EP0533744A1 - Heterocyclic anthracyclione and anthracycline analogs - Google Patents

Heterocyclic anthracyclione and anthracycline analogs

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Publication number
EP0533744A1
EP0533744A1 EP91910808A EP91910808A EP0533744A1 EP 0533744 A1 EP0533744 A1 EP 0533744A1 EP 91910808 A EP91910808 A EP 91910808A EP 91910808 A EP91910808 A EP 91910808A EP 0533744 A1 EP0533744 A1 EP 0533744A1
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EP
European Patent Office
Prior art keywords
compound
formula
group
dioxo
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP91910808A
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German (de)
English (en)
French (fr)
Inventor
Giorgio Attardo
Yao Chang Xu
Jean-François LAVALLEE
Rabindra N. Rej
Bernard Belleau
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BELLEAU Bernard legally represented by BELLEAU Pierrette
Shire Canada Inc
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BELLEAU Bernard legally represented by BELLEAU Pierrette
IAF BioChem International Inc
Biochem Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D311/76—Benzo[c]pyrans
    • 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
    • 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
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • 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
    • C07D407/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/244—Anthraquinone radicals, e.g. sennosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • This invention relates to improved anthracycline derivatives, to processes and to intermediates for preparing the derivatives, to pharmaceutical compositions containing them and to the use of these derivatives as antitumor agents in mammals. More specifically, the present invention relates to 8- heteroanthracycline derivatives.
  • Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B., Sarosy, G., Clagett-Carr, K., Russo, K. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxorubicin, Academic Press, New York, 1980).
  • anthracycline antibiotics The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S.K., Anthracyclines; Current Status and New Developments, Academic Press, N.Y. 1980) and cardiotoxicity (Olson, R.D. et al, Proc. Natl. Acad. Sci., USA 85 3585-3589, 1988 and references therein) as well as the resistance from treated tumors (Mimnaugh, E.G. et al. Cancer Research, 49, 8-15, 1989; McGrath, T. et al, Biochemical Pharmacology, 23.497-501, 1989). In view of the proven effectiveness of known anthracyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
  • anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxorubicin, Academic Press, N.Y. 1980; Thomson, R.H., Naturally Occurring Quinones III: Recent Advances, Chapman and Hall, New York 1987; Anthracyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J.R. and Iman, S.H., Recent Studies on Doxorubicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J.R.
  • Adriaaycin and Related Anthracycline Antibiotics Prog. Med. Chem., 15, 125-164, 1978.
  • the majority of known anthracyclines show two types of structural differences: (i) the substitution pattern of the aglycone tetracyclic ring system, and (ii) the structure and number of glycosides attached at C-7 or C-10 (doxorubicin numbering).
  • Some examples of the structural diversity of anthracycline antibiotics are shown in Figure 1.
  • nanaomycin A (2) and kalafungin (8) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
  • Granaticin (9) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P. and Chang, C.T., J. Antibiot., 28, 156, 1975).
  • the present invention provides, heteroanthracyclines which are structurally distinguished from the prior art compounds by the nature of ring A of the anthracyclinone moiety. More specifically, the compounds of the present invention are structurally distinguished from the prior art compounds by having an hetero atom at position 8 of the ring A of the anthracyclinone.
  • This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity, are active against some adriamycin-resistant tumor cells, and also may potentially display less myelosupression.
  • x 1 and x 2 are independently selected from the group consisting of
  • X 3 is selected from the group consisting of
  • R is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are independently selected from the group consisting of
  • aminoalkylaminoalkylhalide of formula NH(CH 2 ) n NH(CH 2 ) m X where n and m independently range from 1 to 4 and X is a halogen,
  • cycloalkyl acyl, trif luoroacy 1 , aralkyl or aryl, C 1-8 alkenyl, C 1-8 alkynyl,
  • halaoalkylnitrosureido of the formula NH(CO)N(NO) (CH 2 ) n CH 2 X, wherein n is 0 to 4 and X is a halogen,
  • R 6 is selected from the group consisting of
  • a naturally occurring amino acid for example alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like, or a synthetic amino acid;
  • R 6 is selected from the group consisting of
  • amino which may be unsubstituted or mono- or disubstituted by C 1-8 alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl, and a naturally occuring amino acid, for example alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like, or a synthetic amino acid;
  • Y and R 7 are independently selected from the group consisting of hydrogen,
  • amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid as defined above or a synthetic amino acid;
  • mono or oligosaccharides commonly present in other anthracyclines for example one or more sugars selected from rhodosamine, cinerulose-B, L-cinerulose, O-cinerulose, cinerulose-A,
  • amicetose aculose, rednose, rhodinose,
  • R 9 and R 10 are independently selected from the group consisting of
  • R 11 is selected from the group consisting of
  • amino which may be unsubstituted or mono or disub ⁇ tituted by C 1-8 alkyl, C 3 _ 8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl and a naturally occuring amino acid, for example alanine, arginine, cysteine, glycine, leucine, lysine, methionine and the like, or a syntehtic amino acid;
  • R is independently selected from the group consisting of a C 1-16 alkyl, C 1-16 acyl or C 7-16 aroyl and wherein n is 0 to 5,
  • R 12 is selected from the group consisting of
  • alkyl contains 1 to 16 carbon atoms
  • Preferred compounds of formula (10) are those wherein
  • X 1 , and X 2 are independently selected from the group consisting of
  • X 3 is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are independently selected from the group consisting of
  • n and m independently range from 1 to 3.
  • R 6 is selected from the group consisting of
  • alkyl C 3-8 cycloalkyl, acyl,
  • R 6 ' is selected from the group consisting of
  • Y and R 7 are independently selected from the group consisting of
  • R 9 and R 10 are independently selected from the group consisting of
  • R 11 is selected from the group consisting of
  • alkyl C 3-8 cycloalkyl, acyl,
  • R is independently selected from a group consisting of C 1-8 alkyl, C 1-8 acyl or C 7 _ 12 aroyl and wherein n is 1 to 5;
  • R 12 is selected from the group consisting of
  • mono or oligosaccharide commonly present in other anthracyclines for example one or more sugars selected from rhodosamine, cinerulose-B, L-cinerulose, D-cinerulose, cinerulose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine and
  • X 1 , and X 2 are independently selected from the group consisting of
  • X 3 is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of
  • n 0 to 2 , amino
  • R 6 is selected from the group consisting of
  • R 6 ' is selected from the group consisting of
  • Y and R 7 are independently selected from the group consisting of
  • R 9 and R 10 are independently selected from the group consisting of
  • R 11 is selected from the group consisting of
  • R 12 is selected from the group consisting of
  • X 1 and X 2 are both oxygen
  • X 3 is selected from the group consisting of
  • R 1 , R 2 , R 3 and R 4 each are hydrogen; R 5 and R 6 are independently selected from the group consisting of
  • R 6 is selected from the group consisting of
  • R 6 ' is selected from the group consisting of
  • Y and R 7 are independently selected from the group consisting of
  • R 9 and R 10 are independently selected from
  • R 11 is selected from
  • R 12 is selected from hydroxyl, benzoate and p- nitrobenzoate.
  • alkyl as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, Cl, Br, I or CF 3 , an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent or an alkylcycloalkyl substituent.
  • halo substituent such as F, Cl, Br, I or CF 3
  • cycloalkyl as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and cyclooctyl.
  • aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C 1-4 alkyl, halogen, C 1-4 alkoxy or nitro.
  • halogen as used herein means chlorine, bromine, fluorine or iodine.
  • aralkyl refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.
  • aryl refers to a group of the formula -COAr wherein Ar denotes an "aryl” group as defined above.
  • alkoxy or "aralkoxy” as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
  • alkoxyalkyl as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
  • aryloxyalkyl as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethy1.
  • araloxyalkyl as used herein means an aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
  • acyloxyalkyl as used herein means an C 1-8 acyl group linked to an alkyl group as discussed above by an oxygen atom, for example acet ⁇ xymethyl.
  • hydroxyalkyl as used herein means an alkyl group as discussed above bonded to a hydroxyl group, for example hydroxymethyl.
  • This invention also includes all the possible isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stere ⁇ chemical centers, when pertinent, at C-7, C-9 and C-10 as well as in all the chiral centers present in the sugar moiety.
  • This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (10) and (11). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (10) and
  • the compounds of formula (10) can be prepared by the process illustrated in Reaction Scheme I.
  • Heteroanthracyclines of general formula (10) in which Y is a saccharide are best prepared by using scheme I.
  • Reaction Scheme I an aglycone of formula (12) in which R 1 to R 8 are as defined herein is reacted with a sugar derivative of formula (13) in which R g to R 12 are as defined herein and L is a displaceable atom or group.
  • Suitable groups L include halogen, for example iodine, bromine or chlorine, an unsubstituted or substituted benzoyl group such as p-nitrobenzoyl, and -OR or -SR, where R is an unsubstituted or substituted alkyl group, for example a C 1-16 alkyl group such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as a C 1 _ 16 acyl group such as acetyl, or R is an unsubstituted or substituted aryl group.
  • R is an unsubstituted or substituted alkyl group, for example a C 1-16 alkyl group such as methyl, ethyl or butyl
  • R is an unsubstituted or substituted acyl group such as a C 1 _ 16 acyl group such as acetyl
  • R is an unsubstituted or substituted
  • Such sugars are obtained by derivatizing known saccharides of the family of anthracycline antibiotics which are available from commercial or natural sources, (see for example, Manneret, C., Martini, A., Pais, M., Carbohydrate Research, 166, 59-70, 1987 and references therein; Acton, E.M., Tong, G.L., Mosher, C.W., and Wolgemuth, R.L., J. Med. Chem. 27, 638645, 1984 and references therein; Arcamone F., Cancer Research, 45, 5995-5999, 1985 and references therein).
  • the aglycone of formula (12) is typically reacted with the appropriate sugar derivative of formula (13) in a compatible solvent such as methylene chloride using a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-sulfonate.
  • a compatible solvent such as methylene chloride
  • a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-sulfonate.
  • the leaving group of the sugar moiety is a halogen
  • the Koenigs-Knorr glycosidation or its modification may be used.
  • the dioxane acetal (15) can then be treated with an alkyl lithium such as n-butyllithium and the lithio salt reacted with an appropriate alkyl halide of the formula R 7 CH 2 X, wherein X is halogen and R 7 is as defined above, but compatible with the necessary reaction conditions.
  • R 7 is not compatible, functional group interconversion can be carried out at a latter step by using methods which are well known by one familiar with the art of organic synthesis.
  • aqueous acidic treatment can lead to an appropriate 2,5-dimethoxy-6-alkylbenzaldehyde such as (16).
  • Photochemical irradiation of an intermediate such as (16) in a solution of SO 2 in an aryl solvent such as benzene can give a dihydrothiophene-2,2-dioxide of formula (17) which can then be reduced with a bor ⁇ hydride.
  • a ⁇ -sultine of formula (18) can be obtained.
  • This intermediate can then be coupled via cyclocondensation with an appropriately functionalized aldehyde (19) and consequently yield dimethoxyisochroman intermediates such as (20) .
  • the intermediates (20) can subsequently be chlorinated with an hypochlorite such as t-butylhypochlorite to give compounds of formula (21).
  • Oxidative demethylation of (21) with an adequate oxidant such as eerie ammonium nitrate can give chloropyranoquinones of formula (22).
  • These quinones can then be coupled under basic conditions with adequately functionalized homophthalic anhydrides such as (23) to give pyranoquinone tetracyclic derivatives of formula (24).
  • the free phenol can then be protected to give tetracyclic compounds of the general formula (25).
  • Tetracyclic derivative (25) can then be brominated with a free radical brominating agent such as n-bromosuccinimide in the presence of an initiator such as UV light and in a chlorinated solvent such as carbon tetrachloride.
  • a free radical brominating agent such as n-bromosuccinimide
  • an initiator such as UV light
  • a chlorinated solvent such as carbon tetrachloride
  • the resulting unstable bromides can then be treated directly with an aqueous-ethereal solvent system to yield the pyrano-tetracyclic aglycones of formula (12).
  • the aglyc ⁇ nes of formula (12) can further be transformed to a variety of structures by using synthetic methodologies well understood in the art of anthracycline synthesis. Any functional group interconversion or removal of protecting groups is preferentially carried out under neutral or basic conditions at this stage or later in the synthesis, as convenient.
  • dimethoxyisochroman intermediates such as (20) can be directly oxidatively demethylated with an oxidizing reagent such as eerie ammonium nitrate in a polar solvent system such as acetonitrile in water.
  • the resulting pyranoquinones of formula (26) can then be coupled with appropriately functionalized homophthalic anhydrides (23) in an aprotic solvent with basic catalysis, preferentially lithium diisopropylamide or sodium hydride.
  • Tetracyclic derivative (27) can be separated from (24).
  • the free phenol can then be protected to give compounds of the general formula (25). Bromination and solvolysis as described can give the aglycones of formula (12).
  • reaction Scheme IV Preferred processes for the preparation of the compounds of formula (12) are illustrated in reaction Scheme IV.
  • route a of Scheme IV the lithio salt, obtained after treatment of 2,5-dimethoxybenzaldehyde dioxane acetal (15) with an alkyl lithium, is reacted with an epoxide of general formula (31) optionally in the presence of a Lewis acid such as boron trifluoride etherate to give the adduct of formula (32).
  • a Lewis acid such as boron trifluoride etherate
  • Route b represents an alternative approach for the preparation of adduct (32). Consequently, the addition of an aldehyde of general formula (28) to the lithio salt of 2, 5-dimethoxybenzaldehydedioxane acetal (15) can give an adduct of formula (29).
  • R' 1 is a protecting group, which includes, but is not limited to, methoxyraethyl, methoxyethyl, methyl, benzyl, trityl, t-butyldimethylsilyl, t-butyldiphenylsilyl or other groups conveniently used for the protection of alcohols in the art of organic synthesis.
  • the adduct of formula (32) is then cyclized in the presence of a mild aqueous acid to give 1-hydroxyisochroman of the formula (33).
  • the tetracyclic aglycones (39) and (40) can be prepared according to route c.
  • Pyranoquin ⁇ nes of formula (34) are prepared by oxidizing isochromans of formula (33) with an agent such as silver oxide or eerie ammonium nitrate.
  • a group R' 2 selected but not limited to, methyl, ethyl, methoxymethyl, methoxyethyl, tri
  • the tetracyclic aglycones (39) and (40) can also be prepared according to route d. from isochroman (33) which after bis chlorination with a reagent such as t-butyl hypochlorite gives isochromans of formula (36). Subsequent oxidation with an agent such as eerie ammonium nitrate yields bischloropyranoquinones of formula (37). Addition of these quinones to o-quinodimethanes, generated thermolytically from benzosulfones such as (38), can give tetracyclic aglycones of formula (39) and (40). Compounds of the formula (12) are then accessible from these aglycones through functional group interconversion of the phenol group.
  • an o-quin ⁇ dimethane reactive intermediate (42) which can be generated by heating a precursor such as ⁇ -sultine (41) (prepared by the method described for compound (18) in Reaction Scheme II), and a pyranoquinone such as (26) can yield pyranoquinone structures such as (43), after consecutive treatment with silica gel. Bromination and solvolysis as described for intermediate (23) can give pyranoquinone aglycones with no substituents on ring C such as (44).
  • the treatment of pyranoquinone derivatives such as (45), prepared by the method described for the compound (24), with lead tetraacetate in glacial acetic acid can give the acet ⁇ xylated pyranoquinones with structures such as (46). These can then be acetylated by treatment with acetic anhydride or acetyl chloride in the presence of a base such as pyridine.
  • the resulting tetracyclic intermediates of formula (47) can be brominated and solvolyzed to give the diacetoxy pyranoquinone aglycone structures (48). Glycosidation can then give the bisacetoxypyranoquinone glycosides of formula (49). These, upon alkaline removal of the acetyl groups, yield glycosides (50) which would exist preferentially in the tautomeric form illustrated as structure (11).
  • Reaction Scheme VII Preferred processes for the preparation of compounds of formula (11) and (44) are illustrated in Reaction Scheme VII.
  • pyranoquinones such as (34) can be added to o-quinodimethanes, obtained from the thermolysis of ⁇ -sultine (41), as described in reaction scheme V, to give directly pyranoanthraquinone aglycones of general formula (44).
  • 2,5-dimethoxybenzoic acid is transformed to the benzamide of formula (55a) by first converting the acid, into an acid chloride, with oxalyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane, and then treating with diethyl amine in ether.
  • the lithio salt of (55a) is then generated with a strong base such as sec-Butyllithium in a convenient solvent such as tetrahydrofuran in the presence of TMEDA and reacted with an electrophile, L-CH 2 R 7 , wherein R 7 is as defined herein and L is a displaceable atom or group such as an halogen.
  • the resulting benzo derivative of formula (55b) is then treated with a strong base such as lithium diisopropyl amide or n-Butyllithium in a solvent such as tetrahydrofuran and added to a carbonyl electrophile of formula (56) to give an adduct of formula (57).
  • a strong base such as lithium diisopropyl amide or n-Butyllithium in a solvent such as tetrahydrofuran
  • a carbonyl electrophile of formula (56) to give an adduct of formula (57).
  • the latter can then be cyclised to an isochromanone derivative of formula (58) by treating compound (57) with an acid.
  • Reduction of (58) with a hydride such as DIBAL in a compatible solvent such as dichloromethane can give the 1-hydroxylated isochroman of formula (33).
  • Oxidative demethylation of (33) in a solvent system such as acetonitrile-water with, for example, eerie ammonium nitrate can give an isochromandione such as (34) which can then be transformed to a tetracyclic derivative such as (12) as explained in scheme IV.
  • Functional group interconversion of the hydroxyl group of compound (12) into Y can be accomplished readily by employing methodology common to one familiar with the art of organic synthesis.
  • glycosidation as described herein in scheme I of tetracyclic derivative (12) can give structures of formula (10) in which Y is a saccharide; acetylation or benzoylation of compound (12) can give structures of formula (10) in which Y is O-COR and R is an alkyl or aryl; alkylation of the hydroxyl in derivatives of formula (12) can be accomplished with various known electrophiles, for example alkyl halides, orthoformates, or others, with or without catalysis, to give compounds of formula (10) in which Y is an alkoxyl; the hydroxyl group in formula (10) can be converted into a displaceable atom or group L in which L is selected among known leaving groups such as a halide, obtained for example by treating the alcohol with triphenylphosphine in the presence of carbon tetrachloride, carbon tetrabromide or iodine, or a sulfonate such as a mesylate,
  • Y-CN can be obtained by displacement of L with a cyanide
  • Y-alkyl, alkenyl, or alkyne can be obtained by displacement with a carbanion.
  • quinone (34) can be transformed into the isochromandione of formula (59), with the desired Y group as defined herein, by applying readily available techniques in organic chemistry.
  • Reaction of an homophtalic anhydride of formula (23) with an isochroman such as (59) in the presence of a strong base such as lithium diisopropylamide or sodium hydride in a solvent such as tetrahydrofuran can then give the tetracyclic intermediate of formula (60).
  • the phenol of this latter compound can then be transformed into various functional groups by using techniques available to the organic chemists, thus giving the tetracycle of formula (10).
  • scheme IX A more general approach for the preparation of compounds of general formula (10) is shown in scheme IX.
  • known compounds of formula (61) in which L is a displaceable atom or group such as an halogen or a mesylate, tosylate, or triflate, can be reacted with an intermediate of formula (62) in the presence of base to give an adduct of formula (63).
  • the required acyclic compounds of formula (62) are either known or easily obtainable.
  • Cyclization of (63) to give (64) can be accomplished in an aprotic solvent such as tetrahydrofuran or ether and in the presence of a non nucleophilic base such as sodium hydride or lithium diisopropylamide.
  • the ester group of (64) can then be transformed into various groups, as defined herein for R 6 , by using known methodology.
  • Intermediates of general formula (65) can then be used to prepare the desired tetracycie (10) by following route a.
  • oxidative demethylation of (65) with an oxidant such as eerie ammonium nitrate would give quinones of formula (66), which can then be coupled with various homophtalic anhydrides of formula (23) to give tetracyclic heteronaptacenediones of formula (68).
  • Oxidation of (68), for example via free radical bromination with n-bromosuccinamide or bromine in carbon tetrachloride or other compatible solvents, followed by treatment of the bromide with water can lead to aglycones of formula (12).
  • X 3 alternative oxidation procedures may be required.
  • Such approaches are common and well described in the literature.
  • the conversion of compound (12) into (10) can be accomplished as described herein in other schemes.
  • electrochemical reduction of intermediate (65) in methanol in the presence of sodium methoxide can give the bisketal intermediate of formula (69).
  • Mono deprotection in the presence of a weak acid in aqueous media can give the quinone monoketal of formula (70).
  • This latter intermediate can then be coupled under strongly basic conditions achieved for example with NaH in aprotic media, with known benzofuranones of formula (71) in which Z is an electron withdrawing group such as cyano or phenylsulfone.
  • the resulting heteronaphtacenediones of formula (72) can then be converted to the desired tautomer (11) by using the same methodology as described herein for compounds (25) or (68).
  • the leaving group of compound (74) can then be displaced with a nucleophile such as (62), as discussed in scheme IX herein, to give key intermediates of formula (75). These latter compounds can then be deprotected in acidic aqueous media to give benzaldehydes of formula (76). Cyclization of these intermediates can be accomplished with bases such as methoxide, carbonates, sodium hydride or lithium diisopropylamides in compatible solvents. Intermediates of formula (77) can then be further transformed to the desired key compounds of formula (65) by following either routes a. or h.
  • the hydroxyl group of benzoderivative (77) can be transformed into functional groups R 7 to give (64) and subsequently (65), by using simple derivatizing techniques commonly used by the one familiar with organic synthesis.
  • Route b can be employed when R 6 ' is a hydrogen.
  • dehydration of (77) to give (78) can be carried out under basic or acidic media. Transformation of the ester functionality of structure (78) into R 6 , as defined herein, is possible by using known methods.
  • the resulting derivatives of formula (79) can then be oxidized to give compounds of general formula (65) by using known oxidation techniques.
  • a preferred mode for the preparation of compounds with general structure (10) is shown in scheme XI.
  • compounds of formula (61) are coupled, under basic conditions in a suitable solvent such as benzene or tetrahydrofuran, with intermediates of formula (80) to give adducts such as (81).
  • Compounds of formula (80), in which Pg is a protecting group such as benzoyl, and R 6 ' or R 6 are preferably electron withdrawing groups, are accessible by derivatising known compounds.
  • Deprotection of (81) with sodium hydroxide in protic solvent can give intermediates of formula (82) which can thereafter be cyclized under basic media in aprotic solvent to give the bicyclic intermediates of formula (65).
  • compounds of formula (81) for the preparation of quinone derivatives such as (85) or (87).
  • compounds of formula (81) can be oxidized to give (83) by using known methods.
  • benzylic bromides can be oxidised with sodium bicarbonate in dimethylsulfoxide or with other known reagents to give aromatic aldehydes.
  • Deprotection of (83), for example benzoate hydrolysis with sodium hydroxide can directly give hydroxylated heterocyclic compounds of formula (84).
  • These latter derivatives are easily oxidatively demethylated with an agent such as eerie ammonium nitrate to give quinones of formula (85).
  • Compounds of formula (10) are readily prepared from (85) by using methodology described herein in other schemes.
  • a known quinizarin derivative of formula (88) is converted to anthraquinone (90), in which OPg is a protected phenol and L is a displaceable atom or group, by protecting the hydroquinone in (88) as an alkoxyl, an acyl, a silyl or an ether by using known protecting methodology, and then treating for example the resulting protected quinizarin of formula (89) with n-bromosuccinamide or bromine, in a solvent such as carbon tetrachloride under free radical catalysis.
  • compound (90) into (11) can be achieved by using methodology already described herein in other schemes.
  • compound (90) can be converted into (11), via (91), (96) and (95), by using the method as described for the conversion of (61) into (86) in scheme XI;
  • compound (90) can be converted into (93), via (91), by using the method as described for the conversion of (61) into (65) in scheme XI;
  • compound (94) can be obtained from (90), via (92) and (93), by following the sequence as described for converting (61) into (65) in scheme IX.
  • the same methods for transforming (67) into (10) can be used for converting (94) into (11).
  • anthracyclines of formulae (10) and (11) can be transformed into other structures at the X ⁇ and X2 positions using synthetic methods known in the art.
  • Convenient reagents for this oxidation are m-chloroperbenzoic acid, hydrogen peroxide or any other known reagents.
  • hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydro-pyranyl, acyl, (e.g. acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl e.g. methyl, t-butyl or methoxymethyl
  • aralkyl e.g. benzyl, diphenylmethyl or triphenylmethyl
  • heterocyclic groups such as tetrahydro-pyranyl
  • acyl e.g. acetyl or benzoyl
  • silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic conditions.
  • Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions.
  • Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF 3 /etherate and acetic anhydride followed by removal of acetate groups.
  • the compounds of formula (10) and (11) are generally obtained as a mixture of diastereoisomers. These isomers may be separated by conventional chromatography or fractional crystallization techniques.
  • the compound of formula (10) or (11) is desired as a single isomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate.
  • Resolution of the final product, or an intermediate or starting material therefor may be effected by any suitable method known in the art: see for example, “Stereochemistry of Carbon Compounds”, by E.L. Eliel (McGraw Hill, 1962) and “Tables of Resolving Agents", by S.H. Wilen.
  • the compounds of the formula (10) and (11) possess anti-cancer and anti-tumor activity.
  • the compounds are also believed to possess antibacterial, antifungal and antiviral activity. While it is possible to administer one or more of the compounds of the invention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
  • the invention therefore provides pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents, comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in association with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients.
  • All the pharmaceutically acceptable salts for example the HCl and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
  • the compound(s) of this invention can be used in combination with other therapeutic agents, including chemotherapeutic agents (Cancer: Principles and Practices of Oncology, 3rd Edition, V.T. DeVito Jr., S. Hellman and S.A. Rosenberg; Antineoplastic Agents edited by W.A. Remers, John Wiley and Sons, N.Y., 1984).
  • chemotherapeutic agents Cancer: Principles and Practices of Oncology, 3rd Edition, V.T. DeVito Jr., S. Hellman and S.A. Rosenberg; Antineoplastic Agents edited by W.A. Remers, John Wiley and Sons, N.Y., 1984.
  • the compounds or pharmaceutical compositions of the invention may be formulated with the therapeutic agent to form a composition and administered to the patient or the compounds or compositions and the therapeutic agent may be administered separately, as appropriate for the medical condition being treated.
  • a compound or composition of this invention can be used in association with one or more of the therapeutic agents belonging to any of the following groups:
  • Alkylating agents such as:
  • 2-haloalkylamines e.g. melphalan and chlorambucil
  • 2-haloalkylsulfides e.g. melphalan and chlorambucil
  • N-alkyl-N-nitrosoureas e.g. carmustine
  • aryltriazines e.g. decarbazine
  • mitomycins e.g. mitomycin C
  • methylhydrazines e.g. procarbazine
  • bifunctional alkylating agents e.g. mechlorethamine
  • carbinolamines e.g. sibiromycin
  • phosph ⁇ ramide mustards e.g. cyclophosphamide
  • Antimetabolites such as:
  • mercaptopurines e.g. 6-thioguanine and 6- (methylthio]purine
  • folic acid antagonists e.g. amethopterin
  • anthracylines e.g. doxorubicin, daunorubicin,
  • acridines e.g. m-AMSA
  • ellipticines e.g. 9-hydroxyellipticine
  • actinomycins e.g. actinocin
  • anthraquinones e.g. l,4-bis[ (arainoalkyl)- amino]- 9,10- anthracenediones
  • anthracene derivatives e.g. pseudourea
  • aureolic acids e.g. mithramycin and olivomycin
  • dimeric catharanthus alkaloids e.g. vincristine, vinblastine and vindesine
  • colchicine derivatives e.g. trimethylcolchicinic
  • epipodophyllotoxins e.g. etoposide
  • maytansinoids e.g. maytansine and colubrinol
  • terpenes e.g. helenalin, tripdiolide and taxol
  • steroids e.g. 4 ⁇ -hyroxywithanolide E
  • quassiniods e.g. bruceantin
  • methylglyoxals e.g. methylglyoxalbis- (thiosemicarbazone);
  • Hormones e.g. estrogens, androgens, tamoxifen,
  • nafoxidine nafoxidine, progesterone, glucocorticoids, mitotane, prolactin);
  • Immunostimulants e.g. human interferons, levamisole and
  • Radiosensitising and radioprotecting compounds e.g.
  • quinolinequinones e.g. streptonigrin and
  • tricothecanes e.g. trichodermol or vermicarin A
  • cephalotoxines e.g. harringtonine
  • Cardioprotecting compounds such as ( ⁇ )-1,2-bis(3,5- dioxopiperazin-1-yl) propane, commonly known as ICRF- 187, and ICRF-198;
  • Drug-resistance reversal compounds such as P- glycoprotein inhibitors, for example Verapamil;
  • Cytotoxic cells such as lymphokine activated killer - cells or T-cells
  • Immunostimulants such as interleukin factors or antigens.
  • compositions of the invention can be in forms suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intraarterial intraperitoneal, intramuscular, subcutaneous and intravenous administration) by inhalation or by insufflation.
  • the formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and roust be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, chremophor-el, twin 80, glycerol, dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils.
  • polyol for example, chremophor-el, twin 80, glycerol, dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution; as a suspension; or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
  • the expression "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except isofar as any conventional media or agent is incompatible with the active ingredient, its use in the present compositions is contemplated. Supplementary active ingredients can be incorporated into the inventive compositions.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
  • the dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its severity; the particular form of the active ingredient, the potency of the active ingredient, and the route of administration.
  • a daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective and substantially non-toxic. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient.
  • the preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
  • the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.
  • a unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred. Expressed in proportions, the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • Antitumor treatment comprises the administration of any of the compounds of this invention in an acceptable pharmaceutical formulation at the effective therapeutic dosage. It is understood that chemotherapy can require the use of any of the compounds of this invention bound to an agent which facilitates targeting the compound to the tumor cells.
  • the agent may be chosen from, for example, monoclonal or polyclonal antibodies, proteins and liposomes.
  • the compounds of this invention could also be administered as monomeric, dimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
  • the compounds of the invention exhibit antitumor or anticancer activity, most notably, antitumor or anticancer activity with human breast cancer, leukemia, colon cancer, lung cancer, renal cancer, ovarian cancer, CNS cancer and melanoma. This list of conditions is however not exclusive, and it is believed that the compounds of the invention will exhibit activity against other tumors and cancers, such as for example pancreatic cancer and bladder cancer.
  • the intermediates are preferably administered as a pharmaceutical composition for the treatment of the conditions listed above, and may be administered in the dosages noted above for the compounds (10) and (11). Moreover, the intermediates may be administered as pharmaceutically acceptable salts or as metal chelate complexes where appropriate, and may be administered as a mixture with other of the intermediates compounds, and/or with compounds of the formula (10) or (11), and/or with one or more of the therapeutic agents or agents targeting cancer or tumor cells.
  • Procedure 2 For larger scale, under argon, a deoxygenated solution containing 10.0 g (55.5 mmol) of 2,5-dimethoxy-6-methylbenzaldehyde, 50g of SO 2 in 600 ml of thiophene free benzene was irradiated with a medium pressure mercury immersion lamp with pyrex filtration for four days. The resulting sludge was extracted three times with 400 ml of IN NaOH and the combined aqueous layer was washed twice with 200 ml of methylene chloride. The aqueous layer was then neutralised with concentrated aqueous HCl and the resulting mixture was then extracted three times with 500 ml of methylene chloride.
  • Step 8 Ethyl [11-acetoxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl]formate
  • reaction mixture was then stirred for 20 min at -78oC, allowed to warm up to room temperature and stirred for one hour.
  • the reaction was then quenched with 10 ml of saturated ammonium chloride, and partitioned between 10 ml of 5% aqueous HCl and 100 ml CH 2 Cl 2 .
  • the organic layer was then separated and washed with 25 ml of water, 25 ml of brine and dried over Na 2 SO 4 .
  • Step 9 (1S,3S) and (1R,3R)-Ethyl [11-acetoxy-1-hydroxy- 5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl] formate
  • Step 10 (1'S,1R,3S) and (1'S,1S,3R)-Ethyl[11-acetoxy-1- (2',3',6'- trideoxy-3'-trifluoroacetamido-4'-O-pnitrobenzoyl-L- lyxohexopyranose)-5,12-dioxo-3,4,5,12-tetrahydroanthraceno-(2,3-c) pyran-3-yl] formate
  • Step 11 (2R,1R,3S) and (1'S,1S,3R)-Methyl[11-hydroxy-1- (2',3,'6'- trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-5,12-dioxo-3,4,5,12- tetrahydroanthraceno (2,3-C) pyran-3-yl] formate)
  • Step 1 p-Nitrobenzyl(5,8-dimethoxyisochroman-3-yl)formate
  • Example 1 step 5 The same methodology as used in Example 1 step 5 was used but with 40g (.18 mmol) of p-nitrobenzylglyoxalate hydrate. A 58% (4.1g) of the titled compound was obtained after flash chromatography (MP: 140-141°C).
  • Step 4 Methyl [6-and 11-hydroxy-5,12-dioxo-3,4,5,12- tetrahydroanthraceno [2,3-c] pyran-3-yl]formate
  • a solution of 2.5M n-butyl lithium (.20 mmol) is added under argon at 0°C to a stirred solution of 0.07 ml of dry diisopropy-lamine in 2 ml of THF and then stirred for 0.5 hour at -78oC.
  • To the LDA was added dropwise over several minutes a solution of 73 mg (0.45 mmol) of homophthalic anhydride in 2 ml of THF and then 100 mg (0.45 mmol) of the pyranoquinone from step 3 dissolved in 3 ml of THF; The resulting mixture was stirred 20 minutes at -78oC, warmed to room temperature, and stirred for one hour.
  • Step 5 Methyl [6-acetoxy-5,12-dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c] pyran-3-yl] formate
  • Step 6 (1S, 3S) and (1R, 3R)-Methyl [6-acetoxy-1- hydroxy-5,12- dioxo-3,4,5,12-tetrahydroanthraceno [2,3-c]pyran-3-yl)formate
  • Glycosidation of the pyranoanthraquinone from step 6 could be carried out by the procedure as described for example 1 step 10.
  • the titled pyranoanthraquinone glycoside could be obtained in an overall yield of 77% (MP: 158-160*C of 1'S,1S,3R and 225-227oC of 1'S,1R,3S).
  • Step 1 Ethyl(6 and 11 hydroxy-5,12-dioxo-3,4,5,12- tetrahydro-anthraceno[2,3-c]pyran-3-yl)] formate
  • Step 3 (1S,3S) and (1R,3R)-Ethyl-[6-acetoxy-1-hydroxy- 5,12- dioxo-3,4,5,12-tetrahydroanthraceno (2,3-c) pyran-3-yl] formate
  • Step 4 (1'S,1R,3S) and (1'S,1S,3R)-Ethyl [6-acetoxy-1- (2',3', 6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-5,12-dioxo- 3,4,5,12-tetrahydroan-thraceno (2,3-c) pyran-3- yl] formate
  • Glycosidation of the pyranoanthraquinone from step 3 above could be carried out by following the procedure as described in example 1, step 10.
  • the titled pyranoanthraquinone glycoside could be obtained in an overall yield of 77% (MP: 158-160°C of 1'S,1S,3R and 225-227°C of 1'S,1R,3S).
  • Step 5 Ethyl [ 6 - 11 -hydroxy- 5 , 12 - tetrahydx ⁇ anthraceno(2,3-c) pyran-3-yl]formate and Ethyl [11-acetoxy-6-hydroxy-5, 12-dioxo- 3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3- yl]formate
  • Step 6 Ethyl [6,11-diacetoxy-5,12-dioxo-3,4,5,12- tetrahydroan- thraceno (2,3-c) pyran-3-yl] formate
  • step 5 The residue from step 5 above was added to a solution containing 5 ml of acetic anhydride, 6 ml of pyridine and 60 mg of dimethylaminopyridine in 50 ml of CH 2 Cl 2 .
  • the mixture was stirred at room temperature overnight under argon and then added to 50g of ice.
  • the aqueous layer was separated and extracted twice with 50 ml of CH 2 Cl 2 .
  • the combined organic extracts were then consecutively washed once with 25 ml of water, twice with 25 ml of IN HCl, 25 ml of water, 25 ml of brine and then dried over Na 2 SO 4 .
  • Step 7 (1S,3S) and (1R,3R) Ethyl [11-acetoxy-1,6- dihydroxy- 5, 12-dioxo-3,4,5,12- tetrahydroanthraceno (2,3-c) pyran- 3-yl] formate.
  • Step 8 (1'S,1R,3S) and (1'S,1S,3R) Ethyl [11-hydroxy-6- acetoxy-1-(2',3',6'-trideoxy-3'- trifluoroacetamido- 4'-O-p-nitrobenzoyl-L-lyxohexopyranose) 5,12-dioxo-
  • Step 9 (1'S,1S,3R) and (1'S,1R,3S) Methyl[11-hydroxy-1- (2', 3',6'-trideoxy-3'-trifluoroacetamido-4'- hydroxy-L-lyxohexopyranose)-5,12-dioxo-3,4,5,12- tetrahydro-anthraceno[2,3-c]pyran-3-yl]formate, HCH-692 and BCH-691 respectively.
  • Step 10 s (1'S,1S,3R) and 1'S,1R,3S) Methyl (11-hydroxy-6- methoxy- 1-[2 ' ,3 ' , 6 '-trideoxy-3- trifluoroacetamido-4 '-hydroxy- L- lyxohexopyranose]-5,12-dioxo-3,4,5,12- tetrahydroanthra- ceno[2,3-c]pyran-3-yl)formate, BCH-674 and BCH-675 respectively.
  • BCH-706 could be isolated by HPLC in 2% yield. Its NMR spectrum is similar to the one obtained from BCH-684 except for the presence of a proton signal for the methoxy ester group at 3.87 ppm instead of signals for the ethyl ester.
  • BCH-683 was also obtained in 17% yield and was assigned to the compound giving the following data. (MP: 190-215° C dec.)
  • Step 12 (1'S,1R,3S) and (1'S,1S,3R) Ethyl (6-hydroxy-11- methoxy-5,12-dioxo-1-(3'-trifluoroacetamido-1- daunosaminyl)-3,4,5,12-tetrahydroanthraceno[2,3- c]pyran-3-yl)formate
  • Step 1 p-nitrobenzyl (5,8-dioxo-5,8-dihydroisochroman-3- yl)
  • Step 3 (1S, 3S) and (1R, 3R) p-nitrobenzyl [1-hydroxy- 5,12- dioxo-3, 4, 5, 12- tetrahydroanthraceno [2,3-c] pyran- 3-yl] formate
  • Step 4 (1'S, 1R, 3S) and (1'S, 1S, 3R)-p-nitrobenzyl [1- (2',3',6'-trideoxyacetamido-4'-O-p-nitrobenzoyl- L- lyxohexopyranose)-5,12-dioxo-3,4,5,12- tetrahydroanthra-ceno [2,3-c]pyran-3-yl]formate
  • glycosides were obtained by the same procedure as described in step 10 of example 1 and by using the aglycone from step 3 of this example. (MP: 192-195°C for 1'S,1S,3R and 173-174oC for 1'S,1R,3S).
  • Step 5 (1'S,1S,3S) Methyl (1-[2' ,3' ,6'- trideoxyacetamido -4 '- hydroxy-L- lyxohexopyranose]-5,12-dioxo-3,4,5,12-tetrahydroantraceno[2,3-c]pyran-3-yl)formate - BCH-672
  • Step 6 (1'S,1R,3S) Methyl (1-[2',3' ,6'- trideoxyacetamido-4'- hydroxy-L- lyxohexopyranose]-5,12-dioxo-3,4,5,12-tetrahydroanthraceno (2,3-c)pyran-3-yl)formate, BCH- 671.
  • Step 2 Cis and trans p-nitrobenzyl (5,8-dimethoxy-1- methyliso-chr ⁇ man-3-yl) formate
  • Step 6 (1S,3R) and (1R,3S) Trans-p-nitrobenzyl(5,12- dioxo-1-methyl-3,4,5,12-tetrahydroanthraceno[2,3- c]pyran-3-yl)formate
  • step 2 Following the procedure as described in “example 4, step 2", the reaction between 95 mg (0.4 mmol) of the sultine from example 1, step 4, with 71 mg (0.2 mmol) of the quinone from step 3 above gave 42 mg (41% yield) of the titled tetracycle. (MP: 154o-156oC).
  • Step 8 (1R,3R) and (1R,3S) Trans-p-nitrobenzyl(5,12- dioxo-7,10-dimethoxy-1-methyl-3,4,5,12- tetxahydroanthraceno [2,3-c] pyran-3-yl) formate
  • step 2 the reaction between 70 mg (0.3 mmol) of the sultine from “example 1, step 4", and 53 mg (0.15 mmol) of quinone from step 4 above gave 30 mg (44% yield) of the titled tetracycle. (MP: 180*-182*C).
  • Step 4 Methyl ( 11-hydroxy-5,12-dioxo-3,4,5,12- tetrahydroanthra- ceno[2,3-c]pyran-3-yl)ketone and Methyl (5-hydroxy-5, 12-dioxo-3,4,5,12- tetrahydroanthraceno[2,3-c]pyran-3- yl)ketone, BCH-687
  • Step 5 Methyl (6,11-diacetoxy-5,12-dioxo-3,4,5,12- tetrahydroan-thraceno[2,3-c]pyran-3-yl)ketone
  • Step 6 Methyl (11-acetoxy-1,6-dihydroxy-5,12-dioxo- 3,4,5,12-tetrahydroanthraceno[2,3-c]pyran-3- yl)ketone.
  • Step 7 (1'S,1R,3S) and (1'S,1S,3R) Methyl (1-[2',3',6'- trideoxy-3'-trifluoroacetamido-L-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-6-hydroxy-11- ac e t o xy - 5 , 12 -di oxo - 3 , 4 , 5 , 12 - tetrahydroanthraceno(2,3-c)pyran-3-yl)ketone
  • Step 8 (1'S') Methyl [1-(N-trifluoroacyldaunosamlne)-6- hydroxy-11-acetoxy-5,12-dioxo-3,4,5,12- tetrahydroanthraceno(2,3-C)pyran-3-yl]ketone.
  • Ethyl-(5,8-dimethoxyisochroman-3-yl) formate (697 mg, 2.62 mmol) was dissolved in toluene (20 ml) and cooled to - 78°C. DIHAL (2.97 ml, 1.5M, 4.45 mmol) was cooled to -78°C and added slowly to the reaction mixture over a period of 15-20 minutes. A TLC taken right away after the addition revealed that the reaction was over. Cold MeOH (4 ml) was added slowly (H 2 evolutionl) and the mixture was extracted with ethyl acetate (3x50 ml). The organic phases were combined, washed with brine and dried over MgSO 4 .
  • Step 5 3-(2-methoxymethoxy)aceto-6-hydroxy-1,2,3,4- tetrahydro-(2-oxygen)napthacene-5,12-dione and 3-(2-methoxymethoxy)aceto-11-hydroxy-1,2,3,4- tetrahydro-(2-oxygen)-napthacene-5,12-dione
  • Step 8 3-(2-acetoxy-1-propyleneketal)aceto-6-acetoxy- 1,2,3,4-tetrahydro-(2-oxygen)naphthacene-5,12- dione and
  • Step 9 3-(2-acetoxy-1-propyleneketal)aceto-6-acetoxy-1- hydroxy-1,2,3,4-tetrahydro-(2-oxygen)naphthacene- 5,12-dione and
  • Step 10 3-(2-hydroxy)aceto-6-hydroxy-1,2,3,4-tetrahydro- (2-oxygen)naphthacene-5,12-dione and
  • a reaction mixture containing both tetracyclic regioisomers from step 5 above (500 mg, 30%, 0.39 mmol) was diaaolved in 20 ml of CH 3 OH followed by addition of 10 ml of 2.5 HCl solution. The mixture was stirred at room temperature for 0.5h before it was extracted with CH 2 Cl 2 (150 ml). The organic layer was washed with H 2 O, dried over MgSO 4 , filtered and then concentrated to a residue that was purified by flash to give an inseparable mixture of the titled compounds. (20 mg, 15%). The following spectra were recorded on the two regioisomeric mixtures.
  • a mixture of tetracyclic compounds from step 5 above (273 mg, 0.71 mmol) was treated with pb(OAc) 4 (370 mg, 3.1 mmol) in dark in the presence of 10 ml CH 2 Cl 2 and 30 ml AcOH at room temperature for 2 days. The mixture was concentrated in vacuo. The residue was partioned between H 2 O and CHCl 3 . The organic layer was washed with brine, dried over MgSO 4 and concentrated to a residue which was then treated with Ac 2 O (4 ml), pyridine (4 ml) and DMAP (68 mg) for 2 houra. 20 ml of H 2 O and 50 ml of CH 2 Cl 2 were added.
  • Step 12 3-(2-hydroxy)aceto-6-acetoxy-1-hydroxy-1,2,3,4- tetrahydro-(2-oxygen)naphtacene-5,12-dione and
  • 1,4-dim ⁇ thoxy-2,3-dibromomethylbenzene (10.0g, 30.88 mmol) was dissolved in CH 2 Cl 2 and M ⁇ OH (750 ml, 6:4) followed by addition of ethyl 2-mercaptoacetate (4.02 ml, 37.06 mmol) with stirring under argon. The mixture was then cooled to 0oC followed by dropwiae addition of sodium methoxide (4.37M, 8.5 ml, 37.06 mmol) over a period of 2h uaing an automatic syringe pump. After 5 minutes the solvent was evaporated and the crude was rediasolved in THF (400 ml) and cooled to 0*C again.
  • Step 3 3-carbomethoxy-6-hydroxy-1,2,3,4-tetrahydro-(2- sulfur)naphthacene-5,12-dione and
  • Step 4 6-acetoxy-3-carbomethoxy-1,2,3,4-tetrahydro-(2- sulfur) napthacene-5,12-dione and
  • Step 2 3,6-dimethoxy-2-broaomethylene-1-(3-t-Butylcarboxylate), 3-benzoate, 2-butanone 4-yl) benzene
  • Step 9 Methyl 5,8-dimethoxy-1-hydroxyisochroman-3-yl ketone
  • Step 11 Methyl(1-hydroxy-6 and 11-hydroxy-5,12-dioxo-3,4- 5,12- tetrahydroanthraceno(2,3-c)pyran-3- yl)ketone
  • Step 6 6-hydroxy-1-methoxy-l,2,3,4-tetrahydro-3-vinyl- (2-oxygen) naphthacene-5,12-dione
  • Step 7 6-acetoxy-1-methoxy-1,2,3,4-tetrahydro-3-vinyl(2- oxygen)naphthacene-5,12-dione
  • Step 8 6-acetoxy-1-hydroxy-1,2,3,4-tetrahydro-3-vinyl- (2-oxygen)naphthacene-5,12-dione
  • reaction mixture was extracted with CH 2 Cl 2 , washed with water, dried over MgSO 4 , filtered, and then concentrated to a crude residue that was purified by flash chromatography (hexane, CH 2 Cl 2 , ethyl acetate, 2:2:1) to give title compound (4 mg, 11 mmol) in 26% yield.
  • Step 2 Methyl 3-(2'bromomethyl-3'-6'-dimethoxy)phenyl-2- methoxyisopropyloxy propionate
  • Step 4 5 , 8-dimet h oxy-i sochroman-3-y l-formic acid

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