WO2005095376A1 - Antiviral agents - Google Patents

Antiviral agents Download PDF

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Publication number
WO2005095376A1
WO2005095376A1 PCT/AU2005/000453 AU2005000453W WO2005095376A1 WO 2005095376 A1 WO2005095376 A1 WO 2005095376A1 AU 2005000453 W AU2005000453 W AU 2005000453W WO 2005095376 A1 WO2005095376 A1 WO 2005095376A1
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WO
WIPO (PCT)
Prior art keywords
dione
independently selected
dimethyl
pyran
aryl
Prior art date
Application number
PCT/AU2005/000453
Other languages
French (fr)
Inventor
Jonathan Alan Victor Coates
Eric Dale Jones
Susan Cox
Ian Crosby
David Gerard Bourke
Tyrone Pieter Jeynes
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
Priority to BRPI0509533-6A priority Critical patent/BRPI0509533A/en
Priority to CA002561896A priority patent/CA2561896A1/en
Priority to MXPA06011205A priority patent/MXPA06011205A/en
Priority to JP2007505333A priority patent/JP2007530600A/en
Priority to AU2005229153A priority patent/AU2005229153A1/en
Priority to EP05714322A priority patent/EP1737836A1/en
Priority to US10/594,847 priority patent/US20090170926A1/en
Publication of WO2005095376A1 publication Critical patent/WO2005095376A1/en

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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

The present invention provides a method of treatment or prophylaxis of hepatitis B virus in a subject comprising administering an effective amount of a compound of formula (1) or a pharmaceutically acceptable derivative, salt or prodrug thereof. In addition, there is provided compounds of formula (1) and pharmaceutical compositions thereof. Further, methods of preparing compounds of formula (1) are disclosed.

Description

ANTIVIRAL AGENTS
Field of he Invention
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,
Background of the Invention
Infection with human hepatitis B virus is a major public health problem because of the ability of the virus to cause acute and chronic infections. Chronic hepatitis B virus infection (hereinafter referred to as "HBV") causes serious liver disease in humans and frequently results in cirrhosis and hcpatoccllular carcinoma. CurrcnLly there is no completely effective therapy for the successful management of chronic HBV infections. The >250 million chronic HBV carriers throughout the world are unable to benefit from the commercial vaccine presently available.
Currently available therapies for HBV are only partially effective and may be accompanied by deleterious side effects. In addition, many patients develop antiviral resistance resulting in the loss of efficacy. Accordingly, a need exists for new effective treatments for HBV.
It has now been discovered that compounds of Formula (1) are active agents against hepatitis B virus.
Summary of the Invention
According to one aspect of the present invention there is provided 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 ):
Figure imgf000003_0001
(1) wherein X is OH, OR$ or halo;
R and Ri are independently selected from H, Ci.a-uk l, C2-Λalkenyl, Cι t,alkynyl,
C^cycloalkyl, aryl, or together with the carbon atom, to which they are attached foπn a saturated or unsaturated C3.0carbocyclic ring;
R2 and R) are independently selected from H. Ci^ i yl, C2.ealkcnyl, C2_f,alkynyl,
C3.βcycloalkyl or together with tlie bond between t e carbon atoms to which they are attached form a double bond;
R4 and R5 arc independently selected from H,
Figure imgf000003_0002
C^cycloaikyl, OH, OR9, halo or NR10R10 or together with the bond between the carbon atoms to which they arc attached form a double bond;
Rϋ and 7 are independently selected from H, Ci-s-d yl, C2.halkenyl, C2.Λalkynyl,
C3.ficycloalkyl, OH or OR,;
Rs is independently selected from H, Cι.halkyl, Cz*ι*.lkenyl, C2-$aIkyny|, C3 6cyc.oalk.yl, OH. ORy or halo;
Ro is C^alkyl, C2.fialkenyl, C^alkynyl, Cj-ocycloalkyl, aryl, C(=0)Ru or S(0)^R12 or ORy is an amixio acid residue; each R io is independently selected from H and Ch l .!;
Rι ι is C].2|iilkyl, C2.2i lkeπyl, 2 2ial ynyl, C3.6cycloall.yh C -όCyclo l yl i.fi lkyl, aryl or arylC].6alkyl; and
R12 is Ci^alkyl, C2^alkenyl, C2.halkynyl or aryl. According to a further aspect of the present invention there is provided a use of a compound of Formula (1) in the manufacture of a medicament for the treatment or prophylaxis of hepatitis B virus. According to yet a further aspect of the present invention 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.
According to another aspect of the invention there is provided a compound of Formula (1) with the proviso that when R and Ri arc both methyl and R4 is OH or OR,, Rs is not selected from OH, ORy or NHRK).
According to another aspect of the present invention there is provided 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<>, R5 is not selected from OH, ORς or NHR,«.
, According to the present invention the compounds of Formula (1) may be presented in the form of a pharmaceutically acceptable derivative, salt or prodrug. etailed Description
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations .such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), cr-dorine (chloro), bromine (bromo) or iodine (iodo).
As used herein, the term "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. For example, 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,
As used herein, the term "alkenyl" refers to straight chain or branched hyd-cocarbon groups having one or more double bonds between carbon atoms, Suitable alkeπyl groups include, but are not limited to ethenyl, propcnyl, isopropenyl, bulcnyl. pentenyl and hexenyl.
The term "alkynyl" as used herein, 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, butyπyl, pentynyl and hexen l.
The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and eyclohexyl.
The term "aryl" as used herein, refers to -CHJ aromatic hydrocarbon group, for example phenyl or naphthyl.
The term "heterocy lyl" when used alone or in compound words inclu des monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably
Figure imgf000005_0001
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. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms, Suitable examples of hctcrocyclic groups may include pyrrolidiπyl, pyrrolinyl, piperidyl, piperazinyl, inorpholino, indoϋnyl, imiazolidinyl, pyrazolidinyl, thiomorpholino, dioxsuyl, tctrabydrofuranyl, tetrahydropyraπyl, tctrahydropyrrolyl etc.
Each alkyl, alkenyl, alkynyl, cycloalkyl, aiyl or heterocyclyl group may be optionally substituted with Chalky., OH, OCi-3alkyl, halo, CN, NOj, C02H, CO-C^alky!, CONH2, CONH(C,.;>alkyl), CON(Cι.3alkyl)2, trifluoromethyl, NH2, NEi(alkyl) or N(alkyl)3. For example, 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.
As used herein, the term "a ino acid residue" refers to an cx-ammo acid or a β-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 α-position or the β'po-sition with a group selected from -C,-Ctialkyl, -C alkenyl, -Cr alkynyl. -(CH2)tt :ORa. -(CH2) Rh) -P03H, -(CH2 ιeterocyclyl or -(CH2)naryl where R;ι is -OH, -NH2, -r HC1-C3alkyl, -OCι-C3aIkyI or -C,-C3alkyl and Rb is -OH, -SH, -Sd-Cjalkyl, -OCι-C3a]kyl, -C3- cycloalkyl, -C3-Qcyc.0a.ke._yl, -NH , -NHCι-C3alkyl or -NHC(C=NH)N t.2, n is 0 or an integer from 1 to 6 and where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH2, -NHCi-Qsalkyl, -OCι-C3alkyl, -SH, -SCi-C.alkyl, -C02H, -C02C.-C3αlkyl, -CONI f2 or -CONHC,-C.,alkyl.
The term "α-amino acid" as used herein, 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 α-carboπ atom, An α-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 α-amino acid may also be further substituted in the oj-pcjsition with a group selected from -CrCιoa.kyl, -Ca-C.oalkenyl, -C2-Cι0alkynyl, -(CR2)ΆCOR^, -(CH2)_.Rb, -P03H, -(CH2)nlieterocyclyl or -(CHa)„aryl where Ra is -OH, -NH_, -NHCi-C^alkyl, -OCι-C6alkyl or C.-Cjal yl and Rb is -OM, -SH, -SC C3alkyl, -OC]-C6alkyU -Ca-C.acycloaUcyl, -C3-Ciacycloalkcnyi, -NH2, -NHC.- alkyl or -NHC(C=NH)NH2, 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[-C3alkyl, -OC.-Qalkyl, -SH, -SCι-C.,alky], -C02H, -C Ct-Cjalkyl, -CONH2 or -CONHC[-C3alkyl.
As used herein, the term "β-amino acid" refers lo an amino acid that differs from an -amino acid in that there arc two (2) carbon atoms separating the cεirboxyi tertninui. and the amino terminus. As such, β-arnino acids with a specific side chain can exist as the K or 5 enantiomcrs at either of tire (C2) carbon or the β (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 α-amino acids or may be the side chams of no- -naturally occurrhig -UTiino acids,
Figure imgf000007_0001
Furthermore, the β-amiπo 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 ueπts 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, -C2-C<,alkcnyl, -Ca-Cήalkynyl, -(CH2)αCOR., -(Cf .2)πRh, -PO.,H, -(CH2)nheterocyclyl or
Figure imgf000008_0001
where Ru is -OH, -NHj, -NHd-dalkyl, -OCι-C3alkyl or -Cι-C3alkyl and Rb is -OH, -SH, -SC,-C3alkyl, -OCι-C3alkyl, -C.-Cccycloalkyl, -C3-CΛcycloalkenyl, -NH2, -NHCL-C3alkyJ or -NHC(C=NH)NH2, n is 0 or an integer from 1 to 6 and where each alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH2, -NHCι-C alkyl, -OCi-Cgalkyl. -SH, -SC.-Caalkyl, -C02H, -COjCrQjalkyl, -CONH or -CONI ICι-C3alkyl.
The term "non-naturally occurring amino acid" as used herein, refers to amino acids having a side chain that docs not occur' in the naturally occurring L-α-amiι.0 acids. Examples of non-natural amino acids and derivatives include, but are not limited to, use of norlcucinc, 4-amino butyric acid, 4-amiπo-3-hydτoxy-5-ρhenylpcntanoic 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.
It will also be recognised that 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 isσmers may bo prepared, by asymmetric .synthesis, for example using chiral intermediates, or by chiral resolution.
The term "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, propiσπic, butyric, tartaπc, 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, paπtothenic, taπnic, ascorbic and valeric acids.
Base salts mclude, 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 argύϊine, lysinc or histidine.
Basic nitrogen-containing groups may be quarternised with such agents as lower allcyl halide. such as methyl, ethyl, pr pyl, and butyl chlorides, bromides and iodides; diallcyl sulfates like dimethyl and diethyl sulfate; and others.
The term "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). For example, similar to the approach described in US 5,672,607, antiviral naphthopyran prodrugs hav-ing enhanced water-solubility (e.g., which are better for parenterally adiniπi.stό-rcd compositions) 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. Alter in vivo administration of a composition containing such a solubili-.ed antiviral naphtopyran prodrug, the prodrug will be readily hydrolysed to the corresponding quinol, which thereafter will oxidize to re-form in vivo the active parent antiviral naphthopyrandione. Likewise, 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. For example, other types of esterification (e.g., acetylation) may be used to produce antiviral naphlhopyran prodrugs, such as for example 7,8,1Q-triacetoxy-3,3-dimethyl-3t -napthoL2,l-blpyran. Again, after in vivo administration the prodrug would be readily hydrolysed and oxidized to its parent active antiviral naphthopyran compound.
In a first aspect, there is provided a method of treatment or prophylaxis of hepatitis D vims in a subject comprising adiriinistering to said subject an effective amount of u compound of Formula (1):
Figure imgf000010_0001
(1) wherein X is OH, OR9 or halo; R and
Figure imgf000010_0002
arc independently selected from J I, Ci-galkyl, Cj-βalkenyl, C2 6alkynyl, C3_6cycloaIkyl, aryl, or together with the carbon atom to which they arc attached form a saturated or unsa rated C.v_.carbσcyelic ring; R2 and R3 are independently selected from H,
Figure imgf000010_0003
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, C2.6alkenyl, C2.<5alkynyl, C -6cycloalkyl, OH, OR9, halo or NR10R1 or together with the bond between the carbon atoms to which they are attached form a double bond;
Re and R are independently selected from H, Chalky!, C2.≤alkenyl, Ca oalk nyl, Ci-ftcycloalkyl, OH or OR9;
Rg is independently selected from H, C| &alkyl, C .c,alkcnyl,
Figure imgf000011_0001
OH, ORg or halo;
R9 is Ci-ftalkyl, C^alkenyl, C2-6alkynyl, C3.0cycloa.ky I, aryl, C(=0)Rπ or $(0>aRj2 or OR9 is an arnino acid residue; each Rw is independently selected from H and Cwalkyl;
Ri i is Cι.2ialkyl, C2.21 alkenyl, C2.2salkynyl, C3.6cycio lkyl, C3.f,cycloalkylC .6alkyl, aryl or arylCi^alkyl; and
R12 i .galkyl, C .saJkenyl, C2.βalkynyl or aryl,
In another aspect there is provided a compound of Formula ( I ), with the pro iso that when R and Ri are both methyl and R is OH or ORς. R5 is not .selected from OH, ORy or NHRy.
In a preferred embodiment one or more of the following definitions apply;
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
Figure imgf000011_0002
ring; R and R3 are each hydrogen; R4 and s arc independently selected from H, OH, OR9, or halo or together with the bond between the carbon atoms to which they are attached form a double bond; o and R7 are independently selected from H, OH, Ci &alkyl, C| ^alkoxy; R8 is H, OH, ORy, C|.6alkyl or halo; R9 is (=0)Ru or S(0)2R12; Rι ι is Ci.aialkyl; Rι2 is Cj.oalkyl, phenyl or tosyl.
Preferred compounds of the invention include those of formula (2):
Figure imgf000012_0001
wherein R, i , R2, R i, R4 and R5 are defined as for formula (1 ).
Preferred compounds of the invention include: 8-hydroχy-3,3-dimcthyl-3iϊ-naphtho[2,l-fr]ρyran-7,10-dione,
8-hydroxy-3,3'dimethyl-l,2-dihydro-3iϊ-naphtho|2,1-fo]pyran-7.10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-l,2-dihydro-3t -naphthc>[2,l^Jpyran-7,10-dione,
9-bromo-8-hydroxy-3,3-di etlιyl-3H-naphtho[2,l- >Jpyran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbcnzeπesull ιιyloxy)-l ,2-dihydro-3//-ιιaphthoL2,l-&lpy ran-7,10-dione,
9-bromo-3,3-dimethyl-8-(4-methylbenzenesιιlfonyloxy -3/ϊ"-naphtho[2,l-i?Jpyran-7, 10- dione,
S-acctoxy-3,3-dimeihyl-3 -naphtho[2,l-^Jpyran-7,10-dione.
2,9-dibromo-l ,8-dihydroxy-3,3-dήnethyl-l,2-dihydro-3/V-naphtho[2,l-t?Jpyraα-7,10-dione, 8,9-dicWoro-3,3-dimcthyl-1 )2-duiydro-3r7-naphtho[2,l-b|pyraii-7,l0-dione,
7,8,10-triacctoxy-3.3-dimethyl-3/i'-r-aphtho[2,l-bJpyr n,
9-Bromo-8-hydroxy-3,3-dimethyl-3 /-naphtho[2,l-t>jpyran-7,10-dione.
9-βromo-8-hydroxy-3,3-dimethyl-3H'-naphtho[2,l-/7]p>τan-7,10-dione.
9-Bromo-3,3-dimethyI-8-(4-methylben7.enesulfonyloxy)-l ,2-dihydro-3i2r-naphthoL2,1 - ft]pyran-7,10-dionc.
9-Bromo-3,3-dimethyl-8-(4-memy]benzcnesulfonyloxy)-3/2,-naphtlιoL2,l--?Ip> an-7,10- dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-3 V-naphthor2, 1 -ilpyran-7, 10- dione,
8-Bromo-3,3-dimethyl-9-(4-metlιylbenzeresulfonyloxy)-l!2-dih.ydro-3ici-naphthc)[2,l- i>Jpyran-7,10-dione,
8,9-Diclιloro-3 ,3-dimethyl - 1 ,2-dilιydro-3/V-naphtho[2, 1 -fc]pyran-7, 1 -dione,
ScxIiu 3,3-dimethyl-7J -dioxo-7,10-dihydro-3H-berLZθLfJchromen-8-olate;
Sodium 3, -dimethyl-7,S-dioxo-7,8-dihydro-3 ϊ-benzol lchromen-10-olate
8-Hydroχy-3-meihyl-3-phenyl-3H-benzo[/]clrromcne-7,10-dione, and
8-Hydroxy-3,3-diphenyl-3H-benzo[ ]chromene-7,10-dione,
Preferably the compound of Formula (1) is:
8-hydroxy-3,3-dimethyl-3 -naphtho 2,J-fc]pyran-7,10-dione (compound (1)), 8-hydιoxy-3,3-dinιelhyl-l ,2-dihydro-3H'-naphlho|2)l-Z7lpyraιι-7,10-dione (compound (2)). fπ another embodiment the compounds of the invention include those of formula (3):
Figure imgf000013_0001
(3) wherein R, i , R2, R. Rs, R<>- R7, s, and X are as defined for formula ( 1 ) and Rrt is selected from H, Cι-_alkyl, C2
Figure imgf000013_0002
halo or NRioRio or togetlier with R5 and the bond between the carbon aioms to which R4 and R5 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). General synthetic procedures applicable to the synthesis of compounds may be found in standard references such as Comprehensive Organic Transformations, R. C. Larock, 1 89, NCH Publishers and Advanced Organic Chemistry, J. March, 4th Edition <1992), Wiley InterScience. and references therein. It will also be recognised that certain reactive groups may require protection and deprotection during the synthetic process. Suitable protecting and deprotecting methtκis for reactive functional groups are known in the art for example in Protective Grυiφs in Organic Synthesis T. W. Greene & P. Wutz, John Wiley & Son, 3rd Edition, 1 99.
The compounds of the present invention may be prepared according to the general procedure of Scheme 1.
Figure imgf000015_0001
Figure imgf000015_0002
(7) An appropriately substituted 2,6-dihydroxyπaphthaleπe (3) is reacted with an appropriately substituted enal or enone (4) in the presence of a suitable base to effect cyclisation and provide a naphthopyranol (5). The naphthopyranol is then oxidised by a suitable oxidant to the corresponding intermediate oithoquinone (6), before being reduced by a suitable reducing agent and further oxidised by a suitable oxidant to the desired naphthopyrandione (7). Further modification of the substituents on the naphthopyrandione may be effected using chemical approaches known to those skilled in the art for the generation of the desired substituent or substituents. Those skilled in the art may utilise conventional approaches to protect and deprolcct certain functional groups during the reaction sequence. Such methods arc well known in the art and include for example those described by Greene and Wutz (supra). The reaction sequence described in Examples 1 and 2 exemplify the preparation of compounds (1) and (2) and provide an example of how the reaction sequence of Scheme 1 is utilised, Those skilled in the art will appreciate that a wide variety of reaction conditions, including solvents, bases, oxidising agents, reducing agents, temperature and time of the reaction, may be utilised to effect the desired transformation.
A substituted cnone such as (4) may, dependant upon the exact nature of the reagents and conditions used, add to the substituted 2,6-dOιydroxynaρhthalene (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 2
Figure imgf000017_0001
(5)
Alternative synthetic procedures which provide compounds of Formula (1) are shown in Schemes 3 and 4. In Scheme (3) an appropriately substituted butyne (9) is reacted with an appropriately substituted hydroxy tetralone (10). The group L is any suitable leaving group and includes groups such as a bromo, chloro. and hydroxyl. Reaction between the tetralone and the butyne may be acid or base catalysed to provide naphthopyran (12). In some cases the reacliou. may be conducted in one pot however an intermediate (1 1) may be isoIaLed. Intermediate (1 1) may conveniently be cyclised for example by heating in the presence of a suitable base, such as diethylaniline. The cycliscd product (12) is then oxidised to afford the quinonc (13) which may then be further modified to provide other 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.
Many other methods of preparing benzopyrans have been reported in the chemical literature and those skilled in the art may adapt these methods to provide compounds of the present invention, sec for example, Ishiπo et al., Syπ. Comm,, 31, 39-448 (2001).
Scheme 3
Figure imgf000019_0001
(10) OD
Figure imgf000019_0002
Scheme 4
Figure imgf000020_0001
(3) (14)
Figure imgf000020_0002
(15)
Further modification may include rterivatisation of double bonds, For example, when R-t and R5 together with Lhc bond between the carbon atoms to which they are attached form a double bond, 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. Scheme 5
Figure imgf000021_0001
A person skilled in the art would be able to modify such a reaction scheme by using different reagents to open the epoxide, using asymmetric epoxidation catalysts and varying the nature of the substituents.
As used herein, 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 μg 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. In one embodiment, the dosage is in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another preferred 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 lμg 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.
When administered as a combination, 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. Representative examples of suitable second therapeutic agents include immunomodulators, imniuπostimuU-nts and antibiotics. Exemplary antiviral agents include acyclovir, val-acyclovir, pcnciclovir, famciclovir, ganciciovir, foscarnet, ribavirin, interfcron-alpha. FEG-iπlcrferon-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, VX-175, tipranavir other non-nucleoside reverse transcriptase inhibitors and protease inhibitors, Exemplary irnmunomodulators and immυnostimulants include interfcron alpha, PEG-interferon, thymosin alpha 1 , HcpeX-B, HBV immunoglobulin, HBV monoclonal antibodies, and vaccines such as EngerixB, Havrix, H-B- x II, infanrix hep B, twinrix. Preferably the second therapeutic agent is an agent suitable for the trea.ment or prophylaxis of hepatitis B virus in a subject. Such 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-β.
.' Still another aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula (1) and a pharmaceutically acceptable carrier, 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.
The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. 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. In general, 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.
Depending on the disease or condition to be treated, it may or may not be desirable for a compouαd of Formula ( 1 ) to CTOSS the blood/brain barrier, Thus the 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. 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 τnulti-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.
It should be understood that In addition to the active ingredients particularly mentioned above, the 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, aϊspartame or saccharine, Suitable disintegrating agents include corn starcli, methylcellulosc, ' polyvinylpyrrolidone, xanthan gum, bcntoπite, algiπic 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.
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described, It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
The invention will now be described with reference to the following examples which are included for the purpose of illustration only and are not intended to limit the generality of the invention hereinbefore described.
EXAMPLES
Example 1
Compound 1 : 9-llydroxy-3,3-(Umethyϊ-3H'naphtho[2,l-b]pyr n-7, 10-dbne
Step 1: 3,3-Dimethyl-3H-n phthυ[2,l-b]pyran-8-ol A mixture of 2,6-dihydroxynaphthαIene (50.0 g, 0.312 mol), 3-rnethyl-2-butenal (30 ιn-L, 26.24 g, 0.312 mol) and pyridine (38 ml., 37.02 g, 0.468 mol) were heated under reflux For 3,5 h. 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). The solid was stirred for an additional 10 min with cooling, collected by filtration, washed with water and dried under high vaeu-xm at 40 °C to afford the desired crude product as a fluffy white-grey solid (43.9 g, 62 .%). The crude product was used in the subsequent reaction without further purification.
Recrystalliscd from dicthyl ether/hexane m.p. 120-123°. δ Η) (300 MHz, CDCl3) 1.47, s, 2 x CH3; 4.77, s, OH; 5.71, d, J 10.2 Hz, H2; 6 -7, d, / 10.2 Hz, HI; 7.02, d, J 8.7 Hz, H5; 7.08, s, H7; 7.10. dd, J 8.7, 2.7 Hz, H9; 7.48, d, J 8.7 Hz, H6; 7,85, d, / 8.7 Hz, H10. m/z (ES+, 100 V) 471 (2M+H+H20, 100%), 245 (M+-H+I ι20, 62), 227 (M+H, (53).
Step 2: 3>3- imethyl-3H-naphtfw[2,l-b]pyran- ?fS-dwne
To an oxygen saturated solution of 3,3-dimcth»yl-37/-naphtor2,'l-bJpyran-8-ol (3.0 g, 13 mmol) in acetonitrilc (70 mL) was added catalytic amounts of iY.NBis(salicylidenc)ethyIenediamineocobalt(ll) hydrate, ([Co(II)(Salen)2]) (300 mg, 0.91 mmol, 7 mol%). and oxygen was bubbled tlurough the mixture until the reaction was deemed completed (generally 4.5 h) by TLC Chexanc-ethy] acetate 4: 1) or HPLC. 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 elueπt 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 prctϋuct was used in the subsequent reaction without further purification,
The produα was recrystalliscd from ethyl ac tatc/hexaπes to afford red needles; m.p. 189-193° δ (lH) (300 MHz, CDCI3) 1.50, s, 2 x. CH3; 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. m z (ES+, 30 V) 263 (M+Na, 9%), 242 (M+H+l, 19), 241 (M+H, 100). Step 3: 9-Hydroxy-3,3-dimethyl'3H-naphtho[2rI-b]pyrart-7,lϋ-dione A solution of 3,3-dimethyl-3/f-naphtho[2,l-t» |pyra.ι-7,8-dione (4.59 g, 19.1 mmol) in tolucne (340 mL) was washed twice with a solution of sodiixm dithionitc (24.9 g. 0.143 mol) in water (250 mL). 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 hydrocϊiloric acid solution (initially 2 M then 5 M) until the colour turns yellow/orange (pH ~ 1>, then water (~ 40 rαL) was added to dissolve the formed salt, and the layers separated. Thie organic phase was washed with water (1 x 85 mL), and then extracted with a saturated aqueous sodium hydrogen carbonate solution (5 x 85 mL). The combined aqueous extracts were transferred back into the separating funnel and allowed to settle for 1 h (to separate further amounts of toluene) and the layers separated again. The combined base extracts were cooled in an ice-salt bath, carefully acidified (aqueous hydrochloric acid, 5M, ~ 80 ml ) dropwise over 30 min with stirring until the colour Lurns pale yellowish (pH ~ 1-2). The resultant precipitate was further cooled in the ice-salt bath with stirring, the solid c-ollected, washed wilh water (-100 mL) to remove coloured impurities, and the orange/bi-own solid was recrystalliscd (absolute ethanol) to afford the desired product as orange coloured crystals (1.04 g, 21%), m.p. 208" 6 ('H) (300 MHz, CDCI3) 1 -48, s, 2 x CH.,; 5.94, d, J 10.5 Hz, H2; 6.23, s, H9; 7.03. d, .7 8.4 Hz, H5; 7.83, d, J 10,5 Hz, HI; 7.99, d, J 8.4 Hz, Hό, m/z (ES+, 100 V) 279 (M+Na, 100%), 257 (M+H, 46). 159 (46), 137 (49), 86 (44), 59 (50).
Example 2 Compound 2; 8-Hydroxy-3}3-dimethyI-l,2-dihydra-3H-nøp*ιέhύf2,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. The pad was washed with ethyl acetate then the filtrate and washings were combined and cocnelratcd i*\ yacuυ to give a green solid (128 mg, 96%). Recrystallisatioπ from ethyl acetate/hcxanesi using activated charcoal gave 8-hydroxy-3,3-dimethyl-l,2-dihydro-3H-naphιho[2,l-blpγra-n-7,lϋ-dione m.p. 183.5-187°. δ (Η) (300 MHz, CDCI. 1,37, s, 2 x CH3; 1.85, t, J 6,8 H-Ϊ, 2 x H2; 3.30, t, J 6.8 Hz, 2 x HI; 6.20, s, H9; 7.03, d, J 8,6 Hz, 1(5; 7,98, d, 8.6 Hz, H6. m (ES+, 30 V) 259 (M+H, 77%), 174 (88), 159 (100).
Example 3 Compound 3: 8-Acetoxy'3,3-dimethyt-3H-naphtko[2,l-b]pyr*m-7,10-dione
Concentrated sulphuric acid (1 drop) was added to a stirred orange suspension of 8-hydroxy-3,3-dimcthyl-3ic/-naphthoL2,l-fclpyran-7,10-dione (855 mg, 3.34 mmol) in acetic anhydride (10 mL) and the mixture was placed in an c»il bath (oil bath temperature 100' C). The mixture immediately became homogeneous red-black. After 10 min the mixture was cooled (ioe/water bath) and water (50 mL) added. Products were extracted with ethyl acetate (150 mL), the organic phase separated, dried (Na2S04) and filtered through a silica plug, washing the plug with ethyl acetate until no further colour eluted. The filtrate was concentrated in vacua and the residue was uτied overnight under vacuum to afford the title compound as a red solid (965 mg, 97%), Η NMR (300 MHz, CDCl?) δ 1,48 (6H, s, 2 x CH»). 2.37 (3H, s, COCt/,,), 5.94 (1H. d, / 10.5 I fz, H2), 6.34 ( 1 H, s, H9), 7.07 (1H, d, 78,4 Hz, H5), 7.73 (1H, d, J 10.5 Hz, HI), 7.97, <1H, d, J 8,4 Hz, H6).
Example 4
Compound s 7,8,10-triacetoxy-3,3-dimethyl-3 -naphth [^l-b]pyran A stirred solution of 84ιydroxy-3.3-dimcmyl-3H-naphtho l 2,l-blpyτan-7,10-dione (110 mg, 0,93 mmol) in acetic anhydride (3 mL) and pyridine (4 JT L) was heated in an oil bath at 6Q"C for 15 min. Zinc powder (530 mg) was added in one portion and the mixture became pale yellow. After 15 min healing, the mixture was cooled to room temperature and filtered through a sinter (porosity 4), with ethyl acetate washings. The filtrate was poured onto ice water (20 mL) and acidified with aqueous liydrochloric acid solution(2.0 M). The organic phase was separated and the aqueous phase washed with ethyl acetate (3 x 50 L), The combined organic phases were dried (Na2S0 ). filtered and concentrated in va o. The resulting solid was reerystaJlised from ethanol Lo afford the title compound as a colourless solid (96 mg, 58%). 1H NMR (300 MHz, CDC13) δ 1.46 6H, s, 2 x CH3), 2. 1 (3H, s, COCH3), 2.37 (3H, s, COC/W), 2.43 (3H, s, COCH3), 5.64 (1 H, d, J 10.1 Hz, H2). 7.11 (1 H, s, H9), 7.12 (1H, d, X 9.0 Hz, H6), 7.23 (1H, d, J 10.2 Hz, HI ), 7.67 (1 H, d, I 9.0 Hz, H5). Example 5
Compound 5: 9- romo-8-hydroxy-3,3-diniethyI-3 -naphtho[2,l-n]pyran- , 10-dione
Figure imgf000031_0001
A solution of bromine (354 mg, 2.21 mmul) hi dry dichloromcthaπe (4 ml-> was added dropwise to a cooled (0° C) solution of S-hydroxy-3, 3 -dimethyl- l,2-cϋlιydro-3 t'- naphtho|"2,l-b]pyrajι-7, 10-dione (506 g, 1.96 mmol) in dry dichloromethamc (4 mL) containing 3 drops of glacial acetic acid. The cooling bath was removed and the mixture was sLirred at room temperature for 20 min then concentrated in vacua to afford 9-bromo- 8-hydroxy-3,3-dimethyl-l,2-dihydro-3H-naphdιo[2,l-/?jpyran-7,I0-dione as a bright orange powder (635 mg, 96%): m.p. 213-216° C (Found: C, 53.5; H, 4,0, ClsHl3Brϋ4 requires C, 53,4: H, 3.9 %). v 3316m, 1660s, 1642s, 1364s, 12B6s, 12.62s, 1174m, 1 114s, 1048s cm-1. Η NMR (300 MHz, CDC1 ) δ 1.38 (6H, s, 2 x Clf , 1.157 (2H, t, J = 6.8 Hz, H2), 3,32 (2H, t. J = 6.8 1 , HI), 7.06 (1H, d, J = 8.6 H H5), 8.00 (LH, d, / = 8.6 H , Ho), m/z (ESt) 339 (Jvl 'BrJ+H), 337 (M^BrJ+H).
Example 6 Compound 6: 9-Bromo-8'hydroxy-3,3-dimethyl-3H-naphtho[2,l-b]pyran-7>3.0-dione Compound 7: 2,9'dibromo-l,8-dikydroxy-3,3-dimethyl-l!2-dihydro-3_ 'n p_^ιthol2}l- bJpyr n-7, 10-dione
Figure imgf000032_0001
Sodium hydride (42 mg, 80% dispersion in oil, 1.40 mmol) was washed with dry hcxaπe then the supernatant was removed. The residual solid was dried under a stream of nitrogen. A solution of 8-hydroxy-3,3-dimethyl-3/:/'-naphthof -, l- 7]pyι-an-7, 10-dione (327 mg, 1.28 mmol) in tetrahydrofuran (5 mL) was added and the resulting solution was stirred at room temperature for 10 min. This was cooled to 0" C and EX solution of bromine (265 mg, 1.66 mmol) in dry dichloromethane (3 mL) was added. Tbae mixture was allowed to warm to room temperature and stirred for 20 min, after which t-he solvents were concentrated in vacua to afford a brown residue. Rash chi'omε-itography (20-50% ethyl acetate/hexane with 1 % glacial acetic acid) afforded 9-bromo-S-hydroxy-3,3-dimethyl-3/V- naphtlιo[2,l-^]ρyran-7, 10-dione as an orange-brown solid (43 mg, 10%). (Found: M+H, 334.9909, 336.9887. C15Hι2Br04 + requires 334.9919, 336.99O0). 1H NMR (300 MHz, CDC13) δ 1.49 (6H, s, 2 x CH3), 5.99 (IH, d, J= 1 .2 Hz, H2)„ 7.05 (IH, d, J = 8.4 Hz, H5), 7.75 ( I H, bs, OH), 7.82 (IH, d, J = 10.2 Hz, HI), 8.01 (1 IH, d, J = 8.4 Hz, H6). m z (ES1+) 337 (M[s'Br]+H), 335 (ML 7*Brl+H).
Also recovered from the flash chromatography coliunn was crude compound 6 contaminated with a product of pyran ring bro ination (compound 7). This was subjected to preparative HPLC (isocratic 60%A, 40%B) and gave a coinpound suspected of being 2,9-dibrυmo-l , S-dihydroxy-3, 3 -dimethyl- /, 2-dihydro-3U.-nap?ιtho[2, 1 -b] pyran - 7, 10-dione (3 mg, 0.5%). m.p, 202.5-205° (Found: M+H, 412.9011, 414.S981 , 416.8961. LCisHiaβrjOs - H20 |+ requires 412.9024, 414.9005, 416.89871). Vπ^ 3475w, 1 64m, 1582m, 1370m, 1284s, 1262s, 1 184m, 1 122m, 1016m cm-'. S (Η) (300 MHz, CDC13) 1.59, s, CH3; 1.66. s, CH3; 4.42, d, J 3.8 Hz, H2; 4.73, bs, OH; 5.50, d, J 3.8 Hz, HI ; 7.22, d, J 8.7 Hz, H5; 8.13, d, / 8.7 H , H6. m/z (ES+, 70 V) 457 (MIK,Br][ slBrJ -Na, 13%), 455 (M[8iBrl( 7'Tir]+Na, 31), 453 (M[79BrJ[79Br]+Na, 22), 435 (Mf 1Br][ b,BrJ-».H, 7), 433 (Mt81BrR79Br]+H, 18), 431 (M[7QBrj[ 79Brl+H, 12), 417 (M["'BrJ[ SiBrl-H^O+H, 16), 415 (M[81BrR 79B |-H20+H, 36), 413 (M[79Brl[ 79Br]-H20+H, 20), 336 (M-l 75Er +H20]+H, IOO), 334 (M-[ (,1Br +H20]+H, 100).
Example 7
Compound 8: 9-Bro ^3,3-dimethyl-8-(4-methylbenzenesuIfonylnxy}-l,2-dihydro'3H- napfιtho[2fl-b]pyr n-7,10-dhne
Compound 9: 9-Bromύ-3)3-dimethyl-8-(4-methylbenzenesύlfony >xy}-3H'ruiphthυ[2,l- b}pyr n-7,J0-dione
Figure imgf000033_0001
Pyridine (0.40 mL 4.95 mmol) was added to a cooled (0° C), stirred solution of 9-bτomo-8- hydroxy-3,3-dimethyl-l,2-dihydro-3/7-naphtho[2,l-i>|pyran-7, 10-dione (550 mg, 1.63 mmol) in dry di hloromethane (10 mL) under nitrogen. A solution of 4- methylbenzenesulfonyl chloride (350 mg, 1.84 mmol) in dry dichloromethane (8 ml-) was added dropwise, then stirring wax continued for 1.5 h at 0s C Diisoprc ylethylamine (2.5 mL, 14.4 mmol) was added and stirring was continued for a further 3 h when aqueous hydroehioric acid solution (2,0 M) was added. Products were extracted witha dichlorornethaπe and ethyl acetate, and the combined extracts dried, filtered and concentrated in vacua to afford a brown solid (798 mg). Trituration of this with ethyl acetate/hcxane gave a yellow solid (610 mg) which by Η NMR spectroscopy contained - 10% of the unsulurated pyran (compound 9).
A sample of the above yellow solid (560 mg) was dissolved in ethyl acetate (30 mL) an-d. platinum (JV) oxide (25 mg) was added. The resulting mixture was stirred under aj. atmosphere of hydrogen for 8.5 h after which it was filtered through a pad of Celite® atxd the filtrate was stirred in air at room temperature overnight. Concentration in vac σ gave a brown solid which contained ~5% of the unsaturated pyran (compound 9) by JH NM. R spectroscopy. The above hydrogenation was repeated on this solid using platinum (IV) oxide (69 mg) in ethyl acetate (35 ml.) under hydrogen at room temperature overπighil. The mixture was filtered through a pad of Cclite55 and the filtrate concentrated in vacua to afford a brown residue (580 mg). This was dissolved in acetonitrile (45 mL) and a solution of eerie ammonium nitrate (617 mg) in water (20 mL) was added dropwise. The resultia-ig mixture was stirred at room temperature for 2 h and water (35 mL) was added. Oic resulting precipitate was collected by filtration, washed with water, hexane and dried uncHcr vacuum for 2 h at 40° C to give y-brυmo-3,3-dimethyL8-(4-medιy_ben7.eπesu3fonyk.x3')- l,2-dihydro-3 -naphtho[2,l -Λ]pyran-7, 10-dione as a brown solid (300 mg, 41%): iτt.p. 109-1 15° C (Found: C, 53,6; H, 4.1. C22H19Br06S requires C, 53.8; H, 3.9 ). v mB 1672s, 1580m, 1370s, 1302s, 1288s, 1222m, 1202m, 1174s, 994s, 71Ss cm"'. !H NMR (300 MHz, CDCI3) δ 1.37 (6H, s, 2 x CH3), 1,87 (2H, t, / = 6.3 Hz, H2), 2.50 (3H, s, ArCH3), 3.27 (2H, t, J = 6.3 Hz, HI), 7.11 (IH, d, J = 8.4 Hz, H5\ 7.41 (2H, d, / = 7.8 Eiϋ, H31), 7.98 (3H, app d, / =* 8. 1 Hz, 2 x H2' and H6), m/z (ESr") 493 (MfslBr|+H), 4-91 (M[79Br]+H). Example 8
Compound 9: 9-Bromo-3f3-dimethyl-8-(4^ ethylbenzene ulfonyhxy)-3H-naphC o[2,l- b]pyran-7, 10-dione
Figure imgf000035_0001
Pyridine (0.15 L 1.85 mmol) was added to a cooled (0° C), stirred solution of 9-t>-romo-8- hydroxy-3,3-dimethyl-3/i'-naphtho[2,l-fc]pyran-7, 10-dione (235 mg, 0.70 mmo in dry dichloromcthane (5 mL) under nitrogen. A solution of 4-methylbcnzenesulfonyl chloride (0.148 mg, 0.78 mmol) in dry dichloromethane (4 mL) was added dropwise, ancl stirring was continued for 1 h at 0° C. Diisopropylethylamiπe ( 1.0 mL, 5.74 mmol) was added and stirring was continued for a further 3 h when aqueous hydrochloric acid solution (1.0 M) was added. Products were extracted with dichlorome-hanc and ethyl acetate, and the combined extracts dried, Filtered and concentrated in vaciw to afford a brown solid. Flash chromatography (ethyl acetate/hexane 3:7) afforded 9-biomo-3,3-dimet-hyl-8-(4- methylbenzenesulfonyloxy)-3iϊ-naphtho[2,l-&|pyran-7, 10-dione as a brown solid (97 mg, 28%): m.p. 167-168' C (Found: M+H, 490.998, 488.999. ώHigB OήS requires- 490.999, 489.001). vm« 1672s, 1388m, 1288s, 1218m, 1172s, 1 112m, 1018m, 1004m, 732s, 706m, 688 cm'' . Η NMR (300 MHz, CDC13) fi 1.49 (6H, s, 2 x CH. , 2.50 (3H, s, ArCHj), 6.00 ( I H, d, / = 10,5 Hz, H2), 7.10 (IH, d, J = 8.4 Hz, H5). 7.41 (2H. d. 7 = 8.1 Hz, K3'), 7.69 (IH, d, J 10.5 = Hz, HI), 7.98 (2H, d, J = 8, 1 Hz, H2'), 8.00 (IH, d, / = 8.4 H., H6), m/z (ESI+) 491 (M|xlBr]+H), 490 (M[ 9Br]+H+l) Example 9:
Compound 10: 8-Bromo-3f3-dimethyϊ-9-(4-methylbenzenesulfony χy)-3 -naρhtho[2,l- b]pyran-7, 10-dione
Step 1
3,3-Dimethyl-3#-naphtho[2,l-fc]pyran-9-ol
Figure imgf000036_0001
A mixture of 2,7-dihydroxynaphthalene (33.2 g, 207 mmol), 3-ruethyl-2-bute.ιal (20.0 mL, 207 mmol) and pyridine (17.0 mL) was heated at 110° C for 20 h under nitrogen. The mixture was cooled to room temperature and diluted with diethyl ether (150 L). The organic phase was separated and washed successively with aqueous sulphuric acid solution (5%, 150 inL), water (150 mL), aqueous sodium hydrogen carbonate solution (5%, 150 mL) and water (150 mL). The organic phase was dried, filtered and concentrated in vacua to afford 3,3-dimetlιyl-3iϊ-naphQιo[2,l-fc]pyran-9-ol as a buff coloured solid (43.1 g, 92%): Η >JMR (300 MHz, CDClj) δ 1.48 (6H, s, 2 x CH3), 4.99 (IH, br s, OH), 5.67 (IH, d, J = 10 Hz, H2), 6.84-6.93 (3H, m, HI, H5, H8), 7.23 (1 H, d, J 2.3 = Hz, H10), 7.55 (IH, d, J = 8.8 Hz, H6), 7.63 (IH, d, J = 8.8 Hz, H7). m/z (FAB, 3NBA/MeOH) 227 (M+H, 68tø).
Step 2 3,3-Dime yl-3_V-naphtho[2,l- |pyran-9, 10-dione
Figure imgf000037_0001
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. After 1 1 h in total, H LC showed no starting naphthol and the mixture was filtered though a silica pad (5 x 12 cm), washing the pad with ethyl acetate until no further red colour elutcd. The filtrate was concentrated in vacua and the resulting residue recrystalliscd from ethyl acetate hexane to afford 3,3-dirnethyι- 3tf-naphtho[2, l-fc]pyran-9,10-dione. as maroon needles (14.5 g, 32%): m.p. 109-110' C. !H NMR (300 MHz, CDCI3) 6' 1.46 (6H, s, 2 x CH3), 6.00 (IH, d, J = 10.3 Hz, H2), 6.27 ( 1 H, d, J - 10 Hz, H8), 6.98 (1 H, d, / = 8.2 Hz, H5), 7.09 (IH, d, / = 8.2 Hz, H6), 7.32 (IH, d, 7 = 10.3 Hz, HI), m z (FAB, 3NBAtMeOH) 242 (M+H+l , 52%),
Step 3
9-Hydroxy-3,3-dimethyl-3 ϊ-πaphthot2,l-_7jpyran-7,10-dione
Figure imgf000037_0002
A solution of 3, 3-dimethyl-3 /-naphtho[2,l-έι]p\τ:an-9, 10-dione (14.5 g, 60.3 mmol) in toluene (S50 L) was washed Lwice with a solution of sodium riithionite (84 g) in water (850 mL). The resulting pale yellow solution was then added to a solution of potassium fcrt-buloxide (37.0 g, 330 mmol) in crt-butancl (370 mL) saturated with oxygen. The resulting mixture was stirred at ambient temperature for 30 min, after which aqueous hydrochloric acid solution (1.0 M. 250 L) was added. The organic phase was separated and extracted with saturated aqueous sodium hydrogen carbonate (3 x 250 mL). The combined aqueous extracts were cooled (ice/water bath) and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with water (1.0 L) and dried under vacuum for 2 h at 40° C to afford 9-hydroxy-3.3-dimethyl- 3/Y-naphtho[2,l-ft]pyran-7.10-dione as an orange solid (7.10 g, 46%): ]H NMR (300 MHz, CDC13) δ 1.47 (6H, s, 2 x CH3), 5.99 (IH, d, J = 10.4 Hz, H2), 6.25 (IH, s, H8). 7.1 1 (IH, dd, J = 8.4, 0.6 Hz, H5). 7.47 (IH, s, OH), 7.76 (dd, J = 10.4. 0.6 Hz, HI), 7.97 (IH, d, / = 8.5 Hz, H6. /z (FAB, 3NBA/MeOH) 258 (M+H+l. 50%), 257 (M+H, 100).
Step 4
8-BromcH3,3-dimethyl-9-(4-methylbenzcncsulfoιιyloxy)-3/V-naphtho[2,l-fr]pyran-7,10- dione
Figure imgf000038_0001
Sodium hydride (12 mg, 80% dispersion in oil, 0.40 mmol) was added to a solution of 9- hydroxy-313-dimcthyl-3H-naphtho[2,l-&]pyran-7,10-dione (100 mg, 0.39 mmol) in tetrahydrofiiran (2 mL) and the mixture was stirred at room temperature for 10 min, The suspension was cooled to 0° C, and a solution of bromine (70 mg, 0,44 mmol) in dichloromcthane (1 mL) was added. The orange solution was allowed to warm to room temperature then stirred for 20 min. Aqueous hydrochloric acid solution (1.0 M) was added and the product was extracted with dichloromethane and ethyl acetate, The combined organic phases were dried, filtered and concentrated in vacua to give a brown residue (129 mg, 99%), Pyridine (25 μL, 0. 1 mmol) was added to a cooled (0s C), stirred solution of the above 8- bπ)mo-9-hydroxy-3)3-dimethyl-3f/-naphfho[2,l-/7]pyπιn-7.10-dione (25 mg, 0.07 mmol) in dry dichloromethane ( 1 mL). A solution of 4-π.cthylbenzenesulfonyl chloride (17 mg, 0.09 mmol) in dry dichloromethane (1 mL) a added dropwise, then stirring was continued for 1 h at 0° C. Diisopropylethylamine (115 μl-, 0.66 mmol) was added and stirring was continued for a further 3 h when aqueous hydrochloric acid solution (1.0 M) was added and the mixture extracted with dichloromethane and ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to afford 8-bromo- 3,3-dimemyl-9-(4-methylbenzenesulfonyloxy)-3/V-naphthor2,l-i>Jpyran-7, 10-dione as a brown solid (35 mg, 95%): m.p. 181.5-184° C (Found: C, 54.0; H, 3.5. C^HπB OoS requires C, 54.0; H, 3.5 %). v1Mλ 1678m, 1382s, 1294s, 1285s, 1183m, 1128m, 1062m, 986m, 806s, 682s. 564m cm"1. Η NMR (300 MHz, CDC ) δ 1.49 (6H, s, 2 x CH3), 2.50 (3H, s, A1CH3), 5.98 (IH, d, ,/ = 10.5 Hz, H2), 7.09 (IH, d, J = 8.4 Hz, H5), 7.41 (2H, d, J = S.3 Ha, H3'), 7.70 (1 H, d, .7 = 10.5 H?, HI), 7.98 (2H, d, / = 8.3 Hz, H2'), 8.04 (IH, d, / 8.4 Hz, H6), m z (ESf) 491 ( [8iBrl+H), ( 7°Br]+H)
Example 10
Compound 11: 8-Bromo'3,3'dimethyl-9-(4-methylbenzencsulfonyloxy)-li2-dϊhydro-3U- naphtha[2, l-bjpyran -7,10-dion e
Figure imgf000039_0001
Platinum (IN) oxide (25 mg) was added to a solution of 8-bromo-3,3-dimethyl-9-(4- methylbeni.encsuifonylo\y)-3i: -naphtho[2,l-i]pyran-7, 10-dione (199 mg, 0.41 mmol) in ethyl acetate (8 mL) and the resulting suspension was stirred under an atmosphere of hydrogen for 28 h. The reaction was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate and dichloromethane. The filtrate and washings were combined, dried, filtered and concentrated in vacua to afford a brown residue which was dissolved in acetonitrile (20 mL) and cooled to 0° C, A solution of eerie ammonium nitrate (200 mg, 0.36 mmol) in water (6 mL) was then added and the mixture was allowed to warm to room temperature and stirred for 2 h, after which it was diluted with water. Products were extracted with dichloromethane. and the extract dried, filtered and concentrated in vacua to afford 8-bi'omo-3,3-dιmethyl-9-(4- methylbenzcnesulfonyIoxy)-l,2-dihvdro-3/ -naphthof2,l-^]pyran-7, 10-dione a-s an orange-brown s>olid (193 mg, 97%); m.p. 168-169.5' C (Found: C, 53.6; H, 3.8, ∑iHiflBrOβS requires C, 53.8; H, 3.9 %)• Vm„ 1680s, 1668m, 1620m, I578w, 1566w, 1382s, 1290s cm"1. lH NMR (300 MHz, CDC1.,) δ 1.37 (6H, s, 2 x CH3). 1.87 (2H, t. J = 6.2 Hz. H2), 2.50 (3H, ArCH3), 3.27 (2H, t, J = 6.2 Hz, HI), 7.10 (I H, d, 7 8.6 = Hz, H5), 7.41 (2H, d, J = 7.7 Hz, H3'), 7.97 (2H, ά, J = 7.7 Hz, H2'), 8.03 (IH, d, J = 8.6 Hz, H6). rn/z (ESI+) (Mf81Brl+H), 491 (M^Brj+H).
Example 11
Compound 12: 8,9-Dichloro-3,3-dimelhyt -l,2-dihydro-3H-naphtho[2,l-bJpyran-7,10- dione
Ste l
9-Hydroxy-3,3-dimcthyl-l ,2-dihydro-3/V-rιaphtho[2,l-ύJpyran-7, 10-dione
Figure imgf000041_0001
A mixture or 9-hydrσxy-3,3-dimeύιyl-3#-naphtho| 2,1 -b]pyran-7, 10-dione ( 1.20 g, 4.6 rnmol) and platinum(rV) oxide (125 mg) in ethyl acetate (30 mL) was stirred under hydrogen for 3.5 h. The dark mixture was allowed to stir exposed to air for 30 min before filtration ihrough a plug of Celiιec. Concentration of the filtrate in vacua gave a yellow residue which was subjected to flash chromatography (ethyl acetate/hexane 7.3 with 1% glacial acetic acid) followed by recry tallisation from ethyl acetate/hexane to give 9- hydroxy-3,3-dimethyl- 1 , 2-dihydro-3ff-naphtho[2,l-£"|pyi,an-7, 10-dione as yellow needles (948 mg, 79%): m.p. 155° C (subL), >177° C (dec). v∑nax 3328, 3148, 3108, 1656, 1628, 1566 cm-1 , Η NMR (300 MHz, CDCI3) δ 1.38 (6H, s, 2 x CH3), 1.89 (2H, I, J = 6.5 Hz, H2), 3.29 (2H, I, J = 6,5 Hz, H3), 6.25 (IH, s, H8), 7.13 (1 H, d, J = 8.5 Hz, H5), 7.47 (IH, s, OH), 7.97 (IH, . ,/ s g.5 Hz, H6). m/z (FAB, 3NBA/MeOM) 261 (M+H+2, 11%), 260 (M+H+l, 27%), 259 (M+H, 51).
Step 2
9-Chloro-3,3-dimeLhyl-l,2-dihydro-3fV-naphtho|2,l -^]pyran-7,10-dione
Figure imgf000041_0002
9-1 Iydroxy-3,3-dimcthyl-l ,2-dihydro-3//-naphtho[2,l--7lpyran-7, 10-dione (1.1 g, 4.3 mmol) as dissolved in dichloromethane (20 mL) and thionyl chloride (15 mL). The reaction ω stirred at room temperature for 24 h and the volatile? were removed ι>ι vacua. The residue was dissolved in ethyl acetate (30 ml.), washed with water (30 L), dried, filtered and concentrated in vacua. The residue was purified by flash chiomatography (ethyl acetate/hexane 5:95) followed by recrystallisation from ethanol to give 9-chloro-3,3- dimethyl-l ,2-dihydro-3i2r-naphthof2,l-/j]pyran-7, 10-dione as orange needles (633 mg, 53%): m.p. 140-2° C (Found: C, 64.9; H,4.8. C15H13CIO3 requires C, 65.1; H, 4.7%). λm-A (log e) 216, 268, 350 sh, 412 nm (4.35, 4.25, 3.23, 3.44). vmω 37OO-3300s br, 3070w, 30OOw, 1 80s, 1660s, 1620m, 1590m, 1580s cm"1. Η NMR (300 MHz, CDC1,) 8 1.38 (6H. s, 2x CH3), 1.88 (2H, t, / = 7,0 Hz, H2), 3.29 (2H, t, J = 7.0 Hz, HI), 7.12 (IH, d, / = 8.5 Hz, H5), 7.12 (IH, s, H8), 7.95 (IH, d, ./ = 8.5 Hz, H6). m z (FAB, 3NBA 280 (MΓ37C1J+H+1, 14%), 279 (MFCIJ+H, 40), 278 (Ml-"C1]+H+ 1 , 49), 277 (M[35CIJ+H, 100), 276 (44), 233 (17).
Step 3 8,9-Dichloro-3,3-dιmethyl -l,2-dihydro-3r -πaphthoL2.1-blpy)τin-7, 10-dione
Figure imgf000042_0001
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 foτ 5 min. The reaction was stirred for 55 min at 70° C, cooled to room temperature and concentrated in vacua. The residue was purified by flash chromatography (tolucne/hexaiic 7:3) to give 8,9- dichloro- 3,3-dimethyl - l,2-dilιydro-3H-naphtho[2,l-i»Jpyran-7,J 0-dione as an orange solid (508 mg, 71%). A sample of this material was recrystallised from ethanol to give orange micro- cry ials: m.p, 158-60° C (Found: C, 57.9; H, 3,7. C15H12CI2O3 requires C. 57.9; H, 3.9%). λmdX (log ε) 220, 275, 290 sh, 350 sh, 412 n (4.32, 4.19, 4,01 , 3.29, 3.38). vmax 3700- 3330m br, 3050m, 2950m. 1700s, 1680m, 1600m, 1580s cm"1. Η NMR (300 MHz, CDClj) δ 1.38 (6H, s, 2 x CH3), 1.88 (2H, t, J = 7.0 Hz, H2), 3.27 (2H, t, J = 7.0 Hz, HI), 7.12 (IH, d, 7 = 8.5 Hz, H5), 8.04 (l ύ, J = 8.5 Hz, H6). m/z (FAB, 3NBA) 315 (M 7Cl ]+H, 16%), 314 (M[37Q35CIJ+H+1, 32), 313 < CI3sCl|+H, 74), 312 (Mp5Cl2]+H+l , 64), 311 (M[3-SC12]+H, 100), 310 (42), 309 (16).
Example 12
Compound 13: Sodium 3!3-dimethyl-7f]0-dioxθ'7!10-di}ιydro-3H-benzo[f]chromen-8- olate or Sodium 3,3-dimethyt-7,8'dioxσ-7,8-dikydro-3H-benz [f]chr men-10-okιte
Figure imgf000043_0001
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), rύtered (porosity 4 sinter) and freeze dried for 48 h. Compound 13 was obtained ΓΛ a red solid (1.80 g, 96%): JH NMR (300 MHz, DύDMSO) δ 1.38 (6H, s, 2 x CH3), 5.26 (IH, s, H9), 5.82 (IH, d, J = 10.2 I f ., H2), 6.83 (IH, ύ, J = 8.4 Hz, H6), 7.64 ( IH, d, J = 8.4 Hz, H5), 8.14 ( IH, d, / = 10.2 Hz, H I), m/z (ES*, 30 V) 257 (M-Na+H, 100%); HPLC 1 0%/ 4.74 min.
The [H NMR can also be run in DzO, compound 13 is fully soluble in water at 10 mg/rnL HPLC Conditions Performed on Water 2690 Alliance System, using a Waters C18 5 μ Symmetry Column
(Part # WAT046980) and a flow rate of 0.7 inL/min. Column temperature of 30α C and measured at λ=254 nM,
Buffers:
Buffer A: 100% water
Buffer B: 100%
Buffer C: 2 % aqueous formic acid
Gradient (linear gradient curve "6") 10 min 5 mm 45% A:50% B:5% C —*- 95% 3 5% C — ■ »- 95% B:5% C
Figure imgf000044_0001
45% A 50% B:S% C ** 45% A;50% S:5% C
Example 13
Compound 14: 8-Hydroxy-3-methyl-3-phenyl-3H-benzolf]chτomene-7,10-dwne
Ste l
3-Methyl-3-phenyl-3 r/-benzol Jchromen-8-ol
Figure imgf000044_0002
A stirred suspension of 2,6-dihydroxy naphthalene (71 mg, 4.47 rnmol) in toluene (200 mL) was heated to reflux (oil bath temperature 160° C). After 1 h, the mixture was homogeneous and p-toluene sulphonic acid hydrate (54 mg, 0.40 mmol) was added followed by a solution of 2-phenyl-but-3-yn-2-ol (588 mg, 4.02 mmol) in toluene (50 mL) over 20 min while maintaining reflux. TLC (ethyl acet te/hκ.ane 1:4) after 4 h showed very faint 2,6-dihydroxy naphthalene. After a further 2 h, the mixture was cooled to room temperature and washed with aqueous sodium hydroxide solution (10%, 400 ml-). The organic phase was diluted with ethyl acetate ( 100 mL), dried (Na2S04), filtered and concentrated t ι vacua to afford a black semi-solid (804 mg). This was dissolved in ethyl acetate/hexarieΛlichloromethane/methanαl (1 mL: 4 mL: 1 mL: 1 L) and subjected to flask chromatography, eluting with ethyl acetatehexane 1:4. 3-Methyl-3-phcnyI-3Η- bcn7.o[ jchiOmen-S-ol was obtained as a brown solid (230 rngτ 18): MS (ESI) m/z 287 (M- 1). HPLC 99.3 %/ 7.58 min
Step 2
3-Mcthyl-3-phenyl-3i: -ben7.o[f]crιromene-7,8-dione
Co(SALEN)a2,> O w2
Figure imgf000045_0001
Figure imgf000045_0002
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. Volatiles were removed i t vacua to afford 3-methyl-3-phenyI-3 -beπzo[f]chromeπe-7,8- dione as an orange solid (228 mg, 100%): Η NMR (300 MHz, CDCL) 5 1.86 (3H, s, CH?), 6.25 (IH, d, J = 10.2 Hz, H2), 6,43 (IH, d, / = 10.5 H?„ H9), 6.85 (IH, ά, J = 10.2 Hz, HI), 6.97 (IH, d, / == 8.4 Hz, H6), 7.35 (51 f, m, ArH), 7.72 (IH, d, / = 10,5 Hz, H9), 7.99 (I H, d, J = 8.4 Hz, H5) MS (ESf) m/z 303 (M+l). Step 3
8-Hydroxy-3-mcthyl-3-phenyl-3//-benzo[ ]chromene-7, 10-dionc
Figure imgf000046_0001
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. The precipitate was collected by filtration and washed with water (30 L) then dried overnight under vacuum to afford 8-hydroxy-3-n.ethyl-3-phenyl-3.fY- " bcnzo | ] ch o ene-7, 10-dione as an orange solid (27 mg, 82%); Η NMR (300 MHz, CDCI3) δ 1.84 OH, s, CHJ), 6.22 (I H, s, H9), 6,26 (IH, d, 7 = 10.5 Hz, H2), 7.14 ( M l, d, J = 8.7 Hz, H6), 7,20-7.45 (5H, m, ArH), 8.05 (2H, , H5 and HI). MS (ESQ m z 'ill (M- 1 ). HPLC 100 %/ 7.12 min.
Example 14 Compound 15: 8Ηydroxy-3,3-diphenyl-3H-benzυ[f]chromene- 7, li dione
Step 1 3,3-Diphenyl-3H-benzol ]chromcn-S-ol
Figure imgf000047_0001
A stirred suspension of 2,6-dihydroxy naphthalene (502 mg, 3.13 mmol) in toluene (200 mL) was heated to reflux (oil bath temperature 130n C). After 1 h, the mixture was homogeneous and -toluene sulphonlc acid hydrate (54 mg, 0.28 mmol) was added followed by a solution of l ,l-diphcny!-prop-2-yn-l -ol (588 mg, 2.82 mmol) in toluene (40 mL) over 30 min while maintaining reflux. After 2 d, the mixture was cooled to room temperature and washed vvith aqueous sodium hydroxide solution (10%, 400 mL). The organic pha.se was diluted with ethyl acetate (200 mL), dried (Na_S0 ), filtered and concentrated in vacua to afford a black solid. This was dissolved in elύorσroiTn/hexaπe (5 mL; 5 ml.) and subjected to flash chromatography, eluting with chloroforrn/hexanc 1 : 1 then neat chloroform. 3,3-Diphenyl-3iY-ben o[ ]chromen-8-ol was obtained as a brown solid (213 mg, 19%); MS (ESI") m/z 287 (M-l). HPLC 80.3%/ 8.89 min
Step 2
3,3-Diphenyl-3iy-ben2ol Jduomene-7,8-dione
Co(SA EN)2, 02
Figure imgf000047_0002
Figure imgf000047_0003
Co(SALEN)2 (22 mg) was added in one portion to a stirred homogenous yellow solution of 3,3-diphenyl-3iY-bcnzo|yichronιen-8-o! (213 mg, 0.61 mmol) in acetonitrile (3 L). Oxygen was bubbled through the mixture and after 3 h the mixture was filtered tlirough a silica plug, washing the plug with ethyl acetate until no further colour eluted. Volatiles were removed in vacua to afford brown solid which was dissolved in dichloromethane and the solution subjected to flash chromatography, elutiπg with neat dichloromethane. 3,3- Diphenyl-3iY-be-ιzo[/lchromene-7,8-dione was obtained as an orange solid (32 mg, 14%). MS (ESrVn/z 365 (M+l).
Step 3
8-Hydroxy-3,3-diphenyl-37Y-ben-.o[ lchromcne-7, 10-dione
Figure imgf000048_0001
Aqueous sodium hydroxide solution (4 M, 3 mL) was added to stirred orange suspension of 3,3-diphenyl-3iY-bcnzό[ 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). This residue w s dissolved in ethyl acetate (5 mL) and filtered though a silica plug, eluting the plug with ethyl acetate (150 mL) then ethyl acetate/acetic acid (30:1), collecting 3 15 L fractions. Fractions 1 and 2 were combined and concentrated in vacua to afford 8-hydroxy-3,3-diphenyl-3 Y-be .o[ ]cliromcne-7,10-dione as un orange solid (6 mg, 24%). {H NMR (300 MHz, CDC13) δ 6.23 (IH, s, H9), 6.45 (I H, d, J = 10.4 Hz, H2), 7.20 (IH, d, 7 = 8,4 Hz, H6), 7.40 (10H, m, ArH), 8.00 (IH, d, 7 = 8.4 Hz, H5), 8.16 (IH, d, 7 = 10,4 Hz, HI). MS E&t) m/z 381 (M+1). HPLC 86.5%/8.81 min,
Antiviral Activity
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 10th day, viral DNA in the supernatant was measured and the reduction in the amount of virus in the supernatant waϋ 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.
Table 1
Figure imgf000050_0001
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 DΝA 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 μmol-ir is designated +, 50% core reduction at less than 50μmolar is designated ++ and 50% core reduction at less than lOμmolar compound concentration is designated +++.
Table 2
Figure imgf000051_0001

Claims

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) or a pharmaceutically acceptable derivative, salt or prodrug thereof:
Figure imgf000052_0001
(1) wherein X is OH, OR9 or halo: R and Rj are independently selected from H, Cj.galkyl, C2.ealkeιιyl, C2.f,alkynyl, C3.ftcycloalkyl, aryl, or together with the carbon atom to which they arc attached form a saturated or unsaturated C^carboc clic ring; R2 and R3 are independently selected from H, Ci-oalkyl, C2.f,alkenyl, C^alkynyl, C3.6θycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond; R and R5 are independently selected from H, Cs-oalkyl, C2^alkenyl, C2.&alkynyl, C3_ήCycloal yl, OH, OR9, halo or N ioRio or together with the bond between the carbon atoms to which they are attached form a double bond; Re and R7 are independently selected from H, Cι.r,a!kyl, Ci-salkenyl, C2.galkynyl, C^cycloalkyl, OH or OR9; Rg is independently selected from H, Cι.6alkyl, C^salkenyl, C2 oalkynyl, C3.scycloal yI, OH, ORg or halo; Ry is C alkyl, C2.ca!kenyl, C2.nalk.ynyl, C^cycloalkyl, aryl, C(=0)Rπ or S(0)2R;2 or 0R9 is an amino acid residue; each Rio is independently selected from H and Cualkyl;
R11 is Ci.ji lkyl, C2.ϊialkeπyl, Qj.aialkynyl,
Figure imgf000053_0001
aryl or arylCi.βalkyl; and
R12 is C ,alkyl, C_.ftalkcnyl, C2.fialkynyl or aryl.
A method according to claim 1 wherein the compound of formula (1) is a compound of formula (2):
Figure imgf000053_0002
R and Ri are independently selected from H, Cι.calkyl, Cj-oalkenyl, C2.fialky-.yl, C3.6cyeloa.kyl, aryl, or together with the carbon atom to which they arc attached form a saturated or unsaturated C^carbocyclie ring; R and 3 arc independently selected from H. Cualkyl,
Figure imgf000053_0003
C3.(jCycloalky] or togetlier with the bond between the carbon atoms to which they are attached form a double bond; R4 and Rs arc independently selected from H, Ct.ualkyl, C..6alkcny], C2.ήalkynyl, C3.6cyeloalkyl, OH, 0R , halo or NR10R10 o together with the bond between the carbon atoms to which they arc attached form a double bond; R9 is Cualkyl, C^alkenyl, C2.6alkynyL C3.Geycl0a.kyl, aryl, C(=0)Ru or S(0);>Ri2 or 0R9 is an amino acid residue; each Rio is independently selected from H and Cj-βalkyl; Rπ is Cj.ai&lkyl, C2 21 alkenyl, C2.2ιalkynyl, C3.(,cycloalkyl,
Figure imgf000054_0001
aryl or arylCi.galkyl; and [2 is C alkyl, Ca^alkenyl, C2-tsaIkynyl or aryl.
3. The method of claim 1 wherein the compound of formula (1) is selected from the group consisting of: 8-hydroxy-3,3-dimcthyl-3iϊ-naphtho[2,l-έ'Jp)'ran-7, 10-dione, 8-hydroxy-3,3-dimethyl-l,2-dihydro-3r/-naphtiιo[2,l-fe]pyτan-7,10-dionc, 9-bromo-8-hydroxy-3,3-dimethyl-1 ,2-dilιydro-3H'-naphfiιo[2,l-/?]pyran-7, 10-dione, 9-bromo-8-h\droxy-3,3-dimethyl-3H-naphtho[2, l- 5]pyran-7,10-dione, 9-bromo-3,3-dime-hyl-8-(4-mctlιy!hen2cnesulfonyloxy)-l,2-dihydro-3tV-naphtho[2 , 1 -fr]pyran-7 , 10-dione , 9-bromo-3,3-dime0ιyl-8-(4-mcthylbenzcnesulfonyloxy)-37/-naphthor2,l-fc]pyran-7 , 10-dione, S-acetoxy-3,3-dimelhyl-3/:/-naphtho[2)l-Z5]pyran-7,10-dione, 2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-l ,2-dihydro-3//-naphLho|2,l -J7]ρyran-7,l 0-dione, 8,9-dichloro-3,3-dimethyl-l,2-dihydro-3rY-naphtho[2,l-&lpyran-7,10-dionc, 7,8,10-triacetoxy-3,3-dimethyl-3 /-naphtlιo|2,l-b]pyran, 9-Bromo-8-hydroxy-3,3-dimcthyl-3ii'-naphthof2, l- ?]pyran-7, 1 -dione, 9-Bromo-8-hydroxy-3,3-dimethyl-3/Y-naphthol2,l-έlpyran-7,10-dioπe, 9-Bromo-3,3-dimeUιyl-8-(4-mcthylbem_cnesulfonyloxy)-l,2-dihydro-3 ϊ- naphtho[2, 1 -Λ]pyran-7, 10-dione. 9-Bromo-3,3-dimethyl-8-(4-methylben7.encsulfoπyloxy)-3/V-naphtiιo[2,l-ι-'|pyran- 7, 10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloχy)-3/J-naphthol2,l -^]ρyran- 7, 10-dione, 8-BromcH3,3-dimethyl-9-(4-methylbeni.encsulfonyloxy)-l ,2-dihydro-3 - naphtho^.l-i-Jpyran-V.lO-dione, S,9-Dielύoro-3,3-dimethyl -l,2-dihydro-3Λr-naphtho[2,l-έ'|pyran-7, 10-dione, Sodium 3,3-dimethyl-7,l0-dioxo-7,10-dihydro-3H-benzol Jchromen-8-olate; Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3//-benzo [β lιromen-10-olate 8-Hydroχy-3-methyl-3-phenyl-3H-benzo[f]clιromcne-7,10-dionc, and 8-Hydroxy-3,3-diphenyl-3H-benzoj Jchromene-7, 1 -dione.
A method according to claim 1 wherein the compound of formula (1) is selected from the group consisting of:
8-hydroxy-3,3-dimelhyl-3Λf-naph-hoL2,l- ?lpyπin-7, 1 -dione, 8-hydroxy-3,3-dimcώyl-l,2-dihydro-3i:i'-naphthoL2,l-->]pyran-7, 10-dione).
The method of claim 1 wherein the compound of formula (1) is a compound of formula (3):
Figure imgf000055_0001
(3) wherein X is OH, OR9 or halo R and i are independently selected from H, halk ., C2.5alkcnyl, Cj-galkynyl, C3.6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated Cj.gcarbocyclic ring; R2 and R.i are independently selected from H, Ci-ftalkyl, C2.ealken l, C2.6alkynyl, C?_<,cycioallcyl or together with the bond between the carbon atoms to which they are attached form a double bond; 4 is selected from H, mal yl, C2^alkenyl, C2.fial ynyl. Cj.6cyclαalkyl, halo or NR10R10 or together with R5 and the bond between the carbon atoms to which R4 and R5 arc attached, form a double bond; Rs is selected from H, C|.fialkyl, Cj.ealkenyl, C2^al n l, C3.c,cycloalkyl, OH, 0R9, halo or N io io or together with R4 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond; Rfi and R7 are independently selected from H, Cj.ealkyL Cz-ftalkenyl, C2.ealkynyl, C3^cycloalkyl, OH or OR9; R8 is independently selected from H,
Figure imgf000056_0001
C2.&alkcnyl, C2-6al n l, C3.6Cycloalkyl, OH, OR9 or halo; R<? is Ci oalkyl, C2.tialkeπyl, C3 ^ILynyl, C3_iCycloalkyl, aryl, C(=0)R» or S(0)2Rι2 or ORy is an amino acid residue; each R O is independently selected from H and C^alkyl; Rii is Ci.zial yl, C?.2ialkeπyl, C2.21 alkynyl, C3_scycloalkyL C3.6c c.oal lCι-<; l yU aryl or arylCi.galkyl; and R12 is Cι.6alkyl, C2 oalkcnyl, C^alkynyl or aryl.
6. A method according to any one of claims J to 5 further comprising administering a second therapeutic agent.
7, A compound of Formula (1) or a pharmaceutically acceptable derivative, salt or ' prodrug thereof:
Figure imgf000057_0001
(I) wherein X is OH, O y or halo;
R and Ri are independently selected from H, C^alkyl, C2.0a.kcuy!, Cj.galkynyl, C3.6cycloalkyl, aryl. or together with the carbon atom to which they are attached form a saturated or unsaturatcd Cs-Λcarbocyclic ring;
R2 and R3 are independently selected from H, Cι.&alkyl, -sal en l, C2.ήal π l, C3.f,cycloalkyl or togetlier with the bond between the carbon atoms to which they are attached form a double bond;
R4 and R5 arc independently selected from H, Cι.6alkyl, Ci.ealkenyl, C2-salkynyl, C^cycloalkyl, OH, ORo, halo or NR10R10 oτ together with the bond between the carbon atoms to which they arc attached form a double bond; R9 is Chalky), C2.<;alkenyl, C^alkynyl, C3.6cycloalkyl, aryl, C(=0)Rn or S( )2Ri_ or ORy is an amino acid residue; each Rio is independently selected from H a R is Cι-2taLkyl, Ca-aialkcnyl, C2_2ιalkynyl,
Figure imgf000057_0002
aryl or arylC|.f,alkyl; and R]2 is Ci oalkyl, C2.ήalkeπyl, C2.6alkyr. J or aryl; with the proviso that when R and Ri are both methyl and R is OH or OR9, Rs is not selected from OH, ORy or NHR9.
A compound according to claim 7 wherein the coinpound of Formula (1) is a compound of formula (2):
Figure imgf000058_0001
R and Ri are independently selected from H, Ci^alkyl, ∑-dal cn l, C^^alkynyl,
C3.(jcycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsalurated Cj_scarbocyclic ring;
R2 and R3 are independently selected from H, C|.ή-dkyl, C2.6alkenyl, C2-e,alkynyl,
C3^cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
R4 and Rs are independently selected from H,
Figure imgf000058_0002
C2.o"Ikcnyl, C2.<$alkynyl,
C3^cycloalkyl, OH, OR9, halo or NRioRto "f together with the bond between the carbon atoms to which they are attached form a double bond; _t, and R7 are independently selected from H, .eαlkyl, ftal en l, Ca-βalkynyl,
Cs-ccycloalkyl, OH or ORo;
R8 is independently selected from H, C^alkyl, C2.c,alkenyl, C^alkynyl,
C3.6cycloalkyl, OH. OR9 or halo;
Ru is Ci.salkyl, Cj.fialkenyl, C2-salkynyl, C.^cycloalkyl, aryl, C(=0)Rπ or S(0)2Ri2 or OR9 is an amino acid residue; each Rio is independently selected from H and Ci.u . yl;
Rπ is Chal !, C2.21all.enyl, C2.21 alkynyl,
Figure imgf000058_0003
aryl or arylCi-saJkyl; and
R12 is
Figure imgf000058_0004
or aryl, A compound according to claim 7 wherein the compound of formula (1) is selected from the group consisting of:
S-hydroxy-3,3-dimctlιyl-3 ϊ-naρhtho[2,l-&]pyran-7,10-dione, 8-hydroxy-3)3-diιnethyl-l ,2-dihydro-3 -naphtho[2,l-Z»lpyi'an-7, 10-dione, 9-bromo-8-hydπ>xy-3,3-dimethyl-l,2-dilιydro-3 -naphtho[2,l-Λ]pyran-7, 10-dione,
9-bromo-8-hydroxy-3,3-dimethyl-3H-naphthoL2,l-&Jpyran-7, 10-dione,
9-bromo-3,3-dLneihyl-8-(4-methylben-enesulfonyloxy)-l ,2-dihydro-3ri,-naphthor2
,l -&lpyran-7, 10-dione,
9-bromo-3,3-dιmethyl-8-(4-methylben7.encsulfonyloxy)'3/τT-naphtho[2, l -^lpyran-7 , 10-dione,
8-acetoxy-3,3-dimeihy_-3/ϊ-naph.ho[2 -<->]pyran-7,l 0-dione,
2,9-dibromo- l ,8-dihydroxy-3,3-dimethyl-l ,2-dihydro-3iϊ-naphLhol2, l-t>lpyrau-7,l
0-dione,
8,9-dichloro-3,3-dimethyl-l ,2-dihydro-3//-naphtho['2,1 -/;]pyran-7, 10-dione, 7,8,10--riacetoxy-3,3-dimethyl-3/^-naphαιo[2, l-b]pyran,
9-Bromo-8-hydroxy-3,3-dimethyl-3/ϊ-naphαιol2,l-&]p>τan-7, 10-dione.
9-Bromo-8-hydroxy-3,3-dimctlιyl-3/i-naphtho[2.1- ]pyran-7,10-dionc.
9- romo-3,3-dimcthyl-8-(4-me ylbenzeπesulfoπyloxy)-l,2-dihydro-3H- naphtho[2,l- ]pyran-7, 10-dione. 9-Bromo-3,3-dimethyl-8-(4- eαιylberizenesulfonyloxy)-3iϊ-naphthoL2,l--- ]pyran- 7, 10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbeni.enesulfonyIoxy)-3/?-naphtho[2, 1 -ύlpyran- 7, 10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzencsulfonyloxy)-l,2-dihydro-3/i- naphtho[2,l-^lpyran-7, 10-dione, 8,9-Dichloro-3,3-dim ethyl ~l ,2-dmydro-3tf-naphtho[2,1 -fc]pyran-7, 10-dione, Sodium 3,3-dimcthyI-7,10-dioxo-7,10-dihydro-3/3r-benzo[ ]chromen-8-olate; Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3/£-"-beni.o lchromen-10-o!ate; S-Hydroxy-3-nιethyl-3-phcnyl-3H-ben .oI ]chromene-7, 10-dione, and 8-Hydroχy-3,3-diphenyl-3H-benzo[/]chromene-7, 10-dione.
0. A compound according to claim 7 wherein the compound of formula (1) is selected rrom the group consisting of: 8-hydroxy-3,3-dimethyl-3Hr-naphthoL2!l-fclpyran-7, 10-dione, 8-hydroxy-3,3-dimcthyl-l,2-dihydrcj-3 ϊ-naphtho[2,l-fc]pyran-7,10-dione).
1. The compound of claim 7 wherein the compound of formula (1) is a compound of formula (3):
Figure imgf000060_0001
(3) wherein X is OH, ORy or halo R and i are independently selected from H,
Figure imgf000060_0002
Ci.&alkcnyl, Cz sall ynγl, C3-scycloalkyl, aryl, or together witli the carbon atom to which they are attached form a saturated or unsaturatcd C^carbocy ic ring; R2 and R3 are independently selected fiom H,
Figure imgf000060_0003
C2 $alkenyl, Cj f,alkynyl, C3.(,cycloa!kyl or together with the bond between the carbon atoms to which they are attached form a double bond; R4 is selected from H, Chalky!, C2.fialkeπyl, C2-fia. yn l. C3-6cycloalkyl, lialo or NRt Rio or together with 5 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond; Rs is selected from H, Cι-f>alkyl, Ca-βalken l, C2.6alkynyl, C -ficycloalkyl, OH, ORu, halo or N io i or together with 4 and tiic bond between the c irbon atoms to which R4 and R5 are attached, form a double bond;
Ro and Rη are independently selected from H, Ci-ήalkyl, C2.6alkeiiyl, C2_salkynyl, C3.6cycloalkyl, OH or 0R9; g is independently selected from H, Ci^alkyl, Qz.-alkenyl, C2-nalkynyI, C. ^cycloalkyl, OH, OR9 or halo;
R9 is Ci-salkyl,
Figure imgf000061_0001
or OR9 is an amino acid residue; each RJO is independently selected from H and Ci^alk l;
Rn is Cι-2ialkyl, C2.21a-kc1.yl, C2.2ialkynyl, C3 gcycloalkyl,
Figure imgf000061_0002
aryl or arylCι.6alkyl; and
Ri2 is Ci.ftalkyl, C^alkenyl, C2-<,al n l or aryl.
A pharmaceutical composition comprising a compound according to any one of claims 7 to 11 and a pharmaceutically acceptable carrier, diluent orr excipient.
PCT/AU2005/000453 2004-03-31 2005-03-31 Antiviral agents WO2005095376A1 (en)

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