EP1737836A1 - Agents antiviraux - Google Patents

Agents antiviraux

Info

Publication number
EP1737836A1
EP1737836A1 EP05714322A EP05714322A EP1737836A1 EP 1737836 A1 EP1737836 A1 EP 1737836A1 EP 05714322 A EP05714322 A EP 05714322A EP 05714322 A EP05714322 A EP 05714322A EP 1737836 A1 EP1737836 A1 EP 1737836A1
Authority
EP
European Patent Office
Prior art keywords
dione
independently selected
dimethyl
pyran
aryl
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.)
Withdrawn
Application number
EP05714322A
Other languages
German (de)
English (en)
Inventor
Jonathan Alan Victor Coates
Eric Dale Jones
Susan Cox
Ian Crosby
David Gerard Bourke
Tyrone Pieter Jeynes
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.)
Monash University
Original Assignee
Monash University
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 AU2004901755A external-priority patent/AU2004901755A0/en
Application filed by Monash University filed Critical Monash University
Publication of EP1737836A1 publication Critical patent/EP1737836A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of naphthopyrans as agents in the treatment and/or prophylaxis of hepatitis B, pharmaceutical compositions for use in such therapy and novel naphthopyrans,
  • HBV chronic hepatitis B virus infection
  • a method of treatment or prophylaxis of hepatitis B virus in a subject comprising administering to said subject an effective amount of a compound of Formula (1 ):
  • R and Ri are independently selected from H, Ci.a-uk l, C 2 - ⁇ alkenyl, C ⁇ t ,alkynyl,
  • R 2 and R are independently selected from H. Ci ⁇ i yl, C 2 .ealkcnyl, C 2 _ f ,alkynyl,
  • R4 and R5 arc independently selected from H, C ⁇ cycloaikyl, OH, OR9, halo or NR 10 R 10 or together with the bond between the carbon atoms to which they arc attached form a double bond;
  • R ⁇ and 7 are independently selected from H, Ci-s-d yl, C 2 . h alkenyl, C 2 . ⁇ alkynyl,
  • Rs is independently selected from H, C ⁇ . h alkyl, C z * ⁇ *.lkenyl, C 2 - $ aIkyny
  • R ⁇ ⁇ is C]. 2
  • R12 is Ci ⁇ alkyl, C 2 ⁇ alkenyl, C 2 . h alkynyl or aryl.
  • a method of treatment or prophylaxis of hepatitis B virus comprising administering an effective amount of a compound of Formula (1) and a second therapeutic agent.
  • a pharmaceutical composition comprising a compound of Formula (l)and a pharmaceutically acceptable carrier, excipient or adjuvant, with the proviso that in the compound of Formula (1) when R and Ri are both methyl and R is OH or OR ⁇ >, R 5 is not selected from OH, OR ⁇ or NHR, «.
  • the compounds of Formula (1) may be presented in the form of a pharmaceutically acceptable derivative, salt or prodrug. etailed Description
  • halo refers to fluorine (fluoro), cr-dorine (chloro), bromine (bromo) or iodine (iodo).
  • alkyl either used alone or in compound terms such as NH(alkyl) or N(alkyl) 2 , refers to monovalcnt straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate.
  • suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-toutyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-mcthylbutyl, n-h.ex.yl, 2-, 3- or - -methylpcutyl, 2-ethylbulyl, n-hexyl or 2-, 3-, 4- or 5-methylpentyl,
  • alkenyl refers to straight chain or branched hyd-cocarbon groups having one or more double bonds between carbon atoms
  • Suitable alke ⁇ yl groups include, but are not limited to ethenyl, propcnyl, isopropenyl, bulcnyl. pentenyl and hexenyl.
  • alkynyl refers to straight chain or branched hydxocarbon groups containing one or more triple bonds. Suitable alkynyl groups include, bu"t are not limited to ethynyl, propynyl, buty ⁇ yl, pentynyl and hexen l.
  • cycloalkyl refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and eyclohexyl.
  • aryl refers to -C HJ aromatic hydrocarbon group, for example phenyl or naphthyl.
  • heterocyclic lyl when used alone or in compound words include des monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroalom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include, O, N and S.
  • hctcrocyclic groups may include pyrrolidi ⁇ yl, pyrrolinyl, piperidyl, piperazinyl, inorpholino, indo ⁇ nyl, imiazolidinyl, pyrazolidinyl, thiomorpholino, dioxsuyl, tctrabydrofuranyl, tetrahydropyra ⁇ yl, tctrahydropyrrolyl etc.
  • Each alkyl, alkenyl, alkynyl, cycloalkyl, aiyl or heterocyclyl group may be optionally substituted with C h alky., OH, OCi- 3 alkyl, halo, CN, NOj, C0 2 H, CO-C ⁇ alky!, CONH 2 , CONH(C,. ; >alkyl), CON(C ⁇ . 3 alkyl) 2 , trifluoromethyl, NH 2 , NEi(alkyl) or N(alkyl) 3 .
  • an optionally substituted aryl group may be a 4-methylphenyl or 4- hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl or difluoromethyl.
  • a ino acid residue refers to an cx-ammo acid or a ⁇ -amino acid which is attached to the naphthopyrandione structure, preferably through the carboxylic acid group of the amino acid.
  • the amino acid may be a L- or D- isomer and may have a naturally occurring side chain or a non-naturally occurring aide chain.
  • the amino acid may also be further substituted in the ⁇ -position or the ⁇ ' po-sition with a group selected from -C,-C ti alkyl, -C alkenyl, -Cr alkynyl. -(CH 2 ) tt :OR a .
  • ⁇ -amino acid refers to a compound having an amino group and a carboxyl group in which the amino group and the carbox-yl group arc separated by a single carbon atom, the ⁇ -carbo ⁇ atom,
  • An ⁇ -amino acid includes naturally occurring and non-naturally occurring L-amino acids and then' D-isomers and derivatives thereof such as salts or derivatives where functional groups are protected b;y suitable protecting groups.
  • the ⁇ -amino acid may also be further substituted in the oj-pcjsition with a group selected from -C r C ⁇ oa.kyl, -Ca-C.oalkenyl, -C 2 -C ⁇ 0 alkynyl, -(CR 2 ) ⁇ COR ⁇ , -(CH 2 )_.R b , -P0 3 H, -(CH 2 ) n lieterocyclyl or -(CH a ) felicitaryl where R a is -OH, -NH_, -NHCi-C ⁇ alkyl, -OC ⁇ -C 6 alkyl or C.-Cjal yl and R b is -OM, -SH, -SC C 3 alkyl, -OC]-C 6 alkyU -Ca-C.acycloaUcyl, -C3-Ciacycloalkcnyi, -NH 2 , -NH
  • n is 0 or an integer from 1 to 10 and where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH?, -NHC[-C 3 alkyl, -OC.-Qalkyl, -SH, -SC ⁇ -C.,alky], -C0 2 H, -C Ct-Cjalkyl, -CONH 2 or -CONHC[-C 3 alkyl.
  • ⁇ -amino acid refers lo an amino acid that differs from an -amino acid in that there arc two (2) carbon atoms separating the c ⁇ irboxyi tertninui. and the amino terminus.
  • ⁇ -arnino acids with a specific side chain can exist as the K or 5 enantiomcrs at either of tire (C2) carbon or the ⁇ (C3) carbon, resulting in a total of 4 possible isomers for any given side chain.
  • the side chains may be the same as those of naturally occurring ⁇ -amino acids or may be the side chams of no- -naturally occurrhig -UTiino acids,
  • the ⁇ -ami ⁇ o acids may have mono-, di-, tri- or tetra-substitution at the C2 and C3 carbon atoms.
  • Mono-substitution may be at the C2 or C3 carbon atom.
  • Di-substitulion includes two substitucuts at the C2 carbon atom, two subtitituents at the C3 carbon atom or one substituent at each of the C2 and C3 carbon atonis.
  • Tri-substitution includes two substi ue ⁇ ts at the C2 carbon atom and one substituent at the C3 carbon atom or two subsliiuenis at the C3 carbon atom and one substituent at the C2 carbon atom.
  • Tetra-substitution provides for two substituents at the C2 carbon atom and two substituents at the C3 carbon atom.
  • Suitable substituents include -Ci- alkyl, -C 2 -C ⁇ ,alkcnyl, -Ca-C ⁇ alkynyl, -(CH 2 ) ⁇ COR., -(Cf .
  • cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH 2 , -NHC ⁇ -C alkyl, -OCi-Cgalkyl. -SH, -SC.-Caalkyl, -C0 2 H, -COjCrQjalkyl, -CONH or -CONI IC ⁇ -C 3 alkyl.
  • non-naturally occurring amino acid refers to amino acids having a side chain that docs not occur' in the naturally occurring L- ⁇ -ami ⁇ .0 acids.
  • non-natural amino acids and derivatives include, but are not limited to, use of norlcucinc, 4-amino butyric acid, 4-ami ⁇ o-3-hyd ⁇ oxy-5- ⁇ henylpcntanoic acid, 6-aminohexanoic acid, t-butylglycine, norvalinc, phenylglycine, ornithine, sarcosine, 4-amino-3-r.ydrox.y-6- methylhcptanoic acid, 2-thienyl alanine and/or D-isomcrs of amino acids.
  • the compounds of formula (1) may possess asymmetric centres and are therefore capable of existing in more than one sterenisomeric form.
  • the invention thus also relates to compounds in substantially pure isomerio form at one or more asymmetric centres eg., greater than about 90% cc, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such is ⁇ mers may bo prepared, by asymmetric .synthesis, for example using chiral intermediates, or by chiral resolution.
  • pharmaceutically acceptable derivative may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (1 ) or ' an antiviral ly active metabolite or residue thereof.
  • Suitable pharmaceutical ly 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, propi ⁇ ic, butyric, tarta ⁇ c, maleic, hydroxyinaleic, fu aric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phcnylacetic, methancsulphonic, toluenesulphonic, bcnzenesulpbonic, salicylic, sulphanilic, asparti*;, glutamic. edetic, stearic, palmitic, olcic, lauric, pa ⁇ tothenic, ta ⁇ nic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydro
  • Base salts include, but are not limited to, tliose formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, aTk lamnionium such as sails formed from tricth lamine, alkoxyammonium such as tho-se formed with ethanoiamine and salts formed from ethyl nediamine, cholinc or amino acids such as arg ⁇ ine, lysinc or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, aTk lamnionium such as sails formed from tricth lamine, alkoxyammonium such as tho-se formed with ethanoiamine and salts formed from ethyl nediamine, cholinc or amino acids such as arg ⁇ ine, lysinc or histidine.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower allcyl halide.
  • agents such as lower allcyl halide.
  • lower allcyl halide such as methyl, ethyl, pr pyl, and butyl chlorides, bromides and iodides; diallcyl sulfates like dimethyl and diethyl sulfate; and others.
  • prodrug is used in its broadest sense and encompasses those derivatives that sire converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds in which a free hydroxy group is converted into a group, such as an ester, carbonate or carbamate. which is capafcle of being converted in vivo back to a hydroxy group.
  • a prodrug may include modifications of one or more of the functional groups of a compound of formula (1).
  • antiviral naphthopyran prodrugs hav-ing enhanced water-solubility may be prepared by chemical reduction of the quinone functionalities to the corresponding quinols, followed by reaction with phosphorous oxycliloride to give the corresponding phosphoric acid esters.
  • the prodrug will be readily hydrolysed to the corresponding quinol, which thereafter will oxidize to re-form in vivo the active parent antiviral naphthopyrandione.
  • other kinds of derivatives may be prepared from the reduced quinol derivatives of the antiviral naphthopyrandione; these can also serve as prodrugs for use in therapeutic compositions.
  • esterification e.g., acetylation
  • other types of esterification e.g., acetylation
  • acetylation may be used to produce antiviral naphlhopyran prodrugs, such as for example 7,8,1Q-triacetoxy-3,3-dimethyl-3t -napthoL2,l-blpyran.
  • the prodrug would be readily hydrolysed and oxidized to its parent active antiviral naphthopyran compound.
  • a method of treatment or prophylaxis of hepatitis D vims in a subject comprising adudinistering to said subject an effective amount of u compound of Formula (1):
  • X is OH, OR 9 or halo;
  • R 2 and R 3 are independently selected from H, Ca.oalkynyl, C.i-scycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
  • R_ ⁇ and Rs are independently selected from H, C ⁇ a-kyl, C 2 .
  • Re and R are independently selected from H, C h alky!, C 2 . ⁇ alkenyl, Ca oalk nyl, Ci- ft cycloalkyl, OH or OR 9 ;
  • Rg is independently selected from H, C
  • Ri i is C ⁇ . 2 ialkyl, C 2 . 2 1 alkenyl, C 2 . 2 salkynyl, C 3 . 6 cycio lkyl, C 3 . f ,cycloalkylC .6alkyl, aryl or arylCi ⁇ alkyl; and
  • X is OH, OCi-ft'alkyl or halo
  • R and Ri are independently selected from H or Ci-.ialkyl or together with the carbon atom to which they are attached form a saturated or unsamrated ring
  • R and R 3 are each hydrogen
  • R 4 and s arc independently selected from H, OH, OR 9 , or halo or together with the bond between the carbon atoms to which they are attached form a double bond
  • o and R 7 are independently selected from H, OH, Ci &alkyl, C
  • R 8 is H, OH, OR y , C
  • R ⁇ ⁇ is Ci.aialkyl
  • R ⁇ 2 is Cj.oalkyl, phenyl or tosyl.
  • Preferred compounds of the invention include those of formula (2): wherein R, i , R 2 , R i, R4 and R5 are defined as for formula (1 ).
  • Preferred compounds of the invention include: 8-hydro ⁇ y-3,3-dimcthyl-3i ⁇ -naphtho[2,l-fr] ⁇ yran-7,10-dione,
  • the compound of Formula (1) is:
  • R, i , R 2 , R. Rs, R ⁇ > - R 7 , s, and X are as defined for formula ( 1 ) and R rt is selected from H, C ⁇ -_alkyl, C 2 halo or NRioRio or togetlier with R 5 and the bond between the carbon aioms to which R 4 and R 5 arc attached, form a double bond.
  • R rt is selected from H, C ⁇ -_alkyl, C 2 halo or NRioRio or togetlier with R 5 and the bond between the carbon aioms to which R 4 and R 5 arc attached, form a double bond.
  • Compounds of Formula (1) may be prepai'ed using the methods depicted or described herein or known in the art. It will be understood thai minor modifications to methods described herein or known in the art may be required to syn hesise particular compounds of Formula (1).
  • the compounds of the present invention may be prepared according to the general procedure of Scheme 1.
  • a substituted cnone such as (4) may, dependant upon the exact nature of the reagents and conditions used, add to the substituted 2,6-dO ⁇ ydroxyna ⁇ hthalene (3) in the opposite orientation to that shown in Scheme 1 and still provide a naphthopyran product, Such a reaction is shown in Scheme 2, and provides naphthopyranol (8).
  • Naphthopyranol (8) may be isomerised to provide a naphthopyranol effectively r general formula (5), which may then be subject to f.irther reaction in accordance with the general procedures of Scheme 1 to provide compounds of Formula (1).
  • Scheme (4) outlines a similar reaction sequence to that of Scheme (3) which would start with an appropriately substituted hydroxy naphthalene. This is based upon work reported by Bigi et l, J. Org. Chcm., ⁇ S2, 7024-7027 (1997).
  • the cyclised naphthopyran (15) could be treated as per compound (5) of Scheme (1) to provide compounds of the invention.
  • Further modification may include rterivatisation of double bonds,
  • the double bond may be derivatised by addition, oxidation or reduction reactions.
  • An example of possible derivatisation of such a double bond is given in Scheme 5. Following reductive a etylatioii to protect the quinone portion of the compound, epoxidation of the pyran double bond, subsequent ring opening of the epoxide with an amine, and dcprotection and oxidation to regenerate the quinone may be effected.
  • Those skilled in the art could readily determine appropriate reagent's and conditions to effect such transformations.
  • the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired hepatitis B virus treatment or therapeutic activity, or disease prevention. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods,
  • a therapeutic, or treatment, effective amount is an amount of the compound which, when administered according to a desired dosing regimen, is sufficient to at least partially attain the desired therapeutic effect, or delay the onset of, or inhibit the progression of or halt or partially or fully reverse the onset or progression of hepatitis B virus.
  • a prevention effective amount is an amount of compound which when administered according to the desired dosing regimen is sufficient to at least partially prevent or delay the onset of a particular disease or condition.
  • Yet another aspect of the present invention provides a use of a compound of Formula (1) in the preparation of a medicament for treating or preventing hepatitis B virus.
  • Suitable dosages may lie within 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 preTerably in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 jng to 1 g per kg of body weight per dosage.
  • 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.
  • 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.
  • the dosage is in the range of l ⁇ g to lmg per kg of body weight per dosage. Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the severity of the condition as well as the general age, health and weight of the subject.
  • the active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition. According to a further embodiment there is provided a method of treatment or prophylaxis of hepatitis B virus comprising administering an effective amount of a compound of Formula (1) and a second therapeutic agent.
  • the compound of Formula (1) and the second therapeutic agent may be administered simultaneously, separately or sequentially.
  • the second therapeutic agent may be a known antiviral or antiretroviral agent or another pharmaceutical used in the treatment of viral infections.
  • suitable second therapeutic agents include immunomodulators, imniu ⁇ ostimuU-nts and antibiotics.
  • exemplary antiviral agents include acyclovir, val-acyclovir, pcnciclovir, famciclovir, ganciciovir, foscarnet, ribavirin, interfcron-alpha.
  • FEG-i ⁇ lcrferon-alpha la ivudine, adcfovir, thymosin alpha 1, entecavir, tclbivudine, emtricitabine, elvucitabine, MCC-478, hepavir B, MIV-210, valtorcitabine, HcpeX-B, Zidovudine, didanosine, zalcitabine, slavudine, lamivudine, abacavir, tenofovir, emtricitabine, saquinavir, indinavir, nelfinavir, amprenavir, itonavir, azatanavir, nevirapine, delavirdine, efaviren , enfurvitide, trizivir, combivir, kaletra, IV310, mozcnavir, SPD754, SPD746, T1249, Ti C125, TMC114, V
  • the second therapeutic agent is an agent suitable for the trea.ment or prophylaxis of hepatitis B virus in a subject.
  • therapeutic agents include, but are not limited to interfcron-alpha, PEG-interferon-alpha, lamivudine, adcfovir, thymosin alpha 1, entecavir, tclbivudine, emtricitabine., elvucitabine, MCC-478, hepavir B, MfV-210, valtorcitabine, and HepeX- ⁇ .
  • compositions comprising a compound of Formula (1) and a pharmaceutically acceptable carrier, diluent or exeipient.
  • a pharmaceutically acceptable carrier such as a pharmaceutically acceptable diluent or exeipient.
  • the formulation of such compositions is well known to those skilled in the art.
  • the composition may contain pharmaceutically acceptable additives such as carriers, diluents or exeipierils. These include, where appropriate, all conventional solvents, dispersion agents, fillers, solid carriers, coating agents, antirungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
  • compositions include those suitable for oral, rectal, inlialational, nasal, transdermal, topical (including buccal an l sublingual), vaginal or parentcral (including subcutaneous, intramuscular, intraspinal , intravenous and intradermaJ) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepai'ed by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformLy and intimately bringing into association the acLive ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions for use in the rese t invention may be formulated to be water or lipid soluble.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the yjctive ingredient; as a powder or granules; as a solution or a suspension hi an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a watcr-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (eg inert diluent, preservative, disUitegrant (eg. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium c rboxymethyl cellulose)) surface-active or dispersing agent.
  • a binder eg inert diluent, preservative, disUitegrant (eg. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium c rboxymethyl cellulose)
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of Formula (1) may also be administered intrana-sully or via inhalation, for example by atomiser, aerosol or nebulizer means.
  • compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, oinLmcnts and the like.
  • suitable carriers include mineral oil, propylene glycol, polyoxycthylene, polyoxypropylene, emulsifying wa ⁇ c, sorbitan monostearatc, polysorbate 60, cetyl esters wax, cctearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Transdermal devices, such as patches may also be used to administer the compounds of the invention.
  • Compositions for redal administration may be presented as a suppository with a suitable carrier base comprising, for example, cocoa butter, gelatin, glycerin or polyethylene glycol.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes ⁇ foams or spray formulations containing in addition to the active ingredient such carriers as arc known in the art to be appropriate.
  • compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidanls, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or ⁇ nulti-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dricd (lyophilised) condition requiriag only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared, from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage compositions are tliose containing a daily dose or unit, daily sub-dose, as herein above d&scribed, or an appropriate fraction thereof, of the active ingredient.
  • compositions of tliLs invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents binders, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • suitable sweeteners include sucrose, lactose, glucose, a ⁇ spartame or saccharine
  • Suitable disintegrating agents include corn starcli, methylcellulosc, ' polyvinylpyrrolidone, xanthan gum, bcnto ⁇ ite, algi ⁇ ic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring
  • Suitable coating agents include polymers or copoly ers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zcin, shellac or gluten.
  • Suitable preservatives include sodium beni-oate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, sttjaric acid, sodium oleatc, sodium chloride or talc.
  • Suitable time delay agents include glycer l monostearate or glyceryl distearate.
  • Step 1 3,3-Dimethyl-3H-n phth ⁇ [2,l-b]pyran-8-ol
  • 2,6-dihydroxynaphth ⁇ Iene (50.0 g, 0.312 mol)
  • 3-rnethyl-2-butenal (30 ⁇ n-L, 26.24 g, 0.312 mol)
  • pyridine 38 ml., 37.02 g, 0.468 mol
  • the mixture was cooled to room temperature, diluted with dichloromethane (5O0 mL), Filtered through a sintered glass funnel (porosity 3) then washed with aqueous hydrochloric acid solution (I M, 2 x 250 mL) and water (1 x 250 mL).
  • the organic layer was extracted with a solution of aqueous sodium hydroxide (2 M, 1 x 250 L and 1 x 125 mL) and the combined aqueous extracts cooled in an ice-salt bath, acidified (with stilting) with aqueous hydrochloric acid solution (5 M) uiutil a creamy-white precipitate formed (pH ⁇ 2).
  • Step 2 3 > 3- imethyl-3H-naphtfw[2,l-b]pyran- ? f S-dwne
  • the orange/brown reaction mixture was diluted with ethyl acetate and the enLirc mixture filtered tlirough a plug of flash silica (11 x 7 cm) to remove the catalyst.
  • the plug was washed with ethyl acetate until the elue ⁇ t was nicarly colourless, The solvent concentrated in vacua and the residue dried under high vacuum, to afford the desired crude product as an orange solid (2.73 g, 86%).
  • the crude prct ⁇ uct was used in the subsequent reaction without further purification,
  • the produ ⁇ was recrystalliscd from ethyl ac tatc/hexa ⁇ es to afford red needles; m.p. 189-193° ⁇ ( l H) (300 MHz, CDCI3) 1.50, s, 2 x. CH 3 ; 5-92, d, J 10.4 Hz, H2; 6.43, d, J 10.4 Hz, HI; 6.71, d, J 10.5 Hz, H9; 6.84, d, J 8.6 Hz, H5; 7.72, d, / 10.5 Hit, H10; 7,97, d, / 8.6 Hz, H6.
  • the yellow organic layer was then added in one portion to a oxygen saturated solution of potassium ter -butoxide (12.19 g, 115 mmol) in ; ⁇ ?rt-butanol (110 mL) and the resulting mixture was stirred at room tempe-rature with oxygen bubbling for an additional 30 nun (NOTE: longer periods appears to result in reduced yield).
  • the resultant dark red solution was acidified with aqueous hydroc ⁇ iloric acid solution (initially 2 M then 5 M) until the colour turns yellow/orange (pH ⁇ 1>, then water ( ⁇ 40 r ⁇ L) was added to dissolve the formed salt, and the layers separated.
  • Example 2 Compound 2; 8-Hydroxy-3 ⁇ 3-dimethyI-l,2-dihydra-3H-n ⁇ p* ⁇ h ⁇ f2,l-b]pyran-7 > 10-d ne
  • a mixture of 8-hydroxy-3,3-dimcthyl-3H-naphthoL2,l- 3]pyjran-7,10-dione (132 mg, 0,52 mmol) and platinum (IV) oxide ( 15 mg) in ethyl acetate C mL) was stirred under an atmosphere of hydrogen for 7 h, The resulting mixture was stirred in air for 1 h then was filtered through a pad of diatomaccous earth.
  • Example 3 Compound 3: 8-Acetoxy ' 3,3-dimethyt-3H-naphtko[2,l-b]pyr*m-7,10-dione
  • N, iV , -Bis(salicylidene)ethylenediaminocobalt(rr) hydrate (4.5 g, 14 mmol) was added to a stirred solution of 3,3-dimemy!-3H-naphthoL2,l-blpyran-9-ol (43.2 g, 190 mmol) in acetonitrile (1.0 L) and oxygen bubbled through the mixture wit reaction progress monitored by HPI-C. Further portions of the catalyst (4.1g, 3.4 g and 2.7 g) were added after 18.5 h, 24.5 h and 44.5 h respectively.
  • Step 3 8,9-Dichloro-3,3-d ⁇ methyl -l,2-dihydro-3r - ⁇ aphthoL2.1-blpy) ⁇ in-7, 10-dione
  • Chlorine gas was bubbled through a solution of 9-chloro-3,3-dimethyl-l,2-riihydro-3 7- naphtho[.2,l--?]pyrun-7, 10-dione (633 mg, 2.3 mmol) in glacial acetic acid (50 mL) containing concentrated hydrochloric acid (5 drops) at 70° C fo ⁇ 5 min. The reaction was stirred for 55 min at 70° C, cooled to room temperature and concentrated in vacua.
  • Aqueous sodium hydroxide (2.0 M, 3.3S mL, 6.75 mmol) was added dropwise to a stirred orange suspension of compound 1 (1.73 g, 6.75 mmol) in methanol (10 ml-). The mixture became homogeneous red. After 30 min volatiles were removed in vacua and the resulting red residue dissolved in water ( 150 mL), r ⁇ tered (porosity 4 sinter) and freeze dried for 48 h.
  • Buffer C 2 % aqueous formic acid
  • Co(SALEN) 2 (23 mg) was added in one portion to a stirred homogenous yellow solution of 3-mcthyl-3-phcnyl-3H-bcnzo[ Jclvromen-8-ol (217 mg, 0.75 mmol) in acetonitrile (3 mL). Oxygen was bubbled through the mixture and after 90 min the mixture was filtered through a silica plug, washing the plug with ethyl acetate until no further colour eluted.
  • Aqueous sodium hydroxide solution (4 M, 5 L) was added to stirred orange suspension of 3-methyl-3-phenyl-3W-benzo[ lchromene-7,8-dione (32 mg, 0.11 mmol) in ethanol (5 L) and the mixture became homogeneous brown. After 1 h, the mixture was cooled (ice/water bath) and acidified to pH- 2.0 (5.0 M aqueous hydrochloric acid solution). The resulting orange suspension was stirred for 20 min in the cooling bath then at 10 min at room temperature.
  • Aqueous sodium hydroxide solution (4 M, 3 mL) was added to stirred orange suspension of 3,3-diphenyl-3iY-bcnz ⁇ [ lclu'omene-7,8-dione (22 mg, 0,06 mmol) in ethanol (3 L) and the mixture became homogeneous brown. After 30 min, the mixture was cooled (ice/water bath) and acidified to pH- 2.0 (5.0 M aqueous hydrochloric acid solution). The resulting orange suspension was stirred for 20 min in the cooling bath then at 10 min at room temperature. The precipitate was collected by filtration and washed with water (15 mL).
  • Tests of antiviral activity were performed in 2.2.15 human hepaloma cells infected with hepatitis B according to the method of Korba and Gerin, Antiviral Research, 19, 55-70 (1992). Briefly, cells were seeded into 96 well plates and cell media containing various concentrations of the compounds was added”. Media was. changed daily for 9 days and fresh media containing compound was added each day. On the 10 th day, viral DNA in the supernatant was measured and the reduction in the amount of virus in the supernatant wa ⁇ calculated compared to cells incubated without drug. Six separate replicates were performed for each drag concentration. The effective concentration for 50% and 90% Munition of the replication of the virus was determined from dose response eurvcs. Results for some compounds of the invention are shown in Table 1.
  • Antiviral activity was also examined in HepG2 hepatoma cells infected with HBN containing mutations associated with resistance to lamivudine (3TC). Two cell lines containing an L180M mutation in the HBV D ⁇ A polymerase, and a double L180M/M204V mutation were used. Cells were plated out in six well plates and allowed to attach overnight, Next day, the culture medium was replaced with either medium alone or medium containing the desired concentration of antiviral compound. Media was changed for fresh medium with or without, antiviral compound on day 3. On day 5, supernatant and cell lysatcs were analysed for levels of HBV core protein by non-denaturing Western blot using an anti-HBV core antibody,
  • results for some of the compounds are shown in Table 2 where a 50% reduction or more in measured level of the viral core protein compared to controls at a compound concentration of greater than 50 ⁇ mol-ir is designated +, 50% core reduction at less than 50 ⁇ molar is designated ++ and 50% core reduction at less than lO ⁇ molar compound concentration is designated +++.

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Abstract

L'invention concerne un procédé de traitement ou de prophylaxie du virus de l'hépatite B chez un patient, qui consiste à lui administrer une dose efficace d'un composé de formule (I) ou d'un dérivé, d'un sel ou d'un promédicament de celui-ci pharmaceutiquement acceptable. De plus, l'invention concerne des composés de formule (I) et des compositions de ceux-ci pharmaceutiquement acceptables. Elle concerne enfin des procédés de préparation de composés de formule (I).
EP05714322A 2004-03-31 2005-03-31 Agents antiviraux Withdrawn EP1737836A1 (fr)

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AU2004901755A AU2004901755A0 (en) 2004-03-31 Antiviral agents
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