WO2024022411A1 - Composés et compositions pour le traitement de la grippe - Google Patents

Composés et compositions pour le traitement de la grippe Download PDF

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Publication number
WO2024022411A1
WO2024022411A1 PCT/CN2023/109437 CN2023109437W WO2024022411A1 WO 2024022411 A1 WO2024022411 A1 WO 2024022411A1 CN 2023109437 W CN2023109437 W CN 2023109437W WO 2024022411 A1 WO2024022411 A1 WO 2024022411A1
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formula
alkyl
influenza
compounds
group
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PCT/CN2023/109437
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English (en)
Inventor
Guochuan Emil Tsai
Yu-Jung Wu
Han-Yi Hsieh
Jhe-Wei Hu
Tsai-Miao Shih
Yi-Wen Mao
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Syneurx International (Taiwan) Corp.
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Publication of WO2024022411A1 publication Critical patent/WO2024022411A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Influenza is a contagious respiratory disease caused by infection of influenza virus. In general, about 5-15%of the population would have influenza each year with 3-5 million severe cases. Globally, influenza causes about 650,000 respiratory-related deaths each year, commonly occurring in high risk groups, including young children, the elderly, and people with chronic health conditions. Overall, influenza places a substantial burden on the heath of people worldwide.
  • Influenza A virus a main type of influenza viruses that cause influenza, are negative-sense, single-stranded, segmented RNA viruses. It has multiple subtypes based on the types of hemagglutinin and neuraminidase of the virus, making selection of effective influenza vaccines each year a challenging task.
  • the present disclosure is based, at least in part, on the discovery that compounds having the structure of Formula (I) disclosed herein showed (a) superior inhibitory activities against host (human) TMPRSS2 and HAT proteases, which mediate infection of influenza viruses, and (b) superior inhibitory activities of a tannic acid composition enriched with large tannic acid molecules (enriched tannic acid compositions) against viral neuraminidase and human TMPRSS2 and HAT proteases, as well as cytotoxicity against influenza viruses as compared with commercially available tannic acid compositions.
  • the Formula (I) compounds and the enriched tannic acid compositions as disclosed herein are expected to be potent therapeutic agents for treating influenza, e.g., influenza caused by influenza A or influenza B virus.
  • the present disclosure provides a method of treating influenza, comprising administering to a subject in need thereof an effective amount of a composition, wherein the composition comprises one or more compounds of Formula (I) : or a pharmaceutically acceptable salt thereof.
  • a composition comprising one or more compounds of Formula (I) : or a pharmaceutically acceptable salt thereof.
  • Ring X is a 3 to 7 membered monocyclic ring, which has 0, 1, or 2 heteroatoms selected from the group consisting of N, O, P, and S;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 independently is of the formula:
  • R 7 is the formula (II)
  • n and o are, independently, 0 or 1;
  • n and p are each, independently, 1, 2, 3, 4, or 5.
  • the compound of Formula (I) has 2 to 35 galloyl moieties, inclusive.
  • substituents which may be C 1-3 alkyl, halogen, -CF 3 , –CN, –NO 2 , –SH, -OH, –S (C 1-3 alkyl) , –NH 2 , NH (C 1-3 alkyl) , N (C 1-3 alkyl) 2 , -
  • Ring X can be
  • the Formula (I) compounds disclosed herein may have a glucose core.
  • Such compounds may have the structure of Formula (Ia) : in which R 1 is CH 2 -OH, and each of R 2 , R 3 , R 4 , and R 5 each independent is selected from the group consisting of H, OH, provided that when R 1 is CH 2 -OH, at least one of R 2 , R 3 , R 4 , and R 5 is
  • the Formula (Ia) compounds may have a structure of Formula (Ia-1) and each of R 1 , R 2 , R 3 , R 4 , and R 5 is as defined herein.
  • Exemplary Formula (Ia) compounds include Compounds 4- 17.
  • the Formula (I) compounds disclosed herein may have a ribose (e.g., a xylose) core.
  • such compounds may be in the pyranose format, i.e., having the structure of Formula (Ib) in which at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is and the remaining of R 1 , R 2 , R 3 , R 4 , and R 5 each independently is H, OH
  • the Formula (Ib) compounds may have the structure of Formula (Ib-1) in which R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein.
  • Exemplary Formula (Ib) compounds include Compounds 18-31 and 32’-45’.
  • the compounds having a ribose may be in the furanose format, i.e., having the structure of Formula (Ic) in which R 1 is CH 2 -OH, and each of R 2 , R 3 , and R 4 independently is H, OH,
  • R 1 is CH 2 -OH
  • R 3 is CH 2 -OH
  • R 4 is in some examples
  • the Formula (Ic) compounds may have the structure of Formula (Ic-1) in which each of R 1 , R 2 , R 3 , and R 4 is as defined herein.
  • Examples of Formula (Ic) compounds include Compounds 18’-31’ and 32-45.
  • Formula (I) compounds disclosed herein may have the structure of Formula (Id) :
  • Formula (Id) compounds may have the structure of Formula (Id-1)
  • R 1 , R 2 , and R 3 are of the formula:
  • Formula (Id-1) compounds include Compounds 70-75 and 77.
  • Examples of Formula (Id-2) compounds include Compounds 46-69, 76, and 78-129.
  • ring Y in the R 7 group can be Alternatively or in addition, the R 8 moiety in the R 7 group may be absent.
  • the R 7 group may be any organic compound.
  • the R 7 group may be any organic compound.
  • the present disclosure features a method of treating influenza, comprising administering to a subject in need thereof an effective amount of a composition, which comprises a population of tannic acids or a pharmaceutically acceptable salt thereof.
  • the population of tannic acids is from a plant source selected from a group consisting of Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, Rhus punjabensis var. sinica (Diels) Rehder &E.H.
  • Wilson Camellia sinensis, Berry, Bixa orellana, Vitis vinifera, Punica granatum, Quercus infectoria, Quercus cerris, Acacia mearnsii, Pseudotsuga menziesii, Caesalpinia spinosa, Fagus hayata Palib. ex Hayata, and Machilus thunbergii Sieb. &Zucc.
  • about 1-25%tannic acids of the population of tannic acids have 1-4 galloyl moieties; and about 30-99%tannic acids of the population of tannic acids have 5-12 galloyl moieties.
  • the population of tannic acids contain about 1-8%of tannic acids having 1-4 galloyl moieties, about 35-50%of tannic acids having 5-7 galloyl moieties, and about 30-64%of tannic acids having 8-12 galloyl moieties.
  • about 1-30%tannic acids of the population of tannic acids have 5 galloyl moieties; about 10-40%tannic acids of the population of tannic acids have 6-7 galloyl moieties; and/or about 20-85%tannic acids of the population of tannic acids have 8-12 galloyl moieties.
  • the population of tannic acids contain about 1-8%of tannic acids having 5 galloyl moieties, about 15-35%of tannic acids having 6-7 galloyl moieties, and about 60-80%of tannic acids having 8-12 galloyl moieties.
  • the population of tannic acids is substantially homogenous, in which at least 95%of tannic acids have the having a same number of galloyl moieties.
  • the population of tannic acid disclosed herein contains less than 2%by weight tannic acid molecules having 4 or less galloyl moieties.
  • the population of tannic acids disclosed herein may have at least 95% (w/w) tannic acid molecules having 5-12 gallolyl moieties.
  • the population of tannic acids may have at least 96% (w/w) tannic acid molecules having 5-12 gallolyl moieties.
  • the population of tannic acids may have at least 97% (w/w) tannic acid molecules having 5-12 gallolyl moieties.
  • the population of tannic acids may have at least 98% (w/w) tannic acid molecules having 5-12 gallolyl moieties. In still another example, the population of tannic acids may have at least 96% (w/w) tannic acid molecules having 5-12 gallolyl moieties.
  • about 1-30%tannic acids of the population of tannic acids have 5 galloyl moieties; about 10-40%tannic acids of the population of tannic acids have 6-7 galloyl moieties; and/or about 20-85%tannic acids of the population of tannic acids have 8-12 galloyl moieties.
  • the population of tannic acids contain about 1-8%of tannic acids having 5 galloyl moieties, about 15-35%of tannic acids having 6-7 galloyl moieties, and about 60-80%of tannic acids having 8-12 galloyl moieties.
  • influenza virus which can be influenza A, influenza B, influenza C, or influenza D.
  • influenza virus which can be influenza A, influenza B, influenza C, or influenza D.
  • the subject to be treated can be a human subject, e.g., a human patient having influenza.
  • the composition comprising either the Formula (I) compound or the tannic acid population may be administered to the subject by oral administration, by injection, by topical administration, or by inhalation.
  • the composition can be placed in a medical device selected from the group consisting of an inhaler, a nebulizer, a nasal spray, a vaporization aerosol device, and a facial mask for administration to the subject.
  • the subject e.g., a human subject
  • the composition is administered the composition at a frequency of every five minutes to one time every three months.
  • the subject e.g., a human subject
  • the subject is treated concurrently with, prior to, or subsequent to, one or more additional anti-viral agents.
  • the one or more additional anti-viral agents comprise a viral entry inhibitor, a viral uncoating inhibitor, a viral reverse transcriptase inhibitor, a viral protein synthesis inhibitor, a viral protease inhibitor, a viral polymerase inhibitor, a viral integrase inhibitor, an interferon, or the combination thereof.
  • anti-viral agents include amantadine, oseltamivir, zanamivir, peramivir, remdesivir, or baloxavir marboxil.
  • the anti-viral agent is oseltamivir.
  • Exemplary interferon molecules include type I interferon, type II interferon, type III interferon, and peginterferon alfa-2a.
  • Formula (I) compounds or enriched tannic acid compositions as well as pharmaceutical compositions comprising such for use in treating influenza and uses of such compounds/compositions for manufacturing a medicament for use in treating influenza.
  • FIGs. 1A-1F include diagrams showing exemplary compounds of Formula (I) with a glucose core.
  • FIG. 1A Formula (Ia) representing compounds with a glucose core as disclosed herein and Compounds 4-7.
  • FIG. 1B Compounds 8-9.
  • FIG. 1C Compounds 10-11.
  • FIG. 1D Compounds 12-13.
  • FIG. 1E Compounds 14-15.
  • FIG. 1F Compounds 16-17.
  • FIGs. 2A-2L include diagrams showing exemplary compounds of Formula (I) with a ribose core in pyranose format.
  • FIG. 2A Formula (Ib) representing compounds with a ribose core in pyranose format as disclosed herein and Compounds 32’, 33’, 34’, and 35’.
  • FIG. 2B Compounds 36’ and 37’.
  • FIG. 2C Compounds 38’ and 39’.
  • FIG. 2D Compounds 40’ and 41’.
  • FIG. 2E Compounds 42’ and 43’.
  • FIG. 2F Compounds 44’ and 45’.
  • FIG. 2G Compounds 18-21.
  • FIG. 2H Compounds 22-23.
  • FIG. 2I Compounds 24-25.
  • FIG. 2J Compounds 26-27.
  • FIG. 2K Compounds 28-29.
  • FIG. 2L Compounds 30-31.
  • FIGs. 3A-3G include diagrams showing exemplary compounds of Formula (I) with a ribose core in the furanose format.
  • FIG. 3A Formula (Ic) representing compounds with a ribose core in furanose format as disclosed herein and Compounds 18’, 19’, 20’ and 21’.
  • FIG. 3B Compounds 22’, 23’, 24’, and 25’.
  • FIG. 3C Compounds 26’, 27’, 28’, and 29’.
  • FIG. 3D Compounds 30’, 31’, 32’, and 33’.
  • FIG. 3E Compounds 34-37.
  • FIG. 3F Compounds 38-41.
  • FIG. 3G Compounds 42-45.
  • FIGs. 4A-4C include diagrams showing exemplary compounds of Formula (I) with structure of Formula (Id-1) .
  • FIG. 4A Formula (Id-1) general structure and Compounds 70-72.
  • FIG. 4B Compounds 73-74.
  • FIG. 4C Compounds 75 and 77.
  • FIGs. 5A-5N include diagrams showing exemplary compounds of Formula (I) with structure of Formula (Id-2) .
  • FIG. 5A Formula (Id-2) general structure and Compounds 46-51.
  • FIG. 5B Compounds 52-57.
  • FIG. 5C Compounds 58-63.
  • FIG. 5D Compounds 64-67.
  • FIG. 5E Compounds 68, 69, and 76.
  • FIG. 5F Compounds 78-84.
  • FIG. 5G Compounds 85-89.
  • FIG. 5H Compounds 90-95.
  • FIG. 5I Compounds 96-101.
  • FIG. 5J Compounds 102-107.
  • FIG. 5K Compounds 108-113.
  • FIG. 5L Compounds 114-118.
  • FIG. 5M Compounds 119-124.
  • FIG. 5N Compounds 125-129.
  • FIGs. 6A-6C include diagrams showing inhibitory activity of an enriched tannic acid (TA) composition as compared with commercially available TA compositions from Merck (TA (Merck) ) and from CC Biotech (TA (CC Biotech) at a concentrations of 3 ⁇ M or 10 ⁇ M against neuraminidase.
  • FIG. 6A human influenza virus A H1N1 (A/California/04/2009, pdm09) .
  • FIG. 6B human Influenza virus A H3N2 (A/California/2/2014) .
  • FIG. 6C Influenza B/Wisconsin/1/2010 (Yamagata Lineage) in a fluorescence-based assay. The Inhibition percentage (%) was calculated as noted in Material and method and annotated on the top of every column; error bars indicated the standard deviation of at least triplicate.
  • FIGs. 7A-7C include diagrams showing inhibitory activity of the enriched TA composition relative to TA (Merck) and TA (CC Biotech) at 3 ⁇ M against hTMPRSS2 in enzymatic assay.
  • FIG. 7A Influenza A virus H1 subtype.
  • FIG. 7B Influenza A virus H3 subtype.
  • FIG. 7C Influenza B virus.
  • Enzymatic activity of extracellular domain of hTMPRSS2 (149-492) containing a SRCR domain and a catalytic domain was determined by reacting with FRET (fluorescence-resonance energy transfer) peptides that mimics the sequences of hemagglutinin cleavage sites from the viral strains as indicated above.
  • FRET fluorescence-resonance energy transfer
  • FIGs. 8A-8C include diagrams showing inhibitory activity of the enriched TA composition relative to TA (Merck) and TA (CC Biotech) at 3 ⁇ M against HAT in enzymatic assay.
  • FIG. 8A Influenza A virus H1 subtype.
  • FIG. 8B Influenza A virus H3 subtype.
  • FIG. 8C Influenza B virus.
  • Enzymatic activity of extracellular domain of HAT (144-418) containing a partial SEA domain and a catalytic domain was determined by reacting with FRET (fluorescence-resonance energy transfer) peptides that mimics the sequences of hemagglutinin cleavage sites from the viral strains noted above.
  • FRET fluorescence-resonance energy transfer
  • FIG. 9 is a diagram showing cytotoxicity of the enriched tannic acid composition against MDCK cells.
  • MDCK cells was cultured in DMEM supplemented with 10%FBS in a humidified incubator for 48 hours. Error bar at each data indicates standard error of mean (s.e.m. ) of triplicate.
  • FIGs. 10A-10J include diagrams showing efficacies of the enriched tannic acid composition against various influenza A viruses (IAV) in an in vitro influenza virucidal assays.
  • FIGs. 10A an 10B against A/Puerto Rico/8/1934 strain, cell pellet and supernatant, respectively.
  • FIGs. 10C and 10D against A/California/04/2009 (H1N1) pdm09 strain, cell pellet and supernatant, respectively.
  • FIGs. 10E and 10F against A/Taiwan/03773/2015, cell pellet and supernatant, respectively.
  • FIGs. 10G and 10H against A/Taiwan/00710/2017, cell pellet and supernatant, respectively.
  • 10C and 10D against A/California/02/2014 (H3N2) , cell pellet and supernatant, respectively. Viral loads of from cell pellets and supernatants were determined by qRT-PCR, respectively. The percentages of inhibition of the samples were plotted (Y axis) against logarithmic concentrations of the enriched tannic acid, and the concentration-inhibition plot was fitted with non-linear regression using asymmetric (five-parameters) logistic dose-response curve; EC50 (concentrations that inhibits 50%influenza viral counts) were derived from the equation. Error bars indicated the standard deviation of quadruplicate.
  • FIGs. 11A-11D include diagrams showing efficacies of enriched tannic acid against various influenza B viruses (IBV) in an in vitro influenza virucidal assays.
  • FIGs. 11A and 11B IBV-Victoria, cell pellets and supernatant, respectively.
  • FIGs. 11C and 11D IBV-Yamagata, cell pellets and supernatant, respectively. Viral loads from cell pellets and supernatants were determined by qRT-PCR.
  • the percentages of inhibition of the samples were plotted (Y axis) against logarithmic concentrations of the enriched tannic acid, and the concentration-inhibition plot was fitted with non-linear regression using asymmetric (five-parameters) logistic dose-response curve; EC50 (concentrations that inhibits 50%influenza viral counts) were derived from the equation. Error bars indicated the standard deviation of quadruplicate.
  • FIGs. 12A-12D include diagrams showing dose-response curves of eTA alone, eTA/oseltamivir (20: 1) combination, and oseltamivir alone against influenza A H1N1 viruses (FIGs. 12A-12B) and influenza A H3N2 virus (FIGs. 12C-12D) .
  • the present disclosure is based, at least in part, on the discovery that compounds having the structure of Formula (I) disclosed herein showed superior inhibitory activities against host human transmembrane serine protease 2 (hTMPRSS2) and human airway trypsin-like protease (HAT) proteases, which mediate infection of influenza viruses.
  • hTMPRSS2 human transmembrane serine protease 2
  • HAT human airway trypsin-like protease
  • hTMPRSS2 belongs to the type II transmembrane serine proteases (TTSPs) , the largest group of host cell membrane-anchored proteases that is critical to the infection of various viruses, including pandemic human influenza viruses (Bottcher-Friebertshauser et al., 2012) .
  • TTSPs transmembrane serine proteases
  • Development of inhibitors against human TMPRSS2 protease is thus a promising approach to light the burden of healthcare system and patients who suffers from the pandemic of influenza viruses.
  • HAT Human airway trypsin-like protease belongs to the type II transmembrane serine proteases (TTSPs) , the largest group of host cell membrane-anchored proteases that is critical to the infection of various viruses, including pandemic human influenza viruses (Bottcher-Friebertshauser et al., 2012) .
  • TTSPs transmembrane serine proteases
  • Development of inhibitors against human HAT protease is thus a promising approach to light the burden of healthcare system and patients who suffers from the pandemic of influenza viruses.
  • tannic acid compositions enriched with large tannic acid molecules e.g., having at least 5 galloly (G) residues
  • G galloly
  • Host protease-mediated hemagglutinin activation and viral neuraminidase-mediated virion-release are both indispensable to the invasion and the propagation of human influenza viruses. Development of antivirals that aim at both mechanisms are thus a promising approach to halt the pandemic human influenza viruses.
  • the Formula (I) compounds disclosed herein and the enriched tannic acid compositions disclosed herein would be effective in treating influenza.
  • compositions comprising one or more of the Formula (I) compounds disclosed herein or a population of tannic acids such as the enriched tannic acid composition as disclosed herein.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • C1–6 is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6.
  • the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the disclosure contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH 2 -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 -cyclohexyl moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl) , 1-propynyl, and the like.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group or a saturated carbocyclyl ring having from 1 to 10 carbon atoms ( “C1–10 alkyl” ) .
  • an alkyl group has 1 to 9 carbon atoms ( “C1–9 alkyl” ) .
  • an alkyl group has 1 to 8 carbon atoms ( “C1–8 alkyl” ) .
  • an alkyl group has 1 to 7 carbon atoms ( “C1–7 alkyl” ) .
  • an alkyl group has 1 to 6 carbon atoms ( “C1–6 alkyl” ) .
  • an alkyl group has 1 to 5 carbon atoms ( “C1–5 alkyl” ) . In some embodiments, an alkyl group has 1 to 4 carbon atoms ( “C1–4 alkyl” ) . In some embodiments, an alkyl group has 1 to 3 carbon atoms ( “C1–3 alkyl” ) . In some embodiments, an alkyl group has 1 to 2 carbon atoms ( “C1–2 alkyl” ) . In some embodiments, an alkyl group has 1 carbon atom ( “C1 alkyl” ) . In some embodiments, an alkyl group has 2 to 6 carbon atoms ( “C2–6 alkyl” ) .
  • C1–6 alkyl groups include methyl (C1) , ethyl (C2) , propyl (C3) (e.g., n–propyl, isopropyl) , butyl (C4) (e.g., n–butyl, tert–butyl, sec–butyl, iso–butyl) , pentyl (C5) (e.g., n–pentyl, 3–pentanyl, amyl, neopentyl, 3–methyl–2–butanyl, tertiary amyl) , and hexyl (C6) (e.g., n–hexyl) .
  • C1–6 alkyl groups include methyl (C1) , ethyl (C2) , propyl (C3) (e.g., n–propyl, isopropyl) , butyl (C4) (e.g., n–butyl
  • alkyl groups include n–heptyl (C7) , n–octyl (C8) , and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl” ) or substituted (a “substituted alkyl” ) with one or more substituents (e.g., halogen, such as F, or -OH) .
  • the alkyl group is an unsubstituted C1–10 alkyl (such as unsubstituted C1-6 alkyl, e.g., –CH3) .
  • the alkyl group is a substituted C1–10 alkyl (such as substituted C1-6 alkyl or substituted C1-3 alkyl, e.g., –CF3 or -CH2OH) .
  • a “monocyclic ring” refers to a single cyclic ring wherein the atoms on the ring are selected from the group consisting of C, N, O, P and S.
  • a “monocyclic ring” is a carbocyclyl with 3 to 10 carbon atoms (C3–10 carbocyclyl) .
  • a “monocyclic ring” is a heterocyclic ring with 3-10 atoms, including at least one atom from the group consisting of N, O, P and S.
  • a “monocyclic ring” is
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms ( “C3–10 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ( “C3–8 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ( “C3–6 cycloalkyl” ) . In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ( “C5–6 cycloalkyl” ) .
  • a cycloalkyl group has 5 to 10 ring carbon atoms ( “C5–10 cycloalkyl” ) .
  • C5–6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5) .
  • C3–6 cycloalkyl groups include the aforementioned C5–6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4) .
  • Examples of C3–8 cycloalkyl groups include the aforementioned C3–6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8) .
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl” ) or substituted (a “substituted cycloalkyl” ) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3–10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3–10 cycloalkyl.
  • Heterocyclyl or “heterocyclic” refers to a radical of a 3–to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ( “3–10 membered heterocyclyl” ) .
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclic ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclic ring, or ring systems wherein the heterocyclic ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclic ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl” ) or substituted (a “substituted heterocyclyl” ) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ( “5–10 membered heterocyclyl” ) .
  • a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–8 membered heterocyclyl” ) .
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–6 membered heterocyclyl” ) .
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2, 5–dione.
  • Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholilanyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C6–14 aryl” ) .
  • an aryl group has six ring carbon atoms ( “C6 aryl” ; e.g., phenyl) .
  • an aryl group has ten ring carbon atoms ( “C10 aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) . In some embodiments, an aryl group has fourteen ring carbon atoms ( “C14 aryl” ; e.g., anthracyl) .
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl” ) or substituted (a “substituted aryl” ) with one or more substituents.
  • the aryl group is unsubstituted C6–14 aryl.
  • the aryl group is substituted C6–14 aryl.
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, which are divalent bridging groups, are further referred to using the suffix –ene, e.g., alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.
  • “Aralkyl” is a subset of alkyl and aryl and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. In certain embodiments, the aralkyl is optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl. In some embodiments, the aralkyl is a subset of heteroaryl and aryl, optionally linked by alkyl groups.
  • Heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–10 membered heteroaryl” ) .
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl) .
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–10 membered heteroaryl” ) .
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–8 membered heteroaryl” ) .
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ( “5–6 membered heteroaryl” ) .
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl” ) or substituted (a “substituted heteroaryl” ) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl.
  • the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5, 6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6, 6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • “Unsaturated” or “partially unsaturated” refers to a group that includes at least one double or triple bond.
  • a “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) .
  • “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.
  • An atom, moiety, or group described herein may be unsubstituted or substituted, as valency permits, unless otherwise provided expressly.
  • the term “optionally substituted” refers to substituted or unsubstituted.
  • alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group) .
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present disclosure contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • the substituent is a carbon atom substituent.
  • the substituent is a nitrogen atom substituent.
  • the substituent is an oxygen atom substituent.
  • the substituent is a sulfur atom substituent.
  • Halo or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C1–4 alkyl) 4-salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers” .
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R-and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) -isomers respectively) .
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture” .
  • Ring X can be a 3 to 7 membered monocyclic ring. In some examples, Ring X contains 1 or 2 heteroatoms of N, O, P, or S. In other examples, Ring X does not have any heteroatoms. Exemplary Ring X includes:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 independently is of the formula:
  • R 7 is the formula (II) :
  • n and o are, independently, 0 or 1; and m and p are each, independently, 1, 2, 3, 4, or 5.
  • the compound of Formula (I) has 2 to 35 galloyl moieties, inclusive.
  • a compound of Formula (I) has more than 12 galloyl moieties.
  • such a compound of Formula (I) may have 15-35 galloyl moieties, inclusive.
  • the Formula (I) compound has a glucose core with a structure of Formula (Ia) : in which each of R 1 -R 5 is as defined herein, provided that when R 1 is CH 2 -OH, at least one of R 2 , R 3 , R 4 , and R 5 is The glucose core may be in format. Alternatively, the glucose core may be in ⁇ format.
  • Exemplary Formula (Ia) compounds are provided in FIGs. 1A-1F (Compounds 4-17) .
  • the Formula (I) compounds disclosed herein may have a ribose core such as a xylose core.
  • the ribose core may be in a pyranose format.
  • Such compounds may have the structure of Formula (Ib) in which in which at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is and the remaining of R 1 , R 2 , R 3 , R 4 , and R 5 each independently is H, OH,
  • the ribose core may be in ⁇ format.
  • the ribose core may be in ⁇ format.
  • Exemplary compounds of Formula (Ib) are shown in FIGs. 2A-2L (include Compounds 32’-45’ and 18-31.
  • the ribose core in a Formula (I) compound may be in furanose format, having the structure of Formula (Ic) in which R 1 is CH 2 -OH, each of R 2 , R 3 , and R 4 independently is H, OH,
  • R 1 is CH 2 -OH
  • R 2 , R 3 , and R 4 is The ribose core may be in ⁇ format.
  • the ribose core may be in ⁇ format.
  • Exemplary Formula (Ic) compounds are shown in FIGs. 3A-3G (include Compounds 18’-31’ and 32-45) .
  • the Formula (I) compounds disclosed herein may have a phenol core as depicted in Formula (Id) in which R 1 -R 6 are as defined herein.
  • the Formula (Id) compounds may be of the structure of Formula (Id-1) in which at least one of R 1 , R 2 , and R 3 , independently, is of the formula:
  • Exemplary Formula (Id-1) compounds are provided in FIGs. 4A-4C (include Compounds 70-75 and 77) .
  • a Formula (Id) compound may have the structure of Formula (Id-2) at least one of R 1 , R 2 , R 3 , and R 4 independently, is of the formula:
  • FIGs. 5A-5N include Compounds 46-69, 76, and 78-129) .
  • the compounds of Formula (I) as disclosed herein can be serine protease inhibitors.
  • the Formula (I) compounds may inhibit a type II transmembrane serine protease (TTSP) .
  • TTSPs include HAT, DESC1, TMPRSS11A, HAT-like 2, HAT-like 3, HAT-like 4, HAT-like 5, Hepsin, TMPRSS2, TMPRSS3, TMPRSS4, MSPL N, Spinesin, Enteropeptidase, Matriptase, Matriptase-2, Matriptas-3 and Polyserase-1.
  • tannic acid compositions for use in treating influenza.
  • the tannic acid compositions may be isolated from a suitable plant source, e.g., via conventional process or the preparation methods noted herein. Examples include, but are not limited to, Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, Rhus punjabensis var. sinica (Diels) Rehder &E.H.
  • Wilson Camellia sinensis, Berry, Bixa orellana, Vitis vinifera, Punica granatum, Quercus infectoria, Quercus cerris, Acacia mearnsii, Pseudotsuga menziesii, Caesalpinia spinosa, Fagus hayata Palib. ex Hayata, and Machilus thunbergii Sieb. &Zucc.
  • the plant is Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, and Rhus punjabensis var. sinica (Diels) Rehder &E.H. Wilson.
  • the gallnuts may have diameters ranging from 1-8 cm.
  • the gallnuts can be Chinese belly-shaped gallnuts or horned gallnuts. When Chinese horned gallnuts are used, the diameters of such gallnuts may range from 1-8 cm, e.g., from 2-6 cm or from 3-5 cm.
  • the tannic acid composition can be an enriched tannic acid composition.
  • an enriched tannic acid composition refers to a tannic acid composition enriched with tannic acid molecules having at least 5 galloyl (G) residues or a pharmaceutically acceptable salt thereof.
  • G galloyl
  • an enriched tannic acid composition may contain less than 2%by weight tannic acid molecules having 4 or less G residues or a pharmaceutically acceptable salt thereof.
  • the weight%disclosed herein refers to the weight percentage of certain tannic acids (e.g., those having 4 or less G residues) over the total tannic acid population.
  • the enriched tannic acid composition as disclosed herein may contain ⁇ 2%by weight of tannic acid molecules with 4 or less G residues and >95% (e.g., > 96%, > 97%, > 98%, or >99%) by weight tannic acid molecules having 5-12G residues, or a pharmaceutically acceptable salt thereof.
  • the enriched tannic acid composition as disclosed herein may contain at least 90%by weight (e.g., 92%, 95%, 97%, 98%, or higher) of tannic acids having 6-12 G residues or a pharmaceutically acceptable salt thereof.
  • the enriched tannic acid composition described herein may contain ⁇ 60% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, or higher) of tannic acids having 8-12 G residues or a pharmaceutically acceptable salt thereof.
  • the enriched tannic acid composition may comprise a heterologous population of tannic acids including ⁇ 2%1-4G tannic acids, about 25-40% (e.g., about 30-40%) 5-7G tannic acids, and about 55-65% (e.g., about 60-65%) 8-12G tannic acids, or a pharmaceutically acceptable salt thereof.
  • a tannic acid composition disclosed herein may comprise about 1-25% (e.g., about 1-20%, about 1-15%, about 1-10%, about 1-5%, or about 1-3%) tannic acid molecules having 1-4G residues and about 30-99% (e.g., about 40-99%, about 50-99%, about 60-99%, about 70-99%or about 80-99%) tannic acid molecules having 5-12G residues.
  • the tannic acid composition may contain about 1-8%of tannic acids having 1-4 galloyl moieties, about 35-50%of tannic acids having 5-7 galloyl moieties, and about 30-64%of tannic acids having 8-12 galloyl moieties.
  • the enriched tannic acid composition may contain a substantially homogeneous population.
  • a tannic acid population may contain a tannic acid having a defined number of galloyl moieties, for example, any number between 5 and 12 (including 5 and 12) , or a pharmaceutically acceptable salt thereof.
  • the term "substantially homogenous" means that the tannic acid having the defined number of galloyl moieties constitutes at least 85%by weight (e.g., 90%, 95%, 97%, 98%, 99%, or above) of the total tannic acid population in the composition.
  • the substantially homogenous tannic acid population contains tannic acids having 5 G residues.
  • the substantially homogenous tannic acid population contains tannic acids having 6 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 7 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 8 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 9 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 10 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 11 G residues. In some examples, the substantially homogenous tannic acid population contains tannic acids having 12 G residues.
  • any of the tannic acid compositions disclosed herein may have a purity greater than 95% (e.g., at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5%) .
  • purity refers to the weight percentage of tannic acid molecules (with 2-12 G residues) in the total tannic acid composition. In other words, the percentage of impurities (e.g., gallic acid and other impurities) is less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%or less than 0.5%) by weight.
  • any of the tannic acid compositions disclosed herein may be prepared by a conventional approach or by the methods disclosed herein.
  • the enriched tannic acid compositions disclosed herein may be prepared by a method disclosed in WO2017/167168 and WO2019/109300, the relevant disclosures of each of which are incorporated by reference for the subject matter and purpose referenced herein.
  • any of the Formula (I) compounds or any of the tannic acid compositions such as the enriched tannic acid compositions may be used for treating influenza.
  • Such Formula (I) compounds or tannic acid compositions may be formulated as pharmaceutical compositions, health food product such as nutraceutical compositions, and medical food that comprise one or more compound of Formula (I) or the tannic acid composition and a carrier, e.g., a pharmaceutically acceptable carrier and/or an edible carrier.
  • Such carriers may confer various benefits to the compound of Formula (I) or the tannic acid composition, for example, improving in vitro and/or in vivo stability of the Formula (I) compound/tannic acid composition, enhancing bioavailability of the compound of Formula (I) /tannic acid composition, increasing the associated bioactivity and/or reducing side effects.
  • Suitable carriers include, but are not limited to, diluents, fillers, salts, buffers, stabilizers, solubilizers, buffering agents, preservatives, or a combination thereof.
  • one or more of the Formula (I) compounds disclosed herein or the tannic acid composition (e.g., the enriched tannic acid composition) disclosed herein can be formulated as a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier, for use in treating influenza.
  • Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers and other material which are well-known in the art. Exemplary pharmaceutically acceptable carriers in particular are described in U.S. Patent No. 5,211,657. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
  • the salts When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention.
  • Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from a suitable inorganic base, (e.g., sodium hydroxide, barium hydroxide, iron (ii) hydroxide, iron (III) hydroxide, magnesium hydroxide, calcium hydroxide, aluminium hydroxide, ammonium hydroxide, potassium hydroxide, caesium hydroxide, or lithium hydroxide) or a suitable organic base (e.g., pyridine, methyl amine, imidazole, benzimidazole, histidine, phosphazene bases, or a hydroxide of an organic cation such as quaternary ammonium hydroxide and phosphonium hydroxide) .
  • pharmaceutically-acceptable salts can be
  • compositions as described herein can comprise pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions.
  • pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions.
  • Remington The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K.E. Hoover.
  • Such carriers, excipients or stabilizers may enhance one or more properties of the active ingredients in the compositions described herein, e.g., bioactivity, stability, bioavailability, and other pharmacokinetics and/or bioactivities.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations used, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; benzoates, sorbate and m-cresol) ; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine,
  • the pharmaceutical composition described herein includes pulmonary compatible excipients.
  • Suitable such excipients include, but not limited to, richloromono-fluoromethane, dichloro-difluoromethane, dichloro-tetrafluoroethane, chloropenta-fluoroethane, monochloro-difluoroethane, difluoroethane, tetrafluoroethane, heptafluoropropane, octafluoro-cyclobutane, purified water, ethanol, propylene glycol, glycerin, PEG (e.g.
  • PEG400, PEG 600, PEG 800 and PEG 1000) sorbitan trioleate, soya lecithin, lecithin, oleic acid, Polysorbate 80, magnesium stearate and sodium laury sulfate, methylparaben, propylparaben, chlorobutanol, benzalkonium chloride, cetylpyridinium chloride, thymol, ascorbic acid, sodium bisulfite, sodium metabisulfite, EDTA, sodium hydroxide, tromethamine, ammonia, HCl, H2SO4, HNO3, citric acid, CaCl2, CaCO3, sodium citrate, sodium chloride, disodium EDTA, saccharin, menthol, ascorbic acid, glycine, lysine, gelatin, povidone K25, silicon dioxide, titanium dioxide, zinc oxide, lactose, lactose monohydrate, lactose anhydrate, mannitol, and dextrose.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • 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 7 ethyl-L-glutamate copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) , sucrose acetate isobutyrate, and poly-D- (-) -3-hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • sucrose acetate isobutyrate sucrose acetate isobutyrate
  • poly-D- (-) -3-hydroxybutyric acid poly-D- (-) -3-hydroxybutyric acid.
  • compositions to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
  • Therapeutic compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle or a sealed container to be manually accessed.
  • compositions described herein can be in unit dosage forms such as solids, solutions or suspensions, or suppositories, for administration by inhalation or insufflation, intrathecal, intrapulmonary or intracerebral routes, oral, parenteral or rectal administration.
  • the principal active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as powder collections, tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 5 grams of the active ingredient of the present invention.
  • Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g., TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g., SpanTM 20, 40, 60, 80 or 85) .
  • Compositions with a surface-active agent will conveniently comprise between 0.05 and 5%surface-active agent and can be between 0.1 and 2.5%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.
  • Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM.
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emul
  • Suitable emulsions will typically contain up to 20%oil, for example, between 5 and 20%.
  • the fat emulsion can comprise fat droplets between 0.1 and 1.0 ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0.
  • the pharmaceutical composition described herein include a liposome composition.
  • Liposomes are artificially prepared spherical vesicle composition consisting of a lamellar phase lipid bilayer. Liposomes or lipid vesicles are usually composed of phosphatidylcholine-enriched phospholipids and may also contain mixed lipid chains with surfactant properties such as egg phosphatidyl ethanolamine.
  • the liposomal composition is composed of one or more vesicle forming lipid, selected from di-aliphatic chain lipid, such as phospholipids; diglycerides; di-aliphatic glycolipids; single lipids such as sphingomyelin or glycosphingolipid; steroidal lipids; hydrophilic polymer derivatised lipids, or mixtures thereof.
  • the vesicle forming lipid comprises one or more phospholipids, one or more steroidal lipids, and one or more hydrophilic polymer derivatized lipids.
  • the one or more phospholipids that may be used in the liposome composition comprises phospholipids that form bilayer vesicular structure.
  • the phospholipids that may be used include, but are not limited to, phospholipid such as phosphatidyl choline (PC) ; phosphatidyl ethanolamine (PE) ; phosphatidyl serine (PS) , phosphatidylglycerol (PG) , phosphatidylionositol (PI) , sphingomyelin, phosphatidic acid (PA) , lecithin; phosphatidylcholine lipid derivatives such as dipalmitoylphosphatidylcholine (DPPC) , egg phosphatidylcholine (EPC) , hydrogenated egg phosphatidylcholine (HEPC) , partially hydrogenated egg phosphatidylcholine (PHEPC) , distearylphosphatidyl choline (DSPC) , dipalmitoyl phosphatidyl choline (DPPC) , soy phosphatidyl choline (S
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • the compositions are composed of particle sized between 10 nm to 100 mm.
  • compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, endotracheal tube and/or intermittent positive pressure breathing machine (ventilator) . Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • any of the pharmaceutical compositions herein may further comprise a second therapeutic agent based on the intended therapeutic uses of the composition.
  • one or more of the Formula (I) compounds disclosed herein or the tannic acid composition such as the enriched tannic acid composition also disclosed herein may be formulated as a health food product.
  • the terms “health food” or “health food product” refers to any kind of liquid and solid/semi-solid materials that are used for nourishing humans and animals, for improving basic behavioral functioning, hyperactivity, anxiety, depression, suicidal ideation and/or behavior, sensorimotor gating, pain threshold, memory and/or cognitive functioning, body weight, or for facilitating treatment of any of the target diseases noted herein.
  • the term “nutraceutical composition” refers to compositions containing components from food sources and conferring extra health benefits in addition to the basic nutritional value found in foods.
  • the health food product may be a food product (e.g., tea-based beverages, juice, soft drinks, coffee, milk, jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream, and yogurt) ) , a food/dietary supplement, or a nutraceutical formulation.
  • a food product e.g., tea-based beverages, juice, soft drinks, coffee, milk, jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream, and yogurt)
  • a food/dietary supplement e.g., a nutraceutical formulation.
  • the health food product described herein may comprise one or more edible carriers, which confer one or more of the benefits to the composition in the product as described herein.
  • edible carriers include starch, cyclodextrin, maltodextrin, methylcellulose, carbonmethoxy cellulose, xanthan gum, and aqueous solutions thereof.
  • the healthy food products described herein may further include neuroprotective foods, such as fish oil, flax seed oil, and/or benzoate.
  • the healthy food product is a nutraceutical composition, which refers to compositions containing components from food sources and conferring extra health benefits in addition to the basic nutritional value found in foods.
  • a nutraceutical composition as described herein comprises the composition described herein and additional ingredients and supplements that promote good health and/or enhance stability and bioactivity.
  • nutraceutical compositions may be fast or/and short-term or may help achieve long-term health objectives as those described herein, e.g., improving health conditions, in, e.g., human subjects who have or are at risk for virus infection.
  • the nutraceutical compositions may be contained in an edible material, for example, as a dietary supplement or a pharmaceutical formulation. As a dietary supplement, additional nutrients, such as vitamins, minerals or amino acids may be included.
  • the composition can also be a drink or a food product, e.g., tea, soft drink, juice, milk, coffee, cookie, cereal, chocolate, and snack bar.
  • the composition can be sweetened by adding a sweetener such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolyzate, high fructose corn syrup, cane sugar, beet sugar, pectin, or sucralose.
  • a sweetener such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolyzate, high fructose corn syrup, cane sugar, beet sugar, pectin, or sucralose.
  • the nutraceutical composition disclosed herein can be in the form of a solution.
  • the nutraceutical formulation can be provided in a medium, such as a buffer, a solvent, a diluent, an inert carrier, an oil, or a creme.
  • the formulation is present in an aqueous solution that optionally contains a non-aqueous co-solvent, such as an alcohol.
  • the nutraceutical composition can also be in the form of powder, paste, jelly, capsule, or tablet. Lactose and corn starch are commonly used as diluents for capsules and as carriers for tablets. Lubricating agents, such as magnesium stearate, are typically added to form tablets.
  • the health food products may be formulated for a suitable administration route, for example, oral administration.
  • the composition can take the form of, for example, tablets or capsules, prepared by conventional means with acceptable excipients such as binding agents (for example, pre-gelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate) ; lubricants (for example, magnesium stearate, talc or silica) ; disintegrants (for example, potato starch or sodium starch glycolate) ; or wetting agents (for example, sodium lauryl sulphate) .
  • binding agents for example, pre-gelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants for example, magnesium stearate, talc or silica
  • the health food product can be in a liquid form and the one or more edible carriers can be a solvent or dispersion medium comprising but not limited to, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol) , lipids (e.g., triglycerides, vegetable oils, liposomes) or combinations thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropylcellulose; or combinations thereof.
  • an isotonic agent such as, for example, sugars, sodium chloride or combinations thereof.
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • the liquid preparations can be formulated for administration with fruit juice.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats) ; emulsifying agents (for example, lecithin or acacia) ; non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils) ; and preservatives (for example, methyl or propyl-p-hydroxybenzoates, benzoate or sorbate) .
  • suspending agents for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents for example, lecithin or acacia
  • non-aqueous vehicles for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
  • preservatives for example, methyl or propyl-p-hydroxybenzoates, benzoate or sorbate
  • the health food products described herein may further comprise one or more second therapeutic agents, including those described herein.
  • one or more of the Formula (I) compounds disclosed herein or the tannic acid composition such as the enriched tannic acid composition also disclosed herein may be formulated as a medical food product for use in treating influenza.
  • a medical food product is a food product formulated to be consumed or administered enterally. Such a food product is usually used under the supervision of a physician for the specific dietary management of a target disease, such as those described herein.
  • such a medical food composition is specially formulated and processed (as opposed to a naturally occurring foodstuff used in a natural state) for a patient in need of the treatment (e.g., human patients who suffer from illness or who requires use of the product as a major active agent for alleviating a disease or condition via specific dietary management. )
  • a medical food composition described herein is not one of those that would be simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition.
  • any of the medical food compositions described herein comprising one or more compounds of Formula (I) or a tannic acid composition disclosed herein such as an enriched tannic acid composition and at least one carrier (e.g., those described herein)
  • at least one carrier e.g., those described herein
  • the at least one carrier which can be either naturally-occurring or synthetic (non-naturally occurring) , would confer one or more benefits to the composition, for example, stability, bioavailability, and/or bioactivity. Any of the carriers described herein may be used for making the medical food composition.
  • the medical food composition may further comprise one or more additional ingredients selected from the group including, but not limited to natural flavors, artificial flavors, major trace and ultra-trace minerals, minerals, vitamins, oats, nuts, spices, milk, egg, salt, flour, lecithin, xanthan gum and/or sweetening agents.
  • the medical food composition may be placed in a suitable container, which may further comprise at least an additional therapeutic agent such as those described herein.
  • any of the Formula (I) compounds and/or tannic acid compositions e.g., the enriched tannic acid compositions
  • any of the compositions comprising such can be used for treating influenza in a subject such as a human patient having or at risk for influenza virus infection.
  • treating refers to the application or administration of a composition including one or more active agents to a subject, who is in need of the treatment, for example, having a target disease or disorder, a symptom of the disease/disorder, or a predisposition toward the disease/disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom of the disease, or the predisposition toward the disease or disorder.
  • Alleviating a target disease/disorder includes delaying the development or progression of the disease, or reducing disease severity. Alleviating the disease does not necessarily require curative results. As used therein, “delaying” the development of a target disease or disorder means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated.
  • a method that “delays” or alleviates the development of a disease, or delays the onset of the disease is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.
  • “Development” or “progression” of a disease means initial manifestations and/or ensuing progression of the disease. Development of the disease can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset. As used herein “onset” or “occurrence” of a target disease or disorder includes initial onset and/or recurrence.
  • an effective amount of a Formula (I) compound or a tannic acid composition may be administered to a subject in need of the treatment via a suitable route.
  • subject “individual, ” and “patient” are used interchangeably herein and refer to a mammal being assessed for treatment and/or being treated.
  • Subjects may be human, but also include other mammals, particularly those mammals useful as laboratory models for human disease, e.g., mouse, rat, rabbit, dog, etc.
  • a human subject who needs the treatment may be a human patient having, at risk for, or suspected of having influenza, which may be caused by infection of an influenza virus, for example, Influenza A virus or Influenza B virus.
  • a subject having influenza can be identified by routine medical examination, e.g., laboratory tests, organ functional tests, and/or behavior tests.
  • a subject suspected of having any of such target disease/disorder might show one or more symptoms of the disease/disorder. Common symptoms associated with influenza include fever or feeling feverish or chills, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue, vomiting and diarrhea (common in children) , or a combination thereof.
  • a subject at risk for the disease/disorder can be a subject having one or more of the risk factors for influenza, for example having close contact with a patient having influenza or being exposed to influenza viruses.
  • an effective amount refers to the amount of each active agent (e.g., the Formula (I) compounds or the tannic acid composition such as the enriched tannic acid composition as described herein) required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents, such as one or more of the second therapeutic agents described herein. Determination of whether an amount of the Formula (I) compound or the tannic acid composition such as the enriched tannic acid composition as described herein achieved the therapeutic effect would be evident to one of skill in the art.
  • Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any) , the specific route of administration, genetic factors and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.
  • Empirical considerations such as the half-life, generally will contribute to the determination of the dosage.
  • Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment and/or suppression and/or amelioration and/or delay of a target disease/disorder.
  • sustained continuous release formulations of a composition as described herein may be appropriate.
  • Various formulations and devices for achieving sustained release are known in the art.
  • an exemplary daily dosage might range from about any of 0.1 ⁇ g/kg to 3 ⁇ g/kg to 30 ⁇ g/kg to 300 ⁇ g/kg to 3 mg/kg, to 30 mg/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved to alleviate a target disease or disorder, or a symptom thereof.
  • An exemplary dosing regimen comprises administering one or more initial doses at a suitable interval over a suitable period. If necessary, multiple maintenance doses can be given to the subject at a suitable interval over a suitable period of time.
  • other dosage regimens may be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve.
  • dosing from one to four times a day or a week is contemplated.
  • dosing ranging from about 3 ⁇ g/mg to about 2 mg/kg (such as about 3 ⁇ g/mg, about 10 ⁇ g/mg, about 30 ⁇ g/mg, about 100 ⁇ g/mg, about 300 ⁇ g/mg, about 1 mg/kg, and about 2 mg/kg) may be used.
  • dosing frequency can be three times a day, twice a day, once a day, once every other day, once every week, once every 2 weeks, once every 4 weeks, once every 2 months, or once every 3 months.
  • the dosing regimen can vary over time.
  • doses ranging from about 0.3 to 50.00 mg/kg/day (e.g., 0.5 to 40 mg/kg/day, 1-30 mg/kg/day, 5-30 mg/kg/day, or 10-20 mg/kg/day) may be administered.
  • the particular dosage regimen i.e., dose, timing and repetition, will depend on the particular individual and that individual's medical history, as well as the properties of the individual agents (such as the half-life of the agent, and other considerations well known in the art) .
  • the appropriate dosage of a Formula (I) compound or a tannic acid composition such as an enriched tannic acid composition as described herein will depend on the specific compound or tannic acid mixture, and/or other active ingredient employed, severity of the disease/disorder, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and responsiveness to the Formula (I) compound or tannic acid compositions, and the discretion of the attending physician. Typically the clinician will administer a composition, until a dosage is reached that achieves the desired result.
  • compositions e.g., a pharmaceutical composition, a health food composition, a nutraceutical composition or a medical food composition
  • This composition can also be administered via other conventional routes, e.g., administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • it can be administered to the subject via injectable depot routes of administration such as using 1-week, half (or two week) -, 1-, 3-, or 6-month depot injectable or biodegradable materials and methods.
  • the pharmaceutical composition is administered intraocularlly or intravitreally.
  • Injectable compositions may contain various carriers such as vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like) .
  • water-soluble antibodies can be administered by the drip method, whereby a pharmaceutical formulation containing tannic acids and a physiologically acceptable excipient is infused.
  • Physiologically acceptable excipients may include, for example, 5%dextrose, 0.9%saline, Ringer’s solution or other suitable excipients.
  • Intramuscular preparations e.g., a sterile formulation of a suitable soluble salt form of tannic acids
  • a pharmaceutical excipient such as Water-for-Injection, 0.9%saline, or 5%glucose solution.
  • a tannic acid-containing composition is administered via a site-specific or targeted local delivery technique.
  • site-specific or targeted local delivery techniques include various implantable depot sources of the tannic acid-containing compositions or local delivery catheters, such as infusion catheters, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See, e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No. 5,981,568.
  • Treatment efficacy for a target disease/disorder can be assessed by methods well-known in the art.
  • any of the Formula (I) compounds or tannic acid compositions can be used in combination with a second therapeutic agent, such as those described herein, in a combined therapy.
  • the term combined therapy embraces administration of these agents (e.g., a Formula (I) compound or a tannic acid composition in combination with an anti-viral agent) , concurrently or in a sequential manner. Sequential or concurrent administration of the therapeutic agents used in a combined therapy can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues.
  • the agents used in the combined therapy can be administered by the same route or by different routes.
  • a first agent e.g., a Formula (I) compound or a tannic acid composition
  • a second agent e.g., an anti-viral agent
  • the term “sequential” means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of a Formula (I) compound or tannic acid composition and an anti-viral agent, a sequential dosage regimen could include administration of the tannic acid-containing composition before or after administration of the anti-viral agent, but both agents will be administered in a regular sequence or order.
  • the term “separate” means, unless otherwise specified, to keep apart one from the other.
  • the term “concurrently” means, unless otherwise specified, administration at the same time.
  • the combined therapy disclosed herein can also embrace the administration of the agents described herein (e.g., a Formula (I) compound or tannic acid composition or an anti-viral agent) in further combination with other biologically active ingredients (e.g., a different anti-viral agent) and non-drug therapies.
  • agents described herein e.g., a Formula (I) compound or tannic acid composition or an anti-viral agent
  • other biologically active ingredients e.g., a different anti-viral agent
  • anti-viral agents for use in treating influenza include, but are not limited to, amantadine, oseltamivir, zanamivir, peramivir, remdesivir, or baloxavir marboxil.
  • the second therapeutic agent may be an antihistamine for alleviating symptoms of influenza. Examples include brompheniramine and chlorpheniramine.
  • kits for use in treating influenza can include one or more containers comprising one or more Formula (I) compounds or compositions comprising such, or a tannic acid composition such as the enriched tannic acid composition or a composition comprising such, and optionally one or more of the second therapeutic agents as also described herein.
  • Formula (I) compounds or compositions comprising such or a tannic acid composition such as the enriched tannic acid composition or a composition comprising such, and optionally one or more of the second therapeutic agents as also described herein.
  • the kit can comprise instructions for use in accordance with any of the methods described herein.
  • the included instructions can comprise, for example, a description of administration of the Formula (I) compound or tannic acid composition and optionally a description of administration of the second therapeutic agent (s) to treat influenza in a subject.
  • the kit may further comprise a description of selecting an individual suitable for treatment based on identifying whether that individual has influenza, is suspected of having influenza, or is at risk for influenza virus infection.
  • the instructions relating to the use of the Formula (I) compound or the tannic acid composition such as the enriched tannic acid composition to achieve the intended therapeutic effects generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in the kits of the present disclosure are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit) , but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the label or package insert may indicate that the composition is used for the intended therapeutic utilities. Instructions may be provided for practicing any of the methods described herein.
  • kits provided herein are in suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed MYiar or plastic bags) , and the like.
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer) or an infusion device such as a minipump.
  • a kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) .
  • the container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) .
  • Kits may optionally provide additional components such as buffers and interpretive information.
  • the kit comprises a container and a label or package insert (s) on or associated with the container.
  • the invention provides articles of manufacture comprising contents of the kits described above.
  • Example 1 Comparison of In vitro Inhibitory Activities of Various Tannic Acid Composition Preparations against Viral Neuraminidase, Human TMPRSS2, and Human HAT
  • This example investigates the inhibitory activities of an enriched tannic acid composition against host proteases hTMPRSS2-and HAT-mediated virus infection, viral neuraminidase-mediated release, and proliferation of influenza viruses in vitro, as relative to those of the tannic acid compositions purchased from CC Biotech and Merck (TA (Merck) and TA (CC Biotech) .
  • enriched tannic acid compositions were prepared following the methods disclosed in WO2017/167168 and WO2019/109300, the relevant disclosures of each of which are incorporated by reference for the subject matter and purpose referenced herein.
  • Reference tannic acid compositions TA (Merck) and TA (CC Biotech) were used in this study as controls.
  • the contents of the enriched tannic acid composition (eTA) and TA (Merck) and TA (CC Biotech) are provided in Table 1 below.
  • influenza neuraminidase inhibition assay was conducted based on the inactivate virus methods as described previously (Leang &Hurt, 2017) with some minor modifications.
  • Virus stock solutions (PFU/mL) of human influenza A H1N1 (A/California/04/2009, pdm09) , influenza A H3N2 (A/California/2/2014) and influenza virus B (B/Wisconsin/1/2010, Yamagata lineage) with optimized titers were prepared and sterilized in 1X assay buffer (33.3mM MES buffer, 2mM CaCl2, pH 7.5) containing 0.1%NP-40 substitute for 30 minutes at ambient temperature.
  • sterile virus stocks were diluted to 10-fold with 1X assay buffer as virus working stock, which was dispensed into 96-well opaque (black) plates (50 ⁇ L per well) before mixing with equivalent volume (50 ⁇ L) of test article (9 ⁇ M or 30 ⁇ M) dissolved in 1X assay buffer.
  • 4-MU 4-methylumbelliferone
  • a standard curve was established simultaneously by preparing descending concentrations of 4-MU (640 ⁇ M down to 10 ⁇ M by 2-fold dilution) with 1X assay buffer in the same microplate. Both mixtures were allowed to incubate at 37°C for 60 minutes.
  • Neuraminidase reaction was initiated by the addition of 50 ⁇ L assay buffer containing 100 ⁇ M 2′- (4-Methylumbelliferyl) - ⁇ -D-N-acetylneuraminic acid (MUNANA) as the substrate into each reaction, followed by a 30-second shaking in a fluorescence microplate reader (Infinity F200, TECAN) and incubated at 37 °C for another 60 minutes.
  • 4-MU generated by viral neuraminidase was recorded as relative fluorescence unit (RFU) by the same microplate reader with an excitation wavelength set at 355 nm and an emission wavelength set at 460 nm.
  • hTMPRSS2 (NCBI accession no. NM_004262.3) was cloned from total RNA extracts of Calu-3 (ATCC-HTB55) , and the coding sequence of HAT (NCBI accession no. NM_005656.4) was purchased from GenScript (Cat. no OHu04628) . DNA sequences that translate the extracellular domain of hTMPRSS2 (a.a. 149-492) or HAT (a.a. 144-418) were subcloned into kanamycin-resistant pET28a+ expression vector with N-terminal 6xhistidine tag.
  • E. coli strain BL21 (DE3) competent cell was transformed by the heat-shock method with either hTMPRSS2-or HAT-expressing pET28a+ constructs as mentioned above. Stable clones of both constructs were subjected to overnight culture (14-16 hours) at 37°C, 200rpm in 10mL LB broth supplied with 50 ⁇ g/ml kanamycin.
  • Cell pellet (from 100mL culture) was thawed on ice, resuspended in 15mL lysis buffer [50mM tris, 120mM NaCl, 0.1mM ethylenediaminetetraacetic acid (EDTA) , 5 mM dithiothreitol (DTT) , pH 7.6] and disrupted in a 50mL conical plastic tube by ultrasonic processor on ice for 30 mins.
  • lysis buffer 50mM tris, 120mM NaCl, 0.1mM ethylenediaminetetraacetic acid (EDTA) , 5 mM dithiothreitol (DTT) , pH 7.6
  • Insoluble fraction comprising mis-folded recombinant protease was collected by centrifuged at 8000xg, 4°C for 5 mins and washed once with 15mL lysis buffer containing 1%triton X-100, followed by two more rounds of pelleting-washing steps with 15mL lysis buffer each (without triton X-100) .
  • Washed pellet was dispersed briefly by swirling the plastic tip before being denatured in 18 mL binding buffer [10mM tris, 100mM sodium phosphate buffer, 20mM imidazole, 8M urea and 0.1% ⁇ -mercaptoethanol (b-ME) , pH 8] and incubated at 4°C with rotation at 20rpm for 1 hour until no precipitate was visible.
  • binding buffer 10mM tris, 100mM sodium phosphate buffer, 20mM imidazole, 8M urea and 0.1% ⁇ -mercaptoethanol (b-ME) , pH 8
  • Denatured sample was centrifuged at 8000xg, 4°C for 10 mins; clarified supernatant was filter through 0.45 ⁇ m PVDF syringe filter (Pall) before being incubated with 5mL pre-equilibrated affinity resin (Ni Sepharose FF, Cytiva) .
  • protein concentration of purified fraction was adjusted to 0.4mg/mL with washing buffer and subjected to 100-fold dilution with refolding buffer (50mM tris, 100mM NaCl, 0.5M arginine hydrochloride, 20mM CaCl2, 1mM EDTA, 0.01%NP-40 substitute, 0.05mM GSSG, 0.5mM GSH, pH 7.5) by injecting 1mL purified fraction at 1mL/min or slower into 100mL refolding buffer with gentle stir (100 rpm) in a 250-mL glass bottle at ambient temperature.
  • refolding buffer 50mM tris, 100mM NaCl, 0.5M arginine hydrochloride, 20mM CaCl2, 1mM EDTA, 0.01%NP-40 substitute, 0.05mM GSSG, 0.5mM GSH, pH 7.5
  • Refolded fraction was concentrated to 10-fold by centrifugal filter unit ( Ultra-15, 10kD NMWL) and then dialyzed against activation buffer (50mM tris, 500mM NaCl, 0.001%NP-40 substitute, pH 7.5) at 4°C overnight (14-16 hours) .
  • activation buffer 50mM tris, 500mM NaCl, 0.001%NP-40 substitute, pH 7.5
  • Activation of hTMPRSS2 and HAT was achieved by another round of 10-fold concentration through centrifugal filtration at 8-10°C to reach the final volume equal to 1mL before being filtered through 0.2 ⁇ m PES syringe filter (13mm, Pall) to remove unfolded protein precipitates.
  • Activation of hTMPRSS2 and HAT was confirmed by protein electrophoresis and enzymatic assays; the presence of clear autocleavage products (25kD for hTMPRSS2; 26kD for HAT) and strong catalytic activities are indicators of activated hTMPRSS2 and HAT.
  • Concentration of activated protease stock was determined before the addition of 20%glycerol and 5mM b-ME in the final stock, which dilutes protein concentration to 80%comparing to that of the original stock.
  • Inhibitory activity of activated hTMPRSS2 and HAT protease was determined by reacting with FRET (fluorescence-resonance energy transfer) peptides that mimics the representative sequence of hemagglutinin cleavage sites from influenza A viruses H1, H3 subtypes and influenza B viruses as listed in the table below:
  • FRET fluorescence-resonance energy transfer
  • DNP 2, 4-dinitrophenyl moiety
  • assay buffer 50mM tris, 150mM NaCl, 0.001%NP-40 substitute, pH7.4 -diluting protease working stock (12.5nM for influenza A H1 and H3 substrates; 25nM for influenza B substrate) was mixed with 10 ⁇ L of 30 ⁇ M testing compounds in 96-well opaque microplates (black) by shaking (microplate reader: Infinity M1000 pro, TECAN) for 10 seconds, sealed with aluminum foil, and incubated at 37°C for 30 minutes. Enzyme reaction was initiated by the addition of 50 ⁇ L of assay buffer-diluting FRET substrates (40 ⁇ M) and monitored by the same microplate reader.
  • Inhibition (%) 1– [ (fluorescence sample, 4 min -fluorescence sample, 0 min) / (fluorescence vehicle, 4 min –fluorescence vehicle, 0 min) ] ⁇ 100 %.
  • Neuraminidase was one of the major surface glycoproteins of influenza A and B viruses (McAuley, Gilbertson, Trifkovic, Brown, &McKimm-Breschkin, 2019) , and was responsible for the viruses’ release and propagation in host cells by cleaving the sialic acid from the galactose on the cell surface, thus preventing virus progeny from being stuck on the surface of host cells and mucin-rich airway. Development of neuraminidase inhibitors is thus a promising approach to halt the propagation of influenza viruses.
  • TA Merck
  • TA CC Biotech at the concentration of 3 ⁇ M or 10 ⁇ M against influenza neuraminidase
  • a fluorescence-based neuraminidase inhibition assay was conducted.
  • the inhibition percentage of the enriched tannic acid, TA (Merck and TA (CC Biotech at 3 ⁇ M against neuraminidase activity of human influenza viruses A H1N1 (A/California/04/2009, pdm09) was determined to be 90.3%, 57%and 78.8%, respectively (FIG. 6A) .
  • the inhibition percentage of the enriched tannic acid, TA (Merck) and TA (CC Biotech at 10 ⁇ M against neuraminidase activity of human influenza viruses A H3N2 (A/California/2/2014) and influenza virus B (B/Wisconsin/1/2010, Yamagata lineage) were determined to be 82.3%, 49.8%, 68.4%and 76.1%, 47.6%, 68.3%, respectively (FIGs. 6B and 6C) .
  • hTMPRSS2 Human transmembrane serine protease 2
  • HAT human airway trypsin-like protease
  • TTSPs type II transmembrane serine proteases
  • a fluorescence-based enzymatic assay was conducted.
  • the inhibition percentage of enriched tannic acid, TA (Merck) and TA (CC Biotech) at 3 ⁇ M against hTMPRSS2-mediated proteolysis of FRET substrate H1 and H3 were determined to be 85.5%, 65.3%, 75.0%and 81.2%, 49.4%, 68.1%, respectively (FIGs. 7A and 7B) .
  • the inhibition percentage of the enriched tannic acid, TA (Merck) and TA (CC Biotech) at 3 ⁇ M against hTMPRSS2-mediated proteolysis of FRET substrate B were determined to be and 64.2%, 0.0%, 25.3%, respectively (FIG. 7C) .
  • inhibitory activity of the enriched tannic acid, TA (Merck) and TA (CC Biotech) at the concentration of 3 ⁇ M against the cleavage of hemagglutinin-mimicking substrates by HAT was evaluated in the fluorescence-based enzymatic assay.
  • the inhibition percentage of enriched tannic acid, TA (Merck) and TA (CC Biotech) at 3 ⁇ M against HAT-mediated proteolysis of FRET substrate H1 and H3 were determined to be 82.6%, 32.5%, 32.2%and 85.3%, 58.4%, 81.2%, respectively (FIGs. 8A and 8B) .
  • the results provided in this example demonstrate tannic acid compositions as effective inhibitors against viral neuraminidase and host protease hTMPRSS2-and HAT-mediated hemagglutinin activation with the enriched tannic acid composition showing the highest inhibitory activities.
  • the tannic acid compositions would be promising therapeutic agents for treating influenza in human patients.
  • MDCK cells (ATCC #CCL-34) was maintained in Dulbecco’s modified Eagle medium (DMEM, Thermo Fisher Scientific #11995040) containing 10%Fetal bovine serum (FBS, Thermo Fisher Scientific #10437028) in a humidified incubator at 37 with 5%CO2 atmosphere. Cultured cells with 80-90%confluent was treated with 0.25%trypsin for cell detaching and passaging. The treated cells were mixed with DMEM medium and centrifuge at 1000 rpm for 5 min for cell isolation and trypsin removing. After cell counting, MDCK cells were dispensed in 3 x 104 cells per 0.1 ml per well in a 96-well plate and incubated for 24 hours before experiment. For virus infection assay, infection medium (serum free) was used for the entire experiment.
  • DMEM Dulbecco’s modified Eagle medium
  • FBS Thermo Fisher Scientific #10437028
  • the following human influenza A virus strains were used in this study: PR8, A/Taiwan/03773/2015 and A/Taiwan/00710/2016, Influenza A/California/04/2009 (H1N1) pdm09, Influenza A/California/2/2014 (H3N2) , Influenza B/Wisconsin/1/2010 (Yamagata Lineage) and Influenza B/Florida/78/2015 (Victoria Lineage) .
  • MDCK cell was seeded at 3 x 10 4 cells/well cell density and incubated in 96-well plates in a humidified incubator. After 24 hours, culture medium was removed and discarded. Different concentrations of 10 ⁇ l test article was mixed with 100 ⁇ l culture medium (DMEM with 10 %FBS) and added into the MDCK cell cultured well. The cells were incubated for another 48 hours. Afterward, supernatant was removed before adding 110 ⁇ l of cell counting kit-8 (CCK-8; Dojindo, Kumamoto, Japan) mixture solution (100 ⁇ l culture medium + 10 ⁇ l CCK8 kit) , followed by a 2-hour incubation in a humidified incubator. The formazan concentration, converted by WST of CCK-8 kit in cultured well, was determined by measuring the absorbance at 450nm with a microplate reader (Tecan Sunrise, Switzerland) and recorded as an indicator of cell viability.
  • DMEM with 10 %FBS 100 ⁇ l culture medium
  • CCK-8 cell counting kit-8
  • MDCK cell was seeded (3 x 104 cells/100 ⁇ L/well) and incubated in 96 well plate in a humidified incubator. 24 hours later, supernatant (100 ⁇ L) of MDCK cells was replaced with infection medium (serum-free) containing the test article with descending concentrations ranging from 50 down to 0.0488 ⁇ M, incubated for 2 hours, and followed by another replacement of supernatant with 100 ⁇ L of infection medium containing influenza virus and the same test article with aforementioned range of concentration.
  • infection medium serum-free
  • influenza species/strains and key parameters utilized in influenza virucidal assays were listed in table 3.48 hours post-incubation, supernatant of each well was transferred to a new tube and subjected to RNA extraction by QIAamp Viral RNA mini kit (Cat#52906, QIAGEN) .
  • cDNA synthesis from total RNA was performed using HiScript II Q RT SuperMix for qPCR (Cat#R223, Vazyme Biotech) , and Influenza viral genome was quantified using two-step quantitative PCR on the StepOnePlus Real-Time PCR instrument (Applied Biosystems) by SensiFASTTM SYBR Hi-ROX kit (BIOLINE #BIO-92006) .
  • Influenza A M cDNA was amplified using the following primers (see influenza-programme/laboratory-network/quality-assurance/eqa-project/information-for-molecular-diagnosis-of-influenza-virus) :
  • Influenza B H cDNA was amplified using the following primers (see who. int/teams/global-influenza-programme/laboratory-network/quality-assurance/eqa-project/information-for-molecular-diagnosis-of-influenza-virus) :
  • Inhibition (%) [1– (PFU sample /PFU mean of vehicle) ] X100%. Inhibition %from sample was plotted (Y axis) against logarithmic concentrations of test article (X-axis) . This plot was further fitted with non-linear regression using asymmetric five-parameters logistic curve; EC 50 (concentration that inhibits 50 %influenza viral load) was then derived from this equation.
  • the cytotoxicity of the enriched tannic acid composition against MDCK cells was first determined using different concentrations in the CCK-8 assay before conducting influenza virucidal assays.
  • the 50%cytotoxic concentration (CC 50 ) of enriched tannic acid in 0.5%DMSO solution was 118.1 ⁇ M, according to the result of CCK-8 assay (FIG. 9) .
  • the viral RNA was harvested at 48 hours post-infection, extracted from cell pellet and supernatant, and quantified by quantitative real-time PCR.
  • the 50%effective concentrations (EC50) of the enriched tannic acid composition determined from the cell pellet against the following Influenza A H1N1 virus strains was 0.320, 4.832, 0.834 and 0.200 ⁇ M, respectively (FIGs.
  • the results show that the enriched tannic acid compositon has a favorable virucidal activity against oseltamivir-resistant H1N1 strain carrying the H275Y neuraminidase mutation such as A/Taiwan/00710/2016, with excellent therapeutic windows (SI 590.5 ⁇ 747.5) (see Table 3 above) .
  • this virucidal activity was also confirmed in virucidal assays against H3N2 strain of influenza A viruses.
  • the efficacy concentration (EC 50 ) of the enriched tannic acid composition was determined to be 5.249 ⁇ M (from cell pellet) and 1.929 ⁇ M (from supernatant) .
  • pandemic human influenza B lineages B/Yamagata and B/Victoria
  • the enriched tannic acid composition exhibited high virucidal activity against multiple influenza A and B viruses at sub-micromolar concentrations without posing cytotoxicity to host cells.
  • the therapeutic index (CC 50 /EC 50 , higher the better) of enriched tannic acid for multiple influenza virus was ranging from 22.5 up to 747.5 in this study, indicating that the enriched tannic acid composition has a favorable therapeutic window as a promising therapeutic agent for use in treating influenza.
  • hTMPRSS2 protease was prepared and its enzymatic activity was analyzed following the same methods disclosed in Example 1 above.
  • test compounds listed in Table 4 below
  • the inhibitory activity of test compounds was evaluated at the concentration of 3 ⁇ M against cleavage activity of hTMPRSS2 protease on influenza A viruses H1, H3 subtypes and influenza B viruses.
  • the enzymatic assay was conducted by FRET to mimic proteolytic activation of viral hemagglutinin substrates.
  • the inhibitory activity of test compounds at the concentration of 3 ⁇ M was shown in Table 4.
  • the inhibition levels against hTMPRSS2 on influenza A viruses H1 subtype of test compounds including No. 5, 6, 7, 8, 9, 10, 11, 12, 13, 20, 22, 23, 24, 25, 26, 34, 35, 36, 37, 38, 40, 41, 51, 52, 67, 70, 71, 72, and 73 were greater than or equal to 60.00%, and those of compounds 7, 8, 9, 10, 11, 12, 13, 24, 25, 26, 35, 36, 37, 38, 40, 41, 67, 70, 71, 72, and 73 were greater than or equal to 80.00%.
  • the inhibition levels against hTMPRSS2 on influenza A viruses H3 subtype of test compounds 6, 7, 8, 9, 10, 11, 12, 13, 20, 22, 23, 24, 25, 26, 35, 36, 37, 38, 40, 41, 51, 67, 70, 71, 72, and 73 were greater than or equal to 60.00%, and those for compounds 6, 8, 9, 10, 11, 12, 13, 20, 22, 23, 24, 25, 26, 36, 37, 38, 40, 41, 51, 67, 70, 71, 72, and 73 were greater than or equal to 80.00%.
  • the inhibition levels against hTMPRSS2 on influenza B viruses of test compounds 6, 7, 8, 9, 10, 11, 12, 13, 22, 23, 24, 25, 26, 35, 36, 37, 38, 40, 41, 67, and 73 were greater than or equal to 40.00%, and those for compounds 7, 8, 9, 10, 11, 12, 13, 22, 23, 24, 25, 26, 38, 40, 41, 67, and 73 were greater than or equal to 60.00%.
  • test compounds can target hTMPRSS2-mediated proteolysis of hemagglutinin-mimicking substrates of multi-strain influenza viruses, including influenza A (H1 and H3 subtypes) and Influenza B subtypes, thereby being effective in treating influenza, for example, influenza caused by such A or B virus subtypes.
  • Recombinant of human HAT protease was prepared following the methods disclosed in Example 1 above.
  • the Enzymatic activity of the recombinant HAT (activated) determined by reacting with the FRET (fluorescence-resonance energy transfer) peptides provided in Table 2 above, following the same methods disclosed in Example 1 above.
  • test compounds listed in Table 5 below
  • the inhibitory activity of test compounds at the concentration of 3 ⁇ M was shown in Table 5.
  • the levels of inhibiting HAT on influenza A viruses H1 subtype by test compounds 6, 7, 8, 9, 10, 11, 12, 13, 20, 22, 23, 24, 25, 26, 34, 35, 36, 37, 38, 40, 41, 49, 51, 52, 58, 67, 70, 71, 72, and 73 were greater than or equal to 60.00%, and those for compounds 8, 9, 10, 11, 12, 13, 23, 24, 25, 26, 35, 36, 37, 38, 40, 41, 52, 67, 70, 71, 72, and 73 were greater than or equal to 80.00%.
  • the levels of inhibiting HAT on influenza A viruses H3 subtype by test compounds 6, 7, 8, 9, 10, 11, 12, 13, 20, 22, 23, 24, 25, 26, 34, 35, 36, 37, 38, 40, 41, 49, 51, 52, 58, 67, 70, 71, 72, and 73 were greater than or equal to 60.00%, and those for compounds 6, 7, 8, 9, 10, 11, 12, 13, 22, 23, 24, 25, 26, 36, 37, 38, 40, 41, 51, 52, 67, 70, 71, 72, and 73 were greater than or equal to 80.00%.
  • the levels of inhibiting HAT on influenza B viruses by test compounds 6, 7, 8, 9, 10, 11, 12, 13, 22, 23, 24, 25, 26, 34, 35, 36, 37, 38 , 40, 41, 49, 51, 52, 55, 58, 67, 70, 71, 72, 73, 87, and 89 were greater than or equal to 40.00%, and those for compounds 6, 7, 8, 9, 10, 11, 12, 13, 23, 24, 25, 26, 37, 38, 40, 41, 51, 67, 71, 72, and 73 were greater than or equal to 60.00%.
  • test compounds can target HAT-mediated proteolysis of hemagglutinin-mimicking substrates of multi-strain influenza viruses, including influenza A (H1 and H3 subtypes) and Influenza B subtypes, thereby being effective in treating influenza, for example, influenza caused by such A or B virus subtypes.
  • EXAMPLE 5 Synergistic Efficacy of Enriched Tannic Acid Composition (eTA) and Oseltamivir Combination against Influenza Virus Infection In Vitro
  • Table 6 Combination of eTA and Oseltamivir at Different Molarity Ratios against Influenza A Virus H1N1 (A/Puerto Rico/8/1934) infection in an In Vitro Virucidal Assay.
  • the dose-response curve of eTA/OC combination (20: 1) against influenza A H1N1 viruses (A/Puerto Rico/8/1934) and influenza A H3N2 virus (A/California/02/2014) were established by serial dilution, and the EC 50 values against H1N1 and H3N2 were determined to be 0.467 ⁇ M (0.445 ⁇ M for eTA and 0.023 ⁇ M for OC) and 0.104 ⁇ M (0.099 ⁇ M eTA and 0.005 ⁇ M OC) , respectively (FIGs. 12A-12D) .
  • inventive embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed.
  • inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein.
  • a reference to “A and/or B” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B) ; in another embodiment, to B only (optionally including elements other than A) ; in yet another embodiment, to both A and B (optionally including other elements) ; etc.
  • the phrase “at least one, ” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B) ; in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A) ; in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements) ; etc.
  • the hinge domain is a hinge domain of a naturally occurring protein.

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Abstract

L'invention concerne une méthode de traitement d'une infection par la grippe, qui consiste à administrer à un sujet qui en a besoin d'une quantité efficace une composition comprenant un ou plusieurs composés de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/CN2023/109437 2022-07-26 2023-07-26 Composés et compositions pour le traitement de la grippe WO2024022411A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110126501A1 (en) * 2009-10-16 2011-06-02 Woongjin Coway Co., Ltd. Composition for prevention of influenza viral infection comprising tannic acid, air filter comprising the same and air cleaning device comprising the filter
WO2017124831A1 (fr) * 2016-01-18 2017-07-27 中国人民解放军疾病预防控制所 Inhibiteur d'infection virale à large spectre
US20180092935A1 (en) * 2016-03-28 2018-04-05 Syneurx International (Taiwan) Corp. Compositions Containing Tannic Acids and Uses Thereof
US20210162316A1 (en) * 2017-12-07 2021-06-03 Syneurx International (Taiwan) Corp. Improved enrichment methods for preparing tannic acid compositions
US20210251945A1 (en) * 2020-02-08 2021-08-19 Syneurx International (Taiwan) Corp. Compounds and pharmaceutical uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110126501A1 (en) * 2009-10-16 2011-06-02 Woongjin Coway Co., Ltd. Composition for prevention of influenza viral infection comprising tannic acid, air filter comprising the same and air cleaning device comprising the filter
WO2017124831A1 (fr) * 2016-01-18 2017-07-27 中国人民解放军疾病预防控制所 Inhibiteur d'infection virale à large spectre
US20180092935A1 (en) * 2016-03-28 2018-04-05 Syneurx International (Taiwan) Corp. Compositions Containing Tannic Acids and Uses Thereof
US20210162316A1 (en) * 2017-12-07 2021-06-03 Syneurx International (Taiwan) Corp. Improved enrichment methods for preparing tannic acid compositions
US20210251945A1 (en) * 2020-02-08 2021-08-19 Syneurx International (Taiwan) Corp. Compounds and pharmaceutical uses thereof

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