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WO2006007634A1 - Procédés et produits intermédiaires - Google Patents

Procédés et produits intermédiaires Download PDF

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Publication number
WO2006007634A1
WO2006007634A1 PCT/AU2005/001040 AU2005001040W WO2006007634A1 WO 2006007634 A1 WO2006007634 A1 WO 2006007634A1 AU 2005001040 W AU2005001040 W AU 2005001040W WO 2006007634 A1 WO2006007634 A1 WO 2006007634A1
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compound
optionally substituted
formula
ome
group
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PCT/AU2005/001040
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English (en)
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David J. Owen
Mark A. Rizzacasa
Mariana El Sous
Marisa Spiniello
Peter J. Scammells
Georgina Holloway
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Cerylid Biosciences Ltd
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Publication of WO2006007634A1 publication Critical patent/WO2006007634A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/12—1,4-Dioxanes; Hydrogenated 1,4-dioxanes not condensed with other rings

Definitions

  • the present invention relates to synthetic processes for the preparation of compounds bearing a dioxanyl moiety, in particular to compounds bearing a dioxanyl side chain attached to a mono- or polycyclic core moiety, more particularly a cyclopentabenzofuran core moiety.
  • the invention also relates to intermediate compounds used in these processes.
  • Compounds which can be prepared by the process of the invention can be used as candidates for screening for potential therapeutic activity, thus the invention also relates to compounds obtainable or prepared by the methods described herein, in particular to those having cytotoxic or cytostatic activity.
  • the genus Aglala ⁇ Meliaceae comprises over 100 (mostly woody) species occurring in Indo-Malaysia and the Western Pacific region. Isolable from extracts of many
  • Aglaia species are a family of cyclopentabenzofuran lignan compounds known as rocaglamide derivatives, the first such described compound rocaglamide (1) itself which was shown to have significant antileukemic activity against P388 lymphocytic leukemia in CDF mice (US Patent No. 4,539,414) .
  • Insecticidal compounds with a closely related core structure were isolated from Aglaia roxburghiana and are described in WO 96/04284 for use as active ingredients in agrochemical formulations.
  • A is an optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety
  • Z 3 is OR 3 and Z 4 is H, or Z 3 is H and Z 4 is OR 3 ; and R 1 to R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group, a C-I linked saccharide and a protecting group; or
  • R 1 and R 2 together with the oxygen atoms to which they are attached form an optionally substituted 5 to 6 membered ring comprising the step of: (i) coupling the compound of formula (II)
  • R 1 , Z 1 , Z 2 , Z 3 and Z 4 are as defined in formula (I) above;
  • Y is hydrogen or a protecting group with an optionally substituted and/or optionally protected mono- or polycyclic aromatic group.
  • the coupling step (i) preferably involves the use of Mitsunobu reaction conditions .
  • the invention also provides a compound of formula (I) obtainable or prepared by the process defined above.
  • the invention further provides a compound of formula (I 1 ) which is a compound of formula (I) other than when A is
  • X is OR 8 or NR 9 R 10 ;
  • R 4 to R 10 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heterocyclic group and a C-I linked saccharide; and
  • R and R are each independently hydrogen or, alternatively, OR 4 and R 11 , and/or OR 5 and R 12 together form a methylenedioxy group.
  • a preferred compound of formula (I) has the formula (IA 1 ) in which
  • Z 1 to Z 4 are as defined in formula (I) above;
  • Z 9 is an optional substituent.
  • a preferred compound of formula (IA') has the formula
  • R 12 is hydrogen or alternatively OR 5 and R 12 together form a methylenedioxy group.
  • the compound of formula (IA) is one of 2C, 2D, 3A-D, 4A-D or 5A-D.
  • the compound of formula ( II ) is a compound of formula ( II-aa) , ( II-ab) , ( II-ba ) or ( II-bb) , or a salt or prodrug thereof :
  • R 1 , R 2 , R 3 and Y are as defined above.
  • the invention also provides a process for the preparation of a compound of formula (II), particularly compounds of the formula (II-aa) , (II-ba) , (II-ab) and (II-ba) defined above which comprises the steps of: (i) acetal cleavage of compound (Hi)
  • the optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety A is an optionally substituted and/or optionally protected fused polycyclic heterocyclic group having at least one aromatic ring such as an optionally substituted and/or optionally protected cyclopentabenzofuran for example having the formula (A ! )
  • Z 5 to Z 9 , R 4 , R . R 7 and R 11 are as defined in formula (IA') above.
  • Preferred Z 7 -Z 9 independently include optionally substituted phenyl, optionally substituted C 5 -C 6 cycloalkyl, an optionally substituted 5- or 6-membered heterocyclic group (such as optionally substituted pyridyl) , and optionally substituted alkyl (such as i- propyl, sec- and t-butyl) .
  • the compound of formula (A 1 ) has the formula (A")
  • R 4 to R 7 , R ⁇ x i ⁇ , R and Z to Z are as defined in formula (IA") above.
  • the optionally substituted and/or optionally protected mono- or polycyclic aromatic core moiety A is an optionally substituted and/or optionally protected phenyl such as
  • R' and R" are as defined in formula ( above for R 1 to R 3 .
  • the present invention also provides a process for the preparation of a compound of formula (A") which comprises the steps of:
  • R 5 is as defined in formula (A") above, R 13 is hydrogen or a protecting group and L is a leaving group with compound (A"ii)
  • R, R 4 and R 5 are as defined in formula (A") above;
  • R is as defined above and R 4 to R 6 and R 8 are as defined above;
  • R 6 and/or R 7 are other than hydrogen that one or both of these groups can be installed during any suitable step of the process for preparing formula (A") .
  • alkyl refers to a straight chain, branched or cyclic hydrocarbon group, preferably Ci_ 2 o alkyl, more preferably Ci-I 0 alkyl, most preferably C ⁇ - 6 alkyl.
  • Ci-C ⁇ alkyl refers to a straight chain, branched or cyclic alkyl group of 1 to 6 carbon atoms.
  • Ci- 6 alkyl examples include methyl, ethyl, iso-propyl, n-propyl, n- butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 2,2- dimethylpropyl, ⁇ -hexyl, 2-methylpentyl, 2,2- dimethylbutyl, 3-methylpentyl and 2, 3-dimethylbutyl.
  • Examples of cyclic C 3 _ 6 alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkyl examples include heptyl, 5-methylhexyl, 1-methylhexyl, 2,2- dimethylpentyl, 3, 3-dimethylpentyl, 4, 4-dimethylpentyl, 1, 2-dimethylpentyl, 1, 3-dimethylpentyl, 1, 4-dimethyl ⁇ pentyl, 1, 2, 3-trimethylbutyl, 1, 1, 2-trimethylbutyl, 1,1,3- trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl,
  • alkenyl refers to a straight chain, branched or cyclic hydrocarbon group having at least one carbon-carbon double bond, preferably C2-20 alkenyl, more preferably C 2 - ⁇ alkenyl. Examples include ethenyl, propenyl, allyl, butenyl and 4-methyl butenyl.
  • alkynyl refers to straight chain or branched hydrocarbon groups having at least one carbon- carbon triple bond, preferably C 2 - 20 alkynyl, more preferably C 2 - 6 alkynyl. Examples include propargyl and butynyl.
  • aryl denotes single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl and phenanthrenyl. Preferred aryl groups include phenyl and naphthyl.
  • heterocyclic group refers to saturated or unsaturated, monocyclic or polycyclic hydrocarbon groups containing at least one heteroatom atom selected from nitrogen, sulphur and oxygen.
  • Suitable heterocyclic groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridaziny
  • acyl refers to a group -C(O)-R wherein R is any carbon containing moiety such as an optionally substituted alkyl or aryl group.
  • examples of acyl include straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl, such as cyclopropylcarbonyl, cycl
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl
  • Optional substituents for "alkyl”, “alkenyl”, “alkynyl”, “aryl”, “heterocyclic group” and “acyl” include halo (bromo, fluoro, chloro, iodo) , hydroxy, thio, Ci- 6 alkyl (e.g. methyl, ethyl, propyl (n and i- isomers), cyclopentyl and cyclohexyl) , Ci_ 6 alkoxy (e.g.
  • Ci_ 6 alkylthio nitro, amino, C ⁇ - 6 alkylamino (e.g. methylamino, ethylamino, propyl ( ⁇ - and i- isomers) amino) , C ⁇ - 6 dialkylamino (e.g.
  • cyclic group such as piperidyl, pyrrolidinyl, piperazinyl, imidazolidinyl and pyrazolidinyl
  • phenyl hydroxyphenyl
  • Ci- 6 alkyloxyphenyl halomethyl (e.g. trifluoromethyl, tribromomethyl, trichloromethyl)
  • halomethoxy e.g.
  • Preferred C-I linked saccharides are a furanose or pyranose saccharide (sugar) substituent which can be linked through the saccharides' 1-carbon (conventional chemical numbering) to form an acetal at an oxy group, such as any one of positions Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ or R 7 or an ester linkage at the R 8 or an amide at R 9 or Ri 0 position of formula (I 1 ) -
  • Exemplary saccharide groups include reducing sugars such as glucose, ribose, arabinose, xylose, mannose and galactoses, each being linked to an oxygen atom through the C-I carbon of the saccharide group.
  • Glycosidic formation may be effected chemically, e.g. by reacting the starting compound with a protected sugar compound in which C-I has been activated by halogenation for coupling with the hydroxyl or carboxyl groups and the sugar hydroxyls have been blocked by protecting groups or glycosidic formation can be carried out under Lewis acid catalysis.
  • glycoside formation may be effected enzymatically using an appropriate glycosyltransferase such as UDP-galactose dependent galactosyltransferase and UDP-glucose dependent glycosyltransferase (SIGMA) .
  • a "protecting group” refers to an introduced functionality which renders a particular functional group, such as a hydroxy, amino, carbonyl or carboxy group, unreactive under selected conditions and which may later be optionally removed to unmask the functional group.
  • a hydroxy protecting group is one which can temporarily render a hydroxy group unreactive.
  • a protected hydroxy group refers to a hydroxy group which has temporarily been rendered unreactive by a hydroxy protecting group.
  • a protected phenyl group is taken to be one in which attached reactive substituents, such as OH, NH 2 , are protected by a protecting group. Suitable protecting groups are known in the art and are described in Protective Groups in Organic Synthesis, Third Edition, T.W. Greene and P.G.
  • protecting groups which may be used to protect a hydroxy group include, but are not limited to, silyl groups (e.g. trimethylsilyl, fc- butyldimethylsilyl, t-butyldiphenylsilyl) , benzyl groups (e.g. benzyl, methoxybenzyl, nitrobenzyl) , alkyl groups
  • a "mono- or polycyclic aromatic core moiety" refers to a mono- or polycyclic, aromatic, saturated or non-saturated hydrocarbon residue or a mono- or polycyclic, aromatic heterocyclic residue.
  • a polycyclic core moiety may be fused or non-fused, and each ring may independently be aromatic or non-aromatic, saturated or non-saturated provided that at least one of the rings is aromatic.
  • a polycyclic core moiety also includes spirocyclic groups which may be saturated or unsaturated.
  • a polycyclic core moiety may contain 2, 3, 4 or more rings. Where the mono- or polycyclic core moiety is a heterocyclic residue, the residue may contain one or more heteroatoms in one or more rings of the cyclic core moiety. A ring may contain more than one heteroatom. Where the heterocyclic residue is polycyclic, one or more rings may contain one or more heteroatoms while other rings may contain no heteroatoms.
  • Heteroatoms may be wholly contained within one ring or at a ring junction between two or more fused rings.
  • the mono- or polycyclic core moiety may be unsubstituted or substituted with one or more substituents at one or more carbon atoms of the cyclic core moiety.
  • one or more heteroatoms e.g. N
  • heteroatom is intended to refer to any atom which can replace a carbon atom in a cyclic hydrocarbon group.
  • heteroatoms contemplated by the present invention include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, selenium and tellurium.
  • Particularly preferred heteroatoms include nitrogen, oxygen and sulfur.
  • mono- or polycyclic core moieties include: monocyclic hydrocarbon groups such as phenyl, C 3 -C 8 cycloalkyl, and C 3 -C 8 cycloalkenyl; fused polycyclic hydrocarbon groups such as naphthyl, pentalenyl, idenyl, isoidenyl, tetralinyl, azulenyl, heptalenyl, biphenylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, asymm-indacenyl, symm- indacenyl, fluoranthrenyl, acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyl, naphthacenyl, plejadenyl, picenyl, perylenyl, pentaphenyl, pentace
  • One contemplated sub-group of mono- or polycyclic core moieties includes: naphthyl, indanyl, chromanyl, tetralinyl, 2, 3-dihydrobenzofuranyl, 2,3- dihydrobenzo [b] thienyl, azatetralinyl, thiatetralinyl, indolinyl, biphenylenyl, phenanthrenyl, anthracenyl, triphenylenyl, naphthacenyl, indolyl, iso-indolyl, indazolyl, benzofuranyl, isobenzofuranyl cyclopentabenzofuranyl, and benzimidazolyl.
  • Each core moiety may be substituted one or more times by one or more (same or different) optional substituents.
  • the substituents for the mono- or polycyclic core moieties include alkyl (such as methyl, ethyl, (n- and i-) propyl and ⁇ n- r sec- and t-)butyl, and C 5 -C 6 cycloalkyl) , alkyloxy (such as methoxy, ethoxy, ⁇ n- and i-)propoxy and ⁇ n- r sec- and t-)butoxy), acyl (such as acetyl and benzoyl), acyloxy (such as acetoxy and benzoyloxy) , aryl (such as phenyl and pyridyl) , aryloxy (such as phenoxy) , arylalkyl (such as benzyl), arylalkyloxy (such as benzyloxy) ,
  • substituents for the mono- or polycyclic core moieties include hydroxy, thio, nitro, heterocyclyl, C(O)X, wherein X is OR 8 or NR 9 R 10 (R 8 -R 10 are selected from the group as defined for R 1 - R 3 above) or replacement of a CH 2 group by C(O) .
  • Heterocyclyl when used in the context of a substituent for a mono- or polycyclic core moiety, refers to a cyclic hydrocarbon residue wherein one or more carbon atoms is replaced by one or more heteroatoms which may be the same or different. Examples thereof include piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, and thiomorpholinyl.
  • a heterocyclyl group may be further optionally substituted by a substituent as defined for the optional substituents for "alkyl", “aryl” and "acyl”.
  • p is 0 or 1 and X" is selected from O, CH 2 , NH, N-alkyl, N-aryl, N-acyl and S.
  • the above illustrated core moieties are attached to the dioxanyloxy group at the left hand side benzene ring, meta- to the OMe group. It will, however, also be recognised that attachment at the ortho- or para- positions is also possible.
  • the invention includes within its scope pharmaceutically acceptable salts, or prodrugs of compounds of formula (I), particularly of formulae (IA 1 ) and (IA") .
  • salt, or prodrug includes any pharmaceutically acceptable salt, ester, glycoside, solvate, hydrate or any other compound which is not biologically or otherwise undesirable and induces the desired pharmacological and/or physiological effect.
  • Suitable pharmaceutically acceptable salts include salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • Base salts include, but are not limited to those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium
  • salts can be carried out by methods known in the art. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention, since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • the compounds of the invention may be in crystalline form or as a solvate (e.g., hydrates) .
  • solvate e.g., hydrates
  • Prodrugs of compounds of formula (I) are also within the scope of the invention.
  • the term "prodrug” includes derivatives that are converted in vivo to the compounds of the invention and include for example, ester (e.g. acetate) and glycoside derivatives of free hydroxy groups, which may undergo in vivo degradation to release a compound of the invention.
  • Other suitable prodrugs may include esters of free carboxylic acid groups.
  • the preparation of suitable prodrugs is further described in Design of Prodrugs, H. Bundgaard, Elseveir, 1985, the contents of which is incorporated by reference.
  • compound of formula (I) may possess asymmetric centres (both within the dioxanyl side chain and core moiety A) and therefore, unless specified, are capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres, e.g. greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example chiral intermediates, or mixtures may be resolved by conventional methods, e.g. chromatography, or use of a resolving agent.
  • compounds of the invention have a polycyclic core moiety of formula (A 1 ) (to afford compounds of formula (IA 1 ) ) and a particularly preferred polycyclic core moiety has the formula (A") (to afford compounds of formula (IA") ) .
  • substituents for a Z 7 -Z 9 group which is a phenyl group in formula (A 1 ) particularly a Z 9 phenyl group include: methylene dioxy, hydroxy, Ci_ 4 alkoxy (e.g. methoxy, ethoxy) and a C-I linked glucoside group.
  • R A is H
  • R B is selected from H, OH, OMe, sugar 1 and sugar 2
  • R c is OMe
  • R A is selected from H and OMe
  • R B is selected from H and OMe
  • R c is OMe
  • R A is H and R B and R c together form a methylene dioxy group
  • R A is H
  • R B is selected from H, OH and OMe
  • R c is OMe
  • R 6 is selected from H, Me or Et.
  • (A 1 ) , Z 5 or Z 5 is selected from CO 2 Me, CONMe 2 , CONHMe, CONH (CH 2 ) 4 0H and CO 2 H.
  • R 7 is H or Ac.
  • (A') is (A") as defined above.
  • particularly preferred compounds of the invention have the formula (IA") as defined above in which
  • R 6 , R 7 , R 11 and R 12 are all H and Z 6 is CO 2 Me, then Z 7 is not Ph.
  • R 1 is Ac
  • Z 1 or Z 2 is Ac
  • Z 3 is OMe
  • R 4 and R 5 are both Me
  • R 6 , R 7 , R 11 and R 12 are all H and Z 6 is CO 2 Me, then Z 7 is not Ph.
  • Z 3 is OR 3
  • Z 6 is C(O)X
  • R 11 and R 12 are both H, then Z 7 is not Ph.
  • galactose derivative may be used instead of the glucose derivative as the starting material so as to provide the alternative stereochemistry at the non-ring centre of the dioxanyl group for compound (2A) .
  • the next step involves selective protection of the C4 hydroxy group with a protecting group in anticipation of an oxidative cleavage step which forms the dioxanyl ring.
  • Any protecting group able to withstand the oxidative cleavage may be suitable.
  • a preferred protecting group is benzyl or substituted benzyl.
  • the methods for installing the C4 hydroxy protecting group depend on the protecting group chosen and are known in the art and described in Green & Wutz (supra) . Formation of a 1,3 benzylidene acetal and subsequent cleavage affords the benzyl protected C4 hydroxy group.
  • oxidative cleavage (such as described by Heidelberg et al, J. Prakt. Chem. , 1998, 340, 223-232) of the C4 protected compound followed by reduction affords the trioxy dioxanyl compound, as a mixture of C2 epimers which may optionally be separated using standard separating procedures known in the art (e.g. chromatography) .
  • the oxidative cleavage step may be carried out using any suitable oxidising agent, e.g. NaIO 4 or Pd (OAc) 4 .
  • Selective reduction of the resulting aldehyde to the corresponding alcohol may be achieved by protection of any free hydroxy groups followed by treatment with a suitable reducing agent (Scheme 3) .
  • Suitable reducing agents are known in the art and include hydrides such as NaBH 4 , DiBAL and LiAIH 4 .
  • the resulting compound affords the correct stereochemistry at the non-ring chiral centre of the dioxanyl group for compound (2B) .
  • the alternative stereochemistry required for compound (2A) can be obtained using suitable inversion conditions known in the art (e.g. Mitsunobu conditions such as described in Martin and Dodge, Tetrahedron Lett., 1991, 32, 3017) .
  • suitable inversion conditions known in the art (e.g. Mitsunobu conditions such as described in Martin and Dodge, Tetrahedron Lett., 1991, 32, 3017) .
  • the suitably protected (and debenzylated) compound can be subjected to inversion conditions to invert the configuration of the non-ring chiral hydroxy group as per Scheme 4 below.
  • Scheme 7 Another possible synthetic route to the compound of formula (II) is shown in Scheme 8.
  • cyclopentabenzofuran core and indeed any other mono- or polycyclic aromatic group can be coupled to the compound of formula (I) in a manner analogous to the coupling step described for the appropriately substituted phenyl above.
  • the compound of formula (II) and the optionally substituted and/or optionally protected mono- or polycyclic aromatic group may be coupled to form the compound of formula (I) using Mitsunobu reaction conditions .
  • the compound of formula (II) is suitably coupled using the Mitsunobu reaction.
  • the synthetic processes described herein can be used to gain access to compounds (2A) and (2B) .
  • compounds of formula (II) act as useful intermediates in the synthesis of compounds of formula (I), such as (IA 1 ) and (IA") .
  • the invention therefore also provides an intermediate compound formula (II) as defined above.
  • Formation of (2A) requires the formation of the alternative epimer at the non-ring chiral centre of the dioxanyl group. This can be achieved by subjecting a suitably protected form of the dioxy dioxanyl compound to appropriate inversion conditions (e.g. Mitsunobu conditions) . Examples of the inversion processes are shown in Schemes 17 and 18.
  • Another embodiment of the invention provides a compound of formula (II-i-b) where R 3- -R 3 and X are as described above.
  • A is an optionally substituted phenyl group, or a group of formula (A 1 ) , more preferably formula (A") as described above for (IA 1 ) and (IA") , respectively.
  • (3A) - (3D) could be synthesised from 32 via Schemes 8 to 12 above.
  • amide derivatives of formula (IA) can be prepared using either the natural or synthetically prepared compounds of formula (2) as starting materials.
  • the compounds of the invention in particular compounds having a formula (IA 1 ), more particularly (IA"), may be found to possess biological activity, in particular cytostatic and/or cytotoxic activity. Assay methods for determining suitable biological activity are known in the art. Therefore certain compounds described herein may be useful in the treatment of diseases and conditions involving cellular hyperproliferation, or cancer or a cancerous condition.
  • the present invention may also provide a method for the treatment of cancer or a cancerous condition or a disease state or condition associated with cellular hyperproliferation comprising the administration of a treatment effective amount of a compound of formula (I) , such as formula (IA 1 ) or (IA") , or a salt or prodrug thereof, to a subject in need thereof, as well as to the use of compounds of the invention in the manufacture of a medicament therefor.
  • Cancerous conditions which may be treated by biologically active compounds of the present invention include conditions wherein the cancers or tumours may be simple (monoclonal, i.e. composed of a single neoplastic cell type), mixed (polyclonal, i.e. composed of more than one neoplastic cell type) or compound (i.e. composed of more than one neoplastic cell type and derived from more than one germ layer) and may include benign and malignant neoplasia/hyperplasia.
  • cancerous conditions which may be treated by the present invention include leukemia and breast, colon, bladder, pancreatic, endometrial, head and neck, mesothelioma, myeloma, oesophagal/oral, testicular, thyroid, uterine, prostate, renal, lung, ovarian, cervical brain, skin, liver, bone, bowel and stomach cancers, sarcomas, tumours and melanomas.
  • benign hyperplasias include those of vascular (e.g. hemangioma), prostate, renal, adrenal, hepatic, colon (e.g. colonic crypt), parathyroid gland and other tissues.
  • compounds of the invention may have cytostatic as well as cytotoxic properties, they may also have potential use as therapeutic agents in the suppression of the growth of target populations of cells other than cancer or tumour cells, for example disease states or conditions associated with cellular hyperproliferation.
  • Such conditions may include atherosclerosis and restenosis (neointimal hyperplasia) and hyperproliferation due to or accompanying an inflammatory response, e.g. arthritis, (including rheumatoid arthritis, osteoarthritis and inflammatory arthritis) , psoriasis and periodontal disease, or cellular hyperproliferation due to the viral infection of cells such as human papilloma virus.
  • the compounds of the invention having cytostatic and/or cytotoxic activity may be used in therapy in conjunction with other therapeutic compounds, such as anti-cancer compounds, including paclitaxel, camptothecin, vinblastin and doxorubicin.
  • Infrared spectra were run as thin films on NaCl plates and recorded using a Perkin Elmer 1600 series FTIR or a Bio-rad FTS 165 FTIR spectrometer.
  • Proton nuclear magnetic resonance ( 1 H NMR, 300 MHz) and proton decoupled carbon nuclear magnetic resonance spectra ( 13 C NMR, 75.5 MHz) were recorded for deuterochloroform solutions on a Varian Unity 300, Varian Inova 500MHz or a Unity Plus 400 instrument with residual chloroform as internal standard, unless otherwise stated.
  • Chemical shifts ( ⁇ ) are reported in parts per million (ppm) and are followed by multiplicity, coupling constants (J) given in Hertz (Hz), integration and assignments.
  • Flash chromatography was carried out using Merck silica gel 60 according procedure described by Still et al, J. Org. Chem. , 1978, 43, 2923.
  • Anhydrous tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl or sodium metal under a nitrogen atmosphere.
  • Anhydrous diethyl ether (Et 2 ⁇ ) was distilled from sodium benzophenone ketyl and sodium metal under a nitrogen atmosphere.
  • EtOAc refers to AR ethyl acetate.
  • EtOAc refers to AR ethyl acetate.
  • the following Examples illustrate the formation of two isomers of formula (I) . Some alternative reagents and reaction conditions are indicated for each step and it will be recognised that these will also be applicable in the analogous preparation of other compounds of formula (I), particularly compounds of formula (IA 1 ) and (IA") .
  • ⁇ -D-glucose pentaacetate 33.0 g, 84.5 mmol, ALDRICH
  • a 30% solution of HBr in acetic acid 70 mL, 351 mmol
  • TLC 50% EtOAc/Petrol
  • the reaction mixture was then poured into ice and extracted three times with CH2CI 2 .
  • the combined organic extracts were carefully washed with saturated aqueous NaHC0 3 (3x) , brine
  • the crude mixture was purified using silica gel column chromatography eluting with 30-50% EtOAc/Petrol to give the 4-methoxybenzyl 2, 3, 4, 6-Tetra-O- acetyl- ⁇ -D-glucopyranoside (8.5 g) which was contaminated with 4-methoxybenzyl alcohol (70:30 mixture favouring the glucopyranoside) .
  • the crude mixture was then dissolved in AR methanol (80 inL) and a solution of sodium methoxide in methanol (25% wt, 1 mL, 4.62 mmol) was then added under an argon atmosphere. The solution was stirred for 2 h at room temperature and then neutralised by the addition of Amberlite resin IR 120 (H + ) .
  • Alternative acylating agents acetic anhydride
  • Alternative base pyridine
  • TESCl triethylsilylchloride
  • TBDPS tertbutyldiphenylsilylchloride
  • TMSCl trimethylsilylchloride
  • TBDMSCl fcert- butyldimethylsilylchloride
  • TIPSCl triisopropylsilylchloride
  • Ester (2A) (38.5 mg, 0.0588 mmol) was dissolved in 0.4% KOH/aqueous MeOH [MeOH-H 2 O (5:10)] and heated to 5O 0 C for 2h. The reaction mixture was cooled to O 0 C and mixture diluted with ether and saturated aqueous NaCl. The aqueous layer was acidified to pH 2 and the mixture warmed to room temperature until 2 clear layers evolved.
  • the residue still contained some DMF which was removed by azeotroping with toluene (3 x 50 mL) and then dried under vacuum.
  • the residue was immediately loaded onto a flash column and eluted with dichloromethane (1% - 5% methanol) using gradient elution.
  • the first compound to elute from the column was some monomethylated material, followed by the desired target compound 46 (1.144 g, 79% yield) isolated as a golden oil.
  • Suspended chromone (47) was assisted into solution using limited sonication and gentle heating.
  • the apparatus was fitted with the internal cooling finger and the reaction solution was cooled to -10 0 C using an ethylene glycol cooling system connected to the internal cooling finger.
  • the reaction mixture was then irradiated (Hanovia UV lamp, Pyrex filter) at -10 0 C with stirring for 2 - 3 hours. Analysis by TLC indicated no starting material remained. The solvent was removed in vacuo.
  • the reaction was purified on silica gel using petroleum spirit/ethyl acetate, 3:2 - 1:2 using gradient elution. Two compounds were eluted off the column. The first compound to elute off the column was, compound 56 (56 mg, 65% yield) . The material was still contaminated with a bit of DIAD so was re-chromatographed to yield compound 56 (28.7 mg, 33.3 % yield) as a pure white foam. The sample was a mixture of diastereomers so both the 1 H and 13 C NMR spectra were very complicated with each signal being doubled. R f
  • the second compound to elute off the column was compound 57 (20.3 mg, 23 % yield) obtained as a pure white foam.
  • the sample was a mixture of diastereomers so both the IH and 13C NMR spectra were very complicated with each signal being doubled.
  • the first compound to elute off the column was compound 60 (22.8 mg, 12% yield) as brown oil.
  • the sample was a mixture of diastereomers so both the 1 H and 13 C NMR spectra were very complicated with each signal being doubled.
  • R f [petroleum spirit/ethyl acetate (2:1)] 0.65; 1 H NMR (500 MHz, CDCl 3 ) ⁇ 0.05, 0.06, 0.07, 0.08 (4s, 12H), 0.80, 0.83, 0.85, 0.85, 0.89 (5s, 18H), 1.75 (brs, IH), 3.46, 3.48 (2s, 3H), 3.63, 3.64 (2s, 3H), 3.70, 3.71 (2s, 3H), 3.86, 3.86 (2s, 3H), 3.30 - 4.11 (m, 6H), 4.24 - 4.36 (m, 2H), 4.57 - 4.58 (m, IH), 5.01 - 5.05 (m, IH), 5.31 (s, IH), 6.28

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  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des procédés synthétiques pour la préparation de composés portant une fraction dioxanyle, en particulier des composés portant une chaîne latérale dioxanyle fixée à une fraction principale monocyclique ou polycyclique, plus particulièrement une fraction principale de cyclopentabenzofurane. L’invention concerne également des composés intermédiaires utilisés dans ces procédés. Des composés qui peuvent être préparés par le procédé de l’invention peuvent être utilisés comme des candidats pour le criblage d’une activité thérapeutique potentielle, ainsi l’invention concerne également des composés pouvant être obtenus ou préparés par les procédés décrits ci-dessus, en particulier ceux ayant une activité cytotoxique ou cytostatique.
PCT/AU2005/001040 2004-07-16 2005-07-15 Procédés et produits intermédiaires WO2006007634A1 (fr)

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Cited By (7)

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CN101570529B (zh) * 2008-04-30 2011-07-20 上海医药工业研究院 一种黄酮类化合物的制备方法及所用中间体
WO2011140334A3 (fr) * 2010-05-06 2012-03-08 Trustees Of Boston University Composés, méthodes de fabrication ou d'identification de composés et leurs utilisations
WO2014033453A1 (fr) 2012-08-28 2014-03-06 Medical Research Council Formulation de nanoparticules
WO2017214024A1 (fr) 2016-06-06 2017-12-14 Genentech, Inc. Médicaments conjugués d'anticorps silvestrol et procédés d'utilisation
US9957277B2 (en) 2015-11-25 2018-05-01 Effector Therapeutics, Inc. eIF4A-inhibiting compounds and methods related thereto
CN118001268A (zh) * 2024-04-08 2024-05-10 江西中医药大学 一种苯并呋喃木脂素类化合物的应用及其制备方法
US12215090B2 (en) 2018-02-19 2025-02-04 Memorial Sloan Kettering Cancer Center Agents and methods for treating dysproliferative diseases

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101570529B (zh) * 2008-04-30 2011-07-20 上海医药工业研究院 一种黄酮类化合物的制备方法及所用中间体
WO2011140334A3 (fr) * 2010-05-06 2012-03-08 Trustees Of Boston University Composés, méthodes de fabrication ou d'identification de composés et leurs utilisations
WO2014033453A1 (fr) 2012-08-28 2014-03-06 Medical Research Council Formulation de nanoparticules
US9957277B2 (en) 2015-11-25 2018-05-01 Effector Therapeutics, Inc. eIF4A-inhibiting compounds and methods related thereto
US10577378B2 (en) 2015-11-25 2020-03-03 Effector Therapeutics, Inc. EIF4A-inhibiting compounds and methods related thereto
US11440917B2 (en) 2015-11-25 2022-09-13 Effector Therapeutics, Inc. EIF4A-inhibiting compounds and methods related thereto
WO2017214024A1 (fr) 2016-06-06 2017-12-14 Genentech, Inc. Médicaments conjugués d'anticorps silvestrol et procédés d'utilisation
US10639378B2 (en) 2016-06-06 2020-05-05 Genentech, Inc. Silvestrol antibody-drug conjugates and methods of use
US11648315B2 (en) 2016-06-06 2023-05-16 Genentech, Inc. Silvestrol antibody-drug conjugates and methods of use
US12215090B2 (en) 2018-02-19 2025-02-04 Memorial Sloan Kettering Cancer Center Agents and methods for treating dysproliferative diseases
CN118001268A (zh) * 2024-04-08 2024-05-10 江西中医药大学 一种苯并呋喃木脂素类化合物的应用及其制备方法
CN118001268B (zh) * 2024-04-08 2024-06-11 江西中医药大学 一种苯并呋喃木脂素类化合物的应用及其制备方法

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