[go: up one dir, main page]

WO2021062482A1 - Composés antiviraux et leur utilisation - Google Patents

Composés antiviraux et leur utilisation Download PDF

Info

Publication number
WO2021062482A1
WO2021062482A1 PCT/AU2020/051058 AU2020051058W WO2021062482A1 WO 2021062482 A1 WO2021062482 A1 WO 2021062482A1 AU 2020051058 W AU2020051058 W AU 2020051058W WO 2021062482 A1 WO2021062482 A1 WO 2021062482A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkylr
alkyln
alkenylr
alkynylr
alkyls
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2020/051058
Other languages
English (en)
Inventor
Trudi Anne COLLET
Satish Natha DIGHE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Salut Products Pty Ltd
Original Assignee
Salut Products Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2019903724A external-priority patent/AU2019903724A0/en
Application filed by Salut Products Pty Ltd filed Critical Salut Products Pty Ltd
Publication of WO2021062482A1 publication Critical patent/WO2021062482A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • the invention relates to compounds that have antiviral activity, particularly 4- oxochromane derivatives that have antiviral activity against viruses of the Family Flaviviridae. Methods of treating viruses with the 4-oxochromane compounds, particularly viruses of the Family Flaviviridae, are also described.
  • Flaviviruses from the Family Flaviviridae, cause serious infections including haemorrhagic fever and encephalitis. Flaviviruses are transmitted to humans by mosquitoes and ticks and some of these viruses are endemic in tropical and sub-tropical regions of the world.
  • the 2015-16 outbreak of Zika virus in South America resulted in at least 172,830 confirmed cases of Zika virus and many thousands more suspected cases.
  • the Zika virus is transmitted by mosquitoes such as Aedes aegpti and Aedes albopictus.
  • the Zika virus can also be sexually transmitted between partners of any gender and transmitted from pregnant mother to foetus, thereby resulting in microcephaly and other severe brain abnormalities in infants.
  • the present invention is predicated at least in part on the discovery of chromone derivatives that show antiviral activity, particularly against viruses of the Family Flaviviridae.
  • a compound of formula (I) wherein one of R 1 and R 2 is hydrogen and the other is A; is a double or single bond;
  • X is O or S
  • R 3 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2 .
  • R 4 and R 6 are each independently selected from hydrogen or R 7 ;
  • R 5 is selected from hydrogen, hydroxy and a cyclic monosaccharide
  • R 7 is selected from hydrogen, OR 8 , CO 2 R 8 , CON(R 8 ) 2 , SR 8 , N(R 8 ) 2 , N + (R 8 ) 3 and SON(R 8 ) 2 ;
  • R 8 is selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl;
  • A is wherein B is a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group, R 9 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2 - 6alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 ,
  • composition comprising a compound of formula (I) as described herein and a pharmaceutically acceptable carrier or excipient.
  • composition for use in treating or preventing a viral infection caused by a virus of the Family Flaviviridae, wherein the composition comprises a compound of formula (I) as described herein.
  • Figure 1 is a photographic representation showing plaque formation in cells infected with Kunjin virus at concentrations of 10 -1 to 10 -6 and treated with 3.6 mM of Compound 381 at 24 hours after infection (plate a.) and 72 hours after infection (plate b.)
  • alkyl refers to a straight chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, C 1-6 alkyl which includes alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n- pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methyl pentyl, 4- methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl and decyl.
  • alkenyl refers to a straight-chain or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 10 carbon atoms. Where appropriate, the alkenyl group may have a specified number of carbon atoms. For example, C 2 -C 6 as in " C 2 -C 6 alkenyl” includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.
  • alkynyl refers to a straight-chain or branched hydrocarbon group having one or more triple bonds and having 2 to 10 carbon atoms. Where appropriate, the alkynyl group may have a specified number of carbon atoms.
  • C 2- C 6 as in " C 2 -C 6 alkynyl” includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • cycloalkyl refers to a saturated cyclic hydrocarbon.
  • the cycloalkyl ring may include a specified number of carbon atoms.
  • a 3 to 10 membered cycloalkyl group includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
  • aryl is intended to mean any stable, monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, phenanthrenyl, biphenyl and binaphthyl.
  • heterocyclic refers to a cyclic hydrocarbon, such as a cycloalkyl or cycloalkenyl defined above, in which one to four carbon atoms have been replaced by heteroatoms independently selected from the group consisting of N, N(R), S, S(O), S(O) 2 and O where R may be hydrogen or alkyl.
  • a heterocyclic ring may be saturated or unsaturated but not aromatic.
  • heterocyclyl groups include azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl, oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithianyl, trithianyl and oxazinyl.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1- oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4
  • the term “monosaccharide” refers to a furanose or pyranose monosaccharide. Suitable monosaccharides are furanose and pyranose monosaccharides of D-ribose, D-arabinose, D-xylose, D-lyxose, D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-ribulose, D-fructose and D-sedoheptulose.
  • substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro, chloro, bromo, iodo, cyano, nitro, -CO 2 H, -CO 2 CH 3 , trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, phenyl, phenoxy, phenylcarbonyl, benzyl and ace
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, malonic, malic (L), lactic (DL), mandelic (DL), gluconic, carbonic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, camphorsulphonic, benezenesulphonic, salicylic, cinnamic, cyclamic, sulphanilic, aspartic, glutamic, glutaric, galactaric, gentisic, edetic, stearic, palmitic, oleic, la
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, aluminium, zinc, lysine, histidine, meglumine, ammonium and alkylammonium.
  • compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the compounds of the invention may exist as geometric isomers.
  • the invention also relates to compounds in substantially pure cis (Z) or trans (E) or mixtures thereof.
  • the present invention provides compounds of formula (I): wherein one of R 1 and R 2 is hydrogen and the other is A; is a double or single bond;
  • X is O or S
  • R 3 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2- 6 alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 , -C(O)OC 1-6 alkenylR 7 , -C(O)OC 1-6 alkynylR 7 , -C(O
  • R 4 and R 6 are each independently selected from hydrogen or R 7 ;
  • R 5 is selected from hydrogen, hydroxy and a cyclic monosaccharide
  • R 7 is selected from hydrogen, OR 8 , CO 2 R 8 , CON(R 8 ) 2 , SR 8 , N(R 8 ) 2 , N + (R 8 ) 3 and SON(R 8 ) 2 ;
  • R 8 is selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl;
  • A is wherein B is a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group, R 9 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2. 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2.
  • the compound of formula (I) is a compound of formula (II): wherein R 2 is hydrogen, R 5a is hydrogen or , where m is 1 or 2 and X, B, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).
  • the compound of formula (I) is a compound of formula (III): wherein R 2 is hydrogen, R 5a is hydrogen or and X, B, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).
  • the compound of formula (I) is a compound of formula (IV): wherein R 2 is hydrogen and X, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).
  • R 1 is A, where ring B is an aryl group or a heteroaryl group substituted with one or two R 9 substituents, especially one R 9 substituent, especially an aryl group substituted with one or two R 9 substituents, especially one R 9 substituent, and more especially a phenyl group substituted with one or two R 9 substituents, especially one R 9 substituent;
  • R 2 is hydrogen;
  • R 3 is -C 1-6 alkylR 7 , -C 1-6 alkylOC 1-6 alkylR 7 , -C 1-6 alkylSC 1-6 alkylR 7 , -C 1-6 alkylN(R 8 )C 1- 6 alkylR 7 , -C(O)OC 1-6 alkylR 7 , -C(O)C 1-6 alkylR 7 , -C(O)C 1-6 alkylR 7 , -C 1-6 alkylC(O)
  • the compound of formula (I) is selected from compounds 352, 377, 380, 381, 485, 486, 487 and 488, especially compounds 352, 377 and 381.
  • the compounds of formula (I) may be prepared by methods known in the art.
  • a substituted chromone may be prepared from an appropriately substituted phenol, such as set out in Scheme 1 :
  • a protected substituted phenol ring may be subject to Friedel Crafts acylation in the presence of a Lewis Acid such as AICl 3 or a strong Br ⁇ nsted acid such as HF or Triflic acid to provide, after deprotection of the phenolic hydroxyls, an alpha acetyl phenol ring. Further reaction with an aldehyde provides an aryl, cycloalkyl, heterocyclyl or heteroaryl substituted chromone.
  • a Lewis Acid such as AICl 3
  • a strong Br ⁇ nsted acid such as HF or Triflic acid
  • the 4-hydroxy substituted benzaldehyde used in step 3 of Scheme 1 may be prepared by reaction of 4-hydroxybenzaldehyde with an appropriately substituted alkyl halide, such as an alkyl bromide.
  • the 4-hydroxybenzaldehyde may be used in step 3 of Scheme 1 and the hydroxy group subsequently derivatised.
  • the hydroxy or carboxy groups on the aryl substituted chromone ring may be further derivatised to ethers or esters by means known in the art, for example with an alkyl halide in the presence of a base, as shown in Scheme 2:
  • Variation of the alkyl halide may also be used to provide different functional groups.
  • the chromone carboxylic acid may be reduced to a primary alcohol by methods known in the art, before or after reaction with the alkyl halide.
  • the position of the further substitution may be defined by the use of a protection strategy for phenolic hydroxy groups or carboxylic acids to give single or multiple substitutions.
  • the sugar group may be introduced by means known in the art, for example, by reaction of an acyl protected sugar group with the phenolic hydroxy group of the chromone group in the presence of base and a Lewis acid as shown in Scheme 3:
  • a method of treating or preventing a viral infection caused by a virus of the Family Flaviviridae comprising administering to a subject a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.
  • the viral infection caused by a virus from the Family Flaviviridae is a virus selected from the genus Flavivirus, genus Pestivirus, genus Hepacivirus and genus Pegivirus.
  • the virus is a virus of the genus Flavivirus including mosquito-borne, tick-borne, insect-specific Flaviviruses as well as those with an unknown vector.
  • the virus of the genus Flavivirus is selected from dengue virus (DENV) (including serotypes 1 to 4), Zika virus (ZIKV), Kunjin virus, West Nile virus (WNV), yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus (Seabird and Mammalian), Paramatta river virus, Palm Creek virus, Entebbe bat virus, Gadgets Gully virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Louping-ill virus, Murray Valley encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus (Karshi virus), Saint Louis encephalitis virus, Usutu virus, Modoc virus, Rio Bravo virus and Wesselsbron virus.
  • DECV dengue virus
  • ZIKV Zika virus
  • the virus of the genus Flavivirus is selected from dengue virus, Zika virus, Kunjin virus, West Nile virus, yellow fever virus, Japanese encephalitis virus and tick-borne encephalitis virus, especially dengue virus, Zika virus and Kunjin virus.
  • the virus is selected from the genus Pestivirus including Pestiviruses A to K.
  • the virus is selected from the henus Hepacivirus including Hepatitis C virus.
  • the virus is selected from the genus Pegivirus including Hepatitis G (GBV-C).
  • the subjects, individuals or patients to be treated are mammalian subjects including but not limited to humans, primates, livestock animals such as sheep, cattle, pigs, horses, donkeys and goats; laboratory test animals such as mice, rats, rabbits and guinea pigs; companion animals such as cats and dogs or captive wild animals such as those kept in zoos.
  • the subject is a human.
  • the compounds of formula (I) may be administered in an effective amount.
  • An "effective amount” means an amount necessary at least partly to attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular condition being treated. The amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individuals to be treated, the degree of protection desired, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials.
  • An effective amount in relation to a human patient for example, may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • the dosage is preferably in the range of ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1g per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to 500 mg per kg of body weight per dosage.
  • the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 ⁇ g to 1 mg per kg of body weight per dosage. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals, or the dose may be proportionally reduced as indicated by the exigencies of the situation.
  • treatment does not necessarily imply that a subject is treated until total recovery. “Treatment” may also reduce the severity of an existing condition.
  • prevention does not necessarily mean that the subject will not eventually contract a disease condition.
  • prevention may be considered to include delaying the onset of a particular condition. Accordingly, treatment and prevention include amelioration or alleviation of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the compounds of formula (I) or their pharmaceutically acceptable salts thereof may be administered together with another therapy.
  • the compounds of formula (I) may be administered together with an antipyretic agent to reduce fever.
  • Suitable antipyretic drugs include non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, ketoprofen and nimesulide; aspirin and related salicylates such as choline salicylate, magnesium salicylate and sodium salicylate; acetaminophen; metamizole; nabumetone and phenazone.
  • composition for use in treating or preventing a viral infection; wherein the composition comprises a compound of formula (I) as described above.
  • compositions of the invention are provided.
  • a compound of the invention may be administered as a neat chemical, it is preferable to present the active ingredient as a pharmaceutical composition.
  • the present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as described herein and a pharmaceutically acceptable carrier or excipient.
  • the carrier(s) and/or excipients must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual) or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Formulations containing 10 milligrams of active ingredient or, more broadly, 0.1 to 1000 milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt or derivative of the compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or 10 to about 70 percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • composition is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • a dropper or pipette this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • the compounds according to the invention may be encapsulated with cyclodextrins or formulated with their agents expected to enhance delivery and retention in the nasal mucosa.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • HFA hydrofluoroalkane
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound will generally have a small particle size for example of the order of 1 to 50 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical compositions are preferably in unit dosage forms.
  • the composition is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged composition, the package containing discrete quantities of composition, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • ZIKV Zika virus
  • Methyl 2-acetyl-3,5-dihydroxybenzoate (D) [0083] Methyl 2-acetyl-3,5-dihydroxybenzoate (C) (3.0 gm, 1 equiv) was dissolved in dichloromethane and AICI 3 (16.8 gm, 10 mmol) was added slowly at rt. The reaction mixture was heated to reflux for 24 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI (500 mL) was added slowly, and the reaction mixture was extracted with ethyl acetate (3 ⁇ 250 mL).
  • TBDMS-CI (77 mg, 2.2 equiv) was added and stirred at RT for 18 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 mL) was added slowly, and the reaction mixture was extracted with DCM (3 ⁇ 25 mL).
  • Compound 352 may be synthesised according to the following scheme.
  • Example 6 In vitro assays for activity against the Flaviviruses
  • the compounds of the invention were tested for activity against flaviviruses selected from dengue virus, Kunjin virus and Zika virus using an in vitro assay.
  • Vero cells were seeded at 1.25 x 10 5 cells/mL in 1 mL wells in 24 Well flat bottom plates in DMEM (Sigma Aldrich), 10% FBS (Invitrogen) and 1% SPG (Sigma). The cells were in monolayers and 80 - 100% confluent at the time of infection. Serial dilutions of Kunjin virus were prepared (10 -1 to 10 -6 ) in 2% v/v DMEM-HI-FBS + 1 x SPG. The media was removed from each well containing cell monolayers and 200 ⁇ L of the desired virus dilution was added to duplicate wells from highest to lowest dilution.
  • the cells were incubated at 37 °C for 1 hr after which 2 mL per well of 50% w/v double strength media and sterile 8% w/v low viscosity carboxymethylcellulose sodium salt was added. The plates were then incubated for a further 3 days. Compound 381 was added to the wells at a concentration of 3.6 mM at 24 hours or at 72 hours post infection. The culture medium was removed at completion of incubation and the cells were rinsed with phosphate buffered saline. 1 mL of ice cold acetone and methanol solution 1 :1 was added to each well and the plates incubated for 30 minutes to inactivate the virus. The liquid was removed and the plates allowed to air dry.
  • the cells were stained with 1 mL per well of 0.5 % w/v crystal violet in 5% v/v formalin: phosphate buffered saline. The plates were incubated for 60 minutes then the stain solution was removed and the cells rinsed with water and air dried.
  • Example 7 In vitro assays for activity against the Flaviviruses at varying concentrations [0104] The experiment in Example 5 was repeated using compound 381 at concentrations of 2700, 1350, 1000, 500, 250 and 125 mM. The Vero cells infected with Kunjin virus at a multiplicity of infection of 0.1 were treated with compound 381 one hour after virus absorption. Supernatants were collected at 24 hr and 48 hr post infection and viral titres determined using the plaque assay as described in Example 5. The results are shown in Tables 2 (24 hr) and 3 (48 Hr).
  • NS3 RNA helicase and NS5 RNA-dependent RNA polymerase are two enzymes found in all members of the Family Flaviviridae that closely interact to affect the viral replication cycle.
  • NS5 RdRp catalyses the synthesis of the RNA strand complementary to the RNA template.
  • NS3 RNA helicase unwinds the double stranded RNA to create fully mature positive strand RNA virions.
  • Example NS3 and NS5 crystal structures obtained from the RCSB Protein Data Base include, but are not limited, to: 2JLS (NS3; www.rcsb.ora/structure/2JLS) and (NS5; www.rcsb.ora/structure/2J7W), respectively.
  • NTP nucleotide triphosphate
  • amino acids interacting with the compounds of formula (I) tested can be indicated, using the numbering of particular DENV proteins that served as the basis for the molecular structure/docking studies, as:
  • NS3 (numbering based on DENV serotype 4; NCBI RefSeq NP_740321; www.ncbi.nlm.nih.gov/protein/NP_740321): Gly 196, Lys199, Thr200, Lys201, Arg202, Glu230, Glu233, Asn329, Gly414, Asn416, Arg418, Gln456, Arg460, Arg463, Asn464 and Gln467;
  • NS5 (numbering based on DENV serotype 3; NCBI RefSeq YP_001531176; www.ncbi.nlm.nih.gov/protein/YP_001531176): Asp663, Asp664, Ser710, His711 , Arg729, Ser796, His798, His800, His801 and Gln802.
  • the antiviral compounds of formula (I) may bind the conserved amino acids and others functionally equivalent to the DENV residues including, but not limited to (based on the DENV numbering):
  • NS3 Gly196, Lys199, Thr200, Asn329, Gly414, Asn416, Gln456, Arg460 and Arg463,
  • NS5 Asp663, Asp664, Ser710, Arg729, Ser796 and His798.
  • amino acid residue has some level of physicochemically conservative amino acid substitution in non-DENV species.
  • Example 7 Analysis of NS5 RNA-dependent RNA polymerase (NS5-RdRp) and NS3 RNA helicase interactions with compounds 393, 429, 431 and 463
  • Tables 7 and 8 list the (reported) roles of the amino acids of NS3 protein and NS5 protein and their conservation across the various groups (clades) of the Family Flaviviridae. In these tables, the level of conservation is considered between:
  • Table 5 indicates the (antiviral-interacting) amino acids are those involved in binding of the ATP cofactor (Gly196, Lys199, Thr200, Asn416, Gln456, Arg460 and Arg463) as well two residues of unknown function: Gly414 and Asn329. Both Gly414 and Asn429 line the binding pocket and are located quite close to the cofactor when bound. These nine amino acids are conserved, or substituted with a physicochemically similar amino acid, across the Family Flaviviridae.
  • Table 4 indicates the (A V- interacting) amino acids are those involved in binding of the GTP cofactor (Ser710, Arg729 and Ser796) or a metal ion cofactor (D663 and D664) as well as His798, which lines the GTP binding pocket.
  • the metal ion cofactor (Mn 2+ ) also binds directly with the GTP cofactor. These six amino acids are mostly conserved, or substituted with a physicochemically similar amino acid, across the Family Flaviviridae.
  • Tables 9 and 10 then look at which of the lead compounds binds to the most conserved amino acids for NS3 and NS5 proteins, respectively. The assumption is that more binding is better - leading to higher affinity and greater disruption to protein structure in competitive, reversible binding scenarios.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés possédant une activité antivirale, en particulier des dérivés de 4-oxochromane qui possèdent une activité antivirale contre des virus de la famille des Flaviviridae. L'invention concerne également des méthodes de traitement de virus à l'aide des composés de 4-oxochromane, en particulier de virus de la famille des Flaviviridae.
PCT/AU2020/051058 2019-10-03 2020-10-02 Composés antiviraux et leur utilisation Ceased WO2021062482A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2019903724 2019-10-03
AU2019903724A AU2019903724A0 (en) 2019-10-03 Antiviral Compounds and their use

Publications (1)

Publication Number Publication Date
WO2021062482A1 true WO2021062482A1 (fr) 2021-04-08

Family

ID=75336357

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2020/051058 Ceased WO2021062482A1 (fr) 2019-10-03 2020-10-02 Composés antiviraux et leur utilisation

Country Status (1)

Country Link
WO (1) WO2021062482A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387800A (zh) * 2021-06-09 2021-09-14 浙江理工大学 一种3,5-二甲氧基苯甲酸甲酯的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014153000A1 (fr) * 2013-03-14 2014-09-25 Chromocell Corporation Composés, compositions et procédés permettant de moduler le goût de sucré

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014153000A1 (fr) * 2013-03-14 2014-09-25 Chromocell Corporation Composés, compositions et procédés permettant de moduler le goût de sucré

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
DEI, S. ET AL.: "Design and synthesis of aminoester heterodimers containing flavone or chromone moieties as modulators of P-glycoprotein-based multidrug resistance (MDR", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 26, no. 1, 2018, pages 50 - 64, XP085307317, DOI: 10.1016/j.bmc.2017.11.016 *
KENEZ, A. ET AL.: "Synthesis and structure-activity relationship study of monotesone-A, an antifungal component of Monotes engleri", NATURAL PRODUCT RESEARCH, vol. 22, no. 5, 2008, pages 383 - 392, XP018024346 *
OYAMA, K.-I. ET AL.: "Synthesis of oriented anti-virus 7-O-substituted apigenins", HETEROCYCLES, vol. 76, no. 2, 2008, pages 1607 - 1615 *
REICHEL, L. ET AL.: "Zur Synthese von Hydroxyflavanonglucosiden unter milden Bedingungen", JUSTUS LIEBIGS ANNALEN DER CHEMIE, vol. 729, 1969, pages 217 - 24, XP055812292 *
SESHADRI, T. ET AL.: "Synthesis of (+)-selinone", INDIAN JOURNAL OF CHEMISTRY, vol. 8, no. 11, 1970, pages 1041 - 2 *
SU, Z.-R.: "Discovery of xanthine oxidase inhibitors and/or alpha-glucosidase inhibitors by carboxyalkyl derivatization based on the flavonoid of apigenin", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 25, no. 14, 2015, pages 2778 - 2781, XP029236520 *
TEWTRAKUL, S. ET AL.: "Inhibitory effects of flavonoids on human immunodeficiency virus type-1 integrase", JOURNAL OF TRADITIONAL MEDICINE, vol. 18, no. 6, 2001, pages 229 - 238, XP001247379 *
ZHANG, J. ET AL.: "Discovery and synthesis of novel luteolin derivatives as DAT agonists", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 18, no. 22, 2010, pages 7842 - 7848, XP027452445, DOI: 10.1016/j.bmc.2010.09.049 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387800A (zh) * 2021-06-09 2021-09-14 浙江理工大学 一种3,5-二甲氧基苯甲酸甲酯的制备方法

Similar Documents

Publication Publication Date Title
CN113292565B (zh) 核苷类化合物及其制备方法和应用
JP2019089792A (ja) アゼパン誘導体及びｂ型肝炎感染の治療方法
CN112367987A (zh) 活性剂和其用于治疗代谢障碍和非酒精性脂肪性肝病的方法
CN115490681B (zh) 三嗪衍生物
WO2014135107A1 (fr) Nouveau composé nucléoside phosphoramidate et son utilisation
TW200306813A (en) Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
EP4138825A1 (fr) Traitement d'infections virales, d'une lésion d'organe et d'états apparentés à l'aide d'un inhibiteur de hif prolyl hydroxylase ou d'un stabilisateur hif-alpha
CN112010916B (zh) 核苷化合物的氨基磷酸酯衍生物及其用途
CN113321694A (zh) N4-羟基胞苷衍生物及其制备方法和用途
CA2596355A1 (fr) Inhibiteurs du facteur de necrose tumorale
CN102199133B (zh) 2’,2-双噻唑非核苷类化合物及其制备方法、药物组合物和作为肝炎病毒抑制剂的用途
WO2021062482A1 (fr) Composés antiviraux et leur utilisation
KR20140023256A (ko) 바이러스 폴라머라아제 저해제
TWI711448B (zh) 抑制鈣/鈣調蛋白依賴性蛋白激酶ii之化合物及其應用
KR20220166745A (ko) 펜드린 억제 활성을 갖는 신규 화합물 및 이의 의약 용도
US20090182133A1 (en) Benzopyranone derivatives and their use as anti-viral agents
EP3050871B1 (fr) Nouveau dérivé de bis-amide et son utilisation
JP4604147B2 (ja) クマリン誘導体
TW202402296A (zh) 三嗪衍生物
CN105801646B (zh) 炔基取代的核苷氨基磷酸酯
EP2649999A1 (fr) Utilisation de composé de quinazoline dans la préparation de médicament anti-flavivirus
RU2594281C2 (ru) Стильбеноидные соединения в качестве ингибиторов плоскоклеточной карциномы и гепатомы и их применения
EP4415704A1 (fr) Nouveaux dérivés de rhodanine et leurs utilisations
CN114796204B (zh) 安莎三烯类化合物在抗病毒感染药物中的用途及制备方法
RU2839716C1 (ru) Производные аденозина - ингибиторы репродукции вирусов, относящихся к роду Flavivirus

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20873060

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20873060

Country of ref document: EP

Kind code of ref document: A1