyl ligand or a -S-(Ci2 to Ci8)- optionally substituted alkyl ligand,
• R is an -O-(Ci2 to Ci8)-unbranched alkyl ligand or a -S-(Ci2 to Ci8)-unbranched alkyl ligand, • the compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester is for use in treating a viral infection or a disease associated with an HSPG- seeking virus,
• the virus is HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV-A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H or HCV D168A,
• the compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester is part of a virucidal composition including a suitable carrier,
• the compound, pharmaceutically acceptable salt, pharmaceutically acceptable ester or virucidal composition is used in a method of disinfection and/or sterilization of non-living surfaces
• the compound, pharmaceutically acceptable salt, pharmaceutically acceptable ester or virucidal composition is used in a surface coating for device.
Nomenclature
[071] Cyclodextrins are composed of alpha-(1 ->4)-linked D-glucopyranose units. For example, beta-cyclodextrin is composed of seven such units and can be represented by the following detailed structure:
Figure imgf000016_0001
and named according to IUPAC as '^1 8,3/3,5/3,688/3,10/3,1 1 8,13/3,15/3,168,18/3,20/3, 21 S, 23/3, 25/3, 26S, 28/3,30/3,31 8,33/3, 35/3, 36/3, 37/3, 38/3, 39/3, 40/3, 41 /3, 42/3, 43/3, 44/3, 45/3, 46/3, 47/3, 48/3, 49/3)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22, 24,27,29,32,34-tetradecaoxaoctacyclo[31 .2.2.23's.28J 1.213=16.21821.223-26.228’31]nonatetra- contane-36,37,38,39,40,41 ,42,43,44,45,46,47,48,49-tetradecol". Given the complexity of such IUPAC naming, an alternative nomenclature has been adopted for purposes of the present specification.
[072] In the present specification, the cyclodextrins are named according to the following generic format:
(a- p- or y)-CD-(O or S)C#-(alkyl-based ligand branches and/or substituents)-(SO3- or SO4 )-R' in which
• "(a- P- or y)-CD" identifies the CD as having 6, 7 or 8 D-glucopyranose units,
• "(O or S)" identifies whether the ether linkage on the primary face is through an oxygen or a sulfur atom (where sulfur can also be indicated as "M" for mercapto),
• "C#" is the number of carbon atoms counting the shortest chain directly linking the ether to the sulfonate or sulfate,
• "(alkyl-based ligand branches and/or substituents)" describes any branches, substituents or points of unsaturation in the carbon chain,
• "(SO3‘ or SO4j" identifies the terminal moiety as a sulfonate or a sulfate, and
• " R' " identifies any substitutions on the secondary face, or is absent where R' is H.
[073] By way of example, the compound PCD-SCI2SO3' is a compound of Formula I where each R is -S-(CH2)I2SO3‘, R' is H, and x is 7. The compound is also named CD-M12S in Figure 1 F.
[074] The compound pCD-SCi2-(3-ene)-SO3‘ is a compound of Formula I where each R is -S-(CH2)2-(CH=CH)-(CH2)8-SO3-, R' is H, and x is 7.
[075] The compound yCD-OCio-(7-Et)-S04 _ is a compound of Formula I where each R is -O-(CH2)6-C(CH2-CH3)-(CH2)3-SO4-, R' is H, and x is 8.
[076] The compound CD-SCi2SO3 -(R' -(CH2)4-COOH) is a compound of Formula I where each R is -S-(CH2)I2SO3‘, R' is -(CH2)y-COOH, x is 7 and y is 4.
[077] Compounds of Formula I where any of the R groups is OH or SH can be more specifically described including the designation of any isomeric form, if applicable. For example, the compound of Formula I where 1 R group is SH, the other six R groups are -S-(CH2)I4SO3‘, R' is H, and x is 7 can be named " CD-SCi4SO3‘ (one R = SH)". No such designation is made for the compounds where no R groups are OH or SH.
Synthesis of the Compounds of Formula I
[078] Syntheses of the compounds of Formula I are described below with reference to the Reaction Schemes.
Synthetic Reaction Parameters
[079] The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless specified to the contrary the solvents used in the reactions of the present invention are inert organic solvents. Reactions take place at room temperature and 1 atmosphere of pressure unless otherwise indicated. [080] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
Starting Materials
[081] The starting materials, such as mercapto-cyclodextrin are commercially available or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
[082] Reaction Scheme 1
Figure imgf000018_0001
[083] Preparation of Sodium alkene sulfonates: As illustrated in Reaction Scheme 1 , a bromo (or other halo) alk-1 -ene (101 ) where n is an integer from about 5 to 23, is contacted with about a 1 .5 to 5 times molar excess of sodium sulfonate in an aqueous solvent. The reaction is refluxed at about 105 °C over a period of about 1 to 7 days (longer reflux time for greater values of n), and then allowed to cool followed by removal of the solvent. The resulting crude product is conventionally isolatred and purified to afford the corresponding compound (102).
[084] Reaction Scheme 2
Figure imgf000018_0002
[085] Preparation of CD alkyl sulfonates: As illustrated in Raction Scheme 2, a mercapto-cyclodextrin (103) is contacted with a 1.5 to 2 times molar excess (per thiol group) of a sodium alkene sulfonate (102), optionally with a photoinitiator (such as 2,2- dimethoxy-2-phenylacetophenone), in a suitable solvent. The thiol-ene click reaction mixture is placed in front of an untraviolet lamp (250 W or 400 W) or in a dedicated photoreactor. The reaction is stirred during UV exposure for about 3 to 12 hours to afford a crude product that is conventionally isolated and purified to afford the corresponding compound of Formula I.
[086] Reaction Scheme 3
Figure imgf000019_0001
[087] Preparation of Sodium alkene sulfates: As illustrated in Reaction Scheme 3, chlorosulfonic acid is added slowly to pridine in a cooled reaction vessel. An alkenol (104) where n is an integer from about 5 to 23, is dissolved in pyridine and added slowly to the chlorosulfonic acid solution and the temperature increased to about 60 °C and left stirring for about 16 h. A saturated solution of NaHCO3 is prepared and cooled in a separagfe vessel, to which is added the crude reaction mixture followed by stirring at rt for about 12h. The desired sodium alkene sulfate product (105) is conventionally isolated and purified.
[088] Preparation of CD alkyl sulfates: A sodium alkene sulfate (105) is substituted for the sodium alkene sulfonate (102) employed in Reaction Scheme 2 to yield the corresponding CD alkyl sulfate of Formula I.
[089] Other Compounds of Formula I: As will be apparent to those skilled in the art, other sulfate and sulfonate compounds of Formula I, e.g., those bearing branched and/or substituted alkyl-based ligands can be prepared by substituting the corresponding starting materials for those described with reference to Reaction Schemes 1 and 3 to afford intermediates corresponding to (102) and (105), which can be reacted with (103) following the procedures described with reference to Reaction Scheme 2.
[090] Alternative Syntheses: The compounds of Formula I can be synthesized using alternative synthetic routes. A cyclodextrin (alpha, beta or gamma) halogenated on its primary face, preferably using bromine or iodine, can be reacted with a thiolated optionally substituted alkyl-based ligand-sulfonate or -sulfate [i.e., HS-(optionally substituted alkyl- based ligand)-SO3‘ or HS-(optionally substituted alkyl-based ligand)-SO4 ] in a suitable solvent (preferably a dry, polar aprotic solvent such as DMF) in the presence of a base. The compounds of Formula I can also be prepared by reacting a cyclodextrin (alpha, beta or gamma) halogenated on its primary face, preferably using bromine or iodine, with a thiolated optionally substituted alkyl-based hydroxy ligand [i.e., HS-(optionally substituted alkyl-based ligand)-OH], followed by halogenation of the hydroxy moiety that can then be sulfonated. The same can be done to sulfate this terminal hydroxy moiety by using a weaker sulfating agent to avoid sulfation of the hydroxy groups on the cyclodextrin's secondary face.
[091] Similarly, the compounds of Formula I where R is an -O-(C9 to C25)-optionally substituted alkyl-based ligand can be synthesized by contacting a CD that is halogenated on the primary face (I or Br) with an co-hydroxy sulfonate or sulfate reactant corresponding to (102) or (105), under dry, basic conditions.
Preferred Processes and Last Steps
[092] A compound of Formula I is prepared by a thiol-ene click reaction by contacting a cyclodextrin that is thiolated on its primary face with an optionally substituted alkyl-based ligand-(sulfonate or -sulfate)-1 -ene in the presence of UV light.
[093] A cyclodextrin, halogenated on its primary face, is contacted with a thiolated optionally substituted alkyl-based ligand-sulfonate or -sulfate in the presence of a base.
[094] A cyclodextrin having halogenated, optionally substituted alkyl-based ligands on its primary face is contacted with a sulfonating or a sulfating agent.
[095] A compound of Formula I is contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt.
[096] A pharmaceutically acceptable acid addition salt of Formula I is contacted with a base to form the corresponding free base of Formula I.
Preferred Compounds
[097] Preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention are the following combinations and permutations of substituent groups of Formula I (sub-grouped, respectively, in increasing order of preference):
• Formula I is a composition of matter where R' is H. o The ligand of R is an -O-(Ci2 to C25)-optionally substituted alkyl-based ligand or a -S-(Ci2 to C25)-optionally substituted alkyl-based ligand.
■ The ligand of R is an -O-(Ci2 to C20)-optionally substituted alkyl- based ligand or a -S-(Ci2 to C20)-optionally substituted alkyl-based ligand.
The ligand of R is an -O-(Ci2 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci2 to Ci8)-optionally substituted alkyl-based ligand. o The ligand of R is an -O-(Ci2 to C25)-alkyl-based ligand or a -S-(Ci2 to C25)- alkyl-based ligand.
■ The ligand of R is an -O-(Ci2 to C20)-alkyl-based ligand or a -S-(Ci2 to C20)-alkyl-based ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-alkyl-based ligand or a -S-(Ci2 to Ci8)-alkyl-based ligand. o The ligand of R is an -O-(Ci2 to C25)-unbranched alkyl-based ligand or a - S-(Ci2 to C2s)-alkyl-based ligand.
■ The ligand of R is an -O-(Ci2 to C2o)-unbranched alkyl-based ligand or a -S-(Ci2 to C2o)-unbranched alkyl-based ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-unbranched alkyl-based ligand or a -S-(Ci2 to Ci8)-unbranched alkyl-based ligand. o The ligand of R is an -O-(Ci2 to C25)-alkyl ligand or a -S-(Ci2 to C25)-alkyl ligand.
■ The ligand of R is an -O-(Ci2 to C2o)-alkyl ligand or a -S-(Ci2 to C20)- alkyl ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-alkyl ligand or a -S-(Ci2 to Ci8)-alkyl ligand. o The ligand of R is an -O-(Ci2 to C25)-unbranched alkyl ligand or a -S-(Ci2 to C25)-unbranched alkyl ligand.
■ The ligand of R is an -O-(Ci2 to C2o)-unbranched alkyl ligand or a - S-(Ci2 to C2o)-unbranched alkyl ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-unbranched alkyl ligand or a -S-(Ci2 to Ci8)-unbranched alkyl ligand.
• Formula I is a compound useful as an active agent in practice of the methods of treatment, uses, pharmaceutical formulations, virucidal compositions, devices, virucidal surfaces, methods of disinfection and/or sterilization and in the manufacture thereof, and as intermediates in the synthesis of such active agents where R' is H. o The ligand of R is an -O-(C9 to C25)-optionally substituted alkyl-based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand.
■ The ligand of R is an -O-(Ci0 to C2o)-optionally substituted alkyl- based ligand or a -S-(Ci0 to C2o)-optionally substituted alkyl-based ligand.
The ligand of R is an -O-(Ci2 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci2 to Ci8)-optionally substituted alkyl-based ligand. o The ligand of R is an -O-(Ci3 to Ci8)-optionally substituted alkyl-based ligand or a -S-(Ci3 to Ci8)- optionally substituted alkyl-based ligand. o The ligand of R is an -O-(C9 to C25)-alkyl-based ligand or a -S-(C9 to C25)- alkyl-based ligand.
■ The ligand of R is an -O-(Cw to C29)-alkyl-based ligand or a -S-(Cw to C20)-alkyl-based ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-alkyl-based ligand or a -S-(Ci2 to Ci8)-alkyl-based ligand. o The ligand of R is an -O-(Ci3 to Ci8)-alkyl-based ligand or a -S-(Ci3 to Ci8)-alkyl-based ligand. o The ligand of R is an -O-(C9 to C25)-unbranched alkyl-based ligand or a -S- (C9 to C2s)-unbranched alkyl-based ligand.
■ The ligand of R is an -O-(Ci0 to C20)-unbranched alkyl-based ligand or a -S-(Cio to C20)-unbranched alkyl-based ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-unbranched alkyl- based ligand or a -S-(Ci2 to Ci8)-unbranched alkyl-based ligand. o The ligand of R is an -O-(Ci3 to Ci8)-unbranched alkyl-based ligand or a -S-(Ci3 to Ci8)-unbranched alkyl-based ligand. o The ligand of R is an -O-(C9 to C25)-unbranched alkyl ligand or a -S-(C9 to C25)-unbranched alkyl ligand.
■ The ligand of R is an -O-(Cw to C29)-unbranched alkyl ligand or a - S-(Cio to C20)-unbranched alkyl ligand.
• The ligand of R is an -O-(Ci2 to Ci8)-unbranched alkyl ligand or a -S-(Ci2 to Ci8)-unbranched alkyl ligand. o The ligand of R is an -O-(Ci3 to Ci8)-unbranched alkyl ligand or a -S-(Ci3 to Ci8)-unbranched alkyl ligand.
The above-described groups and sub-groups are individually preferred and can be combined to describe further preferred aspects of the invention. In the above-described preferences, it is further preferred that only 0 to 1 of the R groups is OH or SH, most preferably zero. In the above-described preferences, it is further preferred that x is 7 or 8, most preferably x is 7.
[098] Particularly preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention are the following: pCD-SCioS03‘, [BCD- SC11SO3; pCD-SCi2SO3’, pCD-SCi3SO3’, |3CD-SCI4SO3-, pCD-SCi5SO3', pCD-SCi6SO3-, pCD-SCi7SO3-, pCD-SCi8SO3- and pCD-SCiiSO4-.
[099] More preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention is the following: pCD-SCi2SO3 _, 0CD- SCi3SO3', pCD-SCuSOs", pCD-SCi5SO3‘, pCD-SCi6SO3', pCD-SCvSOs', pCD-SCi3SO3' and pCD-SCnSCV
[0100] Most preferred for the compounds, pharmaceutical formulations, methods of manufacture and use of the present invention is the following: pCD-SCi3SO3‘, 0CD- SCi4SO3', pCD-SCi5SO3‘, and pCD-SCnSO4'.
Utility, Testing, Administration and Formulation
General Utility
[0101] The compositions of the invention find use in a variety of applications. As will be appreciated by those in the art, the compositions are antiviral and have demonstrated virucidal activity against HSV-2.
[0102] The compositions of the invention are also useful as antivirals against, and in the treatment of diseases associated with HSPG-seeking viruses including, without limitation, HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV-A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H and HCV D168A.
[0103] Another aspect of the invention provides a method of disinfection and/or sterilization of surfaces using one or more compounds of the invention or the virucidal composition of the invention or the pharmaceutical composition of the invention. The disinfection and/or sterilization is preferably done on living surfaces or non-living surfaces. The living surfaces are human or animal skin and/or hair. The non-living surface are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas. In some other embodiments, the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
[0104] In a preferred embodiment, the method of disinfection and/or sterilization of surfaces comprises the steps of (i) providing at least one compound of the invention or a virucidal composition of the invention, or pharmaceutical composition of the invention, (ii) contacting a virus-contaminated surface or a surface suspected to be contaminated by a virus with the at least one compound of the invention or a virucidal composition of the invention or pharmaceutical composition of the invention for a time sufficient to obtain virucidal effect. In some embodiments, the virus-contaminated surface is human or animal skin and/or hair. In other embodiments, the virus-contaminated surface is a non-living surface. The non-living surface is, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas. In some other embodiments, the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
[0105] Another aspect of the invention provides a use of a compound of the invention or a virucidal composition of the invention or a pharmaceutical composition of the invention for sterilization and/or for disinfection. In some embodiments, sterilization and disinfection is for virus-contaminated surfaces or surfaces suspected to be contaminated by a virus. In some preferred embodiments, the surfaces are human or animal skin and/or hair. Thus in some embodiments, the invention provides a use of a compound of the invention or a virucidal composition of the invention or a pharmaceutical composition of the invention for sterilization and/or for disinfection of human or animal skin and/or hair. In other preferred embodiments, the surfaces are non-living surfaces. The non-living surfaces are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas. In some other embodiments, the non-living surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances). In an embodiment, the virucidal composition of the invention or the pharmaceutical composition of the invention is used as virucidal hand disinfectant for frequent use. In another embodiment, the virucidal composition of the invention or the pharmaceutical composition of the invention is applied by spraying. In a further embodiment, the virucidal composition of the invention of the pharmaceutical composition of the invention is applied on a protective mask.
[0106] Another aspect of the invention provides a use of the compounds of the invention or the virucidal composition of the invention for manufacturing (producing) virucidal surfaces (i.e. able to inactivate viruses). Such surfaces are, but not limited to, textile, clothing, masks, touch screens, medical equipment, furniture. In some other embodiments, the surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances). In some embodiments, the surfaces can be modified with the one or more compounds of the invention either through chemical modification or physical coating known in the art. Examples of physical coating are spraying or dipping the surface in a solution comprising the one or more compounds of the invention.
[0107] Another aspect of the invention provides a method for manufacturing (producing) a virucidal surface, wherein the method comprises coating the surface with the one or more compounds of the invention or the virucidal composition of the invention. The surface is, but not limited to, textile, clothing, masks, touch screens, medical equipment, furniture. In some other embodiments, the surface is fabric surface (masks, gloves, doctor coats, curtains, bed sheet), metal surface (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surface (furniture, floors, partition panels), concrete surface (hospitals, clinics and isolation wards and walls), and plastic surface (medical equipment and instruments, touch screens, switches, kitchen and home appliances). The coating can be done either through chemical modification or physical coating known in the art.
[0108] Another aspect of the invention provides a virucidal surface coating composition comprising the one or more compounds of the invention or the virucidal composition of the invention. The virucidal surface coating composition of the invention can be sprayed or painted on surfaces. The surfaces are, but not limited to, medical equipment, touch screens, textile, clothing, masks, gloves, furniture, and any other surfaces present in rooms, transport means, public spaces such as schools, airports, public transportation and cinemas. In some other embodiments, the surfaces are fabric surfaces (masks, gloves, doctor coats, curtains, bed sheet), metal surfaces (lifts, door handle, nobs, railings, medical equipment and instruments, public transport and places), wood material surfaces (furniture, floors, partition panels), concrete surfaces (hospitals, clinics and isolation wards and walls), and plastic surfaces (medical equipment and instruments, touch screens, switches, kitchen and home appliances).
[0109] Another aspect of the invention provides a device comprising a surface coated with one or more compounds of the invention or with the virucidal composition of the invention. Such an antiviral coated device can be, but is not limited to, clothing, a mask, a glove, a touch screen, medical equipment, furniture, etc.... In one preferred embodiment, the device is a mask, clothing or medical equipment. In another preferred embodiment, the device is a medical device.
Testing
[0110] Cytotoxicity is determined by exposing Vero cells to varying concentrations of test drug and measuring the percentage of cells surviving such exposure. Antiviral activity is determined by plaque reduction assays on infected Vero cells, measuring the number of plaques that form in wells exposed to a mixture of a fixed concentration of the virus and varying concentrations of test drug. Virucidal activity is determined by exposing Vero cells to different dilutions of a prep-incubated mixture of virus and an effective amount of test drug. After incubation, the solution is removed and the cells are incubated again, measuring the plaques that form, evaluating the viral titer. The decrease of viral titer with respect to an untreated control is an indication of virucidal activity. These determinations can be carried out, for example, as described in Cagno, et al., "Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism," Nature Materials 17, 195-203 (2018).
Administration
[0111] The compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. Administration of the compounds of the invention or the pharmaceutically acceptable salts or esters thereof can be via any of the accepted modes of administration for agents that serve similar utilities.
[0112] While human dosage levels have yet to be optimized for the compounds of the invention, generally, a daily dose is from about 0.001 to 2.0 mg/kg of body weight/day, preferably about 0.005 to 0.75 mg/kg of body weight/day, and most preferably about 0.01 to 0.5 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be about 0.07 to 140 mg per day, preferably about 0.35 to 52.5 mg per day, and most preferably about 0.7 to 35 mg per day. Administration can be as a single daily dose or divided into 2 or more doses per day, over a period of treatment lasting from about 1 to about 7 days. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
Formulation [0113] The compounds of the invention that are used in the methods of the present invention can be incorporated into a variety of formulations and medicaments for therapeutic administration. More particularly, the compounds as provided herein can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers, excipients and/or diluents, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols. As such, administration of the compounds can be achieved in various ways, including oral, buccal, inhalation (pulmonary, nasal), rectal, parenteral, intraperitoneal, intradermal, topical, transdermal, intracranial and/or intratracheal administration. Moreover, the compounds can be administered in a local rather than systemic manner, e.g., in a topical cream or gel, a depot or a sustained release formulation. The compounds can be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered by the intramuscular or intravenous routes. The compounds can be administered alone, in combination with each other, or they can be used in combination with other known compounds including oither antiviral agents. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th ed.), which is incorporated herein by reference. Moreover, for a brief review of methods for drug delivery, see, Langer, Science (1990) 249:1527-1533, which is incorporated herein by reference.
[0114] As to the appropriate excipients, carriers and diluents, reference may be made to the standard literature describing these, e.g. to chapter 25.2 of Vol. 5 of "Comprehensive Medicinal Chemistry", Pergamon Press 1990, and to "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", by H.P. Fiedler, Editio Cantor, 2002. The term "pharmaceutically acceptable carrier, excipient and/or diluent" means a carrier, excipient or diluent that is useful in preparing a pharmaceutical composition that is generally safe, and possesses acceptable toxicities. Acceptable carriers, excipients or diluents include those that are acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier, excipient and/or diluent" as used in the specification and claims includes both one and more than one such carrier, excipient and/or diluent.
[0115] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the invention, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and [gamma] ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT(TM) (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3- hydroxybutyric acid.
[0116] The compounds of the invention can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
[0117] The pharmaceutical compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The following methods and excipients are merely exemplary and are in no way limiting. For injection, a compound of the invention (and optionally another active agent) can be formulated into preparations by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives. Preferably, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0118] Preferably, pharmaceutical formulations for parenteral administration include aqueous solutions of the compounds of the invention in water-soluble form. Additionally, suspensions of the compounds of the invention can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds of the invention to allow for the preparation of highly concentrated solutions.
[0119] The amount of a compound of the invention that can be combined with a carrier material to produce a single dosage form will vary depending upon the viral disease treated, the mammalian species, and the particular mode of administration. It will be also understood, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular viral disease undergoing therapy, as is well understood by those of skill in the area.
[0120] Another aspect of the invention provides a virucidal composition comprising an effective amount of one or more compounds of the invention and optionally at least one suitable carrier or aerosol carrier. “An effective amount” refers to the amount sufficient for irreversibly inhibiting viruses; i.e. sufficient for obtaining virucidal effect. In an embodiment, the suitable carrier is selected from the group comprising stabilisers, fragrance, colorants, emulsifiers, thickeners, wetting agents, or mixtures thereof. In another embodiment, the virucidal composition can be in the form of a liquid, a gel, a foam, a spray or an emulsion. In a further embodiment, the virucidal composition can be an air freshener, a sterilizing solution or a disinfecting solution.
[0121] Another aspect of the invention provides a device (or a product) comprising the virucidal composition of the invention or one or more compounds of the invention and means for applying and/or dispensing thereof (i.e. the compounds of the invention or the virucidal composition). In another embodiment, the means comprise a dispenser, a spray applicator or a solid support soaked with the compounds of the invention. In another embodiment, the support is a woven or non-woven fabric, a textile, a paper towel, cotton wool, an absorbent polymer sheet, or a sponge.
[0122] Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
[0123] Formulations of the active compound or a salt may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
[0124] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.
EXAMPLES
[0125] The following examples serve to more fully describe the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety.
Example 1 Synthesis of Ligands
[0126] 1A. Sodium hepta-6-enesulfonate:
7-Bromo-1 -heptene (5 g, 28.24 mmol) and Na2SO3 (7.12 g, 56.48 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 24h at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 6 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium hepta-6-enesulfonate white solid was collected, weighed (~4.2 g - 74% yield) and used as such (no recrystallization was done). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1 .53 (m, 2H), 1 .11 (br s, 6H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for C7HI3SO3“ 177.24; found 177.10.
[0127] 1 B. Sodium octa-7-enesulfonate:
8-Bromo-1 -octene (5 g, 26.16 mmol) and Na2SO3 (6.6 g, 52.32 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 24h at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding ~7 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium octa-7-enesulfonate white solid was collected, weighed (-5 g) was recrystallised in MilliQ water (100mL) yielding 3.1g of a white solid (yield 55.3%). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1.53 (m, 2H), 1.11 (br s, 6H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]~ calculated for CaHisSC 191.27; found 191.1.
[0128] 1C. Sodium nona-8-enesulfonate:
9-Bromo-1 -nonene (5 g, 24.37 mmol) and Na2SO3 (6.14 g, 48.74 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 24h at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 7.5 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The white solid was collected, weighed (~5 g) dissolved in 120mL of MilliQ water inside a 500 mL round bottom flask (a heat gun was used to help solubilize). The solution was kept overnight at 4°C. Thin white crystals formed and the viscous solution was decanted. The wet white suspension was further collected using 45 mL Falcon tubes and centrifugation at 5500 rpm. The resulting sodium nona-8-enesulfonate crystalline wet pellet was frozen in liquid nitrogen and placed under high vacuum to lyophilize for 48h to yield ~3.0g of a fine powder (yield -62.8%). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1.53 (m, 2H), 1.11 (br s, 8H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for C9Hi7SO3“ 205.29; found 205.1 .
[0129] 1D. Sodium deca-9-enesulfonate:
10-Bromo-1 -decene (5 g, 22.8 mmol) and Na2SO3 (5.75 g, 45.6 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 24h at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 8.5 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid (insoluble Na2SO3, NaBr and other inorganics) on the filter. The clear filtrate was evaporated using a rotary evaporator and the white residue was dried overnight under high vacuum. The white solid was collected, weighed (~5 g) dissolved in 150mL of MilliQ water inside a 500 mL round bottom flask (a heat gun was used to help solubilize). The solution was kept overnight at 4°C when white thin crystals formed forming a viscous solution. This solution was decanted and further collected using 45 mL Falcon tubes and centrifugation at 5500 rpm. The resulting sodium deca-9-enesulfonate crystalline pellet was frozen in liquid nitrogen and placed under high vacuum for 48h to yield ~3.8g of a fine powder (yield -71.5%). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1 .53 (m, 2H), 1.11 (br s, 10H). Mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]~ calculated for C10H19SO3- 219.32; found 219.0.
[0130] 1E. Sodium undeca-10-enesulfonate:
11 -Bromo-1 -undecene (2.122 g, 9.1 mmol) and Na2SO3 (3.061 g, 24.3 mmol) were added into a mixture of methanol (25 ml) and H2O (45 ml) and refluxed for 18 hours. The methanol was removed under reduced pressure in vacuo, and the aqueous layer was washed with Et2O (50 ml) and dried. The white solid was extracted with hot MeOH and filtered twice, leaving the insoluble Na2SO3 salt on the filter. The filtrate was recrystallized from EtOH/H2O mixture (20/1 ), and the sodium undeca-10-enesulfonate product was collected as white crystalline needles (1.983 g, 85%). 1H NMR (nuclear magnetic resonance) [400 MHz, dimethyl sulfoxide (DMSO)-d6] 5.78 (ddt, J = 17.0, 10.2, 6.5 Hz, 1 H), 4.98 (d, J = 17.0 Hz, 1 H), 4.92 (d, J = 10.2 Hz, 1 H), 2.41 (dd, J = 9.4, 6.5 Hz, 2H), 1.99 (q, J = 7.1 Hz, 2H), 1.55 (p, J = 7.1 Hz, 2H), 1.25 (m, 14H). 13C NMR (101 MHz, DMSO-d6) 139.27, 115.10, 51.92, 33.64, 29.35, 29.30, 28.98, 28.86, 28.86, 28.74, and 25.50. High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M - Na+]“ calculated for CnH2iO3S“ 233.1217; found 233.1214.
[0131] 1F. Sodium dodeca-11-enesulfonate:
12-Bromo-1 -dodecene (5 g, 20.2 mmol) and Na2SO3 (5.1 g, 40.4 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 24h at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 8 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 2L round bottom flask and additional hot methanol was used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium dodeca-11-enesulfonate white solid was collected, weighed (~4.5 g) was recrystallised in MilliQ water (250mL) yielding 3 g of a white solid (yield 55 %). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1.53 (m, 2H), 1.11 (br s, 14H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]~ calculated for Ci2H23SO3“ 247.47; found 247.1 .
[0132] 1G. Sodium trideca-12-enesulfonate:
13-Bromo-1 -tridecene (1g, 3.8mmol) and Na2SO3 (2 g, 15.8 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 4 days at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 3.3 g of a white solid. The white solid was extracted with hot methanol: the powder was added to 500 mL of methanol under magnetic stirring at 65°C. The suspension was filtered into a clean 1 L round bottom flask and additional hot methanol and ethanol were used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium trideca-12-enesulfonate white solid was collected, weighed (~1 .4 g) was recrystallised in MilliQ water (100mL) yielding 0.7 g of a white solid (yield 64.7 %). 1H-NMR (D2Q): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1.53 (m, 2H), 1.11 (br s, 16H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]~ calculated for CI3H25SO3“ 261 .4; found 261 .1 .
[0133] 1 H. Sodium tetradeca-13-enesu If onate:
14-Bromo-1 -tetradecene (1g, 3.6mmol) and Na2SO3 (2 g, 15.8 mmol) were added into a mixture of methanol (60 mL) and MilliQ Water (135 mL). The mixture was refluxed for 4 days at 105°C. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 3 g of a white solid. The white solid was extracted with a mixture of hot methanol and ethanol. The powder was added to 250 mL of methanol and 250mL of ethanol under magnetic stirring at 80°C. The suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium tetradeca- 13-enesulfonate white solid was collected, weighed (~1.6 g) was recrystallised in MilliQ water (150 mL) yielding 0.85 g of a white solid (yield 79.4%). 1H-NMR (D2O): 5.76 (m, 1 H), 4.78 (m, 2H), 2.69 (t, 2H), 1.53 (m, 2H), 1.11 (br s, 18H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]~ calculated for C14H27SO3" 75.43; found 275.2.
[0134] 11. Sodium pentadeca-14-enesulfonate:
15-Bromo-1 -pentadecene (1g, 3.5mmol) and Na2SO3 (2 g, 15.8 mmol) were added into a mixture of methanol (70 mL) and MilliQ Water (130 mL). The mixture was refluxed for 7 days at 105°C. Thin layer chromatography (TLC) was used to monitor the reaction. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 2.7 g of a white solid. The white solid was extracted with a mixture of hot methanol, ethanol and isopropanol. The powder was added to a mixture of 125 mL of methanol and 125 mL of ethanol and 125 mL of isopropanol under magnetic stirring at 80°C. The suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium pentadeca-14-enesulfonate white solid was collected, weighed (-1.3 g) was recrystallised in MilliQ water (150 mL) yielding 0.6 g of a white solid (yield 54.9%). 1H-NMR (MeOD-d4): 5.83 (m, 1 H), 4.97 (m, 2H), 2.80 (t, 2H), 2.07 (m, 2H), 1.80 (m, 2H), 1.32 (br s, 24H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for Ci5H2gSO3“ 289.45; found 289.2.
[0135] 1J. Sodium hexadeca-15-enesulfonate:
16-Bromo-1 -hexadecene (1 g, 3.3mmol) and Na2SO3 (2.1 g, 16.5 mmol) were added into a mixture of methanol (70 mL) and MilliQ Water (130 mL). The mixture was refluxed for 7 days at 105°C. Thin layer chromatography (TLC) was used to monitor the reaction. The reaction setup was allowed to cool to room temperature and the solvent was removed under reduced pressure (rotary evaporator). The crude white solid was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 2.7 g of a white solid. The white solid was extracted with a mixture of hot methanol, ethanol and isopropanol. The powder was added to a mixture of 125 mL of methanol and 125 mL of ethanol and 125 mL of isopropanol under magnetic stirring at 80°C. The suspension was filtered into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium hexadeca-15-enesulfonate white solid was collected, weighed (~1.5 g) was recrystallised in MilliQ water by adding the white solid to 200 mL of boiling water, yielding 0.75 g of a white solid (yield 69.3%). 1H-NMR (DMSO-d6): 5.80 (m, 1 H), 4.99 (m, 2H), 2.37 (t,2H), 2.01 (m, 2H), 1.53 (m, 2H), 1.24 (br s, 28H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for CI6H3ISO3“ 303.48; found 303.10.
[0136] 1K. Sodium heptadeca-16-enesulfonate:
17-Bromo-1 -hexadecene (2g, 6.3mmol) and Na2SO3 (3 g, 23.8 mmol) were added to 70 mL of MilliQ Water. The mixture was placed inside an autoclave and the reaction was conducted at 200°C for 12h. The resulting white slurry was transferred to two 45mL falcon tubed with the aid of additional MilliQ water, frozen with liquid nitrogen and lyophilised. A white powder was collected after 48h from high vacuum and was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 4.5 g of a white solid. The white solid was extracted on the filter with hot ethanol and isopropanol into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid on the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium heptadeca-16-enesulfonate white solid was collected, weighed (-1.5 g) was recrystallised in a mixture of 20% ethanol in water (100mL) 1.1 g of crystalline needles that form a white powder once dried (yield 52.8%). 1H-NMR (DMSO-d6): 5.80 (m, 1 H), 4.99 (m, 2H), 2.37 (t,2H), 2.01 (m, 2H), 1.53 (m, 2H), 1.24 (br s, 30H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for CI7H33SO3“ 317.51 ; found 317.10.
[0137] 1 L. Sod i u m octadeca-17-enesu If onate :
18-Bromo-1 -hexadecene (2g, 5.6mmol) and Na2SO3 (3 g, 23.8 mmol) were added to 70 mL of MilliQ Water. The mixture was placed inside an autoclave and the reaction was conducted at 200°C for 12h. The resulting white slurry was transferred to two 45mL falcon tubed with the aid of additional MilliQ water, frozen with liquid nitrogen and lyophilised. The white powder was collected after 48h under high vacuum and was washed vigorously for 16h with diethyl ether using magnetic stirring. The white suspension was filtered and dried under high vacuum yielding 4.2 g of a white solid (the target compound is slightly soluble in Et2O). The white solid was extracted on the filter with hot ethanol and isopropanol into a clean 1 L round bottom flask and additional hot ethanol and isopropanol were used to wash the white solid off the filter (insoluble Na2SO3, NaBr and other inorganics). The filtrate clear solution was evaporated using a rotary evaporator, and the white residue was dried overnight under high vacuum. The resulting sodium octadeca-17-enesulfonate white solid was collected, weighed (~1.3 g) was recrystallised in a mixture of 20% ethanol in water (100mL) 0.8 g of crystalline needles that form a white powder once dried (yield 40.4%). 1H- NMR (DMSO-d6): 5.80 (m, 1 H), 4.99 (m, 2H), 2.37 (t,2H), 2.01 (m, 2H), 1.53 (m, 2H), 1.24 (br s, 32H). Mass spectrometry (MS) [electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for Ci8H35SO3“ 331 .51 ; found 331 .10.
[0138] 1 M. Sodium undec-10-ene-1 -sulfate:
Chlorosulfonic acid (5.2 g, 0.03 mol) was added dropwise using an addition funnel into an ice-cooled three-neck round bottom flask with 40 mL of pyridine. While this solution equilibrated, undec-10-ene-1 -ol (6.5 g, 0.038 mol) was dissolved in 10 mL of pyridine, transferred to an addition funnel and connected to a free neck in the round bottom flask. The solution of undec-10-ene-1 -ol was added dropwise over 20 minutes, forming a grey mixture. The ice bath was switched to an oil bath and the temperature brought to 60°C and left stirring at this temperature for 16h. A saturated solution of NaHCO3 was prepared, cooled in an ice bath. The reaction crude was slowly added to the cold NaHCO3 solution while it stirred. A clear solution formed and was allowed to stir for 12h at room temperature. This solution was extracted with 100mL of 1 -butanol three times. The 1 -butanol extracts were combined and washed with 250 mL of brine in a 1 L separatory funnel, collected, dried over MgSO4 and the solvent was removed using a rotary evaporator. The white solid on the walls of the round bottom flask was washed with 300mL of diethyl ether, filtered. The solid on the filter was further washed with 300mL of acetone. The solid was collected and dried under high vacuum. The dry white solid was dissolved in a 1 :3 mixture of methanol and acetone, filtered into a clean 1 L round bottom flask, the solvents were evaporated using a rotary evaporator, the sodium undec-10-ene-1 -sulfate white powder was collected (5g, yield 46%) and used as such. 1H-NMR (DMSO-d6): 5.79 (m, 1 H), 4.97 (m, 2H), 3.67 (t, 2H), 2.01 (m, 2H), 1.48 (m, 2H), 1.25 (br s, 12H). Mass spectrometry (LC-MS) [negative electrospray ionization (ESI)Zquadrupole MS2] mass/charge ratio (m/z): [M - Na+]“ calculated for CH H2ISO4- 249.35; found 249.10.
[0139] 1 N. Other Sulfonates and Sulfates:
By following the procedures of Example 1A-1 L (as appropriate for chain length) and substituting the starting ®-bromoalk-1 -ene reactant with: a) 9-bromo-7-ethylnon-1-ene, b) 9-bromo-6,7-diethylnon-1 -ene, c) 7-(3-bromopropyl)undec-1 -ene, d) 11 ,12-dibromododec-1 -ene, e) 15-bromo-12-methylhexadec-1 -ene, f) 3-(4-bromobutyl)heptadec-16-enenitrile, g) 1 ,19-dibromo-10-vinylnonadecane, h) 22-bromodocos-1 -ene, i) (3E,7E)-9-bromo-5-methylnona-1 ,3,7-triene, j) (3E,7E)-10-bromo-5-methyldeca-1 ,3,7-triene, k) (3E,7E)-11 -bromo-5,6-dimethylundeca-1 ,3,7-triene, l) (3E,5E, 7E,3E)-~\ 2-bromodeca-1 ,3,5,7,9-pentaene, m) (5E,9E)-13-bromotrideca-1 ,5,9-triene, n) (5E,9E)-12,13-dibromotrideca-1 ,5,9-triene, and o) (5E,9E,14E,19E)-21 -bromohenicosa-1 ,5,9,14,19-pentaene, there are obtained the following product compounds, respectively, as illustrated in Figure 1 : a) ((3-ethylnon-8-en-1 -yl)sulfonyl)-X1-oxidane, b) ((3,4-diethylnon-8-en-1 -yl)sulfonyl)-X1-oxidane, c) ((4-butyldec-9-en-1 -yl)sulfonyl)-X1-oxidane, d) (dodec-11 -ene-1 , 2-diyldisulfonyl)bis(X1 -oxy) , e) ((5-methylhexadec-15-en-2-yl)sulfonyl)-X1-oxidane, f) 3-(4((X1-oxidanyle)dioxo-X6-sulfaneyl)butyo)heptadec-16-enenitrile g) (10-vinylnonanadecane-1 ,19-diyldisulfonyl)bis(X1-oxy), h) (docos-21 -en-1 -ylsulfonyl)-X1-oxidane, i) (((2E,6E)-5-methylnona-2,6,8-trien-1 -yl)sulfonyl)-X1-oxidane, j) (((3E,7E)-6-methyldeca-3,7,9-trien-1 -yl)sulfonyl)-X1-oxidane, k) (((4E,8E)-6,7-dimethylundeca-4,8,10-trien-1 -yl)sulfonyl)-X1-oxidane, l) (((3E,5E,7E,9E)-dodeca-3,5,7,9,11-pentaen-1 -yl)sulfonyl)-X1-oxidane, m) (((4E,8E)-trideca-4,8,12-trien- 1 -yl)sulfonyl)-X1-oxidane, n) ((4E,8E)-trideca-4,8,12-triene-1 ,2-disulfonyl)bis(X1-oxy), and o) (((2E,7E, 72E,16E)-henicosa-2,7,12,16,20-pentaen-1 -yl)sulfonyl)-X1-oxidane, or if following the procedure of Example 1 M and substituting the starting ®-bromoalk-1 -ene with reactants a) through o) above, the corresponding sulfate products.
Example 2
Compounds of Formula I
[0140] 2 A. BCD-SC7SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium hepta-6-ene-1 -sulfonate (224 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, PCD-SC7SO3', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 1 kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (180 mg). CiigH2i7O49Si4 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7- calculated for C91 H161049S14- 355.0885; found 355.37226.
[0141] 2B. BCD-SCsSOs :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium octa-7-ene-1 -sulfonate (240 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 mL) and EtOH (45 mL) and collected by centrifugation. The product, PCD-SC8SO3', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (180 mg). Ci I9H2I 7O49S14 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7- calculated for C98H175O49S14- 369.1042; found 369.38781 .
[0142] 2C. BCD-SC9SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium nona-8-ene-1 -sulfonate (255.7 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, PCD-SC9SO3', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-215 mg). C119H217O49S14 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7- calculated for C105H189O49S14- 383.1200; found 383.40390.
[0143] 2D. BCD-SC10SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium deca-9-ene-1 -sulfonate (271 .4 mg, 1 .12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SCwSOs', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-220 mg).
[0144] 2E. BCD-SC11SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (50 mg, 0.040 mmol), sodium undec-10-ene-1 - sulfonate (108 mg, 0.421 mmol), and 2,2-dimethoxy-2-phenylacetophenone (22 mg, 0.084 mmol) were dissolved in DMSO (5 ml). The reaction mixture was placed in front of an ultraviolet (UV) lamp (250 W) and stirred for 18 hours. The crude product was precipitated by into a 20% EtOH in Et2O mixture (45 ml) and collected by centrifugation. The off-white solid was washed with MeOH (45 ml) and EtOH (45 ml) and collected by centrifugation. The product, pCD-SCnSO3', was purified by dialysis against Milli-Q H2O for 3 days, with 3 changes of water, filtered through a 0.2-pm filter, lyophilised and collected as a white solid (92 mg, 76%). C119H217O49S14 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7- calculated for Cn H2iO3S“ 41 1 .5485; found 41 1 .4378.
[0145] 2F. BCD-SC12SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium dodeca-1 1 -ene-1 -sulfonate (303 mg, 1 .12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SCi2SO3', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-gm filter, lyophilised and collected as a white solid (-240 mg). C119H217O49S14 confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7~ calculated for C126H231O49S14- 425.5757; found 425.45099.
[0146] 2G. BCD-SCI3SQ3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium trideca-13-ene-1 -sulfonate (318.5 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et3O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SCi3SO3', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-200 mg).
[0147] 2H. BCD-SCI4SQ3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium tetradeca- 13-ene- 1 -sulfonate (334.5 mg, 1 .12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SC SOa', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-200 mg).
[0148] 2L BCD-SCI5SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium pentadeca-14-ene-1 -sulfonate (350 mg, 1 .12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SCisSOs', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-270 mg).
[0149] 2J. BCD-SCI6SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium hexadeca-15-ene-1 -sulfonate (365.7 mg, 1 .12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 mL) and collected by centrifugation. The white solid was washed with MeOH (45 ml) and EtOH (45 mL) and collected by centrifugation. The product, pCD-SCieSOs', was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-275 mg).
[0150] 2K. BCD-SC17SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium heptadeca-16-ene-1 -sulfonate (365.7 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product, pCD-SCi7SO3', was purified directly by dialysis, first against a 7:3 EtOH/H2O mixture, moving to 30/70 and finally two volumes of pure Milli-Q H2O for 4 days, (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-230 mg).
[0151] 2L BCD-SC18SO3 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), and a 2x excess per thiol of sodium octadeca-17-ene-1 -sulfonate (365.7 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 16 hours. The crude product, pCD-SCi8SO3', was purified directly by dialysis, first against a EtOH/H2O at rations of 80/20, 50/50, 30/70 then finally two volumes of pure Milli- Q H2O for 4 days, (MWCO 2kDa, regenerated cellulose), filtered through a 0.2-pm filter, lyophilised and collected as a white solid (-290 mg). C168H315O49S14 confirmed by High- resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of- flight (QTOF)] mass/charge ratio (m/z): [M]7~ calculated for Ci26H23iO49Si4“ 509.2600; found 509.68668.
[0152] 2M. BCD-SC11SO4 :
Heptakis-(6-deoxy-6-mercapto)-[3-CD (100 mg, 0.080 mmol), sodium undec-10-ene-1 - sulfate (305 mg, 1.12 mmol), were dissolved in DMSO (5 mL). The reaction mixture was placed in front of an ultraviolet (UV) lamp (400 W) and stirred for 12 hours. The crude product was precipitated into a 20% EtOH in Et2O mixture (45 ml) and collected by centrifugation. The off-white solid was washed with MeOH (45 ml) and EtOH (45 ml) and collected by centrifugation. The product, pCD-SCuSO^, was purified by dialysis against Milli-Q H2O for 3 days, with 4 changes of water, filtered through a 0.2-pm filter, lyophilised and collected as a white solid (210 mg). Confirmed by High-resolution mass spectrometry (HRMS) [electrospray ionization (ESI)Zquadrupole time-of-flight (QTOF)] mass/charge ratio (m/z): [M]7- calculated for C119H217O49S14" 427.5471 ; found 427.42900. [0153] 2N. Other Compounds of Formula I:
By following the procedures of Example 2A-2L (as appropriate for chain length) and substituting the starting co-ene sulfonate reactant with: a) ((3-ethylnon-8-en-1 -yl)sulfonyl)-X1-oxidane, b) ((3,4-diethylnon-8-en-1 -yl)sulfonyl)-X1-oxidane, c) ((4-butyldec-9-en-1 -yl)sulfonyl)-X1-oxidane, d) (dodec-11 -ene-1 , 2-diyldisulfonyl)bis(X1 -oxy) , e) ((5-methylhexadec-15-en-2-yl)sulfonyl)-X1-oxidane, f) 3-(4((X1-oxidanyle)dioxo-X6-sulfaneyl)butyo)heptadec-16-enenitrile g) (10-vinylnonanadecane-1 ,19-diyldisulfonyl)bis(X1-oxy), h) (docos-21 -en-1 -ylsulfonyl)-X1-oxidane, i) (((2E,6E)-5-methylnona-2,6,8-trien-1 -yl)sulfonyl)-Z,1-oxidane, j) (((3E,7E)-6-methyldeca-3,7,9-trien-1 -yl)sulfonyl)-X1-oxidane, k) (((4E,8E)-6,7-dimethylundeca-4,8,1 O-trien-1 -yl)sulfonyl)-X1-oxidane, l) (((3E,5E,7E,9E)-dodeca-3,5,7,9,11-pentaen-1 -yl)sulfonyl)-X1-oxidane, m) (((4E,8E)-trideca-4,8,12-trien- 1 -yl)sulfonyl)-X1-oxidane, n) ((4E,8E)-trideca-4,8,12-triene-1 ,2-disulfonyl)bis(X1-oxy), and o) (((2E,7E, 72E,16E)-henicosa-2,7,12,16,20-pentaen-1 -yl)sulfonyl)-X1-oxidane, there are obtained the following product compounds, respectively: a) pCD-SC9-(7-Et)-SO3-, b) pCD-SC9-(6,7-di-Et)-SO3-, c) pCD-SCio-(7-Bu)-S03-, d) pCD-SCi2-(11-SO3 )-SO3-, e) pCD-SCi5-(12,15-di-Me)-SO3-, f) pCD-SCi9-(15-Me-CN)-SO3-, g) pCD-SCi2-(3-C9SO3 )-SO3‘ [alternatively named PCD-SC3-(C9SO3 )2], h) pCD-SC2iSO3-, i) pCD-SC9-(3,7-di-ene-5-Me)-SO3 _, j) pCD-SCio-(3,7-di-ene-5-Me)-S03‘, k) pCD-SCn-(3,7-di-ene-5,6-di-Me)-SO3-, l) pCD-SCn-(3,5,7,9-tetra-ene)-SO3', m) pCD-SCi3-(5,9-di-ene)-SO3', n) pCD-SCi3-(5,9-di-ene-12-SO3 )-SO3-, and o) pCD-SC2i-(5,9,14,19-tetra-ene)-SO3', or if following the procedure of Example 2M and substituting the starting co-ene sulfonate with reactants a) through o) above, the corresponding sulfate products are obtained.
[0154] 20. Other Compounds of Formula I:
By following the procedures of Example 2A-2N (as appropriate for chain length) and substituting the starting heptakis-(6-deoxy-6-mercapto)-[3-CD reactant with hexakis-(6- deoxy-6-mercapto)-a-CD or octakis-(6-deoxy-6-mercapto)-Y-CD, the corresponding a-CD and y-CD products are obtained.
Example 3 Inhibition of HSV-2
[0155] A. Toxicity assay on Vero Cells: Cytotoxicity of the compounds is tested on mammalian cells. Vero cells are plated 24h before the experiment in 96-well plates in order to have a confluent layer. Cells are then incubated with different concentrations of the compound being tested at 37°C for 24 h in DM EM w2% FBS. The solution is then removed and the cells washed with DMEM w2%FBS. 100 ul of DMEM w2% FBS is added in each well with 20 ul of MTS (CellTiter 96® AQueous One Solution Cell Proliferation Assay). After 4 hours of incubation at 37°C, the absorbance of each well is measured through a platereader (X=490 nm). A percentage of cytotoxicity is then calculated comparing the absorbance with a reference, in which cells were incubated with just DMEM w2% FBS.
[0156] B. Inhibition assay against HSV-2: The antiviral effect of compounds of Formula I against HSV-2 is tested following the procedures published in Jones et al., Sci. Adv. 2020; 6: eaax9318 29 January 2020)(copy provided). Specifically, Vero cells were plated 24h before the experiment in 24-well plates at a density of 105 cells. A fixed amount of virus (MOI = 0.0005) was pre-incubated for 1 hour with serial dilutions of the compound of interest. The solution was then transferred onto the cells and incubated for 1 hour. Afterwards, the solution was removed and the cells incubated for 24h in DMEM w2% FBS with 0.45w% Methyl-Cellulose. The cells were then stained with crystal violet and the plaques counted. EC5o values were determined using a non-linear regression analysis using a four-parameter logistic curve by GraphPad Prism 8.0 or superior.
[0157] The compounds of Formula I prepared, e.g., as described in Example 2A-2M were tested as describerd above. The data are reported below in Table 1 in which the data are from at least 2 independent experiments performed in duplicate. Table 1
Figure imgf000044_0001
The EC5o data show notable increases of potency for C9 and above, particularly C13 and above. The corresponding dose-response graphs are presented in Figure 2, where the identification above each graph is another form of the compound name as shown in the upper left corner.
[0158] C. Virucidal assay against HSV-2: The virucidal activity of compounds of Formula I against HSV-2 is tested by virucidal assay. Vero cells are plated 24h before the experiment in 96-well plates in order to have a confluent layer. An effective amount of the compound of interest (100-300-500 pg/ml) is incubated with a fixed amount of viruses (105- 106 pfu/ml) for 1 hour at 37 °C in DMEM - 2%FBS. A serial dilution of this solution is added in each well and incubated for 1 hour at 37°C. Afterwards, the solution is removed and the cells incubated for 24 h in DMEM - 2% FBS with 0.45w% Methyl-Cellulose. The cells are then stained with crystal violet and the plaques counted. The viral titer is evaluated and compared against a reference with no compound.
[0159] The compounds of Formula I prepared, e.g., as described in Example 2A-2M were tested as describerd above. When tested in this manner for virucidal activity, componds having alkyl chain lengths of Cs and below were not virucidal. The componds having alkyl chain lengtrhs of C9 and above were virucidal. The individual virucidal activity graphs are presented in Figure 3, where the number shown for the grey bar corresponds to the number of carbons in the linker. [0160] D. Activity of Other Compounds of Formula I: When tested as described above in Examples 2A, 2B and 2C, the other compounds of Formula I prepared, e.g., as described in Example 2N-2O have acceptable cytotoxicity, antiviral and virucidal effectiveness.
Example 4 Lip Balm Formulation
Figure imgf000045_0001
[0161] As disclosed in US 2013/0150312, polyethylene 1450 and 300 are melted at 50° C with stirring. The pCD-SCnSOf, 2-deoxy-D-glucose, silica gel and stevioside are triturated together. The triturated powders are slowly sifted into the melted PEGs with stirring. The flavoring is added, followed by thorough mixing. The mixture is poured into applicator tubes and allowed to cool to room temperature.
Example 5 Aqueous Cream Formulation
Figure imgf000045_0002
[0162] As disclosed in US 2013/0150312, a part of the PCD-SCBSOS" is dissolved in water with the 2-deoxy-D-glucose and propylene glycol at ambient temperature to produce an aqueous solution. The paraffins and emulsifiers (cetostearyl alcohol and sodium lauryl sulphate) are mixed together, heated to 60° C, and emulsified with the aqueous solution, also at 60° C. The remaining PCD-SCBSOS’ is added, the mixture dispersed, allowed to cool, and filled into lacquered aluminum tubes.
Example 8 Nebulizer Formulation
[0163] A nebuliser, for example, as disclosed in US 9,364,618 B2 or EP 3,517,117 A1 is provided comprising the following pharmaceutical composition in its fluid reservoir: 14.0 mg PCD-SCBSOS’, 0.9% w/v NaCI dissolved in sterile deionised water. The nebuliser is used to deliver the composition by inhalation as an aerosol to the lower respiratory tract of a patient suffering from influenza.
[0164] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All patents and publications cited above are hereby incorporated by reference.

Claims

We claim:
1 . A compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Formula I
Figure imgf000047_0001
wherein: each R, independently, is OH, SH, an -0-(Ci2to C25)-optionally substituted alkyl- based ligand or a -S-(Ci2 to C25)-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate ("SO4") or a sulfonate ("SO3") moiety; each R’, independently, is H, -(CH2)y-COOH, -(CH2)y-SO'3, a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
2. A virucidal compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester for use in treating viral infections or diseases associated with viruses, wherein said compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester is of Formula I
- 46 -
Figure imgf000048_0001
wherein: each R, independently, is OH, SH, an -O-(C9 to C25)-optionally substituted alkyl- based ligand or a -S-(C9 to C25)-optionally substituted alkyl-based ligand, wherein no more than 4 can be OH or SH and at least two of said ligands have a sulfate ("SO4") or a sulfonate ("SO3") moiety; each R’, independently, is H, -(CH2)y-COOH, -(CH2)y-SO'3, a polymer or a water solubilizing moiety; x is 6, 7 or 8; and y is an integer from 4 to 20.
3. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -2 where R' is H.
4. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -3 wherein x is 7.
5. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1-4 wherein for R, no more than 1 can be OH or SH and each of the remaining R groups has a sulfate ("SO4") or a sulfonate ("SO3") moiety.
6. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -5 wherein R is an -O-(Ci2 to C2o)-optionally substituted alkyl- based ligand or a -S-(Ci2 to C20)-optionally substituted alkyl-based ligand.
- 47 -
7. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -5 wherein R is an -O-(Ci2 to C2o)-optionally substituted alkyl ligand or a -S-(Ci2 to C20)-optionally substituted alkyl ligand.
8. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -5 wherein R is an -O-(Ci2 to Cis)-optionally substituted alkyl ligand or a -S-(Ci2 to Ci8)-optionally substituted alkyl ligand.
9. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 -5 wherein R is an -O-(Ci2 to Cis)-unbranched alkyl ligand or a -S-(Ci2 to Ci8)-unbranched alkyl ligand.
10. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 - 9 for use in treating a viral infection or a disease associated with an HSPG-seeking virus.
11. The compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of Claim 10 wherein the virus is HSV-1 , HSV-2, HSV-2 R ACV, HSV-2 clinical, RSV- A, RSV-B, HMPV, PIV3, HIV, DENV-2, ZIKV, HCV, HCV Y93H or HCV D168A.
12. A virucidal composition comprising an effective amount of a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 - 9 and a suitable carrier.
13. A method of disinfection and/or sterilization of non-living surfaces using a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 - 19 or the virucidal composition of Claim 12.
14. A device comprising a surface coated with a compound, pharmaceutically acceptable salt or pharmaceutically acceptable ester of any one of Claims 1 - 9 or the virucidal composition of Claim 12.
- 48 -
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140046061A1 (en) * 2009-06-04 2014-02-13 Jose R. Matos Processes Employing Cyclodextrin Derivative Quaternary Salts
US20160058873A1 (en) * 2011-04-21 2016-03-03 Cerulean Pharma Inc. Cyclodextrin-Based Polymers for Therapeutic Delivery
US20210137966A1 (en) * 2016-07-22 2021-05-13 ECOLE POLYTECHNIQUE FéDéRALE DE LAUSANNE Virucidal compounds and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140046061A1 (en) * 2009-06-04 2014-02-13 Jose R. Matos Processes Employing Cyclodextrin Derivative Quaternary Salts
US20160058873A1 (en) * 2011-04-21 2016-03-03 Cerulean Pharma Inc. Cyclodextrin-Based Polymers for Therapeutic Delivery
US20210137966A1 (en) * 2016-07-22 2021-05-13 ECOLE POLYTECHNIQUE FéDéRALE DE LAUSANNE Virucidal compounds and uses thereof

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Title
JONES SAMUEL T., CAGNO VALERIA, JANEčEK MATEJ, ORTIZ DANIEL, GASILOVA NATALIA, PIRET JOCELYNE, GASBARRI MATTEO, CONSTANT DAVI: "Modified cyclodextrins as broad-spectrum antivirals", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, vol. 6, no. 5, 31 January 2020 (2020-01-31), US , pages eaax9318, XP055823970, ISSN: 0036-8075, DOI: 10.1126/sciadv.aax9318 *

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