WO1994011382A1 - Antineoplastic heteronaphthoquinones - Google Patents

Antineoplastic heteronaphthoquinones Download PDF

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WO1994011382A1
WO1994011382A1 PCT/CA1993/000463 CA9300463W WO9411382A1 WO 1994011382 A1 WO1994011382 A1 WO 1994011382A1 CA 9300463 W CA9300463 W CA 9300463W WO 9411382 A1 WO9411382 A1 WO 9411382A1
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Prior art keywords
dioxo
pyran
lyxohexopyranose
trideoxy
methyl
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PCT/CA1993/000463
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French (fr)
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WO1994011382B1 (en
Inventor
Giorgio Attardo
Tibor Breining
Marc Courchesne
Jean-Louis Kraus
Serge Lamothe
Jean-François LAVALLEE
Elaine Lebeau
Dieu Nguyen
Rabindra Rej
Yves St-Denis
Wuyi Wang
Yao-Chang Xu
France Barbeau
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Biochem Pharma Inc.
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Priority to EP93924460A priority Critical patent/EP0659190A1/en
Priority to CA002146548A priority patent/CA2146548A1/en
Priority to AU54140/94A priority patent/AU5414094A/en
Publication of WO1994011382A1 publication Critical patent/WO1994011382A1/en
Publication of WO1994011382B1 publication Critical patent/WO1994011382B1/en

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    • 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
    • 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
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • 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
    • C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
    • 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

Definitions

  • This invention relates to heterocyclic naphthoquinone derivatives, to processes and to intermediates for preparing these derivatives, to pharmaceutical compositions containing them and to the use of these derivatives as antitumor agents in mammals.
  • Anthracycline antibiotics including doxombicin 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, doxombicin (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, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxombicin, 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., Anthracychnes; 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; McGiath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthncyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
  • FIG. 1 A first figure.
  • Tricyclic variants (3) of daunonibicin have been reported to possess antitumor activity (EPA 91202015.3)
  • R is COCH 3 or C_CH or C_C-Si(CH 3 ) 3
  • R 3 is H or COCF 3 Pyranonaphthoquinones such as nanaomycin A ( 4) and kalafungin (5) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czemiak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
  • Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P.l and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently thiopyranoanthraquinone (7) and pyranoanthraquinone (8) were found to possess antitumor activity (PCT, CA9100208). In contrast antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycles 26 (4), 879-82, 1987).
  • the present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
  • the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused to a hydroxyl group or alternatively to a sugar moiety.
  • This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity.
  • Some of the compounds are active against certain doxorabicin-resistant tumor cells, and are more potent in some cases than the corresponding tetracyclic heteroanthracycline compound.
  • X 1 and X 2 are independently selected from the group consisting of
  • R is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 1-15 acyl and C 1-16 alkylamine.
  • X 3 is selected from the group consisting of O, S, SO, SO 2 , and NR, wherein R is selected from the group consisting of hydroxyl, C 1-16 alkyl, C 1-16 alkyl, C 1-16 aryl, C 1-16 haloacyl, and hydrogen.
  • X 4 is selected from the group consisting of C-Q, nitrogen, and NO.
  • R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 1-16 alkoxyl, C 3-8 cycloalkyl, tosyl, mesylate, acetate optionally substituted with a C 1- 8 alkyl, triflate, trifiuoroacetate, halogen, nitro, cyano, C 1-16 acyl, C 1-16 arylacyl, aminoalkylaminoalcohol of formula NH(CH 2 ) n NH(CH 2 ) m OH wherein n and m are independently 1 to 4, aminoalkylaminoalkylhalide of formula NH(CH 2 ) n NH(CH 2 ) m X wherein n and m are independently 1 to 4 and X is a halogen,
  • C 1-8 alkyl di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl and C 6-18 aryl; C 2-8 alkenyl, and C 2-8 alkynyl,
  • haloalkylnitrosoureido of the formula NH(CO)N(NO) (CH 2 )n CH 2 X, wherein n is 0 to 4 and X is a halogen, and
  • R* and R** are independently selected from hydrogen, C 1-8 alkyl, C 6-18 aryl, C 7-18 aralkyl, C 1-8 acyl, and trifluoroacyl,
  • R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 2-12 alkoxyalkyl, C 7-18 aralkyl, C 7-18 araloxyalkyl, C 7-18 aryloxyalkyl and C 6-18 aryl,
  • Z is one of C-R 6 or C-R 7 .
  • R 6 is selected from the group consisting of C 1-16 hydroxime, C 6-18 hydrazone, C 1-16 hydroxyalkyl, hydrogen, C 6-18 aryl, C 7-18 aryloxyalkyl, C 7-18 araloxyalkyl, phenyl, C 1-16 alkyl, acetoxy, C 1-16 dihydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, squaric acid, C 1-16 alkyl squarate, amino, cyano, dimethylpbosphonato, phenyl sulfone, C 1-8 aryl sulfone, and
  • C 1-8 acetyl, agroup of the formula -C(R) X* wherein X is selected from the group consisting of two hydrogens, one hydrogen and R* is selected firom a C1-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and O, or its dioxolane or dioxane or dialkoxy C1-8 ketal, and wherein R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 1-8 thioalkyl, C 3-8 cycloalkyl, C 6-18 aryl, C 7-18 aralkyl, fluoromethyl, difluoromethyl, C 1-8 hydroxyalkyl, C 2-16 alkene, squaric acid, C 2-16 alkyne, C 1-8 thioalkyl, C 6-18 thioaryl, C 1-4 alkyl squarate, C 2-8 alkoxyalkyl, C 6-18 araloxyalkyl, C 2-18
  • R* and R** are independently selected from the group consisting of C 1-8 alkyl, hydrogen, PO (OR) 2 wherein R is selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, and
  • n O to 7 and Z* is from the group consisting of hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl;
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
  • amino which may be unsubstituted or mono- or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 atyl, C 2-8 alkenyl, C 3-8 alkynyl and hydroxy.
  • Z* can also be a group of the formula -NR* R** wherein R* and R** are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxyalkyl, C 1-8 acyloxyalkyl, C 6-12 araloxyalkyl, and a group of formula -CO(CH 2 ) n C(PO(OR) 2 ) 2 wherein n is 1 to 4 and R is hydrogen or C 1-8 alkyl; and a naturally occurring amino acid;
  • R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxyalkyl, C 7-18 aryloxyalkyl, C 6-18 araloxyalkyl, C 6-18 aryl and C 7-18 aralkyl;
  • n 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkoxyalkyl, C 1-8 alkoxy, C 7-18 aryloxyalkyl, C 7-18 araloxyalkyl, C 6-18 aryl, C 7-18 aralkyl,
  • heterocycle selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C 1-4 alkyl and aryl, said heterocycle being optionally substituted with one or more halogens, C 6-18 arylsulfone, hydroxy, C 1-16 alkoxy, nitro, C 1-16 alkyl, C 1-16 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C 1-8 alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
  • R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkoxyalkyl, C 7-12 aryloxyalkyl, C 7-12 araloxyalkyl, C 6-12 aryl, C 7-18 aralkyl and C 1-16 alkenyl.
  • R 5 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 1-16 alkoxyl, C 1-16 alkyl, C 2-16 acetylenyl, a group of the formula -(CH 2 ) n -NR*R** wherein n is 1 to 6, and R* and R** are independently selected firom a group consisting of C 1-8 alkyl, C 1-4 acyl, C 3-8 cycloalkyl, hydrogen, C 2-8 carboalkoxy, C 2-8 alkene, C 2-8 alkyne, C 6-12 aryl, and (OCH 2 CH(PO(OR) 2 ) 2
  • R is a hydrogen or a C 1-8 alkyl and wherein n is 0 to 5;
  • R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 2-8 alkoxyalkyl, and C 6-12 aryl;
  • R and R* are independently selected from the group consisting of hydrogen, C 1-12 alkyl, C 6-12 aryl, C 2-8 dihydroxyalkyl, C 2-8 alkene, C 2-8 alkyne, C 1-8 alkoxy, C 1-8 alkylamino, C 3-8 cycloalkyl, C 2-8 carboalkoxy, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and NR
  • R is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1- 4 alkyl and C 6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy; mono or oligosaccharides of the formula:
  • Y is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, CR*R**, wherein R* and R** are independently selected from the group consisting of hydrogen, C1-8 alkyl, and NR wherein R is selected from the group consisting of hydrogen, C 1-8 alkyl, and C 1-8 acyl.
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C 1-16 alkoxy, C 1-16 alkyl, C 3-8 cycloalkyl, thiol, amino, trifluoroacetamido, chloroethylnitrosoureido, and chloroethylureido.
  • R 11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, t-butylacyl, C 1-8 alkoxy, tbutyloxycarbonyl, trifluoroacyl, C 7-12 aralkyl, C 6-12 aryl, and a naturally occuring or synthetic amino acid; mono or dibenzylated amino, azido, acylated amino, trifluoroacylated amino, morpholino, cyano substituted morpholino, mono-, di-,- tri- or tetra-methoxy substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, C 1-16 alkoxyl, C 3-8 cycloalkyl, thiol, sulfide;
  • chloroalkylnitrosoureido of the formula NH(CO)N(NO)CH 2 ) n CH 2 Cl wherein n is 0 to 4, and
  • R 12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, memo or bligosaccharides, C 1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C 1-16 alkoxy, C 3-8 cycloalkyl, C 2-8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, one of the group consisting of p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitro-soureido of the formula NH(CO)N(NO)(CH 2 ) n CH 2 Cl wherein n is 0 to 4, and NH(CH 2 ) 2 OCH 2 CH(OA c ) 2 .
  • -OTHP tetrahydropropyl
  • R 5 and R 8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO 2 , P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
  • Preferred compounds of formula (12) 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 O, S, SO, SO 2 , NH, and NOH.
  • X 4 is selected from the group consisting of CQ, N, and NO.
  • R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen, hydroxyl, C 1-4 alkoxyl, tosyl, triflate, fluorine, chlorine, amino, aminoalkylaminoalcohol of formula NH(CH 2 ) n NH(CH 2 ) m OH wherein n and m are independently 1 to 3, aminoalkylaminoalkylchloride of formula NH(CH 2 ) n NH(CH 2 ) m Cl where n and m are independently 1 to 3, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH 2 ) n CH 2 Cl, wherein n is 0 to 4, and a group of the formula -O-
  • R is selected from the group consisting of hydrogen, C 1-6 alkyl, and aryl;
  • R is selected from the group consisting of hydrogen, C 1-8 alkyl, aryl, C 1-8 alkenyl;
  • Y is selected from the group consisting of oxygen, sulfur, and CHR wherein R is hydrogen or C 1-4 alkyl
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl;
  • R 11 is selected from the group consisting of amino which may be unsubstituted or memo- or di- substituted with C 1-8 acetoxy alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl and aryl; morpholino, azido, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, hydroxyl, mono or dialkylated amino with 1 to 16 carbons, C 1-8 alkoxyl, a group of the formula NH(CH 2 ) n CH(OR) 2 wherein R is independently selected from a group consisting of C 1-8 alkyl, C 1-8 acyl and C 7-12 aroyl and wherein n is 1 to 5; chloroalkylnitrosoure
  • R 12 is selected from the group consisting of hydroxyl or its tetrahydropynnyl ether, halogen, mono or oligosaccharide selected from the group consisting of rhodosamine, cineralose-B, L-cineiulose, D- cineralose, cinemlose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, trifluoroacetyl-daunosamine, amino, trifluoroacetamido, mono or dimethylated amino, C 1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkyl-nitrosourea, acetoxy and trifluoroacetoxy.
  • X 1 and X 2 are independently selected from the group consisting of
  • X 3 is selected from the group consisting of 0, S and SO.
  • X4 is selected from the group consisting of CQ and N.
  • R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen, hydroxy, methoxy, halogen, amino-ethylaminoethanol, aminoethylaminoethylchloride, chloroalkyl-nitrosoureido of the formula NE(CO)N(NO)(CH 2 ) n CH 2 Cl wherein n is 0 to 2; amino, and
  • Z is one of C-R 6 or C-R 7 .
  • R 5 and R 8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1-4 alkoxy, C 1-6 alkyl, C 2-4 alkene,a group of the formula -(CH 2 ) n NR*,R** wherein n is 1 to 4 and R* and R** are independently selected from the group consisting of hydrogen, C 1-5 alkyl, C 1-4 acyl; acosamine, 2,6-dideoxy ⁇ hamnose, thiodau nosamine, C 1-5 thioalkyl, a naturally occurring amino acid or dipeptides thereof, a group of the formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH 2 and NR** wherein R** is selected from the group consisting of hydrogen, C 1-4 alkyl and C 2- 4 acyl, and wherein R and R* are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkene, C 1-5 alkylamino,
  • Y is selected from the group consisting of oxygen, sulfur, and CH 2:
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, and iodine.
  • R 11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, a group of the formula NH(CH 2 ) n CH(OR) 2 wherein R is selected from the group consisting of C 1-4 alkyl, C 1-4 acyl or C 7-8 aroyl and wherein n is 2 to 5, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH 2 ) n CH 2 Cl wherein n is 0 to 4, NH(CH 2 ) 4 CH(OAc) 2 , NH(CH 2 ) 2 OCH 2 CH(OAc) 2, and NH(CO 2 )OCH 2
  • R 12 ⁇ s selected firom the group consisting of hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, amino, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine;
  • R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and NR wherein R is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 acyl, said heterocycle being optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-substituted by C 1-4 alkyl, C 1-4 acyl and trifluoroacyl.
  • a still further preferred compound of formula (12) are those wherein X 1 and X 2 are both oxygen;
  • X 3 is 0, S or SO
  • X 4 is selected from the group consisting of N, or CQ;
  • R 1 , R 2 , R 3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl, and methoxy.
  • Z is one of C-R 6 or C-R 7 .
  • R 7 is selected from the group consisting of hydrogen, fluorine, methyl, and cyano;
  • R 5 and R 8 are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl, and
  • Y is selected from oxygen and CH 2 , and
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, and iodine.
  • R 11 is selected from the group consisting of amino, hydroxy, dimethylamino, acetoxy, trifluoroacetamido, morpholino, cyano substituted morpholino, methoxymorpholino and a group of the formula NH(CH 2 ) n CH(OR) 2 wherein R is selected from a group consisting of methyl, acyl or benzoyl and wherein n is 3 to 5, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH 2 ) n CH 2 Cl wherein n is 0 to 4, and NH(CH 2 )OCH 2 CH(OA c ) 2
  • R 12 is hydroxyl,iodine, or bromine.
  • Still further preferred compounds of formula (12) are those wherein
  • X 1 and X 2 are both oxygen.
  • X 3 is O or S.
  • X 4 is CQ.
  • R 2 and R 3 are both hydrogen.
  • R 1 and Q are independently selected from the group consisting of hydrogen, fluorine, and hydroxyl.
  • Z is one of C-R 6 or C-R 7 .
  • R 6 is selected from the group consisting of ethyl, hydroxymethyl,
  • R 7 is selected from the group consisting of hydrogen, methyl, or fluorine
  • R 5 and R 8 are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and a saccharide of the formula
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, and iodine.
  • R 11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino;
  • R 12 is selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine, with the proviso that at least one of R 5 and R 8 is saccharide.
  • the invention also seeks to provide a process for the preparation of a compound of formula ,
  • X 3 is selected from the group consisting NR, O, or S, R 6 is methyl ketone or is as defined in claim 1; and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , X 1 , X 2 X 4 and Z are as defined in claim 1
  • L is a leaving group selected firom the group consisting of halogen, tosyl, benzoyl, p- nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen, C 1-16 alkyl, C 1-16 acyl, C 1-16 acyl, C 3-16 alkylsilane, C 8-16 alkylaryl silane and dimethylamino,
  • R 9 , R 10 , R 11 and R 12 are defined as in claim 1 and L is as defined above;
  • step (I) (1) wherein R 5 is -OH, with a saccharide of the formula
  • step (I) (2) to yield a bicyclic quinone sacharide of the formula
  • A is NR wherein R is selected from the group consisting of H, C 1-16 alkyl, C 7-16 acyl; and L is defined as above;
  • halogens are independently selected firom the group consisting of Cl, Br and I, and X 3 is selected from the group consisting of O, S, and N;
  • A is NR wherein R is selected from the group consisting of H, C 1-16 alkyl, C 7-16 aryl, and L is a leaving group as defined in (I)(2):
  • the resultant compound may optionally be converted to the hydroxyl form of formula
  • the quinones at positions X 1 and X 2 may be converted to other moities such as, for example,
  • the compound may further be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
  • V a dimethoxyisothiochroman of formula
  • 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 , one or more alkoxy sustituent, one or more hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
  • halo substituent such as F
  • 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 firom 6 to 10 carbons in the ring portion, such as phenyl, naphtyl, substituted phenyl, naphtyl, 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, hydroxy 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.
  • aroyl 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 phenoxymethyl.
  • araloxyalkyl as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
  • acyloxyalkyl as used herein means a C 1-8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
  • hydroxyalkyl as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, 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 stereochemical centos, when pertinent, at C 1 , C 2 and C 3 as well as in all the other chiral centers.
  • This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (42) and (43).
  • Heteronaphthoquinones of general formula (12) are prepared by using Scheme I.
  • new or known isochromans of formula 14, where R 5 is not a saccharide (PCT CA 9100208)
  • an oxidant such as cerie ammonium nitrate or- silver oxide in an adequate solvent mixture such as acetonitrile-water
  • Cycloaddition of this latter quinone with dienes of general formula 16 in a solvent such as toluene can give the tricyclic heteronaphthoquinone of formula 17.
  • two independent synthetic routes A 2 or B may be employed.
  • Suitable leaving 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.
  • sugars are obtained by derivatizing known saccharides of the family of anthracycline antibiotics which are available from commercial or natural sources, (see for example, Monneret, 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, 638-645, 1984 and references therein; Arcamone F., Cancer Research, 45, 5995-5999, 1985 and references therein).
  • the aglycone of formula 17 is typically reacted with the appropriate sugar derivative of formula
  • 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 tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g.
  • 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 (42) and (43) are generally obtained as a mixture of diastereoisomers. These isomers may be separated by conventional chromatography or fractional crystallization techniques.
  • 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 (12) and (13) possess anti-cancer and anti-tumor 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 ingredients) 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. It will be appreciated by those familiar with the art of clinical oncology that 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.
  • 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
  • N-alkyl-N-nitrosoureas e.g. carmustine, lomustine or
  • aryltriazines e.g. decaibazine
  • mitomycins e.g. mitomycin C
  • methylhydrazines e.g. procaibazine
  • bifunctional alkylating agents e.g. mechlorethamine
  • carbinolamines e.g. sibiromycin
  • phosphoramide mustards e.g. cyclophosphamide
  • Antimetabolites such as:
  • mercaptopurines e.g. 6-thioguanine and 6-
  • folic acid antagonists e.g. amethopterin
  • anthracylines e.g. doxombicin, daunorubicin, epir ⁇ bicin, esorubicin, idambicin, aclacinomycin A
  • anthracylines e.g. doxombicin, daunorubicin, epir ⁇ bicin, esorubicin, idambicin, aclacinomycin A
  • acridities e.g. m-AMSA
  • ellipticines e.g. 9-hydroxyellipticine
  • actinomycins e.g. actinocin
  • anthraquinones e.g. 1,4-bis[(aminoalkyl)- amino]-9,10-anthracenediones
  • anthracene derivatives e.g. pseudourea and bisanthrene
  • aureolic acids e.g. mithramycin and olivomycin
  • Camptothecins e.g. topotecan
  • colchicine derivatives e.g. trimethylcolchicinic acid
  • etoposide and teniposide etoposide and teniposide
  • maytansinoids e.g. maytansine and colubrinol
  • terpenes e.g. helenalin, tripdiolide and taxol
  • steroids e.g. 4ß-hyroxywithanolide E
  • quassiniods e.g. bniceantin
  • methylglyoxals e.g. methylglyoxalbis-(thiosemicarbazone);
  • Hormones e.g. estrogens, androgens, tamoxifen, nafoxidine, progesterone, glucocorticoids, mitotane, prolactin;
  • tricothecenes e.g. tnchodermol 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, cyclosporin-c, fujimycin;
  • Cytotoxic cells such as lymphol ⁇ ne activated killer -cells or T-cells,
  • Immubostimulants such as interleukin factors or antigens.
  • Taxanes such as taxol and taxotere.
  • 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 must 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, tween
  • 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 antifimgal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include 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 filter sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique. These methods 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, sachets 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 antifimgal 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 calculatpid 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. 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 thempeutic 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, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
  • the compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian 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, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxombicin against P-170 mediated multidrug resistant cancers.
  • Example 4 Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphto[2,3-C] pyran-3-yl) ketone.
  • TMSOTf trimethyl silyl triflate
  • R 1 OH
  • R 2 NHCOCF 3
  • R 1 OH
  • R 2 NHCOCF 3
  • the titled compound was prepared in 62% yield by cyclocondensing the 1'S, 1R, 3S-quinone glycoside from step 1 of this example with 1-methoxy-3-trimethylsilyloxybutadiene. The same procedure as described in step 2, in this example, was used.
  • the titled compound was prepared by applying the same procedure as described in step 8 on the 1'S, 1S, 3R, quinone glycoside of step 1 of this example.
  • Example 6 Tricyclic pyranylnaphthoquinones with a squaric acid molety.
  • Step 3 2-[4'-Hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10- dioxo-3,4,5,10- tetrahydro [2,3-C] pyran-3-yl) ketone
  • Example 7 Tricycle pyranytnaphtoquinone glycosides with a squaric acic moiety.
  • Step l (1'S,1 R,3S) and (1'S,1S,3R)-Bromom ethyl (5,10-dioxo-1-(2',3',6'-trideoxy-4'-O-P- nitrobauoyl-3'-trifluoro acetamido-L-lyxohexopyranose)-(3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
  • Step 1 (1'-S, 1-R, 3-S)-1-(2'-3'-6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoroacetamido-L-
  • Step 2 (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-4'-p-nitrobenzoyI-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-(2,3-c)pyran
  • IR (Nicolet 205 FT, film on NaCl plate): cm -1 , 3455.4 (w), 3346.8 (str), 3119.6 (w), 2923.8, 2850.3, 1731.5 (str), 1665.0 (str), 1532.2 (str), 1273.4 (str), 1217.5, 1182.5 (m), 1161.5 (m), 1101.8, 1005.5, 957.36 (m), 874.2, 721.18 (m).
  • Step 3 (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-3'-tiifluoroacetmido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-(2-aza-3-acetamidoth iazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-
  • IR Nicolet 205 FT, film on NaCl plate: 3539.7 (br,w), 3296.1 (str), 3083.7, 2919.4 (str), 1732.7 (str), 1667.5 (str), 1593.9 (w), 1545.7 (str), 1528.7 (str), 1127.1 (str), 1217.2, 1183.2, 1166.2, 1104.0, 1008.9, 975.46, 956.53, 718.14 (m).
  • Step 4 (1'-S,1-R,3-S)-1-(2',3',6'-tride ⁇ xy-3'-trifluoro acetamido-L-lyxohexopyra nose)-3-(2-aza-3- acetamido thiazolyl)-5,10-di ⁇ xo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
  • IR (Nicolet 205 FT, film on NaCl plate): 3668.0-3119.7 (peaked at 3268.3,br,str), 3073.7 (w), 2925.1, 1711.8 (str), 1669.4 (str), 1591.6 (w), 1549.1, 1375.8, 1290.9 (str), 1170.6, 1006.5 (w), 984.49(str), 716.33 (w).
  • Step 5 (1'-S,1-R,3-S)-1-(2',3',6-'trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5, 0-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C] pyran
  • IR Nicolet 205FT, film on NaCl plate: 3423.9 (str), 3341.1 (str), 2927.0, 2853.4 (w), 1718.5 (str), 1664.4 (str), 1597.5, 1524.7, 1335.0, 1300.1 (str), 1174.0, 100.4, 984.61 (str), 724.51, 707.71.
  • Step 1 (1'-S,1-S,3-R)-1-(2',3'-6'-trideoxy-4'-p-mtrxibenzoyl-3'-trifluro-acetamido-L- lyxohexopyranose)-3-(2-bromoacetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-pyran
  • Step 2 (1'-S,1-S3-R)-1-(2'3'-6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-acetamido)-5,10-dioxo-3,4,5,10 -tetrahydro-1H- naphtho-[2,3-c]-pyran
  • a sample of 1-acetylthiourea (1.06 mg, 9.0 mmol) in ether (2 ml) was stirred at room temperature while a solution of bromomethyl ketone (9 mg, 8mmol), from the previous step, in methylene chloride (0.5 ml) was added.
  • Step 3 (1'-S,1-S3-R)-1-(2',3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- acetamido-thiazolyl)-5,10-di ⁇ xo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
  • a sample of the PNB-derivative (4.0 mg, 5.5 mmol), from the previous step, was taken into a solvent system containing metiiylene chloride (212 ⁇ l) methanol (566 ⁇ l) and water (131 ⁇ l), and cooled to 0°C.
  • Step 2 (1'S,1S,3R) and (1'S,1R3S) methyl (1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-c] pyran-3-yl ketone Under N 2 at room temperature, to 235 mg (0.394 mM) of quinone firom step 1 (example 5) dissolved in 20 ml of dry THF , was added 1.1 eq. (47 mg, 0.399 mol) of hydraztme firom step 1 (example 10), and
  • 6.2 (s,1H,C 1 -H); 6.4 (m, broad, 1H,NH), 8.2 (overlapped m, 1H.C 6 -H-arom), 8.2-8.4 (m,4H,p- nitobenzoyl), 8.2 (m,1H,C 8 -H arom).
  • Step 3 (1'S,1S,3R) and (1'S,1R,3S) methyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-lyxohexopyra nose)-5,10-dioxo-3,4,5,10-tetrahydro-7methyl-O-azanaphtho [2,3- c] pyran-3-yl ketone
  • Step 3 3-Ethyl-1-hydroxy-isochroman-5,8-dione.
  • Step 4 (1'S, 1S, 3S) and (1'S, 1R, 3R)-5,10-dioxo-3-ethyI-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy- L-lyxobexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran
  • the first one (48 mg, 14% overall) contained a 2:1 mixture favoring the (1'S, 1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L-lyoxobexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran over its (1'S, 1R, 3R) isomer and a second fraction (157 mg; 46% overall) consisting in a 1.5:1 mixture of the same major diastereomer that was about 80% pure from 1 H NMR analysis.
  • Step 1 3-Aceto-5,8-dimethoxythioisochroman 1-Thiobenzoate-propan-2-one (10.083g,51.97mmole) was dissolved in MeOH (100ml), cooled to 0°C, followed by the slow addition of NaOMe (4.37M,14.3ml,62.36mmol). The resulting mixture was stirred at 0°C for 3/4 hr. It was then cooled to -78 °C followed by the slow addition of 2,3-dibromomethyl-1,4- dimethoxybenzene (6.74g,20.79 mmol) in CH 2 CI 2 : MeOH (60:20ml). The resulting mixture was slowly warmed to R.T.
  • Step 4 Trans-3-aceto-1-methoxy-l,2,3,4-tetrahydro-(2-sulfur)anthracene-5,10-dione and ds-3- aceto-1-methoxy-1,2,3,4-tetrahydro-(2-sulfur)anthracen e-5,10-dione
  • Trans-3-aceto-1-methoxy-5,8-dioxoisothiochroman (0.66 mmole) was dissolved in dry toluene (14ml), followed by the addition of the diene (120.0 mg, 1.07 mmole). The resulting mixture was stirred at room temperature overnight. Solvent was removed and the crude obtained was flash chromatographed using pure toluene to give the titled compounds in a ratio of about 1:1, in 48% yield.
  • Step 6 cis-3-aceto-1-methoxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione and trans-3- aceto-1-metboxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-S,10-dione
  • Step 7 trans-3-aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione and cis-3- aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione
  • the mixture of compounds obtained from step 6 (example 13) (30.8 mg, 0.102 mmole) was dissolved in CH 3 COOH:H 2 O (2:0,4 ml) at 0°C. The resulting mixture was stirred at 0°C for about 2 hours. NaHCO 3 (5 %) was added and it was extracted with CH 2 CI 2 .
  • EXAMPLE 15 In Vitro Cytotoxidty - Microculture Tetrazolium Assay
  • the microculture tetrazolium assay was used to test in vitro cytotoxicity. This assay is described in Plumb, J.A. et al., 1989 Cancer Research 49, 4435-4440, which is herein incorporated by reference.
  • the cytotoxicity of compounds towards tumor cells is measured in vitro using the assay.
  • This assay method is based upon the ability of live, but not dead cells to reduce the yellow water soluble dye 3- ⁇ 4,5- dimethylthiazol-2-yl)-2,5-diphenyltetnzolium bromide (MTT) to its water insoluble purple formazan product.
  • MTT yellow water soluble dye 3- ⁇ 4,5- dimethylthiazol-2-yl)-2,5-diphenyltetnzolium bromide
  • SKOV3 (Ovarian adenocarcinoma) - provided by Dr. V. Ling, Ontario Cancer Institute.
  • T47D Ductal carcinoma of breast
  • HTB-133 ATCC catalog # HTB-133.
  • the cells were maintained in exponential growth in culture in minimal essential media (MEM) supplemented with non-essential amino acids, and containing 15% (v/v) fetal bovine serum, 5mM L- glutamine, 1 mM sodium pyruvate, and 0.1 U/ml insulin. All cell lines were grown at 37 °C in an atmosphere of 5% CO 2 in air.
  • MEM minimal essential media
  • Sorensen's buffer 0.1M glycine/NaOH, pH 10.5, containing 0.1M NaCl.
  • Test compounds 20 mM in DMSO and diluted to a final concentration of 200 ⁇ M in culture medium before use.
  • doxombicin is included as an inter-assay standard. This allows us to monitor the behaviour of the assay in general, and in particular, to check that the SKVLB line has maintained its resistant phenotype.
  • the plate layout is done in the following manner
  • the assays are carried out in 96-well (8 well x 12 well) microtiter plates. Serial dilutions of the compound are tested along the length of the plate. A 1:3 serial dilution of compound in culture medium covers a concentration range from 100 ⁇ M to 1.7nM. Each concentration of con ⁇ ound is tested in quadruplet, allowing two compounds to be tested per plate. Wells containing no cells (blank) and cells with no test compound (control) are included on each plate.
  • Cells are plated out in 100 ⁇ l of culture medium in the microtiter plates at a density of around 1,500 - 4,000 cells per well. The plates are incubated overnight to allow the cells to become adherent after which the test compound is added (100 ⁇ l of appropriate dilution per well). The cells are incubated with test compound at 37°C for 48h after which the compound is replaced with fresh medium. After a further 48h incubation at 37°C, 50 ⁇ l of MTT solution (2mg/ml) is added to each well. The plates are incubated in the dark for 4h at 37°C after which the medium is removed.
  • the MTT formazan product is extracted firom the cells by the addition of 200 ⁇ l DMSO followed by 50 ⁇ l of Sorensen's buffer. The plates are shaken briefly and the absorbance at 570 nm is read using a Molecular Devices UV max plate reader. Curves are fit to the MTT assay data using a four parameter logistic equation, and the data are normalized to fit a 0% to 100% survival scale.
  • Tables 1 and 2 show the antitumor activity of some of synthetic tricyclic pyranylnaphthoquinones of this invention. A range of potency is observed. In this set of compounds. Several tricyclic naphthoquinones are intensely potent and are effective in the multidrug resistant cell line SKVLB. In breast cancer, MCF- 7, BCH-1146 is less potent than adriamycin but nearly as effective in the sensitive and adriamycin resistant cell line. These results suggest that tricyclic derivatives such as BCH-1184 and 1146 should be usefid in the treatment of certain resistant cancers. Most notably BCH-2051, a "sugarless" tricyclic naphthoquinone, possesses intense in vitro antitumor potency while significantly avoiding multidrug resistance as observed from the SKVLB cell line.
  • Mediyl (5,8-dimethoxy-isochroman-3-yl) formate (15.00 g, 59.46 mmol) and DDQ (16.20 g, 71.35 mmol) were dissolved in dry dichloromethane (500 ml), and dry methanol (7.2 ml, 178.37 mmol) was added. The solution was stirred at ambient temperature overnight, then refluxed for 8 hours. Methanol (1.0 ml, 24.69 mmol) and DDQ (2.00 g, 8.81 mmol) was added and further refluxed for 8 hours. The reaction mixture was cooled down, filtered, and the filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml).
  • Step 3 Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1 H-naphtho[2,3-c]pyran-3-yl) formate
  • Methyl (1-med ⁇ oxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1- acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in toluene (200 ml), silica gel (20 g) was added and stirred over 24 hours in an open flask at ambient temperature. The silica was filtered, the filtrate was concentrated to dryness.
  • Step 4 Methyl (1-metlwxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2 ⁇ -c]pvran-3-yl) formate
  • Mediyl (1-methoxy-5, 10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-3-yl) formate (6.12 g, 20.25 mmol) was dissolved in dichloromethane (120 ml), triethylamine (5.64 ml, 40.49 mmol) was added and stirred at ambient temperature over 1 hour.
  • Step 5 Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl)formate.
  • Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol)
  • 1- acetoxybutadiene (30.00 g, 267.55 mmol)
  • dry toluene 100 ml was stirred overnight at 50 C°.
  • the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g).
  • the crystals formed were filtered and washed with water.
  • the filtrate was extracted with ethyl acetate (4x40 ml). All the oiganic fractions - including the previous extractions as well - were combined, dried (MgSO 4 ) and concentrated to dryness.
  • the residue was combined with the crystals filtered out of the water phase before, and stirred with methanol (50 ml), for 15 minutes.
  • the yellow crystals were filtered, washed with methanol to give the tide product (5.21 g, 86.6 %).
  • Step 7 1-Methoxy-5,10-dioxo-5,1 0-dihydro-1H-naphtbo[2,3-c]pyran-3-[N-(3- dimethylamino-propyl)carboxamide]
  • 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid (4.6 g, 16.13 mmol) was suspended in tetrahydrofuran (46 ml) and DMF (0.1 ml) was added. The suspension was cooled to 0 C° and oxalyl chloride (3.24 ml, 37.09 mmol) was added dropwise over 10 minutes.
  • the reaction mixture was stirred at 0 C° over 30 minutes, then evaporated to diyness at reduced pressure.
  • the residue was dissolved in tetrahydrofuran (50 ml), cooled to 0 C° and N,N-dimethylaminopropylamine (2.23 ml, 17.74 mmol) was added dropwise over 10 minutes.
  • the solution was stirred at 0 C° over 15 minutes, men it was poured onto a saturated solution of potassium carbonate (20 ml).
  • the organic layer was separated, the water layer was extracted with dichloromethane (3x10 ml).
  • the combined organic phases were dried (MgSO 4 ) and concentrated to dryness.
  • the residue was dissolved in methanol (50 ml) and stirred with charcoal at ambient temperature over 30 minutes.
  • Step 8 1-Methoxy-5,10-dioxo-5,10-dihydro-1 H-naphtho[2,3-c]pyran-3- ⁇ N-(3- dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
  • 1-Methoxy-5, 10-dioxo-5, 10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino- propyl)carboxamide] (4.15 g, 11.23 mmol) was dissolved in anhydrous dichloromethane (10 ml) and 1 M hydrochloric acid solution in ether (11.3 ml, 11.23 mmol) was added dropwise at 0 C°.
  • Step 2 (1S,2'S,3R,5'S) and (1R,2'S,3S,5'S)-1-[O-N-BOC-Serine-Leucine-Me ester]-3- aceto-5,8-dimethoxy-isochroman
  • a solution of 5,8-dimethoxy-3-aceto-isochroman (0.46g, 1.93 mmole)
  • the peptide from step 1 (example 17) (0.71 g, 1.1 eq)
  • activated 4A molecular sieves 500 mg
  • dry CH 2 CI 2 (19 ml) was added DDQ (0.57 g, 1.3 eq).
  • Step 3 (1S,2'S,3S,5'S)-Methyl-(1-O-[N-BOC-Serine-Leucine-Me ester]-5,10-dioxo-
  • the crude quinone was then dissolved in dry toluene (7 ml) and acetoxybutadiene was added (0.4 ml, 5 eq). The solution was stirred for 18 hours. Silica gel was then added (1 g) and air was bubbled through the solution for 30 minutes. The silica gel was filtered through Celite and the solvent was evaporated. The brown oil obtained was purified by flash chromatography (silica gel, 1:1 hexanes/EtOAc) to give 115 mg (29%) of the tided tricyclic compound.
  • Step 4 (1S,2'S,3S,5'S)-Methyl-(1-O-[Serine-Leudne-Me ester]-5,10-dioxo -3,4,5,10- tetrahyd ⁇ o-1-H-naphtho [2,3-c] pyran-3-yI) ketone hydrochloride BCH-2000
  • Step 1 N-BOC-serine methyl ester
  • serine methyl ester hydrochloride 0.12 g, 0.78 mmol
  • (BOC) 2 O 0.19 g, 1.1 eq.
  • the soluticm was stirred for 60 minutes. It was then poured in cold 2% HCl and the aqueous layer was extracted with CH 2 CI 2 (3x). The combined organic extracts were dried over MgSO 4 , the solids were filtered and the solvents evaporated to give 0.17 g (100 %) of the titled compound as a clear oil.
  • Step 2 (1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-serine methyl ester]-3-aceto-5,8-dimethoxy isochroman.
  • the titled compounds were obtained as per procedure described in step 2, example 17. They were purified via flash chromatography (silica gel, 2: 1 hexanes/EtOAc). The mixture of isomers is not separable by chromatography.
  • Step 3 (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyI-(1-[O-N-BOC-serine methyl ester]-5,10- dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone.
  • step 3 The same procedure as described in step 3, example 17, was used for the tided compound, which was purified via flash chromatography (silica gel, 2: 1 hexanes/EtOAc).
  • the mixture of isomers is not separable by chromatography.
  • Step 4 (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-seri ⁇ e methyl ester]-5,10-dioxo-
  • Step 1 N-BOC-Prolinol The titled compound was obtained as per procedure described in step 1, example 18.
  • Step 2 (1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-N-BOC-prolinol]-3-acetyl-5,8-dimethoxy isochroman
  • the titled compounds were obtained as per procedure described in step 2, example 17. They were purified via flash chromatography (silica gel, 7:3 hexanes/EtOAc). The mixture of isomers is not separable by chromatography.
  • Step 3 (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10- tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone BCH-2067
  • the titled compounds were obtained as per procedure described in step 3, example 17. They were purified via preparative thin layer chromatography (silica gel, 7:3 hexanes/ethyl acetate).
  • Step 4 (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-prolinol]-3,4,5,12-tetrahydronaphtho-
  • Step 1 5,8-dimethoxy-3-phenylsulphone isochroman
  • 3-chloroperbenzoic acid 80% (18 g, 83 mmol) in portions over 15. minutes.
  • magnesium sulfate (6.8 g, 56 mmol) and sulfinic acid (10 g, 70 mmol) were added.
  • a saturated solution of potassium carbonate was added then the reaction mixture was washed with water and brine. The organic layer was dried over MgSO 4 and evaporated.
  • the titled compound was purified by trituration in ether (11 g, 60%), m.p.: 118-119°C.
  • the titled compound was obtained in 77% yield by applying the procedure described in step 3, example 12, to the precursor of step 3 of this example.
  • Step 5 and 6 (1'S, 1S, 3R) and (1'S, 1R, 3S)-5,10-dioxo-3-cyano-1-(2'3',6',- trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1-H-naphtho-[2,3-c] pyran
  • Step 7 (1'-S, 1-R, 3-S) and (1'-S, 1-S, 3-R)-3-cyano-1-[2',3',6'-trideoxy-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-C] pyran-3-yl BCH-1688
  • Step 4 1-t-Butyl dimethylsUyioxy-3-trifluoroacetamido-4-O-bromoacetyl-2,3,6-trideoxy-L- lyxohexopyranose
  • Step l (1'-S, 1-S, 3-R) and (1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'- trifluoroacetamido-4'-O-methane-sulfonyl-L-lyxohexopyranose)-5,10-dioxo- 3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2095
  • Step 2 (1'-S, 1-S, 3-R)-methyl-(1-[2',3 ',4',6' tetra ⁇ eoxy-3'-trifluoroacetamido-4'-O-(2- bromo-acetyl)-L-lyxopyranose]-5, 10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2105
  • 4-bromoacetyl-1-t-butyl dimethylsilyloxy-3-trifiuoro-acetamido daunosamine derivative (76 mg, 0.13 mmol) molecular sieves ⁇ (62 mg) in CH 2 Cl 2 (1.2 ml) at -50°C under argon was added trimethylsilyl trifluoromethanesulfonate (23 ⁇ l,
  • Step 3 (1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O- methanesulfonyl-L-lyxobexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3- c] pyran-3-yl) ketone BCH-2070
  • the titled compound was obtained in 22% yield by applying the procedure described in step 4, example 12, to the aglycone from example 3 and the glycal from step 2, example 21. Purification was carried out by flash chromatography (toluene/acetone:95/5) M.P. 85-89°C.
  • Step 3 (1'-S, 1'S, 3-R)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-
  • the titled compound was obtained in 11% yield by using the procedure described in step 3 of this example but using the 1,3-diepimeric aglycone. M.P. 139-141°C.
  • Step 4 (1-S, 3-R) and (1-R, 3-S)-methyl-(1-(1-m ethoxy-4-oxocyclohexyloxy)-5,10-dioxo-
  • step 1 of this example was decaiboxylated, in 91 % yield, with concentrated aqueous
  • Step 3 5,8 -Dimethoxy-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
  • the isochroman from 2 herein was glycosidated as per procedure described in step 3, example 34.
  • the title compound was obtained in 97% yield.
  • Step 4 5,8-Dioxo-3-(propane-2 one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p nitrobenzoyl-L-lyxohexopyranose)-isochroman
  • the titled compound was obtained in 94% yield via oxidative demethylation of the isochroman obtained from step 3 herein as per procedure described in step 4, example 34.
  • Step 5 5,10-Dioxo-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-nsphtho-[2,3-c] pyran
  • Step 6 (1'-S, 1-S, 3-R) and (1'-S, 1-R, 3-S)-1-(6-hydroxy-1-(2',3',6'-trideoxy-3'- trifluoroacetamido,4-hydroxy-L-lyxopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) propane-2-one BCH-2098
  • the titled compound was obtained following deprotection of the glycoside from step 5 herein as per procedure described in step 6, example 34.
  • Step 1 (1R, 3S) and (1-S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzyloxy-1,5-dihydro-L-lyxohexo-pyranose-2-yl)-5,8-dimethoxy-3- acetoisochroman
  • Step 2 (1R, 3S)-1-(2',3',6 '-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,8-dioxoisochroman
  • the (1R, 3S) product from step 1 herein was oxidatively demethylatod as per procedure in step 3, example 12.
  • Step 3 (1R, 3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyx oh exopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran
  • Step 4 (1R, 3S)-1-(2',3',6 , -tri deoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L- lyxobcxopyrano6e-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
  • Step 5 (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,8-dioxoisochroman
  • the (1S, 3R) product from step 1 herein was oxidatively demethylated as per procedure in step 3, example 12.
  • Step 6 (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
  • Step 7 (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
  • Step 2 5,8-dioxo-3,3 bis ( methoxycarhonyl)-5,8-dihydro-isochroman
  • acetonitrile 5 ml
  • acetonitrile 5 ml
  • eerie ammonium nitrate 378 mg; 0.69 mmol
  • water 1 ml
  • Example 26 Preparation of (1'S, 1R, 3S) and (1'S, 1R, 3R)-5,10-dioxo-3- methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10 -tetrahydro-1H-naphtbo-[23-c]-pyran (BCH- 1691) and BCH-1693)
  • Step 1 5,8-dimethoxy-3-hydroxy methyl-isochrom an To a solution of 5,8-dimethoxy-3-methoxycarbonyl-isochroman (310 mg; 1.23 mmol) in 5 ml of tetrahydrofuran at 0°C was added lithium aluminum hydride (47 mg; 1.23 mmol). The mixture was stirred at 0°C for 15 minutes and was quenched witii 1 N HCl.
  • Step 3 (1'S, 1R, 3S)-5,8-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexo-pyranose)-5,8- dihydroisochroman and its (1'S, 1S, 3R) diastereomer
  • Step 4 (1'S, 1R, 3S)-5,10-dr ⁇ o-3-methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5,10-tetrahydro-
  • Step 5 (1'S, 1R, 3S)-5,10-dioxo-3-meth oxym ethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran (BCH-1691)
  • Step 6 (1'S, 1S, 3R)-5,10-dioxo-3- methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoaceamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH-1693)
  • Example 27 Preparation of (1'S,1 R,3S) and 1'S,1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',6'- trideoxy-3'trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
  • 1,4-dimethoxybenzene 10.0 g (72.37 mmol) was dissolved in dry THF and this solution was cooled to 0°C.
  • n-BuLi (2.5 M/hexanes) 28.8 ml (72.37 mmol) was then added and the reaction mixture was warmed up to room temperature and stirring was left for 4 hours. After 4 hours, the reaction was cooled to -78°C and 1,2-epoxybutane 5.2 g (72.37 mmol) was added followed by 10.2 g (72.37 mmol) of boron trifluoro etherate. Stirring was then continued for a period of 1 hour.
  • the reaction mixture was then quenched by pouring it into 125 ml of aqueous NH 4 CI. Extractions of the aqueous layer were done using CH 2 Cl 2 . The combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed. The crude material was purified by flash chromatography with hexanes- ethyl acetate (9: 1) then (8:2) as the eluent. The isolated titled compound was a white solid (11.4 g, 75%).
  • the starting material from step 1 of this example 5.00 g (23.78 mmol) was dissolved in 100 ml of dry ether. Dimethoxy methane 3.0 ml (33.90 mmol) and boron trifluoro etherate 9.0 ml (71.35 mmol) were then added and stirring was left overnight. The reaction was then quenched using aqueous NaHCO 3 . Extractions were done using ether and the combined organic extracts were dried over Na 2 SO 4 , filtered and the solvent was removed. The isolated residue was then purified by flash chromatography; hexanes-ethyl acetate (8:2) was used as the eluent. The desired titled compound was isolated as a white solid (4.9 g; 92%).
  • Step 3 (1'S, 1R, 3R)-5,8-dimethoxy-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'- O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman
  • step 3 Application of the first part of the procedure described in step 3, example 26, on the isochroman precursor from step 2 herein resulted with the titled compound as a yellow solid; 62%.
  • Step 5 (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohecopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
  • the titled compound was obtained via Diels-Alder cycloaddition between 1-acetoxylbutadiene and the quinone from step 4 from this example Using the procedure described in step 4 from example 26.
  • Step 6 (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranc ⁇ se)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2026)
  • the titled compound was in 64 % yield from the glycoside of step 5 of this example as per procedure described in step 5 of example 26.
  • Step 7 (1'S, 1S, 3S)-5,8-dioxo-3-ethyI-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-5,8-dihydro-isochroman
  • a solution of (1'S, 1S, 3S)-5,8-dimethoxy-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitro-benzoyl-L-lyxohexopyranose)-isochroman (372 mg; 0.60 mmol) in acetonitrile (12 ml) was added a solution of CAN prepared by dissolving eerie ammonium nitrate (2.0 g; 3.6 mmol) in 6 ml of water and then slowly adding solid sodium bic
  • Step 8 (1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- mtrobenzoyl-L-lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
  • Step 9 (1'S, 1S, 3S)-5,10-dioxo-3 ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2020)
  • Step 10 (1'S, 1S, 3S)-5,10-dioxo-3-emyl-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-
  • Step 1 (trans)-1-acetamido-5,8-dioxo-3-ethyl-5,8-dihydro-isochroman
  • Step 2 Trans-5,10-dioxo-1-acetamido-3-ethyl-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran
  • Step 4 3-ethyI-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
  • step 3 the starting quinone from step 3 herein (250 mg; 1.30 mmol) and 1-acetoxy-1,3-butadiene (876 ⁇ l; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2 % ethyl acetate in toluene the title compound (62 mg; 20 %) along with mixed fractions containing a lot of desired titled product (230 mg), M.P.: 98-101°C.
  • Example 29 Preparation of (1'S,1R,3S) and (1'S,1S,3R)-5,10-dioxo-3-isopropyl-1- (2'3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H- naphtho-[2,3-c]-pyran: (BCH-2053) and (BCH-2052)
  • Step 2 (1'S, 1R, 3S) and (1'S, 1R, 3R)-5,8-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro- isochroman (40:60)
  • step 3 the starting isochroman from step 1 herein (300 mg; 1.27 mmol) afforded a cnide diastereomeric mixture of glycosidated isochromans (515 mg) which was reacted with CAN as described in step 3, example 26, to afford a diastereomeric title quinones mixture (450 mg; 59 %) in a ratio of (40:60) favoring the 1'S, 1R, 3R isomer which were used as such for the next reactions.
  • Step 3 (1'S, 1R, 3R)-5,10-dioxo-3-isopropyI-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-
  • Step 4 (1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'trifluoroacetamido-L-
  • step 5 the starting protected alcohol from step 3 herein (11 mg; .017 mmol) was treated with NaOMe/MeOH (4.37 M; 1 ⁇ l; .26 eq) to yield after column chromatography (7% acetone in benzene) the title compound (5 mg; 59%), M.P.: 180-185°C.
  • Step 5 (1'S, 1S, 3R)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoacetamido-L- lyxoh exopyranose)-3,4,5,10-tetrahydro-1 H-naphtho-[2,3-c]-pyran (BCH-2052)
  • step 5 the starting protected alcohol from step 3 herein (32 mg; .0495 mmol) afforded after flash chromatography using 7% acetone in benzene as eluent, a gummy product which was dissolved in dichloromethane and precipitated with pentane yielding the title product
  • Example 30 Preparation of (1'S,1R,3S) and (1'S,1S,3R)-5,10-dioxo-3-isopropenyl-1- (2',3',6'-trideoxy-3'-trifl uor oacetamido-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H-naphtbo-[2,3-c]-pyran: (BCH-2153) and (BCH-2152) and trans-5,10-dioxo-3-isopropenyl-1-methoxy-3,4,5.10-tetrahydro-1H- naphtho-[2,3-c]-pyran: (BCH-2148)
  • Step 2 (trans)-5,10--dioxo-3-isopropenyl-1-methoxy-3,4,5,10-tetrahydro-1H-nsphtho-[2,3- c]-pyran (BCH-2148)
  • step 3 the starting isochroman (150 mg; .64 mmol) and methanol (25 mg; .76 mmol) were treated with DDQ to afford a crude adduct (160 mg) which was then treated with CAN.
  • This reaction yielded an impure erode quinone (91 mg) which was treated with 1- acetoxy-1,3-butadiene as described in step 4, example 26, affording after chromatographic purification (0-2% ethyl acetate in toluene) the title compound as 18 mg of slightly impure form and 5 mg of pure product (13 % overall).
  • Step 3 (1'S, 1S, 3R)-5,8-dimethoxy-3-isopropenyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-Iyxobexo-pyranose) isochroman.
  • step 1 the starting isochroman from step 1 herein (250 mg; 1.07 mmol) was treated with ⁇ -2,3,6-trideoxy-3-trifiuoroacetamido-4-O-p- nitrobenzoyl-L-lyxohexopynnose (461 mg; 1.17 mmol) and DDQ (337 mg; 1.49 mmol) in
  • Step 4 (1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido- 4'-O-p-nitrobenzoyl-L-lyxohex o-pyranose) 3,4,5,10-tetrahydro -1H-naphtho-[2,3-c]- pyran
  • step 6 of this example Using the same procedure as described in step 6 of this example, the starting isochroman from step 3 herein (80 mg; .13 mmol) afforded after CAN oxidation and Diels-Alder the title product (35 mg; 42% overall) contaminated by what looks like aglycone systems.
  • Step 5 (1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido- L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2153)
  • the starting protected alcohol from step 6 herein (slightly impure, 30 mg; .047 mmol) afforded the title compound (11 mg; 48%), M.P.: 170°C (dec).
  • Step 6 (1'S, 1S, 3R)-5,10-draxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluroacetamido- 4'-O-p-nitrobenzoyl-L-lyxohexo-pyran ose) 3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran
  • step 3 To a solution of the starting isochroman from step 3 herein (120 mg; 0.19 mmol) in acetonitrile (4 ml) at 0°C was added a solution of CAN (prepared by dissolving eerie ammonium nitrate (630 mg; 1.15 mmol) in water (2 ml) and then adding slowly sodium bicarbonate (169 mg)). After the addition, the mixture was stirred for 10 minutes and was then quenched with saturated sodium bicarbonate solution.
  • CAN prepared by dissolving eerie ammonium nitrate (630 mg; 1.15 mmol) in water (2 ml) and then adding slowly sodium bicarbonate (169 mg)
  • Step 7 (1'S, 1S, 3R)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoracetamido- L-lyxohexopyranose)-3,4,5,10-tetrahydro- 1H-naphtho-[2,3-c]-pyran (BCH-21-52)
  • step 3 the starting protected alcohol from step 6 herein (16 mg; .0248 mmol) afforded the title compound (11 mg; 90%), M.P.: 102-105°C.
  • Step 1 (1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dimetboxy-3-m ethoxycarbonyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyI-L-lyxohexopyranose)- isochroman.
  • step 2 example 32
  • the starting isochroman 500 mg; 1.98 mmol
  • flash chromatography 5-20% acetone in benzene containing a trace of triethylamine
  • Step 2 (1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dioxo-3-meth ⁇ xycarbonyl-1-(2',3',6'-trideoxy- 3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro- isochroman.
  • A is (1'S, 1R, 3S) diastereomer and B is (1'S, 1S, 3R) diastereomer.
  • Step 3 (1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-mtrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
  • step 4 the starting quinone from step 2 herein (400 mg; .658 mmol of a 1:1 mix of 1'S, 1R, 3S and 1'S, 1S, 3R) afforded pure title product (13 mg) along with a -1:1 mixture of (1'S, 1R, 3S) and (1'S, 1S, 3R) isomers (275 mg).
  • Step 4 (1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6',trideoxy-3'- trifluoroacetamido-L-lyxobexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyrano (BCH-2128)
  • the starting protected alcohol from step 3 herein (12 mg; 0.018 mmol) afforded after column chromatography (10% acetone in dichloromethane), the title compound (5 mg; 54%) as a yellow solid.
  • Example 32 Preparation of (1'S,1R,3S)-isopropyl-[5,10-dioxo-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-pyranyl]-ketone: (BCH-2112)
  • Step 1 isopropyl-(5,8-dimethoxy-isochroman-3-yI)-ketone
  • Step 2 (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- mtrobenzoyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphyho-
  • Step 3 (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyranyl]- ketone (BCH-2112)
  • Example 33 Preparation of (1'S,1S,3R) and (1'S,1R,3S)-5,10-dioxo-3- isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1 H-naphtho-[2,3-c]-pyran:
  • Step 1 (1'S, 1R, 3S), and (1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2' ,3',6'- trideoxy-3',trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran
  • step 2 the starting isochroman from step 1, example 32, (300 mg; 1.07 mmol) afforded a crude glycosylated adduct (417 mg) which was treated with CAN to give a crude quinone mixture (355 mg) of which 250 mg were reacted with acetoxybutadiene.
  • This reacaion yielded a slightly impure mixture of the title compounds (113 mg; 15 % overall) (-55:45) favoring the (1'S, 1R, 3S) isomer.
  • Step 2 (1'S, 1R, 3S)-5,10 dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran (BCH-2122)
  • step 3 the starting protected alcohol from step 1 herein (113 mg; .16 mmol) afforded (after multiple chromatographic separations using 10% acetone in benzene or in dichloromethane) the pure title compound (7 mg; 8%). M.P.: 93-101°C.
  • Example 34 Preparation of (1'S,1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-4'-O-p-nitroben zoyl-L-lyxohexopyranose)- isochroman (BCH-1697)
  • Step l 5,8-dimethoxy-3,3 bis (dihydroxymethyl)-isochroman
  • Step 3 (1'S, 1S)-5,8-dimetboxy-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenroyl-L-lyxohexopyranose)-isochroman Under argon atmosphere, the following reagents: product from step 2 herein, 0.477 g (1.70. mmol),
  • DDQ 0.452 g (2.00 mmol) were dissolved in 50 ml of dichloromethane.
  • the reacticm mixture was stirred at room temperature for a period of 16 hours. After that time, an excess of DDQ was then added to the reaction mixture and stirring was left for another hour.
  • the reaction mixture was then quenched with aquous NH 4 Cl and extractions of the aqueous layer was done using CH 2 Cl 2 .
  • the combined organic layers were dried over Na 2 SO 4 , filtered and the solvent was removed.
  • the crude material was purified by flash chromatography; eluent:hexanes-ethyl acetate (70:30) then (60:40). The obtained titled compound was a pale yellow solid (0.434 g; 39%).
  • step 3 The starting material from step 3 herein, 0.430 g (0.65 mmol), was dissolved in acetonitrile at 0°C. A solution of NaHCO 3 0.107 g (1.30 mmol) in 7 ml of water was then added and the soluticm was stirred for 10 minutes. After that time, 1.053 g (1.95 mmol) of CAN diluted in 12 ml of water were then added to the reaction mixture in a dropwise manner. The reaction was complete after 10 minutes. A very diluted solution of NaHCO 3 in water was then added to the reaction mixture. Extractions of the reaction mixture were done using CH 2 Cl 2 - The combined organic layere are dried over Na 2 SO 4 , filtered and the solvent was removed. The titied compound was used for next step without further purification, (0.387 g; 95%).
  • Step 5 (1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'
  • Step 6 (1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexo-pyranose)-isochroman (BCH-
  • Example 35 Preparation of (1'S,1R,4R)-5,10-di ⁇ xo-4-ethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c] pyran (BCH-2091)
  • Step 1 methyl-2-(2',5'-dimethoxypbenyI) butanoate
  • ethyliodide 5.0 ml (47.56 mmol) was then added to the reaction mixture.
  • the reaction mixture was then stirred for 30 minute before removal of the dry ice-acetone bath to allow the temperature to reach room temperature and the reaction was monitored by TLC.
  • the reaction mixture was left stirring at room temperature for 15 hours.
  • the reaction mixture was then quenched by adding aqueous NH 4 Cl and extracting with ether.
  • the combined oiganic layers were washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed.
  • the crude was purified by flash chromatography using hexanes-ethyl acetate as eluent; 3.36 g of pure titled compound as a white solid were obtained.
  • step 1 Under argon atmosphere, the product from step 1 herein, 3.36 g (14.08 mmol) was dissolved in 100 ml of dichloromethane. This solution was cooled to 0°C and DIBAL-H, 31.0 ml (30.98 mmol) was added in a dropwise manner. The reaction was complete after 20 minutes so HCl 1N was then added to the reaction mixture and extractions were done using dichloromethane. The combined oiganic layers were dried over Na 2 SO 4 , filtered, and the solvent was removed. The isolated titied compound was used for next step without furhter purification.
  • Step 3 5,8-dimethoxy-4-ethyl-isochroman Under argon atmosphere, the product firom step 2 herein, 2.74 g (13.03 mmol) was dissolved in 55 ml of dry ether. Dimethoxy methane 1.65 ml (19.55 mmol) and boron trifluoro etherate 4.9 ml (39.09 mmol) were then added to this solution. The obtained reacticm mixture was left stirring overnight. The reaction mixture was quenched using aqueous NaHCO 3 and extractions were done using ether. The combined oiganic extracts were dried over Na 2 SO 4 , filtered, and the solvent was removed. The residue was purified by flash chromatography using hexanes-ethyl acetate (80:20) and (70:30) as eluent. The isolated titled product was a white solid (1.56 g; 54%).
  • Step 4 (1'S, 1R, 4R)-5,8-dimethoxy-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-
  • O-p-mtrobenzoyI-L-lyxohexo-pyranose)-isochroman The titled compound was obtained by applying the procedure from step 3, example 34, to the isochroman from step 3 herein.
  • Step 5 (1'S, 1R, 4R)-5,8-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluo roacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
  • Step 6 (1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyI-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3,-c]-pyran
  • the titied compound was obtained in 19% yield following cycloaddition between the quinone from step 5 herein and 1-acetoxybutadiene, as per procedure as described in step 5, example 34.
  • Step 7 (1'S, 1R, 4R)-5,10- dioxo-4-ethyl-1-(2',3',6'-trideoxy3'-trifluoracetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2091)
  • the titled compound was obtained via deprotection of the tricyclic glycoside from step 6 herein as per procedure from step 6, example 34.
  • Example 36 Preparation of (1'S,1R,3S)-5,lu-di ⁇ xo-3-ph enyloxymethyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
  • Step 1 ⁇ -phenoxymethyI-2,5-dimethoxy-phenetyl alcohol
  • Step 2 5,8-dimethoxy-3-phenoxymethyI-isochroman
  • ⁇ -phenoxymethyl-2,5-dimethoxyphenetyl alcohol 2.1 g; 7.24 mmol
  • ether 40 ml
  • dimethoxymethane 966 ⁇ l; 10.8 mmol
  • boron trifluoride etherate 2.68 ml; 21.6 mmol
  • Step 3 (1'S, 1R, 3S)-5,8-dim eth oxy-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido -4'-O-p- nitrobenzoyl -L-lyxohexopyranose)-isochroman
  • the isochroman from step 3 herein was glycosydated in 57% yield as per procedure described in step 3, example 34.
  • Step 4 (1'S, 1R, 3S)-5,8-dioxo-3-phenyloxymethyl-1-(2',3',6'trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman
  • Step 5 (1'S, 1R, 3S)-5,10-dioxo-3-phenytoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzol-L-lyxohexopyranose)-3,4,5, 10-tetrahydro-
  • Step 6 (1'S, 1R, 3S)-5,10-dioxo-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2032)
  • step 5 The glycoside from step 5 herein was deprotected as per procedure described in step 6, example 34, to afford the titled compound in 81 % yield.
  • Step 1 5,8-dimethoxy-3-(2-propenyl)-isochroman o a stirred solution of pyranosulfone (670 mg, 2.0 mmol) in CH 2 Cl 2 (20 ml) at -78°C were added allyltrimethylsilane (636 ⁇ l, 4.0 mmol) and AICl 3 (533 mg, 4.0 mmol). Temperature was then raised to -35°C few minutes, then HCl (0.1 N, 10 ml) was added. The reaction mixture was worked up with CH 2 Cl 2 and water. The organic layer was washed with brine and dried over MgSO 4 . The solvent was evaporated to give the allyl isochroman (450 mg, 96%).
  • Step 2 (1'S,1S,3S) and (1'S,1-R,3-R)-1-(2',3',6',-trideoxy-3'-trifluoroacetamido-4'-O- paranitrobenzoyl-L-lyxohexopyranose)-5,8-dimethoxy-3-(2-propenyl)-isochroman

Abstract

Tricyclic heteronaphthoquinone derivatives, that have antineoplastic activity, are disclosed, together with processes for their synthesis. Some of these anti-neoplastics compounds have a saccharide moiety. Some members of this structurally distinct group exhibit activity against multiple drug resistant cancer cells.

Description

ANTINEOPLASTIC HETERONAPHTHOQUINONES
This invention relates to heterocyclic naphthoquinone derivatives, to processes and to intermediates for preparing these derivatives, to pharmaceutical compositions containing them and to the use of these derivatives as antitumor agents in mammals.
BACKGROUND OF THE INVENTION
Anthracycline antibiotics including doxombicin 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, doxombicin (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, M. and Leyland-Jones, B., Cancer Chemother. Pharmacol., 18, 185-197, 1986; Arcamone, F., Doxombicin, Academic Press, New York, 1980).
Figure imgf000003_0001
The usefulness of known anthracycline antibiotics is compromised by dose limiting toxicities such as myelosuppression (Crooke, S.K., Anthracychnes; 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; McGiath, T. et al, Biochemical Pharmacology, 38 497-501, 1989). In view of the proven effectiveness of known anthncyclines in the treatment of cancer, efforts have been undertaken to develop anthracycline analogs with either an improved therapeutic index or with reduced cross-resistance.
Several thousand anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxombicin, 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 Doxombicin and its Analogues, Prog. Med. Chem. 21 170-236, 1984; Brown, J.R. Adriamycin and Related Anthracycline Antibiotics, Prog. Med. Chem., 15, 125-164, 1978). The majority of known anthracychnes 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 (doxombicin numbering). Some examples of the structural diversity of anthracycline antibiotics are:
Figure imgf000004_0002
FIG. 1
Tricyclic variants (3) of daunonibicin have been reported to possess antitumor activity (EPA 91202015.3)
Figure imgf000004_0001
R is COCH3 or C_CH or C_C-Si(CH3)3
R3 is H or COCF3 Pyranonaphthoquinones such as nanaomycin A ( 4) and kalafungin (5) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czemiak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
Figure imgf000005_0001
Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P.l and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently thiopyranoanthraquinone (7) and pyranoanthraquinone (8) were found to possess antitumor activity (PCT, CA9100208). In contrast antitumor activity of other 9-oxa-heteroanthracylines such as (9), (10), and (11) was not significant (Heterocycles, 26 (2), 341-5, 1987; Heterocycles 26 (4), 879-82, 1987).
Figure imgf000005_0002
Figure imgf000006_0001
DESCRIPTION OF THE INVENTION
The present invention provides heteronaphthoquinones which are structurally distinguished from prior art compounds.
More specifically, the compounds of the present invention are structurally distinguished from the prior art compounds by having a tricyclic heteronaphthoquinone moiety fused to a hydroxyl group or alternatively to a sugar moiety. This structurally distinct class of compounds exhibits therapeutic activity, in particular anticancer and antitumor activity. Some of the compounds are active against certain doxorabicin-resistant tumor cells, and are more potent in some cases than the corresponding tetracyclic heteroanthracycline compound.
In one aspect of the invention, there is provided a compound of the formula (12):
Figure imgf000006_0002
wherein
X1 and X2 are independently selected from the group consisting of
O, S, and N(R), wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-15 acyl and C1-16 alkylamine.
X3 is selected from the group consisting of O, S, SO, SO2, and NR, wherein R is selected from the group consisting of hydroxyl, C1-16 alkyl, C1-16 alkyl, C1-16 aryl, C1-16 haloacyl, and hydrogen.
X4 is selected from the group consisting of C-Q, nitrogen, and NO.
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-16 alkoxyl, C3-8 cycloalkyl, tosyl, mesylate, acetate optionally substituted with a C1- 8 alkyl, triflate, trifiuoroacetate, halogen, nitro, cyano, C1-16 acyl, C1-16 arylacyl, aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2) mOH wherein n and m are independently 1 to 4, aminoalkylaminoalkylhalide of formula NH(CH2)nNH(CH2)mX wherein n and m are independently 1 to 4 and X is a halogen,
amino, which may be unsubstituted or mono or
di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl and C6-18 aryl; C2-8 alkenyl, and C2-8 alkynyl,
haloalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)n CH2X, wherein n is 0 to 4 and X is a halogen, and
-NH(CH2)n N R* R** wherein n is 1 to 6, R* and R** are independently selected from hydrogen, C1-8 alkyl, C6-18 aryl, C7-18 aralkyl, C1-8 acyl, and trifluoroacyl,
a group of the formula -O-C(R)=O wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-12 alkoxyalkyl, C7-18 aralkyl, C7-18 araloxyalkyl, C7-18 aryloxyalkyl and C6-18 aryl,
Z is one of C-R6 or C-R7.
R6 is selected from the group consisting of C1-16 hydroxime, C6-18 hydrazone, C1-16 hydroxyalkyl, hydrogen, C6-18 aryl, C7-18 aryloxyalkyl, C7-18 araloxyalkyl, phenyl, C1-16 alkyl, acetoxy, C1-16 dihydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, squaric acid, C1-16 alkyl squarate, amino, cyano, dimethylpbosphonato, phenyl sulfone, C1-8 aryl sulfone, and
C1-8 acetyl, agroup of the formula -C(R) = X* wherein X is selected from the group consisting of two hydrogens, one hydrogen and R* is selected firom a C1-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and O, or its dioxolane or dioxane or dialkoxy C1-8 ketal, and wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8 cycloalkyl, C6-18 aryl, C7-18 aralkyl, fluoromethyl, difluoromethyl, C1-8 hydroxyalkyl, C2-16 alkene, squaric acid, C2-16 alkyne, C1-8 thioalkyl, C6-18 thioaryl, C1-4 alkyl squarate, C2-8 alkoxyalkyl, C6-18 araloxyalkyl, C2-18 acyloxyalkyl, C1-8 alkoxy, hydroxy, acetoxy methyl, bromomethyl, C1-8 aceto, amino which may be unsubstituted or mono- or di- substituted by hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl,
a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1-8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, and
a group of the formula -(CH2)nZ* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl;
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 atyl, C2-8 alkenyl, C3-8 alkynyl and hydroxy.
Z* can also be a group of the formula -NR* R** wherein R* and R** are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C1-8 acyloxyalkyl, C6-12 araloxyalkyl, and a group of formula -CO(CH2)n C(PO(OR)2)2 wherein n is 1 to 4 and R is hydrogen or C1-8 alkyl; and a naturally occurring amino acid;
a group of the formula -C(OR)=0, where R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C7-18 aryloxyalkyl, C6-18 araloxyalkyl, C6-18 aryl and C7-18 aralkyl;
a group of the formula -(CH2)n C(R)=O, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C1-8 alkoxy, C7-18 aryloxyalkyl, C7-18 araloxyalkyl, C6-18 aryl, C7-18 aralkyl,
amino which may be unsubstituted, mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C2-12 aralkyl, C2-12 aryl,
a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and NR wherein R is
selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl and aryl, said heterocycle being optionally substituted with one or more halogens, C6-18 arylsulfone, hydroxy, C1-16 alkoxy, nitro, C1-16 alkyl, C1-16 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; C2-8 alkenyl, C2-8 alkynyl and hydroxy..
R7 is selected from the group consisting of hydrogen, C1-16 alkyl, halogen, amino, hydroxy, C1-16 alkoxy, thiol, cyano, sulfide, acyl of the formula -C(R)=O wherein R is selected from
the group consisting of hydrogen, C1-16 alkyl, C1-16 alkoxy, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C7-18 araloxyalkyl, C2-8 alkoxyalkyl, C2-8 acyloxyalkyl, C6-12 aryloxyalkyl, squaric acid or squarate, amino which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, cyano, trifluoroacyl, C7-18 aralkyl or C6-12 aryl, and a naturally occuring amino acid;
a group of the formula -C(OR)=O wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 aryloxyalkyl, C7-12 araloxyalkyl, C6-12 aryl, C7-18 aralkyl and C1-16 alkenyl.
R5 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-16 alkoxyl, C1-16 alkyl, C2-16 acetylenyl, a group of the formula -(CH2)n-NR*R** wherein n is 1 to 6, and R* and R** are independently selected firom a group consisting of C1-8 alkyl, C1-4 acyl, C3-8 cycloalkyl, hydrogen, C2-8 carboalkoxy, C2-8 alkene, C2-8 alkyne, C6-12 aryl, and (OCH2CH(PO(OR)2)2
wherein R is a hydrogen or a C1-8 alkyl and wherein n is 0 to 5;
C3-8 cycloalkyl, C2-16 alkenyl, C1-16 alkoxyalkylamino, cyano;
a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-8 alkoxyalkyl, and C6-12 aryl;
an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen, thiol, C1. 16 thioalkyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 araloxyalkyl, C2-8 acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid or a synthetic amino acid;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl and C3-8 cycloalkyl, acosamine, glucosamine, N-chloroethyl-nitrosoureidoglucosamine, 2,6- dideoxyrhamnose, thioglucose, thiodaunosamine, thiol, C1-12 thioalkyl, a naturally occuring amino acid or di- and tri-peptides thereof, a group of the formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH2, NR** wherein R** is from the group consisting of hydrogen, C1-8 alkyl, C2-8 acyl or C6-12 aryl,
R and R* are independently selected from the group consisting of hydrogen, C1-12 alkyl, C6-12 aryl, C2-8 dihydroxyalkyl, C2-8 alkene, C2-8 alkyne, C1-8 alkoxy, C1-8 alkylamino, C3-8 cycloalkyl, C2-8 carboalkoxy, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and NR
wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1- 4 alkyl and C6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy; mono or oligosaccharides of the formula:
Figure imgf000009_0001
wherein Y is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, CR*R**, wherein R* and R** are independently selected from the group consisting of hydrogen, C1-8 alkyl, and NR wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 acyl.
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol, amino, trifluoroacetamido, chloroethylnitrosoureido, and chloroethylureido.
R11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, tbutyloxycarbonyl, trifluoroacyl, C7-12 aralkyl, C6-12 aryl, and a naturally occuring or synthetic amino acid; mono or dibenzylated amino, azido, acylated amino, trifluoroacylated amino, morpholino, cyano substituted morpholino, mono-, di-,- tri- or tetra-methoxy substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, C1-16 alkoxyl, C3-8 cycloalkyl, thiol, sulfide; a group of the formula NH(CH2)nCH(OR)2 wherein R is selected from the group consisting of C1-16 alkyl, C1-16 acyl and C7-18 aroyl and wherein n is 0 to 5.
chloroalkylnitrosoureido of the formula NH(CO)N(NO)CH2)nCH2Cl wherein n is 0 to 4, and
NH(CH2)2 OCH2CH(OAc)2.
R12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, memo or bligosaccharides, C1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C1-16 alkoxy, C3-8 cycloalkyl, C2-8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, one of the group consisting of p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitro-soureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)2 OCH2CH(OAc)2.
R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy.
Preferred compounds of formula (12) are those wherein
X1 and X2 are independently selected from the group consisting of
O, S, and NH.
X3 is selected from the group consisting of O, S, SO, SO2, NH, and NOH.
X4 is selected from the group consisting of CQ, N, and NO.
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C1-4 alkoxyl, tosyl, triflate, fluorine, chlorine, amino, aminoalkylaminoalcohol of formula NH(CH2) nNH(CH2) mOH wherein n and m are independently 1 to 3, aminoalkylaminoalkylchloride of formula NH(CH2)nNH(CH2)mCl where n and m are independently 1 to 3, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)n CH2 Cl, wherein n is 0 to 4, and a group of the formula -O-
C(R)=O, wherein R is selected from the group consisting of hydrogen, C1-6 alkyl, and aryl;
Z is one of C-R6 or C-R7. R6 is selected from the group consisting of hydrogen, C1-8 hydroxyalkyl, C1-8 dihydroxyalkyl, squaric acid, C1-16 alkylsquarate, C1-4 alkyl, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 hydroxylalkyl, squaric acid, C1-4 alkyl squarate, alkoxyalkyl, aminoacetaldehyde diethyl acetal, aminoacet alde h yde diacetoxy acetal, aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl and amino which may be unsubstituted or mono- or di-substituted with C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, aralkyl; and a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of hydrogen, straight or branched C1-8 alkyl, and amino which may be unsubstituted or mono- or di-substituted with C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, and a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, NH; said heterocycle being optionally substituted with one or more halogen, hydroxy, C1-8 alkoxy, C1-8 alkyl, C1-8 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, C3-5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy;
R7 is selected from the group consisting of hydrogen, fluorine, C1-4 alkyl, C1-4 alkoxy, cyano acyl of the formula -C(R)=0 where R is selected from the group consisting of hydrogen, C1-8 alkyl, hydroxyalkyl, acyloxyalkyl,
amino, cyano, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, aryl, C1-8 alkenyl;
R5 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-8 alkoxy, C2-8 acetylenyl, C2-8 alkenyl, cyano, a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen and C1-8 alkyl; acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen, thiol, C1-8 alkyl, hydroxyalkyl, amino; a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen and C1-8 alkyl, glucosamine, and a saccharide of formula:
Figure imgf000011_0001
wherein Y is selected from the group consisting of oxygen, sulfur, and CHR wherein R is hydrogen or C1-4 alkyl,
R9 and R10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl; R11 is selected from the group consisting of amino which may be unsubstituted or memo- or di- substituted with C1-8 acetoxy alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl and aryl; morpholino, azido, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, hydroxyl, mono or dialkylated amino with 1 to 16 carbons, C1-8 alkoxyl, a group of the formula NH(CH2)nCH(OR)2 wherein R is independently selected from a group consisting of C1-8 alkyl, C1-8 acyl and C7-12 aroyl and wherein n is 1 to 5; chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, NH(C H2)2 OCH2CH(OAc)2.fluorine;
R12 is selected from the group consisting of hydroxyl or its tetrahydropynnyl ether, halogen, mono or oligosaccharide selected from the group consisting of rhodosamine, cineralose-B, L-cineiulose, D- cineralose, cinemlose A, amicetose, aculose, rednose, rhodinose, 2-deoxyfucose, daunosamine, trifluoroacetyl-daunosamine, amino, trifluoroacetamido, mono or dimethylated amino, C1-8 alkoxy, benzoate, p-nitrobenzoate, chloroalkyl-nitrosourea, acetoxy and trifluoroacetoxy.
More preferred compounds of formula (12) are those wherein
X1 and X2 are independently selected from the group consisting of
O and NH;
X3 is selected from the group consisting of 0, S and SO.
X4 is selected from the group consisting of CQ and N.
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxy, methoxy, halogen, amino-ethylaminoethanol, aminoethylaminoethylchloride, chloroalkyl-nitrosoureido of the formula NE(CO)N(NO)(CH 2)nCH2Cl wherein n is 0 to 2; amino, and
fluorine.
Z is one of C-R6 or C-R7.
R 6 is selected from the group consisting of C1-4 hydroxime, C6-10 hydrazone, C1-4 alkyl, C1-4 hydroxyalkyl, phenyl, C1-4 dihydroxyalkyl, a group of the formula -C(R)=X, wherein X is selected from the group of hydrogen, and O, and wherein R is selected from the group consisting of C1-4 alkyl, hydroxymethyl, hydrogen, acyloxymethyl, C2-4 alkenyl, C2-4 actylyl, C1-4 alkoxy, hydroxy, C1-4 aceto, amino which may be unsubstituted or mono- or di-substituted by hydrogen, C1-4 alkyl, C1-4 acyl, trifluoroacyl, and a group of the formula -CHR*R** wherein R* and R** are independently selected firom a group consisting of C1-4 alkyl, hydrogen, C1-4 acyl, a group of the formula -(CH2)nZ* wherein n is 0 to 3 and Z* is a hydrogen, or C1-4 acyl, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C1-4 alkoxy, C1-4 alkyl, and amino which may be unsubstituted, mono-or di-substituted by a C1-4 alkyl, C1-4 acyl, trifluoroacyl and C2-4 alkynyl, Z* can also be a group of the formula -NR*R** wherein R* and R** are independently selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 acyl;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, C1-4 alkyl; a group of the formula -(CH2)nC(R)= O, wherein n is 1 to 3 and R is selected from the group consisting of hydrogen, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, amino, dimethylamino; a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, NH said heterocycle being optionally substituted with one or more halogens, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, amino which may be unsubstituted or mono-or disubstituted by methyl, cyclopropyl, acyl, and hydroxy.
R7 is selected from the group consisting of hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen, C1-5 alkyl, C1-4 hydroxyalkyl, amino, cyano, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, C1-5 alkyl, aryl, and C1-4 alkenyl:
R5 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-4 alkoxy, C1-6 alkyl, C2-4 alkene,a group of the formula -(CH2)n NR*,R** wherein n is 1 to 4 and R* and R** are independently selected from the group consisting of hydrogen, C1-5 alkyl, C1-4 acyl; acosamine, 2,6-dideoxyιhamnose, thiodau nosamine, C1-5 thioalkyl, a naturally occurring amino acid or dipeptides thereof, a group of the formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH2 and NR** wherein R** is selected from the group consisting of hydrogen, C1-4 alkyl and C2- 4 acyl, and wherein R and R* are independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkene, C1-5 alkylamino, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and NR wherein R is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 acyl, said heterocycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-substituted by C1-4 alkyl, C1-4 acyl and trifluoroacyl; methoxy, cyano, C1-4 acetate, C1-4 acetyl and a group of the formula
Figure imgf000013_0001
wherein Y is selected from the group consisting of oxygen, sulfur, and CH2:
R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, and iodine. R11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano substituted morpholino, mono-, di-, tri-, or tetra-methoxy substituted morpholino, a group of the formula NH(CH2) nCH(OR)2 wherein R is selected from the group consisting of C1-4 alkyl, C1-4 acyl or C7-8 aroyl and wherein n is 2 to 5, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, NH(CH2)4CH(OAc)2, NH(CH2)2OCH2CH(OAc)2, and NH(CO2)OCH2)CH2CH(OAC)2:
R12 ιs selected firom the group consisting of hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, amino, trifluoroacetamido, chloroethylnitrosoureido, fluorine, and iodine;
R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and NR wherein R is selected from the group consisting of hydrogen, C1-4 alkyl, and C1-4 acyl, said heterocycle being optionally substituted by C1-4 alkyl, C1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-substituted by C1-4 alkyl, C1-4 acyl and trifluoroacyl.
A still further preferred compound of formula (12) are those wherein X1 and X2 are both oxygen;
X3 is 0, S or SO;
X4 is selected from the group consisting of N, or CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl, and methoxy.
Z is one of C-R6 or C-R7.
R6 is selected from the group consisting of C1-3 hydroxime, methyl, ethyl, C1-3 alkyl, hydroxymethyl, 1,2 dihydroxymethyl, a group of the formula -C(R)= X, wherein X is selected from the group of hydrogen and oxygen, and wherein R is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, hydroxymethyl, acetoxymethyl, bromomethyl and C1-4 alkoxy, C2-3 alkenyl, C1-3 aceto, amino which may be unsubstituted or mono-or di-substituted by hydrogen, C1-3 alkyl, C2-3 acyl or a group of the formula -CHR*R** wherein R* and R** are independently selected from a hydrogen, C1-3 alkyl, a group of the formula -{CH2)nZ* wherein n is 0 to 2 and Z* is a C1-3 alkyl, and a group of the formula -NR*R** wherein R* and R** are independently selected from hydrogen, C1-3 alkyl and C1-3 acyl, Z* can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C1-3 alkoxy, and cyano; a 5 or 6 membered aromatic or non aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, S, N, and NH, said heterocycle being optionally substituted with one or more fluorine, hydroxy, methoxy, methyl, hydroxymethyl, cyano, amino and acylamino groups.
R7 is selected from the group consisting of hydrogen, fluorine, methyl, and cyano;
R5 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl, and
a saccharide of the formula
Figure imgf000014_0001
wherein Y is selected from oxygen and CH2, and
wherein R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, and iodine.
R11 is selected from the group consisting of amino, hydroxy, dimethylamino, acetoxy, trifluoroacetamido, morpholino, cyano substituted morpholino, methoxymorpholino and a group of the formula NH(CH2)nCH(OR)2 wherein R is selected from a group consisting of methyl, acyl or benzoyl and wherein n is 3 to 5, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)OCH2CH(OAc)2
R12 is hydroxyl,iodine, or bromine.
Still further preferred compounds of formula (12) are those wherein
X1 and X2 are both oxygen.
X3 is O or S.
X4 is CQ.
R2 and R3 are both hydrogen.
R1 and Q are independently selected from the group consisting of hydrogen, fluorine, and hydroxyl.
Z is one of C-R6 or C-R7.
R6 is selected from the group consisting of ethyl, hydroxymethyl,
1,2-dihydroxyethyl, carbonyl, squarate, acyl of the formula -C(R)=0 wherein R is selected from the group consisting of methyl, fiuoromethyl, difluoromethyl, hydroxymethyl.
R7 is selected from the group consisting of hydrogen, methyl, or fluorine;
R5 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and a saccharide of the formula
Figure imgf000015_0001
wherein R9 and R10 are independently selected from the group consisting of hydrogen, fluorine, and iodine.
R11 is selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino;
R12 is selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine, with the proviso that at least one of R5 and R8 is saccharide.
The invention also seeks to provide a process for the preparation of a compound of formula ,
Figure imgf000016_0001
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected from the group consisting NR, O, or S, R6 is methyl ketone or is as defined in claim 1; and R1, R2, R3, R5, R6, R7, R8, X1, X2 X4 and Z are as defined in claim 1
selected from the group of processes consisting of
1. 1) selecting a precursor isochroman compound of formula
Figure imgf000016_0002
wherein R5, R6, R7 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula
Figure imgf000016_0003
2) and cyclo-adding said quinone with a diene of formula
Figure imgf000017_0001
wherein L is a leaving group selected firom the group consisting of halogen, tosyl, benzoyl, p- nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C1-16 acyl, C1-16 acyl, C3-16 alkylsilane, C8-16 alkylaryl silane and dimethylamino,
wherein R1, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula
Figure imgf000017_0002
and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is -OH, to a saccharide of formula
Figure imgf000017_0003
wherein R9, R10, R11 and R12 are defined as in claim 1 and L is as defined above;
to yield a tricyclic saccharide of formula
Figure imgf000018_0001
II. a) coupling the isochroman (14) of reaction (I)(1), above, wherein R5 is H, with a saccharide of formula
Figure imgf000018_0002
wherein R9, R10, R1 1 and R12 are as defined in claim 1 to yield a bicyclic saccharide of formula
Figure imgf000018_0003
b) oxidatively demethylating the methoxy groups from formula (21) to yield a bicyclic quinone saccharide of formula
Figure imgf000019_0001
c) and cycloadding said chemical (19) with said diene (16) of reaction (I)(2) to yield the tricyclic saccharide
Figure imgf000019_0002
III. 1) coupling the quinone of formula 15,
Figure imgf000019_0003
of step (I) (1), wherein R5 is -OH, with a saccharide of the formula
Figure imgf000020_0001
of step (I) (2) to yield a bicyclic quinone sacharide of the formula
Figure imgf000020_0002
2) and cycloadding said quinone saccharide with the said diene of formula
Figure imgf000020_0003
A is NR wherein R is selected from the group consisting of H, C1-16 alkyl, C7-16 acyl; and L is defined as above;
to yield a tricyclic saccharide of formula
Figure imgf000021_0001
IV. a) selecting a precursor benzoate compound of formula
Figure imgf000021_0002
and condensing it with a dihalomethyl dimethoxybenzene wherein said halogens are independently selected firom the group consisting of Cl, Br and I, and X3 is selected from the group consisting of O, S, and N;
Figure imgf000021_0003
to yield a dimethoxyisochroman of formula,
Figure imgf000021_0004
b) oxidatively demethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman;
the resulting dioxoisochroman is cyclically coupled with the diene of formula
Figure imgf000022_0001
A is NR wherein R is selected from the group consisting of H, C1-16 alkyl, C7-16 aryl, and L is a leaving group as defined in (I)(2):
to yield an anthracenedione of formula
Figure imgf000022_0002
the resultant compound may optionally be converted to the hydroxyl form of formula
Figure imgf000022_0003
The quinones at positions X1 and X2 may be converted to other moities such as, for example,
OH, S, NR, where R is hydrocarbon, and others. Such conversions are carried out using known methodology by chemists skilled in the art. For example, these conversions are taught in "The chemistry of the quinonoid Coumponds" V 1 and 2. John Wiley and Sons, 1988, which is incorporated by reference.
The compound may further be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula
Figure imgf000023_0003
may be optionally coupled with a saccharide of formula
Figure imgf000023_0002
1) to yield a dimethoxybicyclic saccharide of formula
Figure imgf000023_0001
2) oxidatively demethylating the methoxy groups to yield a dioxobicyclic isochroman of formula
Figure imgf000024_0001
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29
Figure imgf000024_0002
to yield a thiotricyclic saccharide of formula
Figure imgf000024_0003
Compounds of formula:
Figure imgf000024_0004
One obtained by treatmg a compound of formula:
Figure imgf000025_0001
with a base in the presence of air at an appropriate synthetic stage.
The term "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 CF3, one or more alkoxy sustituent, one or more hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
The term "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.
The term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing firom 6 to 10 carbons in the ring portion, such as phenyl, naphtyl, substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C1-4 alkyl, halogen, C1-4 alkoxy, hydroxy or nitro.
The term "halogen" as used herein means chlorine, bromine, fluorine or iodine.
The term "aralkyl" as used herein refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.
The term "aroyl" as used herein refers to a group of the formula -COAr wherein Ar denotes an "aryl" group as defined above.
The term "alkoxy" or "aralkoxy" as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
The term "alkoxyalkyl" as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
The term "aryloxyalkyl" as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
The term "araloxyalkyl" as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
The term "acyloxyalkyl" as used herein means a C1-8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl. The term "hydroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl.
It will be appreciated by those skilled in the art that when R* = R4 = hydroxyl and X1 =X2=0 that compounds of formula (42) exist in equilibrium with tautomers of formula (43). Therefore, compounds of formula (43) are included within the scope of the invention.
Λ
Figure imgf000026_0001
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 stereochemical centos, when pertinent, at C1, C2 and C3 as well as in all the other chiral centers.
This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (42) and (43).
Heteronaphthoquinones of general formula (12) are prepared by using Scheme I. With reference to Scheme I, new or known isochromans of formula 14, where R5 is not a saccharide (PCT CA 9100208), are oxydatively demethylated with an oxidant such as cerie ammonium nitrate or- silver oxide in an adequate solvent mixture such as acetonitrile-water, to give key isochromandiones of formula 15. Cycloaddition of this latter quinone with dienes of general formula 16 in a solvent such as toluene can give the tricyclic heteronaphthoquinone of formula 17. In the case when R5 is a saccharide, two independent synthetic routes (A2 or B) may be employed.
With respect to route A2, glycosides of formula 12 (R5 = Saccharide, X1 = X2 = O) are obtained by reacting appropriate aglycones of general structure 17, in which R5 is an hydroxy, with known sugar derivatives of formula 18 in which R9 to R*2 are as defined herein and L is a displaceable atom or group.
Suitable leaving 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 C1-16 alkyl group such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as a C1-16 acyl group such. as acetyl, or R is an unsubstituted or substituted aryl group or R is a C3 to C10 trialkyl silyl such as trimethylsilyl or dimethyl-t-butylsilyl. 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, Monneret, 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, 638-645, 1984 and references therein; Arcamone F., Cancer Research, 45, 5995-5999, 1985 and references therein).
The aglycone of formula 17, is typically reacted with the appropriate sugar derivative of formula
18 in a compatible solvent such as methylene chloride using a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-sulfonate. Alternatively, as it is known in the art of anthracycline chemistry, when the leaving group of the sugar moiety is a halogen, the Koenigs-Knorr glycosidation or its modification may be used.
Alternatively glycosidation of 17 can he effected with known sugar derivates of formula 18b under protic catalysis to yield 12 (R5 = Saccharide, X1 = X2 = 0).
In the event that the glycosidation of aglycone 17 is impractical then route B1 or B2 can be used to prepare glycosides of formula 12 (R5 = saccharide, X1 = X2 = 0). With reference to route B1, an isochromandione of formula 15, in which R5 = OH, is glycosidated as described above for 17. Cycloaddition of intermediate !£ with dienes of formula 16 in a compatible solvent such as toluene or tetrahydrofuran yield the desired pyranonaphthoquinone glycosides of formula 12 (R5 = saccharide, X1 = X2 = 0). Alternatively, glycosidated isochromandiones
Figure imgf000028_0001
Figure imgf000029_0001
of formula 19 can be obtained via route B2 by reacting isochromans of formula 14 with a saccharide of formula 20 in the presence of DDQ in a compatible solvent such as dichloromethane, and subsequent treatment of the glycosidated isochroman 21 with eerie ammonium nitrate using standard procedures.
It will also be appreciated that the following reactions may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus; for example, amino groups may be protected by a group selected from aralkyl (e.g. benzyl), acyl or aryl (e.g. 2,4-dinitrophenyl), subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in "Protective Groups in Organic Chemistry'', Ed.
J.F.W. McOmie (Plenum Press, 1973) or "Protective Groups in Organic Synthesis" by Theodora W.
Greene (John Wiley and Sons, 1981, 1991). Examples of suitable 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 tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, 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 BF3/etherate and acetic anhydride followed by removal of acetate groups.
In the above processes, the compounds of formula (42) and (43) are generally obtained as a mixture of diastereoisomers. These isomers may be separated by conventional chromatography or fractional crystallization techniques.
Where the compound of formula (42) or (43) 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 (12) and (13) possess anti-cancer and anti-tumor 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 ingredients) as a pharmaceutical composition.
In another aspect, 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. It will be appreciated by those familiar with the art of clinical oncology that 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. Renters, John Wiley and Sons, N.Y., 1984). Thus, it will be understood that 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.
Therefore, for therapeutic purposes, 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:
1) Alkylating agents such as:
2-haloalkylamines (e.g. melphalan and chlorambucil);
2-haloalkylsulfides;
N-alkyl-N-nitrosoureas (e.g. carmustine, lomustine or
semustine);
aryltriazines (e.g. decaibazine);
mitomycins (e.g. mitomycin C);
methylhydrazines (e.g. procaibazine);
bifunctional alkylating agents (e.g. mechlorethamine);
carbinolamines (e.g. sibiromycin);
streptozotocins and chlorozotocins;
phosphoramide mustards (e.g. cyclophosphamide);
urethane and hydantoin mustards 2) Antimetabolites such as:
mercaptopurines (e.g. 6-thioguanine and 6-
[methylthio]purine);
azapyrimidines and pyrimidines;
hydroxyureas;
5-fluorouracil;
folic acid antagonists (e.g. amethopterin);
cytarabines;
prednisones;
diglycoaldehydes;
methotrexate;
3) Intercalators such as:
bleomycins and related glycoproteins;
anthracylines (e.g. doxombicin, daunorubicin, epirυbicin, esorubicin, idambicin, aclacinomycin A);
acridities (e.g. m-AMSA);
hycanthones;
ellipticines (e.g. 9-hydroxyellipticine);
actinomycins (e.g. actinocin);
anthraquinones (e.g. 1,4-bis[(aminoalkyl)- amino]-9,10-anthracenediones);
anthracene derivatives (e.g. pseudourea and bisanthrene);
phleomycins;
aureolic acids (e.g. mithramycin and olivomycin);
Camptothecins (e.g. topotecan);
4) Mitotic inhibitors such as:
dimeric catharanthus alkaloids
(e.g. vincristine, vinblastine and vindesine);
colchicine derivatives (e.g. trimethylcolchicinic acid)
epipodophyllotoxins and podophylotoxins
(e.g. etoposide and teniposide);
maytansinoids (e.g. maytansine and colubrinol);
terpenes (e.g. helenalin, tripdiolide and taxol);
steroids (e.g. 4ß-hyroxywithanolide E);
quassiniods (e.g. bniceantin);
pipobroman;
methylglyoxals (e.g. methylglyoxalbis-(thiosemicarbazone);
5) Hormones (e.g. estrogens, androgens, tamoxifen, nafoxidine, progesterone, glucocorticoids, mitotane, prolactin);
6) Immunostimulants
(e.g. human interferons, levamisole and tilorane);
7) Monoclonal and polyclonal antibodies;
8) Radiosensitiziiig and radioprotecting compounds
(e.g. metronidazole and misonidazole);
9) Other misodlaneous cytotoxic agents such as:
camptothecins;
quinolinequinones
(e.g. streptonigrin and isopropylidene azastreptonigrin);
cisplatin, cisrhodium and related platinum series complexes;
tricothecenes (e.g. tnchodermol or vermicarin A); cephalotoxines (e.g. harringtonine);
10)Cardioprotecting compounds, such as (±)-1,2-bis(3,5-dioxopiperazin-1-yl) propane, commonly known as ICRF-187, and ICRF-198;
11) Drug-resistance reversal compounds such as P-glycoprotein inhibitors, for example Verapamil, cyclosporin-c, fujimycin;
12) Cytotoxic cells such as lympholάne activated killer -cells or T-cells,
13) Other Immubostimulants such as interleukin factors or antigens.
14) Polynuckotides of sence or antisensing nature.
15) Polynuckotides capable of forming triple helices with DNA or RNA.
16) Polyethers
17) Distamycin and analogs.
18) Taxanes such as taxol and taxotere.
The above list of possible therapeutic agents is not intended to limit this invention in any way.
The pharmaceutical 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. Where appropriate, 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.
For injectable use, the pharmaceutical composition forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, 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 must 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, tween
801, 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 antifimgal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include 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 filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the
1denotes trademark required other ingredients from those enumerated above. In the case of sterile powders for
the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique. These methods yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, sachets 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.
As used herein, the expression "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifimgal 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.
It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. 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 calculatpid 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. 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 thempeutic 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, trimeric or oligomeric metal chelate complexes with, for example iron, magnesium or calcium.
The compounds of the invention exhibit antitumor activity, most notably, antitumor activity with human breast cancer, leukemia, colon cancer, ovarian 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, bladder cancer, lung cancer, and central nervous system (CNS) cancer. Most notably the compounds of this invention are more potent than doxombicin against P-170 mediated multidrug resistant cancers.
EXAMPLE 1 Methyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3- C] pyran-3-yl) ketone BCH-1125
A mixture of methyl (5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pynn-3-yl) ketone (100 mg, 0.485 mmol) and acetoxybutadiene (75 μl, 0.630 mmol) in dry benzene (5 mL) was heated for 12 hours at 60°C under argon atmosphere. The solvent was then removed in vacuo and the resulting adduct dried under reduced pressure. The adduct was dissolved in 10 mL of ethanol and to this solution was added 1 mL of 1 % K2CO3 aqueous solution. After stirring for 2 hours at R.T., the reactitm mixture was neutralized (pH=6) and extracted with CH2CI2 (2x50 mL). The organic layer was then washed with water (3x50 mL) and dried over MgSO4. Flash chromatography (toluene: ethyl acetate; 95 % :5 %) of the residue gave 69 mg (55 % yield) of pure titled compound. (MP: 135-136°C).
PMR (CDCl3,250MHz): 2.31 (s,3H,CH3), 2.54 (dddd,1H,J= 18.0, 10.3,3.6 and 1.8Hz,HCHa-CH), 2.97 (dm,1H,J =19 and 3.0Hz,HCHe-CH=), 4.05 (dd, 1H,J= 10.3 and 3.9Hz, CH2-CH), 4.58 (dt,1H,J= 18.7 and 3.6Hz,HCHa-O), 4.92 (dd,1H,J= 18.7 and 1.8Hz,HCHe-P), 7.72 (m,2H,Ar-H), 8.04 (m,2H,Ar-H).
CMR _(CDCl3,75.44 MHz): 24.42 (CH2-CH), 26,57 (COCH3), 63.97(CH2-O-), 78.63 (CH2-CH), 126.70, 127.08, 132.36 and 134.52 (CH aromatic); 132.20, 134.42, 141.30, and 142.41 (C quaternary), 183.51 and 183.63 (C=O quinone), 207.25 (CO-CH3).
EXAMPLE 1
Figure imgf000036_0001
EXAMPLE 2
Methyl (7-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-1129
A mixture of 1-methoxy-3-trimethylsilyloxy butadiene (776 mg, 4.51 mmol) and methyl (5,8- dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (309 mg, 1.50 mmol) in 6mL of dry toluene was stirred for 90 minutes at room temperature under argon atmosphere. The solvent was then removed in vacuo and the dried residue was dissolved in 10 mL of THF. To this solution was added 2 mL of a 4% aq. HCl solution. The combined organic layers were then washed with water and dried over MgSO4. Flash chromatography (toluene: ethyl acetate; 95%:5%) of the residue gave 180 mg (65% yield) of the titled compound (MP: 169-170°C).
PMR (DMSO-d6, 250 MHz): 2.24 (s,3H,CH3), 2.45 (m,1H,HCHa-CH=), 2.77 (dd,1H,J=19 and 3.0Hz,HCHe-CH),4.20 (dd,1H,J=9.8 and 3.9Hz,CH2-CH), 4.55 (d overlapped, 1H, J=22 Hz,HCHa-
O-), 4.78 (d overlapped, 1H, J= 18.0Hz,HCHe-O), 7.15 (dd,1H,J=8.5 and 2.4Hz,Ar-H), 7.30 (2d,
1H, J=2.5Hz,Ar-H), 7.88 (2d,1H,J=9.1Hz,Ar-H), 10.96 (s,1H,Ar-OH).
EXAMPLE 2
Figure imgf000036_0002
EXAMPLE 3 Methyl (1-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-1148
A mixture of methyl (1-methoxy-5,8 dioxo-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone (100 mg, 0.450 mmol) and acetoxy butadiene (80 μg, 0.675 mmol) in dry benzene (5 mL) was heated for 3 hours at 60°C under argon atmosphere. The solvent was then removed in vacuo and the resultting adduct was dissolved in 10 mL of toluene and then aromatized on silica gel by flash chromatography (toluene: ethyl acetate; 90%:10% followed by 70%:30%). Evaporation of the solvents gave 37 mg (31% yield) of pure titled compound.
PMR (Acetone d6, 250 MHz): 2.26 (s,3H,COCH3), 2,50 (dd,1H,J=11.6, 19.5Hz,HCHa-CH), 2.89 (dd,1H,J=4.2,19.5Hz,HCHe-CH), 4.71 (dd,1H, J=4.2,11.6 Hz,CH-CH2); 6.12 (broad s,1H,CHOH); 7.87 (m,2H,ArH); 8.07 (m,2H, ArH).
EXAMPLE 3
Figure imgf000037_0001
EXAMPLE 4 - Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-
3-yl) ketone Step 1: Monobromomethyl (5,8-dimethoxy-3,4-dihydrobenzo [2,3-C]
pyran-3-yl) ketone
To a stirred solution of methyl (5,8-dimethoxy-3,4-dihydrobenzo [2,3-c] pyran-3-yl) ketone (1.905g, 8.04 mmol) and trimethylsilyl chloride (1,530 μl, 12.0 mmol) in tetrahydrofuran (48ml) under nitrogen, at -78°C, was slowly added lithium diisopropyl amide (diisopropyl amine 10.71 mmol, n-butyl lithium 4.26 ml of a 2.5M solution in tetrahydrofuran, and 6.0 ml of tetrahydrofuran). After stirring for 10 minutes the temperature was raised to 0°C, and stirring was continued for 10 more minutes. Solvent was removed and the crude product was dissolved in 48 ml of tetrahydrofuran, N-bromosuccinamide (1,716 mg, 9.66 mmol) was added slowly to the solution. After 10 minutes, the reaction system was worked up with saturated aqueous sodium bicarbonate and washed with brine. The titled compound was obtained following flash chromatography (hexanes:ethyl acetate, 9:1) of the crude product. 1H NMR (benzene-d6, 250 MHz) _: 2.68 (dd, 1H,HCHa), 3.16 (dd,1H,HCHe), 3.28 (s,3H,OCH3), 3.32 (s,3H,OCH3), 3.73 (dd,1H,J=4.0,11.5Hz,CH), 3.81 (dd,2H,CH2Br), 4.51 (d,1H, J= 15.8Hz, HCHaO), 5.05 (d,1H,J= 15.8Hz,HCHeO), 6.335 (dd,2H,ArH),
Example 4: Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphto[2,3-C] pyran-3-yl) ketone.
Figure imgf000038_0001
Step 2: Monofluoromethyl (5,8-dimethoxy-3,4-dihydrobenzo [2,3-C]-pyran-3-yl) ketone
To a solution of 1 equivalent (3.75 mM, 1.18 g) of bromomethyl ketone isochroman from step 1 and 3 equivalents (11.25 mM, 2.160 g) of pTSA in 20 mL of dry THF was added slowly, at R.T., 6 equi. (22.5 mM, 22.5 mL) of a 1M solution in THF of N+(Bu)4F-. After stirring one night at R.T., 15 mL of H2O were added and the mixture was extracted with 3x20 mL of ethyl acetate. After drying with NaSO4 and solvent evaporation, the residue was flash chromatographed (Toluene: Ethyl acetate; 9.5:0.5) to give a 50% yield of pure titled compound .
1H NMR (250 MHz, CDCI3): 2.61 (dd,1H,HCHa), 3.11 (dd,1H,HCHe), 4.27 (dd,1H,CH), 4.63 (d,1H,HCHaO), 4.99 (d,1H,HCHeO), 5.33 (d, 2H, CH2F), 6.67 (dd,2H,ArH).
Step 3. Monofluoromethyl (5,8-diaxo-3,4,5,8-tetrahydrobenzo
[2,3-C] pyran-3-yl) ketone
To 1 equivalent (0.220 mM, 56 mg) of the fluoromethylketone isochroman from step 2 dissolved in 3 mL of acetonitrile at 0°C was added 3 equivalents of eerie ammonium nitrate (0.66 mM). After 10 minutes, the reaction mixture was brought to R.T., stirred for 20 minutes, and then extracted with dichloromethane/THF (1/1). The organic layer was dried over MgSO4. The titled quinone was obtained (67 mg) following evaporation of solvent.
1H NMR (250 MHz, CDCI3): 1H NMR (250 MHz, CDCI3) _: 2.46 (dddd,1H,J=3.0,4.0,10.4,18.9Hz,HCHa), 2.91 (dt, 1H, J=3.5, 18.9Hz, HCHe), 4.25 (dd,J=3.8,10.4Hz,CH), 4.445 (dt,J=3.5,18.4Hz,HCHaO), 4.77 (dd,J=2.2,18.5Hz,HCHeO), 5.25 (d,2H,CH2F), 6.75 (dd,2H,HC=CH).
Step 4. Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho
[2,3-C] pyran-3-yI) ketone
To 1 equivalent (0.220 mM, 50 mg) of the fluoroquinone from step 3 dissolved in 5 mL of dry toluene was added 1.3 equivalents (0.286 mM, 32.0 mg, 35 μl) of acetoxy butadiene and stirred overnight. The reaction mixture was passed directly on a silica gel column. 20 mg of pure titled compound was isolated after two flash chromatography (2% EtOAc in toluene).
PMR (Acetone-d6, 250 MHz): 2.62 (dddd,1H,HCHa), 2.94 (dt,1H,HCHe), 4.46 (dd,1H,CH), 4.62 (dt,1H,HCHa), 4.84 (dd,1H,HCHe), 5.43 (d, 2H, CH2F), 7.83 (m,2H,ArH), 8.03 (m,2H,ArH).
EXAMPLE 5
Step 1.
(1'S,1R,3S) and (1'S,1S,3R)-Methyl (5,8-dioxo-1-(2',3', 6'- trideoxy-3'- trifluoroacetamido-4'-0-p-nitrobenzoyl-L-lyxohexopyranose)-3,4,5,8- tetrahydrobenzo [2,3-C] pyran-3-yl) ketone
To a stirred solution of 1,4-di-O-p-nitrobenzoyl-N-trifluoroacyl daunosamine (1.584 g, 2.93 mmol) in 160 mL of dry dichloromethane and 40 mL of anhydrous ether, maintained at -35°C under argon atmosphere, was added dropwise 1.132 mL (5.85 mmol) of trimethyl silyl triflate (TMSOTf). After stirring for 1.5 hours at 0°C, the temperature was lowered to -15°C and a cooled (0°C) solution of methyl (1-hydroxy-5,8-dioxo-3,4,5,8-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone in dry dichloromethane (40 mL) was added. After 5 hours of stirring, the reaction mixture was put into a solution of 150 mL of ethyl acetate and 50 mL of a saturated NaHCO3 solution. The organic layer was washed with water and dried (Na2SO4). Flash chromatography of the residue gave 917 mg (69 % yield) of the mixture of titled stereoisomers. Example 5: Glycosidated derivatives of pyranonaphtoquinones with a methyl ketone side chain.
Figure imgf000040_0001
R1 = OPNB R2=NHCOCF3 R1 = OPNB R2= NHCOCF3
Figure imgf000040_0002
R1 = OH R 2=NHCOCF3
Figure imgf000040_0003
R1 = OH R 2= NHCOCF3
A second flash chromatography seperated the individual diastereomers.
The 1'S,1S,3R titled diastereomer had 1H NMR (250 MHz, acetone-d6) _: 1.28 (d.3H,J=6.4Hz,CH3), 2.05 (hidden m, 1H,2'-CH2), 2.30 (s,1H, COCH3), 2.42-2.49 (m,2H,2'-CH2 overlapped with HCHa), 2.84 (dd,1H,HCHe.) 4.53-4.65 (broad m,1H,3'-CH), 4.635 (dd,2H,J=4.2, 11.6Hz,O-CH-COCH3), 4.76 (broad q,1H,5'-CH), 5.50 (broad s.1H,4'-CH), 5.69 (broad s,1H,1'-CH), 6.02 (s,1H,0-CH-O), 6.90 (dd,2H,2X C= CH), 8.37 (m,4H,ArH), 8.68 (broad d,1H,NH). The 1'S,1R,3S titled diastereomer had 1H NMR (250 MHz, acetone-d6) _: 1.19 (d,3H,J=6.6Hz,CH3), 1.89 (dd,1H,J=4.6,13.1Hz,2'-CH2),2.32 (s, 3H,COCH3), 2.29-2.47 (m,2H,2'-CH2 overlapped with HCHa), 2.89 (dd,1H, J=4.1Hz,HCHe), 4.60 (m,2H,3'-CH overlapped with 5'-CH), 4.71 (dd,1H, J=4.1,11.5Hz,O-CH-COCH3), 5.48 (broad s, 1H,4'-CH), 5.64 (broad s, 1H,1'-CH), 5.89 (s.1H.O- CH-O), 6.87 (dd,2H,2XC=CH), 8.37 (dd,4H, ArH), 8.69 (broad d, 1H, NH).
Step 2.
(1'S,1R3S)-Methyl (5,10-dioxo-1-(2'3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L -lyxohexo-pyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
To a stirred solution of 1'S, 1R, 1S -diastereomer, from step 1 (Example 5), (0.464 mmol) in dry benzene (10 mL) under argon was added 78μl (696 mL) of 1-acetoxybutadiene. After stirring for 16 hours at room temperature, the reaction mixture was flash chromatographed (toluene:ethyl acetate; 90%: 10%) to give 244 mg (82% yield) of the pure titled compound.
1H NMR (250 MHz, acetone-d6): 1.22 (d,3H,J=6.4Hz,CH3), 1.94 (dd,1H,J=4.7,13.1Hz,2'-CH2), 2.35 (s,3H,COCH3), 2.42 (m,1H,2'-CH2), 2.52 (dd,1H,J=11.6,19.8Hz,HCHa), 3.04 (dd,1H,J=3.9,19.6 Hz, HCHe), 4.55-4.68 (overlapped m,2H,3'-CH and 5'-CH), 4.79 (dd,1H,J=4.0,11.5 Hz,O-CH-COCH3), 5.49 (broad s,1H,4'-CH), 5.75 (broad s,1H,1'-CH), 6.07 (s,1H,O-CH-O), 7.83-7.93 (m,2H,ArH), 8.06-8.14 (m,2H,ArH), 8.32-8.43 (m,4H,ArH), 8.67 (broad d,1H,NH).
Step 3.
(1'S,1R3S)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'- hydroxy-L-lyxohexopyranose)-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-1184
To a stirred solution of the glycoside from step 2, (30 mg, 4.65x10-5 mmol) in 4 mL of dry methanol and 1 mL of anhydrous THF at 0°C and under argon, was added 11μl (4.66x10-5 mmol) of NaOCH3 (4.37 M) solution in methanol. After 5 minutes of stirring, the reaction was quenched with 1 mL of saturated NH4CI solution and extracted with CH2CI2 . Following evaporation of solvent, flash chromatography of the residue gave 23 mg (100% yield) of pure titled compound .
1H NMR (250 MHz, Acetone-d6): 1.25 (d,3H,J=6.5Hz,CH3), 1.76 (dd,1H, J=4.5,12.9Hz,2'-CH2), 2.16 (m,1H,2'-CH2), 2.32 (s,3H,COCH3), 2.48(dd, J=11.6,19.5Hz,HCHa), 2.99 (dd,1H,J=4.1,19.5 Hz,HCHe), 3.68 (broad s.1H,4'-CH), 4.17-4.41 (overlapped m,2H,3'-CH and 5'-CH), 4.69 (dd,
1H,J=4.0,11.0Hz,O-CH-COCH3), 5.53 (broad s,1H,1'-CH), 5.97 (s,1H,O-CH-O), 7.82-7.90 (m,2H,ArH), 8.01-8.05 (m,2H,ArH), 8.13 (broad d, 1H,NH). Step 4:
(1'S,1S,3R)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroaceta mido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyra nose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
Application of the procedure described in step 2 of the present example on the 1'S, 1S, 3R quinone glycoside from stop 1 gave the titled compound which had:
1H NMR (250 MHz, Acetone-d6): 1.33 (d,3H,J=6.6Hz,CH3),1.94 to 2.08 (m,1H,2'-CH2), 2.33 (s,3H,COCH3), 2.49 (m,1H,2'-CH2), 2.58 (dd,1H, J=11.7,19.6Hz,HCHa), 3.01 (dd,1H,J=4.1,19.7Hz,HCHe), 4.53-4.65 (m, 1H,3'-CH), 4.71 (dd,1H,J =4.1,11.5 Hz, O-CH-COCH3), 4.90 (broad q.1H, 5'-CH), 5.53 (broad s,1H,4'-CH), 5.75 (broad s,1H,1'-CH), 6.21 (s, 1H.O-CH-O), 7.88-7.92 (m,2H,ArH), 8.08-8.16 (m,2H,ArH), 8.34-8.43 (m,4H,ArH), 8.69 (broad d, 1H,NH).
Step 5:
(1'S,1S,3R)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'- hydroxy-L-lyxohexopyranose)-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-1146
Treatment of the glycoside obtained firom step 5 with sodium methoxide as described in step 3 of this example yielded the titled compound, which had:
1H NMR (250 MHz, Acetone-d6) 1.35 (d,3H,J=6.4Hz,CH3), 1.77(dd,1H, J=4.5,12.9Hz,2'-CH2), 2.17 (dt,1H,J= 3.7,12.9Hz,2'-CH2), 2.30 (s,3H, COCH3), 2.56 (dd,1H,J=10.7,19.6Hz,HCHa), 2.98 (dd,1H,J=4.2,19.8 Hz, HCHe),3.70 (broad s,1H,4'-CH), 4.2-4.4 (m,1H,3'- CH), 4.60 (broad quartet,1H,5'-CH), 4.66 (dd,1H,J=4.2,11.5Hz,O-CH-COCH3), 5.52 (broad d,1H,1'-CH), 6.15 (s,1H,O-CH-O), 7.86-7.92 (m,2H,ArH), 8.07-8.11 (m,2H,ArH), 8.15 (broad d,1H,NH).
Step 6:
(1'S,1R,3S)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-7-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yI) ketone
The titled compound was prepared in 62% yield by cyclocondensing the 1'S, 1R, 3S-quinone glycoside from step 1 of this example with 1-methoxy-3-trimethylsilyloxybutadiene. The same procedure as described in step 2, in this example, was used.
1H NMR (250 MHz, Acetone-d6): 1.21 (d,3H,J=6.6Hz,CH3), 1.93 (m,1H, 2'-CΗ2), 2.34 (s,3H,COCH3), 2.49 (dd,1H,J=11.6,19.5Hz,HCHa), 3.00 (dd,1H,J=4.1,19.5Hz,HCHe), 4.57-4.69 (overlapped multiplets, 2H,3'-CH and 5'-CH),4.76 (dd,1H,J=4.0,11.5Hz,0-CH-COCH3), 5.49 (broad s, 1H,4'-CH), 5.73 (broad d,1H,1'-CH), 6.04 (s.1H.O-CH-O), 7.25 (dd, 1H,J=2.5,8.5Hz,ArH), 7.46 (d,1H,J=2.5Hz,ArH), 7.98 (d,1H,J= 8.6Hz, ArH), 8.38 (m,4H,ArH), 8.58 (broad d,1H,NH) 10.23 (broad s,1H, ArOH).
Step 7:
(1'S,1R,3S)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxobexopyranose)-7-hydroxy-3,4,5, 10-tetrahydro [2,3-C] pyran-3-yl) ketone
BCH-1181
Application of the hydrolysis procedure described in step 3 of this example to the 1'S, 1R, 3S tricyclic glycoside of step 8 resulted in the removal of the p-nitrobenzoyl protecting group. The titled compound had:
1H NMR (250 MHz, Acetone-d6): 1.63 (d,3H,J=6.4Hz,CH3), 2.14 (m,1H, 2'-CH2), 2.53 (m,1H,2'- CH2), 2.70 (s,3H,COCH3), 2.87 (dd,1H,J=11.7, 19.4Hz,HCHa), 3.35 (dd,1H,J =4.1,19.4Hz,HCHe), 4.07 (broad s,1H,4'-CH), 4.65 (overlapped m,2H,3'-CH and 5'-CH), 5.07 (dd,1H,J=4.1,11.7 Hz,0- CH-COCH3), 5.91 (broad d,1H,1'-CH), 6.35 (s,1H,O-CH-O), 7.64 (dd,1H,J=2.5,8.5Hz,ArH), 7.84 (d,1H,J=2.5Hz,ArH), 8.35 (d,1H,J= 8.5 Hz,ArH), 8.48 (broad d,1H,NH), 10.23 (broad s,1H,ArOH). Step 8:
(1'S,1S,3R)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-7-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
The titled compound was prepared by applying the same procedure as described in step 8 on the 1'S, 1S, 3R, quinone glycoside of step 1 of this example.
1H NMR (250 MHz, Acetone-d6): 1.32 (d,3H,J=6.4Hz,CH3),2.08 (m,1H, 2'-CH2), 2.51 (m,1H,2'- CH2) 2.55 (dd,1H,J=11.5,19.5Hz,HCHa), 2.96 (dd,1H,J=4.2,19.6Hz,HCHe), 4.51-4.62 (m,1H,3'- CH), 4.68 (dd,1H,J= 4.2, 1 1.5Hz,0-CH-COCH3), 5.52 (broad s,1H,4'-CH), 5.73 (broad s,1H, 1'-CH), 6.18 (s.1H,O-CH-O), 7.28 (dd,1H,J=2.6,8.5Hz,ArH), 7.47 (dd, 1H,J=2.6,8.5Hz,ArH), 8.03 (d,1H,J=8.5Hz,ArH), 8.38 (m,4H,ArH), 8.68 (broad d,1H,NH), 9.85 (broad s,1H,ArOH).
Step 9:
(1'S,1S,3R)-Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-7-hydroxy-3,4,5, 10-tetrahydro [2,3-C] pyran-3-yl) ketone BCH-1180
Application of the hydrolysis procedure described in step 3 of this example to the 1'S, 1S, 3R tricyclic glycoside of step 11 resulted in the removal of the p-nitrobenzoyl protecting group. The titled compound had:
1H NMR (250 MHz, Acetone-d6) 1.73 (d,3H,J=6.6Hz,CH3), 2.17 (m,1H, T-CH2), 2.58 (m,1H,2'- CH2), 2.68 (s,3H,COCH3), 2.90 (dd,1H,J=11.6, 19.7Hz,HCHa), 3.33 (dd,1H,J=4.3,19.8Hz,HCHe), 4.09 (broad s,1H,4'-CH), 4.63 (m,1H,3'-CH), 4.95-5.06 (overlapped m,2H,5'-CH, and OCH-COCH3), 5.91 (broad d,1H,1'-CH), 6.51 (s,1H,0-CH-0), 7.65 (dd,1H, J=2.6,8.5Hz,ArH), 7.85 (d,1H,J=2.6 Hz,ArH), 8.38 (d,H,J=8.5Hz, ArH), 8.52 (broad d,1H,NH), 10.18 (broad s,1H,ArOH).
EXAMPLE 6
2-[4,-Hydroxy-1'3'-dioxo-3'-cyclobutenoxy] methyl-(5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yI) ketone
Example 6: Tricyclic pyranylnaphthoquinones with a squaric acid molety.
Figure imgf000044_0001
Step 1: Bromomethyl (5,8-dioxo-5,8-dihydrobenzo [2,3-C] pyran-3-yl) ketone
To a solution containing one equivalent of 5,8-dimethoxy-3-bromoacetoisochroman (380mg,1.1mmol) in acetonitrile (18ml), at 0°C under argon, was added dropwise an aqueous solution of eerie ammonium nitrate (6.5g in 28ml H2O). After stirring for 10 minutes, the mixture was extracted with 3 x 20ml of CH2CI2. The combined organic layer was dried over MgSO4 and then evaporated to yield 263 mg of pure titled compound.
1H NMR (250 MHz,CDCl3): 2.43-2.69 (m,1H,CH2), 2.82-3.07 (m,1H,CH2), 4.24 (dd,2H,CH2Br), 4.4-4.6 (m,2H,CH2O and CHCOCH2Br), 4.52 (d,1H, CH2O), 6.74 (dd,2H,HC=CH).
Step 2: Bromomethyl (5,10-dioxo-5,10-dihydronaphtho [2,3-C] pyran-3-yl) Ketone
To a solution containing one equivalent of isochromandione (263mg, 0.92mmol) from step 1 (example 6) in 25ml of dry toluene was added three equivalents (2.7mmol) of acetoxybutadiene. The reaction mixture was stirred overnight under argon at room temperature and then two hours at 60°C. After removal of solvent, the crude product was flash chromatographed (toluene/EtOAc,9:1). The titled orange compound was isolated (192mg) in 62% yield.
1H NMR (250 MHz,CDCl3): 2.4-2.6 (m,1H,CH2), 2.7-3.2 (m,1H,CH2), 4.3-4.4 (m,2H,CH2Br), 4.45 (m,1H,CH-O), 4.6-4.7 (m,1H,CH2O), 4.9-5.05 (m,1H,CH2O), 7.6 (m,2H,ArH), 8.1 (m,2H,ArH).
Step 3: 2-[4'-Hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10- dioxo-3,4,5,10- tetrahydro [2,3-C] pyran-3-yl) ketone
Under argon at room temperature, two equivalents (0.9mmol) of squaric acid and two equivalents of
CsCO3 (0.9mmol) were diaolved in 10ml of dry dimethyl formamide (DMF) (non homogeneous solution). To this solution was added one equivalent (0.45mmol) of the pyranonaphthoquinone from step
3 (example 6). The solution was treated at 60°C for two hours. After cooling, 10ml of H2O was added, and extraction was carried out with 3 x 10ml ETOAc. After drying and evaporation, the residue was purified twice by preparative TLC. The titled compound was obtained in 30% yield.
1H NMR (250 MHz.Acetono-d6): 2.5-2.6 (m,1H,CH2), 2.8-3.0 (rn.1H, CH2), 4.4 (m,1H,CH-O), 4.6
(overlapped m,2H,COCH2O), 4.8-5.0 (m,2H, CH2O), 7.7 (m,2H,ArH), 8.1 (m,2H,ArH). EXAMPLE 71
Tricyclic pyranylnaphthoquinone glycosides with a squaric add side chain
Example 7: Tricycle pyranytnaphtoquinone glycosides with a squaric acic moiety.
Figure imgf000045_0001
+ 1,3-diepimer + 1,3-diepimer + 1,3-diepimer Step l: (1'S,1 R,3S) and (1'S,1S,3R)-Bromom ethyl (5,10-dioxo-1-(2',3',6'-trideoxy-4'-O-P- nitrobauoyl-3'-trifluoro acetamido-L-lyxohexopyranose)-(3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
At room temperature, under N2, to one equivalent (0.482 mmol) of a 1:1 mixture starting quinone glycosides from steps 3 and 6 (example 1) dissolved in 6 ml dry tetra hydro furan (THF) was added 1.1 equivalent of pyridinium hydrobromide perbromide. After two hours, to the solution was added 7 ml 5%
NaHCO3 solution and extracted with 3 x 10 ml EtOAc. After drying over Na2SO4 and evaporation, the residue was chromatograpbed using 95% toluene -5% EtOAc solvent Two major fractions were isolated corresponding to the 2 isomers (yield 40% of pure compounds, ratio # 1/1 isomer). PMRs of the separated isomers are described in step 1 (example 8) and step 1 (example 9). Step 2:
(1'S,1R,3S) and (1'S,1S,3R)-2-[4'-hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10-dioxo-1-[2"3",6"-trideoxy-4"-O-p-nitrobenzoyl-3"-trifluoroacetamido-L- lyxobexopyranose]-3,4,5,10-tetrahy dronaphtho [2,3,c] pyran-3-yl) ketone
The title compounds were obtained by applying the procedure described in step 4 (example 6) to the tricyclic glycosides from step 1 (example 7).
1H NMR (250 MHz, CD3OD): 1.2 (d,3H,5"-CH3), 1.9 (dd,1H,2"-CH2), 2.42 (m,1H,2"-CH2), 4.6 (m,2H,CO-CH2-O), 4.8 (m,1H,OCH-CO), 5.5 (m, 1H,4"-CH), 5.8 (m,1H, 1 "-CH), 6.1 (m,1H.O-C1H- O), 7.7-7.9 (m,2H, arom H), 8.05-8.1 (m,2H, arom H), 8.3-8.45 (m,4H, arom H), 8.7 (broad d, 1H,NH), 3.1 (m,1H,C4-H), 2.6 (m,1H,C4-H), 4.6-4.2 (overiapped m, 2H, 3"-CH and 5"-CH). EXAMPLE 8
Step 1: (1'-S, 1-R, 3-S)-1-(2'-3'-6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoroacetamido-L-
Iyxohexopyranose)-3-(2-bromo-acetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
(2,3-c)-pyran
Example 8
Figure imgf000046_0001
This example exemplifies interconversion of functional groups wherein a methyl ketone; at R6 is eventually converted to a substituted thiazole ring. Step 1
To a solution of (1'-S,1-R,3-S)-1-(2',3',6'-trideoxy-4'-p-nitro-benzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-(2,3-c)-pyran (87 mg, 0.135 mmole) in tetrahydrofuran (THF) (4.5 ml), stirred at room temperature, was added slowly a solution of pyridinium hydrobromide perbromide (43.1 mg, 0.136 mmole) in 3 ml of THF. The resulting yellow liquid was stirred for 2 hours at room temperature, then poured into water. Methylene chloride was used to extract the crude product from the aqueous layer. The combined methylene chloride extracts were washed with brine (10 ml) then dried over anhydrous sodium sulfate. The organic solvent was evaporated and the crude product was obtained as a orange oil (98 mg). Chromatographic purification (by volume, ethyl acetate:toluene - 1:5) of the crude product gave a yellow sticky solid (40 mg) as a pure compound. A mixture (48 mg) containing the product (>34% mol) and unreaceted starting material (< 66% mol) was also obtained.
M.P. (Electrothermal IA-9100): 125-130°C; decomposed at 175°C.
1H NMR (250MHz, acetone-d6): 1.25 (d,3H,J=6.5Hz,6'-CH3), 1.97 (dd, 1H,J=4.8Hz,13.7Hz,2'- HCHa), 2.48 (dt,1H,J=4.2Hz,13.7Hz,2'-HCHe), 2.64 (dd,1H,J=11.6Hz,25.6Hz,4-HCHa), 3.14 (dd,1H,J=5.7Hz,25.6Hz,4-HCHe). 4.66 (S,2H,COCH2Br), 4.71 (qua,1H,J =6.5Hz,5'-CH), 4.83 (overlapped m,1H,3'-CH), 5.08 (dd, 1H, J=5.7Hz,11.6Hz,3-CH), 5.52 (bs,1H,4'-CH), 5.79 (bd,1H,J=3.0Hz,1'-CH), 6.10 (S,1H,1-CH), 7.90 (m,2H,7,8-ArH), 8.08 (m,2H,6,9-ArH), 8.36 (d,2H,J=7.4Hz,PNB-COC (CH)2). 8.41 (d,2H,J=7.4.Hz,PNB-NC2C(CH)2), 8.75 (d,1H,J=7.7Hz,3'- NHCOCF3).
IR(Nicolet 205 FT, film on Nacl tablet), cm-1, 3625.9 (br,w), 3346.4 (str) 3079.5, 2955.5, 1732.6 (str), 1665.4 (str), 1596.0, 1530.9, 1274.5 (str), 1173.7, 1100.1, 974.04, 959.33 (m), 875.28, 721.29 (m).
Step 2: (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-4'-p-nitrobenzoyI-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-(2,3-c)pyran
To a suspension of thiourea (2.2mg, 0.027 mmole) in ether (2 ml) was added a solution of bromomethyl ketone (20 mg, 0.026 mmole), from the previous step in methylene chloride (1 ml). The reaction mixture was stirred at room temperature for 20 minutes when a newly formed white suspension was observed. The reaction mixture was further stirred for 3 hours.
Solvents were removed under reduced pressure to give a white solid which was treated with saturated sodium bicarbonate aqueous solution and extracted with methylene chloride (4x3 ml). The organic layer was dried (over sodium sulfate) and evaporated to give a crude product which was chromatographed (by volume, chloroform:methanol 100:3, with one drop of pyridine) to yield the titled substance (3.5 mg) as a light colored solid.
M.P. (Electrothermal IA-9100): 142°C (decomposed). 1H NMR (250 MHz, acetone-d6), δ: 1.13 (d,3H,J=6.7Hz,6'-CH3), 1.92 (dd,1H,J=5.4Hz, 12.8Hz,2'-HCHa), 2.42 (dt,1H,J=3.4Hz,12.8Hz,2'- HCHe), 2.71 (dd,1H, J=12.2Hz,20.3Hz,4-HCHa), 3.12 (dd,1H,J=3.4Hz,20.3Hz,4-HCHe), 4.65 (m,1H,3'-CH), 4.67 (qua,1H,J=6.7Hz,5'-CH), 5.18 (dd,1H,J=3.4Hz, 12.2Hz.3-CH), 5.50 (bs,1H,4'- CH), 5.68 (d,1H,J=2.7Hz,1'-CH), 5.99 (s,1H,1-CH), 6.67 (S,1H,thiazole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.35 (d,2H,1=9.4Hz,PNB-COC(CH2), 8.42 (d,2H,J=9.4 Hz, PNB- NO2C(CH)2).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3455.4 (w), 3346.8 (str), 3119.6 (w), 2923.8, 2850.3, 1731.5 (str), 1665.0 (str), 1532.2 (str), 1273.4 (str), 1217.5, 1182.5 (m), 1161.5 (m), 1101.8, 1005.5, 957.36 (m), 874.2, 721.18 (m).
Step 3: (1'S,1-R,3-S)-1-(2',3',6'-trideoxy-3'-tiifluoroacetmido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-(2-aza-3-acetamidoth iazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]-pyran
A solution of bromomethyl ketone (10mg, 8mmol), from step 1 (example 8), in methylene chloride (0.5 ml) was added to an ether solution (2 ml) of 1-methylthiourea (1.1mg, 1.0 mmol). The reaction mixture was stirred for 3 hours at room temperature then 3 hours at 40°C. Solvent was evaporated and the crude product was analyzed by 1H NMR to see if the reaction was incomplete. The reaction mixture was redissolved in methylene chloride (0.5 ml) and ether (4 ml) and then stirred with newly added 1- acetylthiσurea (1 mg, 1.0 mmol) and sodium iodide (0.06 mg, 0.05 mol. eqv.) at 40°C for 1 hour. Solvent was evaporated to give a crude product which was chromatographed (Eluent in volumn ratio, chloroform:methanol 20: 1, with 1 drop of pyridine) to yield the title substance as a light colored solid (6 mg).
M.P. (Electrothermal IA-9100): 145-150°C, decomposed at 195°C.
1H NMR (250 MHz, acetone-d6), δ: 1.09 (d,3H,J=7.4Hz,6'-CH3), 1.92 (dd, 1H,J= 4.7Hz, 12. 1Hz,2'- HCHa), 2.42 (dt,1H,J=2.3Hz,12.1Hz,2'-HCHe), 2.75 (dd,1H,J=11.7Hz,19.5Hz,4-HCHa), 3.14 (dd,1H,J=2.3Hz,
19.5Hz,4-HCHe), 4.62 (qua,1H,J-7.4Hz,5'-CH), 4.64 (m,1H,3'-CH), 5.31
(dd,1H,J=2.3Hz,11.7Hz,3-CH), 5.47 (bs,1H,4'-CH), 5.68 (bs,1H, 1'-CH), 6.00 (s,1H,l-CH), 7.20 (s,1H,thiazole-CH), 7.90(m,2H,7.8-ArH), 8.11 (m,2H,6.9-ArH), 8.34 (d,2H,J=7.8Hz,PNB:CO-C- (CH)2), 8.40 (d, 2H,J=7.8Hz,PNB:NO2-C-(CH)2), 8.72 (d,1H,J=7.4Hz, 3'-NHCOCF3), 11.08 (S,1H,thiazole-NHAc).
IR (Nicolet 205 FT, film on NaCl plate): 3539.7 (br,w), 3296.1 (str), 3083.7, 2919.4 (str), 1732.7 (str), 1667.5 (str), 1593.9 (w), 1545.7 (str), 1528.7 (str), 1127.1 (str), 1217.2, 1183.2, 1166.2, 1104.0, 1008.9, 975.46, 956.53, 718.14 (m). Step 4: (1'-S,1-R,3-S)-1-(2',3',6'-trideαxy-3'-trifluoro acetamido-L-lyxohexopyra nose)-3-(2-aza-3- acetamido thiazolyl)-5,10-diαxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
To an ice-cold solution of PNB-derivative (3mg, 4.1 mmol), from the previous step, in a tri-solvent system containing water (98 μl), MeOH (422 μl) and methylene chloride (158 μl) was added an aqueous solution (20 μl) of sodium bicarbonate (0.51 mg, 6.11 mmol). The reaction mixture was then stirred at room temperature for 1 hour. When the reaction was completed, (as judged by thin-layer- chromatography), the reaction mixture was poured into a bi-layer system of methylene chloride and saturated aqueous ammonium chloride solution (5 ml/5 ml). The well-shaken mixture was thai allowed to settled and the organic layer was separated, dried over aodium sulfate, and evaporated to give the titled substance as a light colored solid (1.4 mg).
M.P. (Electrothermal IA-9100): 160-165ºC, decomposed at 195 °C.
1H NMR (250 MHz, acetone-d6), δ: 1.12 (d,3H,J=7.9Hz,6'-CH3), 1.24 (dd,1H,J=6.7Hz,15.0Hz,2'- HCHa), 2.14 (dt,1H,J= 4.2Hz,15.0Hz,2'-HCHe), 2.25 (s,3H,COCH3), 2.64 (dd,1H,J=12.5Hz,20.9Hz,4-HCHa), 3.13 (dd,1H,J=4.2Hz,20.9Hz,4-HCHe), 3.63 (bs,1H,4'-CH), 4.21 (qua,1H, J=7.9Hz, S'-CH), 4.30 (m,1H,3'-CH), 5.26 (dd,1H,J=4.2Hz,12.5Hz,3'-CH), 5.50 (d,1H,J=2.4HZ,l'-CH), 5.97 (s,1H,1-CH), 7.12 (s, 1H, thiazole-CH), 7.90 (m,2H,7.8,ArH), 8.10 (m,2H,6.9,ArH), 11.07 (s,1H,thiazole-NHAc).
IR (Nicolet 205 FT, film on NaCl plate): 3668.0-3119.7 (peaked at 3268.3,br,str), 3073.7 (w), 2925.1, 1711.8 (str), 1669.4 (str), 1591.6 (w), 1549.1, 1375.8, 1290.9 (str), 1170.6, 1006.5 (w), 984.49(str), 716.33 (w).
Step 5: (1'-S,1-R,3-S)-1-(2',3',6-'trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5, 0-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C] pyran
To a sample of PNB-derivative (2.5 mg, 3.5 μmol) from step 2, dissolved in a tri-solvent system containing water (85.7μl), methanol (370μl) and methylene chloride (138μl), at 0°C, was added a solution of sodium bicarbonate (0.66 mg, 7.0 μmol, in 30μl of water). The reaction mixture was stirred at room temperature for 1.5h untill a total consumption of the starting material. It was poured into a saturated sodium bicarbonate solution (4ml) and evaporated with methylene chloride (5x2ml). The organic layer was dried over aodium sulfate and then evaporated to give a crude product which was further purified by recrystalization from methylene chloride/hexane to give an off-white solid (1.5mg). M.P. (Electrothermal IA-9100): 142-146°C.
1H NMR (250 MHz, acetone-d6), 6: 1.14 (d,1H,J=5.9Hz,6'-CH3), 1.74 (dd,1H,J=12.5Hz,4.8Hz,2'- HCHa), 2.11 (m,1H,2'-HCHe), 2.62 (dd,1H, J=11.8Hz,18.4Hz,4'-HCHa), 3.12 (dd,1H,J=4.2Hz,18.4Hz,4-HCHe), 3.65 (bs,1H,4'-CH), 4.24 (qua,1H,J=5.9Hz,5'-CH), 4.33 (m,1H,3'-CH), 5.11 (dd,1H,J=4.2Hz,11.8Hz,3-CH), 5.48 (bd,1H,J=3.0Hz,1'-CH), 5.92 (s, 1H.1- CH), 6.57 (s,1H,thiazole-CH), 7.87 (m,2H,7.8,ArH), 8.08 (m,2H, 6.9,ArH).
IR (Nicolet 205FT, film on NaCl plate): 3423.9 (str), 3341.1 (str), 2927.0, 2853.4 (w), 1718.5 (str), 1664.4 (str), 1597.5, 1524.7, 1335.0, 1300.1 (str), 1174.0, 100.4, 984.61 (str), 724.51, 707.71.
EXAMPLE 9
Figure imgf000050_0001
Step 1: (1'-S,1-S,3-R)-1-(2',3'-6'-trideoxy-4'-p-mtrxibenzoyl-3'-trifluro-acetamido-L- lyxohexopyranose)-3-(2-bromoacetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-pyran
To a solution of (1'-S,1-S,3-R)-1-(2',3',6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (50 mg, 0.077 mmol) in tetrahydrofuran (3 ml), stirred at room temperature, was added a solution of pyridinium hydrobromide perbromide (24.5 mg, 0.077 mmol) in THF. The reaction mixture was stirred for 2 hours at room temperature, then poured into water (10 ml) and extracted with methylene chloride (3x5 ml). The condoned organic extracts were washed with brine (5 ml), and dried over aodium sulfate. The solvent was evaporated to give a erode product (68 mg) from which, via flash chromatography (eluent in volume ratio, toluene:ethyl acetate- 10:3), a pure sample of the titled substance (27 mg) was obtained as a light yellow solid. Unreacted starting material (10 mg) was also obtained.
1H NMR (250 MHz.acetone-d6), δ: 1.33 (d,3H,J=6.8Hz,6'-CH3), 2.02 (dd, 1H,J -4.9Hz, 13.5Hz,2'- HCHa), 2.48 (dt,1H,J=5.8Hz,13.5Hz,2'-HCHe), 2.78 (dd,1H,J=12.1Hz,20.3_Hz,4-HCHa), 3.12 (dd,1H, J=4.0Hz, J=20.3 Hz,4-HCHe), 4.29 (m,1H,3'-CH), 4.52 (d,1H,J =13.8Hz,BrHCHre), 4.67 (d,1H,J=13.8Hz,BrHCHsi), 4.88 (qua,1H,J=6.8Hz,5'-CH), 5.04 (dd,1H, J=4.0Hz,12.1Hz,3-CH), 5.53 (bs,1H,4'-CH), 5.85 (bd,1H,J=3.4Hz,1'-CH), 6.24 (s,1H,1-CH),7.90 (m,2H,7,8-ArH), 8.10 (m,2H,6,9-ArH), 8.48 (qua-like m,4H,PNB-ArH), 8.70 (bd,1H,J=7.4Hz,3'-NHCOCF3).
Step 2: (1'-S,1-S3-R)-1-(2'3'-6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-acetamido)-5,10-dioxo-3,4,5,10 -tetrahydro-1H- naphtho-[2,3-c]-pyran A sample of 1-acetylthiourea (1.06 mg, 9.0 mmol) in ether (2 ml) was stirred at room temperature while a solution of bromomethyl ketone (9 mg, 8mmol), from the previous step, in methylene chloride (0.5 ml) was added. The resulting mixture was stirred for 3 hours at room temperature and then for 4 hours at 40°C. Solvent was evaporated to give a crude product which was purified via flash chromatography (eluent in volume ratio chloroform:methanol- 100:7, with 1 drop of pyridine added), to yield a product, which was further purified by recrystallization from C^C^/hexane. The titled substance was obtained as an off-white solid (4mg).
1H NMR (250 MHz, aoetone-d6), δ: 1.33 (d,3H,J=7.5Hz,6'-CH3), 1.96 (dd,1H,J=5.8Hz,15.2Hz,2'- HCHa), 2.28 (s,3H,COCH3), 2.49 (dt,1H, J = 3.8Hz,15.2Hz,2'-HCHe), 2.76 (dd,1H,J=12.5Hz,20.0Hz,4-HCHa), 3.15 (dd,1H,J=4.2Hz,20.0Hz,4-HCΗe), 4.60 (m,1H,3'-CH), 4.92 (qua,1H, J=7.5Hz,5'-CH), 5.24 (dd,1H,J=4.2Hz,12.5Hz,3-CH), 5.55 (bs,1H,4'-CH), 5.68 (bd,1H,J=3.0Hz,1'-CH), 6.16 (s,1H,1-CH), 7.18 (s,1H, thiazole-CH), 7.92 (m,2H,7,8-ArH), 8.14 (m,2H,6,9-ArH), 8.36 (d,2H, J =8.3Hz,PNB-OCOC(CH)2), 8.42 (d,2H,J=8.3Hz,PNB-NO2C(CH)2), 8.74 (bd, 1H,J=7.9Hz, 3'-NHCOCF3), 11.07 (s,1H,thiazole-NHAC).
Step 3: (1'-S,1-S3-R)-1-(2',3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- acetamido-thiazolyl)-5,10-diαxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran A sample of the PNB-derivative (4.0 mg, 5.5 mmol), from the previous step, was taken into a solvent system containing metiiylene chloride (212 μl) methanol (566 μl) and water (131 μl), and cooled to 0°C. An aqueous solution of sodium bicarbonate (0.69 mg, 8.2 mmol in 20 μl of water) was then added to the reaction mixture. The reaction proceeded at 0°C for 1 hour and at room temperature for 20 minutes. The reaction mixture was poured into a mixture of methylene chloride and saturated ammonium chloride aqueous solution (5ml/5ml). The organic layer was separated, dried over aodium sulfate and then evaporated to dryness. The crude product was recrystalized from dichloromethane/hexane to yield the titled substance as a light-colored solid.
M.P. (Electrothermal IA-9100): Decomposed at 195°C.
1H NMR (250 MHz, acetone-d6), 6: 1.35 (d,3H,J=7.5Hz,6'-CH3), 1.76 (dd,1H,J=5.8Hz,14.2Hz,2'- HCHa), 2.16 (dt,1H,J =4.2Hz,14.2Hz,2'-HCHe). 2.75 (dd,1H,J=12.1Hz,20.2Hz,4-HCHa), 3.12 (dd,1H,J= 4.0Hz, 20.2Hz,4-HCHe), 3.72 (bs,1H,4'-CH), 4.28 (m,1H,3'-CH), 4.58 (qua,1H, J=7.5Hz,5'-CH), 5.18 (dd,1H,J =4.0Hz,12.1Hz,3-CH), 5.48 (bd,1H, J=2.9Hz,1'-CH), 6.10 (s,1H,1- CH), 7.16 (s,1H,thia2ole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.17 (d,1H,overlapped,3'- NHCOCF3), 11.07 (s,1H,thiazole-NHAc).
IR (Nicolet 205 FT, film on NaCl plate): 3746-3048 (peaked at 3388.3, br,str), 2923.2, 1712.9 (str), 1664.9 (str), 1591.9, 1550.1, 1535.5 (str), 1289.3 (str), 1243.4 (m), 1145.4 (w), 1124.5, 1080.7, 1001.5, 971.57 (str), 936.11, 709.75 (w). EXAMPLE 10
Example 10
Figure imgf000052_0001
Step 1: Methacrolein-N,N-dimethylhydrazone
Under N2, at room temperature, was mixed 3g (50mM) of dimethylhydrazine in sodium phosphate solution 7.1g (50mM) in 50 ml H2O and 3.5g (50mM) methacrolein. The mixture was vigorously stirred for 10 minutes at 60°C and then 30 minutes at room temperature. The solution was extracted with Et2O (3x40 ml), dried over MgSO4, and evaporated. The residue was flash chromatograpbed using CH2CI2 as eluent; 5.1g of colorless oil was isolated.
1H NMR (250 MHz, CDCl3)δ: 2.13 (s,3H,CH3), 3.04 (s,6H,N(CH3)2), 5.23 (broad s,1H,C=CH2), 5.32 (broad s,1H,C=CH2), 7.25 (s,1H,C=CH).
Step 2: (1'S,1S,3R) and (1'S,1R3S) methyl (1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-c] pyran-3-yl ketone Under N2 at room temperature, to 235 mg (0.394 mM) of quinone firom step 1 (example 5) dissolved in 20 ml of dry THF , was added 1.1 eq. (47 mg, 0.399 mol) of hydraztme firom step 1 (example 10), and
1.1 eq of p-toluene sulfonic acid (0.4 mM, 76 mg). After stirring 1 day at room temperature, the mixture was poured into 20 ml of H2O, and extracted with EtOAc (3x15 ml). After drying and evaporation, the residue was flash chromatographed [EtOAc 1: toluene 3] to give 95.1 mg of titled compound (40% yield).
1H NMR (250 MHz, CDCl3)δ: 1.22 (d,3H,5'-CH3), 1.75 (dd,1H,2'-CH2), 2.18 (m, 1H,2'-CH2), 2.32 (s,3H,COCH3), 2.59 (s,3H,C7-CH3), 2.62 (overlapped m,1H,H-C4-H), 3.1-3.3 (m,1H,HC4H), 4.32 (m,1H,5'-CH), 4.53 (m,1H,CHCOCH3), 5.4 (m,1H,3'-CH); 5.5 (m,1H,4'-CH), 5.7 (m,1H, 1'-CH),
6.2 (s,1H,C1-H); 6.4 (m, broad, 1H,NH), 8.2 (overlapped m, 1H.C6-H-arom), 8.2-8.4 (m,4H,p- nitobenzoyl), 8.2 (m,1H,C8-H arom).
Step 3: (1'S,1S,3R) and (1'S,1R,3S) methyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-lyxohexopyra nose)-5,10-dioxo-3,4,5,10-tetrahydro-7methyl-O-azanaphtho [2,3- c] pyran-3-yl ketone
To 80 mg (0.121 mM) of azaquinone from step 2 (example 10), dissolved in 13 ml MeOH and 3.2 ml H2O, was added 10.4 mg (0.121 mM) of NaHCO3. After stirring for 2 hours, the reaction was over, and 15 ml of H2O was added. The mixture was extracted with 3x15 ml EtOAc. After drying and evaporation, the residue was purified by preparative TLC and yielded 30.4 mg of pure titled compounds (50% yield).
1H NMR (250 MHz, CDCl3)δ: 1.24 (d,3H,J=6.5Hz,CH3), 1.76 (dd,1H,2'-CH2), 2.16 (m,1H,2'- CH2), 2.30 (s,3H,COCH3), 2.58 (s,3H,C7-CH3), 4.3 (m,1H;5'-CH), 4.52 (m,1H,CH-COCH3), 5.3 (dd,1H,3'-CH), 5.5 (dd,1H, 4'-CH), 5.6 (m,1H, 1'-CH), 6.1 (s,1H,C1-H), 6.4 (m, broad, 1H,NH), 8.2 (m,1H,C6-H arom), 8.9 (m,1H, C8-H arom).
EXAMPLE 11 Example 11 Preparation of naphto[2,3-C] pyran glycosides of 2-deoxyfucose.
Figure imgf000054_0001
Step 1: Di-p-nitrobenzoyl-L-fucal
To a stirred solution of diacetyl-L-fucal (114 mg, 0.53 mmol) in methanol (2.5 ml) was added a solution of sodium methoxide in methanol (25μl, 4.37 M, 0.1 mmol) after 45 minutes, methanol was evaporated under vacuum. The crude product was dissolved in CH2CI2 (2.5 ml) and pyridine (1.5 ml) and at 0°C, p-nitrobenzoyl chloride (2.1 mmol, 390 mg) was added. After a few minutes at 0°C, the reaction mixture was poured in CH2CI2 (20 ml) and washed with water, NaHCO3 10%, and then brine. The titled product was purified by flash chromatography (hexanes/acyl acetate (AcOet 5:1)) (MP: 130-132°C) (210mg, 90%).
1H NMR (250 MHz, CD2Cl2)δ: 1.40 (d,3H,-CH3), 4.40 (q,1H,H-5), 4.85 (m,1H,H-2), 5.65 (m,1H,H-4), 5.90 (m,1H,H-3), 6.6 (m,1H,H-1). Step 2:
(1'S,1S,3R) and l'S,1R,3S)-methyl-1-(2',6'-dideoxy-3\4'-di-O-p-nitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
To a mixture of methyl (1-hydroxy-5,8-dioxo-5,8-dihydroisochromaa-3-yl) ketone (698 mg, 3.1 mmol), l,5-anhydro-3,4-di-O-para-nitrobenzoyl-2,6-dideoxy-L-lyxohex-1-enitol (1.58g, 3.7 mmol), and molecular sieves 4 °A (3.8g) in CH2Cl2 (150 ml), at -60°C, was added triethylamine (0.24 ml, 1.7 mmol), and trimethylsilyl trifluoromethanesulfonate (0.64 ml, 3.3 mmol), subsequently. After stirring for 40 minutes, the reaction was quenched by adding aqueous NaHCO3 (50 ml) at -60°C and gradually warmed up to room temperature. Insolubles were filtered off and the filtrate was extracted into CH2CI2. The organic phase was washed with aqueous HCl (0.1N), 100ml, water and brine, dried over MgSO4 and the solvent evaporated to give 2.36 g of crude isochromandione glycoside. This was used without any further purification. To a solution of the quinone (mixture of diastereomers: 0.16g, 0.25 mmol) in 2.5 ml of dry toluene, undo' argon at room temperature, was added 1 -acetoxybutadiene (0.15 ml, 5 eq) and the reaction mixture was stirred for 18 hours. Silica gel (1.0 g) was then added and air was bubbled through the suspension. After 15 minutes, the mixture was chromatographed (silica gel, 3:1 hexanes/ethyl acetate) to give 0.13 g (74%) of compound 178-24-01 (1:1 mixture of diastereomers) as a yellow solid:mp. 129-132. 1H NHMR (CDCl3)δ: 8.34-7.73 (m,12H), 6.23+6.06 (2s,1H), 5.82+5.72 (2d,1H,J=2.8), 5.62-5.52 (m,2H), 4.88+4.43 (2q,1H,J=6.5), 4.62+4.58 (2dd,1H,J=4.1,11.5), 3.10+3.02 (2dd,1H,J=4.1,6.1), 2.62-2.10 (m,3H), 2.35+2.33 (2s,3H), 1.42+1.28 (2d,3H,J =6.5).
EXAMPLE 12
Figure imgf000056_0001
BCH-1607
Step 1: 2,5-Dimethoxy-6-(2-hydroxybutyl)-benzaldehydedioxane acetal
To a cooled (-15°C) solution of 2,5-dimethoxybenzaldehydedioxane acetal (13.2 g; 44.6 mmol) in 300 ml of anhydrous diethylether was added dropwise, under argon, n-Butyllithium (32.2 ml of a 2.5M solution in hexanes,80.3 mmol). The mixture was warmed to -7°C and was stirred at this temperature for 5 hours. The resulting mixture was cooled to -78ºC, treated with boron trifluoride etherate (21.8 ml; 177 mmol), and 1,2 epoxybutane (10.2 ml; 119 mmol). After stirring at -78°C for 60 minutes the reaction mixture was quendied with a saturated solution of bicaibonate and then extracted with ether. The organic layers were combined, washed witii water, and brine, and were dried over MgSO4. Removal of the solvent gave a crude oil which was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford 2.39 g of pure starting material (18%) and 5.21 g (52% based on S.M. recovered) of 2,5 dimethoxy-6-(2 hydroxybutyl) benzaldehydedioxane acetal as an oil.
1H NMR (250 MHz, CDCl3)δ: 0.95 (t,J=7.3 Hz,3H,-CH2CH3), 1.35 (1H, dm,J=13.6Hz,-CH2- CHHeq-CH2), 1.55 (2H,m,-CH2-CH3), 2.18 (1H,m,-CH2-CHHax-CH2.) 2.98 (1H,dd,J=2.7 and 13.7 Hz,=C-CH2-CH-O-). 3.36 (1H,dd, J=10.3 and 13.6 Hz=C-CH2-CH-O) 3.65 (3H,s,-OCH3), 3.66 (3H,s,-OCH3), 3.60 - 4.10 (4H,m,-CHHeq-O-,-CH-OH), 4.16 (2H,m,-CHHqx-O-), 6.16 (1H, s,-O-CH- O-), 6.61 (1H,d,J=9.0 Hz,Ar-H), 6.70 (1H,d,J=9.0 Hz,Ar-H).
Step 2: 5,8-Dimethoxy-3-ethyl-1-hydroxy-isochrom an
To a stirred solution of 2,5 dimethoxy-6-(2-hydroxybutyl) benzaldehydedioxane acetal (5.2 g; 17.6 mmol) in 700 ml of THF at room temperature was added dropwise 25 ml of a 1N solution of HC1. The resulting mixture was stirred for an hour at room temperature and then quenched with a saturated solution of sodium bicarbonate. It was then diluted with 1000 ml of dichloromethane and the aqueous layer, after separation, was extracted twice with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. Evaporation of the solvent gave pure 5,8-dimethoxy-3-ethyl-1-hydroxy- isochroman (4.1 g; 98%) which could be recrystalized in dichloromethane/hexane to give white crystals (M.P.: 108.9-110.1ºC).
1H NMR (250 MHz, C6D6)δ: 1.02 (3H,t,J=7.4 Hz,CH2-CH3), 1.60 (1H,m,
-CHH-CH3), 1.76 (1H,m,-CHH-CH3), 2.48 (1H,dd,J=11.6 and 17.3 Hz, Ar-CH-Ha x-), 2.88 (1H,dd,J=3.3 and 17.3 Hz, Ar-CH-Heq), 2.98 (1H,d,J=3.9 Hz,-OH), 3.34 and 3.38 (6H,2S,-O-CH3), 4.28 (1H,m,-CH-CH2-CH3), 6.40 (2H,m,ArH and -O-CH-O-), 6.46 (1H,d,J=8.8 Hz,ArH).
Step 3: 3-Ethyl-1-hydroxy-isochroman-5,8-dione.
To a stirred solution of 5,8-dimethoxy-3-ethyl-1-hydroxy-isochroman (760 mg; 3.19 mmol) in 160 ml of acetonitrile at 0°C was added dropwise a solution of eerie ammonium nitrate (CAN) (5.25 g; 9.57 mmol) and sodium bicaibonate (1.45 g; 17.2 mmol) in 40 ml of water. The resulting mixture was stirred for an hour at 0°C and was quenched by adding a saturated bicarbonate solution. The aqueous layer was extracted 3 times with dichloromethane and the combined organic layer was washed with water, brine, and dried ova- MgSO4. Evaporation of solvent gave a crude quinone which was suitably pure to undergo further reactions (600 mg; 90 %).
1H NMR (CDCl3)δ: 1.02 (3H,U=7.4 Hz,-CH2-CH3), 1-70 (2H,m,-CH2-CH3), 2.15 (1H,ddd,J= 1.1,12.4 and 19.5 Hz,Az-CH-Hax-), 2.60 (1H,ddJ=3.2 and 19.5 Hz.Ar-CH-Heq-), 3.20 (1H,br 8,-OH), 4.08 (1H,m,-CH-CH2-CH3), 5.91 (1H,s,-O-CH-O-), 6.76 (2H, 2 parts of an AB system, Ar-H). Step 4: (1'S, 1S, 3S) and (1'S, 1R, 3R)-5,10-dioxo-3-ethyI-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy- L-lyxobexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran
To a cooled solution (-60°C) of 3-ethyl-1-hydroxy-isochroman-5,8-dione (150 mg;.72 mmol) in dichloromethane (40 ml) were added sequentially molecular sieves (4A, 864 mg), 3,4-di-O-acetyl-L-fucal (246 mg; 1.15 mmol), triethylamine (56 μl) and trimethylsilyl trifluoromethanesulfonate (138 μl; .72 mmol). The resulting mixture was stirred at -60°C for 3 hours and was quenched with an aqueous saturated bicaibonate solution. Extraction with dichloromethane was followed by washing of the combined organic layers with 1N HCl, brine, and then drying over MgSO4. Following evaporation, 407 mg of the resulting crude thick oil was dissolved in 20 ml of toluene. To this solution was added 1- acetoxy-1,3-butadiene (521 mg; 4.82 mmol) and the resulting mixture was stirred at room temperature for 18 hours. Solvent was then partially evaporated to about 4 ml volume and the residue was applied to a column of silica gel (eluent, toluene, ethyl acetate 90:10) affording 2 fractions. The first one (48 mg, 14% overall) contained a 2:1 mixture favoring the (1'S, 1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L-lyoxobexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran over its (1'S, 1R, 3R) isomer and a second fraction (157 mg; 46% overall) consisting in a 1.5:1 mixture of the same major diastereomer that was about 80% pure from 1H NMR analysis.
1H NMR (1'S,1S,3S isomer, CD2Cl2)δ: 1 00 (3H,t,J=7.3Hz,-CH2-CH3), 1.23 (3H,d,J=6.4Hz,6'- CH3), 1.55-2.20 (4H,m,-CH2-CH3 and H-2'), 1.89 and 2.12 (6H,2s,O=C-CH3), 2.27 (1H,dd,J=11.3 and 19.3Hz,Hax-4), 2.74 (1H,dd,J=3.3 and 19.5Hz,Heq-4), 3.95 (1H,m,H-3), 4.58 (1H, q,J= 6.5 Hz,H-5'), 5.10 (2H,m,H-3'and H-4'), 5.46 (1H,dJ=3.5Hz,H-1'), 5.95 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H).
1H NMR (1'S,1R,3R isomer, CD2Cl2)δ: 1.01 (3H,t,J=7.3Hz,-CH2-CH3), 1.11 (3H,d,J=6.5Hz,6'- CH3), 1.55-2.35 (5H,m,-CH2-CH3,H-2' and Hax-4), 1.89 and 2.12 (6H,2s,O=C-CH3), 2.74 (1H,dd,J=3.3 and 19.5Hz, Heq-4), 4.00 (1H,m,H-3), 4.22 (1H,q,J=6.5Hz,H-5')f 5.10 (2H,m,H-3' and H-4'), 5.54 (1H,d,J =3.0Hz,H-1'), 5.79 (1H,s,H-1), 7.75 and 8.05 (4H,2m,Ar-H). The (1'S,1S,3S) diastereoisomer was obtained pure by recrystalization.
EXAMPLE 13
Example 13 Preparation of naphto[2,3-C] thiopyran aglycones.
Figure imgf000059_0001
Step 1: 3-Aceto-5,8-dimethoxythioisochroman 1-Thiobenzoate-propan-2-one (10.083g,51.97mmole) was dissolved in MeOH (100ml), cooled to 0°C, followed by the slow addition of NaOMe (4.37M,14.3ml,62.36mmol). The resulting mixture was stirred at 0°C for 3/4 hr. It was then cooled to -78 °C followed by the slow addition of 2,3-dibromomethyl-1,4- dimethoxybenzene (6.74g,20.79 mmol) in CH2CI2: MeOH (60:20ml). The resulting mixture was slowly warmed to R.T. and stirred for 2 1/2 hrs. NH4CI (saturated solution) was added and it was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed to give the titled compound (2.08g,8.25mmol) in 41 % yield.
1H NMR (250MHz, CD3COCD3)δ: 2.31 (s,3H,CH3),2.83(dd,1H,J=1.06, 8.55 Hz, HCHaCH-S), 2.99 (dd,1H,J=2.44,6.17Hz, HCHeCH-S), 3.44 (m,1H, CH-S), 3.78 (2s,6H,OCH3), 3.85 (2H,CH2-S), 6.78 (dd,2H, J=8.95, 12.58Hz, ArH). IR (cm-1): 2900: CH, 1707: C=O.
Step 2: Trans-3-aceto-1,5,8-trimethoxythioisochroman
and cis-3-aceto-1,5,8-trim eth oxythioisochrom an
The thioisochroman from step 1 (Example 13) (100.0mg,0.40 mmmol) was dissolved in CH2CI2 (12ml) and MeOH (4ml) followed by the addition of DDQ (109.0mg,0.48mmol,1.2eq [I]) at R.T. The resulting mixture was stirred at room temperature overnight. H2O was added and it was extracted with CH2CI2. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed using toluene: ethylacetate (95:5) to give the trans titled compound (65.0mg,0.23mmol) in 58% yield (MP: 84°C).
1H NMR (250MHz,CDCl3)δ: 2.34 (s,3H,CH3CO), 2.91 (dd,1H, J=11.73,17.78Hz,HCHaCHC-S), 3.27 (dd,1H,J=4.10,17.77Hz,HCHeCHC-S), 3.54 (s,3H,OCH3), 3.78 (s,3H,OCH3), 3.82 (s,3H,OCH3), 4.16 (dd,1H, 4.13,11.79Hz,CH-S), 5.69 (s,1H,O-CH-S), 6.75 (dd,2H,J=8.96, 14.36 Hz,ArH). IR (cm-1): 2925: CH, 1705.7: C=O. Cis-3-aceto-1,5,8-trimethoxydιioisochroman (32.4mg,0.11mmol) was obtained in 30% yield (MP: 129 °C).
1H NMR (250MHz,CDCl3)δ: 2.34 (s,3H,CH3), 3.25 (d,2H,J=6.58Hz, HaCHeCHC-S), 3.46 (s,3H,OCH3), 3.59 (dd,1H,J=6.75,13.55Hz,CH-S), 3.79 (2s,6H,OCH3), 5.73 (s,1H.O-CH-S), 6.76 (dd,2H,J=9.50,21.30Hz, ArH).
Step 3: Trans-3-aceto-1-methoxy-5,8-dioxoisothiochroman
The thioisochroman derivative from step 2 (example 13) (178.2 mg, 0.63 mmole) was dissolved in acetonitrile (10 ml) and H2O (10 ml), followed by the addition of NaHCO3 (100.8 mg, 1.22 mmole). The mixture was cooled to 0°C, followed by the slow addition of CAN (1.04g, 1.89 mmole). After 20 minutes of stirring, H2O was added and the mixture was extracted with CH2CI2. The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated in vacuum. The crude obtained was found to be pure titled compound by 1NMR and was used in the following step (>95% yield). 1H NMR (250 MHz, CDCl3)δ: 1.73 (s,3H,COCH3), 2.62 (dd.1H, J=11.32, 19.81Hz,HCHaCH-S), 2.87 (dd,1H,J=4.28, 20.20Hz,HCHeCH-S), 3.21 (s, 3H,OCH3), 3.61 (dd,1H,J=4.31, 11.42Hz,CHS); 5.97 (m,2H,HC=CH). Step 4: Trans-3-aceto-1-methoxy-l,2,3,4-tetrahydro-(2-sulfur)anthracene-5,10-dione and ds-3- aceto-1-methoxy-1,2,3,4-tetrahydro-(2-sulfur)anthracen e-5,10-dione
Trans-3-aceto-1-methoxy-5,8-dioxoisothiochroman (0.66 mmole) was dissolved in dry toluene (14ml), followed by the addition of the diene (120.0 mg, 1.07 mmole). The resulting mixture was stirred at room temperature overnight. Solvent was removed and the crude obtained was flash chromatographed using pure toluene to give the titled compounds in a ratio of about 1:1, in 48% yield.
1H NMR (250MHz, CDCl3)δ: 2.37, 2.39 (2s,6H,CH3, cis and/or trans), 2.75 (dd,1H,J=6.42,19.81Hz,HCHaCH-S, cis or trans), 2.90 (dd,1H, J=11.79, 20.08 Hz,HCHa-CH-S, cis or trans), 3.27 (dd,1H,J=3.98, 20.0Hz,HCHeCH-S, cis or trans), 3.58 (s,3H,OCH3, cis or trans), 3.60 (s,3H,OCH3, cis or trans), 3.64 (m,2H,CH-S, cis or trans), 4.11 (dd,1H,J=3.92,11.80Hz,CH-S, cis or trans), 5.30 (s,1H,OCH-S, cis or trans), 5.49 (s,1H,OCH-S, cis or trans), 7.74 (m, 4H,ArH, cis and trans), 8.10 (m,4H,ArH, cis and trans). IR (cm-1): 2900.CH; 1709.4:C=O; 1668.1, 1631.9:C=O quinone. Step 5: cis-3-aceto-1-methoxy-5,8-dioxoisothiochroman
Oxidative demethylation, by using the procedure from step 3 (example 13), of cis-3-aceto-1,5,8- trimethoxythioisochroman gave the titled compound in 98% yield.
H1 NMR (250 MHz, CDCl3)δ: 2.04 (s,3H,CH3), 2.23 (dd,1H,J=4.88, 19.49Hz, HCHaCH-S), 2.54 (d,1H,J=5.68Hz,HCHeCH-S), 3.56 (dd, 1H, J=2.10, 19.23Hz,HCHa,e-S), 5.09 (s,1H,CH-S), 5.96 (dd,2H,J= 10.30, 12.20Hz,ArH).
Step 6: cis-3-aceto-1-methoxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione and trans-3- aceto-1-metboxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-S,10-dione
Application of the procedure described for step 4 (example 13) to trans-3-aceto-1-methoxy-5,8- dioxoisothiochroman gave pure titled compounds.
1H NMR (250 MHz, CDCl3)δ: 2.37 (s,3H,CH3), 2.75 (dd,1H,J=6.42, 19.81Hz,HCHaCH-S), 3.58
(s,3H,OCH3), 3.64 (m,2H,CH-S,HCHeCH-S), 5.49 (s,1H,O-CH-S), 7.74 (m,2H,ArH), 8.10 (m,2H,ArH). IR (cm-1): 2900:CH; 1707.8:C=O; 1660.0, 1630.2, 1594.4:C=O quinone.
Step 7: trans-3-aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione and cis-3- aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-sulfur) anthracene-5,10-dione The mixture of compounds obtained from step 6 (example 13) (30.8 mg, 0.102 mmole) was dissolved in CH3COOH:H2O (2:0,4 ml) at 0°C. The resulting mixture was stirred at 0°C for about 2 hours. NaHCO3 (5 %) was added and it was extracted with CH2CI2. The combined organic phases were washed with H2O, dried over MgSO3, filtered and concentrated in vacuum. The crude product obtained was flash chromatographed using hexanes:ethyl acetate (7:3) to give the titled compounds in 7% yield. According to NMR one isomer is major:
1H NMR (250 MHz, CDCl3)δ: 2.74 (s,3H,CH3), 3.00 (dd,1H, J= 11.99, 20.74Hz,HCHaCH-S), 3.26 (dd,1H,J=3.96, 20.61Hz,HCHeCH-S), 4.37 (dd, 1H,J=3.99,12.0Hz,CH-S), 6.67 (s,1H.O-CH-S), 7.73 (m,2H,ArH), 8.08 (m,2H,ArH).
EXAMPLE 14 - Thiopyranylnaphthoquinone
glycosides
Example 14 Preparation of naphto[2,3-C] thiopyran glycosides.
Figure imgf000063_0001
Step l:
(1'S,1R,3S) and (1'S,1S,3R) methyl (5,8-dimethoxy-1-(2,3,,4,,6,-tetradeoxy-3,,4'- diacetoxy-L-lyxohexo-pyranose)-3,4,-dihydrobenzo [2,3-c] thiopyran-3-yl) ketone
A mixture of thioisochroman firom step 1 (example 13) (96.0 mg, 0.38 mmol), dicyano dichloro benzoquinone (DDQ) (104.0 mg, 0.46 mmol) and 3,4-di-O-acetyl-2,6-dideoxy-L-lyxohexopyranose (_- anomer/β-anomer= 1:3; 106.4 mg, 0.46 mmol) in 5 ml of CH2CI2 was stirred at room temperature under argon for 2.5 hours. After additions of 5 ml of NaHCO3 solution (5%) and 10 ml of H2O, the products were extracted with CH2CI2 (25 ml x 4). The combined organic phase was washed with H2O (15 ml), dried over MgSO4, filtered and tiien concentrated. The residue was purified by flash chromatography (hexanes/CH2Cl2/ethyl acetate, 2=1 = 1) to provide a mixture of titled compounds (2=1, 116.9 mg, 0.24 mmol) in 64% yield along with recovered sugar (48 mg, 0.21 mmol).
1H NMR (CDCl3), the major isomersδ: 1.20 (d,3H,J=6.2Hz), 1.70-2.30 (m,2H), 1.94 (s,3H), 2.20 (s,3H), 2.29 (s,3H), 2.98 (dd,1H, J=16.5Hz,10.5Hz), 3.28 (dd,1H,J=16.5Hz,5.1Hz), 3.80 (s,6H), 4.14 (dd,1H,J=10.5Hz,5.1Hz), 4.42 (q,1H,J=6.3Hz), J6.3Hz), 5.10-5.25 (m, 2H), 5.65 (d,1H,J=3.2Hz), 6.27 (s,1H), 6.72 (d,1H,J=9.8Hz), 6.81 (d,1H,J=9.5Hz); the minor isomer: 1.19 (s,3H), 1.70-2.30 (m,2H), 1.95 (s,3H), 2.19 (s,3H), 2.34 (s,3H), 2.96 (dd,1H,J=16.5Hz, 10.5Hz), 3.30 (dd,1H,J= 16.5Hz,5.1Hz), 3.81 (s,6H), 4.22 (dd,1H, J=10.5Hz,5.1Hz), 4.42 (q,1H,J=6.3Hz), 5.10-5.25 (m,2H), 5.50 (d,1H, J=3.2Hz), 6.03 (s.1H), 6.70 (d,1H,J=9.8Hz, 6.79 (d,1H,J=9.8Hz). Step 2:
(1'S,1R,3S) and (1'S,1S,3R) methyl (5,8-dioxo-1-(2',3', 4',6'-tetradeoxy-3',4'- diacetoxy-L-Iyxohexo-pyranose)-3,4,5,8-tetrahydrobenzo [2,3-c] thiopyran-3-yI) ketone To a stirred solution of the thioisochroman glycosides from step 1 (example 14) (106.0 mg, 0.22 mmol) in 5 ml of CH3CN was added a solution of NaHCO3 (35.0 mg, 0.42 mmol) in 2 ml of water. After cooling to 0°C, a soluticm of CAN (362.0 mg, 0.66 mmol) in 2 ml of water was added dropwise. After being stirred at 0°C for 20 minutes, the mixture was extracted with CH2CI2 (25 ml x 2). The organic layer was washed with H2O, dried over MgSO4, filtered and then concentrated. The residue (94.3 mg, 0.21 mmol) was found to be the tide compounds (2: 1) by 1H NMR. The yield was 95 % .
1H NMR (CDCl3), the major isomer. δ: 1.28 (d,3H,J=7.6Hz), 1.53-2.40 (m.2H), 1.99 (s,3H), 2.17 (s,3H), 2.33 (s,3H), 2.74 (dd,1H,J=18.8Hz,11.0Hz), 3.14 (dd,1H,J=18.8Hz,4.8Hz), 4.00 (dd,1H,J=11.0Hz,4.8Hz), 4.24 (q,1H,J=7.6Hz), 4.95-5.20 (m,2H), 5.56Hz (d,1H,J=3.2Hz), 6.00 (s,1H), 6.19 (d,1H,J= 11.0Hz), 6.85 (d,1H,J=11.0Hz); the minor isomer: 1.18 (d,3H,J=7.5Hz), 1.53- 2.40 (m,2H), 1.99 (s,3H), 2.17 (s,3H), 2.37 (s,3H), 2.70 (dd,1H,J=19.0Hz,10.5Hz) 3.15 (dd,1H,J=19.0Hz,4.8Hz), 4.07 (dd,1H,J=10.5Hz,4.8Hz), 4.33 (q,1H,J=7.5Hz), 4.95-5.20 (m,2H), 5.52 (d,1H,J=3.2Hz), 5.77 (s,1H), 6.70 (d,1H,J=11.0Hz), 6.78 (d,1H,J=11.0Hz).
Step 3:
(1'S,1R,3S) and (1'S,1S,3R) methyl (5,8-dioxo-1-(2',3', 4',6'-tetradeoxy-3',4'- diacetoxy-L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-c] thiopyran-3-yl) ketone
The procedure for the preparation of the titled compound is as described previously in step 1 (example 1). Thus, the reaction of the isochromandiones (94.3 mg, 0.21 mmol), obtained from the previous step with 1-acetoxy butadiene (0.10 ml, 94.5 mg, 0.84 mmol) gave the titled compounds 2:1 (74.2 mg, 0.15 mmol) in 70% yield after flash chromatography.
1H NMR (CDCl3), the major isomer had δ: 1.32 (d,3H,J=6.5Hz), 1.70-2.40 (m,2H), 1.94 (s,3H), 2.17 (s,3H), 2.36 (s,3H), 2.91 (dd,1H, J=20.0Hz,11.9Hz), 3.30 (dd,1H,J=19.9Hz,4.2Hz), 4.06 (dd,1H, J=12.0Hz,4.1Hz), 4.38 (m,1H), 5.05-5.22 (m,2H), 5.61 (d,1H, J=3.8Hz), 6.23 (s,1H), 7.70-7.80 (m,2H), 8.05-8.15 (m,2H); the minor isomer had δ: 1.19 (d,3H,J=6.5Hz), 1.70-2.40 (m,2H), 1.95 (s,3H), 2.17 (s,3H), 2.39 (s,3H), 2.87 (dd,1H,J= 20.0Hz, 12.0Hz), 3.32 (dd,1H,J=20.0Hz,4.1Hz), 4.15 (dd,1H,J=12.0Hz,4.1Hz), 4.38 (m, 1H), 5.05-5.22 (m,2H), 5.63 (d,1H,J=3.8Hz), 6.00 (s,1H), 7.70-7.80 (m,2H), 8.05-8.15 (m,2H), IR (neat): 3866, 2987-2939, 1745(s), 1715, 1667, 1645, 1597, 1368, 1285, 1252, 1229, 1021, 988, 737 cm-1.
EXAMPLE 15 - In Vitro Cytotoxidty - Microculture Tetrazolium Assay The microculture tetrazolium assay was used to test in vitro cytotoxicity. This assay is described in Plumb, J.A. et al., 1989 Cancer Research 49, 4435-4440, which is herein incorporated by reference. The cytotoxicity of compounds towards tumor cells is measured in vitro using the assay. This assay method is based upon the ability of live, but not dead cells to reduce the yellow water soluble dye 3-{4,5- dimethylthiazol-2-yl)-2,5-diphenyltetnzolium bromide (MTT) to its water insoluble purple formazan product.
The following reagents were used for :
tissue Culture, (Irvine Scientific Catalog)
-MEM containing nucleosides (Catalog # 9144)
Fetal Bovine Serum (Catalog # 3000)
Non-essential amino acids (Catalog # 9304)
Dulbecco's phosphate buffered saline (Catalog # 9240)
Sodium pyruvate (Catalog # 9334).
All other tissue culture and general reagents were from Sigma Chemical Company. Human Tumor Cell lines, used were:
SKOV3 (Ovarian adenocarcinoma) - provided by Dr. V. Ling, Ontario Cancer Institute.
SKVLB (Ovarian; multidrug resistant) - Dr. V. Ling, Ontario Cancer Institute.
T47D (Ductal carcinoma of breast) - ATCC catalog # HTB-133.
Lox (Melanoma) - Southern Research Institute.
HT 29 (Colon adenocarcinoma) ATCC catalog # HTB-38.
The cells were maintained in exponential growth in culture in minimal essential media (MEM) supplemented with non-essential amino acids, and containing 15% (v/v) fetal bovine serum, 5mM L- glutamine, 1 mM sodium pyruvate, and 0.1 U/ml insulin. All cell lines were grown at 37 °C in an atmosphere of 5% CO2 in air.
Stock solutions, used were the following; MTT: 2 mg/ml in phosphate buffered saline (stable at 4°C in dark for 1 week).
Sorensen's buffer: 0.1M glycine/NaOH, pH 10.5, containing 0.1M NaCl.
Test compounds: 20 mM in DMSO and diluted to a final concentration of 200 μM in culture medium before use.
The following is the generic description of the assay metiiod. - It should be noted that although the conditions described work well with the cells listed above, the initial plating density and the MTT concentration used should be verified for each new cell line used to test compounds.
For each assay, doxombicin is included as an inter-assay standard. This allows us to monitor the behaviour of the assay in general, and in particular, to check that the SKVLB line has maintained its resistant phenotype. The plate layout is done in the following manner
The assays are carried out in 96-well (8 well x 12 well) microtiter plates. Serial dilutions of the compound are tested along the length of the plate. A 1:3 serial dilution of compound in culture medium covers a concentration range from 100 μM to 1.7nM. Each concentration of conφound is tested in quadruplet, allowing two compounds to be tested per plate. Wells containing no cells (blank) and cells with no test compound (control) are included on each plate.
Cells are plated out in 100 μl of culture medium in the microtiter plates at a density of around 1,500 - 4,000 cells per well. The plates are incubated overnight to allow the cells to become adherent after which the test compound is added (100 μl of appropriate dilution per well). The cells are incubated with test compound at 37°C for 48h after which the compound is replaced with fresh medium. After a further 48h incubation at 37°C, 50 μl of MTT solution (2mg/ml) is added to each well. The plates are incubated in the dark for 4h at 37°C after which the medium is removed. The MTT formazan product is extracted firom the cells by the addition of 200 μl DMSO followed by 50 μl of Sorensen's buffer. The plates are shaken briefly and the absorbance at 570 nm is read using a Molecular Devices UV max plate reader. Curves are fit to the MTT assay data using a four parameter logistic equation, and the data are normalized to fit a 0% to 100% survival scale.
RESULTS Tables 1 and 2 show the antitumor activity of some of synthetic tricyclic pyranylnaphthoquinones of this invention. A range of potency is observed. In this set of compounds. Several tricyclic naphthoquinones are intensely potent and are effective in the multidrug resistant cell line SKVLB. In breast cancer, MCF- 7, BCH-1146 is less potent than adriamycin but nearly as effective in the sensitive and adriamycin resistant cell line. These results suggest that tricyclic derivatives such as BCH-1184 and 1146 should be usefid in the treatment of certain resistant cancers. Most notably BCH-2051, a "sugarless" tricyclic naphthoquinone, possesses intense in vitro antitumor potency while significantly avoiding multidrug resistance as observed from the SKVLB cell line.
EXAMPLE 15
BIOLOGICAL RESULTS
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Example 16: Preparation of naphthopyran derivatives
Figure imgf000073_0001
Step 1: Methyl (1,5,8-trimethoxyisochrom an-3-yI) formate
Mediyl (5,8-dimethoxy-isochroman-3-yl) formate (15.00 g, 59.46 mmol) and DDQ (16.20 g, 71.35 mmol) were dissolved in dry dichloromethane (500 ml), and dry methanol (7.2 ml, 178.37 mmol) was added. The solution was stirred at ambient temperature overnight, then refluxed for 8 hours. Methanol (1.0 ml, 24.69 mmol) and DDQ (2.00 g, 8.81 mmol) was added and further refluxed for 8 hours. The reaction mixture was cooled down, filtered, and the filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml). The organic phase was separated, washed with saturated sodium bicarbonate solution (100 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title product (white crystals, 14.34 g, 85.1 %).
1H-NMR (250 MHz, Biucker, CDCl3), d: 2.70 (1H, dd, J= 11.8 and 17.1 Hz, 4-Hax), 3.08 (1H, dd, J=4.2 and 17.1 Hz, 4-Heq), 3.57 (3H, s, 1-MeO), 3.77 (3H, s, Ar-OMe), 3.80 (3H, s, Ar-OMe), 3.83 (3H, s, COOMe), 4.79 (1H, dd, J=4.2 and 11.8 Hz, 3-Hax), 5.70 (1H, s, 1-H), 6.68 (1H, d, J=8 Hz, Ar-H), 6.74 (2H, d, J=8 Hz, Ar-H). Step 2: Methyl (1-Methoxy-5,8-dioxo-5,8-dihydro-isochrom an-3-yl) formate
The solution of CAN (83.24 g, 151.84 mmol) and sodium bicarbonate (8.50 g, 101.22 mmol) in water (500 ml) was added to the solution of methyl (1,5,8-trimethoxy-isochroman-3-yl) formate (14.34 g, 50.61 mmol) in acetonitrile (700 ml) at 0 - 5 C° over 20 minutes. The reaction mixture was stirred at 0 C° for 20 minutes, then extracted with dichloromethane (4x200 ml). The combined organic phases were washed with brine (200 ml), dried (MgSO4) and evaporated under reduced pressure to give a light yellow solid (12.76 g, quantitative yield) which was used for the next step without further purification.
1H-NMR (250 MHz, Brucker, CDCl3), d: 2.52 (1H, dd, J=11.4 and 19.4 Hz, 4-Hax), 2.83 (1H, dd, J=4.2 and 19.4, 4-Heq), 3.56 (1H, s, 1-MeO), 3.82 (1H, s, COOMe), 4.66 (1H, dd, J=4.2 and 11.4 Hz, 3-Hax), 5.48 (1H, s, 1-H), 6.62 (1H, d, CHCO), 6.78 (1H, d, CHCO).
Step 3: Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1 H-naphtho[2,3-c]pyran-3-yl) formate
Methyl (1-medιoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1- acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in toluene (200 ml), silica gel (20 g) was added and stirred over 24 hours in an open flask at ambient temperature. The silica was filtered, the filtrate was concentrated to dryness. The residue was recrystallized in methanol. The mother liquor was concentrated to dryness and the silica gel treatment was repeated as above. After recrystallization the mother liquor was concentrated to dryness and the residue was purified by flash chromatography on silica. Eluent: toluene/ethyl acetate (4/1). All the crystals and the clean fraction from flash chromatography were combined to give 9.07 g, (59.6 %) tide product.
1H-NMR (250 MHz, Btucker, CDCl3), d: 2.68 (1H, dd, J= 11.1 and 19.9 Hz, 4-Hax), 3.07 (1H, dd, J=4.4 and 19.9 Hz, 4-Heq), 3.62 (1H, s, 1-MeO), 3.83 (1H, s, COOMe), 4.72 (1H, dd, J=4.4 and 11.1 Hz, 3-Hax), 5.70 (1H, s, 1-H), 7.75 (2H, m, Ar-H), 8.08 (2H, m Ar-H).
Step 4: Methyl (1-metlwxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2^-c]pvran-3-yl) formate Mediyl (1-methoxy-5, 10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-3-yl) formate (6.12 g, 20.25 mmol) was dissolved in dichloromethane (120 ml), triethylamine (5.64 ml, 40.49 mmol) was added and stirred at ambient temperature over 1 hour. The reaction mixture was poured onto water (100 ml) and ethyl acetate(400 ml), then neutralized with acetic acid. The oiganic layer was separated, the water layer was extracted with ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO4) and concentrated to dryness. To the residue dichlorometane (60 ml) and saturated sodium bicaibonate solution (20 ml) was added, then stirred for 5 minutes. After separation the oiganic layer was dried (MgSO4) and concentrated to 10 ml. This solution was filtered through a short silica gel column. Eluent:
dichloromethane and 5 % ethyl acetate in dichloro-methane. The clean fractions were combined and concentrated to dryness to give the tide product (5.49g, 90.3 %).
1H-NMR (250 MHz, Brucker, CDCl3), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, s, COOMe), 6.38 (1H, s, 1- H), 7.33 (1-H, s, 4-H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 5: Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl)formate. Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1- acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in dichloromethane (200 ml), triethylamine (10.2 ml, 73.11 mmol) was added and stirred at ambient temperature over 1 hour. The reaction mixture was poured onto water (200 ml) and ethyl acetate(800 ml), then neutralized with acetic acid. The oiganic layer was separated, the water layer was extracted with ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO4) and concentrated to dryness. To the residue dichlorometane(120 ml) and saturated sodium bicarbonate solution (40 ml) was added, stirred for 5 minutes. After separation the organic layer was dried (MgSO4) and concentrated to diyness to give the tide product (8.98 g, 59.4 %).
1H-NMR (250 MHz, Brucker, CDCl3), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, S, COOMe), 6.38 (1H, s, 1- H), 7.33 (1-H, s, 4-H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 6: 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid
Methyl (1-medιoxy-5,10-dioxo)-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl) formate (6.31 g, 21.01 mmol) was suspended in tetrahydrofuran (126 ml) and sodium hydroxide (0.92 g, 23.12 mmol) dissolved in water (63 ml) was added dropwise at 0 C° over 30 minutes. The reaction mixture was stirred at 0 C° over 1 hour, then it was acidified to pH = 3 with 5% hydrochloric acid. Sodium chloride (2 g) was added. The water layer was separated and extracted with ethyl acetate (3x40 ml). The water layer was acidified to pH = 2. The crystals formed were filtered and washed with water. The filtrate was extracted with ethyl acetate (4x40 ml). All the oiganic fractions - including the previous extractions as well - were combined, dried (MgSO4) and concentrated to dryness. The residue was combined with the crystals filtered out of the water phase before, and stirred with methanol (50 ml), for 15 minutes. The yellow crystals were filtered, washed with methanol to give the tide product (5.21 g, 86.6 %).
1H-NMR (250 MHz, Brucker, DMSO-d6), d: 3.50 (3H, s, 1-MeO), 6.37 (1H, s, 1-H), 7.02 (1H, s, 4- H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 7: 1-Methoxy-5,10-dioxo-5,1 0-dihydro-1H-naphtbo[2,3-c]pyran-3-[N-(3- dimethylamino-propyl)carboxamide] 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid (4.6 g, 16.13 mmol) was suspended in tetrahydrofuran (46 ml) and DMF (0.1 ml) was added. The suspension was cooled to 0 C° and oxalyl chloride (3.24 ml, 37.09 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0 C° over 30 minutes, then evaporated to diyness at reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml), cooled to 0 C° and N,N-dimethylaminopropylamine (2.23 ml, 17.74 mmol) was added dropwise over 10 minutes. The solution was stirred at 0 C° over 15 minutes, men it was poured onto a saturated solution of potassium carbonate (20 ml). The organic layer was separated, the water layer was extracted with dichloromethane (3x10 ml). The combined organic phases were dried (MgSO4) and concentrated to dryness. The residue was dissolved in methanol (50 ml) and stirred with charcoal at ambient temperature over 30 minutes. After filtration the filtrate was concentrated to diyness. The residue was dissolved in a minimal amount of methanol and ether (15 ml) was added. The crystals were filtered, washed with ether to give the title product (4.15 g, 69.6 %).
1H-NMR (250 MHz, Brucker, CDCl3), d: 1.74 (2H, quint., CH2), 2.29 (6H, s, NMe2), 2.47 (2H, m, CH2), 3.35 - 3.65 (2H, m, CH2), 3.63 (3H, s, 1-MeO), 6.37 (1H, s, 1-H), 7.33 (1H, s, 4-H), 7.75 (2H, m, Ar-H), 8.15 (2H, m, Ar-H), 8.70 (1H, broad, NH).
Step 8: 1-Methoxy-5,10-dioxo-5,10-dihydro-1 H-naphtho[2,3-c]pyran-3-{N-(3- dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051 1-Methoxy-5, 10-dioxo-5, 10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino- propyl)carboxamide] (4.15 g, 11.23 mmol) was dissolved in anhydrous dichloromethane (10 ml) and 1 M hydrochloric acid solution in ether (11.3 ml, 11.23 mmol) was added dropwise at 0 C°. At the end more ether (20 ml) was added and the suspension was stirred at 0 C° over 30 minutes. The crystals were filtered under argon atmosphere, washed with dry ether and hexane to give the tide product (4.32 g, 90.5
%).
1H-NMR (250 MHz, Brucker, DMSO-d6), d: 1.90 (2H, m, 2'-CH2), 2.72 (6H, s, NMe2), 3.00 (2H, m, 3'-CH2), 3.30 (2H, m, 1'-CH2), 3.60 (3H, s,MeO), 6.35 (1H, s, 1-H), 7.00 (1H, s, 4-H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.92 (1H, t, CONH), 10.53 (1H, broad, NH+).
13C-NMR (250 MHz, Brucker, DMSO-d6), d: 23.8, 36.1, 41.8, 54.0, 56.2, 94.9, 98.1, 124.5, 125.6,
126.1, 130.9, 131.5, 134.1, 134.5, 149.9, 159.6, 181.2, 181.4.
Example 17: Dipeptide substituted naphthoquinone derivative
3 d
Figure imgf000077_0001
Step 1: N-BOC-Serine-Leucine-OMe
To a solution of Leucine-Me ester.HCl (0.91 eq, 0.40 g) and triethylamine (1.2 eq, 0.3 ml) in dry chloroform (24 ml), under argon, at room temperature, was added N-Boc-Serine (0.50 g, 2.43 mmols) and then EEDQ (1.3 eq, 0.71 g). The solution was stirred for 18 hours after which the solvent was evaporated. The residue was taken up in EtOAc and washed with 5% HCl (2x), sat. aq. NaHCO3 and brine. The oiganic phase was dried over Na2SO4, the solids filtered and the solvant evaporated to give 0.71 g (87 %) of N-Boc-Ser-Leu-OMe as a clear oil that was used without further purification.
1H NMR (CDCl3): δ 7.30 (bs, 1H, NH), 5.72 (bs, 1H, NH), 4.51 (m, 1H), 4.19 (m, 1H), 3.90 (m, 1H), 3.68 (s, 3H), 3.62 (m, 2H), 1.55 (m, 3H), 1.34 (s, 9H), 0.79 (m, 6H). Step 2: (1S,2'S,3R,5'S) and (1R,2'S,3S,5'S)-1-[O-N-BOC-Serine-Leucine-Me ester]-3- aceto-5,8-dimethoxy-isochroman To a solution of 5,8-dimethoxy-3-aceto-isochroman (0.46g, 1.93 mmole), the peptide from step 1 (example 17) (0.71 g, 1.1 eq) and activated 4A molecular sieves (500 mg) in dry CH2CI2 (19 ml) was added DDQ (0.57 g, 1.3 eq). The solution was stirred for 18 hours after which it was filtered through celite. It was then poured in sat. aq. NaHCO3 and the phases were separated. The aqueous phase was extracted with CH2CI2 (2x) and the combined oiganic extracts were dried over MgSO4. The solids were filtered and the solvent was evaporated to give the tided mixture of diastereomers that were separated by chromatography (silica gel, 1:1 hexanes/EtOAc).
The first running fraction: 0.395 g (36%). 'H NMR (CDCl3): δ 7.00 (bs, 1H, NH), 6.74 (d, 1H, J = 9.0, ArH), 6.68 (d, 1H, J = 9.0, ArH), 5.81 (s, 1H, H-1), 5.64 (bs, 1H, NH), 4.52 (m, 2H), 4.29 (m, 1H), 4.05 (m, 1H), 3.88 (dd, 1H, J *= 7.4, 10.6), 3.81 (s, 3H, ArOMe), 3.73 (s, 3H, ArOMe), 3.57 (s, 3H, CO2Me), 3.00 (dd, 1H, J = 4.1, 17.6, H-4), 2.47 (dd, 1H, J = 12.3, 17.6, H-t), 2.29 (s, 3H, COMe), 1.57-1.46 (m, 3H, CH2-CH(Me)2), 1.41 (s, 9H, t-Bu), 0,84 (d, 3H, J = 3.3, isopropyl), 0.82 (d, 3H, J = 3.3, isopropyl).
The second running fraction: 0.420 g (38 %), 'H NMR (CDCl3): δ 6.79 (m, 3H, 2ArH +NH), 6.10 (bs, 1H, NH), 5.74 (s, 1H, H-1), (4.62-4.33 (m, 3H), 3.91 (m, 2H), 3.77 (s, 6H, 2 ArOMe), 3.68 (s, 3H, CO2Me), 3.01 (dd, 1H, J = 4.0, 17.6, H-4), 2.50 (dd, 1H, J = 12.3, 17.6, H-4), 2.33 (s, 3H, COMe), 1.50 (s, 9H, t-Bu), 1.48-1.25 (m, 3H, CH2-CH(Me)2), 0.70 (d, 3H, J = 5.7, isopropyl), 0.61 (d, 3H, J = 5.7, isopropyl).
Step 3: (1S,2'S,3S,5'S)-Methyl-(1-O-[N-BOC-Serine-Leucine-Me ester]-5,10-dioxo-
3,4,5,10-tetrahydro-1-H-naphtho [2,3-c] pyran-3-yl) ketone
To a solution of the peptido-isochroman from step 2 (example 17) (0.40 g, 0.68 mmols) in CH3CN (9.7 ml), at 0°C, was added slowly a aolution of CAN (1.5 g, 4 eq) and NaHCO3 (0.4 g, 7 eq) in water (7.8 ml). The solution was stirred at 0°C for 30 minutes after which it was poured in sat. aq. NaHCO3. The aqueous layer was then extracted with CH2CI2 (3x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the solvent evaporated. The crude quinone was then dissolved in dry toluene (7 ml) and acetoxybutadiene was added (0.4 ml, 5 eq). The solution was stirred for 18 hours. Silica gel was then added (1 g) and air was bubbled through the solution for 30 minutes. The silica gel was filtered through Celite and the solvent was evaporated. The brown oil obtained was purified by flash chromatography (silica gel, 1:1 hexanes/EtOAc) to give 115 mg (29%) of the tided tricyclic compound. 1H NMR (CDCl3): δ 8.12-8.02 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 4.91 (bs, 1H, NH), 5.92 (s, 1H, H-1), 5.52 (bs, 1H, NH), 4.62-4.47 (m, 3H, H-2' + H-5' + H-3), 4.17 (dd, 1H, J = 4.4, 10.9, H- 1'), 3.83 (dd, 1H, J = 8.6, 10.9, H-1'), 3.56 (s, 3H, CO2Me), 3.02 (dd, 1H, J = 4.0, 19.9, H-4), 2.51 (dd, 1H, J = 11.6, 19.9, H-4), 2.33 (s, 3H, COMe), 1.74-1.52 (m, 3H, CH2-CH(Me)2), 1.44 (s, 9H, t- Bu), 0.90 (d, 6H, J = 6.3, isopropyl). Step 4: (1S,2'S,3S,5'S)-Methyl-(1-O-[Serine-Leudne-Me ester]-5,10-dioxo -3,4,5,10- tetrahydτo-1-H-naphtho [2,3-c] pyran-3-yI) ketone hydrochloride BCH-2000
A solution of the Boc protected tricyclic from step 3 (example 17) (54 mg, 0.092 mmol) in 96 % formic acid (1 ml) was stirred at room temperature for 2 hours. The formic acid was evaporated and the residue dissolved in 0.1 M HCl. The aqueous phase was washed with CH2CI2 (2x) and the water was evaporated. The titled compound was obtained as a yellow oil was dried under high vacuum for 18 hours after which it had crystallized: 40 mg (83 %).
1H NMR (DMSO-d6): δ 8.98 (bs, 1H, NH amide), 8.42 (bs, 3H, NH3CI), 8.06-7.98 (m, 2H, ArH), 7.93-7.87 (m, 2H, ArH), 5.82 (s, 1H, H-1), 4.61 (dd, 1H, J = 3.9, 11.4), 4.34-4.23 (m, 2H), 4.13 (m, 1H), 4.02 (dd, 1H, J = 5.7, 9.8), 3.61 (s, 3H, CC^Me), 2.88 (dd, 1H, J = 3.9, 19.6, H-4), 2.47 (m, 1H, H-4 hidden under the DMSO peak), 2.30 (s, 3H, COMe), 1.62-1.49 (m, 3H, CH2-CH(Me)2). 0.88- 0.82 (m, 6H, isopropyl). Example 18: Amino acid substituted naphthoquinone derivatives
Figure imgf000079_0001
Step 1: N-BOC-serine methyl ester To a solution of serine methyl ester hydrochloride (0.12 g, 0.78 mmol) in 1.6 ml of dry MeOH, at room temperature, under argon, were added successively triethylamine (10% solution, 0.16 ml) and (BOC)2O (0.19 g, 1.1 eq.) and the soluticm was stirred for 60 minutes. It was then poured in cold 2% HCl and the aqueous layer was extracted with CH2CI2 (3x). The combined organic extracts were dried over MgSO4, the solids were filtered and the solvents evaporated to give 0.17 g (100 %) of the titled compound as a clear oil.
1H NMR (CDCl3): δ 5.56 (bs, 1H, NH), 4.34 (m, 1H, C H-CO2Me), 3.88 (m, 2H, CH2-OH), 3.75 (s, 3H, CO2Me), 2.96 (bs, 1H, OH), 1.44 (s, 9H, BOC).
Step 2: (1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-serine methyl ester]-3-aceto-5,8-dimethoxy isochroman. The titled compounds were obtained as per procedure described in step 2, example 17. They were purified via flash chromatography (silica gel, 2: 1 hexanes/EtOAc). The mixture of isomers is not separable by chromatography.
1H NMR (CDCl3): δ 6.73 (m, 2H, ArH), 6.07+5.78 (2d, 1H, NH), 5.72+5.70 (2s, 1H, H-1), 4.56- 4.35 (m, 3H, H-1' and H-2'), 3.98 (m, 1H, H-3), 3.90+3.81+3.78+3.77+3.76+3.67 (6s, 18H
[6x3H], Ar-OMe and CO2Me), 3.04 (2dd, 1H, H-4), 2.50 (2dd, 1H, H-4), 2.32 (d, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 3: (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyI-(1-[O-N-BOC-serine methyl ester]-5,10- dioxo-3,4,5,10-tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone.
The same procedure as described in step 3, example 17, was used for the tided compound, which was purified via flash chromatography (silica gel, 2: 1 hexanes/EtOAc).
The mixture of isomers is not separable by chromatography.
1H NMR (CDCl3): δ 8.05 (m, 2H, ArH), 7.73 (m, 2H, ArH), 5.90+5.52 (2d, 1H, NH), 5.73+5.72 (2s, 1H, H-1), 4.60-4.05 (m, 4H, H-3, H-1' and H-2'), 3.81+3.70 (2s, 3H, CO2CH3), 3.01 (2m, 1H,
H-4), 2.48 (m, 1H, H-4), 2.35 (2s, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 4: (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-seriιιe methyl ester]-5,10-dioxo-
3,4,5,10-tetrahydronaphtaleno [2,3-C] pyran-3-yl) ketone hydrochloride.
The titled compounds were obtained as per procedure described in step 4, example 17.
1H NMR (DMSO): δ 8.05-7.82 (m, 4H, ArH), 5.83+5.78 (2s, 1H, H-1), 4.69-4.40 (m, 2H, H-1'), 4.27 (m, 1H, H-3), 4.16 (m, 1H, H-2'), 3.79+3.73 (2s, 3H, CO2Me), 2.91+2.87 (2m, 1H, H-4), 2.50 (m, 1H, H-4), 2.31+2.29 (2s, 3H, COCH3).
Example 19: Amino alcobol substituted naphthoquinone derivative
Figure imgf000081_0001
Step 1: N-BOC-Prolinol The titled compound was obtained as per procedure described in step 1, example 18.
1H NMR (CDCl3): δ 4.19 (bs, 1H, OH), 3.95 (m, 1H, H-2), 3.59 (m, 2H, CH2-OH), 3.42 (m, 1H, H- 5), 3.30 (m, 1H, H-5), 2.01 (m, 1H, H-3), 1.83 (m, 2H, H-4), 1.60 (m, 1H, H-3), 1.45 (s, 9H, BOC).
Step 2: (1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-N-BOC-prolinol]-3-acetyl-5,8-dimethoxy isochroman
The titled compounds were obtained as per procedure described in step 2, example 17. They were purified via flash chromatography (silica gel, 7:3 hexanes/EtOAc). The mixture of isomers is not separable by chromatography.
1H NMR (CDCI3): δ 6.72 (m, 2H, ArH). 5.82+5.77 (2s, 1H, H-1), 4.54 (m, 1H, H-3), 4.18-3.20 (m, 5H, H-1', H-2' and H-5'), 3.82+3.79 (2s, 6H, ArOMe), 3.05 (2m, 1H, H-4), 2.53 (m, 1H, H-4), 2.31 (s, 3H, COCH3), 2.07-1.75 (m, 4H, H-3' and H-4'), 1.46 (s, 9H, BOC).
Step 3: (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10- tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone BCH-2067 The titled compounds were obtained as per procedure described in step 3, example 17. They were purified via preparative thin layer chromatography (silica gel, 7:3 hexanes/ethyl acetate).
1H NMR (CDCl3): δ 8.02 (m, 2H, ArH), 7.70 (m, 2H, ArH), 5.75+5.73 (2s, 1H, H-1), 4.47 (m, 1H, H-3), 4.15-3.18 (m, 5H, H-1', H-2' and H-5'), 2.97 (2m, 1H, H-4), 2.5 (m, 1H, H-4), 2.33+2.32 (2s, 3H, COCH3), 2.05-1.72 (m, 4H, H-3' and H-4'), 1.48 (s, 9H, BOC).
Step 4: (1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-prolinol]-3,4,5,12-tetrahydronaphtho-
[2,3-C] pyran-3-yI) ketone hydrochloride salt.
The titled compounds were obtained as per procedure described in step 4, example 17.
1H NMR (DMSO): δ 8.02 (m, 2H, ArH), 7.88 (m, 2H, ArH), 5.73+5.71 (2s, 1H, H-1), 4.68 (m, 1H, H-3), 4.19-3.48 (m, 3H, H-2' and H-1'), 3.10 (m, 2H, H-5'), 2.39 (dd, 1H, H-4), 2.35 (m, 1H, H-4), 2.32+2.31 (2s, 3H, COCH3), 2.10-1.55 (m, 4H, H-3' and H-4').
Example 20: Preparation of naphtho-[2,3-c] pyran derivative with a cyano side chain
Figure imgf000083_0001
Step 1: 5,8-dimethoxy-3-phenylsulphone isochroman To a stirred solution of 5,8-dimethoxy-3-aceto isochroman (12.8 g, 54 mmol) in methylene chloride (350 ml) at room temperature was added 3-chloroperbenzoic acid 80% (18 g, 83 mmol) in portions over 15. minutes. After 2 hours, magnesium sulfate (6.8 g, 56 mmol) and sulfinic acid (10 g, 70 mmol) were added. After 2 hours, a saturated solution of potassium carbonate was added then the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4 and evaporated. The titled compound was purified by trituration in ether (11 g, 60%), m.p.: 118-119°C.
1H NMR (250 MHz, C6D6), δ: 7.99 (dd, J = 1.5 and 8.0 Hz, 2H, Ar-H), 6.90 (m, 3H, Ar-H), 6.29 (2d, J = 8.9 Hz, 2H, Ar-H), 5.08 (d, J = 15.5 Hz, 1H, H-1), 4.53 (d, J = 15.5 Hz, 1H, H-1), 4.40 (dd, J = 4.7 and 9.2 Hz, 1H, H-3), 3.40 (dd, J = 4.7 and 17.0 Hz, 1H, H-4), 3.28 (s, 3H, -OCH3), 3.27 (dd, 9.2 and 17.0 Hz, 1H, H-4), 3.19 (s, 3H, -OCH3). Step 2: 5,8-dimethoxy-3-cyano isochroman
To a stirred solution of AICI3 (1.39 g, 10.4 mmol) and TMS-CN (1.4 ml, 10.4 mmol) in CH2Cl2 (40 ml) at -78°C under argon was added the pyranylsulfone from step 1 (example 2) (1.16 g, 3.5 mmol) then the temperature was slowly raised to -20°C. After 4 hours, the reaction mixture was worked up in methylene chloride and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated and the residue was purified by flash chromatography (hexanes/AcOEt 3/1) to give the titled compound (596 mg, 78 %).
1H NMR (250 MHz, CDCl3), δ: 6.30 (2d, J = 8.2 Hz, 2H, Ar-H), 5.08 (d, J = 16.3 Hz, 1H, H-1), 4.78 (d, J = 16.3 Hz, 1H, H-1), 4.03 (t, J = 5.1 Hz, 1H, H-3), 3.27 (s, 3H, -OCH3), 3.18 (s, 3H, - OCH3), 2.80 (dd, J = 5.1 and 17.2 Hz, 1H, H-4), 2.66 (dd, J = 5.1 and 17.2 Hz, 1H, H-4).
Step 3: 1-hydroxy-3-cyano-5,8-dimetboxy isochroman
To a stirred solution of 2,5-dimethoxy-3-cyano isochroman (670 mg, 3.06 mmol) in CCl4 (60 ml) were added N-bromosuccinimide (653 mg, 3.67 mmol) and a catalytic amount of AIBN. The mixture was heated to reflux and after 45 minutes, the solvent was evaporated and tetrahydrofurane (40 ml) and water (40 ml) were added. After 1 hour, the reaction mixture was worked up in ether. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated and the residue purified by trituration in a small amount of ether to give the titled compound (453 mg, 63 %).
1H NMR (250 MHz, acetone D6): 6.90 (2d, J = 9.0 Hz, 2H, Ar-H), 6.06 (2d, J = 5.2 Hz, 2H, H-1, - OH), 5.27 (dd, J = 4.1 and 12.1 Hz, 1H, H-3), 3.81 (s, 3H, -OCH3), 3.78 (s, 3H, -OCH3), 3.09 (dd, J = 4.1 and 17.1 Hz, 1H, H-4), 2.82 (dd, J = 12.1 and 17.1 Hz, 1H, H-4).
Step 4: 1-hydraxy-3-cyano-5,8-dioxo-5,8-dihydroisochroman
The titled compound was obtained in 77% yield by applying the procedure described in step 3, example 12, to the precursor of step 3 of this example.
1H NMR (250 MHz, acetone D6) δ: 6.86 (2d, J = 10.1 Hz, 2H, -CH=CH-), 6.61 (d, J = 5.7 Hz, 1H, H-1), 5.88 (d, J = 5.7 Hz, 1H, -OH), 5.20 (dd, J = 3.8 and 11.6 Hz, 1H, H-3), 2.98 (dd, J = 3.8 and 18.9 Hz, 1H, H-4), 2.73 (dd, J = 11.6 and 18.9 Hz, 1H, H-4).
Step 5 and 6: (1'S, 1S, 3R) and (1'S, 1R, 3S)-5,10-dioxo-3-cyano-1-(2'3',6',- trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1-H-naphtho-[2,3-c] pyran
The titled compounds were obtained in 27 % yield by following the procedure described in step 4, example 12, on the precursor of step 4 of this example.
1H NMR (250 MHz, CD2Cl2) δ: 8.30 (m, 4H, Ar-H), 8.10 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H), 6.55 (m, 1H, -NH), 6.15 and 5.95 (2s, 1H, H-1), 5.70 (m, 1H, H-4'), 5.60 and 5.55 (m, 1H, H-1'), 5.10 (m, 1H, H-3), 4.70-4.20 (m, 2H, H-3', H-5'), 3.25-2.80 (m, 2H, H-4), 2.40-2.00 (m, 2H, H-2'), 1.30 and 1.20 (2d, J = 6.7 Hz, 3H, H-6').
Step 7: (1'-S, 1-R, 3-S) and (1'-S, 1-S, 3-R)-3-cyano-1-[2',3',6'-trideoxy-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-C] pyran-3-yl BCH-1688
The titled compounds were obtained in 63% yield by following the procedure described in step 3, example 5, cm the precursor from step 6 of this exanφle.
1H NMR (250 MHz, CD2Cl2) δ: 8.07 (m, 2H, Ar-H), 7.79 (m, 2H, Ar-H), 6.80 (m, 1H, N-H), 6.09 and 5.92 (2s, 1H, H-1), 5.52 and 5.42 (2d, 1H, H-1'), 5.04 (1m, 1H, H-3), 4.40-4.05 (m, 2H, H-3', H- 5'), 3.70 (m, 1H, H-4'), 3.20-3.05 (1m, 1H, H-4), 3.00-2.80 (1m, 1H, H-4), 2.30-2.00 (m, 3H, -OH, H-2'), 1.38 and 1.29 (2d, J = 6.7 Hz, 3H, H-6').
Example 21: Preparation of some sugar derivatives
χ
v
Figure imgf000086_0001
M Step 1: 3,4-dimethoxy-L-fucal, and 3-methoxy-L-fucal
To a stirred solution of L-fucal (400 mg, 3.1 mmol) in dimethylfbrmamide (7.5 ml) were added methyl iodide (0.85 ml, 3.6 mmol) and silver oxide (1.16 g, 5.0 mmol). After 1.5 hour, the reaction mixture was worked up in CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated. The products were separated by flash chromatography (hexanes/AcOEt 2/1) to give dimethoxy fucal (79 mg, 16 %).
1H NMR (250 MHz, CDCl3) δ: 6.29 (dd, J = 1.3 and 6.2 Hz, 1H, H-1), 4.72 (m, 1H, H-2), 4.05 (m, 2H, H-5, H-4), 3.57 (s, 3H, -OCH3), 3.44 (m, 1H, H-3), 3.39 (s, 3H, -OCH3), 1.31 (d, J = 6.6 Hz, 3H, H-6).
The 3-methoxy-L-fucal (20% yield) had:
1H NMR (250 MHz, CDCl3) δ: 6.36 (dd, J = 1.2 and 6.2 Hz, 1H, H-1), 4.60 (m, 1H, H-2), 4.05- 3.80 (m, 3H, H-3, H-4, H-5), 3.40 (s, 3H, -OCH3), 2.37 (d, J = 3.9 Hz, 1H, -OH), 1.36 (d, J = 6.6 Hz, 3H, H-6). Step 2: 3-methoxy-4-mesyl-L-fucal
Mesylation of 3-methoxy-L-fucal yielded (84%) of the titled compound. 1H NMR (250 MHz, CDCl3) δ: 6.34 (dd, J = 2.1 and 6.5 Hz, 1H, H-1), 4.95 (m, 1H, H-2), 4.73 (m, 1H, H-4), 4.13 (m, 2H, H-3, H-5), 3.45 (s, 3H, -OCH3), 3.15 (s, 3H, -SO2CH3), 1.40 (d, J = 6.6 Hz, 3H, H-6). Step 3: 1-t-Butyl dimethylsilyloxy-3-trifluoroacetamido-4-methanesulfonyl-2,3,6-trideoxy-
L-iyxobexopynumse
To a stirred solution of 1-t-butyl dimethylsilyloxy, 3-trifluoroacetamido-2,3,6-trideoxy-L- lyxohexopyranose (504 mg, 1.41 mmol) in CH2Cl2 (7 ml) at 0°C were added methanesulfonyl chloride . (218 μl, 2.82 mmol) and triethylamine (590 μl, 4.2 mmol). After 2 hours the reaction mixture was worked up with CH2Cl2 and HCl 0.1 N. The oiganic layer was washed with a solution of NaHCO3 and brine then dried over MgSO4. The solvent was evaporated to give 1-t-butyl dimethyl silyloxy, 3- trifluoroacetamido-2,3,6 trideoxy-4 methanesulfonyl-L-lyxohexopyranose (604 mg, 98%).
1H NMR (250 MHz, CDCl3) δ: 7.28 (d, J = 7.7 Hz, 1H, N-H), 4.83 (dd, J = 2.1 and 9.1 Hz, 1H, H- 1), 4.71 (d, J = 2.2 Hz, 1H, H-4), 4.25 (m, 1H, H-3), 3.75 (q, J = 6.4 Hz, 1H, H-5), 3.18 (s, 3H, - SO2-CH3), 2.0 (m, 1H, H-2), 1.75 (m, 1H, H-2), 1.31 (d, J = 6.4 Hz, 3H, H-6), 0.89 (s, 9H, - C(CH3)3), 0.12 and 0.11 (2s, 6H, -Si(CH3)2).
Step 4: 1-t-Butyl dimethylsUyioxy-3-trifluoroacetamido-4-O-bromoacetyl-2,3,6-trideoxy-L- lyxohexopyranose
To a stirred solution of 1-t-butyl diinethylsilyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L- lyxohexopyranose (81 mg, 0.18 mmol) in CH2Cl2 (2 ml) at 0°C were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, the reaction mixture was worked up with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (76 mg, 74%).
1H NMR (250 MHz, CDCI3) δ: 6.47 (d, J = 8 Hz, 1H, N-H), 5.03 (d, J = 3.0 Hz, 1H, H-4), 4.84 (dd, J = 2.3 and 9.0 Hz, 1H, H-1), 4.35 (m, 1H, H-3), 4.00 and 3.80 (2d, J = 10.5 Hz, 2H, -CH2-Br), 3.75 (dq, J m 1 Hz, 6.5 Hz, 1H, H-5), 2.05-1.70 (m, 2H, H-2), 1.20 (d, J = 6.5, 3H, -H6), 0.9 (s, 9H, -C(CH3)3), 0.13 (2s, 6H, -Si(CH3)2).
Example 22: Preparation of few naphtho-[2,3-c] pyran derivatives
Figure imgf000088_0001
Step l: (1'-S, 1-S, 3-R) and (1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'- trifluoroacetamido-4'-O-methane-sulfonyl-L-lyxohexopyranose)-5,10-dioxo- 3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2095
The titled compound was obtained in 45% yield by using the procedure described in step 2 of this example but with the sugar obtained from step 3, example 21. It was purified by flash chromatography (toluene/acetone 95/5). 1H NMR (250 MHz, CDCl3) δ: 8.10 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H), 7.15 (2d, J = 8.0 Hz, 1H, N-H), 6.16 and 6.00 (2s, 1H, H-1), 5.62 and 5.50 (2d, J = 1.5 Hz, 1H, H-1'), 4-89 and 4.84 (2 broad s, 1H, H-4'), 4.75 and 4.25 (2q, J = 6.6 Hz, H-5'), 4.50 (m, 2H, H-3, H-3'), 3.23 and 3.21 (2s, 3H, -SO2CH3), 3.10 (m, 1H, H-4), 2.55 (m, 1H, H-4), 2.33 and 2.32 (2s, 3H, -CO-CH3), 2.00 (m, 2H, H- 2'), 1.45 and 1.30 (2d, J = 6.6 Hz, H-6').
Step 2: (1'-S, 1-S, 3-R)-methyl-(1-[2',3 ',4',6' tetraαeoxy-3'-trifluoroacetamido-4'-O-(2- bromo-acetyl)-L-lyxopyranose]-5, 10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2105 To a stirred solution of the aglycone from example 3 (30 mg, 0.11 mmol), 4-bromoacetyl-1-t-butyl dimethylsilyloxy-3-trifiuoro-acetamido daunosamine derivative (76 mg, 0.13 mmol) molecular sieves Å (62 mg) in CH2Cl2 (1.2 ml) at -50°C under argon was added trimethylsilyl trifluoromethanesulfonate (23 μl, 0.12 mmol). After 2 hours at -30°C, the reaction mixture was worked up with a solution of NaHCO3 10% and CH2Cl2. The organic layer was washed with brine and dried over MgSO4, the residue was purified by flash chromatography (hexanes/AcOEt 2:1) to give the titled compound (8 mg, 12%).
1H NMR (250 MHz, CDCl3) δ: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 6.33 (d, J = 8.1 Hz, 1H, N-H), 6.00 (s, 1H, H-1), 5.67 (s, 1H, H-1'), 5.16 (s, 1H, H-4'), 4.53 (dd, J = 3.9 and 11.6 Hz, 1H, H-3), 4.53 (m, 1H, H-3'), 4.23 (q, J = 6.7 Hz, 1H, H-5'), 3.90 (2d, J = 10.9 Hz, 2H, -CH2-Br), 3.08 (dd, J = 3.9 and 19.8 Hz, 1H, H-4), 2.53 (dd, J = 11.6 and 19.8 Hz, 1H, H-4), 2.34 (s, 3H, -CO- CH3), 2.02 (m, 2H, H-2'), 1.19 (d, J = 6.7 Hz, 3H, H-6').
Step 3: (1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O- methanesulfonyl-L-lyxobexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3- c] pyran-3-yl) ketone BCH-2070
The titled compound was obtained in 22% yield by applying the procedure described in step 4, example 12, to the aglycone from example 3 and the glycal from step 2, example 21. Purification was carried out by flash chromatography (toluene/acetone:95/5) M.P. 85-89°C.
1H NMR (250 MHz, CDCl3) δ: 8.11 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 5.98 (s, 1H, H-1), 5.62 (d, J = 2.8 Hz, 1H, H-1'), 4.85 (s, 1H, H-4'), 4.46 (dd, J = 4.0 and 11.6 Hz, 1H, H-3), 4.04 (q, J = 6.5 Hz, 1H, H-5'), 3.62 (m, 1H, H-3'), 3.39 (s, 3H, -OCH3), 3.14 (s, 3H, -SO2-CH3), 3.05 (dd, J = 4.0 and 19.5 Hz, 1H, H-4), 2.50 (dd, J = 11.6 and 19.5 Hz, 1H, H-4), 2.33 (s, 3H, -CO-CH3), 2.00 (m, 2H, H-2'), 1.33 (d, J = 6.5 Hz, 3H, H-6').
Step 3 (Cont'd): (1'-S, 1'S, 3-R)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-
4'-O-methanesulfonyI-L-lyxohexopyranose)-5,10-dioxo- 3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH- 2072
The titled compound was obtained in 11% yield by using the procedure described in step 3 of this example but using the 1,3-diepimeric aglycone. M.P. 139-141°C.
1H NMR (250 MHz, CDCl3) δ: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 6.15 (s, 1H, H-1), 5.52 (d, J = 1.5 Hz, 1H, H-1'), 4.95 (d, J = 1.5 Hz, 1H, H-4'), 4.59 (q, J = 6.5 Hz, 1H, H-5'), 4.49 (dd, J = 4.1 and 11.6 Hz, 1H, H-3), 3.60 (m, 1H, H-3'), 3.38 (s, 3H, -SO2CH3), 3.15 (s, 3H, -OCH3), 3.07 (dd, J = 4.1 and 19.9 Hz, 1H, H-4), 2.55 (dd, J = 11.6 and 19.9 Hz, 1H, H-4), 2.33 (s, 3H,
-CO-CH3), 1.95 (m, 2H, H-2'), 1.50 (d, J = 6.5 Hz, 3H, H-6'). Step 4: (1-S, 3-R) and (1-R, 3-S)-methyl-(1-(1-m ethoxy-4-oxocyclohexyloxy)-5,10-dioxo-
3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2096
To a stirred solution of the aglycone from example 3 (7 mg, 0.026 mmol) in tetrahydrofu rane (1.6 ml) were added 5,6-dihydro-4-methoxy-2H-pyran (29 μl, .26 mmol) and a catalytic amount of PTSA. After 4 hours, the reaction was worked up with CH2Cl2 and NaHCO3 5 % . The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (10 mg, 96%).
1H NMR (250 MHz, CDCl3) δ: 8.10 (m, 2H, Ar-H), 7.70 (m, 2H, Ar-H), 6.34 (s, 1H, H-1), 4.66 (dd, J = 4.3 and 11.6 Hz, 1H, H-3), 3.80-3.50 (m, 4H, -CH2-O-CH2-), 3.40 (s, 3H, -OCH3), 3.06 (dd, J = 4.3 and 19.7 Hz, 1H, H-4), 2.52 (dd, J = 11.6 and 19.0 Hz, 1H, H-4), 2.30 (s, 3H, -CO- CH3), 2.20-1.85 (m, 4H, -CH2-C-CH2-).
Example 23: Preparation of naphtho-[2,3,-c] pyran derivative with a homo methyl ketone side chain
Figure imgf000091_0001
Step 1: 5,8-Dimetboxy-3-(t-butyl acetoacetato) isochroman
To a stirred soluticm of pyranosulfone from step 1, example 20, (1.12 g, 3.35 mmol) in CH2Cl2 (40 ml) at -78°C were added a solution of silyl enol ether of t-butyl acetoacetato (10 mmol) in CH2Cl2 (10 ml) and AICI3 (1.33 g, 10 mmol). Temperature was then raised to -30°C for 2 hours. The reaction mixture was worked up with CH2Cl2 and HCl 0.1 N. The oiganic was washed with brine and dried over MgSO4. The solvent was evaporated to give the title β-ketoester (519 mg, 43 %).
1H NMR (250 MHz, CDCl3), δ: 6.63 (m, 2H, Ar-H), 4.91 and 4.85 (2d, J = 9.8 Hz, 1H, H-1), 4.60 and 4.53 (2d, J = 7.9 Hz, 1H, H-1), 4.20 (m, 1H, H-3), 3.76-3.74 (3s, 6H, -OCH3), 3.62 (t, J = 9.5 Hz, 1H), 2.90 (m, 1H, H-4), 2.45 (m, 1H, H-4), 2.32 and 2.28 (2s, 3H, -CO-CH3), 1.49 and 1.47 (2s, 9H, -C(CH3)3).
Step 2: 5,8-Dimethoxy-3-(propane-2-one) isochroman
The product from step 1 of this example was decaiboxylated, in 91 % yield, with concentrated aqueous
HBr in acetone.
1H NMR (250 MHz, CDCl3) δ: 6.63 (2d, J = 9.0 Hz, 2H, Ar-H), 4.88 (d, J = 15.9 Hz, 1H, H-4),
4.58 (d, J = 15.9 Hz, 1H, H-4), 4.06 (m, 1H, H-3), 3.77 and 3.75 (2s, 6H, -OCH3), 2.85 (m, 2H, - CH2-CO-), 2.63 (dd, J = 4.8 and 16.5 Hz, 1H, H-4), 2.40 (dd, J = 10.9 and 16.5 Hz, 1H, H-4), 2.24
(s, 3H, -CO-CH3).
Step 3: 5,8 -Dimethoxy-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
The isochroman from 2 herein was glycosidated as per procedure described in step 3, example 34. The title compound was obtained in 97% yield.
1H NMR (250 MHz, CDCl3) δ: 8.26 (d, J = 2.0 Hz, 4H, Ar-H), 6.74 (m, 2H, Ar-H), 6.50 and 6.35
(2d, J = 7.0 Hz, 1H, -NH), 6.02 and 5.88 (2s, 1H, H-1), 5.59 (s, 1H, H-1'), 5.49 and 5.46 (2s, 1H, H- 4'), 4.70 (m, 2H, H-3', H-3), 3.80 and 3.78 (2s, 6H, -OCH3), 3.00-2.50 (m, 2H, H-4, -CH2-CO-),
2.50-2.00 (m, 2H, H-4, -CH2-CO-), 2.24 and 2.22 (2s, 3H, -CO-CH3), 1.25 and 1.15 (2d, J = 6.5 Hz,
3H, H-6').
Step 4: 5,8-Dioxo-3-(propane-2 one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p nitrobenzoyl-L-lyxohexopyranose)-isochroman
The titled compound was obtained in 94% yield via oxidative demethylation of the isochroman obtained from step 3 herein as per procedure described in step 4, example 34.
1H NMR (250 MHz, CDCl3), δ: 8.30 (d, J = 5.7 Hz, 4H, ArH), 6.80 (m, 2H, Ar-H), 6.42 and 6.35 (2d, J = 7.0 Hz, 1H, N-H), 5.81 and 5.70 (2s, 1H, H-1), 5.59 and 5.54 (2s, 1H, H-1'), 5.45 (2d, J = 1.5 Hz, 1H, H-4'), 4.80-4.40 (m, 3H, H-3', H-5', H-3), 2.90 (m, 1H, H-4), 2.70 (m, 2H, -CH2-CO), 2.40-1.90 (m, 3H, H-4, H-2'), 2.23 and 2.21 (2s, 3H, -CO-CH3), 1.28 and 1.15 (2d, J = 6.5 Hz, 3H, H-6'). Step 5: 5,10-Dioxo-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-nsphtho-[2,3-c] pyran
The titled compound was obtained via cycloaddition between 1 -acetoxybutadiene and the quinone from step 4 herein by following the procedure described in step 5, example 34. 1H NMR (250 MHz, CDCl3), δ: 8.31 (2d, J = 9.1 Hz, 4H, Ar-H), 8.11 (m, 2H, Ar-H), 7.78 (m, 2H, Ar-H), 6.45 and 6.33 (2d, J = 7.3, 1H, N-H), 5.99 and 5.88 (2s, 1H, H-1), 5.71 and 5.60 (2s, 1H, H- 1'), 5.48 (1s, 1H, H-4'), 4.80-4.40 (m, 3H, H-3, H-3', H-4'), 3.00-2.60 (m, 3H, H-4, -CH2-CO-), 2.50-2.00 (m, 3H, H-4, H-2'), 2.25 and 2.23 (2s, 3H, -CO-CH3), 1.33 and 1.17 (2d, J = 6.5 Hz, 3H, H-6').
Step 6: (1'-S, 1-S, 3-R) and (1'-S, 1-R, 3-S)-1-(6-hydroxy-1-(2',3',6'-trideoxy-3'- trifluoroacetamido,4-hydroxy-L-lyxopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) propane-2-one BCH-2098
The titled compound was obtained following deprotection of the glycoside from step 5 herein as per procedure described in step 6, example 34.
1H NMR (250 MHz, CDCl3) δ: 8.10 (m, 2H, Ar-H), 7.75 (m, 2H, Ar-H), 6.73 (d, J = 7.5 Hz, 1H,
N-H), 5.93 and 5.81 (2s, 1H, H-1), 5.52 and 5.41 (2d, J = 2.7 Hz, 1H, H-1'), 4.80-4.20 (m, 3H, H-3, H-3', H-5'), 3.70 (m, 1H, H-4'), 3.00-2.60 (m, 3H, H-4, -CH2-CO-), 2.40-1.70 (m, 4H, H-4, H-2', -
OH), 2.23 and 2.20 (2s, 3H, -CO-CH3), 1.41 and 1.20 (2d, J = 6.6 Hz, 3H, H-6').
Example 24: Preparation of naphtho-[2,3-c] pyran derivative with a C-2' glycoside linkage
4
Figure imgf000094_0001
Step 1: (1R, 3S) and (1-S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzyloxy-1,5-dihydro-L-lyxohexo-pyranose-2-yl)-5,8-dimethoxy-3- acetoisochroman
2,5-Dimethoxy-1-hydroxy-3-acetoisochroman was reacted with 1,4-di-O-p-nitrobenzoyl-N-trifluoroacyl daunosamine as per procedure from step 1, example 5. The titled products were separated by flash chromatography (CH2Cl2/acetone 99/1).
1H NMR (250 MHz, CDCI3) δ: 8.30 (m, 3H, Ar-H, N-H), 8.09 (d, J = 8.7 Hz, 2H, Ar-H), 6.71 (2d, J = 8.8 Hz, 2H, Ar-H), 6.02 (s, 1H, H-1'), 5.84 (d, J = 3.6 Hz, 1H, H-4'), 5.62 (s, 1H, H-1), 5.30 (m, 1H, H-3'), 4.45 (m, 2H, H-3, H-5'), 3.81 (Is, 3H, -OCH3), 3.76 (1s, 3H, -OCH3), 3.11 (dd, J = 3.9 Hz and 17.3 Hz, 1H, H-4), 2.61 (dd, J = 12.1 and 17.3 Hz, 1H, H-4), 1.95 (s, 3H, -COCH3), 1.28 (d, J = 6.6 Hz, 3H, H-6').
The second diastereomer had: 1H NMR (250 MHz, CDCl3) δ: 8.28 (2d, J = 9.0 Hz, 4H, Ar-H), 6.90 (d, J = 7.8 Hz, 1H, N-H), 6.70 (2d, J = 9.0 Hz, 2H, Ar-H), 6.18 (d, J = 1.5 Hz, 1H, H-1'), 5.75 (d, J = 4.8 Hz, 1H, H-4'), 5.55 (s, 1H, H-1), 5.30 (m, 1H, H-3'), 4.30 (m, 2H, H-5', H-4), 3.80 (s, 3H, -OCH3), 3.60 (s, 3H, - OCH3), 3.02 (dd, J = 4.3 and 17.6 Hz, 1H, H-4), 2.57 (dd, J = 11.6 and 17.6 Hz, 1H, H-4), 2.29 (s, 3H, -CO-CH3), 1.29 (d, J = 6.6 Hz, 3H, H-6').
Step 2: (1R, 3S)-1-(2',3',6 '-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,8-dioxoisochroman The (1R, 3S) product from step 1 herein was oxidatively demethylatod as per procedure in step 3, example 12.
1H NMR (250 MHz, CDCl3) δ: 8.23 (d, J = 8.7 Hz, 2H, Ar-H), 8.03 (d, J = 8.7 Hz, 2H, Ar-H),
7.65 (d, J = 6.6 Hz, 1H, N-H), 6.75 (2d, J = 10.3 Hz, 2H, Ar-H), 6.28 (d, J = 1.4 Hz, 1H, H-1),
5.78 (d, J = 3.8 Hz, 1H, H-4'), 5.37 (s, 1H, H-1'), 5.21 (m, 1H, H-3'), 4.43 (q, J = 6.5 Hz, 1H, H- 5'), 4.24 (dd, J = 3.8 and 11.2 Hz, 1H, H-3), 2.90 (dd, J = 3.8 and 19.5 Hz, 1H, H-4), 2.40 (ddd, J =
1.6, 11.2 and 19.5 Hz, 1H, H-4), 1.88 (s, 3H, -COCH3), 1.26 (d, J = 6.5 Hz, 3H, H-6').
Step 3: (1R, 3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyx oh exopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran
The quinone from step 2 herein was cycloadded with 1-acetoxybutadiene as per procedure from step 4, example 12. The product had:
1H NMR (250 MHz, CDCl3) 6: 8.30 (d, J = 8.7 Hz, 2H, Ar-H), 8.10 (m, 4H, Ar-H), 7.80 (m, 2H,
Ar-H), 6.36 (d, J = 1.9 Hz, 1H, H-1), 5.86 (d, J = 3.9 Hz, 1H, H-4'), 5.60 (s, 1H, H-1'), 5.31 (m, 1H, H-3'), 4.49 (q, J = 6.6 Hz, 1H, H-5'), 4.35 (dd, J = 3.9 Hz, and 11.4 Hz, 1H, H-3), 3.12 (dd, J
= 3.9 Hz and 19.4 Hz, 1H, H-4), 2.62 (ddd, J = 1.9, 11.4 Hz, 19.4 Hz, 1H, H-4), 1.98 (s, 3H, -CO-
CH3), 1.31 (d, J = 6.6 Hz, 3H, H-6').
Step 4: (1R, 3S)-1-(2',3',6,-tri deoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L- lyxobcxopyrano6e-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
BCH-2144
The tricyclic product from step 3 herein was deprotected as per procedure from step 3, example 5. The title product had:
1H NMR (250 MHz, CDCl3) δ: 8.20 (m, 2H, Ar-H), 7.75 (m, 3H, N-H, Ar-H), 6.25 (d, J = 1.7 Hz, 1H, H-1), 5.55 (s, 1H, H-1'), 5.11 (m, 1H, H-3'), 4.32 (dd, J = 4.0 Hz and 11.1 Hz, 1H, H-3), 4.23 (q, J = 6.5 Hz, 1H, H-5'), 4.05 (d, J = 3.7 Hz, 1H, H-4'), 3.00 (dd, J = 4.0 and 19.8 Hz, 1H, H-4), 2.59 (ddd, J = 1.7, 11.1 and 19.8 Hz, 1H, H-4), 2.28 (s, 3H, -CO-CH3), 1.70 (broad s, 1H, -OH), 1.34 (d, J = 6.5 Hz, 3H, H-6'). Step 5: (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,8-dioxoisochroman The (1S, 3R) product from step 1 herein was oxidatively demethylated as per procedure in step 3, example 12.
1H NMR (250 MHz, CDCl3) δ: 8.32 (d, J = 9.0 Hz, 2H, Ar-H); 8.20 (d, J = 9.0 Hz, 2H, Ar-H), 7.58 (d, J = 8.3 Hz, 1H, N-H), 6.80 (2d, J = 10.1 Hz, 2H, Ar-H), 6.46 (d, J = 1.3 Hz, 1H, H-1), 5.73 (d, J = 4.8 Hz, 1H, H-4'), 5.33 (d, J = 1.9 Hz, 1H, H-1'), 5.25 (m, 1H, H-3'), 4.35 (q, J = 6.6 Hz, 1H, H-5'), 4.20 (dd, J = 4.1 Hz and 10.5 Hz, 1H, H-3),.2.88 (dd, J = 4.1 and 19.9 Hz, 1H, H-4), 2.40 (ddd, J = 1.9, 10.5 and 19.9 Hz, 1H, H-4), 2.27 (s, 3H, -COCH3), 1.32 (d, J = 6.6 Hz, 3H, H- 6').
Step 6: (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5- dihydro-L-lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-c] pyran
The quinone from step 5 herein was cycloadded with 1-acetoxybutadiene as per procedure from step 4, example 12. The titled product had:
1H NMR (250 MHz, CDCl3) δ: 8.30 (d, J = 8.9 Hz, 2H, Ar-H), 8.22 (d, J = 8.9 Hz, 2H, Ar-H), 8.20 (m, 1H, Ar-H), 8.00 (m, 2H, N-H, Ar-H), 7.86 (m, 2H, Ar-H), 6.53 (s, 1H, H-1), 5.77 (d, J = 4.7 Hz, 1H, H-4'), 5.50 (s, 1H, H-1'), 5.30 (m, 1H, H-3'), 4.37 (q, J = 6.6 Hz, 1H, H-5'), 4.27 (dd, J = 4.0 and 10.7 Hz, 1H, H-3), 3.08 (dd, J = 4.0 and 19.8 Hz, 1H, H-4), 2.55 (ddd, J = 1.0, 10.7 and 19.8 Hz, 1H, H-4), 2.31 (s, 3H, -CO-CH3), 1.31 (d, J = 6.6 Hz, 3H, H-6').
Step 7: (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
BCH-2145
The tricyclic product from step 6 herein was deprotected as per procedure from step 3, example 5. The titled product had:
1H NMR (250 MHz, CDCl3) δ: 8.19 (d, J = 8.9 Hz, 1H, N-H), 8.10 (d, J = 7.3 Hz, 1H, Ar-H), 7.90 (d, J = 7.3 Hz, 1H, Ar-H), 7.70 (m, 2H, Ar-H), 6.26 (s, 1H, H-1), 5.47 (s, 1H, H-1'), 5.10 (m, 1H, H-3'), 4.20 (m, 2H, H-3, H-5'), 3.97 (d, J = 4.0 Hz, 1H, H-4'), 3.00 (dd, J = 4.0 and 20.0 Hz, 1H, H-4), 2.55 (dd, J = 10.8 Hz, and 20.0 Hz, 1H, H-4), 2.32 (s, 3H, -CO-CH3), 1.70 (broad s, 1H, -OH), 1.36 (d, J = 6.4 Hz, 3H, H-6').
Example 25: Preparation of 3,3-bis-(methoxycarbonyl)-5,10-dioxo-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]-pyran (BCH-1665)
Figure imgf000097_0001
Step 1: 5,8-dimethoxy-3,3 bis (methoxycarbonyl)-isochroman
To a solution of 2,3 bis (bromomethyl)-1,4-dimethoxybenzene (1.30 g; 4.00 mmol) in 40 ml of a 1:1 mixture of tetrahydrofuran and dimethylformamide were added benzoyloxy-dimethylmalonate (1.06 g; 4.19 mmol), potassium carbonate (1.16 g; 8.38 mmol) and cesium carbonate (1.37 g; 4.19 mmol). The resulting mixture was stirred at 80°C (oil bath temperature) for 2.5 hours. It was then cooled to room temperature and filtered on a pad of silica gel and the solvents were evaporated using a vacuum pump to yield 2.3 g of crude alkylated product which was dissolved in methanol (60 ml). To this solution was added a solution of aodium methoxyde in methanol (4.57 ml; 4.37 M; 5 eq). The resulting mixture was stirred at room temperature for 2 hours and was then concentrated to a volume of -10 ml. It was quenched with 1 N HCl and extracted with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by column chromatography on silica gel using 10-25% ethyl acetate in hexane to afford the tide compound (452 mg; 36% overall):
1H NMR (250 MHz; CDCl3) δ: 3.25 (2H, a, H-4), 3.72, 3.78, 3.79 (12H, 3s, 4xOCH3), 4.88 (2H, s, H-1), 6.59 and 6.65 (2H, AB doublets, Ar-H).
Step 2: 5,8-dioxo-3,3 bis ( methoxycarhonyl)-5,8-dihydro-isochroman To a aolution of 5,8-dimethoxy-3,3 bis (methoxycarbonyl)-isochroman (70 mg; 0.23 mmol) in acetonitrile (5 ml) at room temperature was added dropwise a solution of eerie ammonium nitrate (378 mg; 0.69 mmol) in water (1 ml). The resulting mixture was then stirred at room temperature for 5 minutes and was quenched by adding saturated sodium bicaibonate soluticm. The product was extracted with dichloromethane and the combined oiganic layers were washed with brine and dried over MgSO4. Evaporation afforded the crude quinone (60 mg; 95 %) which was used without further purification: 1H NMR (CDCl3, 250 MHz) δ: 3.03 (2H, t, J = 3Hz, H-4), 3.81 (6H, s, OCH3), 4.67 (2H, t, J = 3Hz, H-1), 6.70 and 6.77 (2H, AB doublets, Ar-H). Step 3: 3,3 bis (methoxycarbonyI)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
To a solution of 5,8-dioxo-3,3 bis (methoxycarbonyl)-5,8-dihydroisochroman (50 mg; 0.17 mmol) in toluene (4 ml) at room temperature was added 1-acetoxy-1,3 butadiene (113 μl; 1 mmol). The resulting mixture was stirred at room temperature for 24 hours. Air was then bubbled dirough for 30 minutes and the mixture was concentrated to a volume of -1 ml and applied to silica gel column. Elution with 30% ethyl acetate in hexane afforded pure tide compound (20 mg; 34%) as a yellow solid; m.p.: 210-222°C (dec):
1H NMR (250 MHz, CDCl3) δ: 3.22 (2H, t, J = 2.5 Hz, H-4), 3.84 (6H, a, CO2CH3), 4.86 (2H, t, J = 2.5 Hz, H-1), 7.75 (2H. m, Ar-H), 8.10 (2H, m, Ar-H).
IR (film): 2963, 1743, 1662, 1641, 1591, 1438, 1288, 1175, 1055, 791 and 692 cm-1.
Example 26: Preparation of (1'S, 1R, 3S) and (1'S, 1R, 3R)-5,10-dioxo-3- methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10 -tetrahydro-1H-naphtbo-[23-c]-pyran (BCH- 1691) and BCH-1693)
Figure imgf000099_0001
Step 1: 5,8-dimethoxy-3-hydroxy methyl-isochrom an To a solution of 5,8-dimethoxy-3-methoxycarbonyl-isochroman (310 mg; 1.23 mmol) in 5 ml of tetrahydrofuran at 0°C was added lithium aluminum hydride (47 mg; 1.23 mmol). The mixture was stirred at 0°C for 15 minutes and was quenched witii 1 N HCl. The product was extracted with ether and the combined organic layers were washed with brine and dried over MgSO4 affording crude tide alcohol (246 mg; 90%) used as such for subsequent steps: 1H NMR (250 MHz, CD Cl3) δ: 2.42 (1H, m, H-4 ax), 2.55-2.75 (2H, m, H-4 eq and -OH), 3.60-3.90 (2H, m, CH2-OH), 3.76 (3H, s, -OCH3), 3.77 (3H, s, -OCH3), 4.62 (1H, br d, J = 16.0 Hz, H-1), 4.97 (1H, d, J = 16.0 Hz, H-1), 6.61 and 6.65 (2H, AB doublets, ArH). Step 2: 5,8-dimethoxy-3-meth oxymethylisochroman
To a suspension of sodium hydride (70 mg of 60% in oil; 1.78 mmol) in tetrahydrofuran (3 ml) was added a solution of 5,8-dimethoxy-3-hydroxymethyl-isochroman (330 mg; 1.48 mmol) in 7 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature until H2 evolution ceased (-15 minutes) and iodomethane (500 μl; 5 eq) was added. The mixture was then stirred at room temperature for 30 minutes. Since the reaction was not complete, another equivalent of aodium hydride was added along witii 20 mg of cesium caibonate. The mixture was stirred for 15 minutes and was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with brine and dried over MgSO4. The crude was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford the title compound (301 mg; 86%):
1H NMR (250 MHz, CDCl3) δ: 2.45 (1H, br dd, J = 11.0 and 17 Hz, H-4 ax), 2.69 (1H, dm, J = 17.0 Hz, H-4 eq), 3.44 (3H, s, CH2-O-CH3), 3.55 (2H, d, J = 5.5 Hz, -CH2-O), 3.75 (3H, s, OCH3), 3.77 (3H, s, OCH3), 4.63 (1H, br d, J = 16.0 Hz, H-1), 4.97 (1H, d, J = 16.0 Hz, H-1), 6.61 and 6.64 (2H, AB doublets, Ar-H).
Step 3: (1'S, 1R, 3S)-5,8-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexo-pyranose)-5,8- dihydroisochroman and its (1'S, 1S, 3R) diastereomer
To a aolution of 5,8-dimethoxy-3-methoxymethyl-isochroman (280 mg; 1.18 mmol) in 16 ml of dichloromethane were added 2,3,6-trideoxy-3-trifluoroacetamido-4-O-p-nitrobenzoyl-α-L- lyxohexopyranose (555 mg; 1.42 mmol), 4Å molecular sieves (500 mg) and 2,3 dichloro-5,6- dicyanobenzoquinone (360 mg; 1.6 mmol). The dark green reaction mixture was stirred at room temperature for 14 hours. It was quenched with saturated NaHCO3 aolution and extracted with dichloromethane. The combined oiganic layers were washed with saturated NaHCO3, brine and were dried ova Na2SO4 affording, after evaporation, 671 mg of a crude adduct which was dissolved in acetonitrile (20 ml) at 0°C. A aolution of cerie ammonium nitrate (3.3 g; 6 mmol) in 10 ml of water was treated by portions with solid sodium bicarbonate (886 mg). The resulting yellow solution was added dropwise to the isochroman solution. After the addition, tiie mixture was stirred at 0°C for 20 minutes, quenched with saturated NaHCO3 aolution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over Na2SO4 to afford after evaporation a crude quinone which was recrystallized from dichloromethane:pentane yielding 225 mg of a diastereomeric quinone mixture favoring the tide compound (2: 1):
1H NMR (250 MHz, CDCl3): 1.20 (3H, t, J = 6.5 Hz, H-6'), 1.90-2.70 (4H, m, H-2' and H-4), 3.41 (3H, s, -OCH3), 3.35-3.65 (3H, m, CH2-OCH3 and H-3'), 4.15-4.70 (2H, m, H-3 and H-5'), 5.44 (1H, br s, H-1'), 5.60 (1H, br s, H-4'), 5.78 (1H, s, H-1), 6.30 (1H, m, NH), 6.65-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB): signals for minor (1'S, 1R, 3R) isomer are δ: 1.30 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.70 (4H, m, H-2' and H-4), 3.43 (3H, s, -OCH3), 3.35-3.65 (3H, m, CH2-O-CH3 and H-3'), 4.15-4.70 (2H, m, H-3 and H-5'), 5.40 (1H, br s, H-1'), 5.59 (1H. br s. H-4'), 5.91 (1H, s, H-1), 6.40 (1H, m, NH), 6.65-6.90 (2H, m, Ar-H), 8.30 (2H, m, Ar-H).
Step 4: (1'S, 1R, 3S)-5,10-drøo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]-pyran
To a solution of the quinone mixture from step 3 of this example, (100 mg; 0.17 mmol) in 6 ml of toluene at room temperature was added 1-acetoxy-1,3-butadiene (113 μl; 1 mmol). The rest of the procedure is identical to step 2, example 5, affording the tide compound (42 mg; 40%):
1H NMR (CD2Cl2, 250 MHz) δ: 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.20 (2H, m, H-2'), 2.37 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.70 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.38 (3H, s, O-CH3), 3.55 (2H, m, -CH2-OCH3), 4.25-4.70 (3H, m, H-3, H-3' and H-5'), 5.41 (1H, br s, H-1'), 5.65 (1H, br s, H-4'), 5.90 (1H, s, H-1), 6.44 (1H, br d, J = 7 Hz, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, ArH ), 8.27 (4H, m, PNB).
The second diastereomer:
(1'S, 1S, 3R)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroscetamido-4'-O-p- nitrobenzoyl-L -lyxohexo-pyranose)-3,4,5,10--tetrahydro-1H-naphtho-[2,3-c] pyran was obtained in 19% yield and had:
1H NMR (250 MHz, CD2Cl2) δ: 1.30 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.30 (2H, m, H-2'), 2.47 (1H, dd, J = 11 and 19.5 Hz, H-4 ax), 2.71 (1H, dd, J = 4 and 19.5 Hz, H-4 eq), 3.89 (3H, s, -OCH3), 3.57 (2H, d, J = 5 Hz, CH2-OCH3), 4.27 (1H, m, H-3), 4.52 (1H, m, H-3'), 4.75 (1H, q, J = 6.5 Hz, H-5'), 5.41 (1H br a, H-1'), 5.56 (1H, br s, H-4'), 6.03 (1H, s, H-1), 6.46 (1H, br d, J = 7.5 Hz, NH), 7.75 (2H, m. Ar-H), 8.07 (2H, m. Ar-H), 8.28 (4H, m, PNB).
Step 5: (1'S, 1R, 3S)-5,10-dioxo-3-meth oxym ethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran (BCH-1691)
To a solution of (1'S, 1R, 3S)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido- 4'-O-p-nitro-benzoyl-L-lyxohexopyranose)-3,4,5, 10-tetrahydro-1H-naphtho-[2,3-C] pyran (19 mg; .029 mmol) in medianol (.4 ml) and tetrahydrofuran (1.5 ml) at 0°C was added .86 μl (.1 eq) of a 4.37 M solution of sodium methoxyde in methanol. The resulting mixture was stirred at 0°C for 20 minutes and was quenched with saturated NH4Cl. Extraction with dichloromethane followed by washing of the combined organic layers with brine and drying with Na2SO4 furnished a crude product which was purified by column chromatography on silica gel using 5-10% acetone in benzene as eluent yielding the title compound (14 mg; 96%) which was recrystallized from dichloromethane:ether:pentane to give yellow crystals: M.P.: 140-159°C; IR (neat): 3500, 3422, 3320, 2938, 1715, 1667, 1597, 1295, 1178 and 980 cm-1:
1H NMR (250 MHz, CD2CI2) δ: 1.21 (3H, d, J = 7.6 Hz, H-6'), 1.52 (1H, br s , O-H), 1.70-2.20 (2H, m, H-2'), 2.35 (1H, dd, J = 11.7 and 19.3 Hz, H-4 ax), 2.68 (1H, dd, J = 3.4 and 19.3 Hz, H-4 eq), 3.56 (3H, s, OCH3), 3.52 (2H, d, J = 4.8 Hz, CH2-OCH3). 3.58 (1H, br a, H-4'), 4.15-4.40 (3H, m, H-3, H-3', H-5'), 5.46 (1H, br s, H-1'), 5.83 (1H, s, H-1), 6.73 (1H, br d, J = 7 Hz, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 6: (1'S, 1S, 3R)-5,10-dioxo-3- methoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoaceamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH-1693)
The starting protected alcohol from step 4 of this example (18 mg; 0.028 mmol) in .4 ml medianol and 1.5 ml of tetrahydrofuran was treated with .83 μl of a 4.37 M solution of sodium methoxide in methanol following the procedure from step 5 herein to afford the title compound (12.5 mg; 90%): m.p.: 92-102° C; IR (neat): 3485, 3424, 3323, 2937, 1715, 1666, 1595, 1296, 1175, 1117, 980 cm-1.
1H NMR (CD2Cl2, 250 MHz) δ: 1.35 (3H, d, J = 6.5 Hz, H-6'), 1.85 (2H, m, H-2'), 2.01 (1H, br d, J = 7 Hz, O-H), 2.46 (1H, dd, J = 11.5 and 20 Hz, H-4 ax), 2.69 (1H, dd, J = 3.7 and 20 Hz, H-4 eq), 3.36 (3H, s, OCH3), 3.54 (2H, d, J = 4.7 Hz, CH2-OCH3), 3.60 (1H, m, H-4'), 4.15-4.40 (2H, m, H-3' and H-3), 4.55 (1H, q, J = 6.5 Hz, H-5'), 5.39 (1H, br s, H-1'), 5.98 (1H, s, H-1), 6.78 (1H, br d, J = 7 Hz, -NH), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Example 27: Preparation of (1'S,1 R,3S) and 1'S,1S,3S)-5,10-dioxo-3-ethyl-1-(2',3',6'- trideoxy-3'trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]-pyran: (BCH-2026) and BCH-2020) and (1'S,1S,3S)- 5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-a mino-L-lyxohexopyranose)- 3,4,5,10-tetrahydro-1H-naphtho -[2,3-c]-pyran hydrochloride: (BCH-2021)
*
Figure imgf000103_0001
Step 1: 1-(2,5-dimethoxyphenyl)-2-butanoI
Under argon atmosphere, 1,4-dimethoxybenzene 10.0 g (72.37 mmol) was dissolved in dry THF and this solution was cooled to 0°C. n-BuLi (2.5 M/hexanes) 28.8 ml (72.37 mmol) was then added and the reaction mixture was warmed up to room temperature and stirring was left for 4 hours. After 4 hours, the reaction was cooled to -78°C and 1,2-epoxybutane 5.2 g (72.37 mmol) was added followed by 10.2 g (72.37 mmol) of boron trifluoro etherate. Stirring was then continued for a period of 1 hour. The reaction mixture was then quenched by pouring it into 125 ml of aqueous NH4CI. Extractions of the aqueous layer were done using CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The crude material was purified by flash chromatography with hexanes- ethyl acetate (9: 1) then (8:2) as the eluent. The isolated titled compound was a white solid (11.4 g, 75%).
NMR 1H (250 MHz) (CDCl3; ppm): 6.75 (3H, m, aromatics), 3.79 (3H, s, OCH3), 3.77 (1H, m, H2,), 3.76 (3H, s, OCH3), 2.85 (1H, dd, J1 = 3.8 Hz, J2 = 13.5 Hz, H1'a), 2.65 (1H, dd, J1 = 8.1 Hz, J2 - 13.5 Hz, H1b), 2.16 (1H, d, J = 3.7 Hz, OH), 1.52 (2H, m, H3,) 0.99 (3H, dd, J1 = J2 = 7.4 Hz, -CH3). Step 2: 5,8-dimethoxy -3-ethyl-isochroman
Under argon atmosphere, the starting material from step 1 of this example, 5.00 g (23.78 mmol) was dissolved in 100 ml of dry ether. Dimethoxy methane 3.0 ml (33.90 mmol) and boron trifluoro etherate 9.0 ml (71.35 mmol) were then added and stirring was left overnight. The reaction was then quenched using aqueous NaHCO3. Extractions were done using ether and the combined organic extracts were dried over Na2SO4, filtered and the solvent was removed. The isolated residue was then purified by flash chromatography; hexanes-ethyl acetate (8:2) was used as the eluent. The desired titled compound was isolated as a white solid (4.9 g; 92%).
NMR 1H (250 MHz) (CDCl3; ppm): 6.63 (2H, d, J = 3.4 Hz, aromatics), 4.93 (1H, d, J = 15.9 Hz, H1a), 4.57 (1H, d, J = 15.9 Hz, H1b), 3.78 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.47 (1H, m, H3), 2.74 (1H, ddd, H4a), 2.38 (1H, dd, H4b), 1.68 (2H, m, -CH2- side chain) 1.03 (3H, dd, J1 = J2 = 7.4 Hz, -CH3).
Step 3: (1'S, 1R, 3R)-5,8-dimethoxy-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'- O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman
Application of the first part of the procedure described in step 3, example 26, on the isochroman precursor from step 2 herein resulted with the titled compound as a yellow solid; 62%.
NMR 1H (250 MHz) (C6D6; ppm): 7.72 (4H, m, aromatics), 6.48 (2H, d, J = 4.7 Hz, aromatics), 6.17 (1H, s, H1), 5.95 (1H, m, NH), 5.67 (1H, d, H4'), 5.29 (1H, d, H1'), 4.67 (1H, m, H3'), 4.26 (1H, q, H5'), 4.20 (1H, m, H3), 3.49 (3H, s, OCH3), 3.40 (3H, s, OCH3), 3.01 (1H, dd, H4a), 2.52 (1H, dd, H4b), 1.90 (1H, m, -CH2 side chain), 1.75 (1H, m, -CH2- side chain), 1.61 (2H, m, -CH2- sugar), 1.06 (3H, d, -CH3 sugar), 1.03 (3H, m, CH3 side chain).
IR (film) (cm-1): 3316 (NH), 2933 (CH aliphatic), 1733 (C=O), 1707 (C=O), 1603 (C-=C), 1532 (C- N), 1259 and 1175 (C-O). Step 4: (1'S, 1R, 3R)-5,8-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido -4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
Application of the second part of the procedure (CAN) described in step 3, example 26, on die glycosylated isochroman precursor from the previous step resulted in an 87% yield of the titled compound.
NMR 1H (250 MHz) (C6D6; ppm): 7.80 (4H, m, aromatics), 6.92 (1H, sbroad, NH), 6.08 (2H, m, quinone ring), 5.72 (1H, s, H1), 5.54 (1H, s, H4.), 5.53 (1H, s, H1'), 4.74 (1H, m, H3'), 4.36 (1H, m, H5.), 3.68 (1H, m, H3), 2.28 (1H, dd, J1 = 3.2 Hz, J2 = 19.3 Hz, H4a), 1.88 (2H, m, -CH2- sugar), 1.80 (1H, dd, H4b), 1.49 (2H, m, -CH2- side chain), 1.15 (3H, d, J = 6.5 Hz, CH3 sugar), 0.89 (3H, dd, J1 = J2 = 7.4 Hz, -CH3 side chain).
Step 5: (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohecopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
The titled compound was obtained via Diels-Alder cycloaddition between 1-acetoxylbutadiene and the quinone from step 4 from this example Using the procedure described in step 4 from example 26.
NMR 1H (250 MHz) (CD2Cl2; ppm): 8.28 (4H, d, J = 4.3 Hz, aromatics), 8.05 (2H, m, aromatics), 7.73 (2H, m, aromatics), 6.31 (1H, d, NH), 5.87 (1H, s, H1), 5.67 (1H, s, H4'), 5.42 (1H, s, H1'), 4.58 (1H, m, H3.), 4.42 (1H, q, J = 6.3 Hz, H5'), 4.05 (1H, m, H3), 2.78 (1H, dd, J1 = 3.4 Hz, J2 = 19.5 Hz, H4a), 2.24 (1H, dd, J1 = 11.3 Hz, J2 = 19.0 Hz, H4b), 2.05 (2H, m, -CH2- sugar), 1.70 (2H, m, -CH2- side chain), 1.18 (3H, d, J = 6.5 Hz, -CH3 sugar), 1.05 (3H, dd, J1 = J2 = 7.4 Hz, - CH3 side chain).
IR (film) (cm-1): 3332 (NH), 2955 and 2929 (CH aliphatic), 1740 (C-O), 1669 (C=C), 1529 (C-N), 1279 and 1180 (C-O).
Step 6: (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyrancιse)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2026) The titled compound was in 64 % yield from the glycoside of step 5 of this example as per procedure described in step 5 of example 26.
NMR 1H (250 MHz) (CD2Cl2; ppm): 8.03 (2H, m, aromatics), 7.71 (2H, m, aromatics), 6.77 (1H, d, NH), 5.81 (1H, s, H1), 5.50 (1H, d, J = 2.8 Hz, H1'), 4.26 (1H, m, H3'), 4.22 (1H, m, H5'), 4.05 (1H, m, H3), 3.58 (1H, d, J = 2.2 Hz, H4'), 2.76 (1H, dd, J1 = 3.5 Hz, J2 = 19.5 Hz, H4a), 2.21 (1H, ddd, J1 = 0.9 Hz, J2 = 11.0 Hz, J3 = 19.5 Hz, H4b), 2.07 (1H, s(broad), OH), 1.83 (2H, m, - CH2-sugar), 1.67 (2H, m, -CH2- side chain), 1.23 (3H, d, J = 6.6 Hz, -CH3 sugar ), 1.02 (3H, dd, J1 = J2 = 7.5 Hz, -CH3 side cham). Step 7: (1'S, 1S, 3S)-5,8-dioxo-3-ethyI-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-5,8-dihydro-isochroman To a solution of (1'S, 1S, 3S)-5,8-dimethoxy-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitro-benzoyl-L-lyxohexopyranose)-isochroman (372 mg; 0.60 mmol) in acetonitrile (12 ml) was added a solution of CAN prepared by dissolving eerie ammonium nitrate (2.0 g; 3.6 mmol) in 6 ml of water and then slowly adding solid sodium bicaibonate (531 mg). The resulting mixture was stirred at 0°C for 20 minutes and was then quenched with saturated bicaibonate solution. The product was extracted with dichloromethane and the combined organic layers were washed with brine and dried over Na2SO4 to give after evaporation the crude title compound:
(360 mg; 100%): 1 NHMR (250 MHz; CDCl3) δ: 1.02 (3H, t, J = 7.5 Hz, CH2-CH3), 1.29 (3H, d, J = 6.5 Hz, H-6'), 1.65 (2H, m, CH2-CH 3), 1.80-2.30 (3H, m, H-2' and H-4 ax), 2.60 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.89 (1H, m, H-3), 4.50-4.80 (2H, m, H-3' and H-5'), 5.41 (1H, br s, H-1') 5.55 (1H, br s, H-4'), 5.87 (1H, s, H-1), 6.58 (1H, br d, J = 7.5 Hz, NH), 6.75 and 6.81 (2H, AB doublets, ArH), 8.28 (4H, br s, PNB).
Step 8: (1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- mtrobenzoyl-L-lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
Using the procedure described in step 4, example 26, the starting quinone from step 7 herein (330 mg;
0.57 mmol) was treated with 1-acetoxy-1,3-butadiene (379 μl; 3.4 mmol) in 20 ml of toluene to afford after chromatography the title compound (165 mg; 46%).
1H NMR (250 MHz, CD2Cl2) δ: 1.03 (3H, d, J = 7.5 Hz, CH2-CH3), 1.30 (3H, d, J = 6.5 Hz, H- 6'), 1.68 (2H, qn, J = 7.5 Hz, CH2-CH3), 1.95 (1H, m, H-2 eq), 2.12 (1H, td, J = 13 and 3-5 Hz, H-
2' ax), 2.29 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.76 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.97 (1H, m, H-3), 4.55 (1H, m, H-3'), 4.78 (1H, q, J = 6.5 Hz, H-5'), 5.41 (1H, br s, H-1'), 5.57 (1H, d,
J = 6.5 Hz, H-4'), 6.01 (1H, s, H-1), 6.51 (1H, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, ArH), 8.07 (2H, m, Ar-H), 8.27 (4H, s, PNB).
Step 9: (1'S, 1S, 3S)-5,10-dioxo-3 ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2020)
The starting protected alcohol from step 8 herein (20 mg; .032 mmol) was treated with sodium methoxide in methanol (4.37 M, 1 μl) in 1 ml of tetrahydrofuran and .3 ml of methanol according to the procedure described in step 5, example 26, affording after chromatography (15 % acetone in benzene) the title compound (11.5 mg, 75%), M.P. 208-211°C.
IR (neat): 3540, 3292, 2978, 1705, 1666, 1556, 1295, 1187, 1165 and 990 cm-1. 1H NMR (250 MHz, CD2CI2): 1.00 (3H, t, J = 7.5 Hz, CH2-CH3), 1.35 (3H, d, J = 6.5 Hz, H-6'), 1.66 (2H, qn, J = 7.5 Hz, CH2-CH3), 1.80-2.20 (3H, m, H-2' and O-H), 2.27 (1H, dd, J = 11.0 and 19.5 Hz, H-4 ax), 2.75 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.61 (1H, br s, H-4'), 3.96 (1H, m, H- 3), 4.25 (1H, m, H-3'), 4.58 (1H, q, J = 6.5 Hz, H-5'), 5.40 (1H, t, J = 2.0 Hz, H-1'), 5.97 (1H, s, H-1), 6.77 (1H, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 10: (1'S, 1S, 3S)-5,10-dioxo-3-emyl-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyram (BCH-2021) To a solution of the starting protected amino-alcohol from step 9 herein (43 mg; 0.07 mmol) in acetonitrile (6 ml) was added dropwise .1 N sodium hydroxide (3 ml). The mixture was stirred at 0°C for 30 minutes and an extra 1 ml of sodium hydroxide solution was added and the resulting mixture was stirred for 1 hour at 0°C. It was then quenched with .1 N HCl and extracted with dichloromethane. The water layer was neutralized to pH -7 by addition of dilute sodium hydroxide. It was then extracted with dichloromethane. To the organic extract were added 1.5 ml of .1 N HCl, 5 ml of methanol and 25 ml of ether and the mixture was evaporated partially in order to induce crystallization. Since no crystallization occured, the solvents were evaporated completely and the residue was dissolved in methanol (1 ml) and 200 μl of .1 N HCl were added followed by 25 ml of ether. A precipitate formed which was filtered and washed with ether yielding the crude title compound (3.8 mg; 13 %).
1H NMR (250 MHz, DMSO-D6), δ: 0.97 (3H, t, J = 7.0 Hz, CH2-CH3), 1.23 (3H, d, J = 6.5 Hz, H-6'), 1.50-1.80 (3H, m, CH2-CH3 and H-2' eq). 1.97 (1H, m, H-2' ax), 2.23 (1H, dd, J = 11.0 and 19.5 Hz, H-4 ax), 2.72 (1H, dd, J = 3.0 and 19.5 Hz, H-4 eq), 3.63 (1H, m, H-4'), 3.87 (1H, m, H-3), 4.33 (1H, m, H-5'), 5.29 (1H, br s, H-1'), 5.53 (1H, m, H-3'), 5.82 (1H, s, H-1), 7.85 (2H, m, Ar-H), 8.05 (5H, m, Ar-H and N-H).
Example 28: Preparation of trans-5,10 dioxo-1-acetamido-3-ethyl-3,4,5,10-tetrahydro-
1H-naphtho-[23-c]-pyran: (BCH-2027) and 3-ethyl-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran: (BCH-2154)
Figure imgf000108_0001
Step 1: (trans)-1-acetamido-5,8-dioxo-3-ethyl-5,8-dihydro-isochroman
To a solution of 5,8-dimethoxy-3-ethyl-isochroman (1.0 g; 4.5 mmol) in dichloromethane (30 ml) at room temperature were added methanol (211 μl; 5.4 mmol), 4A molecular sieves (2 g) and 2,3-dichloro- 5,6-dicyano-benzoquinone (1.21 g; 5.4 mmol). The resulting dark mixture was stirred for 5 hours and was then quenched with saturated NaHCO3 aolution. It was extracted with dichloromethane and the combined organic layere were washed with bicaibonate, brine and then dried over Na2SO4 affording after evaporation 1.0 g of crude adduct of which 300 mg (1.19 mmol assumed) were placed in a pear-shaped flask along with acetamide (70 mg; 1.19 mmol). The solid mixture was then heated to 130 °C for 30 minutes. It was then cooled to room temperature and dichloromethane was added followed by pentane yielding a precipitate (160 mg) of which 120 mg (.43 mmol assumed) was dissolved in acetonitrile (15 ml) and treated with a soluticm of CAN prepared by slowly dissolving sodium bicarbonate (384 mg) in water (5 ml) containing cerium ammonium nitrate (1.46 g; 2.5 mmol). The resulting mixture was stirred at room temperature for 15 minutes and was quenched with saturated NaHCO3 solution followed by extraction with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4 to afford the titled compound as a yellow solid (125 mg; 42% overall).
1H NMR (250 MHz, CDCl3) δ: 0.99 (3H, t, J = 7.5 Hz, CH3-CH2), 1.65 (2H, m, -CH2-CH3), 2.02 (3H, s, -CH3), 2.20 (1H, m, H-4 ax ), 2.60 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.70 (1H, m, H-3), 6.12 (2H, br s, H-1 and N-H), 6.73 and 6.78 (2H, AB system, Ar-H). Step 2: Trans-5,10-dioxo-1-acetamido-3-ethyl-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran To a solution of the starting quinone from step 1 herein (56 mg; .22 mmol) in toluene (50 ml) was added 1-acetoxy-1,3-butadiene (30 μl; 11 eq). The mixture was stirred overnight at room temperature and was than concentrated and applied to a column of silica gel using 1-15% acetone in benzene to elute the product which was then recrystallized from dichloromethane:pentane affording the title compound as a yellow solid (10 mg; 15 %).
1H NMR (250 MHz, DMSO-D6), δ: 0.90 (3H, t, J = 7.5 Hz, CH3-CH2). 1.58 (2H, m, CH2-CH3), 1.82 (3H, s, CH3-C=O), 2.20 (1H, m, H-4 ax), 2.64 (1H, br d, J = 16.0 Hz, H-4 eq), 3.71 (1H, m, H-3), 6.17 (1H, d, J = 8.0 Hz, H-1), 7.88 (2H, m, Ar-H), 8.01 (2H, m, Ar-H), 8.78 (1H, d, J = 8.0 Hz, N-H). Step 3: 5,8-dioxo-3-ethyl-5,8-dihydro-isochroman
To a solution of 3-ethyl-5,8-dimethoxy-isochroman (300 mg; 1.35 mmol) in acetonitrile (10 ml) at room temperature was added dropwise a solution of CAN (prepared by dissolving eerie ammonium nitrate (2.22 g; 4.0 mmol) in water (5 ml)). The resulting mixture was quenched with saturated bicarbonate solution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over Na2SO4 affording the crude title compound (251 mg; 97 %) which was used as such for subsequent steps.
1H NMR (250 MHz, CDCl3) δ: 0.97 (3H, t, J = 7.5 Hz, CH2-CH3), 1.60 (2H, m, -CH2-CH3), 2.10 (1H, m, H-4), 2.52 (1H, m, H-4), 3.35 (1H, m, H-3), 4.30 (1H, m, H-1), 4.62 (1H, br d, J = 16 Hz, H-1), 6.68 (2H, m, Ar-H).
Step 4: 3-ethyI-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
Following the procedure described in step 4, example 26, the starting quinone from step 3 herein (250 mg; 1.30 mmol) and 1-acetoxy-1,3-butadiene (876 μl; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2 % ethyl acetate in toluene the title compound (62 mg; 20 %) along with mixed fractions containing a lot of desired titled product (230 mg), M.P.: 98-101°C.
IR (neat): 2963, 2938, 2876, 1658, 1636, 1593, 1337, 1299, 1176 and 698 cm-1.
1H NMR (250 MHz, CDCl3) δ: 1.04 (3H, t, J = 7.5 Hz, CH3-), 1.70 (2H, m, CH2-CH3), 2.30 (1H, m, H-4 ax), 2.75 (1H, br d, J = 19.0 Hz, H-4 eq), 3.45 (1H, m, H-3), 4.50 (1H, dt, J = 4.0 and 18.5 Hz, H-1), 4.86 (1H, dd, J = 2.5 and 18.5 Hz, H-1), 7.72 (2H, m, Ar-H), 8.18 (2H, m, Ar-H). Example 29: Preparation of (1'S,1R,3S) and (1'S,1S,3R)-5,10-dioxo-3-isopropyl-1- (2'3',6'-trideoxy-3'-trifluoro acetamido-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H- naphtho-[2,3-c]-pyran: (BCH-2053) and (BCH-2052)
Figure imgf000110_0001
Step 1: 3-isopropyl-5,8-dimetboxy-isochroman
To a solution of the starting aldehyde (1.16 g; 6.44 mmol) in tetrahydrofuran (25 ml) at 0°C was added a solution of isopropyl magnesium chloride (2 M in THF; 6.4 ml; 12.88 mmol). The resulting mixture was stirred at 0°C for 1 hour and at room temperature for 30 minutes. It was then quenched with saturated ammonium chloride solution and extracted with ether. The combined organic layers were washed with brine and dried over MgSO4 to yield a crude alcohol (1.29 g) which was dissolved in ether (40 ml). To this solution were added dimethoxymethane (777 μl; 8.55 mmol) and boron trifluoride- etherate (2.02 ml; 17.1 mmol). The resulting mixture was stirred at room temperature for 20 hours and was then quenched with saturated sodium bicarbonate solution. It was then extracted with ether and the combined organic layers were washed with brine and dried over MgSO4. The crude product was then purified by column chromatography on silica gel using 20-30% ethyl acetate in hexane as eluent to give the title compound (607 mg; 40% overall).
1H NMR (CDCl3) δ: 1.00 and 1.05 (6H, 2d, J= 7 Hz, -CH-(CH3)2), 1-84 (1H, sept., J = 7 Hz, CH- (CH3)2), 2.42 (1H, dd, J = 11 and 17 Hz, H-4 ax), 2.74 (1H, dm, J = 17 Hz, H-4 eq), 3.22 (1H, m, H-3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.56 (1H, dm, J = 16 Hz, H-1), 4.95 (1H, d, J = 16 Hz, H-1), 6.63 (2H, AB system, Ar-H).
Step 2: (1'S, 1R, 3S) and (1'S, 1R, 3R)-5,8-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro- isochroman (40:60)
Using the procedure described in step 3, example 26, the starting isochroman from step 1 herein (300 mg; 1.27 mmol) afforded a cnide diastereomeric mixture of glycosidated isochromans (515 mg) which was reacted with CAN as described in step 3, example 26, to afford a diastereomeric title quinones mixture (450 mg; 59 %) in a ratio of (40:60) favoring the 1'S, 1R, 3R isomer which were used as such for the next reactions.
For minor isomer: 1H NMR (250 MHz, CDCl3) δ: 0.90-1.40 (9H, m, H-6' and -CH(-CH3)2), 1.70- 2.35 (4H, m, H-2', H-4 ax and CH-CH3), 2.62 (1H, m, H-4 eq), 3.80 (1H, m, H-3), 4.42 (1H, q, J = 6.5 Hz, H-5'), 4.50-4.70 (1H, m, H-3'), 5.44 (1H, br s, H-1'), 5.63 (1H, br s, H-4'), 5.74 (1H, s, H- 1), 6.32 (1H, m, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
For major isomer: 0.90-1.40 (9H, m, H-6' and CH(-CH3)2), 1.70-2.35 (4H, m, H-2', H-4 ax and CH- CH3), 2.62 (1H, m, H-4 eq), 3.69 (1H, m, H-3), 4.50-4.75 (2H, m, H-3' and H-5'), 5.42 (1H, br s, H- 1'), 5.56 (1H, d, J = 3 Hz, H-4'), 5.88 (1H, s, H-1), 6.43 (1H, br d, J = 7.5 Hz, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
Step 3: (1'S, 1R, 3R)-5,10-dioxo-3-isopropyI-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-
O-p-nitrobenzoyl-L-lyxohexo-pyranose)-3,4,5,10 -tetrahydro-1H-naphtho-[2,3-c]- pyran Using the procedure described in step 4, example 26, the starting quinone mixture from step 2 herein (100 mg; .167 mmol) was treated with 1-acetoxy-1,3-butadiene (112 μl; 1 mmol) in 5 ml of toluene to afford the title compound (34 mg pure + 9 mg of 1:1 mixture of diastereomers).
1H NMR (250 MHz, CD2CI2) δ: 1.01 and 1.04 (6H, 2d, J = 6.5 Hz, -CH-(CH3)2), 1.31 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.02 (2H, m, H-2' and CH(CH3)2), 2.13 (1H, t d, J = 3.5 and 13 Hz, H-2'), 2.34 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.78 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.76 (1H, m, H- 3), 4.55 (1H, m, H-3'), 4.80 (1H, q, J = 6.5 Hz, H-5'), 5.42 (1H, d, J = 2.5 Hz, H-1'), 5.58 (1H, d, J = 3 Hz, H-4'), 6.03 (1H, s, H-1), 6.52 (1H, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.28 (4H, s, PNB).
The second diastereomer: (1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetam ido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran, obtained in 16% yield, had 1H NMR (250 MHz, CD2Cl2) δ: 0.90-1.10 (6H, m, CH-(CH 3)2), 1.17 (3H, d, J = 6.5 Hz, H-6')' 1-70-2.40 (4H, m, H-2', CH-(CH3)2) and H-4), 2.60-2.90 (1H, m, H-4), 3.87 (1H, m, H-3), 4.44 (1H, q, J = 6.5 Hz, H-5'), 4.58 (1H, m, H-3'), 5.42 (1H, br s, H-1'), 5.69 (1H, br s, H-4'), 5.89 (1H, s, H-1), 6.40 (1H, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.06 (2H, m, Ar-H), 8.28 (4H, m, PNB).
Step 4: (1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'trifluoroacetamido-L-
Iyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2053)
Using the procedure described in step 5, example 26, the starting protected alcohol from step 3 herein (11 mg; .017 mmol) was treated with NaOMe/MeOH (4.37 M; 1 μl; .26 eq) to yield after column chromatography (7% acetone in benzene) the title compound (5 mg; 59%), M.P.: 180-185°C.
IR (neat): 3491, 3423, 3325, 2962, 2938, 1721, 1670, 1596, 1293, 1179, 982 cm-1.
1H NMR (250 MHz, CD2CI2): 1.00 and 1.01 (6H, 2d, J = 6.5 Hz, -CH-(CH3)2), 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.60-2.00 (4H, m, -CH-CH3)2, H-2' and OH), 2.27 (1H, br dd, J = 11.0 and 19.5 Hz, H-4 ax), 2.74 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.58 (1H, d, J = 2.5 Hz, H-4'), 3.85 (1H, m, H- 3), 4.25 (2H, m, H-3' and H-5'), 5.52 (1H, d, J = 3.0 Hz, H-1'), 5.82 (1H, s, H-1), 6.75 (1H, m, NH), 7.74 (2H, m, Ar-H), 8.03 (2H, m, Ar-H).
Step 5: (1'S, 1S, 3R)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoacetamido-L- lyxoh exopyranose)-3,4,5,10-tetrahydro-1 H-naphtho-[2,3-c]-pyran (BCH-2052)
Using the procedure described in step 5, example 26, the starting protected alcohol from step 3 herein (32 mg; .0495 mmol) afforded after flash chromatography using 7% acetone in benzene as eluent, a gummy product which was dissolved in dichloromethane and precipitated with pentane yielding the title product
(16 mg; 65%), M.P.: 212-213°C.
IR (neat): 3509, 3421, 3333, 2961, 2944, 1718, 1667, 1592, 1292, 1166 and 979 cm-1.
1H NMR (250 MHz, CD2Cl2): 0.98 and 1.00 (6H, 2d, J - 6.7 Hz, -CH(CH3)2), 1.36 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.00 (4H, m, -CH(CH3)2, H-2' and -OH), 2.32 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.76 (1H, dd, J - 3.5 and 19.5 Hz, H-4 eq), 3.61 (1H, br s, H-4'), 3.74 (1H, ddd, J = 3.5, 6.5 and 11.5 Hz, H-3), 4.24 (1H, m, H-3'), 4.59 (1H, q, J - 6.5 HzH-5'), 5.39 (1H, t, J = 2.0 Hz, H-1'),
5.97 (1H, s, H-1), 6.77 (1H, m, NH), 7.72 (2H, m, Ar-H), 8.05 (2H, m, Ar-H). Example 30: Preparation of (1'S,1R,3S) and (1'S,1S,3R)-5,10-dioxo-3-isopropenyl-1- (2',3',6'-trideoxy-3'-trifl uor oacetamido-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H-naphtbo-[2,3-c]-pyran: (BCH-2153) and (BCH-2152) and trans-5,10-dioxo-3-isopropenyl-1-methoxy-3,4,5.10-tetrahydro-1H- naphtho-[2,3-c]-pyran: (BCH-2148)
Figure imgf000113_0001
Step 1: 5,8-dinethoxy-3-isopropenyl-isochroman
To a solution of methyltriphenylphosphonium bromide (2.26 g; 6.4 mmol) in ether (75 ml) at room temperature (not totally soluble) was added n-BuLi (2.5 M in hexanes; 2.03 ml; 5.1 mmol). The resulting mixture was stirred at room temperature for 1 hour. A solution of 5,8-dimethoxy-3-(1-acethyl)- isochroman (1.0 g; 4.2 mmol) was then added to the yellow-orange mixture and the resulting solution was stirred at room temperature for 3 hours. The mixture was then quenched with NH4Cl (sat.) and extracted with ether. The combined organic layers were washed with brine and dried over Na2SO4. The crude mixture was then purified by column chromatography in silica gel using 25 % ethyl acetate in hexane as eluent to afford the title compound (541 mg; 55 %). 1H NMR (250 MHz, CDCl3) δ: 1.86 (3H, s, =C-CH3), 2.58 (1H, br dd, J = 11 and 17 Hz, H-4 ax), 2.85 (1H, ddd, J = 1.5, 3.5 and 17 Hz, H-4 eq), 3.77 and 3.79 (6H, 2s, -O-CH3), 4.00 (1H, dd, J = 3.5 and U Hz, H-3), 4.66 (1H, br d, J = 16 Hz, H-1), 4.93 (1H, br s, =CH2), 4.99 (1H, d, J = 16Hz, H-1), 5.09 (1H, br s, = CH2), 6.62 and 6.67 (2H, 2d (AB), J = 9 Hz, Ar-H).
Step 2: (trans)-5,10--dioxo-3-isopropenyl-1-methoxy-3,4,5,10-tetrahydro-1H-nsphtho-[2,3- c]-pyran (BCH-2148)
Using the procedure described in step 3, example 26, the starting isochroman (150 mg; .64 mmol) and methanol (25 mg; .76 mmol) were treated with DDQ to afford a crude adduct (160 mg) which was then treated with CAN. This reaction yielded an impure erode quinone (91 mg) which was treated with 1- acetoxy-1,3-butadiene as described in step 4, example 26, affording after chromatographic purification (0-2% ethyl acetate in toluene) the title compound as 18 mg of slightly impure form and 5 mg of pure product (13 % overall).
1H NMR (CDCl3, 250 MHz) δ: 1.87 (3H, s, =C-CH3), 2.49 (1H, dd, J = 11.5 and 19.5Hz, H-4 ax), 2.84 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.61 (3H, s, -OCH3), 4.50 (1H, dd, J = 3.5 and 11.5 Hz, H-3), 5.00 (1H, s, =CH), 5.15 (1H, s, =CH), 5.63 (1H, s, H-1), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H). Step 3: (1'S, 1S, 3R)-5,8-dimethoxy-3-isopropenyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-Iyxobexo-pyranose) isochroman.
Following the procedure described in the first part of step 3, example 26, the starting isochroman from step 1 herein (250 mg; 1.07 mmol) was treated with α-2,3,6-trideoxy-3-trifiuoroacetamido-4-O-p- nitrobenzoyl-L-lyxohexopynnose (461 mg; 1.17 mmol) and DDQ (337 mg; 1.49 mmol) in
dichloromethane (20 ml) containing 4A molecular sieves (500 mg) to yield after chromatography on silica gel using 25% ethyl acetate in hexane with .1 % triethylamine, the title compound as a mixture with its (1'S, 1R, 3S) diastereomer (1:1; 310 mg). Another fraction gave pure titled compound (131 mg; 19%).1H NMR (250 MHz, CD2CI2) δ: 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.83 (3H, s, =C-CH3), 1.75-2.20 (2H, m, H-2'), 2.48 (1H, dd, J = 12 and 17.5 Hz, H-4 ax), 2.89 (1H, dd, J = 3.5 and 17.5 Hz, H-4 eq), 3.77 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.404.65 (2H, m, H-3 and H-3'), 4.73 (1H, q, J - 6.5 Hz, H-5'), 4.92 (1H, s, =CH), 5.09 (1H, s, =CH), 5.42 (1H, br s, H-1'), 5.57 (1H, d, J = 3 Hz, H- 4'), 6.12 (1H, s, H-1), 6.31 (1H, br d, J = 6 Hz, N-H), 6.73 and 6.79 (2H, AB doublets, Ar-H), 8.27 (4H, m, PNB).
The (1'S, 1R, 3S)-5,8-dimethoxy-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose) isochroman had NMR (CD2Cl2, 250 MHz) δ: 1.10 (3H, d, J = 6.5 Hz, H-6'), 1.83 (3H, s, =C-CH3), 1.90-2.20 (2H, m, H-2'), 2.39 (1H, dd, J = 12 and 17.5 Hz, H- 4 ax), 2.89 (1H, dd, J = 3.5 and 17.5 Hz, H-4 eq), 3.76 (3H, s, OCH3), 3.77 (3H, s, OCH3), 4.35 (1H, q, J = 6.5 Hz, H-5'), 4.50-4.70 (2H, m, H-3 and H-3'), 4.90 (1H, br s, =CH), 5.10 (1H, br s, =CH), 5.38 (1H, br s, H-1'), 5.54 (1H, br s, H-4'), 5.94 (1H, s, H-1), 6.31 (1H, m, N-H), 6.71 and 6.77 (2H, AB system, Ar-H), 8.27 (4H, m, PNB).
Step 4: (1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido- 4'-O-p-nitrobenzoyl-L-lyxohex o-pyranose) 3,4,5,10-tetrahydro -1H-naphtho-[2,3-c]- pyran
Using the same procedure as described in step 6 of this example, the starting isochroman from step 3 herein (80 mg; .13 mmol) afforded after CAN oxidation and Diels-Alder the title product (35 mg; 42% overall) contaminated by what looks like aglycone systems.
1H NMR (250 MHz, CDCl3) δ: 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.87 (3H, s, =C-CH3), 2.09 (2H, m, H-2'), 2.45 (1H, m, H-4 ax), 2.90 (1H, m, H-4 eq), 4.34 (1H, q, J = 6.5 Hz, H-5'), 4.50-4.75 (2H, m, H-3 and H-3'), 5.00 (1H, s, =C-H), 5.17 (1H, s, =C-H), 5.44 (1H, br s, H-1'), 5.72 (1H, s, H-4'), 5.99 (1H, s, H-1), 6.40 (1H, br d, J = 7.5 Hz, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H), 8.28 (4H, m, PNB).
Step 5: (1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido- L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2153) Using the procedure described in step 3, example 32, the starting protected alcohol from step 6 herein (slightly impure, 30 mg; .047 mmol) afforded the title compound (11 mg; 48%), M.P.: 170°C (dec). IR (neat): 3417, 2936, 1716, 1664, 1596, 1293, 1167 and 983 cm-1.
1H NMR (250 MHz, CDCl3) 6: 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.10 (3H, m, H-2' and O-H), 1.85 (3H, s, =C-CH3), 2.41 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.89 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.59 (1H, m, H-4'), 4.16 (1H, q, J = 6.5 Hz, H-5'), 4.35 (1H, m, H-3'), 4.52 (1H, dd, J = 3.5 and 11.5 Hz, H-3), 4.96 (1H, s, -CH), 5.13 (1H, s, =CH), 5.54 (1H, d, J = 3.5 Hz, H-1'), 5.93 (1H, s, H-1), 6.71 (1H, br d, J = 8.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, ArH).
Step 6: (1'S, 1S, 3R)-5,10-draxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluroacetamido- 4'-O-p-nitrobenzoyl-L-lyxohexo-pyran ose) 3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran
To a solution of the starting isochroman from step 3 herein (120 mg; 0.19 mmol) in acetonitrile (4 ml) at 0°C was added a solution of CAN (prepared by dissolving eerie ammonium nitrate (630 mg; 1.15 mmol) in water (2 ml) and then adding slowly sodium bicarbonate (169 mg)). After the addition, the mixture was stirred for 10 minutes and was then quenched with saturated sodium bicarbonate solution. The product was extracted with dichloromethane and the combined organic extracts were washed with brine and dried over Na2SO4 to yield a crude quinone (112 mg) which was dissolved in toluene (5 ml) and reacted with 1-acetoxy-1,3-butadiene (113 μl; 1 mmol) at room temperature for 15 hours. After this time, silica gel was added and air was bubbled through for 30 minutes. The residue was applied to a silica gel column and eluted with 0-5 % ethyl acetate in toluene affording slightly impure title compound (54 mg) along with pure product (17 mg; total yield 57 %).
1H NMR (250 MHz, CD Cl3) δ: 1.36 (3H, d, J = 6.5 Hz, H-6'), 1.86 (3H, s, =C-CH3), 1.99 (1H, br dd, J = 5 and 12.5 Hz, H-2' eq), 2.13 (1H, td, J = 3.5 and 12.5 Hz, H-2' ax), 2.52 (1H, dd, J = 11.5 and 19 Hz, H-4 ax), 2.91 1H, dd, J = 3.5 and 19 Hz, H-4 eq), 4.48 (1H, br d, J = 11.5 Hz, H-3), 4.62 (1H, m, H-3'), 4.84 (1H, q, J = 6.5 Hz, H-5'), 5.00 (1H, br s, -CH), 5.14 (1H, br s, -C-H), 5.47 (1H, br s, H-1'), 5.62 (1H, d, J = 2.5 Hz, H-4'), 6.13 (1H, s, H-1), 6.47 (1H, br d, J = 7.5 Hz, -NH), 7.78 (2H, m, Ar-H), 8.12 (2H, m, Ar-H), 8.29 (4H, m, PNB).
Step 7: (1'S, 1S, 3R)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoracetamido- L-lyxohexopyranose)-3,4,5,10-tetrahydro- 1H-naphtho-[2,3-c]-pyran (BCH-21-52)
Using the procedure described in step 3, example 32, the starting protected alcohol from step 6 herein (16 mg; .0248 mmol) afforded the title compound (11 mg; 90%), M.P.: 102-105°C.
IR (neat): 3418, 2934, 1718, 1669, 1295, 1167, 982 and 965 cm-1.
1H NMR (250 MHz, CDCl3) δ: 1.42 (3H, d, J = 6.5 Hz, H-6'), 1.84 (3H, s, =C-CH3), 1.86 (2H, m, H-2'), 1.99 (1H, d, J = 8.0 Hz, -OH), 2.51 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.89 (1H, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.65 (1H, m, H-4'), 4.35 (1H, m, H-3'), 4.46 (1H, dd, J = 3.5 and 11.5 Hz, H-3), 4.63 (1H, q, J = 6.5 Hz, H-5'), 4.98 (1H, s, -CH), 5.12 (1H, s -CH), 5.43 (1H, br s, H-1'), 6.07 (1H, s, H-1), 6.72 (1H, m, -NH), 7.75 (2H, m, Ar-H), 8.12 (2H, m, Ar-H).
Example 31: Preparation of (1'S,1 R,3S)-5,10-dioxo-3-metboxycarbonyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtbo-[2,3-c]-pyran: (BCH-2128)
Figure imgf000117_0001
Step 1: (1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dimetboxy-3-m ethoxycarbonyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyI-L-lyxohexopyranose)- isochroman.
Using the procedure described in step 2, example 32, the starting isochroman (500 mg; 1.98 mmol) afforded after flash chromatography (5-20% acetone in benzene containing a trace of triethylamine) the mixture of title compounds (490 mg; 40% (-1:1)).
1H NMR (250 MHz, CD2Cl2) δ: (for 1'S, 1R, 3S): 1.15 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.25 (2H, m, H-2'), 2.65 (1H, m, H-4 ax), 3.10 (1H, m, H-4 eq), 3.76-3.78 (9H, superimposed singlets, OCH3), 4.38 (1H, q, J = 6.5 Hz, H-5'), 4.45-4.85 (2H, m, H-3 and H-3'), 5.41 (1H, m, H-1'), 5.57 (1H, m, H-4'), 5.97 (1H, s, H-1), 6.45 (1H, br d, J = 7.5 Hz, -NH), 6.65-6.85 (2H, m, Ar-H), 8.26 (4H, m, PNB); δ (for 1'S, 1S, 3R): 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.20 (2H, m, H-2'), 2.66 (1H, m, H- 4 ax), 3.10 (1H, m, H-4 eq), 3.76-3.78 (9H, superimposed singlets, OCH3), 4.45-4.85 (3H, m, H-3, H- 3' and H-5'), 5.42 (1H, m, H-1'), 5.57 (1H, m, H-4'), 6.16 (1H, s, H-1), 6.45 (1H, br d, J = 7.5 Hz, - N-H), 6.65-6.85 (2H, m, Ar-H), 8.26 (4H, m, PNB).
Step 2: (1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dioxo-3-methαxycarbonyl-1-(2',3',6'-trideoxy- 3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro- isochroman.
To a solution of the starting isochroman from step 1 herein (475 mg; 0.74 mmol) in acetonitrile (15 ml) at 0°C was added a solution of CAN (prepared by dissolving eerie ammonium nitrate (2.42 g) in water (7 ml) and then buffering with aodium bicaibonate (652 mg) added slowly). After the addition, the mixture was stirred at 0°C for 15 minutes and was then quenched with saturated sodium bicaibonate solution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over Na2SO4 giving a erode mixture of the title quinones (422 mg; 93 %) used as such for the next reaction.1H NMR (250 MHz, CD2Cl2) δ: 1.15 (3H, d, J = 6.5 Hz, H-6', A*), 1-27 (3H, d, J = 6.5 Hz, H-6', B), 1.70 -2.25 (2H, m, H-2', A and 2H, m, H-2', B), 2.55 (1H, m, H-4 ax, A and 1H, m, H-4 ax, B), 2.85 (1H. m, H-4 eq, A and 1H, m, H-4 eq, B), 3.76 (3H, s, OCH3, B), 3.77 (3H, s, OCH3, A), 4.34 (1H, q, J = 6.5 Hz, H-5', A), 4.40-4.70 (2H, m, H-3' and H-3, A end 3H, m, H-3', H-3 and H-5', B), 5.39 (1H, m, H-1*. A and 1H, m, H-1', B), 5.54 (1H, d, J =3H, H-4', B), 5.57 (1H, d, J = 3Hz, H-4', A), 5.80 (1H, s, H-1, A). 5.95 (1H, s, H-1, B). 6.60 (1H, m, NH, A and 1H, m, NH, B), 6.80 (2H, m, Ar-H, A and 2H, m, Ar-H, B), 8.26 (4H, m, PNB, A and 4H, m, PNB, B).
* A is (1'S, 1R, 3S) diastereomer and B is (1'S, 1S, 3R) diastereomer.
Step 3: (1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-mtrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c)-pyran.
Using the procedure described in step 4, example 26, the starting quinone from step 2 herein (400 mg; .658 mmol of a 1:1 mix of 1'S, 1R, 3S and 1'S, 1S, 3R) afforded pure title product (13 mg) along with a -1:1 mixture of (1'S, 1R, 3S) and (1'S, 1S, 3R) isomers (275 mg).
1H NMR (250 MHz, CD2Cl2) δ: 1.18 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.20 (2H, m, H-2'), 2.68 (1H, dd, J = 11.5 and 19 Hz, H-4 ax), 3.08 (1H, dd, J = 4 and 19 Hz, H-4 eq), 3.80 (3H, s, OCH3), 4.38 (1H, q, J = 6.5 Hz, H-5'), 4.57 (1H, m, H-3'), 4.75 (1H, dd, J = 4 and 11.5 Hz, H-3), 5.42 (1H, br s, H-1'), 5.69 (1H, br s, H-4'), 5.99 (1H, s, H-1), 6.42 (1H, br d, J = 7 Hz, -NH), 7.75 (2H, m, Ar-H), 8.08 (2H, m, Ar-H), 8.28 (4H, m, PNB).
Step 4: (1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6',trideoxy-3'- trifluoroacetamido-L-lyxobexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyrano (BCH-2128) Using the procedure described in step 5, example 26, the starting protected alcohol from step 3 herein (12 mg; 0.018 mmol) afforded after column chromatography (10% acetone in dichloromethane), the title compound (5 mg; 54%) as a yellow solid. M.P. 92-105°C.
1H NMR (250 MHz, CD2Cl2) δ: 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.55 (1H, br s, OH), 1.70-2.00 (2H, m, H-2'), 2.66 (1H, dd, J = 12.0 and 19.0 Hz, H-4 ax), 3.06 (1H, dd, J = 4.0 and 19.0 Hz, H-4 eq), 3.59 (1H, br s, H-4'), 3.79 (3H, s, -CO2CH3), 4.17 (1H, q, J = 6.5 Hz, H-5'), 4.28 (1H, m, H-3'), 4.73 (1H, dd, J = 4.0 and 11.5 Hz, H-3), 5.52 (1H, br s, H-1'), 5.92 (1H, s, H-1), 6.75 (1H, m, -NH), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Example 32: Preparation of (1'S,1R,3S)-isopropyl-[5,10-dioxo-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-pyranyl]-ketone: (BCH-2112)
Figure imgf000120_0001
Step 1: isopropyl-(5,8-dimethoxy-isochroman-3-yI)-ketone
To a solution of the starting ester (1.0 g; 3.97 mmol) in tetrahydrofuran (30 ml) at 0°C was added isopropyl magnesium chloride (2M, 4.17 mmol). The mixture was stirred at 0°C for 20 minutes and at room temperature for 1 hour. It was then quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over
MgSO4 to afford after evaporation, the title compound (240 mg; 23 % (40% based on S.M. recovered)). 1H NMR (250 MHz, CDCl3) δ: 1.13 (3H, d, J = 6.5 Hz, CH3-CH), 1.16 (3H, d, J = 6.5 Hz, CH3- CH), 2.59 (1H, br dd, J = 11.5 and 17 Hz, H-4 ax), 3.04 (1H, dm, J = 17 Hz, H-4 eq), 3.17 (1H, m, CH-CH3), 3.76 (3H, s, OCH3), 3.78 (6H, s, OCH3), 4.17 (1H, dd, J = 3.5 and 11.5 Hz, H-3), 4.64 (1H, br d, J = 16 Hz, H-1), 5.03 (1H, d, J = 16 Hz, H-1), 6.65 (2H, AB system, Ar-H).
5,8-dimethoxy-3-isopropoxycarbonyl-isochroman was obtained as a by-product resulting from oxidation of the Grignard reagent.
1H NMR (250 MHz, CDCl3) δ: 1.29 (3H, d, J = 6Hz, CH3-CH), 1.30 (3H, d, J = 6 Hz, CH3-CH),
2.74 (1H, br dd, J = 11 and 17 Hz, H-4 ax), 3.05 (1H, dm, J = 17 Hz, H-4 eq), 3.75 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.19 (1H, dd, J = 4 and 11 Hz, H-3), 4.65 (1H, br d, J = 16 Hz, H-1), 5.04 (1H, d, J = 16 Hz, H-1), 5.15 (1H, sept., J = 6 Hz, CH-CH3), 6.64 (2H, AB system, Ar-H).
Step 2: (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- mtrobenzoyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphyho-
[2,3-c]-pyranyI]-ketone
To a solution of α-2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose (408 mg; 1.04 mmol) and starting ketone from step 1 herein (230 mg; 0.87 mmol) in dichloromethane (15 ml), were added 4Å molecular sieves (400 mg) and 2,3-dichloro-5,6-dicyano-benzoquinone (270 mg; 1.2 mmol). The mixture was stirred at rocmi temperature for 14 hours and was then quenched with saturated bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 to afford a crude adduct (590 mg) which was dissolved in acetonitrile (20 ml) at 0°C and treated dropwise with a solution of eerie ammonium nitrate (3.15 g; 5.7 mmol) in water (10 ml) containing sodium bicaibonate (847 mg). After the addition, the mixture was stirred at 0°C for 15 minutes and was quenched with saturated NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 to afford a cnide quinone mixture (557 mg) of which 100 mg (.16 mmol) were dissolved in toluene (6 ml) and treated with 1- acetoxy-1,3-butadiene (113 μl; 1 mmol) at room temperature for 14 hours. Silica gel was added to the mixture and air was bubbled through for 1 hour while toluene partly evaporated. The residue was applied to a column of silica gel and eluted with 0-10% ethyl acetate in toluene affording the title compound (20 mg) slightly contaminated by its (1S, 3R) diastereomer (-3:1).
1H NMR (250 MHz, CDCl3) δ: 1.00-1.30 (9H, m, H-6' and CH-(CH3)2), 1.60-2.40 (2H, m, H-2'), 2.52 (1H, m, H-4 ax), 3.00-3.35 (2H, m, H-4 eq and CH-(CH3)2), 4.32 (1H, q, J = 6.5 Hz, H-5'), 4.50-4.90 (2H, m, H-3 and H-3'), 5.44 (1H, br s, H-1'), 5.75 (1H, br s, H-4'), 6.06 (1H, s, H-1), 6.49 (1H, br d, J = 7.5 Hz, -NH), 7.78 (2H, m, Ar-H), 8.07 (2H, m, Ar-H), 8.27 (4H, m, PNB), apparent signals for (1S, 3R) diastereomer are: 6.22 (1H, s, H-1) and 6.58 (1H, br d, J = 7.5 Hz, NH).
Step 3: (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyranyl]- ketone (BCH-2112)
To a soluticm of starting protected alcohol from step 2 herein (20 mg; 0.0296 mmol) in methanol (.3 ml): tetrahydrofuran (1 ml) at 0°C was added sodium methoxide in methanol (4.37 M; .7 μl; .1 eq). The mixture was stirred at 0°C for 20 minutes and was then quenched with saturated NH4Cl solution and was extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2SO4 to afford a crude residue which was purified by column chromatography on silica gel using 10% acetone in benzene yielding the titled compound (6.4 mg; 63%). 1H NMR (CD2Cl2. 250 MHz), δ: 1.11 (6H, d, J = 6.5 Hz, -CH-(C H3)2), 1.20 (3H- d, J = 6-5 Hz, H-6'), 1.65 (1H, s, OH), 1.75-2.05 (2H, m, H-2'), 2.48 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 3.01 (1H, dd, J = 4.0 and 19.5 Hz, H-4 eq), 3.15 (1H, sept., J = 6.5 Hz, CH-(CH3)2), 3.58 (1H, d, J = 2.5 Hz, H-4'), 4.10 (1H, q, J = 7.0 Hz, H-5'), 4.28 (1H, m, H-3'), 4.68 (1H, dd, J = 4.0 and 11.5 Hz, H-3), 5.55 (1H, d, J = 3.5 Hz, H-1'), 5.97 (1H, s, H-1), 6.72 (1H, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Example 33: Preparation of (1'S,1S,3R) and (1'S,1R,3S)-5,10-dioxo-3- isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1 H-naphtho-[2,3-c]-pyran:
(BCH-2122) and (BCH-2121)
Figure imgf000122_0001
Step 1: (1'S, 1R, 3S), and (1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2' ,3',6'- trideoxy-3',trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran
Using the procedure described in step 2, example 32, the starting isochroman from step 1, example 32, (300 mg; 1.07 mmol) afforded a crude glycosylated adduct (417 mg) which was treated with CAN to give a crude quinone mixture (355 mg) of which 250 mg were reacted with acetoxybutadiene. This reacaion yielded a slightly impure mixture of the title compounds (113 mg; 15 % overall) (-55:45) favoring the (1'S, 1R, 3S) isomer.
1H NMR (250 MHz, CDCl3) δ: (for 1'S, 1R, 3S): 1.15-1.42 (9H, m, H-6' and CH-(CH3)2), 1.90- 2.20 (2H, m, H-2'), 2.68 (1H, dd, J = 12 and 19 Hz, H-4 ax), 3.i2 (1H, m, H-4 eq), 4.40 (1H, q, J = 6.5 Hz, H-5'), 4.50-4.80 (2H, m, H-3 and H-3'), 5.18 (1H, m, CH-(CH3)2), 5.44 (1H, br s, H-1'), 5.74 (1H, br s, H-4'), 6.03 (1H, s, H-1), 6.55 (1H, br d, J = 7.5 Hz, N-H), 7.77 (2H, m, Ar-H), 8.11 (2H, m, ArH), 8.27 (4H, m, PNB); (for 1'S, 1S, 3R): 1,15-1.42 (9H, m, H-6' and CH(C H3)2), 1.90- 2.20 (2H, m, H-2'), 2.69 (1H, dd, J = 12 and 19 Hz, H-4 ax), 3.12 (1H, m, H-4 eq), 4.50-4.80 (3H, m, H-3, H-3' and H-5'), 5.18 (1H, m, CH(CH3)2), 5.45 (1H, br s, H-1'), 5.65 (1H, d, J = 3 Hz, H- 3'), 6.18 (1H, s, H-1), 6.61 (1H, br d, J = 7.5 Hz, -NH), 7.77 (2H, m, Ar-H), 8.11 (2H, m, Ar-H), 8.27 (4H, m, PNB).
Step 2: (1'S, 1R, 3S)-5,10 dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran (BCH-2122)
Using the procedure described in step 3, example 32, the starting protected alcohol from step 1 herein (113 mg; .16 mmol) afforded (after multiple chromatographic separations using 10% acetone in benzene or in dichloromethane) the pure title compound (7 mg; 8%). M.P.: 93-101°C.
1H NMR (CDCl3) δ: 1.29 and 1.33 (6H, 2d, J = 6.5 Hz, -CH-(CH3)2), 1.33 (3H, d, J = 6.5 Hz, H- 6'), 1.70-2.10 (3H, m, H-2' and O-H), 2.68 (1H, dd, J = 11.5 and 19.5 Hz, H-4 ax), 3.11 (1H, dd, J = 4.0 and 19.5 Hz, H-4 eq), 3.65 (1H, m, H-4'), 4.21 (1H, q, J = 6.5 Hz, H-5'), 4.38 (1H, m, H-3'), 4.66 (1H, dd, J = 4.0 and 11.5 Hz, H-3), 5.18 (1H, sept., J = 6.5 Hz, CH-(CH3)2), 5.56 (1H, br s, H- 1'), 5.98 (1H, s, H-1), 6.72 (1H, m, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H).
(1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxobexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2121) was isolated after multiple chromatographic separations (5 mg; 6%). M.P.: 155°C (dec).
1H NMR (CDCl3) δ: 1.32 (6H, d, J = 6.5 Hz, CH-(CH3)2), 1.41 (3H, d, J = 6.5 Hz, H-6'), 1.87 (2H, m, H-2'), 2.05 (1H, m, OH), 2.70 (1H, dd, J = 12.0 and 19.5 Hz, H-4 ax), 3.10 (1H, dd, J - 4.0 and 19.5 Hz, H-4 eq), 3.63 (1H, m, H-4'), 4.32 (1H, m, H-3'), 4.55 (1H, q, J = 6.5 Hz, H-5'), 4.62 (1H, dd, J = 4.0 and 12.0 Hz, H-3), 5.16 (1H, sept., J = 6.5 Hz, CH(CH3)2), 5.47 (1H, br s, H-1'), 6.14 (1H, s, H-1), 6.75 (1H, m, N-H), 7.75 (2H, m, Ar-H), 8.12 (2H, m, Ar-H). Example 34: Preparation of (1'S,1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-4'-O-p-nitroben zoyl-L-lyxohexopyranose)- isochroman (BCH-1697)
Figure imgf000124_0001
Step l: 5,8-dimethoxy-3,3 bis (dihydroxymethyl)-isochroman
Under argon atmosphere, 110 mg (2.90 mmol) of LAH were added to 15 ml of dry THF, previously cooled to 0°C. To this solution was added 0.450 g (1.45 mmol) of 5, 8-dimethoxy-3,3-bis
(dicarbomethoxy)-isochroman dissolved in 15 ml of THF. The temperature was allowed to warm up to room temperature, and stirring was continued for 3 hours. After that time, another 160 mg (4.22 mmol) of LAH was then added and the reaction mixture was stirred for another hour. After that time, the reaction mixture was poured into 50 ml of a 0.1 N aqueous solution of HCl. Extractions of the aqueous layer are done using CH2Cl2. The combined organic layers are dried over Na2SO4, filtered, and the solvent is removed. The isolated titled compound is used without further purification (0.333 g; 90%). NMR 1H (250 MHz) (CDCl3:ppm): 6.64 (2H, 2d, aromatics); 4.80 (2H, s, H1a- H1b); 3.76 (6H, s, 2xOCH3); 3.71 (4H, m, 2-CH2-); 2.53 (2H, s, 2xOH); 1.85 (2H, m, Hfe-I^b).
Step 2: 5,8-dimethoxy-3,3 bis (dimethoxymethyl)-isochro man
Under argon atmosphere, 0.333 g (1.31 mmol) of the starting material from step 1 herein were placed in 70 ml of dry THF. To this solution were then added 0.105 g (2.62 mmol) of NaH. After a few minutes of stirring, 0.41 ml (6.55 mmol) of Mel were added to the reaction mixture and stirring was left for 1.5 hour. After that time, another 0.145 g of NaH and 0.7 ml of Mel were added to the reaction which was completed after another hour of stirring. Aqueous HCl (0.1 N) was then added and extractions were done using CH2Cl2. The combined oiganic extracts were washed with an aqueous solution of sodium bicaibonate, dried over Na2SO4, filtered, and the solvent was removed. The obtained titled compound was used for next step without further purification. Isolated product (0.470 g; >99%).
NMR 1H (250 MHz) (CDCl3:ppm): 7.26 (2H, 2d, aromatics); 4.74 (2H, s, H1a-H1b); 3.76 (6H, 2s, 2xOCH3); 3.54 (2H, d, J = 9.7 Hz, -CH2- side chain); 3.41 (2H, d, J = 9.7 Hz, -CH2- side chain); 3.38 (6H, s, 2xOCH3); 2.64 (2H, s, H4a-H4b).
IR (film) (cm-1) 2925 (CH aliphatic), 1580 (C=C), 1475 (CH2), 1450 and 1360 (CH3), 1100 and 1248 (C-O).
Step 3: (1'S, 1S)-5,8-dimetboxy-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenroyl-L-lyxohexopyranose)-isochroman Under argon atmosphere, the following reagents: product from step 2 herein, 0.477 g (1.70. mmol),
2,3,6-trideoxy-3-trifluoroacetamido-4-O-p-nitrobenzoyl-a-L-lyxohexopyranose 0.378 g (2.00 mmol) and
DDQ 0.452 g (2.00 mmol) were dissolved in 50 ml of dichloromethane. The reacticm mixture was stirred at room temperature for a period of 16 hours. After that time, an excess of DDQ was then added to the reaction mixture and stirring was left for another hour. The reaction mixture was then quenched with aquous NH4Cl and extractions of the aqueous layer was done using CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and the solvent was removed. The crude material was purified by flash chromatography; eluent:hexanes-ethyl acetate (70:30) then (60:40). The obtained titled compound was a pale yellow solid (0.434 g; 39%).
NMR 1H (250 MHz) (C6D6; ppm): 7.89 (2H, m, aromatics), 7.68 (2H, m, aromatics), 6.53 (2H, m, aromatics), 6.52 (1H, NH), 6.08 (1H, s, Hx), 5.62 (1H, s, Hr). 4.70 (1H, m, H5'), 4.60 (1H, m, H3 '), 3.82 (2H, m, CH2-OMe), 3.74 (1H, m, H4'), 3.55 (2H, m, CH2-OMe), 3.48 and 3.42 (6H, 2s, 2xOCH3), 3.40 (2H, m, H2,a and H2,b), 3.18 and 3.11 (6H, 2s, 2xOCH3), 2.13 (1H, m, H4a), 1.86 (1H, m, H4b), 1.21 (3H, d, J = 6.2 Hz, CH3 sugar). Step 4: (1'S, 1S)-5,8-dkno-33-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-
4'-O-p-nitrobenzoyI-L-lyxohexopyranose)-isochroman
The starting material from step 3 herein, 0.430 g (0.65 mmol), was dissolved in acetonitrile at 0°C. A solution of NaHCO3 0.107 g (1.30 mmol) in 7 ml of water was then added and the soluticm was stirred for 10 minutes. After that time, 1.053 g (1.95 mmol) of CAN diluted in 12 ml of water were then added to the reaction mixture in a dropwise manner. The reaction was complete after 10 minutes. A very diluted solution of NaHCO3 in water was then added to the reaction mixture. Extractions of the reaction mixture were done using CH2Cl2- The combined organic layere are dried over Na2SO4, filtered and the solvent was removed. The titied compound was used for next step without further purification, (0.387 g; 95%).
NMR 1H (250 MHz) (C6D6-, ppm): 7.94 (2 7.5 Hz, aromatics), 7.75 (2H, d, J = 7.5 Hz, aromatics), 7.42 (1H, m, NH), 6.20 (2H, m, quinone ring), 5.98 (1H, s, H 1 ), 5.92 (1H, s, H1'), 5.41 (1H, s, H4'), 4.90 (1H, q, H5'), 4.67 (1H, m, H3'), 3.47 (2H, CH2-OMe), 3.29 (2H, CH2-OMe), 3.16 (3H, s, OCH3), 3.11 (3H, s, OCH3), 2.50 (2H, 2d, H2,a, H2,b). 2.22 (1H, m, H4a), 1.97 (1H, m, H4b), 1.27 (3H, d, J = 6.3 Hz, -CH3 sugar).
Step 5: (1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'
trifluoroacetsmido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtbo-[2,3-c] pyran
Under argon atmosphere, 0.173 g (0.27 mmol) of the product from step 4 herein was dissolved in 10 ml of dry toluene. To this solution was added 0.2 ml (1.65 mmol) of 1-acetoxy-1,3-butadiene. The reaction mixture was left stirring overnight at room temperature. Silica gel was then added to the reaction mixture and air was bubbled in it for a period of 2 hours. Whitout removing the solvent, the reaction mixture was put on top ofa silica gel column and toluene was used as the first eluent. Toluene-ethyl acetate (1:1) was then used to elute the desired compound. The titled compound was isolated (0.06 g, 32%) as a yellow solid.
NMR 1H (250 MHz) (CD2Cl2; ppm): 8.29 (4H, m, aromatics), 8.07 (2H, m, aromatics), 7.76 (2H, m, aromatics), 6.45 (1H, d, NH), 6.05 (1H, s, H1), 5.70 (1H, s, H1), 5.43 (1H, s, H3'), 4.82 (1H, m, H5'), 4.52 (1H, m, H4'), 3.27-3.52 (4H, m, 2x-CH2- side chains), 3.35 (3H, s, OCH3), 3.27 (3H, s, OCH3), 2.72 (2H, 2d overlapped, H4a and H4b), 1.87-2.18 (2H, m, -CH2- sugar), 1.28 (3H, d, J = 6.5 Hz, -CH3 sugar). Step 6: (1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexo-pyranose)-isochroman (BCH-
1697) Undor argom atmosphere, the product from step 5 herein, 0.06 g (0.09 mmol) was dissolved in a mixture of 5 ml of dry methanol and 2 ml of dry THF. This solution was cooled to 0°C. 2 μl ofa 4.37 M solution of sodium methoxide in methanol were then added to the reaction mixture. The reaction was completed in 10 minutes, it was then quenched by adding aqueous NH4Cl. Extractions of the aqueous layer was done using dichloromethane. The combined oiganic layers were dried over Na2SO4, filtered and the solvent was removed. The crude material was then purified by flash chromatography, eluentiethyl acetate-dichloromethane (35:75). The isolated titled compound was a yellow solid (0.03 g, 67%).
NMR1H (250 MHz) (CDCl3; ppm): 8.05 (2H, m, aromatics), 7.74 (2H, m, aromatics), 6.81 (1H, d, NH), 6.00 (1H, s, H1), 5.49 (1H, d, J = 2.8 Hz, H1), 4.58 (1H, q, H5'), 4.23 (1H, m, H4'), 3.60 (1H, d, J = 2.3 Hz, H3'), 3.45 (2H, m, -CH2-(OMe)), 3.37 (2H, m, -CH2-(OMe)), 3.34 (3H, s, OCH3), 3.25 (3H, s, OCH3), 2.71 (2H, d, J = 3.5 Hz, H 4a and H4b), 2.09 (1H, (broad)s, OH), 1.79 (2H, m, -CH2- sugar), 1.32 (3H, d, J = 6.6 Hz, -CH3 sugar).
IR (film) (cm-1): 3450 (OH bonded), 2950 (CH aliphatic), 1675 (C=C), 1000 and 1290 (C-O).
Example 35: Preparation of (1'S,1R,4R)-5,10-diαxo-4-ethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c] pyran (BCH-2091)
Figure imgf000128_0001
Step 1: methyl-2-(2',5'-dimethoxypbenyI) butanoate
Under argon atmosphere, 3.08 ml (26.16 mmol) of disopropylamine was added to 85 ml of THF precooled to 0°C. n-BuLi 10.5 ml (26.16 mmol) was then added to this solution and this mixture was then stirred for 30 minutes. After that time, the reaction mixture was cooled to -78°C and the ester 5.00 g (23.78 mmol), 208-186-01 in 65 ml of THF was then added dropwise. After the addition, the mixture was stirred for 5 minutes before HMPA 4.55 ml (26.16 mmol) was added. After another 10 minutes of stirring following the last addition, ethyliodide 5.0 ml (47.56 mmol) was then added to the reaction mixture. The reaction mixture was then stirred for 30 minute before removal of the dry ice-acetone bath to allow the temperature to reach room temperature and the reaction was monitored by TLC. The reaction mixture was left stirring at room temperature for 15 hours. The reaction mixture was then quenched by adding aqueous NH4Cl and extracting with ether. The combined oiganic layers were washed with brine, dried over Na2SO4, filtered and the solvent was removed. The crude was purified by flash chromatography using hexanes-ethyl acetate as eluent; 3.36 g of pure titled compound as a white solid were obtained.
NMR 1H (250 MHz) (CDCl3; ppm): 6.84 (1H, m, aromatic), 6.76 (2H, m, aromatics), 3.90 (1H, t, J = 7.6 Hz, H3), 3.77 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.64 (3H, s, (CO2)-CH3), 2.03 (1H, m, H3a), 1.72 (1H, m, H3b), 0.88 (3H, t, J = 7.3 Hz, -CH3 terminal).
Step 2: 2-(2',5'-dimethoxyphenyl)-1-butanol
Under argon atmosphere, the product from step 1 herein, 3.36 g (14.08 mmol) was dissolved in 100 ml of dichloromethane. This solution was cooled to 0°C and DIBAL-H, 31.0 ml (30.98 mmol) was added in a dropwise manner. The reaction was complete after 20 minutes so HCl 1N was then added to the reaction mixture and extractions were done using dichloromethane. The combined oiganic layers were dried over Na2SO4, filtered, and the solvent was removed. The isolated titied compound was used for next step without furhter purification.
NMR 1H (250 MHz) (CDCl3; ppm): 6.76 (3H, m, aromatics), 3.77 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.75 (2H, m, H1a and H1b), 3.19 (1H, m, H2), 1.74 (2H, m, H3a and H3b), 1.51 (1H, t, J = 6.2 Hz, OH), 0.85 (3H, t, J = 7.4 Hz, -CH3 terminal).
Step 3: 5,8-dimethoxy-4-ethyl-isochroman Under argon atmosphere, the product firom step 2 herein, 2.74 g (13.03 mmol) was dissolved in 55 ml of dry ether. Dimethoxy methane 1.65 ml (19.55 mmol) and boron trifluoro etherate 4.9 ml (39.09 mmol) were then added to this solution. The obtained reacticm mixture was left stirring overnight. The reaction mixture was quenched using aqueous NaHCO3 and extractions were done using ether. The combined oiganic extracts were dried over Na2SO4, filtered, and the solvent was removed. The residue was purified by flash chromatography using hexanes-ethyl acetate (80:20) and (70:30) as eluent. The isolated titled product was a white solid (1.56 g; 54%).
NMR 1H (250 MHz) (CDCl3; ppm): 6.64 (2H, m, aromatics), 4.85 (1H, d, J = 16.1 Hz, H1a), 4.55 (1H, d, J = 16.0 Hz, H1b), 4.09 (1H, d, J = 11.3 Hz, H3a), 3.79 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.58 (1H, dd, J1 = 2.7 Hz, J2 = 11.4 Hz, H3b), 2.62 (1H, m, H4), 1.67 (2H, m, -CH2- ethyl), 1.01 (3H, t, J = 7.5 Hz, -CH3).
Step 4: (1'S, 1R, 4R)-5,8-dimethoxy-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-
O-p-mtrobenzoyI-L-lyxohexo-pyranose)-isochroman The titled compound was obtained by applying the procedure from step 3, example 34, to the isochroman from step 3 herein.
NMR 1H (250 MHz) (C6D6; ppm): 7.81 (2H, d, J = 8.8 Hz, aromatics), 7.65 (2H, d, J = 8.9 Hz, aromatics), 6.48 (2H, dd, J1= 9.0 Hz, J2 - 18.1 Hz, aromatics), 6.35 (1H, s, H1), 6.26 (1H, d, J = 6.9 Hz, NH), 5.81 (1H, s, H1'), 5.52 (1H, s, H3'), 4.75 (1H, q, H5'), 4.58 (1H, m, H4'), 4.24 (1H, dd, J1 = 2.9 Hz, J2 = 11.4 Hz, H3a), 3.88 (1H, d, J = 11..4 Hz, H3b), 3.38 (3H, s, OCH3), 3.37 (3H, s, OCH3), 2.84 (1H, m, H4), 1.89 (2H, m, -CH2- sugar), 1.85-1.55 (2H, m, -CH2- side chain), 1.18 (3H, d, J = 6.6 Hz, -CH3 sugar), 1.05 (3H, t, J = 7.3 Hz, -CH3 side chain).
(1'S, 1S, 4S)-5,8-dimethoxy-4-eth yl- (2',3',6'-trideoxy-3'-trifluoroacetamido-4'O-p-nitrobenzoyl-L- lyxohexo-pynnose)-isochroman was also obtained.
NMR 1H (250 MHz) (C6D6; ppm): 7.81 (2H, d, J = 8.7 Hz, aromatics), 7.61 (2H, d, J = 8.7 Hz, aromatics), 6.54 (2H, m, aromatics), 6.55 (1H, NH), 6.09 (1H, s, H1), 5.69 (1H, s, H1) , 5.45 (1H, s, H3'), 4.72 (1H, m, H4'), 4.32 (1H, m, H5'), 4.26 (1H, dd, J1 = 2.9 Hz, J2 = 11.4 Hz, H3a), 3.89 (1H, d, J = 11.2 Hz, H3b), 3.45 (3H, s, OCH3), 3.39 (3H, s, OCH3), 2.80 (1H, m, H4), 1.88 (2H, m, -CH2- sugar), 1.82 (2H, m, -CH2- side chain), 1.12 (3H, d, J = 6.4 Hz, CH3 sugar), 1.04 (3H, t, J = 7.4 Hz, -CH3 side chain).
Step 5: (1'S, 1R, 4R)-5,8-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluo roacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
The (1'S,1R,4R) glycoside from step 4 herein was oxidatively demethylated as per procedure described in step 4, example 34. The titled compound had:
NMR 1H (250 MHz) (C6D6; ppm): 7.80 (2H, d, J = 8.9 Hz, aromatics), 7.62 (2H, d, J = 8.8 Hz, aromatics), 6.89 (1H, d, J = 6.9 Hz, NH), 6.04 (2H, dd, J1 = 10.1 Hz, J2 = 18.3 Hz, quinone ring),
5.87 (1H, s, H1), 5.63 (1H, 8, H1) , 5.16 (1H, s, H3'), 4.80 (1H, q, J = 6.5 Hz, H5'), 4.56 (1H, m
H4'), 3.75 (1H, dd, J1 = 3.0 Hz, J2 = 11.6 Hz, H3a), 3.54 (1H, d, J = 11.5 Hz, H3b), 2.25 (1H, m,
H4), 1.89 (2H, m, -CH2- sugar), 1.47 (2H, m, -CH2- side chain), 1.27 (3H, d, J = 6.5 Hz, -CH3 sugar), 0.86 (3H, t, J = 7.3 Hz, -CH3 side chain).
Step 6: (1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyI-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3,-c]-pyran
The titied compound was obtained in 19% yield following cycloaddition between the quinone from step 5 herein and 1-acetoxybutadiene, as per procedure as described in step 5, example 34.
NMR 1H (250 MHz) (C6D6; ppm): 8.02 (2H, m, aromatics), 7.77 (2H, d, J = 8.9 Hz, aromatics), 7.63 (2H, d, J = 8.9 Hz, aromatics), 6.02 (2H, m, aromatics), 6.53 (1H, d, NH), 6.11 (1H, s, H1), 5.67 (1H, d, H1'), 4.97 (1H, s, H3'), 4.95 (1H, m, H4'), 4.49 (1H, m, H5'), 3.83 (1H, dd, H3a), 3.60 (1H, d, J = 11.4 Hz, H3b), 2.50 (1H, m, H4), 1.95 and 1.72 (2H, 2dd, -CH2- side chain), 1.58 (2H, m, -CH2- sugar), 1.31 (3H, d, J = 6.4 Hz, -CH3 sugar), 0.92 (3H, t, J = 7.3 Hz, -CH3 side chain).
Step 7: (1'S, 1R, 4R)-5,10- dioxo-4-ethyl-1-(2',3',6'-trideoxy3'-trifluoracetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2091)
The titled compound was obtained via deprotection of the tricyclic glycoside from step 6 herein as per procedure from step 6, example 34.
NMR 1H (250 MHz) (CDCl3; ppm): 8.10 (2H, m, aromatics), 7.75 (2H, m, aromatics), 6.72 (1H, d, NH), 5.91 (1H, s, H1), 5.41 (1H, s, H1'), 4.59 (1H, q, J = 6.6 Hz, H5'), 4.46 (1H, m, H4'), 4.32 (1H, m, H3'), 4.03 (1H, dd, J1 = 3.0 Hz, J2 = 11.6 Hz, H3a), 3.85 (1H, d, J = 11.6 Hz, H3b), 3.64 (1H, m, OH), 2.66 (1H, m, H4), 1.99 (1H, d, J = 8.3 Hz, -CH2- side chain), 1.86 (2H, m, H2'a and -
CH2- side chain), 1.65 (1H, m, H2'b), 1.41 (3H, d, J = 6.5 Hz, -CH3 sugar), 1.06 (3H, t, J = 7.3 Hz,
-CH3 side chain).
IR (film) (cm-1): 3422 (OH), 2932 (CH aliphatic), 1710 (C-O), 1668 (C-C), 1299 and 1165 (C-O).
Example 36: Preparation of (1'S,1R,3S)-5,lu-diιιxo-3-ph enyloxymethyl-1-(2',3',6'- trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c] pyran
Figure imgf000132_0001
Step 1: α-phenoxymethyI-2,5-dimethoxy-phenetyl alcohol
To a solution of 1,4-dimethoxybenzene (2.0 g; 14.5 mmol) in tetrahydrofuran at 0°C was added n-butyl- lithium (2.5 M in hexane; 5.8 ml; 14.5 mmol). The mixture was warmed to room temperature and stirred for 4 hours. It was then cooled to -78°C and 1,2 epoxy-3-phenoxy-propane (1.95 g; 13 mmol) was added followed by boron trifluoride etherate (1.85 g; 13 mmol). The resulting mixture was stirred at -78°C for 2 hours. It was quendied with saturated NaHCO3 soluticm and extracted with dichloromethane. The combined organic layers were washed with bicarbonate, brine and were dried over MgSO4. The crude residue was purified by column chromatography on silica gel using 25 % ethyl acetate in hexane to yield the title product (2.4 g; 64%).
1H NMR (250 MHz, CDCl3) δ: 2.75 (1H, d, J = 4 Hz, -OH), 2.85-3.10 (2H, m, Ar-CH2-). 3.71 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.95 (2H, m, CH2-O), 4.29 (1H, m, -CH-O), 6.70-7.00 (6H, m, Ar- H), 7.28 (2H, m, Ar-H).
Step 2: 5,8-dimethoxy-3-phenoxymethyI-isochroman To a solution of α-phenoxymethyl-2,5-dimethoxyphenetyl alcohol (2.1 g; 7.24 mmol) in ether (40 ml) at room temperature was added dimethoxymethane (966 μl; 10.8 mmol) and then boron trifluoride etherate (2.68 ml; 21.6 mmol). The rest of the procedure is identical to the second part, step 1, example 29, to yield the title product (715 mg; 33%).
1H NMR (250 MHz, CDCl3) 5: 2.65 (1H, dd, J = 11 and 17 Hz, H-4 ax), 2.89 (1H, dd, J = 2 and 17 Hz, H-4 eq), 3.79 (3H, s, -OCH3), 3.82 (3H, s, -OCH3), 4.00-4.30 (3H, m, -CH 2-OPh and H-3), 4.73 (1H, d, J = 16 Hz, H-1), 5.07 (1H, d, J = 16 Hz, H-1), 6.68 (2H, AB doublets, Ar-H), 7.01 (3H, m, Ar-H), 7.33 (2H, m, Ar-H).
Step 3: (1'S, 1R, 3S)-5,8-dim eth oxy-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido -4'-O-p- nitrobenzoyl -L-lyxohexopyranose)-isochroman
The isochroman from step 3 herein was glycosydated in 57% yield as per procedure described in step 3, example 34.
NMR 1H (250 MHz) (CDCl3; ppm): 8.31 (4H, m, aromatics), 7.31 (2H, m, aromatics), 6.97 (3H, m, aromatics), 6.76 (2H, m, aromatics). 6.22 (1H, d, NH), 6.02 (1H, s, H1), 5.63 (1H, s, H1'), 5.42 (1H, s, H3'), 4.67 (1H, m, H4'), 4.66 (1H, m, H5'), 4.57 (1H, m, H3), 4.18 (2H, m, -CH2- side chain), 3.82 (3H, s, OCH3), 3.81 (3H, s, OCH3), 2.90 (1H, dd, H 4a), 2.56 (1H, dd, H4b), 2.00-2.18 (2H, m, -CH2- sugar), 1.16 (3H, d, J = 6.5 Hz, -CH3 sugar). Step 4: (1'S, 1R, 3S)-5,8-dioxo-3-phenyloxymethyl-1-(2',3',6'trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman
The (1'S,1R,3S) glycoside from step 3 herein was oxidatively demethylated as per procedure described in step 4, example 34.
NMR 1H (250 MHz) (C6D6; ppm): 7.73 (4H, dd, aromatics), 7.17 (2H, m, aromatics), 6.90 (3H, d, aromatics), 6.71 (1H, d, NH), 6.08 (2H, d, quinone ring), 5.80 (1H, s, H1), 5.76 (1H, s, H1'), 5.50 (1H, s, H3'), 4.70 (1H, m, H4'), 4.62 (1H, m, H5'), 4.22 (1H, m, H3), 3.85 (1H, m, CH2 side chain), 3.66 (1H, dd, CH2 side chain), 2.27 (1H, dd, H4a), 1.94 (1H, dd, H4b), 1.85 (2H, m, -CH2 side chain), 1.34 (2H, m, -CH2- sugar), 1.18 (3H, d, -CH3 sugar). Step 5: (1'S, 1R, 3S)-5,10-dioxo-3-phenytoxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzol-L-lyxohexopyranose)-3,4,5, 10-tetrahydro-
1H-naphtho-[2,3-c] pyran
Cycloaddition between 1-acetoxybutadiene and the quinone from step 4 herein as per procedure described in step 5, example 34, afforded the titled compound, yield 148%.
NMR 1H (250 MHz) (CDCl3; ppm): 8.30 (3H, m, aromatics), 8.11 (2H, m, aromatics), 7.77 (2H, m, aromatics), 7.30 (4H, m, aromatics), 6.96 (2H, m, aromatics), 6.40 (1H, d, J = 7.5 Hz, NH), 6.01 (1H, s, H1), 5.75 (1H, s, H1'), 5.43 (1H, s, H3'), 4.63 (1H, m, H4'), 4.61 (1H, m, H3), 4.60 (1H, m, H5'), 4.20 (2H, m, -CH2- side chain), 2.89 (1H, dd, J1 = 3.4 Hz, J2 = 19.3 Hz, H4a), 2.57 (1H, dd, J1 = 11.5 Hz, J2 = 19.4 Hz, H4b), 2.07 (2H, dd, -CH2- sugar), 1.19 (3H, d, J = 6.5 Hz, -CH3 sugar).
Step 6: (1'S, 1R, 3S)-5,10-dioxo-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2032)
The glycoside from step 5 herein was deprotected as per procedure described in step 6, example 34, to afford the titled compound in 81 % yield. NMR 1H (250 MHz) CDCl3; ppm): 8.11 (2H, m, aromatics), 7.78 (2H, m, aromatics), 7.33 (2H, m, aromatics), 6.98 (1H, m, aromatic), 6.91 (2H, d, J = 8.3 Hz, aromatics), 6.69 (1H, d, NH), 5.95 (1H, s, H1), 5.55 (1H, d, H1'). 4.61 (1H, m, H4'), 4.41 (1H, m, H5 '), 4.38 (1H, m, H3), 4.16 (2H, m, - CH2- side chain), 3.64 (1H, m, OH), 2.89 (1H, dd, H4a), 2.57 (1H, dd, H4b), 1.93 (2H, m, -CH2- sugar), 1.24 (3H, d, J = 6.5 Hz, -CH3 sugar). IR (film) (cm-1): 3425 (OH, NH), 2929 (Ch aliphatic), 1716 (C-O), 1668 (C-C), 1596 (C-N), 1297 and 1160 (C-O).
Example 37: Preparation of naphtho-[2,3-c] pyran derivatives with an allyl side chain
Figure imgf000135_0001
Step 1: 5,8-dimethoxy-3-(2-propenyl)-isochroman o a stirred solution of pyranosulfone (670 mg, 2.0 mmol) in CH2Cl2 (20 ml) at -78°C were added allyltrimethylsilane (636 μl, 4.0 mmol) and AICl3 (533 mg, 4.0 mmol). Temperature was then raised to -35°C few minutes, then HCl (0.1 N, 10 ml) was added. The reaction mixture was worked up with CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the allyl isochroman (450 mg, 96%). 1H NMR (250 MHz, CDCl3) δ: 6.63 (2d, J = 8.9 Hz, 2H, Ar-H), 5.96 (m, 1H, -CH=C), 5.17 (d, J = 17 Hz, 1H, -CH=CH2), 5.10 (d, J = 9.9 Hz, 1H, -CH=CH2), 4.93 (d, J = 16.0 Hz, 1H, H-1), 4.58 (d, J = 16.0 Hz, 1H, H-1), 3.78 and 3.75 (2s, 6H, 2xOCH3), 3.65 (m, 1H, H-3), 2.75 (broad d, J = 17.0 Hz, 1H, H-4), 2.45 (m, 3H, H-4, -CH2-CH=C).
Step 2: (1'S,1S,3S) and (1'S,1-R,3-R)-1-(2',3',6',-trideoxy-3'-trifluoroacetamido-4'-O- paranitrobenzoyl-L-lyxohexopyranose)-5,8-dimethoxy-3-(2-propenyl)-isochroman
To a mixture of 5,8-dimethoxy-3-(2-propenyl)-isochroman (400 mg, 1.72 mmol), 2',3',6'-trideoxy-3- trifluoroacetamido-4-O-paranitrobenzoyl-1-α,β-hydroxy-lyxohexopyranose 2 (1.2 eq., 810 mg, 2.06 mmol) and MS4Å (500 mg) in CH2Cl2 (17 ml) at room temperature was added DDQ (1.5 aq., 586 mg, 2.58 mmol). The reaction mixture was stirred for 3 hours and 30 minutes, then filtered and the filtrate was washed by extraction with NaHCO3 sat. solution. Evaporation of the solvent and purifying by FC (CH2Cl2:Hex:EtOAc 8:12:1) gave 427 mg of the titled product (50%) and 531 mg of its diastereoisomer (50%). The (1'S,1S,3S) diastereomer was prepared using the same procedure.
1H NMR (250 MHz, acetone-d6) δ (ppm): 8.65 (bd,1H,NH), 8.4 (d,8.9Hz,2H,PNB-H), 8.34
(d,8.9Hz,2H, PNB-H), 6.86 (d,8.8Hz,1H,Ar-H), 6.8 (d,8.8Hz,1H,Ar-H), 6.0 (m,1H,C=CH-C), 5.88 (s,1H,H-1), 5.56 (bs, 1H.H-1'), 5.47 (bs,1H,H-4'), 5.14 (bm,2H,C=CH2), 4.6 (m,2H,H-3',H-5'), 4.3 (m,1H,H-3), 3.8 (s,3H,ACOCH3), 3.78 (s,3H,Ar-OCH3), 2.75 (m.1H.H-4), 2.47 (m,2H,C=C-CH2), 2.4 (m,1H,H-4), 2.3 (m,1H,H-2'), 1.9 (m,1H,H-2'), 1.16 (d,6.4Hz,3H,H-6').
Step 3: (±)-Methyl ketone hydroxy-1-isochroman quinone
To a stirred solution of the methyl ketone hydroxy-1 isochromane (3.000g, 11.891mmol) in 180ml of acetonitrile at 0°C was added dropwise an aqueous aolution of CAN (26.076g, 47.56 mmol) and
NaHCO3 (7.19g, 85.6 mmol) in water. The reaction mixture was then droped in a mixture of 200 ml of CH2Cl2 and 200 ml of water and extracted with CH2Cl2 and back extracted with Ethyl Acetate.
Combined organic layers were washed with water (3x300 ml)and then dried (Na2SO4). Recristallisation of the residu gave 2.237 g (85 % yield) of the pure methyl ketone hydroxy-1 isochromane quinone. PMR (CDCl3, 300MHz)δ: 2.30 (s, 3H, COCH3), 2.39 (ddd, 1H, J = 20.0 Hz, 12.0 Hz and 1.2 Hz, CHaCHCO), 2.88 (dd, 1H, J = 19.5 Hz and 3.9 Hz, CHeCHCO), 3.42 (broad m, 1H, OH-1), 4.64 (dd, 1H, J = 11.7 Hz and 4 Hz, H-3), 6.03 (broad s, 1H, H-1), 6.78 (2xd, 2H, quinone-H).
Step 4: (1'S,1S,3S) and (1'-S.1-R,3-R)-3([2',3',6'-trideoxy-3'-trifluoroacetamidoo-4'- paramitrobenzoyI-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-
[2,3-c]-pyran-3-yl)-propene
To a solution of (1,-S,1-R,3-R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-aranitrobenzoyl-L- lyxohexopyranose)- 5,8-dioxo-3-propenyl-1,4,5,8-tetrahydrobenzo-[2,3-c]-pyran (205 mg, .34 mmol) in toluene (10 ml) at room temperature was added 1-acetoxy-1,3-butadiene (0.250 ml, 1.72 mmol). The mixture was stirred overnight followed by adding silica gel (4.2 g) and bubbling air. After 2 hours, the solution was filtered and solvent removed form the filtrate. Purifying of the crude by FC (Tol.: EtOAc 15: 1) and recrystalization gave 133 mg of the titled inoduct. The (1'S, 1S,3S) diastereomer was prepared the same way.
1H NMR (250 MHz, CD2Cl2) δ (ppm): 8.3 (m,4H,PNB-H), 8.1 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.35 (bd,1H,NH), 5.95 (1H,C=CH-C), 5.9 (s,1H,H-1), 5.7 (s,1H,H-1'), 5.43 (bs,1H,H-4') , 5.25 (m,2H,C-CH2), 4.6 (m,1H,H-3'), 4.43 (q,6.4Hz,1H,H-5'), 4.21 (m,1H,H-3), 2.8
(dd,19.4Hz,3.2Hz,1H,H-4), 2.47 (m,2H,C=C-CH2), 2.33 (dd,19.4Hz, 11HZ,1H,H-4), 2.07 (m,2H,H- 2'), 1.2 (d,6.4Hz,3H,H-6').
Step 5: (1'S,1S,3S) and (l'S,1-R,3-R)-3-([2',3',6' -trideoxy-3'-trifluoroacetamido -4'- hydroxy-L-lybohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]- pyran-3-yl)-propene (BCH-2031)
To a solution of (1'-S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-paranitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl] propene (133 mg, 0.2 mmol) in MeOH (2 ml) at 0°C was added NaOMe (4.37M in MeOH, 60μl, .26 mmol) and stirred for 15 minutes. The reaction was quenched by adding NH4Cl sat. and extracted with CH2Cl2. The organic phase was then dried over MgSO4, evaporated to give 64 mg crude. Purifying by preparative TLC (Tol.: EtOAc 6:1) gave 25 mg (25%) of the desired product. The (1'S,1S,3S) diastereomer BCH-2163 was prepared the same way.
1H-NMR (250MHz,CD2Cl2) δ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,1H,NH), 5.95 (m, 1H,C=CH), 5.84 (s,1H,H-1), 5.51 (bd,1H,H-1'), 5.2 (m,2H,C=CH2), 4.25 (m,4H,H-3,3',4',5'), 3.6 (bs, 1H,OH), 2.78 (dd,19.4Hz,3.3Hz,1H,H-4), 2.44 (m,2H,C=C-CH2), 2.3
(dd, 19.4Hz, 11HZ,1H,H-4), 1.85 (m.2H,H-2'), 1.25 (d,6.6Hz,3H,H-6').
Example 38: Preparation of naphtho-[2,3-c] pyran derivatives with a methyl ketone side chain from a bicyclic quinone aglycal
Figure imgf000138_0001
Step 1 and 2: (1'-S,1-R,3-S)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido- 4'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl)-ketone (BCH-1620)
1) To a stirred suspension of molecular sieves 4A (1.3g), 2-(dimethyl-t-butyl-silyloxy)-3- acetamido-4-iodo-2,3,6-trideoxy-α, β-L-lyxohexopyranose (478 mg, 1.02 mmol) and 3-acetyl- 5,8-dioxo-1-hydroxy-l,4,5,8-tetrahydrobenzo-[2,3-c]-pyran (178 mg, 0.8 mmol) in a solution of CH2Cl2/acetone (15.4 ml, 10: 1) at -50°C was added trimethylsilyl trifiuoromethanesulfonate
(TMS-OTf, .222 ml, 1.15 mmol). The reaction mixture was then stirred at -30°C for 50 minutes, followed by addition of aq. NaHCO3 5 % and warmed up to room temperature. After filtering off solids, the filtrate was extracted with CH2Cl2. The oiganic phase was then washed with brine and dried over MgSO4. Evaporation of the solvent gave 563 mg of the crude.
2) From the crude product obtained as described above, 116 mg was utilized in the next step by stirring with 1-acetoxy-1,3-butadiene (98 μl, .82 mmol) in toluene (10 ml) for overnight at room temperature and under argon. Silica gel was next added and air was bubbled into the reaction mixture and stirring for 2 hours. The crude product was recovered by filtering and washing of the silica gel with ethyl acetate. Evaporation of the solvent gave 139 mg of the crude product.
Purifying by preparative TLC (hex:OAc 4:1) gave 7.4 mg of the title product and 2.2 mg of its diastereoisomer for a total of 9% yield. The (1'S,1S,3R) diastereomer BCH-1621 was prepared using the same method.
1H NMR (250 MHz, acetone) δ (ppm): 8.43 (bd,1H,N-H), 8.0 (m,2H,ArH), 7.9 (m,2H,Ar-H), 6.0 (s,1H, H-1), 5.6 (bd, 5.4Hz, 1H,H-1'), 4.89 (bs,1H,H-3'), 4.75 (dd,11.6Hz,4.0Hz,1H,H-3), 3.75 (m,1H,H-4'), 3.7 (q,6.1Hz,1H,H-5'), 3.0 (dd,19.6Hz,4Hz,1H,H-4), 2.55 (dd, 19.6Hz, 11.6Hz, 1H,H- 4), 2.3 (s,3H,COCH3), 2.26 (m,1H,H-2'), 1.8 (m,1H,H-2'), 1.25 (d,6.1Hz,3H,H-6'). Step 3: (1'-S,1-R ,3-S)-3-([2',3',6'-trideoory-3'-triflu oroaceta mido-4'-hydroxy-L- lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)- propene (BCH-1649)
To a solution of (1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-paranitrobenzoyI-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) propene (133 mg, 0.2 mmol) in MeOH (2 ml) at 0°C was added NaOMe (4.37M in MeOH, 60 μl, .26 mmol) and stirred for 15 minutes. The reaction was quenched by adding NH4Cl sat. and extracted with CH2Cl2. The organic phase was then dried over MgSO4, evaporated to give 64 mg crude. Purifying by preparative TLC (tol: EtOAc 6:1) gave 25 mg (25%) of the desired product. The (1'S,1S,3R), BCH-1648, diastereomer was obtained using the same method.
1H NMR (250MHz,CD2Cl2) δ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,1H,NH), 5.95 (m, 1H.C-CH), 5.84 (s,1H,H-1), 5.51 (bd,1H,H-1'), 5.2 (m,2H,C=CH2), 4.25 (m,4H,H-3,3',4',5'), 3.6 (bs, 1H.OH), 2.78 (dd,19.4Hz,3.3Hz,1H,H-4), 2.44 (m,2H,C=C-CH2), 2.3
(dd,19.4Hz, 1 1Hz,1H,H-4), 1.85 (m,2H,H-2'), 1.25 (d,6.6Hz,3H,H-6').
Example 39: Preparation of 4a,10a-epoxy-naphtho-[2,3-c] pyran derivatives
Figure imgf000139_0001
Step 1: (1'-S,1-R,3-S,4a-S,10a-S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O- methanesulfonyI-L-lyxohexopyranose)-4a,10a-epoxy-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone (BCH-2141) To a solution of (1'-S,1-R,3-S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methansulfonyl-L- lyxohexopyranose)-5,10-dioxo-3,4-dihydronaphtho-[2,3-c] pyran-3-yl) ketone (15 mg, 30 μmol) in THF (1 ml) at 0°C was added H2O3 (30% aq. solution , 5.2 μl, 46 μmol). After 10 minutes, NaOH (.1N, .364 ml) was added and the reaction mixture was stirred at 0ºC for 30 minutes. Workup was carried out by adding brine to the mixture, extracting with CH2Cl2 and drying the organic phase over MgSO4. The crude obtained after evaporation of the solvent was purifying by recrystalization to give 8 mg (50%) of the pure titled product. The (1'S,1S,3R,4aR,10aR), BCH-2149, diastereomer was obtained using the same method
1H NMR (250MHz, CDCl3) δ (ppm): 8.05 and 7.8 (m,4H,ArH), 6.15 (s,1H,H-1), 5.55 (bd,1H,H-1'), 4.86 (bs,1H,H-4'), 4.3 (dd,9Hz,3Hz,1H,H-3), 4.05 (q,6.6Hz,1H,H-5'), 3.65 (m,1H,H-3'), 3.45 (s,3H,SO2CH3), 3.15 (s,3H,OMe), 2.75 (dd,12.3Hz,3Hz,1H,H-4), 2.35 (m,1H,H-4), 2.3
(s,3H,COCH3), 1.9-2.2 (m,2H,H-2'), 1.25 (d,6.6Hz,3H,H-6').
Example 40: Monoaminosugar substituted naphthoquinone derivative
3
3
Figure imgf000141_0001
Step 1: (2R,4R,5S,6S) and (2R,4S,5S,6S)-2-tert-butyldimethylsilyloxy-4-thioacetoxy-5- acetoxy-6-methyl-tetrahydropyran
A solution of rhamnal diacetate (0.514 g, 2.4 mmols) in H2O (24 ml) is heated at 80°C for 30 minutes. The solution is then cooled down to 0°C and CH3COSH (0.51 ml, 3 eq.) is then added. The cloudy solution is stirred at room temperature for 2 hours after which NaHCO3 (1.2 g, 6 eq.) is added to neutralize the excess CH3COSH. The water is evaporated and the residue is dissolved in CH2Cl2 and dried over MgSO4. The solids are filtered and die solvent evaporated. A solution of the oil obtained after evaporation in CH2Cl2 (24 ml) is treated with imidazole (0.33 g, 2 eq.) and t-BuMe2SiCl (0.43 g, 1.2 eq.). The solution is stirred at room temperature, under argon, for 18 hours. It is poured in sat. aq. NaHCO3 and the phases are separated. The aqueous layer is extracted with CH2Cl2 (2x) and the combined oiganic extracts are dried over MgSO4. The solids are filtered and the solvents evaporated. The oil obtained is purified by flash chromatography (silica gel, 9:1 bexanes/EtOAc) to give a 1:1 mixture of titled isomers: 0.50 g (60 %) as a clear oil.
1H NMR (CDCl3): δ 4.90+4.85 (2dd, 1H, H-1), 4.73+4.62 (2dd, 1H, H-4), 4.30+3.75 (q+m, 1H,
H-5), 3.71+3.55 (2ddd, 1H, H-3), 2.36+2.30 (2s, 3H, SAc), 2.19 (m, 1H, H-2), 2.03+1.99 (2s, 3H, OAc), 1.77 (m, 1H, H-2), 1.22+1.18 (2d, 3H, H-6), 0.88 (s, 9H, t-Bu), 0.09+0.10 (2s, 6H, SiMe2).
Step 2: (2R,5R,6S)-2-tert-butyldimethylsilyloxy-5-acetoxy-4-methyl-tetrahydropyran
A solution of the thio-sugar from step 1 herein (51 mg, 0.14 mmol) in ethanol (2 ml) was treated with an excess of Raney-Ni. The suspension was vigorously stirred for 30 minutes and was then filtered through Celite. The ethanol was evaporated to give 36 mg (89%) of the titled compound as a clear oil.
1H NMR (CDCl3): δ 4.74 (dd, 1H, J = 2.0, 8.6, H-1), 4.42 (ddd, 1H, J = 4.7, 10.5, 10.5, H-4), 3.98 (dq, 1H, J = 6.16, 9.23, H-5) 2.10 (m, 1H, H-2 or H-3), 2.02 (s, 3H, OAc), 1.86-1.35 (m, 3H, H-2 and H-3), 1.17 (d, 3H, J = 6.16, H-6), 0.88 (s, 9H, t-Bu), 0.10 (s, 3H, SiMe), 0.08 (s, 3H, SiMe). Step 3: (2R,5R,6S)-2-tert-butyldimethylsilyloxy-5-hydroxy-6-methyl-tetrahydropyran
To a solution of the acetate from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), at room temperature, was added 1 N NaOH (0.14 ml, 1.1 eq.) and the solution was stirred for 45 minutes. It was then poured in H2O and the aqueous phase was extracted 3x with CH2Cl2. The combined organic extracts were dried over MgSO4, the solids were filtered and the solvent evaporated to give 30 mg (96 %) of the pure titled alcohol.
1H NMR (CDCl3): δ 4.72 (dd, 1H, J = 1.9, 8.7, H-1), 3.28-3.24 (m, 2H, H-4 and H-5), 2.04-1.41 (m, 4H, H-2 and H-3), 1.27 (d, 3H, J = 5.5, H-6), 0.88 (s, 9H, t-Bu), 0.10 (s, 3H, SiMe), 0.09 (s, 3H, SiMe).
Step 4: (2R,5S,6S)-2-tert-butyldimethylsilyloxy-5-azido-6-methyl-tetrahydropyran
To a solution of the alcohol from step 3 herein (62 mg, 0.25 mmol) in dry THF (2.5 ml), at room temperature, under argon, were added successively Ph 3P (66 mg, 1 eq.), DEAD (40 μl, 1 eq.) and (PhO)2PON3 (54 μl, 1 eq.) and the solution was stirred for 18 hours. The THF was evaporated and the crude oil was purified by flash chromatography (silica gel, 95:5 hexanes/EtOAc) to give 38 mg (56 %) of the titled azide as a clear oil.
1H NMR (CDCl3): δ 4.71 (dd, 1H, J = 3.0, 7.9, H-1), 3.64 (dq, 1H, J = 1.7, 6.3, H-5), 3.33 (m, 1H, H-4), 2.15-1.60 (m, 4H, H-2 and H-3), 1.26 (d, 3H, J = 6.3, H-6), 0.89 (s, 9H, tBu), 0.11 (s, 3H, SiMe), 0.09 (s, 3H, SiMe).
Step 5: (2R,5S,6S)-2-tert-butyldimethylsilyloxy-5-trifluoroacetamido-6-methyI- tetrahydropyran To a solution of the azide from step 4 herein (0.20 g, 0.72 mmol) in dry EtOAc (7.2 ml) at room temperature, was added Pd/C 10% (0.10 g, 50% wt) and the black suspension was placed under a H2 atmosphere for 3 hours. The catalyst was then filtered dirough Celite and the solvent was evaporated to diyness. The erode amine (0.18 g, 0.72 mmol) was dissolved in dry CH2Cl2 (7.2 ml) and Et3N (0.20 ml, 2 eq.) was added. The solution was cooled to 0°C and TFA2O (0.11 ml, 1.1 eq.) was added slowly. The solution was stirred at 0°C for 5 hours and was then poured in sat aq. NaHCO3. The phases were separated and the aqueous layer was extracted with CH2Cl2 (2x). The combined organic extracts were dried over MgSO4, the solids filtered and the solvent evaporated to give 0.17 g (71 %) of the crude titied trifluoroacetamide that was used as such.
1H NMR (CDCl3): δ 6.70 (be, 1H, NH), 4.75 (dd. 1H, H-1), 3.92 (m, 1H, H-4), 3.73 (dq, 1H, H-5), 2.06-1.45 (m, 4H, H-2 and H-3), 1.19 (d, 3H, H-6), 0.88 (s, 9H, t-Bu), 0.11 (s, 3H, SiMe), 0.09 (s, 3H, SiMe).
Step 6: (1S,3R,1'S,5'S,6'S) and (1R,3S,1'S,5'S,6'S)-methyl-(1 -[4'trifluoroacetamido-5'- methyltetrahydropyranyl]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-1673)
The titled compounds were obtained in 30% yield by following the procedure described in step 4, example 12, on the precursor of step 5 herein. The titled compounds were purified via flash chromatography (silica gel, 3:1 hexanes/EtOAc). The mixture of isomers was not separable by chromatography.
1H NMR (CDCl3): δ 8.14-8.07 (m, 2H, ArH), 7.79-7.73 (m, 2H, ArH), 6.17+5.99 (2s, 1H, H-1), 5.50+5.39 (2bs, 1H, H-1'), 4.68+4.24 (2q, 1H, J = 6.5, H-5'), 4.56+4.49 (2dd, 1H, J = 4.2, 11.8, H-3), 4.05 (m, 1H, H-4'), 3.08+3.07 (2dd, 1H, J = 4.2, 19.9, H-4), 2.57 (dd, 1H, J = 11.8, 19.9, H- 4), 2.34+2.33 (2s, 3H, COCH3), 2.00-1.53 (m, 4H, H-2' and H-3'), 1.31 + 1.13 (2d, 3H, J = 6.5, H- 6').
Bxaaple 41: (1'S,1S,3R)-3-(oximoethyl)-5,10-dioxo-1(2,3,6- trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)- 3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH- 2101) and 1,3-diepimer (BCH-2115)
Figure imgf000144_0001
Step 1: (1S,3R)-3 (oxiaoethyl)-1 (2,3,6-trideoxy-3- trifluoroacetamido-4-p-nitrobenzoyl-L-lyxohexopyranose)-5,8- dimethoxy-isochroman
To a solution of hydroxylamine-hydrochloride (60 mg; .86 mmol) in a mixture of ethanol (4 ml) and water (.4 ml) was added sodium hydroxide (33 mg) in ethanol (2 ml). The mixture was stirred at room temperature for .5 hour. The solution was filtered. The filtrate was added to 3- acetyl-isochroman glycoside from step 1, example 5, (92 mg; .147 mmole). The reaction was complete in 10 minutes. The mixture was evaporated down to dryness, dissolved in small volume of water (5 ml), extracted with CH2Cl2 (3x50 ml), washed with eat. NaCl, dried and evaporated. The crude product was passed through a small column of silica gel prewashed with 0.2% triethylamine in hexane (eluent: 15%, 20% and 25% EtOAc in hexane) yielding pure oxime (63 mg; 67%). NMR (acetone-d6; δ) : 1.26 (3H, d, J = 6.8 Hz; -CH3 ) , 1.26 (3H, d, J = 8.3 Hz; -CH3) , 1.89 (1H, dd, J = 4.4, 13.2 Hz; H-2 of the sugar) , 1.96 (3H, s, CH3 of the side chain) , 2.47 (1H, dt, J = 3.6, 13.1 Hz; H-2 ) , 3.81, 3.88 (3H, s each; Ar-OCH3) , 4.60-4.66 (1H, m; sugar-H) , 4.72 (1H, t, J = 7.8 Hz; H-3 ) , 4.83 (1H, q; J = 6.5 Hz; H-5 of the sugar) , 5.51 (1H, br singlet; H-1 of the sugar) , 5.61 (1H, d, J = 2.9 Hz; H-4 of the sugar) , 6.15 (1H, s; H-1) , 6.87, 6.90 (1H, d each; J = 8.9 Hz; Ar-H) , 8.36, 8.41 (2H, d each; J = 8.8 Hz; Ar-H of PNB-group) , 8.70 (1H, d, J = 8.0 Hz; -NHTFA) , 10.02 (1H, s; =NOH) .
Step 2: (1 'S, 1S,3R)-3 (oximoethyl)-5, 10-dioxo-1 (2,3,6-trideoxy-3- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c] pyran (BCH-2101) Acetylation was done on the oxime from step 1 herein (33mg; 0.051 mmole) in CH2Cl2 (4ml) using pyridine (0.2 ml), acetic anhydride (0.1 ml) and catalytic amount of DMAP. After stirring at room temperature for 3 hours, the mixture was poured into ice, extracted with CH2Cl2 (3x50 ml), washed with water (15 ml), dried and evaporated. The crude product was pumped for 16 hours before using in the next step.
CAN oxidation was done on the crude acetate (40 mg) using sodium bicarbonate following the general procedure as described in other examples. It resulted in 32 mg of crude quinone. The quinone was reacted with acetoxy butadiene (100 μl) in toluene following the general procedure. On purification through a column of silica gel (30% EtOAc in toluene, 50% EtOAc in toluene and CH2Cl2: MeOH=9:1 as eluents) pure tricyclic glycoside (29 mg) was obtained. Finally, deprotection of acetate and PNB groups was done by using sodium methoxide (catalytic) in methanol (3 ml) at 0°C. After stirring at 0°C for 14 minutes, the mixture was neutralized with dil. HCl to pH-7, diluted with water (5ml), extracted with CH2Cl2 (3x30 ml), washed with water (10 ml), dried and evaporated. The crude product was purified by column chromatography over a small column of silica gel (1% methanol in CH2Cl2 as eluent) and preparative TLC (CH2Cl2: MeOH=9:1) yielding pure titled oxime (3.7 mg; 14% in 4 steps), m.p.-125-27ºC.
NMR (acetone-d6) δ: 1.35 (3H,d,J=6.6Hz; CH3 of the sugar), 1.75
(1H,dd,J=4.6,13.0Hz;H-2 of the sugar), 1.95 (3H,s,CH3 of the side- chain), 3.71 (1H, br.signal; H-4 of the sugar), 4.27 (2H,m;sugar-H), 4.57 (1H,q,J=6.6Hz;H-5 of the sugax), 4.70 (1H,t,J=7.5Hz;H-3), 5.44 (1H,d,J=3.3Hz;H-1 of the sugar) , 6.07 (1H,S;H-1) , 7.87-7.90 (2H,m;Ar-H) , 8.08-8.12 (2H,m;Ar-H) , 10.15 (1H,bit br. ainglet;=NOH) .
Step 3: (1R,3S)-3-(oxiaoethyl)-1 (2,3,6-trideoxy-3- trifluoroacetamido-4-p-nitrobensoyl-L-lyxohexopyranose)-5,8- dimethoxy-isochroman
Oxime was prepared from 3-acetyl isochroman glycoside (60 mg; .096 mmol) using hydroxylamine hydrochloride (39 mg; 0.56 mmole) in EtOH (2.6 ml) and water (0.26 ml), and sodium hydroxide (21.5 mg) in EtOH (1.3 ml) following the procedure described in step 1 herein. After
chromatography over silica gel prewashed with triethylamine titled oxime (in diastereomeric mixture of 5:1 ratio) was obtained in 81% yield (50 mg).
NMR (acetone-d6; 6): 1.10 (3H, d, J = 6.6 Hz; CH3 of sugar), 1.98 (3H, s; methyl of the side-chain), 2.39 (1H, dt, J = 3.6, 12.9 Hz; H-4), 3.81 (6H, s; Ar-OCH3), 4.63-4.73 (1H, m; H-3 of sugar), 5.45 (1H, br signal; H-1 of sugar; same of the other diastereomer overlapped), 5.56 (1H, br signal; H-4 of the sugar; same of the other diastereomer overlapped), 5.95 (1H, s, H-1), 6.81-6.95 (m; Ar-H), 8.30-8.43 (m; A-H of PNB group), 8.66 (1H, br d, J = 5.9 Hz; NHTFA), 10.05 (1H, s; =N-OH), (There were few other signals which were due to the other diastereomer and to a small impurity which were not detailed.). Step 4: (1'S, 1R, 3S)-3 (oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3- trifluoroacetaaido-L-lyxohexopyranose)-3,4,5,10-tetrahydro- 1H-naphtho-(2,3-c)-pyran (BCH-2115)
Acetylation of the oxime (50 mg; .078 mmole) was done following the procedure described in step 2, first part. CAN oxidation was done on the acetate (54 mg) using sodium bicarbonate following the general procedure. It resulted in 50 mg of crude quinone. Quinone (50 mg) was reacted with acetoxybutadiene (0.1 ml) in toluene (2 ml) following the general procedure. On purification by column chromatography over silica gel (20% EtOAc in toluene, 50% EtOAc in toluene and 5% methanol in CH2Cl2 as eluents) gave 33 mg of slightly impure tricyclic compound. Finally, deprotection of acetate and PNB groups was done by using sodium methoxide (catalytic) in methanol (2 ml) at 0°C following the procedure described in step 2, last part. The titled crude product was passed through two columns of silica gel (1% and 2% methanol in CH2Cl2 as eluents) yielding the oxime in 12.5% yield (5 mg) (contaminated with the other diastereomer in 5.6:1 ratio).
NMR (acetone-d6; δ): 1.18 (3H,d,J=6.4Hz;CH3 of the sugar), 1.76
(1H,dd,J=4.8,12.9Hz;H-2 of the sugar), 1.98 (3H,s,CH3 of the side chain), 2.18 (1H, dd,J=3.7,12.9Hz,H-4), 3.67 (1H,br.d,J=3.9Hz;sugar-H), 4.21-4.29 (2H,m,sugar-H), 4.77 (1H,dd,J=5.4, 9.6Hz;H-3), 5.48
(1H,d,J=3.2; H-1 of the sugar), 5.91 (1H,s,H-1), 7.86-7.92 (2H,m;Ar-H), 8.06-8.10 (2H,m;Ar-H), 10.14 (1H,s,-N-OH) , (there were small signals due to the other diastereomer present in the spectrum which were not detailed).
Example 42: Preparation of (1'S,1S,3R)-3
(trifluoroacetamidoethel)-5, 10-dioxo-1 (2,3,6- trideoxy-3,4-dihydroxy-L-lyxohexopyranose)-3,4,5, 10- tetrahydro-1H-naphtho [2,3-c] pyran (BCH-2018)
Figure imgf000147_0001
Step 1: 3-(Trifluoroacetamido-ethyl)-5,8-dimethoxy isochroman
To a solution of hydroxylamine-hydrochloride (1.4 g; 20.1 mmole) in a mixture of ethanol (30 ml) and water (3 ml) was added sodium hydroxide (720 mg) in ethanol (15 ml). The mixture was stirred for .5 hour. The solution was filtered. The filtrate was added to 5,8-dimethoxy-3- acetyl-isochroman (1 g; 4.23 mmole). The mixture was stirred at room temperature for 1.5 hour and evaporated to dryness. The residue was dissolved in small volume of water (10 ml), extracted with CH2Cl2 (3x100 ml), washed with brine (20 ml), dried and evaporated. The crude product (900 mg) obtained was dissolved in toluene (30 ml) and cooled to -40°C. Red-Al (9 ml) was added during 25 minutes. The mixture was stirred at - 40°C for 40 minutes. The temperature of the cooling mixture was raised slowly to 25°C and the reaction was stirred at 25°C for 16 hours.
Excess reagent was destroyed by careful addition of cold water (6 ml) followed by 10% sodium hydroxide (1 ml). The mixture was extracted with ether (3x100 ml), washed with brine (25 ml), dried and evaporated. The crude product (800 mg) was dissolved in CH2Cl2 (50 ml). Pyridine (8 ml) and DMAP (15 mg) were added and the mixture was cooled to 0°C.
Trifluoroacetic anhydride (3 ml) was added slowly and the mixture was stirred at room temperature for 16 hours. It was poured into ice, neutralized with saturated sodium bicarbonate, extracted with CH2Cl2 (3x100 ml), washed with water (25 ml), dried and evaporated. The solid residue was recrystallized twice from a mixture of hexane and ether (4:1) yielding pure titled product (purity by NMR: >92%; yield = 330 mg; 23.4% in three steps).
NMR (CDCl3; δ) : 1.29 (3H, d, J = 6.8 Hz; -CH3), 2.52 (1H, dd, J = 11.3, 16.9 Hz; H-4), 2.69 (1H, dd, J = 2.2, 16.4 Hz; H'-4), 3.65 (1H, ddd, J = 3.2, 6.3, 11.2 Hz; H-3), 3.75, 3.78 (3H, s each, Ar-OCH3), 4.24 (1H, m; -CH(NHCOCF3)CH3), 4.58 (1H, d, J = 15.8 Hz; H-1), 4.97 (1H, d, J = 15.8 Hz; H'-1), 6.62, 6.67 (1H, d each, J = 8.9 Hz; Ar-H). step 2: (1S' ,1S,3R)-3-(trifluoroacetamidoethyl)-5,8-dimethoxy-1- (2',3',6'-trideoxy-3',4'-dihydroxy-L-lyxohexopyranose)- isochroman
Coupling with sugar was done using DDQ in CH2Cl2 following general procedure (step 1, example 14). The product was isolated as
diastereomeric mixture from crude reaction mixture by column
chromatography over silica gel prewashed with .5% triethylamine
(eluent:hexane:ethyl acetate = 80:20) in 75% yield.
To a solution of the diastereomeric mixture (100 mg) in CH3CN (6 ml) at 0°C was added 0.1 N NaOH (4 equiv.). The mixture was stirred at 0°C for .5 hour. Ice bath was removed and it was stirred at room
temperature for 1.5hr. The mixture was diluted with water (10 ml), extracted with CH2Cl2 (3x100 ml), washed with water (20 ml), dried and evaporated. The crude product was chromatographed over silica gel (prewashed with .2% triethylamine) eluent: 50%, 60%, 70%, 80% EtOAc in hexane and finally by pure EtOAc) yielding pure title compound (yield = 25 mg; 29.4%), and 1,3-diepimer (37 mg; 80% pure; 34.5%).
NMR (Acetone-d6;δ) of the title compound: 1.28, 1.35 (3H,d each, J = 6.5 Hz; CH3 of the side chain and CH3 of the sugar), 1,58 (1H, dd,
J = 5.1,12.6 Hz; H-2 of the sugar), 1.91 (1H, dt, J = 3.8, 12.3 Hz; H-2 of the sugar), 2.41 (1H, dd, J = 11.6, 17.4 Hz, H-4), 2.79 (1H, dd, J = 3.4, 17.6 Hz; H'-4), 3.42 (1H, d, J = 4.4, sugar-H), 3.55 (1H, br signal; H-4 of the sugar), 3.64 (1H, d, J = 6.7 Hz; sugar-H), 3.77, 3.78 (3H, s, each, Ar-OCH3), 4.16-4.29 (2H, m, -CH(NHTFA)CH3 and sugar-H), 4.36 (1H, q, J = 6.5 Hz; H-5 of sugar), 5.36 (1H, d, J = 3.3 Hz; H-1 of the sugar), 6.04 (1H, s, H-1), 6.79, 6.88 (1H, d each, J = 8.9Hz; Ar-H), 8.50 (1H, br d, J = 7.0; NHTFA).
NMR of 1,3-diepimer (acetone-d6; δ): 1.21 (3H, d, J = 6.5 Hz; CH3), 1.36 (3H, d, J = 6.3 Hz; CH3), 2.37 (1H, dd, J = 6.1, 11.3 Hz; H-4), 2.80 (1H, dd, J = 3.3, 17.3 Hz; H'-4), 3.45 (1H, d, J = 4.8 Hz; sugar- H), 3.53 (1H, br signal; sugar-H), 3.66 (1H, d, J = 6.9 Hz; sugar-H), 3.78, 3.81 (3H, s each; Ar-OCH3), 4.08 (1H, q, J = 6.7 Hz; H-5 of the sugar), 4.16-4.29 (2H, m; CH(NHTFA)CH3 and sugar-H), 5.36 (1H, br singlet, H-1 of sugar), 5.85 (1H, s; H-1), 6.78-6.89 (2H, m; A-H), (There were few signals due to the other diastereomer which are not detailed.).
Step 3: (1'S,1S,3R)-3-(trifluoroacetamidoethyl)-5,10-dioxo-1- (2',3',6'-trideoxy-3',4'-dihydroxy-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2018)
CAN oxidation was done on dimethoxy-compound following the general procedure (step 3, example 12).
The crude quinone was reacted with acetoxy-butadiene in toluene following the general procedure. Pure titled product was obtained by column chromatography over silica gel (eluent: toluene: EtOAc=70:30 and 60:40) followed by preparative TLC (eluent: CH2Cl2: MeOH=9:1) (5 mg;19% yield) as a light yellow solid, mp: 180-3°C (dec).
NMR (acetone-d6;δ): 1.34 (3H,d,J=6.4Hz;-CH3), 1.38 (3H,d,J=6.7Hz;-CH3), 1.60 (1H,dd,J=4.7,12.6Hz;H-2 of the sugar), 1.92 (1H,dd,J=3.7,12.2Hz;H-2 of the sugar), 2.47 (1H,dd,J=10.2,19.0Hz;H-4), 2.82
(1H,dd,J=2.9,19.0Hz;H'-4), 3.49 (1H,d,J=4.3Hz;-OH of the sugar), 3.59 (1H,br.signal which became sharp on D2O-exchange;H-4 of sugar), 3.68 (1H,d,J=6.7Hz;-OH of the sugar), 3.82 (1H,m;H-3), 4.19-4.30
(2H,m,overlapping-CBCH3(NHTFA) and sugar-proton), 4.42 (1H,q, J=6.5Hz,H-5 of the sugar), 5.36 (1H,d,J=3.5Hz,H-1 of the sugar), 6.0 (1H,s,H-1), 7.86-7.90 (2H,m;Ar-H), 8.05-8.10 (2H,m;Ar-H), 8.56 (1H,br. signal;- NHTFA). (Stereochemistry of NHTFA is not yet determined).
Example 43: Preparation of (1'R,1R,3S)-3-acato-5,10-dioxo-1-(2- deoxy-2-chloroethylnitrosoureido-D-glucopyranose)- 3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH- 2038)
Figure imgf000150_0001
Step 1: (1'R, 1R, 3S)-3-aceto-5,8-dimethoxy-1(2-deoxy-2- chloroethylureido-3,4,6-triacetyl-D-glucopyranose)- isochroman. 2-Deoxy-2-chloroethylureido-3,4,6-triacetyl-D-glucopyranoae was prepared following known procedure (Ref: T.P. Johnston, G.S. McCaleb and J.A. Montgomery, J. Med. Chem., 18, 104 (1975)). This compound was coupled with 3-aceto-5,8-dimethoxy-iaochroman uaing DDQ following the general procedure outlined before (step 1, example 14). Purification was done by column chromatography over silica gel (eluent:hexane:EtOAc = 7:3) yielding the title compound (29.4%) and 1,3-diepimer (31%).
NMR (acetone-d6; δ) of the title compound: 1.91, 1.95, 2.00 (3H, s each; acetyl groups) 2.32 (3H, s, keto-methyl), 2.50 (1H, dd, J = 12.3, 17.6 Hz; H-4), 3.01 (1H, dd, J = 4.0, 17.6 Hz; H'-4), 3.49 (2H, m; -NH- CH2- group), 3.63 (2H, t, J = 6.2 Hz; -CH2-Cl group); 3.83, 3.88 (3H, s each; Ar-OCH3), 4.14 (4H, m; H-5, H-2, H-6 and H-6 of the sugar overlapping), 4.60 (1H, dd, J = 4.1, 12.2 Hz; H-3), 5.08 (pair of double-doublets overlapping; H-3 and H-4 of the sugar), 5.46 (1H, d, J = 3.5 Hz; H-1 of the sugar), 5.49 (1H, broad s; -NH-CO-), 6.02 (1H, s; H- 1), 6.15 (1H, br signal; CONH-CH2), 6.87, 6.96 (1H, d each, J = 9.0 Hz; Ar-H).
NMR (acetone-d6; δ) of the 1,3-diepimer: 1.92, 2.00, 2.06 (3H, s each; acetate-groups), 2.28 (3H, s; keto-methyl), 2.48 (1H, dd, J = 12.0, 17.8 Hz; H-4), 2.91 (1H, dd, J = 4.2, 11.7 Hz; H'-4), 3.26-3.51 (2
multiplets, 1H each; -HN-CH2-), 3.56 (2H, t, J = 6.2 Hz; -CH2Cl), 3.84 (6H, s; Ar-OCH3), 4.14-4.23 (2H, m; sugar-H), 4.34 (1H, dd, J = 4.7; 12.1 Hz; sugar-H), 4.62 (2H, dd, another proton overlapped; J = 4.3, 12 Hz; H-3), 5.05-5.18 (2H, m; H-3 and H-4 of sugar), 5.51 (1H, d, J = 3.7 Hz; H-1 of the sugar), 5.81 (1H, d, J = 9.6 Hz; -NH-CO), 5.98 (1H, br, triplet; -NH-CH2), 6.16 (1H, s; H-1), 6.91, 6.99 (1H, d each, J = 9.0 Hz;Ar-H).
Step 2: (1'R, 1R, 3S)-3-aceto-5,8-diimethoxy-1(2-deoxy-2- chloroethylureido-4,6-benaylidene-D-glucopyranose)- isochroman
To a cold solution of triacetyl derivative (120 mg; .19 mmol) in CH3CN was added .1 N NaOH (8.6 ml; 4.6 eq.). The mixture was stirred at 0°C until TLC revealed complete reaction. It was carefully neutralized with .1 N HCl to pH ~8 and extracted with ethyl acetate (3x100 ml), washed with 2.5% NaHCO3-NaCl-aolution (1:1) (10 ml), dried and evaporated. To a solution of the crude product in DMF (5 ml), benzaldehyde dimethyl acetal (30 μl; 1.2 eq.) and p-TSA (10 mg; catalytic) was added. The reaction flask was connected to water aspirator and held at 50°C for 15 minutes. Sodium bicarbonate solution (2.5%; 10 ml) was added and the mixture was extracted with CH2Cl2 (3x50 ml), washed with saturated NaCl solution, dried and evaporated. The crude product was washed with a mixture of hexane and ether, yielding pure titled benzylidene derivative (77 mg; 68%).
NMR (acetone-d6; δ) : 2.33 (3H, a, keto-methyl), 2.50 (1H, dd, J = 12.2, 17.6 Hz; H-4), 2.99 (1H, dd, J = 4.1, 17.6 Hz; H'-4), 3.49 (2H, t, J = 5.8 Hz; -CH2-Cl), 3.63 (2H, m, -NH-CH2-), 3.82, 3.91 (3H, a, Ar-OCH3), 4.19 (1H, dd, J = 4.5, 9.6 Hz; sugar-H), 4.62 (1H, dd, J = 4.1, 12.2 Hz; H-3), 5.46 (1H, d, J = 3.8 Hz; H-1 of the augar), 5.62 (1H, s, -CH Ph), 5.68 (1H, d,J = 8.5 Hz; -NH-), 6.00 (1H, s, H-l), 6.18 (1H, br s, -NH CH2-), 6.87, 6.95 (1H, d each, J = 8.9 Hz; Ar-H), 7.34 (3H, m; Ar-H), 7.46 (2H, m; Ar-H).
Step 3 (1'R, 1R, 3S)-3-aceto-5,10-dioxo-1-(2-deoxy-2- chloroethylureido-4,6-benaylidene-D-glucopyranose)-3,4,5,10- tetrahydro-1H-naphtho-[2,3-C] pyran To a aolution of benzylidene derivative (77 mg; .127 mmol) in
acetonitrile (6 ml) was added a solution of eerie ammonium nitrate (146 mg; .266 mmol) in water (2.5 ml) at room temperature. The mixture was stirred for 5 minutes, diluted with water (10 ml), extracted with CH2Cl2 (3x75ml), waahed with water (15 ml), dried, evaporated. The crude product (60 mg) was pumped for 2 hours before going to the next step. The crude product waa taken up in dry toluene (3 ml) and acetoxybutadiene (1.2 ml) was added. The mixture was stirred at room
temperature for 16 hours. The solution was not quite homogeneous and TLC showed some starting material. Acetoxy-butadiene ( .5 ml) was further added and stirred for 20 hours. The mixture was diluted with toluene (10 ml). Silica gel (500 mg) waa added and air was bubbled through the mixture for 1 hour. The crude reaction mixture was passed through a column of ailica gel (eluent:toluene:EtOAc = 7:3 and
CH2Cl2:MeOH = 9:1). Fraction containing the product was further purified by preparative TLC (eluent:EtOAc) yielding 12 mg of pure titled product (15%) (poor yield because of separation problem).
NMR (acetone-d6; δ): 2.35 (3H, s; keto-methyl), 2.58 (1H, dd, J = 11.4, 19.7 Hz; H-4), 3.01 (1H, dd, J = 3.9, 19.6 Hz; H'-4) 3.55, 3.67 (m each, HN CH2-CH2Cl), 4.22 (1H, dd, J = 4.6, 9.7 Hz; sugar-H), 4.65 (1H, d, J = 3.9 Hz; -OH) , 4.73 (1H, dd, J = 4.0, 11.4 Hz; H-3) , 5.52 (1H, d, J = 3.8 Hz; H-1 of the sugar) , 5.63 (2H, br s; CH-Ph and -NH-CO) , 5.94 (1H, t, J = 5.7 Hz; -NH-CH2 ) , 6.04 (1H, s; H-1) , 7.33 (3H, m, Ar-H) , 7.46 (3H, m; Ar-H) , 7.91 (2H, m, Ar-H) , 8.14 (2H, m; Ar-H) .
Step 4: (1 'R, 1R, 3S)-3-aceto-5, 10-dioxo-1-(2-deoxy-2-chloroethyl- nitroaoureido-D-glucopyranose)-3,4,5, 10-tetrahydro-1H- naphtho-[2,3-C] pyran To a aolution of benzylidene derivative (6 mg; .01 mmol) in 96% formic acid (1 ml) at 5°C was added NaNO2 (10 mg) in two portions. The reaction was complete in 2 minutes. It was diluted with water (5 ml), extracted with CH2Cl2 (3x25 ml), washed with water (10 ml; 15 ml), dried over Na2SO4 and evaporated. The crude product (4.5 mg) was pasaed through a small column of silica gel (eluent:EtOAc and 10% methanol in CH2Cl2) yielding pure titled product (yield = .9 mg; 17%) (HPLC:92%) NMR (acetone-d6; δ): 2.35 (3H, a, keto-methyl), 2.51 (1H, dd, J = 12.9, 19.2 Hz; H-4), 2.98 (1H, dd, J = 4.1, 19.6 Hz; H'-4), 3.52-3.89 (two multiplets; some of the sugar protons, and overlapping A2B2 system due to -HN(CH2)2Cl), 4.08 (H, dd, J = 3.5, 6.0 Hz; sugar-H), 4.26 (1H, dd, J = 6.6, 11.3 Hz; sugar-H), 4.43 (1H, dd, J = 4.7, 7.5 Hz; sugar-H), 4.66 (1H, dd, J = 4.0, 11.5 Hz; H-3), 5.66 (1H, d, J = 3.6; H-1 of the sugar), 5.99 (1H, s, H-1), 7.59 (1H, d, J = 8.6 Hz; NH-CO), 7.88, 8.08 (two multiplets, Ar-H). Example 44: Preparation of 3-aceto-5, 10-dioxo-1-methoxy-5,10- dihydro-1H-naphtho [2,3-c] pyran (BCH-2129)
Figure imgf000153_0001
Step 1: 3-Aeeto-5,10-dioxo-1-methoxy-5,10-dihydro-1H-naphtho-(2,3- c)-pyran (BCH-2129)
To a solution of 3-acetyl-5,10-dioxo-1-methoxy-3,4-5,10-tetrahydro-1H- naphtho (2,3-c) pyran (50 mg, .175 mmole) in CH3CN (8 ml) and THF (4 ml) at 0°C was added 0.5N aodium hydroxide (1 equiv.). The mixture was stirred at 0°C for 15 minutes and it was allowed to come to room temperature. After 1.5 hour at room temperature the mixture was acidified with dil. HCl to pH-6. Saturated NH4Cl (5 ml) was added and the mixture was extracted with CH2Cl2 (3x50 ml), washed with water (10 ml), dried and evaporated. The crude titled product was subjected to preparative TLC (eluent: toluene:EtOAc-96:4) and pure product was isolated as a light yellow aolid, mp. 154-56°C (3mg; 6%).
NMR (acetone-d6, δ) : 2.50 (3H,a,ketomethyl), 3.63 (3H,s,-OCH3), 6.42 (1H,s,H-1), 7.11 (1H,s;H-4), 7.92 (2H,m;Ar-H), 8.14 (2H,m;Ar-H).
Example 45: Preparation of (1R,3S) and (1S,3R)-3-aceto-5,10-dioxo- 1 (4-chloroethylnitrosoureido cyclohexyl-oxy)- 3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH- 2114)
Figure imgf000154_0001
Step 1: (1R,3S) and (1S,3R)-3-Aceto-1 (4-chloroethylureido- eyclohexyloxy)-5,8-dimethoxy-iaochroman
3-Acetyl isochroman was coupled to 4-chloroethyl ureido-cyclohexanol (prepared by known procedure, ref.: T.P. Johnston, G.S. McCaleb, P.S. Opliger, H.R. Laater and J.A. Montgomery, J. Med. Chem., 14, 600 (1971)) using DDQ following the general procedure (step 1, example 14).
Enantiomeric mixture of the titled products was isolated from the crude reaction mixture by column chromatography over silica gel (eluent: 50% and 80% EtOAc in hexane) yield=100mg (52%).
NMR (acetone-d6;δ) : 1.26-1.48 (two multiplets; CH2-groups of cyclohexyl ring), 1.78-1.80 (multiplet,-CH2 of cyclohexyl ring), 2.27 (3H, s, keto- methyl), 2.45 (1H, dd, J = 12.1, 17.8 Hz; H-4), 2.90 (1H, dd, J = 4.2, 17.7 Hz; H'-4), 3.42 (2H, m; -HNCH2Cl), 3.59 (2H, t, J = 6.0 Hz; -CH2- Cl), 3.78, 3.79 (3H, s each,Ar-OCH3), 3.86 (1H, m; H-1 of the
cyclohexyl ring), 4.61 (1H, dd, J = 4.2, 12.0 Hz; H-3), 5.51 (1H, d, J = 7.4 Hz; -NH-CO-), 5.67 (1H, br signal; -CONHCH2-), 5.90 (1H, a, H- 1), 6.79, 6.87 (1H, d each, J = 8.9 Hz;Ar -H).
Step 2: (1R,3S) and (1S,3R)-3-Aceto-5,10-dioxo-1 (4- chloroethylureido cyclohexyl-oxy)-3,4,5,10-tetrahydro-1H- naphtho-(2,3-c)-pyran
CAN oxidation was performed on the dimethoxy-isochrαman from atep 1 herein (35 mg; .077 mmole) following the general procedure (atep 2, example 14).
The crude product (32 mg) was diasolved in dry toluene (3 ml) and acetoxybutadiene (0.5 ml) was added. The mixture was stirred at room temperature for 18 hours. Silica gel (500 mg) was added and air was bubbled for .5 hour. The crude product was passed through a column of ailica gel (30% EtOAc in toluene, 50% EtOAc in Toluene, and CH2Cl2:
MeOH=19:1 as eluents) yielding pure tricyclic titled compounds (15 mg; yield 41%).
NMR (acetone-d6;δ) : 1.24-1.54 (6H, m, CH2 group of the cyclohexyl ring), 2.30 (3H, s, ketomethyl), 2.51 (1H, dd, J = 11.6, 19.5 Hz; H-4), 3.42 (2H, m; -NHCH2-CH2Cl), 3.60 (2H, t, J = 6.2 Hz; -CH2Cl), 3.95 (1H, m, H- 1 of the cyclohexyl ring), 4.64 (1H, dd, J = 4.2, 11.5 Hz; H-3), 5.54 (1H, br d, J = 6.9 Hz; NHCO-), 5.69 (1H, br signal; -CONH-CH2-), 5.92 (1H, s; H-1), 7.86-7.91 (2H, m;Ar-H), 8.06-8.10 (2H, m;ArH).
Step 3: (1R,3S) and (1S,3R)-3-aceto-5,10-dioxo-1 (4- chloroethylnitroaoureido cyclohexyl-oxy)-3,4,5,10- tetrahydro-1H-naphtho-(2,3-c)-pyran (BCH-2114)
To a solution of chloroethyl ureido-derivative from atep 2 herein (14 mg, .03 mmole) in formic acid (1.2 ml) at 5°C was added sodium nitrite (20 mg) in two portions. Reaction was complete in 3 minutes. It was diluted with water (10 ml), extracted with CH2Cl2 (3x50 ml), washed with water (2x10 ml), dried and evaporated. The crude product was purified by passing through a email column of silica gel (eluent: 1% methanol in CH2Cl2) and finally by washing with hexane-ether mixture yielding pure titled nitroso-derivative, mp=58-63ºC (yield=5 mg;34%).
NMR (acetone-d6;δ): 1.48-1.80 (6H,m;CH2 of the cyclohexyl group), 2.32 (3H,a,ketomethyl), 2.52 (1H,dd,J-11.6, 19.6Hz;H-4), 2.93
(1H,dd,J=4.3,19.7Hz;H'-4), 3.60 (2H,t,J=6.5Hz;-CH2-Cl), 3.76-4.05 (m,H-1 and H-4 of the cyclohexyl group), 4.16 (2H,t,J=6.6Hz;-N(NO)CH2-), 4.66 (1H,dd,J=4.3,11.4Hz;H-3), 5.97 (1H,s,H-1), 7.77 (1H,br.d, J=7.8Hz;-NHCO- ), 7.87-7.90 (2H,m;Ar-H), 8.07-8.11 (2H,m;Ar-H).
Example 46: Using the same carboxylic acid as deacribed in Example
16, 1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-c]-pyran-3-carboxamides were prepared
Figure imgf000156_0001
Step 1: 1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10-dihydro-1H- naphtho-[2,3-c]-pyran (BCH-2044)
Using a similar procedure as described in step 7, example 16, the carboxylic acid from step 6, example 16, was converted to the titled compound.
dec. 140°C; m.p. 200°C. 1H NMR (CDCI3, 250 MHz, Bruker) : δ, 3.68 (3H, s, OCH3 ) , 6.48 (1H, s, 1- CH) , 7.18 (1H, tr, J = 7.6 Hz, p-Ani-H) , 7.49 (2H, tr, J = 8.0 Hz, m- Ani-H) , 7.50 (1H, s, 4-CH) , 7.66 (2H, d, J = 7.8 Hz, O-Ani-H) , 7.79 (2H, m, 7, 8-ArH) , 8.15 (2H, m, 6, 9-ArH) , 8.40 (1H, s, NHCO) .
IR (Nicolet , 205 FT, film on NaCl plate) : cm-1, 3322.9, 2929.3 2848.3, 1682.9, 1659.8, 1594.2, 1527.7, 1443.7, 1374.2, 1297.0, 1258.4, 1063.2, 947.6, 863.1, 719.7, 693.6.
Step 2: 1-methoxy-3-(3-N-pyrrolidinomylpropylaminocarbonyl)-5 , 10- dioxo-5, 10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2166)
60 mg of the acid from atep 6, example 16, was dissolved in 6.8 ml of dry THF, cooled to 0°C and 63 μl of oxalyl chloride was added. The mixture was allowed to stir at 0°C for 20 minutes, and then at room temperature for 20 minutes. The solvent was then evaporated, the residue was redissolved in dichloromethane and evaporated, and then the residue was again dissolved into dry THF. The solution was cooled to - 10°C. 29.3 μl of triethylamine and 19.90 μl of 1-(3-aminopropyl)-2- pyrrolidinone was added and allowed to stir for 45 minutes at -10°C and then 2 hours at room temperature. The solvent was then evaporated to half of ita original volume, the remaining aolution was poured onto sat. brine and extracted into dichloromethane. The organic layer was then washed with aat. sodium bicarbonate aolution, dried over sodium sulfate, and evaporated to dryness to give 24 mg of pure titled product.
NMR (CDCl3 250 MHz, Bruker): δ, 1.86 (2H, Quin, J = 6.6 Hz, C-CH2-C), 2.08 (2H, Quin, J = 7.5 Hz, 4'-pyrr-CH2), 2.45 (2H, t, J = 7.5 Hz, 3'- pyrr-CH2), 3.15-3.34 (2H, m, CONHCH2), 3.36-3.55 (4H, m, CH2-pyrr, 5'- pyrr-CH2), 3.74 (3H, s, -OCH3), 6.43 (s, 1H, 4-CH), 7.32 (s, 1H, 1-CH), 7.70-7.78 (2H, m, 6, 9-ArH), 8.08-8.16 (3H, m, 7, 8-ArH, NH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3320.9, 2936.7, 2871.3, 1679.9, 1658.1, 1597.0, 1527.2, 1335.2, 1291.5, 1278.4, 1082.1, 947.98, 857.41, 801.34, 723.70.
Step 3: (3-N-imidasolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho-[2,3-c]-pyran-3-carboxamide
To a stirred solution of acod from step 6, example 16, (0.185 mmol, 53 mg) and catalytic amounts of DMF in 6 ml of THF at 0°C was added oxalyl chloride (0.426 mmol). After stirring at 0°C for one hour, and at room temperature for a further 20 minutes, the solvent was evaporated to dryness. 6 ml of THF was then added, and the mixture divided into two. 3 ml of solution was then cooled to -10°C, and 1-(3-amminopropyl)- imidazole (8.39 μl, 0.20 mmol) dissolved in 1 ml of THF was added dropwiae. The mixture was allowed to stir for one hour at which time it was poured onto sat. sodium bicarbonate solution, extracted into methylene chloride, washed with brine, dried over- sodium sulfate and the solvent evaporated. Purification on TLC using 8% methanol/chloroform system produced 6 mg of pure titled product.
1H NMR (acetone -d6, 250 MHz, Bruker), δ: 2.10 (m, 2H, CH2-imidazol), 3.42 (m, 2H, C-CH2-C), 3.60 (a, 3H, OCH3), 4.14 (t, 2H, CH2NCO, 6.34 (s, 1H, 4-CH), 6.96 (s, 1H, 4-CH (imidazol)), 7.16 (s, 1H, 1-CH), 7.18 (s, 1H, 5-CH (imidazol)), 7.70 (s, 1H, 2-CH (imidazol)), 7.90 (m, 2H, 6, 9-ArH), 8.12 (m, 2H, 7, 8-ArH), 8.29 (m, 1H, NH).
IR (Nicolet 205 FT, film on NaCl plate), cm-1: 3313.5, 2932.1, 2853.4, 1676.1, 1665.4, 1593.2, 1552.8, 1334.1, 1274.0, 1087.5, 950.72, 859.52, 718.64.
Step 4: (3-N-hydrochloroimidasolylpropyl)-1-aethoxy-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran-3-carboxamide (BCH-2157)
6 mg of product from step 3 herein was dissolved in 2 ml of ether. To this was added 6 μl of 1M HCl/ether aolution (from Aldrich). The mixture was stirred, and then the solvent evaporated to give 6.7 mg of the HCl salt.
1H NMR (acetone-d6, 250 MHz, Bruker) for salt, δ: 2.29 (m, 2H, CH2- imidazol), 3.53 (m, 2H, C-CH2-C), 3.62 (s, 3H, OCH3), 4.50 (m, 2H, CH2NHCO), 6.33 (s, 1H, 4-CH), 7.14 (s, 1H, 1-CH), 7.55 (s, 1H, 5- CH(imi)), 7.76 (s, 1H, 4-CH(imi)), 7.88 (m, 2H, 7, 8-ArH), 8.05 (m, 2H, 6, 9-ArH), 8.64 (m, 1H, NH), 9.285 (e, 1H, 2-CH(imi)).
IR (Nicolet 205 FT, film on NaCl plate) cm-1: 3345.8, 1676.5, 1652.2, 1527.0, 1280.4, 1090.9, 955.01.
Example 47: Preparation of 3-ethylthiocarbonyl-1,3,4,5,10- pentahydro-5,10-dioxo-naphtho-[2,3-c] pyran (BCH-2003) and 3-(5'-tosyloxasolyl)-1,3,4,5,10-pentahydro-5,10- dioxo-naphtho-[2,3-c]-pyran (BCH-2155)
Figure imgf000159_0001
Step 1: 3-ethylthiocarbonyl-5,8-dimethoxy-iaochroman 5,8-dimethoxy-3-carboxyiaochroman (300 mg, 1.26 mmol) in THF (6 ml) was stirred with 1,1'-carbonyldiimidazole (225 mg, 1.386 mmol) at room temperature for 30 minutes. More THF (6 ml) was added to dilute the forming suspension. After one hour, ethanethiol (103 μl, 1.40 mmol) was added and the mixture was stirred for 18 hours at room temperature.
Solvent was evaporated and the crude titled product was chromatographed (hex:EtOAc = 4:1) to give desired product as a solid (200 mg, m.p. 99.2° C).
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.28 (3H, tr, J = 7.6 Hz, CH3), 2.68 (1H, dd, J = 17.6 Hz, 11.2 Hz, 4-HCHa), 2.92 (1H, qua, J = 7.6 Hz, -CH2-) , 3.12 (1H, dd, J = 11.2 Hz, 3.5 Hz, 4-HCHe) , 3.76 (3H, s, OCH3) , 3.78 (3H, s, OCH3) , 4.24 (1H, dd, J = 11.2 Hz, 3.0 Hz, 3-CH) , 4.70 (1H, d, J = 15.3 Hz, 1-HCHa) , 5.06 (1H, d, J = 15.3 Hz, l-HCHe) , 6.64 (1H, d, J = 8.0 Hz, ArH) , 6.67 (1H, d, J = 8.0 Hz, ArH) .
IR (Nicolet , 205 FT, film on NaCl plate) : cm-1, 2936.2 2836.2, 1679.2 1604.8, 1486.8, 1461.8, 1258.5 , 1094.3, 1078.9, 1022.5, 796.81, 714.69.
Step 2: 3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,8-penta-1H-benso-[2,3- c]-pyran The compound from step 1 herein (100 mg, 0.35 mmol) was dissolved in acetonitrile (6 ml), then cooled to 0°C. Sodium bicarbonate (58.8 mg, 0.7 mmol) was added. This was followed by addition of a aolution of ammonium cerium nitrate (583 mg, .0063 mmol) in 2 ml. of water. The reaction mixture was allowed stirred for 5 minutes at 0°C. TLC showed completion of the reaction. It was poured to water and extracted with methylene chloride. The organic layer was dried over Na2SO4 and evaporated to give a crude titled product (83 mg).
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.24 (3H, tr, J = 7.6 Hz, CH3), 2.51 (1H, dd tr, J = 17.6 Hz, 9.2 Hz, 3 Hz, 4-HCHa), 2.85 (1H, d, J = 17.6 Hz, 4-HCHe), 2.88 (1H, qua, J = 7.6 Hz, -CH2-), 4.18 (1H, dd, J = 9.2 Hz, 3 Hz, 3-CH), 4.47 (1H, d tr, J = 17.5 Hz, 3 Hz, 1-HCHa), 4.81 (1H, br d, J = 17.6 Hz, 1-HCHe), 6.71 (1H, d, J = 9.7 Hz, Quin-H), 6.76 (1H, d, J = 9.7 H, Quin-H).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 2972.6, 2929.5, 2882.4, 1678.5, 1655.5, 1599.3, 1418.9,. 1313.1, 1147.5, 1125.6, 993.09, 827.00, 766.77, 729.32, 667.58, 629.13. Step 3: 3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,10-pentahydro-naphtho- [2,3-c]-pyran (BCH-2003)
The compound from step 2 herein (42 mg, 0.167 mmol) in toluene (6 ml) was atirred with 1-acetoxy-1,3-butadiene (119 μl, 1.0 mmol) at 60°C for 22 hours. Solvent was evaporated and the crude product was
chromatographed (toluene/EtOAc = 100/15) to give desired titled product
(41 mg) as a aolid (m.p. 95.4-96.5°C).
1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.26 (3H, tr, J = 7.6 Hz, CH3),
2.65 (1H, dd tr, J = 19.4 Hz, 9.4 Hz, 3 Hz, 4-HCHa), 2.91 (2H, qua, J = 7.6 Hz, CH2), 3.04 (1H, d tr, J = 19.4 Hz, 3 Hz, 4-HCHe), 4.25 (1H, dd, J = 9.4 Hz, 3 Hz, 3-CH), 4.61 (1H, d tr, J = 18.2 Hz, 3 Hz, l-HCHa),
4.97 (1H, dd, J = 18.2 Hz, 1.8 Hz, 1-HCHe), 7.71 (2H, m, 7, 8-ArH), 8.04
(2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 2969.3, 2931.3,
2874.3, 1680.8, 1661.8, 1641.4, 1594.2, 1334.2, 1296.4, 1175.1, 1108.9,
1027.0, 874.2, 787.5, 694.6.
Step 4: 3-(5'-toayloxasolyl)-5,8-dimethoxy isochroman To 5,8-dimethoxy-3-carboxyisochroman (211 mg, 0.887 mmol) dissolved in THF (2.0 ml) cooled to 0°C was added oxalyl chloride (86.09 μl,
0.975 mmol). The mixture was atirred for 20 minutes then at room temperature for 20 minutes. The reaction mixture was evaporated to dryness to give desired acid chloride. It was rediasolved in THF (4 ml) and cooled to -78°C. A aolution of tosylmethyl isocyamide anion (made from the treatment of tosylmethyl isocyamide, 180 mg, 0.92 mmol, by n- butyllithium, 1.6 M in hexane, 0.61 ml, 0.975 mmol at -78°C for 10 minutes) was added to the above cold acid chloride aolution. The reaction mixture was atirred for 24 hours as it warmed to room
tempeture. Then, it was poured to NH4CI (sat.) and extracted with methylene chloride. The organic layer was dried (over Na2SO4) and evaporated to give a crude product which was chromatographed to give the desired titled product as a white solid 115 mg, m.p. 138-140°C.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 2.41 (3H, s, tosy-CH3), 2.99 (2H, d, J = 7.4 Hz, 4-CH2), 3.76 (6H, s, 2xCH3), 4.85 (1H, d, J = 17.5 Hz, 1- HCHa), 4.03 (1H, d, J = 17.5 Hz, 1-HeCH), 5.54 (1H, tr, J = 7.4 Hz, 3- CH), 6.67 (2H, br s, 6, 7-ArH), 7.33 (2H, d, J = 8.2 Hz, 3', 5', tosyl- H), 7.82 (1H, s, oxa-H), 7.92 (2H, J = 8.2 Hz, 2, 6-tosyl-H).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3134.2, 2951.5, 2837.5, 1595.5, 1511.7, 1485.6, 1463.6, 1437.5, 1331.7, 1261.6, 1194.3, 1149.0, 1089.9, 1072.0, 809.60, 798.61.
Step 5 : 3-(5'-tosyloxaxolyl)-5,8-dioxo-1,3,4,5,8-pentahydrobenzo- [2,3-c]-pyran
The compound from step 4 herein (10 mg, 0.024 mmol) was diaaolved in acetonitrile (2 ml) and cooled to 0°C. A aolution of ammonium cerium nitrate (39.5 mg, 0.072 mmol) in 0.5 ml of water was added dropwise. The reaction mixture was stirred at 0°C for 5 minutes, then poured to water and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to give the titled compound as a white aolid (9 mg, dec. 150°C; m.p. 177°C).
1H NMR (CDCI3, 250 MHz, Bruker): δ, 2.42 (3H, s, tosyl-CH3), 2.82 (2H, m, 4-CH2), 4.65 (1H, d tr, J = 17.6 Hz, 4.1 Hz, 1-HCHa), 4.82 (1H, d tr, J = 17.6 Hz, 1.8 Hz, 1-HCHe), 5.52 (1H, tr, J = 7.0 Hz, 3-CH), 6.75 (1H, d, J = 9.1 Hz, quin-H), 6.81 (1H, d, J = 9.1 Hz, quin-H), 7.35 (2H, d, J = 8.2 Hz, 3', 5'-tosyl-H), 7.83 (1H, s, oxa-H), 7.90 (2H, d, J = 8.2 Hz, 2', 6'-tosyl-H). Step 6: 3-(5'-tosyloxazolyl)-5,10-dioxo-1,3,4,5,10-pentahydro- naphtho-[2,3-c]-pyran (BCH-2155) A aolution of toayloxazolyl pyranoquinone from atep 5 herein in 4 ml of toluene and 0.5 ml of tetrahydrofuran (9 mg, 0.023 mmol) was heated with 1-acetoxy 1,3-butadiene (55 μl, 0.47 mmol) at 50°C for 20 hours.
Solvent was evaporated to dryness and the crude product was purified by means of chromatography (Tol:EtOAc-100:15) to give desired titled product as a light colored aolid (6.6 mg obtained).
M.P. >240°C.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 2.43 (3H, s,Ar CH3), 2.99 (2H, m, 4-CH2), 4.78 (1H, d tr, J = 18.8 Hz, 3.3 Hz, 1-HCHa), 4.96 (1H, d, J = 18.8 Hz, 1-HCHe), 5.57 (1H, dd, J = 8.9 Hz, 5.0 Hz, 3-CH), 7.36 (2H, d, J = 8.2 Hz, 3', δ'-tosyl-H), 7.75 (2H, m, 7, 8-ArH), 7.85 (1H, s, oxa- H), 7.92 (2H, d, J = 8.2 Hz, 2', 6'-tozyl-H), 8.11 (2H, m, 6, 9-ArH). IR (Nicolet 205 FT, film on NaCl plate): cm-1, 2955.7, 2921.3, 2854.0, 1662.8 (str), 1592.2, 1508.6, 1398.6, 1334.6, 1319.9, 1298. 5, 1147.6, 1106.6, 1086.9, 1013.0, 811.2, 794.8.
Example 48: Preparation of (1 ' S, 1S ,3R)-1-(3 ' -trifluoroacetamido-
2 ' ,3 ' ,6 ' -trideoxy-lyxo-L-hexopyranoae)-3- methoxycarbonyl-3-methyl-3,4,5 , 10-tetrahydro-5, 10- dioxo-naphtho-[2,3-c] pyran (BCH-2076)
Figure imgf000163_0001
Step 1: (1'S, 1S, 3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy-carbonyl-3- mathyl-5,8-dioxo-4,5,8-trihydro-1H-benso-[2,3-c]-pyran
(1'S,1S,3R) 1-(2',3',6'-trideoxy-3-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose-5,8-dimethoxy-3-aceto-3-methyliaochroman (62 mg, 0.0945 mmol) in acetonitrile (3 ml) was stirred at 0°C while a solution of ammonium cerium nitrate (165.5 mg, 0.284 mmol) in water (1.5 ml), pre-treated with aodium bicarbonate (15.1 mg, 0.18 mmol), was added dropwise. The solution was stirred for 5 minutes at 0°C then poured to water and extracted with dichloromethane. The organic layer was dried and evaporated to give desired titled product (40 mg, 0.064 mmol).
1H NMR (CDCl3 250 MΑz- Bruker): δ, 1.27 (3H, d, J = 6.5 Hz, 6'-CH3), 1.57 (3H, s, 3-CCH3), 1.91 (1H, dd, J = 11.8 Hz, 4.7 Hz, 2'-CH), 2.10 (1H, d tr, J = 11.8 Hz, 3.6 Hz, 2'-CH), 2.72 (1H, d, J = 17.9 Hz, 4-CH), 2.94 (1H, dd, J = 17.9 Hz, 0.9 Hz, 4-CH), 3.75 (3H, s, OCH3), 4.54 (1H, m, 3'-CH), 4.64 (1H, qua, J = 6.5 Hz, 5'-CH), 5.40 (1H, a, 4'-CH), 5.65 (1H, d, J = 2.4 Hz, 1'-CH), 6.06 (1H, a, 1-CH), 6.52 (1H, d, J = 8.2 Hz, NHCOCF3), 6.77 (1H, d, J = 10 Hz, Quin-H), 6.83 (1H, d, J = 10Hz, Quin- H), 8.27 (4H, m, PNB). IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3336.1, 3083.4, 2956.1, 2849.7, 1734.5, 1664.2, 1529.4, 1352.7, 1272.9, 1162.7, 989.8, 949.9, 839.70, 721.95. Step 2: (1'S, 1S, 3R)-1-(4'-p-nitrobensoyl-3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy-earbonyl-3- methyl-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran
The titled compound was obtained aa per procedure described in step 2, example 5, but using the quinone from atep 1 herein.
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.32 (3H, d, J = 6.6 Hz, 6'-CH3), 1.95 (1H, dd, J = 12.4 Hz, 5.0 Hz, 2'-CH), 2.10 (1H, d tr, J = 12.4 Hz, 3.5 Hz, 2'-CH), 2.88 (1H, d, J = 18.2 Hz, 4-CH), 3.13 (1H, dd, J = 18.2 Hz, 1.0 Hz, 4-CH), 3.75 (3H, s, OCH3), 4.56 (1H, m, 3'-CH), 4.76 (1H, qua, J = 6.6 Hz, 5'-CH), 5.45 (1H, s, 4'-CH), 5.72 (1H, d, J = 2.0 Hz, l'-CH), 6.26 (1H, s, 1-CH), 6.45 (1H, d, J = 7.1 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH), 8.29 (4H, m, PNB). IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3329.3, 2955.6, 2926.9, 2855.3, 1732.9, 1709.5, 1668.3, 1596.8, 1532.3, 1349.5, 1272.6, 1217.6, 1184.7, 1164.1, 996.5, 952.5, 729.90, 720.30.
Step 3: (1'S, 1S, 3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-5,10-dioxo-4,5,10-trihydro-1H-naphtho- [2,3-c]-pyran (BCH-2076)
The titled compound was obtained from the glycoside from step 2 herein via base hydrolysis as per procedure described in step 3, example 5. 1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.38 (3H, d, J = 6.0 Hz, 6'-CH3), 1.60 (3H, s, 3-CCH3), 1.85 (1H, d, J = 6.8 Hz, 4'-OH), 1.85 (1H, dd, J = 9.4 Hz, 2.6 Hz, 2'-HCHa), 1.96 (1H, d, J = 9.4 Hz, 2'-HCHe), 2.87 (1H, d, J = 18.8 Hz, 4-HCHa), 3.12 (1H, dd, J = 18.8 Hz, 0.6 Hz, 4-HCHe), 3.63 (1H, br d, J = 6.8 Hz, 4'-CH), 3.75 (3H, s, OCH3), 4.28 (1H, qua, J = 8.8 Hz, 3'-CH), 4.55 (1H, qua, J = 6.0 Hz, 5'-CH), 5.54 (1H, s, 1'- CH), 6.21 (1H, s, 1-CH), 6.71 (1H, br d, J = 9.4 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-ArH), 8.11 (2H, m, 6, 9-ArH),
IR (Nicolet , 205 FT, film on NaCl plate) : cm-1, 3420.1 (br str) , 2955.6, 1718.7, 1668.3, 1595.5, 1377.3 , 1329.7, 1287.7, 1161.8, 982.68, 921.12 , 730.64. Example 49: (1,3-trana)-anline-(1-methoxy-5, 10-dioxo-3, 4,5, 10- tetrahydro-1H-naphtho-[2,3-c]-pyran)-3-earboxam ide (BCH-2041) and (1,3-cis )-anline-(1-methoxy-5, 10-dioxo- 3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran)-3- earboxamide (BCH-2042)
Figure imgf000165_0001
Step 1:
The compound from atep 3, example 16, (21 mg, 0.0695 mmol) was diaaolved in acetonitrile (10 ml) and then cooled to 0°C. NaOH (0.1 N, 1.4 ml, 0.14 mmol) aolution was then added alowly. After 10 minutes, the brown solution was poured to water, extracted with ethyl acetate. The aqueous layer was acidified with dilute HCl and extracted with ethyl acetate. The organic layer containing acid was dried and evaporated to give a mixture of 3 products (18 mg). Chromatography (CHCl3/MeOH/HOAc =
100:15:2) allowed separation of the 3 compounds. One of the products was the same as the one obtained in atep 6, example 16, and had:
1H NMR (CD3COCD3, 250 MHz, Bruker): δ, 3.58 (3H, 8, OCH3), 6.36 (1H, s, 1-CH), 7.22 (1H, s, 4-CH), 7.91 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9- ArH). The second product ( 1, 3-trans )-1-methoxy-3-carboxyl-5 , 10-dioxo-3 , 4 , 5 , 10- tetrahydro-1H-naphtho- (2 , 3-c ]-pyran, BCH-2045 had:
1H NMR (CD3SOCD3 250 MHz, Bruker) : δ, 2.55 (1H, dd, J = 18.5 Hz, 12.4 Hz, 4-HCHa) , 2.88 (1H, dd, J = 18.5 Hz, 3.5 Hz , 4-HCHe), 3.47 (3H, s , OCH3 ) , 4.49 (1H, dd, J = 12.4 Hz, 3.5 Hz, 3-CH) , 5.55 (1H, 8, 1-CH) ,
7.88 (2H, m, 7 , 8-ArH) , 8.00 (2H, m, 6, 9-ArH) .
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3549.2-3183.8, 2922.8, 1722.1, 1289.0, 1107.4, 1012.3, 951.08, 808.9, 793.5.
The third product: (1,3-cis)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran, (BCH-2119), had:
1H NMR (CD3SOCD3 250 MHz, Bruker): δ, 1.28 (1H, dd, J = 15.3 Hz, 11.5 Hz, 4-HCHa), 2.58 (1H, dd, J = 11.5 Hz, 2.9 Hz, 4-HCHe), 3.45 (3H, 8, OCH3), 4.17 (1H, dd, J = 11.5 Hz, 2.9 Hz, 3-CH), 5.62 (1H, a, 1-CH),
7.89 (4H, m, 6, 7, 8, 9-ArH) .
Step 2: (1,3-trana)-1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo- 3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran, BCH-2041: A aolution of acid from atep 1 herein (20 mg, 0.069 mmol) in THF (4 ml) was cooled to 0°C. To the solution.was added DMF (1 μl, aa a catalyst) and then oxalyl chloride (12 μl, 0.138 mmol). The mixture was stirred at 0°C for 45 minutes and at room temperature for 20 minutes. Solvent was evaporated. The residue was redissolved in methylene chloride and then evaporated. The reaidue was dissolved again in methylene chloride (4 ml) and half of the volume was taken for coupling with aniline (4 μl, 0.044 mmol) as follows: To the ice-cold solution of the acid chloride was added aniline (1 eq. ) in 1 ml of methylene chloride. The reaction mixture was stirred for 10 minutes. It was poured to water and extracted with methylene chloride. The organic layer was dried and evaporated to give a crude product which was purified by
recrystallization from methylene chloride and hexane. The desired titled product was obtained (11 mg) as a light yellow solid.
M.P. 183-184°C.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 2.63 (1H, dd, J = 19.4 Hz, 12.5 Hz, 1-HCHa), 3.30 (1H, dd, J = 19.3 Hz, 4.2 Hz, 1-HCHe), 3-67 (3H, s, OCH3), 4.74 (1H, dd, J = 12.5 Hz, 4.5 Hz, 3-CH), 5.77 (1H, s, 1-CH), 7.16 (1H, tr, J = 8.5 Hz, 4'-Ani-H), 7.47 (2H, tr, J = 8.5 Hz, 3', 5'-Ani-H), 7.52 (2H, d, J = 8.5 Hz, 2', 6'-Ani-H), 7.75 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.31 (1H, s, NHCO). IR (Nicolet , 205 FT, film on NaCl plate) : cm-1, 3278.8, 2923.0, 1665.0, 1593.4, 1533.0, 1445.7, 1798.0, 1060.7, 960.0, 755.6, 688.2, 679.0. Step 3: (1,3-cis )-1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran, BCH-2042, A similar to the procedure described previously in step 2, the cis acid from step 1 herein was converted to the titled product.
M.P. 217-219°C.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 2.49 (1H, dd, J = 15.6 Hz, 11.2 Hz, 4-HCHa), 3.08 (1H, dd, J = 15.6 Hz, 3.2 Hz, 4-HCHe), 3.65 (3H, s, OCH3), 4.50 (1H, dd, J = 11.2 Hz, 3.2 H, 3-CH), 5.94 (1H, s, 1-CH), 7.14 (1H, tr, J = 7.6 Hz, p-Ani-H), 7.35 (2H, tr, J = 7.6 Hz, m-Ani-H), 7.56 (2H, d, J = 7.6 Hz, O-Ani-H), 7.78 (2H, m, 7, 8-ArH), 8.00 (2H, m, 6, 9-ArH), 8.21 (1H, 8, NHCO) .
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3353.5, 3052.9,
2928.1, 2853.9, 1694.6, 1597.5, 1531.8, 1443.3, 1300.6, 1172.1, 1117.8, 1060.7, 1043.6, 1026.5, 906.7, 750.6, 712.5, 692.6.
Example 50: Preparation of (1'S,1R,3S)-1-(3'-trifluoroacatamido-
2',3',6'-trideoxy-lyxohexpyranose)-3-(5"- tosyloxazolyl)-3,4,5,10-tetrahydro-5,10-dioxo-naphtho- [2,3-c] pyran (BCH-2150)
Figure imgf000168_0001
BCH-2150
Step 1: (1'S, 1S, 3R)-1-(4'-p-nitrobensoyl-2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohaxopyranose)-3-(5"-toayloxaaolyl)- 5,8-dimethoxy isochroman
To the compound from atep 4, example 47, (50 mg, 0.120 mmol) in dichloromethane (15 ml) atirred with 5'-p-nitrobenzoyl-3',4',7'- trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose (49 mg, 0.125 mmol) was added 1,2-dichloro-4,5-dicyano-benzoquinone (35.6 mg, 0.157 mmol). The resulting mixture was stirred for 18 hours at 40°C. Solvent was evaporated and the crude product was chromatographed (hexane/ethyl acetate=3/2) to give the titled compound (17 mg) and the (1'S,1R,3S) diastereomer (12 mg).
The titled compound had:
1H NMR (acetone-d6, 250 MHz, Bruker): δ, 1.27 (3H, d, J = 5.9 Hz, 6'- CH3), 2.14-2.30 (2H, m, 2'-CH2), 2.44 (3H, s, tosyl-CH3), 3.01 (2H, d, J = 6.5 Hz, 4-CH2 ) , 3.82 (3H, s , OCH3 ) , 3.92 (3H, s, OCH3 ) , 4.65 (1H, m, 3 '-CH) , 4.86 (1H, qua, J = 5.9 Hz, 5 ' -CH) , 5.71 (1H, d, J = 2.4 Hz, 4- CH) , 6.17 (1H, tr, J = 6.5 Hz, 3-CH) , 6.24 (1H, s, 1-CH) , 6.95 (2H, m, 6, 7-ArH) , 7.48 (2H, d, J = 7.4 Hz, 3" , 5"-tosyl-H) , 7.95 (2H, d, J = 7.4 Hz, 2 " , 6"-tosyl-H) , 8.38 (4H, m, PNB) , 8.37 (1H, s , oxa-H) , 8.66 (1H, d, J = 7.4 Hz, NHCOCF3 ) .
The (1'S, 1R, 3S)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3-(5"-tosyloxa-zolyl)-5,8- dimethoxy isochroman had:
1H NMR (acetone-d6, 250 MHz, Bruker): δ, 0.80 (3H, d, J = 6.8 Hz, 6'- CH3), 2.19 (1H, m, 2'-HCHa), 2.48 (1H, d tr, J = 11.8 Hz, 4.1 Hz, 2'- HCHe), 2.46 (3H, s, tosyl-CH3), 2.88 (1H, dd, J = 17.6 Hz, 11.8 Hz, 4- HCHa), 3.04 (1H, dd, J = 17.6 Hz, 4.4 Hz, 4-HCHe), 3.83 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.42 (1H, qua, J = 6.8 Hz, 5'-CH), 4.84 (1H, m, 3'- CH), 5.48 (1H, a, 4.'-CH), 5.58 (1H, d, J = 3.5 Hz, 1'-CH), 6.01 (1H, 8, 1-CH), 6.92 (1H, d, J = 6.5 Hz,Ar H), 6.96 (1H, d, J = 6.5 Hz, ArH), 7.54 (2H, d, J = 9.1 Hz, 3", 5"-tosyl-H), 8.06 (2H, d, J = 9.1 Hz, 2", 6"-tosyl-H), 8.35 (1H, s, oxa-H), 8.49 (4H, m, PNB), 8.62 (1H, d, J = 6.8 Hz, NHCOCF3).
Step 2: (1'S, 1S, 3R)-1-(4'-p-nitrobansoyl-2',3',6'-trideoxy-3'- trifluoroacetamaido-L-lyxohexopyranose)-3-(5"-tosyloxaaolyl)- 5,8-dioxo-3,4,5,8-tetrahydrobenso-[2,3-c]-pyran. The compound from step 1 herein (17 mg, 0.021 mmol) in acetonitrile (2 ml) was cooled to 0°C and ammonium cerium nitrate (35.5 mg, 0.0648 mmol, pretreated with sodium bicarbonate, 3.6 mg, 0.042 mmol) was added dropwise. The reaction mixture was stirred for 15 minutes at 0°C then poured to water. It was extracted with dichloromethane. The organic phase was washed with brine, dried (over sodium sulfate) and evaporated to give a crude product which was purified on silica gel (hexane/EtOAc = 2:1) to give the desired titled product (7 mg).
1H NMR (acetone-d6, 250 MHz, Bruker): δ, 1.04 (3H, d, J = 6.5 Hz, 6'- CH3), 2.12-2.35 (2H, m, 2'-CH2), 2.45 (3H, a, tosyl-CH3), 2.80-2.93 (2H, m, 4-CH2), 4.55 (1H, qua, J = 6.5 Hz, 5'-CH), 4.86 (1H, m, 3'-CH), 5.49 (1H, s, 4'-CH), 5.61 (1H, d, J = 2.1 Hz, 1'-CH), 5.85 (1H, s, 1-CH), 6.12 (1H, dd, J = 10.6 Hz, 4.7 Hz, 3-CH), 6.80 (1H, d, J = 10.6 Hz, Quin-H), 6.85 (1H, d, J = 10.6 Hz, Quin-H), 7.48 (2H, d, J = 8.8 Hz, 3", 5"-tosyl-H) , 7.88 (1H, s , oxa-H) , 7.94 (2H, d, J = 8.8 Hz, 2" , 6"-tosyl- H) , 8.28 (4H, m, PNB) .
Step 3: (1'S, 1R, 3S)-1-(4'-p-nitrobensoyl-3-trifluoroacetamido- 2 ',3',6,-trideoxy-L-lyxohexopyranose)-3-(5"-tosyl-oxaaolyl)-
5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
The compound from step 2 herein (9 mg, 0.012 mmol) was stirred with 1- acetoxy-1,3-butadiene (28 μl, 0.236 mmol) in toluene (4 ml) and THF (0.5 ml) at 50°C for 18 houra. Solvent was evaporated and the crude product was chromatographed (toluene/ethyl acetate = 5/1) to give the desired titled product (4.8 mg).
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.06 (3H, d, J = 6.2 Hz, 6'-CH3), 2.00 (1H, d tr, J = 11.5 Hz, 2.9 Hz, 2'-HCHa), 2.25 (1H, dd, J = 11.5 Hz, 4.4 Hz, 2'-HCHe), 2.44 (3H, 8, tosyl-CH3), 2.98 (1H, d, J = 5.6 Hz, 4-CH), 2.99 (1H, d, J = 11.0 Hz, 4-CH), 4.60 (1H, qua, J = 6.2 Hz, 5'- CH), 4.87 (1H, m, 3'-CH), 5.40 (1H, 8, 4'-CH), 5.72 (1H, d, J = 2.0 Hz, 1'-CH), 6.05 (1H, 8, 1-CH), 6.19 (1H, dd, J = 11.0 Hz, 5.6 Hz, 3-CH), 6.66 (H, d, J = 6.5 Hz, NHCOCF3), 7.49 (2H, d, J = 8.8 Hz, 3", 5"-tosyl- H), 7.79 (2H, m, 7, 8-ArH), 7.90 (1H, 8, oxa-H), 7.95 (2H, d, J = 8.8 Hz, 2", 6"-toayl-H), 8.13 (2H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
Step 4: (1'S, 1R, 3S)-2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose-3-[5'-tosyloxasolyl)-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2150)
To the compound from step 3 herein (4.8 mg, 5.92 mmol) in THF (0.5 ml) and methanol (1.5 ml) cooled to 0°C was added aodium methoxide (4.37 M, 1.4 μl, 5.92 mmol). After 5 minutes, the reaction was quenched with dilute hydrochloride acid and extracted with methylene chloride. The organic layer was dried (over Na2SO4) and evaporated to give a crude product which was purified on TLC (CHCl3:MeOH = 100:7) to give desired titled product as an off-white solid (1.3 mg).
M.P. 130-135°C.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.13 (3H, d, J = 6.5 Hz, 6'-CH3), 1.78 (1H, tr d, J = 11.2 Hz, 2'-HCHa), 2.05 (1H, m, 2'-HCHe, due to solvent overlap, this is an estimation), 2.43 (3H, s, tol-CH3), 2.92 (1H, d, J = 5.9 Hz, 4-HCHa), 2.94 (1H, d, J = 10.5 Hz, 4-HCHe), 3.71 (1H, m, 4'-OH), 4.20 (1H, dd, J = 5.9 Hz, 3-2 Hz, 4'-OH), 4.47 (1H, qua, J = 6.5 Hz, 5'-CH3), 4.58 (1H, m, 3'-CH), 5.55 (1H, d, J = 3.0 Hz, 1'- CH), 5.99 (1H, s, 1-CH), 6.16 (1H, dd, J = 10.6 Hz, 5.9 Hz, 3-CH), 6.77 (1H, d, J = 10.6 Hz, NHCOCF3), 7.36 (2H, d, J = 8.8 Hz, tosyl-H), 7.79 (2H, m, 7, 8-ArH), 7.90 (1H, s,. oxa-H), 7.91 (2H, d, J = 8.8 Hz, tosyl- H), 8.11 (2H, m, 6, 9-ArH).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3379.1, 2956.4, 2927.8, 2854.7, 1716.9, 1669.3, 1335.6, 1297.4, 1148.0, 985.2.
Example 51: Preparation of (1'S,1S,3R)-1-(3'trifluoroacetamido- 2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-(5"- tosyloxasolyl)-3,4,5,10-tetrahydro-5,10-dioxo-naphtho- [2,3-c] pyran (BCH-2151)
Figure imgf000171_0001
Step 1: (1'S, 1S, 3R)-1-(4'-p-nitrobensoyl-2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3-(5"-tosyloxasolyl)- 5,8-dioxo-3,4,5,8-tetrahydrobenao-[2,3-c]-pyran Starting with the (1'S,1S,3R) diastereomer from step 1, example 50, (12 mg, 0.015 mmol), using the same materials (amm onium cerium nitrate, 25 mg, 0.046 mmol; NaHCO3, 2.55 mg, 0.0304 mmol; acetonitrile, 1.5 ml; H2O, 0.4 ml) and following the same procedures as described in atep 2, example 50, the desired titled product was obtained (9 mg). 1H NMR (acetone-d6, 250 MHz, Bruker) : δ, 1.27 (3H, d, J = 6.6 Hz, 6 ' - CH3 ) , 2.20 (2H, m, 2 '-CH2 ) , 2.45 (3H, 8, tosyl-CH3) , 2.95 (1H, d, J = 6.8 Hz, 4-CH) , 2.95 (1H, d, J = 8.8 Hz, 4-CH) , 4.56 (1H, m, 3 '-CH) , 4.74 (1H, qua, J = 6.6 Hz, 5 ' -CH) , 5.53 (1H, s, 4 '-CH) , 5.68 (1H, d, J = 2.9 Hz, 1 '-CH) , 6.01 (1H, s, 1-CH) , 6.09 (1H, dd, J = 8.8 Hz, 6.8 Hz, 3-CH) , 6.93 (1H, d, J = 11.8 Hz, Quin-H) , 6.96 (1H, d, J = 11.8 Hz, Quin-H) , 7.49 (2H, d, J = 8.8 Hz, 3" , 5"-tosyl-H) , 7.93 (2H, d, J = 8.8 Hz, 2" , 6"-tosyl-H) , 8.36 (1H, s, oxa-H) , 8.39 (4H, m, PNB) , 8.68 (1H, d, J = 8.8 Hz, NHCOCF3) .
Step 2 : (1 ' S, 1S, 3R)-1-(4 ' -p-nitrobensoyl-3-trifluoroacetamido-
2',3',6'-trideoxy-L-lyxohexopyranose)-3-(5"-tosyl-oxasolyl)- 5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran The compound from step 2 herein (7 mg, 0.009 mmol) was reacted with 1- acetoxy-1,3-butadiene (21 μl, 0.184 mmol) in toluene (3 ml) at 50°C for 18 hours. The solvent was evaporated to give a crude product, After chromatography (toluene/ethyl acetate = 5:1) desired titled product was obtained (6.4 mg ).
4H NMR (CDCI3 250 MHz, Bruker): δ, 1.34 (3H, d, J = 7.1 Hz, 6'-CH3), 2.15 (1H, d tr, J = 12.9 Hz, 4.1 Hz, 2'-HCHa), 2.32 (1H, dd, J = 12.9 Hz, 4.1 Hz, 2'-HCHe), 2.45 (3H, a, tosyl-CH3), 2.96 (1H, dd, J = 18.2 Hz, 4.1 Hz, 4-HCHa), 3.13 (1H, dd, J = 18.2 Hz, 11.2 Hz, 4-HCHe), 4.64 (1H, m, 3'-CH), 4.77 (1H, qua, J = 7.1 Hz, 5'-CH), 5.52 (1H, s, 4'-CH), 5.76 (1H, d, J = 2.0 Hz, 1'-CH), 6.08 (1H, dd, J = 11.2 Hz, 4.1 Hz, 3- CH), 6.20 (1H, 8, 1-CH), 6.21 (1H, m, HNCOCF3), 7.37 (2H, d, J = 8.2 Hz, 3", 5"-tosyl-H), 7.71 (2H, m, 7, 8-ArH), 7.89 (2H, d, J = 8.2 Hz, 2", 6"-tosyl-H), 7.90 (1H, s, oxa-H), 8.15 (1H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
Step 3: (1'S, 1S, 3R)-2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose-3-[5'-tosyloxasolyl))-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-C]-pyran (BCH-2151) To PNB derivative from step 2 herein (6.4 mg, 0.0079 mmol) stirred in tetrahydrofuran (0.5 ml) and methanol (1.5 ml) at 0°C was added aodium methoxide (4.373 M, 1.8 μl, 0.0079 mmol). After 5 minutes, the pink solution was quenched with dilute HCl. The product was extracted with methylene chloride. The organic layer was dried and evaporated to give a crude product which was purified by thin-layer-chromatography
(CHCl3:MeOH = 100:7) to desired titled product as an off-white solid
(0.8 mg).
M.P. 100-105°C.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.41 (3H, d, J = 5.9 Hz, 6'-CH3),
1.92 (1H, tr d, J = 11 Hz, 3.5 Hz, 2'-HCHa, estimation), 2.20 (1H, m,
2'-HCHe, estimation), 2.44 (3H, s, tol-CH3), 2.95 (1H, dd, J = 18.5 Hz,
4.7 Hz, 4-HCHe), 3.12 (1H, dd, J = 18.5 Hz, 11.2 Hz, 4-HCHa), 4.00 (1H, m, 4'-CH), 4.37 (m, 1H, 3'-CH), 4.60 (1H, qua, J = 5.9 Hz, 5'-CH), 5.10 (1H, br 8, 4'-OH, estimation), 5.58 (1H, d, J = 3.5 Hz, 1'-CH), 6.05 (1H, dd, J = 11.2 Hz, 4.7 Hz, 3-CH), 6.15 (1H, s, 1-CH), 6.66 (1H, m,
NHCOCF3), 7.36 (2H, d, J = 8.8 Hz, tosyl-H), 7.78 (2H, m, 7, 8-ArH),
7.87 (1H, s, oxa-H), 7.88 (2H, d, J = 8.8 Hz, tosyl-H), 8.12 (2H, m, 6,
9-ArH).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3368.3 2961.8, 2930.2,
2848.9, 1715.0, 1669.9, 1463.0, 1332.8, 1289.0, 1153.4, 975.46.
Example 52: Preparation of (1,3-trans)-1-methoxy-3-(3'- aminothiasolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho [2,3-c]-pyran (BCH-1616) and (1,3-trans)-1- methoxy-3-dimethoxyphosphonoacetyl-5,10-dioxo- 3,4,5,10-tetrahydro-1H-naphtho [2,3-c]-pyran (BCH- 1674)
Figure imgf000173_0001
Step 1: 1-methoxy-3-acetyl-5,8-dioxo-3,4,5,8-tetrahydrobenso-[2,3- c]-pyran A sample of 5,8-dimethoxy-1-hydroxy-3-acetoisochroman (200 mg, 0.79 mmol) in MeOH (10 ml) was stirred at room temperature while a solution of CAN (2.16 g, 3.95 mmol) in water (9 ml) was added dropwiae. After 5 minutes, the reaction mixture was poured to water and then extracted with methylene chloride. The organic layer was dried (over sodium sulfate), and evaporated to give a yellow sticky solid (157 mg). 1H NMR showed that desired titled product was obtained with 89% purity.
1H NMR (CDCl3, 250 MHz Bruker), δ: 2.28 (s, 3H, COCH3), 2.35 (dd, 1H, J = 20.5 Hz, 12.1 Hz, 4-Ha), 2.78 (dd, 1H, J = 20.5 Hz, 4.3 Hz, 4-He), 3.56 (s, 3H, OCH3), 4.44 (dd, 1H, J = 12.1 Hz, 4.3 Hz, 3-H), 5.46 (s, 1H, 1-H), 6.73 (m, 2H, 6.7-quinone).
Step 2: 1-methoxy-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-c]-pyran The bicyclic quinone from step 1 herein (157 mg, 0.66 mmol) was stirred with 1-acetoxy-1,3-butadiene (632 μl, 5.32 mmol) in toluene (20 ml) at 40°C for 16 hours. Solvent was evaporated and the crude product was chromatographed (toluene:EtOAc = 100:25) to give desired titled tricyclic quinone as a yellow solid (190 mg).
M.P. 169.8-170.8°C.
1H NMR (CDCl3, 250 MHz Bruker), δ: 2.34 (s, 3H, COCH3), 2.53 (dd, 1H, J = 20.7 Hz, 10.7 Hz, 4-Ha), 3.00 (dd, 1H, J = 10.7 Hz, 4.3 Hz, 4-He), 3.63 (s, 3H, OCH3), 4.54 (dd, 1H, J = 10.7 Hz, 4.3 Hz, 3-H), 5.66 (s, 1H, 1-H), 7.73 (m, 2H, 7.8-ArH), 8.06 (m, 2H, 6.8-ArH).
IR (Nicolet 205 FT, film on NaCl plate), cm-1: 2923.4, 2827.6, 1717.7, 1668.2, 1637.3, 1597.1, 1368.3, 1331.3, 1300.3, 1281.8, 1179.8, 1105.6, 1083.9, 1046.8, 875.5, 799.8, 714.2, 686.1.
Step 3: 3-broaoacethyl-1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-c]-pyran
To a solution of product from step 2 herein (50 mg, 0.175 mmol) in THF (3 ml) at room temperature was added pyridinium hydrobromide perbromide (1.3 eq. ) in THF (2 ml). The mixture was stirred for 45 minutes at room temperature. It was poured to water and extracted with methylene chloride. The organic layer was dried and evaporated to give a product. TLC and 1H NMR both ahowed that the desired titled product (76 mg) was obtained with purity >90%.
M.P. 169.8-170.8°C.
1H NMR (CDCl3, 250 MHz Bruker), δ: 2.53 (dd, 1H, J = 20.3 Hz, 11.0 Hz, 4-Ha), 3.02 (dd, 1H, J = 20.3 Hz, 4.1 Hz, 4-He), 3.64 (8, 3H, OCH3), 4.15 (d, 1H, J = 12.7 Hz, BrCHAH), 4.35 (d, 1H, J = 12.7 Hz, Br CHHB), 4.84 (dd, 1H, J = 11.0 Hz, 4.1 Hz, 3-H), 5.65 (s, 1H, 1-H), 7.72 (m, 2H, 7.8-ArH), 8.02 (m, 2H, 6.9-ArH).
Step 4: (1,3-trans)-1-methoxy-3-(3'-aminothiasolyl)-5,10-dioxo- 3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH-1616) Bromomethyl ketone from step 3 herein (20 mg, 0.054 mmol) was atirred with thiourea at room temperature for 3.5 hours in ether (2 ml) and dichloromethane (2 ml). It was poured to sat. sodium bicarbonate and extracted with dichloromethane. The organic layer was evaporated to give crude product which was chromatographed (MeOH:CHCl3:HOAc = 4:100:1) to give desired titled product (5.3 mg). A polar by-product was also obtained (8 mg).
1H NMR (CDCI3, 250 MHz Bruker), δ: 2.77 (1H, dd, J = 18.8 Hz, 11.8 Hz, 4-HCHa), 3.00 (1H, dd, J = 18.8 Hz, 5.2 Hz, 4-HCHe), 3.63 (3H, s, OCH3), 5.03 (1H, dd, J = 11.8 Hz, 5.2 Hz, 3-CH), 5.67 (1H, B, 1-CH), 6.53 (1H, s, thia-H), 7.73 (2H, m, 6, 9-ArH), 8.08 (2H, m, 7, 8-ArH).
IR (Nicolet 205 FT, film on NaCl plate), cm-1: 3429.8, 3346.7, 3130.7, 2957.8, 2921.3, 2854.8, 1664.9, 1641.6, 1591.7, 1521.9, 1455.5, 1408.9, 1327.1, 1294.1, 1102.0, 1039.9, 731.92, 708.07. Step 5: 1-methoxy-3-dimethyl phosphonoacetyl-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1674) A solution of bromomethylketone from step 3 herein (10 mg, 0.027 mmol) was refluxed with trimethylphosphite (3.54 μl, 0.03 mmol) and sodium iodide (0.2 mg, 0.05 mmol) in THF at 70°C overnight. Solvent was evaporated and the brown residue was chromatographed (CHCl3:MeOH 50:1) to give desired titled product as a light-colored solid (2 mg).
2H NMR (CDCI3, 250 MHz, Bruker): δ, 2.60 (1H, dd, J = 19.8 Hz, 11.6 Hz 4-HCHa), 2.94 (1H, dd, J = 19.8 Hz, 3.5 Hz, 4-HeCH), 3.62 (3H, s, 1- OCH3), 3.85 (3H, s, POCH3), 3.88 (3H, 8, POCH3), 4.59 (1H, dd, J = 11.6 Hz, 3.5 Hz, 3-CH), 5.02 (1H, br s, CHP), 5.15 (1H, br s, CHP), 5.62 (1H, s, 1-CH), 7.73 (2H, m, 6, 9 -ArH), 8.08 (2H, m, 7, 8 -ArH). Example 53: Preparation of (1'S,1R,3S)-1-(3'-trifluoroacetamido- 2',3',6'-trideoxy-L-lyxohexopyranoas)-3- methoxycarbonyl-3-methyl-3,4,5,10-tetrahydro-5,10- dioxo-1H-naphtho-[2,3-c] pyran (BCH-2077)
Figure imgf000176_0001
Step 1: 3-methoxycarbonyl-3-methyl-5,8-dimethoxy isochroman A solution of di-iaopropylamine (616.8 μl, 4.37 mmol) in THF (10 ml) was cooled to 0°C and degassed briefly. n-Butyl lithium (1.6 M in hexane, 2.60 ml, 4.17 mmol) was added, After stirred for 30 minutes at 0°C, the solution was further cooled to -78°C. A solution of 5,8-dimethoxy-3- methoxycarbonylisochroman (1.0 g, 3.97 mmol) in THF (10 ml), predegassed, was added slowly. The resulting yellow solution was stirred for 1 hour at -78°C before the addition of methyliodide (1.01 ml, 16 mmol). After atirred further for 45 minutes, sat. NH4Cl aolution was added. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and evaporated to give a crude product which was chromatographed (hexane:EtOAc = 3:1) to give the desired product as a solid (650 mg, m p. 73.0-74.5°C) and another fraction (192 mg) which contained 66% of titled product and 34% of the starting material.
M.P. 73-74.5°C
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.50 (3H, s, 3-CCH3), 2.58 (1H, d, J = 17.1 Hz, 4-CH), 3.25 (1H, d, J = 17.1 Hz, 4-CH), 3.64 (3H, s, OCH3), 3.68 (3H, s, OCH3), 3.72 (3H, 8, OCH3), 4.76 (1H, d, J = 17.1 Hz, 1-CH), 4.84 (1H, d, J = 17.1 H, 1-CH), 6.53 (1H, d, J = 7.1 Hz, ArH), 6.59 (1H, d, J = 7.1 Hz,ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 2949.9, 2833.2, 1736.6, 1489.0, 1365.2, 1344.0, 1259.1, 1206.0, 1142.3, 1114.0, 1060.7, 295.7, 713.8.
Step 2: (1'S, 1R, 3S)-1-(4'-p-nitrobensoyl-3'-trifluoroacatamido-
2 ' ,3 ' ,6 ' -trideoxy-Llyxohexopyranose)-3-methoxy-carbonhyl-3- methyl-5,8-dimethoxy-isochroman .
The compound from step 1 herein (133 mg, 0.5 mmol) was reacted with DDQ (136 mg, 0.6 mmol) and 5'-p-nitrobenzoyl-3',4',7'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose (196 mg, 0.5 mmol) at 45°C for 16 hours, the same way as described in step 2, example 13. After
chromatography (hexane:EtOAc = 2.5:1), four isomers were obtained: C, 49 mg; B, 24 mg; D, 73 mg; A, 56 mg.
For C, 1H NMR (CDCl3 250 MHz, Bruker): δ, 1.22 (3H, d, J = 6.1 Hz, 6'- CH3), 1.45 (3H, s, 3-CCH3), 1.89 (1H, dd, J = 11.8 Hz, 4.7 Hz, 2'-CH), 2.05 (1H, d, tr, J = 11.8 Hz, 3.0 Hz, 2'-CH), 2.77 (1H, d, J = 17.1 Hz, 4-CH), 3.82 (1H, d, J = 17.1 Hz, 4-CH), 3.64 (3H, a, OCH3), 3.78 (3H, s, OCH3), 3.81 (3H, 8, OCH3), 4.52 (1H, m, 3'-CH), 4.60 (1H, qua, J = 6.1 Hz, 5'-CH), 5.42 (1H, 8, 4'-CH), 5.74 (1H, d, J = 1.7 Hz, 1'-CH), 6.22 (1H, s, 1-CH), 6.36 (1H, d, J = 8.2 Hz, NHCOCF3), 6.71 (1H, d, J = 8.8 Hz, ArH), 6.80 (1H, d, J = 8.8 Hz, ArH), 8.28 (4H, m, PNB). IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3328.4, 3077.3, 2946.4, 2843.8, 1740.1, 1527.9, 1492.5, 1259.1, 1114.0, 1054.2, 974.90, 947.90, 803.50, 716.80
The (1'S, 1S, 3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'- trideoxylyxohexopyranose)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- isochroman had:
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.16 (3H, d, J = 7.3 Hz, 6'-CH3), 1.63 (3H, s, 3-CCH3), 2.02 (2H, m, 2'-CH2), 2.86 (1H, d, J = 15.9 Hz, 4- CH), 3.21 (1H, d, J = 15.9 Hz, 4-CH), 3.65 (3H, 8, OCH3), 3.76 (6H, s, 2xOCH3), 4.10 (1H, qua, J = 7.2 Hz, 5'-CH), 4.61 (1H, m, 3'-CH), 5.45 (1H, s, 4'-CH), 5.55 (1H, s, 1'-CH), 6.24 (1H, a, 1-CH), 6.68 (1H, d, J = 9.4 Hz,Ar H), 6.76 (1H, d, J = 9.4 Hz,Ar H), 6.23 (1H, a, NHCOCF3), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3332.0, 2924.7, 2857.1, 1732.5, 1708.0, 1531.6, 1488.5, 1353.3, 1265.1, 1167.0, 957.18, 718.76. The (1'S, 1S, 3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'- trideoxy-L-lyxohexopyranose)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- isochroman had:
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.19 (3H, d, J = 6.1 Hz, 6'-CH3), 1.60 (3H, a, 3-CCH3), 1.87 (1H, dd, J = 12.4 Hz, 4.7 Hz, 2'-CH), 2.11 (1H, d tr, J = 12.4 Hz, 3.0 Hz, 2'-CH), 2.86 (1H, d, J = 16.5 Hz, 4-CH), 3.33 (1H, d, J = 16.5 Hz, 4-CH), 3.62 (3H, a,OCH3), 3.78 (6H, s,
2xOCH3), 4.54 (1H, qua, J = 6.1 Hz, 5'-CH), 4.57 (1H, m, 3'-CH), 5.41 (1H, s, 4'-CH), 5.69 (1H, d, J = 2.9 Hz, 1'-CH), 6.40 (1H, 8, 1-CH), 6.45 (1H, d, J = 7.6 Hz, NHCOCF3), 6.71 (1H, d, J = 8.9 Hz,ArH), 6.81 (1H, d, J = 8.9 Hz,Ar H), 8.24 (4H, 8, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3325.5, 3077.2 2951.9, 2541.1, 1737.3, 1705.9, 1609.5, 1530.0, 1489.0, 1354.1, 1264.9, 970.9, 951.60, 804.80, 720.90.
The (1'S, 1R, 3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'- trideoxy-L-lyxohexopyranose)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- isochroman had:
1H NMR (CDCI3 250 MHz, Bruker): δ, 1.20 (3H, d, J = 6.0 Hz, 6'-CH3), 1.53 (3H, s, 3-CCH3), 1.93 (1H, dd, J = 11.8 Hz, 2.9 Hz, 2'-CH), 2.05 (1H, m, 2'-CH), 2.60 (1H, d, J = 16.5 Hz, 4-CH), 3.39 (1H, d, J = 16.5 Hz, 4-CH), 3.73 (3H, 8, OCH3), 3.76 (3H, 8, OCH3), 3.80 (3H, s, OCH3), 4.71 (1H, m, 3'-CH), 4.86 (1H, qua, J = 6.0 Hz, 5'-CH), 5.45 (1H, s, 4'-CH), 5.55 (1H, d, J = 1.74 Hz, 1'-CH), 6.01 (1H, s, 1-CH), 6.49 (1H, d, J = 6.8 Hz, NHCOCF3 ) , 6.24 (1H, d, J = 10.2 Hz, ArH) , 6.82 (1H, d, J = 10.2 Hz, ArH) , 8.29 (4H, s , PNB) .
Step 3: (1'S, 1R, 3S)-1-(4'-p-nitrobensoyl-3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxohexopyranose)-3-methoxycarbonyl-3- methyl-5,8-dioxo-4,5,8-trihydro-1H-benso-[2,3-c]-pyran
The titled compound was obtained via CAN oxidation (step 3, example 13) of the (1'S,1R,3S) precursor from step 2 herein.
1H NMR (CDCI3 250 MHz, Bruker): δ, 1.30 (3H, d, J = 6.5 Hz, 6'-CH3),
1.57 (3H, s, 3-CCH3), 1.93-2.05 (2H, m, 2'-CH2), 2.36 (1H, d, J = 20 Hz, 4-CH), 3.31 (1H, d, J = 20 Hz, 4-CH), 3.67 (3H, s, OCH3), 4.46 (1H, m, 3'-CH), 4.66 (1H, qua, J = 6.5 Hz, 5'-CH), 5.36 (1H, s, 4'-CH), 5.62 (1H, B, 1'-CH), 5.93 (1H, 8, 1-CH), 6.56 (1H, d, J = 7.1 Hz, NHCOCF3), 6.77 (1H, d, J = 9.7 Hz, Quin-H). 6.85 (1H, d, J = 9.7 Hz, Quin-H), 8.30 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3347.1, 2924.7, 2851.4, 1736.3, 1663.1, 1527.9, 1351.4, 1272.6, 1167.4, 951.60, 837.00, 718.80. step 4: (1'S, 1R, 3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido- 2 ',3',6'-trideoxy-lyxohexopyranose)-3-methoxy-carbonyl-3- methyl-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran
The titled compound was obtained following cycloaddition between 1- acetoxybutadiene and the precursor from step 3 herein as per previoualy deacribed procedure.
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.34 (3H, d, J = 6.5 Hz, 6'-CH3),
1.59 (3H, s, 3-CCH3), 1.90-2.10 (2H, m, 2'-CH2), 2.50 (1H, d, J = 19.4
Hz, 4-CH), 3.49 (1H, d, J = 19.4 Hz, 4-CH), 3.65 (3H, s, OCH3), 4.46 (1H, m, 3'-CH), 4.79 (1H, qua, J = 6.5 Hz, 5'-CH), 5.40 (1H, br a, 4'-
CH), 5.65 (1H, d, J = 2.5 Hz, 1'-CH), 6.10 (1H, a, 1-CH), 6.51 (1H, d, J = 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH),
8.31 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate) : cm-1, 3333.8, 2919.5, 2851.0, 1739.0, 1667.4, 1533.4, 1790.5, 1271.8, 1212.6, 1187.7, 1103.6, 994.58,
949.75, 723.70. Step 5: (1'S, 1R, 38)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-5,10-dioxo-4,5,10-trihydro-1H-naphtho- [2,3-c]-pyran (BCH-2077) The titled compound was obtained following methanolysis of the precursor from step 4.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.39 (3H, d, J = 6.0 Hz, 6'-CH3), 1.58 (3H, s, 3-CCH3), 1.77 (1H, dd, J = 12.0 Hz, 4.1 Hz, 2'-HCHa), 1.84 (1H, dd, J = 12.1 Hz, 5.9 Hz, 2'-HCHa), 1.96 (1H, d, J = 8.7 Hz, 4'-OH), 2.48 (1H, d, J = 19.5 Hz, 4-HCHa), 3.47 (1H, d, J = 19.5 Hz, 4-HCHe), 3.60 (1H, d, J = 8.7 Hz, 4'-CH), 3.64 (3H, s, OCH3), 4.17 (1H, m, 3'- CH), 3.56 (1H, qua, J = 6.0 Hz, 5'-CH), 5.46 (1H, d, J = 2.9 Hz, 1'-CH), 6.05 (1H, s, 1-CH), 6.71 (1H, d, J = 8.8 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3420.6, 2934.5, 1735, 1721.8, 1665.8, 1291.8, 1182.3, 1166.3, 1112.9, 776.7, 944.6, 912.6, 728.97.
Example 54: Preparation of (1'S,1S,3R)-1-(3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3- methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c] pyran (BCH-2082)
Figure imgf000180_0001
Step 1: (1'S, 1S, 3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-3-methyl-5,10-dioxo-4,5,10- trihydro-1H-naphtho-[2,3-c)-pyran (BCH-2082) Methanolysis of the p-nitrobenzoylated precuraor yielded the titled product.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.31 (1H, d, J = 6.6 Hz, 6'-CH3), 1.45 (3H, s, 3-CCH3), 1.80 (1H, d, J = 8.8 Hz, 2'-CH), 1.81 (1H, d, J = 10 Hz, 2'-CH), 2.24 (3H, S, COCH3), 2.52 (1H, d, J = 18.5 Hz, 4-HCHa), 3.38 (1H, d, J = 18.5 Hz, 4-HCHe), 3.60 (1H, br 8, 4'-CH), 4.19 (1H, br qua, J = 10 Hz, 3'-CH), 4.41 (1H, qua, J = 6.6 Hz, 5'-CH), 5.45 (1H, a, 1'-CH), 6.13 (1H, s, 1-CH), 6.63 (1H, d, J = 10 Hz), 7.75 (2H, m, 7, 8- ArH), 8.09 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3375.1 (br str), 3091.1, 2929.6, 1715.2, 1671.2, 1597.7, 1293.3, 1172.9, 981.5, 729.22.
Example 55: Preparation of (1'S,1S,3R)-1-(3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxo-L-hexopyranose)-3- dimathoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH-1690)
Figure imgf000181_0001
Step 1: (1'S,1S,3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3-dimethylphoaphonoacetyl-5,10-dioxo- 3,4,5-10-tetrahydro-1H-naphtho-[2,3-c)-pyran (BCH-1690) The p-nitrobenzoyl precuraor was hydrolyzed with catalytic sodium methoxide in methanol aa per previously described procedure. The titled compound had:
M.P. 91-93°C,
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.40 (3H, d, J = 7.6 Hz, 6'-CH3), 1.89 (2H, m, 2'-CH2), 2.62 (1H, dd, J = 18.2 Hz, 11.8 Hz, 4-HCHa), 3.00 (1H, dd, J = 18.2 Hz, 4.1 Hz, 4-HCHe), 3.65 (1H, br s, 4-CH), 3.83 (3H, s, POCH3), 3.87 (3H, 8, POCH3), 4.32 (1H, qua, J = 7.6 Hz, 5'-CH), 4.56 (1H, m, 3-CH), 4.99 (1H, br s CHP), 5.13 (1H, br s, CHP), 5.44 (1H, s, 1'-CH), 6.09 (1H, s, 1-CH), 6.83 (1H, br d, J = 7.6 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-ArH), 8.09 (2H, m, 6, 9-ArH).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3421.9, 2958.3, 1716.0, 1665.6, 1592.5, 1287.6, 1181.8, 1045.7, 977.7, 858.4, 727.5. Example 56 : Preparation of (1 ' S, 1S,38)-1-(3 ' -trifluoroacetamido- 2 ' ,3 ' ,6 '-trideoxy-lyxo-L-hexopyranose)-3- methoxycarbonyl-3-methyl-3,4,5, 10-tetrahydro-5, 10- dioxo-naphtho- [2, 3-c] pyran (BCH-2081)
Figure imgf000182_0001
Step 1: (1'S, 1S, 3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido- 2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy-carbonyl-3- methyl-5,8-dioxo-4,5,8-trihydro-1H-benxo-[2,3-c]-pyran.
CAN oxidation of the (1'S,1R,3S)' precuraor from step 2, example 53, yielded the titled compound.
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.14 (3H, d, J = 6.0 Hz, 6'-CH3), 1.61 (3H, 8, 3-CCH3), 1.96 (1H, d tr, J = 11.7 Hz, 4.1 Hz, 2'-CH), 2.10 (1H, dd, J = 11.7 Hz, 2.9 Hz, 2'-CH), 2.58 (1H, d, J = 18.2 Hz, 4-CH), 3.00 (1H, d, J = 18.2 Hz, 4-CH), 3.71 (3H, 8, OCH3) 4.50 (1H, qua, J = 6.0 Hz, 5'-CH), 4.60 (1H, m, 3'-CH), 5.42 (1H, s, 4'-CH), 5.56 (1H, s, 1'-CH), 6.03 (1H, B, 1-CH), 6.58 (1H, d, J = 7.4 Hz, NHCOCF3), 6.72 (1H, d, J = 8.8 Hz, Quin-H), 6.78 (1H, d, J = 8.8 Hz, Quin-H), 8.24 (4H, br s, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3340.0, 3084.6, 2950.7, 2857.2, 1732.8, 1664.3, 1533.4, 1349.7, 1268.7, 1159.7, 1013.3, 955.70, 837.03, 735.00. Step 2 : (1 ' S, 1S, 3S)-1-(4 '-p-nitrobensoyl-3 ' -trifluoroacetamido-
2 ' ,3 ' ,6 '-trideoxy-lyxohexopyranose)-3-methoxy-carbonyl-3- methyl-5, 10-dioxo-4,5, 10-trihydro-1H-naphtho-[2,3-c]-pyran
The titled compound was obtained following cycloaddition between 1- acetoxybutadiene and the quinone from step 1 herein.
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.16 (3H, d, J = 6.0 Hz, 6'-CH3), 1.67 (3H, a, 3-CCH3), 2.05 (2H, m, 2'-CH2), 2.77 (1H, dd, J = 17.6 Hz, 0.6 Hz, 4-HCHa), 3.22 (1H, dd, J = 17.6 Hz, 1.8 Hz, 4-HCHe), 3.73 (3H, s, OCH3), 4.57 (1H, qua, J = 6.0 Hz, 5'-CH), 4.64 (1H, m, 3'-CH), 5.45 (1H, d, J = 2.1 Hz, 4'-CH), 5.67 (1H, a, 1'-CH), 6.22 (1H, s, 1-CH), 6.34 (1H, d, J = 8.2 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-ArH), 8.08 (2H, m,
6, 9-ArH), 8.28 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3331.7, 2957.1, 1734.1, 1708.5, 1666.4, 1595.6, 1527.9, 1271.3, 1216.2, 1181.61, 1165.8, 1104.5, 1013.2, 954.94, 731.40, 721.98.
Step 3: (1'S, 1S, 38)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy- lyxohexopyranose)-3-methoxycarbonyl-3-methyl-5,10-dioxo-
4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (BCH-2081)
The precuraor from step 2 herein was hydrolyzed with sodium methoxide (catalytic) as per previously described procedure. The product had: 1H NMR (CDCI3 250 MHz, Bruker): δ, 1.23 (3H, d, J = 6.1 Hz, 6'-CH3),
1.64 (3H, a, 3-CH3), 1.79 (1H, d tr, J = 12.9 Hz, 3.8 Hz, 2'-HCHa), 1.88 (1H, dd, J = 13.0 Hz, 4.7 Hz, -2'-HCHe), 1.94 (1H, d, J = 7.6 Hz, 2'- OH), 2.74 (1H, d, J = 18.8 Hz, 4-HCHa), 3.17 (1H, d, J = 18.8 Hz, 4- HCHe), 3.61 (1H, d, J = 7.8 Hz, 4'-CH), 3.71 (3H, s, OCH3), 4.32 (1H, m, 3'-CH), 4.40 (1H, qua, J = 6.1 Hz, 5'-CH), 5.50 (1H, d, J = 3.5 Hz, 1'- CH), 6.15 (1H, a, 1-CH), 6.67 (1H, d, J = 8.8 Hz, NHCOCF3), 7.74 (2H, m,
7, 8-ArH),8.07 (2H, m, 6,9-ArH).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3422.1 (br str), 2928.1, 2853.9, 1720.3, 1668.9, 1594.7, 1292.0, 1183.5, 1166.4, 1009.3, 986.49, 728.24.
Example 57: Preparation of (1'8,18,3S)-1-(3'-trifluoroacetamido-
2 ',3',6'-trideoxy-lyxo-L-hexopyranose)-3- dimethoxyphosphonoacetyl-3 , 4 , 5 , 10-tetrahydro-5 , 10- dioxo-maphtho- [2 , 3-c) thiopyran (BCH-2037 .001 )
Figure imgf000184_0001
Example 1
Step 1: Preparation of (1'S, 1S,3S) and (1'S,1R,3R)-1-(3'- trifluoroacetamido -2',3',6'-trideoxy-L-lyxohexopyranose)-3- acetyl-5,8-dimethoxy-thioisochroman
The compound from step 1, example 13, and daunosamine precursor (259 mg, 0.66 mmole) were dissolved in CH2Cl2 (25 ml) and left stirring in presence of molecular sieve for 30 minutes before DDQ (150 mg, 0.66 mmole) was added. The resulting mixture was stirred for 2 1/2 hours. NaHCO3 (5% solution) was added and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The crude obtained was flash chromatographed using Tol:EE (9:1) to give a pure mixture of two titled isomers (in 60% yield) which was used to carry out the next step. Step 2: Preparation of (1'S,1S,3S) and (1'S,1R,3R)-1-(4'-p- nitrobensoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-5,8-dioxo-4,5,8-trihydro-1H- benso-[2,3-c]-pyran
The compound from step 1 herein (112.7 mg, 0.18 mmole) was diaaolved in acetonitrile (5 ml), cooled to 0°C, followed by the addition of NaHCO3 (29 mg, 0.34 mmole) and some H2O. The resulting mixture was stirred for 5 minutes before CAN (296 mg, 0.54 mmole) was added, After all CAN was added, the reaction mixture was atirred 10 minutea extra 0°C, then warmed to room temperature. H2O was added and it was extracted with CH2Cl2. The combined organic phases were washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The crude containing a mixture of two titled diastereoisomers was used in the following step.
Step 3: (1'S,1S,3S)-1-(4'-p-nitrobenaoyl-3'-trifluoroacetamido-
2',3',6'-trideoxy-L-lyxohexopyranose)-3-acetyl-5,10-dioxo- 3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-thiopyran Following the example 1, atep 1, a mixture of the two titled adducts was obtained which could be seperated via flash chromatography. The first eluent had:
1H NMR (acetone-d6, 250 MHz, Bruker): δ, 1.23 (3H, d, J = 5.6 Hz, 6'- CH3), 1.70-1.90 (2H, m, 2'-CH2), 2.44 (3H, a, COCH3), 2.84 (1H, dd, J = 17.8 Hz, 11.8 Hz, 4-HCHa), 3.36 (1H, dd, J = 17.8 Hz, 4.1 Hz, 4'-HCHe), 4.53 (1H, dd, J = 11.8 Hz, 4.1 Hz, 3-CH), 4.60 (1H, m, 3'-CH), 4.75 (1H, qua, J = 5.6 Hz, 5'-CH), 5.53 (1H, a, 4'-CH), 5.70 (1H, d, J = 2.3 Hz, 1'-CH), 6.13 (1H, a, 1-CH), 7.90 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9- ArH), 8.39 (4H, m, PNB), 8.65 (1H, d, J = 5.8 Hz, NHCOCF3).
The aecond eluent had:
1H NMR (acetone-d6, 250 MHz, Bruker) : δ, 1.32 (3H, d, J = 6.8 Hz, 6 ' - CH3) , 2.39 (3H, a, COCH3 ) , 1.94 (1H, dd, J = 12.3 Hz, 4.1 Hz, 2 ' -HCHa) , 2.50 (1H, tr d, J = 12.3 Hz, 2.9 Hz, 2 ' -HCHe) , 2.89 (1H, dd, J = 18.2 Hz, 11.2 Hz, 4-HCHa) , 3.35 (1H, dd, J = 18.2 Hz, 3.5 Hz, 4-HCHe) , 4.41 (1H, dd, J = 11.2 Hz, 3.5 Hz, 3-CH) , 4.52 (1H, m, 3 '-CH) , 4.66 (1H, qua, J = 6.8 Hz, 5 ' -CH) , 5.47 (1H, 8, 4 '-CH) , 5.74 (1H, d, J = 2.9 Hz, 1 ' - CH) , 6.31 (1H, s, 1-CH) , 7.91 (2H, m, 7, 8-ArH) , 8.14 (2H, m, 6, 9-ArH) , 8.38 (4H, m, PNB) , 8.68 (1H, d, J = 7.1 Hz, NHCOCF3) . Step 4: (1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-thiopyran (BCB-2037.001) 1H NMR (CDCl3 250 MHz, Bruker): δ, 1.43 (3H, a, 6'-CH3), 1.83-1.98 (2H, m, 2'-CH2), 2.37 (3H, s, COCH3), 2.90 (1H, dd, J = 17.8 Hz, 12 Hz, 4- HCHa), 3.32 (1H, dd, J = 17.8 Hz, 4.1 Hz, 4-HCHe), 3.61 (1H, br s, 4'- CH), 4.07 (1H, dd, J = 12.0 Hz, J = 4.1 Hz, 3-CH), 5.53 (1H, s, 1'-CH), 6.21 (1H, s, 1-CH), 6.74 (1H, d, J = 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-ArH), 8.12 (2H, m, 6, 9-ArH).
Example 58: Preparation of (1'S,1R,3R)-1-(3'trifluoroacetamido-
2',3',6'-trideoxy-lyxo-L-hexopyranose)-3- dimethoxyphoaphonoacetyl-3,4,5,10-tetrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH-2127)
Figure imgf000186_0001
Step 1: (1'S, 1R, 3R)-1-(3'-trifluoroacetamido-2',3',6'-tridaoxy-L- lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]-thiopyran (BCH-2127)
The second eluent from atep 3, example 57, was hydrolyzed with catalytic sodium methoxide in methanol. The titled compound had:
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.43 (3H, d, J = 6.5 Hz, 6'-CH3), 1.80-2.00 (2H, m, 2'-CH2), 2.37 (3H, s, COCH3), 2.91 (1H, dd, J = 18.3 Hz, 11.8 Hz, 4-HCHa), 3.33 (1H, dd, J = 18.3 Hz, 4.7 Hz, 4-HCHe), 3.60 (1H, br 8, 4-CH), 4.07 (1H, dd, J = 11.8 Hz, 4.7 Hz, 3-CH), 4.25 (1H, m, 3'-CH), 4.35 (1H, qua, J = 6.5 Hz, 5'-CH), 5.53 (1H, d, J = 2.4 Hz, 1'- CH), 6.21 (1H, 8, 1-CH), 6.74 (1H, d, J = 7.6 Hz, NHCOCF3), 7.76 (1H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH).
Example 59: Preparation of (1'S,1S,3S)-1-(3'-trifluoroacetamido-
2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3- methyl-3,4,5,10-tetrahydro-5,10-dioxo-1H-naphtho-[2,3- c] pyran (BCH-2090)
Figure imgf000187_0001
Step 1: 3-acetyl-3-methyl-5,8-dimethoxy isochroman
The compound from atep 1, example 53, (126.5 mg, 0.474 mmol) was dissolved in ether and then cooled to -78°C. Methyllithium (1.4 M in ether (0.71 ml, 0.995 mmol) was added, After 10 minutea methanol was added. The reaction mixture was acidified with HCl (0.5 N) and extracted with ethyl acetate. The organic layer was dried over aodium sulfate and then evaporated to give a crude product (121 mg). 1H NMR ahowed that it was a mixture of starting material and product in 1:1 ratio. Chromatography allowed iaolution of the desired titled product as a gel.
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.37 (3H, s, 3-CCH3), 2.24 (3H, s, COCH3), 2.59 (1H. d, J = 17.6 Hz, 4-CH), 2.99 (1H, d, J = 17.6 Hz, 4- CH), 3.74 (3H, s, OCH3), 3.76 (3H, 8, OCH3), 4.77 (2H, s, 1-CH2), 6.57 (1H, d, J = 9.4 Hz,ArH), 6.62 (1H, d, J = 9.4 Hz,Ar H).
IR (Nicolet, film on NaCl plate): cm-1, 2941.9, 2834.4, 1721.6, 1482.4, 1340.2, 1257.0, 1061.4, 795.30, 716.80
Step 2: (1'S,1S,3S) and (1'S,1S,3R)-1-(4'-p-nitrobensoyl-3'- trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3- acetyl-3-methyl-5,8-dimethoxy-isochroman The compound from step 1 herein (67 mg, 0.268 mmol) was stirred with DDQ (91.3 mg, 0.422 mmol) and 4',5'-protected daunosamine (157 mg, 0.402 mmol) in methylene chloride at 40°C for 24 hours. The solvent was evaporated. The crude product was chromatographed (hex:EtOAc = 10:4) to give the titled compounds (88 mg containing two isomers in 2:1 ratio inseparable).
1H NMR (CDCl3250 MHz, Bruker): δ, 1.23 (3H, d, J = 6.0 Hz, A-6'-CH3), 1.22 (3H, d, J = 6.0 Hz, B-6'-CH3), 1.44 (3H, a, A-3-CCH3), 1.66 (3H, s, B-3-CCH3), 1.84 (1H, m, A-2'-CH), 1.84 (1H, m, A-2'-CH), 1.84 (1H, m, B-2'-CH), 2.14 (1H, m, A-2'-CH), 2.15 (1H, m, B-2'-CH), 2.80 (1H, d, J = 15.9 Hz, A-4-CH), 3.02 (2H, s, B-4-CH2), 3.14 (1H, d, J = 15.9 Hz, A-4- CH), 3.77 (6H, s, B-OCH3), 3.80 (6H, s, A-OCH3), 4.41 (1H, qua, J = 6.0 Hz, B-5'-CH), 4.47 (1H, m, B-3'-CH), 4.56 (1H, qua, J = 6.0 Hz, A-5'- CH), 4.61 (1H, m, A-3'-CH), 5.40 (1H, 8, B-4'-CH), 5.44 (1H, 8, A-4'- CH), 5.61 (1H, d, J = 2.5 Hz, B-1'-CH), 5.70 (1H, d, J = 2.2 Hz, A-1'- CH) , 6.35 (1H, 8, B-1-CH) , 6.37 (1H, 8, A-1-CH) , 6.41 (1H, d, J = 7.6 Hz, B-NHCOCF3) , 6.46 (1H, d, J = 7.8 Hz, A-NHCOCF3) , 6.76 (2H, m, B- ArH) , 6.81 (2H, m, A-ArH) , 8.25 (8H, br a, A-PNB, B-PNB) .
IR (Nicolet, 205 FT, film on NaCl plate) : cm-1, 3327.9, 2945.2 , 2840.3, 1732.6, 1528.4, 1489.4, 1351.8, 1263.4, 1167.8, 1116.3, 1105.2, 969.06, 948.80, 801.62, 720.66.
Also obtained from this reaction (34 mg) was (1'S, 1R, 3S)-1-(4'-p- nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxylyxohexopyranose)-3- acetyl-3-methyl-5,8-dimethoxy-isochroman which had:
1H NMR (CDCI3 250 MHz, Bruker): δ, 1.18 (3H, d, J = 7.6 Hz, 6'-CH3), 1.51 (3H, s, 3-CCH3), 2.00-2.10 (2H, m, 2'-CH2), 2.84 (1H, d, J = 17.1 Hz, 4-CH), 2.96 (1H, d, J = 17.1 Hz, 4-CH), 3.77 (3H, s, OCH3), 3.78 (3H, s, OCH3), 4.54 (1H, qua, J = 7.6 Hz, 5'-CH), 4.62 (1H, m, 3'-CH), 5.46 (1H, d, J = 2.1 Hz, 4'-CH), 5.56 (1H, s, 1'-CH), 6.14 (1H, s, 1-CH), 6.41 (1H, d, J = 7.6 Hz, NHCOCF3), 6.70 (1H, d, J = 8.8 Hz,ArH), 6.76 (1H, d, J = 8.8 Hz,Ar H), 8.26 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3336.5, 2940.0, 2834.3, 1730.3, 1527.2, 1481.4, 1266.3, 1163.6, 975.8, 718.02.
Step 3: (1'S, 1S,3S) and (1'S, 1S, 3R)-1-(4'-p-nitrobensoyl-3'- trifluoroacetamido -2',3',6'-trideoxy-lyxohexopyranose)-3- acetyl-3-methyl-5,8-dioxo-4,5,8-trihydro-1H-benso-[2,3-c]- pyran
CAN oxidation of the producta from atep 2 herein gave the titled quinones (as per procedure step 2, example 14).
1H NMR (CDCl3 250 MHz, Bruker): δ, 1.30 (3H, d, J = 6.0 Hz, A-6'-CH3), 1.27 (3H, d, J = 6.1 Hz, B-6'-CH3), 1.44 (3H, 8, A-3-CCH3), 1.44 (3H, s, B-3-CCH3), 1.80-2.30 (4H, m, A-2'-CH2, B-2'-CH2), 2.62 (1H, d, J =
18.1 Hz, A-4-HCHa), 2.72 (1H, d, J = 18.1 Hz, A-4-HCHe), 2.70 (1H, d, J = 18.0 Hz, B-4-CH), 3.25 (1H, d, J = 18 Hz, B-4'-CH), 4.41 (1H, m, B-3'- CH), 4.56 (1H, m, A-3'-CH), 4.57 (1H, qua, J = 6 Hz, B-5'-CH), 4.72 (1H, qua, J = 6 Hz, A-5'-CH), 5.38 (1H, s, B-4'-CH), 5.42 (1H, s, A-4'-CH), 5.58 (1H, d, J = 2.4 Hz, B-1'-CH), 5.66 (1H, d, J = 2.9 Hz, A-1'-CH), 5.98 (1H, s, B-1-CH), 6.02 (1H, 8, A-1-CH), 6.45 (1H, d, J = 8.1 Hz, B-NHCOCF3), 6.55 (1H, d, J = 8 Hz, A-NHCOCF3), 6.70-6.87 (4H, m, A-6, 7- Quin, B-6, 7-Quin), 8.28 (8H, m, A-PNB, B-PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3327.5, 3084.6, 2984.9, 2938.2, 1723.4, 1661.1, 1533.4, 1352.8, 1278.0, 1215.7, 1169.0, 1122.3, 948.30, 730.86.
Step 4: (1'8,1S,3S) and (1'S, 1S, 3R)-1-(4'-p-nitrobensoyl-3'- trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3- acetyl-3-methyl-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3- c)-pyran
The quinone from step 3 herein was cycloadded with 1-acetoxybutadiene as per procedure described in step 3, example 14. The (1'S,1S,3R) titled compound had:
1H NMR (CDCI3 250 MHz, Bruker): δ, 1.35 (3H, d, J = 5.9 Hz, 6'-CH3), 1.49 (3H, s, 3-CCH3), 1.95 (1H, dd, J = 12.6 Hz, 4.7 Hz, 2'-CH), 2.12 (1H, d tr, J = 12.6 Hz, 2.9 Hz, 2'-CH), 2.71 (1H, d, J = 18.2 Hz, 4-CH), 2.89 (1H, d, J = 18.2 Hz, 4-CH), 4.60 (1H, m, 3'-CH), 4.85 (1H, qua, J = 5.9 Hz, 5'-CH), 5.47 (1H, br s, 4'-CH), 5.71 (1H, d, J = 2 Hz, 1'-CH), 6.21 (1H, d, J = 1.2 Hz, 1-CH), 6.42 (1H, d, J = 7.6 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-ArH), 8.14 (2H, m, 6, 9-ArH), 8.31 (4H, m, PNB).
IR (Nicolet, 205 FT, film on NaCl plate): cm-1, 3336.3, 2922.6, 2852.6, 1728.0, 1666.8, 1532.8, 1346.3, 1273.5, 1212.3, 1165.6, 1119.0, 1098.6, 996.7, 952.96, 836.3, 722.58.
The (1'S,1S,3S) diastereomer had:
1H NMR (CDCI3 250 MHz, Bruker): δ, 1.31 (3H, d, J = 5.9 Hz, 6'-CH3), 1.47 (3H, a, 3-CCH3), 1.89 (1H, dd, J = 11.8 Hz, 5.3 Hz, 2'-HCHa), 2.06 (1H, d tr, J = 11.8 Hz, 4.1 Hz, 2'-HCHe), 2.55 (1H, d, J = 17.8 Hz, 4- HCHa), 3.40 (1H, d, J = 17.8 Hz, 4-HCHe), 4.45 (1H, m, 3'-CH), 4.66 (1H, qua, J = 5.9 Hz, 5'-CH), 5.43 (1H, s, 4'-CH), 5.63 (1H, d, J = 2.3 Hz, 1'-CH), 6.17 (1H, a, 1-CH), 6.30 (1H, d, J = 11.8 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-ArH), 8.13 (2H, m, 6, 9-ArH), 3.30 (4H, m, PNB).
Step 5: (1'S, 1S, 3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-3-methyl-5,10-dioxo-4,5,10- trihydro-1H-naphtho-[2,3-c)-pyran (BCH-2090) Hydrolysis of the (1'S,1S,3S) precursor from step 4 herein gave the titled compound.
M.P. 95°C.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.41 (3H, d, J = 5.9 Hz, 6'-CH3),
1.46 (3H, a, 3-CCH3), 1.85 (2H, m, 2'-CH2), 2.27 (3H, a, COCH3), 2.84 (2H, d, J = 5.9 Hz, 4-CH2), 3.65 (1H, s, 4'-CH), 4.31 (1H, m, 3'-CH),
4.64 (1H, qua, J = 6.0 Hz, 5'-CH), 5.53 (1H, br a, 1'-CH), 6.15 (1H, a,
1-CH),-6.71 (1H, br d, J = 8.8 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-ArH),
8.11 (2H, m, 6, 9-ArH).
IR (Nicolet , 205 FT, film on NaCl plate): cm-1, 3423.2, 3342.2,
3087.5, 2987.2, 2933.2, 1717.6, 1667.5, 1590.3, 1289.3, 1216.0, 1179.1,
1167.6, 1124.2, 980.89, 940.05, 918.55, 734.22.
Example 60: Preparation of (1'S,1R,3S)-1-(3'-trifluoroacetamido-
2',3',6'-trideoxy-lyxo-L-hexopyranose)-3- dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH-1689)
Step 1 : 3-bromoacetyl-5,8-dimethoxy-isochroman The titled compound was prepared by using 5,8-dimethoxy-3- acetoisochroman and the procedure from step 1, example 8.
1H NMR (CDCl3, 250 MHz, Bruker): 2.59 (1H, dd, J = 15.9 Hz, 11.8 Hz, 4- HCHa), 3.03 (1H, dd, J = 15.9 Hz, 2.9 Hz, 4-HCHe), 3.74 (3H, s, OCH3), 3.75 (3H, B, OCH3), 4.23 (1H, dd, J = 11.8 Hz, 2.9 Hz), 4.27 (1H, d, J = 13.5 Hz, CHBr), 4.34 (1H, d, J = 13.5 Hz, CHBr), 4.63 (1H, d, J = 15.9 Hz, 1-HCHa), 4.96 (1H, d, J = 15.9 Hz, 1-HCHe), 6.63 (2H, m,ArH).
Step 2: 3-dimethoxy phosphinoacetyl-5,8-dimethoxy-isochroman The titled compound was obtained following treatment of the product from step 1 herein with P(OCH3)3.
1HNMR (CDCl3, 250 MHz, Bruker), δ:2.57 (dd, 1 H, J = 16.9 Hz, 11 Hz, 4 - HCHa), 2.98 (dd, 1 H, J = 16.9 Hz, 2.9 Hz, 4 - HCHe), 3.26 (dd, 1 H, J = 21.5 Hz, 14.5 Hz, COCHP), 3.54 (dd, 1 H, J = 21.5 Hz, 14.5 Hz, COCHP), 3.71 (s, 3 H,ArOCH3), 3.72 (e, 3 H,ArOCH3), 3.74 (d, 3 H, J = 4.3 Hz, POCH3), 3.78 (d, 3 H, J = 4.3 Hz, POCH3), 4.11 (dd, 1 H, J = 11 Hz, 3.4 Hz, 3 - CH), 4.63 (d, 1 H, J = 16.3 Hz, 1 HCHa), 4.97 (d, 1 H, J = 16.3 Hz, 1 - HCHe), 6.60 (m, 2 H, 6.7 -ArH).
IR (Nicolet, 205FT, film on NaCl plate), cm-1: 2954.3, 2836.7, 1725.5 (str), 1603.9 (W), 1482.2, 1259.2 (str), 1034.7, 799.10, 715.8.
Step 3: (1'S,1S,3R) (1'S,1R,3S)-5,8-dimethoxyl(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-p-nitrobensoyl-L-lyxohexopyranose)-3- dimethylphoaphonoacetyl isochroman
To a stirred solution of the phosphonate from atep 2 herein (199 mg, 0.58 mmole) with 4 - PNB - 3 - TFA - daunosamine (270 mg, 0.69 mmole) in clichloromethane (60 ml) was added 4 peleta of molecular sieves (4A-). This was followed by addition of dichlorodisyanoquinone (DDQ, 170 mg,
0.75 mmole) in one portion. The reaulting green liquid was atirred at 40 °C (controlled by an Ikamag-Ret-G-Heating-Stirring system) in a enclosed system for 25 hours then at room temperature (without heating) for 48 hours. The resulting muddy mixture was evaporated and then directly chromatographed (Hex:EA = 1:1.5) to yield the desired titled glycosides
(diastereomeric mixture A and B, aa light-colored glaasy material, 407 mg).
1HNMR (CDCI3, 250 MHz, Bruker), δ:1.20 (d, 3 H, J = 7.0 Hz, 6' - CH3A),
1.23 (d, 3 H, J = 7.0 Hz 6' - CH3B), 1.82 (dd, 1 H, J = 12.2 Hz, 4.5 Hz, 2' - HCHAa), 1.91 (dd, 1 H, J = 12.3 Hδ, 4.6 Hz, 2' - HCHBa), 2.07 (dt,
1 H, J = 12.3 Hz, 3.5 Hz, 2' - HCHAe), 2.20 (dt, 1 H, J = 12.4 Hz, 4 Hz, 2' - HCHBe), 2.54 (dd, 1 H, J = 16.9 Hz, 13.4 Hz, 4 - HCHBa), 2.60 (dd,
1 H, J = 17 Hz, 11 Hz, 4 - HCHAa), 2.96 (dd, 1 H, J = 11 Hz, 3.5 Hz, 4 - HCHAe), 3.03 (dd, 1 H, J = 11.1 Hz, 3.3 Hz, 4 - HCHBe), 3.74 - 3.87 (8xs, 24 H, 2 x ArOCH3A, 2 xArOCH3B, 2 x POCH3A, 2 x POCH3B), 4.41
(qua, 1 H, J = 6.0 Hz, 5' - CHB), 4.50 - 4.68 (M, 4 H, 3' - CHA, 3' - CHB, 3 - CHA, 3 - CHB), 4.70 (qua, 1 H, J = 7.0 Hz, 5' - CHA), 4.99 (d,
2 H, J = 16 Hz, COCH2AP), 5.03 (d, 2 H, J = 16.7 Hz, CoCH2BP), 5.41 (8, 1 H, 4' - CHB), 5.47 (s, 1 H, 4' - CHA), 5.57 (8, 1 H, 1' - CHB), 5.61 (s, 1 H, 1' - CHA), 5.98 (s, 1 H, 1 - CHB), 6.15 (s, 1 H, 1 - CHA), 6.71 (qua, 2 H, J = 8.7 Hz, 6.7 - ArHB), 6.75 (qua, 2 H, J = 8.5 Hz, 6.7 - ArHA), 6.89 (d, 1 H, J = 7.0 Hz, NHBCOCF3), 7.05 (d, 1 H, J = 7.0 Hz, NHACOCF3), 8.21 (m, 8 H, 4 x COArHANO2, 4 x COArHBNO2). Step 4: [(1'S,1S,3R) and (1'S,1R,3S)-1-(2',3,6'-trideoxy-3'- trifluoroacetamido-4'-p-nitrobensoyl-L-lyxohexopyranose)-3- dimethylphosphonoacethyl-3,4,5,8-tetrahydronaphthaleno-[2,3- e]-pyran
To a aolution of glycoaide from step 3 herein (98 mg, 0.13 mmole) in 8 ml of acetonitrile cooled to 0°C was added aodium bicarbonate powder (22 mg, 0.27 mmole). This was followed by dropwise addition of aqueous cerium ammonium nitrate (CAN, 298 mg, 0.54 mmole in 3.0 ml of water). After 10 minutea at 0°C, the reaction mixture was poured to water (20 ml) and extracted with dichloromethane (4 x 10 ml). The organic layer was dried (over sodium sulfate) and evaporated to give the titled quinones as a glassy mixture (85 mg).
1HNMR (CDCl3, 250 MHz, Bruker), δ:1.15 (d, 1 H, J = 6.4 Hz, 6' - CH3B), 1.30 (d, 1 H, J = 6.4 Hz 6' - CH3A), 2.44-1.80 (M, 4 H, 2 - HCHAa, 2 - HCHBa, 2 - HCHAe, 2 - HCHBe), 2.41 (dd, 1 H, J = 16.6 Hz, 11.6 Hz, 4 - HCHBa), 2.48 (dd, 1 H, J - 16.6 Hz, 11.3 Hz, 4 - HCHAa), 2.83 (dd, 1 H, J = 17.0 Hz, 5.23 Hz, 4 - HCHAe), 2.85 (dd, 1 H, J = 16.8 Hz, 5.0 Hz, 4 - HCHBe), 3.79 (B, 3 H, POCH3A), 3.84 (s, 3 H, POCH3A), 3.82 (d, 3 H, J = 2.1 Hz, POCH3B), 3.87 (d, 3 H, J = 2.1 Hz, POCH3B), 4.34 (qua, 1 H, J = 7.0 Hz, 5' CHB), 4.48 - 4.60 (m, 4 H, 3 - CHA, 3 CHB, 3' - CHA, 3' - CHB), 4.64 (qua, 1 H, J = 7.0 Hz, 5' - CHA), 5.04 (d, 2 H, J = 25 Hz, COCH2AP), 5.05 (d, 2 H, J = 31 Hz, COCH2BP), 5.43 (s, 2 H, 4', CHA, 4' - CHB), 5.55 (s, 1 H, 1'- CHA), 5.61 (s, 1 H, 1' - CHB), 5.81 (s, 1 H , 1 - CHB), 5.97 (s, 1 H, 1 - CHA), 6.79 (m, 2 H, 6.7 -ArHB), 6.82 (m, 2 H, 6.7 -Ar HA), 8.27 (8, 8 H, 4 x COArHANO2, 4 x COArHBNO2).
Step 5: (1'S,1R,3S)-1-(2',3',6'-trideoxy-4'-p-niprobenaoyl-3'- trifluoroacetamido-L-lyxohexo pyranose)-3-dimethyl phosphonoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho[2,3-c]-pyran
The compounds from step 4 herein (85 mg, 0.121 mmol) were heated with 1- acetoxy-1,3-butadiene (86 μl, 0.723 mmol) in toluene at 45°C for 28 hours. Solvent was evaporated and the crude product was chromatographed three times (toluene:EtOAc: HOMe: acetone:HOAc = 240:75:10:10:1) to give the (1'S,1R,3S) isomer (21 mg) and the (1'S,1S,3R) isomer (18 mg). The titled compound had: 1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.19 (3H, d, J = 7.0 Hz, 6'-CH3), 2.03 (1H, m, 2-HCHa), 2.07 (1H, m, 2-HCHe), 2.56 (1H, dd, J = 18.2 Hz, 11.8 Hz, 4-HCHa), 3.05 (1H, dd, J = 18.2 Hz, 4.7 Hz, 4-HCHe), 3.85 (3H, d, J = 2.0 Hz, POCH3), 3.91 (3H, d, J = 2.0 Hz, POCH3), 4.40 (1H, qua, J = 7.0 Hz, 5'-CH), 4.60 (1H, m, 3'-CH), 4.65 (1H, dd, J = 11.8 Hz, 4.7 Hz), 5.04 (1H, br s, CHP), 5.17 (1H, tr, J = 2.0 Hz, CHP), 5.42 (1H, s, 4'-CH), 5.71 (1H, s, 1'-CH), 6.00 (1H, s, 1-CH), 6.48 (1H, d, J = 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-ArH), 8.10 (2H, m, 6, 9-ArH), 8.27 (2H, d, J = 8.0 Hz, PNB), 8.32 (2H, d, J = 8.0 Hz, PNB).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3323.0, 3242.5, 3077.6, 2965.0, 1730.3, 1661.9, 1593.5, 1529.2, 1271.8, 1193.2, 1050.8, 864.0, 835.7, 722.1.
The aecond compound, (1'S,1S,3R)-1-(2',3',6'-trideoxy-4'-p-niprobenzoyl- 3'-trifluoroacetamido-L-lyxohexo pyranose)-3-dimethyl phoaphonoacetyl- 5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]-pyran had:
M.P. 135-137°C.
1H NMR (CDCl3, 250 MHz, Bruker): δ, 1.33 (3H, d, J = 6.4 Hz, 6'-CH3),
2.01 (1H, br tr, J = 11.8 Hz, 3'-HCHa), 2.15 (1H, br tr, J = 11.8 Hz, 3'-HCHe), 2.62 (1H, dd, J = 18.8 Hz, 12.1 Hz, 4-HCHa), 3,01 (1H, dd, J = 18.8 Hz, 4.4 Hz, 4-HCHe), 3.81 (3H, s, POCH3), 3.86 (3H, 8, POCH3), 4.58 (1H, m, 4'-CH), 4.60 (1H, dd, J = 12.1 Hz, 4.4 Hz, 3-CH), 4.79 (1H, qua, J = 6.4 Hz, 6-CH), 5.02 (1H, br s, PCH), 5.13 (1H, br s, PCH), 5.46 (1H, 8, 5'-CH ), 5.62 (1H, 8, 1'-CH), 6.14 (1H, 8, 1-CH), 6.63 (1H, d, J =
8.2 Hz, NHCOCF3), 7.79 (2H, m, 7, 8-ArH), 8.16 (2H, m, 6, 9-ArH), 8.30 (4H, m, PNB).
IR (Nicolet 205 FT, film on NaCl plate): cm-1, 3322.0, 3242.5, 3083.5, 2959.0, 2853.0, 1729.5, 1668.6, 1597.0, 1525.5, 1276.4, 1183.7, 1045.9, 853.9, 724.2. Step 6: (1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3-dimethylphoaphonoacatyl-5,10-dioxo- 3,4,5-10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1689)
The PNB-protected ketophosphonate from step 5 herein (21 mg, 0.028 mmol) was diaaolved in THF-MeOH (3 ml of each) and cooled to 0°C. Sodium methoxide (4.3 m, 6.5 μl) was added, After stirred for 5 minutes at 0° C, the crude mixture (pink) was acidified with 0.1 N aqueous hydrogen chloride. It was extracted with methylene chloride, dried (over sodium sulfate) and evaporated to give a crude product which was recrystallized from methylene chloride and hexane to give the desired product (10 mg) as an off-white solid.
M.P. 95-97ºC.
1H NMR (CDCI3, 250 MHz, Bruker): δ, 1.25 (3H, d, J = 8.2 Hz, 6'-CH3), 1.83-1.98 (2H, m, 2'-CH2), 2.53 (1H, dd, J = 17.6, 11.8 Hz, 4-HCHa),
3.00 (1H, dd, J = 17.6 Hz, 3.5 Hz, 4-HCHe), 3.62 (1H, br s, 4'-CH), 3.82 (3H, s, POCH3), 3.86 (3H, B, POCH3), 4.16 (1H, qua, J = 8.2 Hz, 5'-CH), 4.34 (1H, m, 3'-CH), 4.62 (1H, dd, J = 11.8 Hz, 3.5 Hz, 3-CH), 5.01 (1H, s, CHP) , 5.12 (1H, 8, CHP) , 5.54 (1H, s, 1 ' -CH) , 5.94 (1H, 8, 1-CH) , 6.82 (1H, d, J = 7.1 Hz, NHCOCF3), 7.74 (2H, m, 7, 8-ArH), 8.06 (2H, m, 6, 9-ArH).
IR (Nicolet 205FT, film on NaCl plate) : cm-1, 3421.4 (br) , 3080.8, 2960.1, 1718.4, 1664.5, 1556.7, 1457.6, 1283.0, 1188.1, 1043.7, 983.4, 858.9, 728.4.
Example 61 : Various C-2 ' axialy iodinated pyranyInaphthoquinone glycosides
Figure imgf000196_0001
Step 1: 3,4-Di-O-acetyl-2-iodo-2,6-dideoxyfucose
To a mixture of di-O-acetyl fucal (3.029 g, 14.140 mmol) in 180 ml of acetonitrile and 18 ml of water was added portionwiae the NIS (3.590 g, 15.554 mmol). After stirring for 30 minutea the mixture was extracted with CH2Cl2 (2x) and the combined organic extracta were washed with 10% aodium thiosulfate aolution, water and finally dried (Na2SO4) to give
4.403 g (87% yield) of the desired sugar.
PMR (acetone-d6, 250 MHz) δ: 1.12 (d, 3H, J=6.4Hz, CH3-6'), 1.99 and 2.11 (2s, 2X3H, 2XOAc), 4.36 (d, 1s , J=5.1Hz, H-2), 4.48 (q, 1H,
J=6.6Hz, H-5), 4.98 (unresolved dd, 1H, H-3), 5.18 (broad s,1H, H-4),
5.59 (broad s, 1H, H-1), 5.94 (d, 1H, OH). Step 2: (1'8,1R,38) and (1'S,1S,3R) - 2,5-Dimethoxy-1-(2',6'- dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose)-3- acetoisochroman To a mixture of sugar from step 1 herein (910 mg, 2.539 mmol) and methyl ketone isochroman (500 mg, 2.116 mmol) in dry CH2Cl2 under argon atmosphere and room temperature was added aome - molecular sieve (4A). After stirring for 20 minutes DDQ (577 mg, 2.539 mmol) was added, After Btirring for 72 hours, while additions of 0.5 equivalent of sugar and 0.5 equivalent of DDQ were done after 24 and 48 houra, the reaction was worked up by addition of 100 ml of NaHCO3 5% and water mixture (1:3). Extractions with CH2Cl2 (3x100 ml) following by washing with the same aqueous mixture and drying (Na2SO4). Flash chromatography of the crude (CH2Cl2:Hex:BtOAc; 9:4:1) gave 361 mg of the non-natural
(1'S,1S,3R) glycoside and 435 mg of the natural (1'S,1R,3S) one. The arbitrarily assigned (1'S,1S,3R) titled compound had:
PMR (acetone-d6, 250 MHz) δ: 1.27 (d,3H, J=6.5Hz, CH3-6'), 1.94 and 2.16 (2s, 2X3H, 2XOAc), 2.30 (s,3H,COCH3), 2.50 (dd, 1H, J=17.8Hz and 12.1Hz, CHaCHO), 2.95 (dd, 1H, J=17.8 and 4.3Hz, CHeCHO), 3.80 and 3.83 (2s, 2X3H, 2XOCH3), 5.52 (d, 1H, J=5.0Hz, H-2'), 4.75 (m, 3H, H-3, H-3' and H-5'), 5.24 (broad a, 1H, H-4'), 5.89 (a, 1H, H-1'), 6.15 (s, 1H, H-1), 6.90 (2d, 2H, Ar-H).
The second (1'S,1S,3R) titled compound had:
PMR (acetone-d6, 250 MHz) δ: 1.16 (d, 3H, J=6.6Hz, CH3-6'), 1.97 and 2.15 (2a, 2X3H, 2XOAc), 2.30 (s, 3H, COCH3), 2.45 (dd, 1H, J=17.6Hz and 12.2Hz, CHaCHO), 2.96 (dd, 1H, J=17.6HZ and 4.1Hz, CHeCHO), 3.80 and 3.82 (2s, 2X3H, 2XOCH3), 4.48 (d, 1H, J=5.0Hz, H-2'), 4.54 (m, 2H, H-3, H-5'), 4.83 (unresolved dd, 1H, H-3'), 5.20 (broad s, 1H, H-4'), 5.86 (s, 1H, H-1'), 6.03 (a, 1H, H-1), 6.88 (2d, 2H,Ar-H).
Step 3: (1'S,1R,38)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-2'-iodo- L-lyxohexopyranose)-isochroman
To mixture of the compound from step 2 herein (500 mg, 0.844 mmol) in 90 ml of dry THF maintained at 0°C and under argon atmosphere were added 90 ml of NaOH 0.5N. After stirring for 1 hour the reaction mixture was neutralized with 160 ml of NH4CI sat.:NaHCO3 sat. (4:1) and extracted with CH2Cl2 (3x200 ml). The combined organic layere were dried over MgSO4. Flash chromatography (toluene:ethyl acetate; 8:2) of the crude gave 248 mg (49% yield) of pure titled compound.
PMR (acetone-d6, 250 MHz) δ: 1.26 (d, 3H, J=6.5Hz, CH3-6'), 2.29 (s, 3H, COCH3), 2.44 (dd, 1H, J=17.5Hz and 12.2Hz, CHaCHO), 2.93 (dd, 1H, J=17.7Hz and 4.1Hz, CHeCHO), 3.16 (d, 1H, J=6.0Hz, OH), 3.49 (m, 1H, H- 3'), 3.77 (m, 1H, H-4'), 3.79 and 3.84 (2Xs, 2X3H, OCH3), 4.09 (d, 1H, J=7.4Hz, OH), 4.25 (q, 1H, J=6.6Hz, H-5'), 4.37 (d, 1H, J=5.OHz, H-2'), 4.54 (dd, 1H, J=12.2Hz, 4.1Hz, H-3), 5.84 (s, 1H, H-1'), 5.99 (8, 1H, H- 1), 6.88 (2Xd, 2XH,ArH)
Step 4: (1'8,1R,3S)-3-aceto-1-(2',6'-dideoxy-2'-iodo-L- lyxohexopyranose)-5,8-dioxo-5,8-dihydroisochroman
The titled compound was obtained following CAN oxidation of the product from step 3 herein as per previous procedure.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J=6.6Hz, CH3-6'), 1.86 (large d, 1H, OH), 2.33 (s, 3H, COCH3), 2.39 (dd, 1H, J=19.9 and 11.9Hz, CHa-CHO), 2.81 (large s, 1H, OH), 2.90 (dd, 1H, J=19.7Hz and 3.9Hz, CHe-CHO), 3.32 (large s, 1H, H-3'), 3.78 (large unreaolved d, 1H, H-4'), 4.17 (broad q, 1H, J=5.0Hz, H-5'), 4.39 (m, 2H, H-3 and H-2'), 6.81 (a, 1H, H-1'), 6.89 (s, 1H, H-1), 6.81 (2Xd, 2H, quinone ring-H).
IR (film) Vmax: 3486, 3400, 2937, 1711, 1657, 1307, 968 cm-1.
Step 5: (1'S,1R,38)- methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'- iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-2015)
Starting from 50 mg (0.105 mmol) of the compound from step 4 herein and 1 ml of 1-acetoxybutadiene, the procedure described in step 2, example 5, haa been followed, After purification, 15.8 mg (29% yield) of pure titled compound was isolated.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J=6.7Hz, CH3-6'), 1.91 (large d, 1H, J=11.0Hz, OH), 2.36 (s, 3H, COCH3), 2.53 (dd, 1H, J=19.5Hz, 11.4Hz, CHaCHO), 2.81 (large d, 1H, J=10.4Hz, OH), 3.08 (dd, 1H, J=19.9Hz and 4.1Hz, CHeCHO), 3.34 (m, 1H, H-3'), 3.80 (m, 1H, H-4'), 4.17 (broad q, 1H, 6.9Hz, H-5'), 4.45 (m, 2H, H-3 and H-4'), 5.98 (2Xs, 2X1H, H-1 and H-1'), 7.78 and 8.11 (2Xm, 2X2H, ArH).
IR (film) Vmax: 3477 broad, 2928, 1722, 1670, 1298, 961, 732 cm-1. Step 6: (1'8,1R,3S)- 5,8-Dioxo-3-acato-1-(2',6'-dideoxy-3',4'- diacetoxy-2'-iodo-L-lyxohexopyranose)-5,8-dihydroisochroman
CAN oxidation of the (1'S,1R,3S) diastereomeric product from step 2, example 61, yielded the titled compound.
PMR (CDCl3, 250 MHz) δ: 1.21 (d, 3H, J=6.6Hz, CH3-6'), 2.07 and 2.22 (2s, 2X3H, 2XOAC), 2.32 (8, 3H, COCH3), 2.41 (dd, 1H, J=24.1Hz, 11.8Hz, CHaCHO), 2.92 (dd, 1H, J=19.7Hz and 3.9Hz, CHeCHO), 4.29 (q, 1H, J=6.5 Hz, H-5'), 4.36 (d, 1H, J=5.1Hz, H-2'), 4.41 (dd, 1H, J=11.2Hz and 4.0Hz, H-3), 4.78 (dd, 1H, J-4.0Hz, H-3'), 5.23 (broad s, 1H, H-4'),
5.82 (1s, 1H, H-1'), 5.87 (1s, 1H, H-1), 6.81 (2d, 2H, quinone ring-H).
Step 7: (1'S,1R,3S)-methyl-(1-[2',6,-dideoxy-3'-4'-diacetoxy-2'- iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1666)
To a mixture of glycoaide from step 6 herein (55 mg, 0.098 mmol) in 1.5 ml of dry toluene and under argon atmoaphere, was added 1- acetoxybutadiene (66 mg, 0.587 mmol). After 18 houra of stirring the mixture was directly flaah chromatographed (toluene:ethyl acetate; 9:1) to give 17 mg of pure titled compound (28% yield).
PMR (CD2Cl2, 250 MHz) δ: 1.20 (d, 3H, J=1.20Hz, CH3-6'), 2.13 and 2.44 (2s, 2X3H, 2XOCH3), 2.31 (s, 3H, COCH3), 2.62 (dd, 1H, J=19.5Hz and 11.5Hz, HCHaCHC=O), 3.16 (dd, 1H, J=19.5Hz, 4.0Hz, HCHeCHC=O), 4.45 (broad q, 1H, J=6.6Hz, H-5'), 4.51 (d, 1H, J=5.0Hz, H-2'), 4.62.
(unresolved dd, 1H, J=11.7Hz and 4.0Hz, H-3), 4.88 (dd, 1H, J=4.0Hz, H- 3'), 5.32 (broad a, 1H, H-4'), 6.06 (a, 1H, H-1'), 6.16 (a, 1H, H-1), 7.71 and 8.22 (2Xm, 2X2H, ArH).
IR (film) Vmax: 2991, 2935, 1746, 1668, 1238, 970, 730 cm-1.
Step 8: (1'S,1S,3R)-5,8-Dioxo-3-aceto-1-(2',6'-dideoxy-3',4'- diacetoxy-2'-iodo-L-lyxohexopyranose)-5,8-dihydroisochroman
CAN oxidation of the (1'S,1S,3R) glycoside from step 2, example 61, gave the titled compound.
PMR (CDCI3, 250 MHz) δ: 1.35 (d, 3H, J=6.6Hz, CH3-6'), 2.07 and 2.23 (2s, 2X3H, 2XOAc), 2.32 (s, 3H, COCH3), 2.46 (dd, 1H, J=20.3 Hz and 11.7 Hz, CHaCHO), 2.90 (dd, 1H, J=19.7Hz and 4.1Hz, CHeCHO), 4.25 (d, 1H, J=5.2Hz, H-2'), 4.43 (dd, 1H, J=11.6Hz and 4.1Hz, H-3), 4.61 (q, 1H, J=6.2Hz, H-5'), 4.75 (dd, 1H, J=3.6 Hz, H-3'), 5.26 (broad s, 1H, H- 4'), 5.82 (s, 1H, H-1'), 5.97 (s, 1H, H-1), 6.81 (2d, 2H, quinone ring- H).
IR (film) Vmax: 2945, 1747 broad, 1663, 1237, 969 cm-1.
Step 9: (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'- iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1667) Starting from 70 mg (0.118 mmol) of compound from step 8 herein and 79.6 mg of 1-acetoxybutadiene and following the procedure described in step 2, example 5, we obtained after purification 25 mg (35% yield) of titled compound.
PMR (CDCl3, 250 MHz) δ: 1.40 (d, 3H, J=6.4 Hz, CH3-6'), 2.05 and 2.24 (2s, 2x3H, 2xOCH3), 2.35 (a, 3H, COCH3), 2.57 (dd, 1H, J=20.0 and
12.4Hz, HCHaCHCO), 3.07 (dd, 1H, J=20.0Hz and 4.2Hz, HCHeCHC=O), 4.27 (d, 1H, J=5.OHz, H-2'), 4.49 (dd, 1H, J=11.6, 4.2 Hz, H-3), 4.75 (m, 2H, H-3' and H-5'), 5.28 (large s, 1H, H-4'), 5.86 (a, 1H, H-1'), 6.14 (s, 1H, H-1), 7.77 and 8.11 (2m, 2X2H, ArH).
IR (film) Vmax: 2945, 1743 broad, 1668, 1236 broad, 958, 734 cm-1.
Step 10: (1'S,1S,3R)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-2'-iodo- L-lyxohexopyranose)-isochroman The titled compound was obtained via base hydrolyaia of the (1'S,1S,1R) precuraor from step 2 herein as per procedure from step 3 herein.
PMR (acetone-d6, 250 MHz) δ: 1.35 (d, 3H, J=6.6Hz, CH3-6'), 2.30 (a, 3H, COCH3), 2.50 (dd, 1H, J=17.6 and 11.5 Hz, CHaCHO), 2.94 (dd, 1H, J=17.9 and 4.3Hz, CHeCHO), 3.20 (d, 1H, OH), 4.44 (m, 1H, H-3'), 3.80 (large s, 7H, 2XOCH3 and H-4'), 4.12 (d, 1H, OH), 4.41 (d, 1H, J=5.0Hz, H-2'), 4.55 (q, 1H, J=6.4Hz, H-5'), 4.70 (dd, 1H, J=12.1 Hz and 4.5 Hz, H-3), 5.87 (1S, 1H, H-1'), 6.14 (1s, 1H, H-1), 6.88 (2d, 2H, ArH).
Step 11: (1'S,1S,3R)-3-aceto-1-(2',6'-dideoxy-2'-iodo-L- lyxohexopyranose)-5,8-dioxo-5,8-dihydroisochroman
The titled compound was obtained following CAN oxidation of the product from step 10 herein as per previous procedure. PMR (CDCl3, 250 MHz) δ: 1.45 (d, 3H, J=6.6Hz, CH3-6'), 1.90 (broad s, 1H, OH), 2.31 (s, 3H, COCH3), 2.43 (dd, 1H, J=20.1Hz and 11.8 Hz, CHaCHO), 2.80 (m, 1s, OH), 2.88 (dd, 1H, J=19.8Hz and 4.1Hz, CHeCHO), 3.32 (m, 1H, H-3'), 3.84 (m, 1H, H-4'), 4.24 (d, 1H, J=4.4Hz, H-2'), 4.42 (dd, 1H, J=11.8Hz and 4.2Hz, H-3), 5.82 (a, 1H, H-1'), 5.95 (s, 1H, H-1), 6.79 (2Xd, 2H, quinone ring-H).
Step 12: (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'- iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c)-pyran-3-yl)-ketone (BCH-2014)
A mixture of compound from step 11 herein (1 ml) and 1-acetoxy-butadiene (96 mg, 0.201 mmol) in 2 ml of dry toluene was stirred for 18 hours under argon atmosphere and then flash chromatographed (Toluene:Ethyl acetate; 8:2) to give .42 mg (40% yield) of pure titled compound.
PMR (CDCl3, 250 MHz) δ: 1.52 (d, 3H, CH3-6'), 2.36 (a, 3H, COCH3), 2.58 (dd, 1H, J=19.7Hz and 11.4Hz, HCHaCHCO), 2.78 (broad m, 1H, OH), 3.09 (dd, 1H, J=20.0Hz and 4.2Hz, HCHeCHCO), 3.34 (m, 1H, H-3'), 3.89 (m, 1H, H-4'), 4.27 (d, 1H, J=4.5Hz, H-2'), 4.49 (dd, 1H, J=11.7Hz and 4.2Hz, H- 3), 4.66 (broad q, 1H, J-6.4Hz, H-5'), 5.30 (s, 1H, H-1'), 5.89 (8, 1H, H-1), 7.53 and 8.13 (2m, 2X2H,Ar-H).
IR (film) Vm ax: 3434 broad, 2934 broad, 1720, 1669, 1292, 995, 955 cm-1.
Example 62: Various C-2' axialy brominated pyranylnaphthoquinone glycosides
Figure imgf000202_0001
Step 1: 3,4-Di-O-acetyl-2-bromo-2,6-dideoxyfucose
Following the procedure described in step 1, example 61, we obtained after work-up 89% yield of a mixture of four compounds. Probably axial and equatorial bromo sugars and α and β isomers of each.
Step 2: (1'S,1R,3S) and (1'S,1S,3R)-2,5-Dimethoxy-1-(2',6'-dideoxy-
3 ',4'-diacetoxy-2'-bromo-L-lyxohexopyranoae)-3- acetoisochroman
Following the procedure described in step 2, example 61, we obtained after purification (Dichloromethane:Hexane:Ethyl acetate; 12:7:1) 35% yield of a separable (1'S,1R,3S and 1'S,1S,3R) 1:1 mixture of titled diastereoisomers. (1'S,1S,3R): PMR (acetone-d6, 250 MHz) δ: 1.27 (d, 3H, J=6.5Hz, CH3- 6'), 1.94 and 2.11 (2Xa, 2X3H, 2XOAc), 2.29 (s, 3H, COCH3), 2.50 (dd, 1H, J=17.7Hz and 12.1Hz, CHaCHO), 2.96 (dd, 1H, J=17.8 and 4.2Hz, CHeCHO), 3.80 and 3.84 (2Xa, 2X3H, 2XOCH3), 4.42 (d, 1H, J=4.2Hz, H- 2'), 4.71 (dd, 1H, J=12.2Hz and 4.2 Hz,H-3), 4.81 (q, 1H, J=6.4Hz, H- 5'), 5.22 (m, 2H, H-3' and H-4'), 5.74 (s,1H, H-1'), 6.17 (8, 1H, H-1), 6.90 (2Xd, 2H,Ar -H).
IR (film) Vmax: 2937, 1748, 1486, 1260 and 1237, 970 cm-1.
(1'S,1R,3S): PMR (acetone, 250 MHz) δ: 1.16 (d, 3H, J=6.6Hz, CH3-6'), 1.97 and 2.10 (2Xs, 2X3H, 2XOAc), 2.30 (s, 3H, COCH3), 2.45 (dd, 1H, J=17.6Hz and 12.2Hz, CHaCHO), 2.97 (dd, 1H, J=17.6Hz and 4.0Hz, CHeCHO), 3.80 and 3.82 (2Xs, 2X3H, 2XOCH3), 4.38 (d, 1H, J=4.6Hz, H-2'), 4.53 (q, 1H, J=6.4Hz, H-5'), 5.16 (broad s, 1H, H-4'), 5.27 (dd, 1H, J=4.2Hz, H- 3'), 5.71 (s, 1H, H-1'), 6.05 (s, 1H, H-1), 6.89 (2Xd, 2H,Ar -H).
Step 3: (1'S,1R,3S)-5,8-dioxo-1-(2',6'-dideoxy-3',4'-diacetoxy-2'- bromo-L-lyxohexopyranose)-5,8-dihydroisochroman
CAN oxidation of the compound from step 2 herein yielded the titled compound.
PMR (CDCl3, 250 MHz) δ: 1.19 (d, 3H, J=6.6Hz, CH3-6'), 2.04 and 2.16 (2Xs, 2X3H, 2XOAc), 2.29 (s, 3H, COCH3), 2.38 (dd, 1H, J=19.9Hz and 11.6Hz, CHaCHO), 2.88 (dd, 1H, J=19.8Hz and 3.9Hz, CHeCHO), 4.25 (m, 2H, H-2' and H-5'), 4.39 (dd, 1H, J=11.6Hz and 3.8Hz, H-3), 5.16 (broad s, 1H, H-4'), 5.19 (dd, 1H, J=4.0Hz, H-3'), 5.71 (s, 1H, H-1'), 5.81 (s, 1H,H-1), 6.79 (2Xd, 2H,Ar-H).
Step 4: (1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'- bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2100)
The titled compound was obtained following the procedure described in step 2, example 5, from the compound from step 3 herein. HPLC
purification gave 9% of deaired (1'S,1R,3S) natural titled glycoside. PMR (CDCl3, 250 MHz) δ: 1.23 (d, 3H, J=6.4Hz, CH3-6'), 2.06 and 2.19 (2s,2X3H, 2XOAC), 2.35 (s, 3H, COCH3), 2.54 (dd, 1H, J=19.7Hz and
11.7Hz, CHaCHO), 3.09 (dd, 1H, J=19.8Hz and 4.0Hz, CHeCHO), 4.29 (m, 2H, H-2' and H-5'), 4.47 (dd, 1H, J=11.7Hz and 4.0Hz, H-3), 5.18 (broad s, 1H, H-4'), 5.23 (unresolved dd, 1H, H-3'), 5.83 (s, 1H, H-1'), 6.01 (s, 1H, H-1), 7.77 and 8.11 (2m, 2X2H, Ar-H).
IR (film) Vmax : 2991 and 2943, 1748,1665, 1241, 975 cm-1. Step 5: (1'S,1R,3S)-5,8-dioxo-3-aceto-1-(2',6'-dideoxy-3',4'- diacetoxy-2'-bromo-L-lyxohexopyranose)-5,8-dihydroisochroman
CAN oxidation of the (1'S,1R,3S) diastereomer from step 2 herein yielded the titled product.
IR (film) Vmax: 2939, 1743, 1674, 1241, 968 cm-1.
Step 6: (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'- bromo-L-lyxobaxopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c)-pyran-3-yl) ketone (BCH-2099)
The titled compound was obtained following the procedure described in step 2, example 5, from the quinone from step 5 herein. Flash
chromatography (Toluene:Ethyl acetate; 9:1) gave 30% of desired titled compound.
PMR (CDCl3, 250 MHz) δ: 1.41 (d, 3H, J=6.4Hz, CH3-6'), 2.05 and 2.21 (2s, 2X3H, 2XOAc), 2.34 (s, 3H, COCH3), 2.58 (dd, 1H, J=20.1Hz and 11.6Hz, CHaCHO), 3.08 (dd, 1H, J=20.0Hz and 4.2Hz, CHeCHO), 4.16 (d, 1H, J=4.5Hz, H-2'), 4.48 (dd, 1H, J=11.6Hz and 4.1Hz, H-3), 4.76 (q, 1H, J=5.9HZ, H-5'), 5.20 (unresolved dd, 1H, H-3'), 5.25 (broad a, 1H, H- 4'), 5.72 (1s, 1H, H-1'), 6.17 (1s, 1H, H-1), 7.78 and 8.12 (2m, 2X2H, Ar-H).
IR (film) Vmax : 2937, 1750, 1672, 1243, 964.cm-1.
Example 63: C-2'-axialy iodinated daunosaminyl
pyranylnaphthoquinone glycosides
Figure imgf000205_0001
Step 1: 2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-o-acetyl- L-lyxohexopyranose
Following the procedure described in step 1, example 61, we obtained after work-up 94% yield of a non-separable α-β mixture (2:1) of titled halogenated augar.
PMR (acetone-d6, 250 MHz) δ: 1.08 (d, 3H, J=6.6Hz, CH3-6), 2.13 (s, 3H, OAc-4), 4.47 (m, 1H, H-3), 4.53 (d, 1H, J=4.3Hz, H-2), 4.56 (broad q, 1H, J=5.2Hz, H-5), 5.17 (broad s, 1H, H-4), 5.65 (d, 1H, J=3.8Hz, H-1), 6.04 (d, 1H, J=3.8Hz, OH).
Step 2: (1'S,1R,3S) and (1'S,1S,3R)-2,5-Dimethoxy-3-aceto-1- (2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-O- acetyl-L-lyxohexopyranose)-isochroman Following the same procedure as described in step 2, example 61, we obtained after purification (Toluene:Ethyl acetate; 9:1) 38% yield of a separable (1'S,1R,3S and 1'S,1S,3R) mixture of titled diastereoisomers (1:1).
The natural (1'S,1R,3S) glycoside: PMR (acetone-d6, 250 MHz) δ: 1.16 (d, 3H, J=6.6Hz, CH3-6'), 2.15 (s, 3H, AcO-4'), 2.30 (s, 3H, COCH3), 2.41 (unresolved dd, 1H, CHaCHCO), 2.97 (dd, 1H, J=17.7Hz and 3.89Hz, CHeCHO), 3.80 and 3.84 (2xs, 2x3H, 2xOCH3), 4.36 (m, 1H, H-3'), 4.63 (m, 3H, H-3, H-2' and H-5'), 5.19 (broad s, 1H, H-4'), 5.90 (s, 1H, H-1'), 6.06 (a, 1H, H-1), 6.87 (2xd, 2H,Ar -H), 7.95 (broad s, 1H, NHCOCF3). The non-natural glycoside (1'S,1S,3R): PMR (acetone-d6, 250 MHz) δ: 1.23 (a, 3H, J=6.5Hz, CH3-6'), 2.16 (s, 3H, AcO-4'), 2.30 (s, 3H, COCH3), 2.51 (dd, 1H, J=18.2Hz and 12.0Hz, CHaCHO), 2.97 (dd, 1H, J=17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.83 (2Xs, 2X3H, 2XOCH3), 4.30 (m, 1H, H-3'), 4.69 (d, 1H, J=4.72Hz, H-2'), 4.74 (dd, 1H, J=12.1Hz and 4.3Hz, H-3), 4.88 (q, 1H, J=5.0Hz, H-5'), 5.24 (broad a, 1H, H-4'), 5.92 (s, 1H, H-1'), 6.18 (s, 1H, H-1), 6.90 (2Xd, 2X1H,Ar-H), 7.95 (broad s, 1H, NHCOCF3).
Step 3: (1'S,1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-2'-iodo-L-lyxohexopyranose)-isochroman
Base hydrolysis of the compound from step 2 herein as per procedure from step 3, example 61, yielded the titled compound. PMR (acetone-d6, 250 MHz) δ: 1.28 (d, 3H, J=6.6Hz, CH3-6'), 2.30 (s, 3H, COCH3), 2.45 (dd, 1H, J=17.6Hz and 12.2Hz, CHaCHO), 2.95 (dd, 1H, J=17.6Hz and 4.0Hz, CHeCHO), 3.79 and 3.84 (2a, 2X3H, 2XOCH3), 4.03 (m, 2H, H-4' and OH-4'), 4.44 (broad q, 1H, J=6.4Hz, H-5'), 4.58 (m, 2H, H-3 and H-2'), 5.89 (s, 1H, H-1'), 6.04 (s, 1H, H-1), 6.89 (2d, 2XH,Ar-H), 7.65 (broad s, 1H, NHCOCF3).
IR (film) Vmaχ: 3539 and 3414, 2941 and 2844, 1728, 1488, 1260, 1175, 970 cm-1. Step 4: (1'S,1R,3S)-3-aceto-1-(2',3',6'-trideoxy -2'-iodo-3'- trifluoroacetamido-L-lyxohaxopyranose)-5,8-dioxo-5,8- dihydrois ochroman CAN oxidation of the product from step 3 herein yielded the titled product.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J=6.6Hz, CH3-6'), 2.06 (broad d, 1H, OH-4'), 2.32 (s, 3H, COCH3), 2.41 (dd, 1H, J=20.4Hz and 11.7Hz, CHaCHO), 2.93 (dd, 1H, J=19.6 and 3.9Hz, CHeCHO), 3.75 (broad d, 1H, H- 4'), 3.96 (m, 1H, H-3'), 4.28 (q, 1H, J=6.7Hz, H-5'), 4.42 (m, 2H, H-3 and H-2'), 5.82 (8, 1H, H-1'), 5.90 (s, 1H, H-1), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, 1H, NHCOCF3).
IR (film) Vmax: 3541 and 3417, 2992 and 2944, 1729, 1664, 1174, 967 cm- 1.
Step 5: (1'S,1R,3S)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2023)
The titled compound was obtained as per procedure described in step 2, example 5, but using the product from step 4 herein. Purification was effected by flash chromatography (Toluene:Ethyl acetate; 8:2).
PMR (CDCI3, 250 MHz) δ: 1.34 (d, 3H, J=6.6Hz, CH3-6'), 2.35 (s, 3H, COCH3), 2.53 (dd, 1H, J=19.6Hz and 11.5Hz, CHaCHO), 3.11 (dd, 1H,
J=19.6Hz and 4.1Hz, CHeCHO), 3.76 (broad s, 1H, H-4'), 3.97 (m, 1H, H- 3'), 4.30 (q, 1H, J=6.6Hz, H-5'), 4.49 (dd+d, 2H, H-3 and H-2'), 6.00 (1s, 2H, H-1 and H-1'), 7.01 (broad d, 1H, NHCOCF3), 7.78 and 8.13 (2Xm, 2X2H, Ar-H).
IR (film) Vmax: 3529 and 3414, 2991 and 2930, 1727, 1666, 1298, 1177, 963 cm-1.
Step 6: (1'S,1S,3R)-5,8-dimothoxy-3-aceto-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-2'-iodo-L-lyxohexopyranose) isochroman
To a mixture of (1'S,1S,3R) glycoside from step 2 herein (103 mg, 0.16 mmol) in 15 ml of anhydrous methanol was added, at 0°C and under argon atmosphere, 2 drops of NaOCH3, 4.37M (cat.). After stirring for 45 minutes, the reaction was worked up by adding 10 ml of a mixture NH4CI sat.:NaHCO3 sat. (8:3) and extracted with CH2Cl2 (2x30 ml). The combined organic layers were washed with the same aqueous mixture (30 ml) and dried (MgSO4). Flash chromatography (Toluene:Ethyl acetate; 9:1) gave 70mg of pure titled glycoside (73% yield). PMR (acetone-d6, 250 MHz) δ: 1.38 (d, 3H, J=6.5Hz, CH3-6'), 2.30 (s, 3H, COCH3), 2.50 (dd, 1H, J=17.7Hz and 12.0Hz, CHaCHO), 2.97 (dd, J=17.8Hz and 4.3Hz, CHeCHO), 3.80 and 3.81 (2Xs, 2X3H, 2XOCH3), 4.00 (m, 3H, H- 3', H-4' and OH-4'), 4.62 (d, 1H, J=4.8Hz, H-2'), 4.74 (m, 2H, H-3 and H-5'), 5.92 (1s, 1H, H-1'), 6.18 (1s, 1H, H-1), 6.88 (2Xd, 2H, Ar-H), 7.65 (broad s, 1H, NHCOCF3).
IR (film) Vmax: 3530, 3410, 2942 and 2837, 1723 broad, 1491, 1263, 1175, 958 cm-1. Step 7: (1'S,1S,3R)-3-aceto-1-(2',3',6'-trideoxy-2'-iodo-3'- trifluoroacetamido-L-lyxohexopyranose)-5,8-dioxo-5,8- dihydroisochroman
CAN oxidation of the product from step 6 herein yielded the titled product.
PMR (CDCI3, 250 MHz) δ: 1.47 (d, 3H, J=6.61Hz, CH3-6'), 2.22 (broad d, 1H, OH-4'), 2.32 (1s, 3H, COCH3), 2.46 (dd, 1H, J=19.6Hz and 11.7Hz, CHaCHO), 2.92 (dd, 1H, J=19.9Hz and 4.2Hz), 3.78 (broad d, 1H, H-4'), 3.91 (m, 1H, H-3'), 4.37 (d, 1H, J=4.8Hz, H-2'), 4.43 (dd, 1H, J=11.7Hz and 4.1Hz, H-3), 4.64 (q, 1H, J=6.3Hz, H-5'), 5.84 (s, 1H, H-1'), 5.97 (s, 1H, H-1), 6.82 (2xd, 2H,Ar-H), 7.06 (broad d, 1H, NHCOCF3).
IR (film) Vmax: 3531 and 3406, 2929, 1726, 1663, 1181 broad, 960 cm-1.
Step 81 (1'S,1S,3R)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2022)
The titled compound was obtained as per procedure described in step 2, example 5, but using the product from step 7 herein. Purification by flash chromatography (Toluene:Ethyl acetate; 9:1).
PMR (CDCI3, 250 MHz) δ: 1.51 (d, 3H, J=6.5Hz, CH3-6'), 2.11 (broad d, 1H, OH-4'), 2.34 (a, 3H, COCH3), 2.58 (dd, 1H, J=19.4Hz and 11.6Hz,
CHaCHO), 3.10 (dd, 1H, J=19.8Hz and 4.1Hz, CHeCHO), 3.82 (broad d, 1H, H-4'), 3.92 (dd, 1H, J=11.6Hz and 4.1Hz, H-3), 4.79 (q, 1H, J=6.5Hz, H-
5'), 5.88 (s, 1H, H-1'), 6.14 (s, 1H, H-1), 7.07 (broad d, 1H, NHCOCF3),
7.78 and 8.11 (2Xm, 2X2H,Ar-H).
IR (film) Vmax: 3539 and 3414, 2946, 1731, 1666, 1293, 1174, 961 cm-1. Example 64:
Figure imgf000209_0001
Step 1 : 2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-arabinohexopyranose
Following the procedure described in step 1, example 61, we obtained after work-up a quantitative yield of the desired compound which was used in the next step without purification:
PMR (Benzene-d6, 250 MHz) δ: 1.17 (d, 3H, J=6.2Hz, CH3-6), 4.04 (m, 1H, H-5), 4.48 (d, 1H, J=4.2Hz, H-2), 4.84 (dd, 1H, J=9.5Hz and 4.2Hz, H-3), 5.01 (large s, 1H, H-1), 5.51 (dd, 1H, J=9.7Hz, H-4).
Step 2: (1'S,1S,3R) and (1'S,1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',6'- dideoxy-3',4'-diacetoxy-2'-iodo-L-arabinohexopyranose) isochroman Following the same procedure as described in step 2, example 61, we obtained after flash chromatography (Toluene:Ethyl acetate; 9:1) a mixture of the titled stereoisomers (non-separable).
PMR (Benzene-d6, 250 MHz) δ: 1.20 and 1.38 (2d, 2X3H, 2XCH3-6'), 1.61, 1.66, 1.67 and 1.69 (4s, 4X3H, 4X0Ac), 1.95 and 2.12 (2a, 2X3H, 2XOCH3), 2.76 (m, 2XH, 2XCHaCHO), 3.20 (m, 2H, 2XCHeCHO), 2.30, 2.31 and 2.32 (3s, 4X3H, 4XOCH3), 4.18 (m, 1H, H-5'), 4.35 and 4.47 (2Xdd, 2H,
J=12.0Hz and 4.2Hz, 2XH-3), 4.82 (m, 5H, 2XH-3', 2XH-2'; and H-5'), 5.62 and 5.70 (2Xdd, 2H, J=9.5Hz, 2XH-4'), 5.84 and 5.93 (2 large s, 2H, 2XH- 1'), 5.95 (s, 1H, H-1), 6.33 (m, 5H, 2X2Ar-H and H-1).
Step 3: (1'S,1R,3S) and (1'S,1S,3R)-3-aceto-1-(2',6'-dideoxy-2'- iodo-L-arabinohexopyranose)-5,8-dioxo-5,8-dihydroisochroman The titled compounds were obtained following CAN oxidation of the products from step 2 herein as per previous procedures.
PMR (CDCl3, 250 MHz) δ: 1.23 and 1.36 (2d, 2X3H, J=6.2Hz, 2XCH3-6'), 2.03, 2.04, 2.06 and 2.07 (4a, 4X3H, 4XOAc), 2.29 and 2.30 (2S, 2X3H, 2XCOCH3), 2.46 (m, 2H, 2XCHaCHO), 2.90 (dd, 2H, J=19.7Hz and 3.8Hz, 2XCHeCHO), 4.02 (m, 1H, H-5'), 4.49 (m, 7H, 2XH-2 ', 2XH-3', 2XH-3 and H- 5'), 5.15 (m, 2H, 2XH-4'), 5.62 and 5.68 (2S, 2H, 2XH-1'), 5.79 and 5.95 (2s, 2H, 2XH-1), 6.75 (2X2d, 4H, 4XAr-H).
Step 4x (1'S,1R,1S) and (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'- diacetoxy-2'-iodo-L-arabino-hexopyranose)-5,10-dioxo-
3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH- 2065)
Following the reported procedure in step 2, example 5, and starting from the two stereoisomers from step 3 herein, titled compounds (9%) were isolated after flash chromatography (Toluene:Ethyl acetate; 19:1).
PMR (CDCI3, 250 MHz) δ: 1.41 (d, 3H, J=6.2Hz, CH3-6'), 2.06 and 2.08
(2s, 2X3H, 2XOAC), 2.33 (a, 3H, COCH3), 2.57 (dd, 1H, J=19.5Hz and
11.7Hz, CHaCHO), 3.09 (dd, 1H, J=19.8Hz and 4.2Hz, CHeCHO), 4.46 (m, 4H, H-3, H-2', H-3' and H-5'), 5.21 (dd, 1H, J-9.5Hz, H-4"), 5.67 (s, 1H, H-
1'), 6.14 (s, 1H, H-1), 7.78 and 8.13 (2m, 2X2H,Ar-H).
IR (film) Vmax: 2941, 1750 and 1739, 1665, 1298, 1236 large, 971 cm-1.
Example 65: C-2' deoxyfucose pyranylnaphthoquinone glycosides
Figure imgf000211_0001
Step 1: (1'8,1S,3R) and (1'S,1R,3S)-5,8-dimethoxy-3-aceto-1-(2',6'- dideoxy-3',4'-diacetoxy-L-lyxohexopyranose) isochroman
The procedure described in step 2, example 61, was applied to 5,8- dimethoxy-3-acetoisochroman and 3,4-diacetoxy-2,6-dideoxy fucose. Flash chromatography (dichloromethane:Hexane:Ethyl acetate; 6:3:1) gave a 50% yield of the two non-separable titled atereoisomers mixture (1:1).
PMR (acetone-d6, 250 MHz) δ: 1.11 and 1.20 (2d, 2X3H, J=6.6Hz, CH3-6'), 1.87, 1.88, 2.10 and 2.10 (4a, 4X3H, 4xOAc), 2.28 and 2.29 (2a, 2X3H, 2XCOCH3), 2.45 (m, 2X3H, 2XCHaCHO), 2.94 (m, 2H, 2XCHeCHO), 3.79, 3.81 and 3.83 (3s, 4X3H, 4XOCH3), 4.34 (q, 1H, J=6.53Hz, H-5'), 4.62 (m, 3H, 2XH-3 and H-5'), 5.14 (m, 4H, 2xH-3' and 2XH-4'), 5.54 and 5.61 (2 broad s, 2H, 2XH-1'), 5.97 and 6.16 (2s, 2H,H-1), 6.88 (m, 2X2H, 2XAr- H).
Step 2: (1'S,1S,3R) and (1'S,1R,3S)-5,8-dimethoxy-3-aceto-1-(2',6'- dideoxy-L-lyxohexopyranose) isochroman The same procedure described in step 3, example 61, was applied to the products from step 1 herein. Flash chromatography of the crude
(Toluene:Ethyl acetate; 6:4) gave 39% yield of non-separable titled diastereoisomers (1:1).
PMR (acetone-d6, 250 MHz)δ: 1.16 and 1.25 (2d, 2X3H, J=6.6Hz, 2XCH3- 6'), 1.80 (m, 4H, 4XH-2'), 2.24 (s, 2X3H, 2XCOCH3), 2.45 (unresolved dd, 2H, CHaCHO), 2.87 (dd, 2H, CHeCHO), 3.37 (8, 1H, H-3'), 3.56 (m, 3H, H- 3' and 2XH-4'), 3.75 (s, 3X3H, 3xOCH3), 3.77 (s, 3H, OCH3), 4.00 and 4.34 (2d, 2H, J=6.6Hz, 2XH-5'), 4.54 (2 unresolved dd, 2H, H-3), 5.35 and 5.41 ( 2 broad a, 2H, 2XH-1'), 5.89 and 6.10 (2s, 2H, 2XH-1), 6.83 (2X2d, 4H,Ar -H).
Step 3: (1'S,1S,3R) and (1'S,1R,3S)-5,8-dioxo-3-aceto-1-(2',6'- dideoxy-L-lyxohexopyranose)-5,8-dihydroisochroman
The titled producta were obtained following CAN oxidation of the producta from step 2 herein.
PMR (CDCl3, 250 MHz) δ: 1.29 and 1.42 (2d, 2X2H, J=6.6Hz, 2XCH3-6'),
1.70 (m, 4H, 4XOH), 1.89 (m, 4H, 4XH-2'), 2.30 and 2.31 (2s, 2X3H, 2XCOCH3), 2.43 (2 overlapping dd, 2H, 2XCHaCHO), 2.89 (2 overlapping dd,
2H, 2XCHeCHO), 3.65 and 3.70 (2 broad a, 2H, 2XH-4'), 3.90 (m, 2H, 2XH-
3'), 3.99 (unresolved q, 1H, H-5'), 4.36 (q, 1H, J=6.8Hz, H-5'), 4.43 (2 overlapping, 2H, 2XH-3), 5.41 and 5.49 (2 broad s, 2H, 2XH-1'), 5.81 and 5.98 (2s, 2H, 2xH-1), 6.79 (2X2d, 4H, Ar-H).
Step 4: (1'8,18,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'- dihydroxy-3',4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2117) The titled compounds were obtained in 43% yield by following the procedure described in step 2, example 5, and using the products from step 3 herein. Flash chromatography (Toluene:Ethyl acetate; 4:6) and final purification by preparative TLC (same solvent conditions) was required.
PMR (DMSO-d6, 250 MHz) δ: 1.10 and 1.23 (2d, 2X3H, J=6.3Hz, 2XCH3-6'), 1.54 and 1.87 (2m, 2X2H, 2X2H-2'), 2.25 (s, 6H, 2XCOCH3), 2.46 (m, 2H, 2XCHaCHO), 2.86 (2 overlapping dd, 2H, CHeCHO), 3.73 (m, 2H, 2XH-3'), 3.89 (q, 1H, J=6.5Hz, H-5'), 4.28 (q, 1H, J=6.3Hz, H-5'), 4.38 (broad s, 1H, H-4'), 4.52 (2X unresolved dd, 2H, 2XH-3), 4.54 (broad s, 1H, H-4'), 5.11 (m, 2H, 2XOH), 5.31 and 5.38 (2 broad s, 2H, 2XH-1'), 5.49 (m, 2H, 2XOH), 5.86 and 5.94 (2a, 2H, 2XH-1), 8.32 and 9.58 (2m, 8H,Ar-H).
Step 5: (1'S,1S,3R) and (1'8,1R,3S)-5,8-dioxo-3-aceto-1-(2',6'- dideoxy-3',4'-diacetoxy-L-lyxohexopyranose) isochroman
The titled compounds were obtained following CAN oxidation of the producta obtained from step 1 herein.
PMR (CDCL3, 250 MHz) δ: 1.10 and 1.22 (2d, 2X3H, J=6.5Hz, 2XCH3-6'), 1.93 (large m, 2X2H, 2X2H-2'), 1.92, 1.96, 2.11 and 2.12 (4s, 4X3H,
4XOAc), 2.23 and 2.25 (2s, 2X3H, 2XCOCH3), 2.39 (2 overlapping dd, 2H, 2XCHaCHO), 2.80 (2 overlapping dd, 2H, 2XCHeCHO), 4.10 (q, 1H, J=6.5Hz, H-5'), 4.40 (m, 3H, 2XH-3 and H-5'), 5.10 (m, 4H, 2XH-3', and 2XH-4'), 5.44 and 5.50 (2 broad s, 2H, 2XH-1'), 5.76 and 5.94 (2s, 2H, 2XH-1), 6.57 (2X2d, 4H,Ar-H).
Step 6: (1'S,18,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'- diacetoxy-3',4'-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2118)
The titled compounds were obtained in 51% yield by following the procedure deacribed in step 2, example 5, and using the products from step 5 herein, Aromatization by flash chromatography (Toluene:Ethyl acetate; 8:2). Final purification by preparative TLC (same solvent conditions).
PMR (CDCl3, 250 MHz) δ: 1.17 and 1.33 (2d, 2X3H, J=6.6Hz, 2XCH3-6'), 1.88 (m, 2H, 2XH-2'), 1.96 (s, 2X3H, 2XOAc), 2.16 (large m, 2H, 2XH-2'), 2.18 and 2.19 (2s, 2X3H, 2XOAc), 2.32 and 2.34 (2s, 2X3H, 2XCOCH3), 2.54 (2X overlapping dd, 2H, 2XCHaCHO), 3.07 (2X overlapping dd, 2H,
2XCHeCHO), 4.17 (q, 1H, J=6.7Hz, H-5'), 4.51 (2X aoverlapping dd, 2H, 2X H-3), 4.63 (q, 1H, J=6.4Hz, H-5'), 5.19 (m, 4H, 2XH-3'; and 2XH-4'), 5.55 and 5.67 (2 broad a, 2H, 2XH-1'), 6.00 and 6.18 (2a, 2H, 2XH-1), 7.76 and 8.10 (2m, 8H, Ar-H). Example 66 : Phenolic pyranylnaphthoqui nono glycosides
Figure imgf000214_0001
Step 1: Methyl-(6-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-
[2,3-c]-pyran-3-yl) ketone and methyl-(9-hydroxy-5,10-dioxo- 3,4,5,10-tetrahydronaphtho- [2,3-c]-pyran-3-yl) ketone (BCH-2062) The titled compounda were obtained by following the procedure described in step 2 herein and using 1-acetoxybutadiene and 3-acetoisochroman-5,8- dione.
PMR (CDCl3, 250 MHz) δ: 2.33 (2s, 2X3H, COCF3), 2.56 (m, 2H, CHaCHO), 3.00 (m, 2H, CHeCHO), 4.07 (dd, 2H, J=10.1Hz and 3.9Hz, H-3), 4.60 (m, 2H, H-1), 4.95 (m, 2H, H-1), 7.26 (m, 2H,Ar-H), 7.62 (m, 2X2H,Ar-H), 11.84 and 11.96 (2s, 2H, OH-5 and OH-8).
Step 2: (1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobensoyl-L-lyxohexopyranose)- 5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran-3- yl) ketone To a mixture of (1'S,1S,3R) glycoside from step 1, example 5, (200 mg, 0.335 mmol) in dry toluene (2.5 ml) under argon atmoaphere, was added dropwise the 1-trimethylailyloxy-1,3-butadiene. After stirring for 18 hours at room temperature, the solvent was removed in vacuo. The reaidue was dried over vacuum for 10 minutes, dissolved in 5 ml of THF and cooled to 0C. Addition of HCl 1N (5 ml) gave after 30 minutes stirring a complete cleavage of the silyl group. Extractions were done with CH2Cl2 (3x30 ml) and the combined organic layers were dried with Na2SO4 and then evaporated. The reaidue was dissolved with 10 ml of dry CH2Cl2, at room temperature and under argon, and treated with 200 mg of PCC. After 30 minutes stirring, the reaction mixture was dropped on SiO2 and flash chromatographed (Toluene:Ethyl acetate; 8:2) to give 162 mg (72% yield) of a non-separable titled regioisomers (1:1).
PMR (CDCl3, 250 MHz) δ: 1.36 and 1.37 (2d, 2X3H, J=6.4Hz, CH3-6'), 2.14 (2X m, 2X2H, H-2'), 2.34 and 2.35 (2a, 2X3H, COCH3), 2.57 (dd, 2X1H, J=20.1Hz and 11.8Hz, CHaCHO), 3.09 (dd, 2X1H, J=19.9Hz and 4.1Hz, CHeCHO), 4.53 (2X unresolved dd, 2X1H, H-3), 4.61 (2Xm, 2X1H, H-3'), 4.77 (2X unresolved q, 2X1H, H-5'), 5.45 (broad s, 2X1H, H-4'), 5.63 (broad a, 2XH, H-1'), 6.19 and 6.21 (2s, 2H, H-1), 6.46 (broad a, 2H, NHCOCF3), 7.32 (m, 2H,Ar-H), 7.67 (m, 2X2H,Ar-H), 8.32 (m, 2X2H, Ar - H) , 11.89 and 11.90 (2a, 2H, OH-5 and OH-8) .
Step 3: (1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-[2',3',6'-trideoxy-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl-ketone (BCH-2078)
Hydrolysis of the glycosides from step 2 herein with catalytic sodium methoxide in methanol yielded the titled compounds. Flash
chromatography (Toluene:Ethyl acetate:acetone; 6:4:2) of the crude gave 83% yield of pure titled regioisomers mixture (1:1).
PMR (CDCI3, 250 MHz) δ: 1.40 and 1.42 (2Xd, 2X3H, J=6.4Hz, CH3-6'), 1.91 (m, 2X2H, H-2'), 2.31 and 2.32 (2Xs, 2X3H, COCH3), 2.56 (dd, 2X1H, J=19.7Hz and 11.4Hz, CHaCHO), 3.08 (dd, 2H, J=19.9Hz and 4.2Hz, CHeCHO), 3.67 (broad d, 2H, H-4'), 4.33 (m, 2H, H-3'), 4.53 (m, 4H, H-3 and H- 5'), 5.44 and 5.45 (2s, 2H, H-1'), 6.13 and 6.15 (2S, 2H, H-1), 6.74 (broad d, 2H, NHCOCF3), 7.30 (m, 2H,Ar -H), 7.65 (m, 2X2H,Ar-H), 11.89 and 11.91 (2s, 2H, OH-5 and OH-8). Example 67: 3-(3'-aminothiasolyl)-5,10-dioxo-1,3,4,5,10- pentahydro-naphtho-[2,3-c]-pyran (BCH)
Figure imgf000216_0001
Step 1: 3-aceto-5,8-dioxo-3,4,5,8-tetrahydro-1H-benzo-[2,3-c]-pyran
CAN oxidation of 5,8-Dimethoxy-3-acetoisochroman yielded the titled compound.
1H NMR (CDCl3, 250 MHz, Bruker) δ: 2.23 (3H, s, COCH3), 2.36 (1H, dd tr, J=17.8Hz, 11.0Hz, 2.9Hz, 4-HCHa), 2.75 (1H, d tr, J=17.8Hz, 2.9Hz, 4- HCHe), 3.96 (1H, dd, J=11Hz, 5.3Hz, 3-CH), 4.41 (1H, d tr, J=17.8Hz, 3.5Hz, 1-HCHa), 4.72 (1H, d tr, J=17.5Hz, 1Hz, 1-HCHe), 6.71 (2H, m, ArH).
Step 2: 3-aceto-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- pyran The titled compound was obtained by following the procedure described in step 2, example 5, and using the product from step 1 herein.
1H NMR: (CDCI3, 250 MHz, Bruker) δ: 2.30 (3H, s, COCH3), 2.56 (1H, dd tr, J=18Hz, 11.2Hz, 2.9Hz, 4-HCHa), 3.01 (1H, d, J=18.0Hz, 4-HCHe), 4.05 (1H, dd, J=11.2Hz, 3.8Hz, 3-CH), 4.60 (1H, d tr, J=17.8Hz, 4.1Hz, 1- HCHa), 4.95 (1H, d m, J=17.8Hz, 1-HCHe), 7.73 (2H, m, 7, 8-ArH), 8.08 (2H, m, ArH). Step 3: 3-bromoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho- [2,3-c]-pyran
The titled compound was obtained by following the procedure described in step 1, example 7, and using the product from step 2 herein.
1H NMR (CDCl3, 250 MHz, Bruker) δ: 2.57 (1H, dd tr, J=18.8Hz, 11.2Hz, 3Hz, 4-HCHa), 3.02 (1H, d m, J=18.8Hz, 4-HCHe), 4.21 (1H, d, J==12.9Hz, CHBr), 4.30 (1H, d, J=12.9Hz, CHBr), 4.34 (1H, dd, J=11.2Hz, 4.7Hz, 3- CH), 4.58 (1H, d tr, J=18.0Hz, 3.0Hz, 1-HCHa), 4.90 (1H, d m, J=18.0Hz, 1-HCHe), 7.70 (2H, m, 7, 8-ArH), 8.04 (2H, m, 6, 9-ArH).
Step 4: 3-(3'-aminothiasolyl)-5,10-dioxo-1,3,4,5,10-pentahydro- naphtho-[2,3-c]-pyran Bromomethyl ketone from step 3 herein (270 mg, 0.81 mmol) was stirred with thiourea (60 mg, 0.88 mmol) in ether (80 ml) and methylene chloride (10 ml) at room temperature for 4 houra. Three pellets of molecular sieves were used to take up water. Solvent was evaporated to give a white solid. The crude product was washed with chloroform/ether (8:1) first, then basified with potassium carbonate. It was extracted with chloroform. The organic phase was evaporated to give a crude product which was chromatographed to give desired titled product. dec. 130°C.
1H NMR (CDCl3, 250 MHz, Bruker) , 2.80 (1H, m, 4-HCHa) , 3.09 (1H, br d, J = 18.2 Hz, 4-HCHe) , 4.58 (1H, dd, J = 10.0 Hz, 3.5 Hz, 3-CH) , 4.68 (1H, d tr, J = 18.8, 2.9 Hz, 1-HCHa) , 4.95 (1H, dd, J = 18.8 Hz, 2.3 Hz, 1-HCHe) , 5.54 (1H, br 8, NH) , 6.54 (1H, s, thia-H) , 7.73 (1H, m, ArH) , 8.08 (1H, m, ArH) .
Example 68 : Cyclic amine substituted naphthoquinone derivative
Figure imgf000218_0001
step 1: N-BOC-isonipecotic acid
The titled compound was obtained following standard conditions.
1H NMR (CDCl3): δ 4.02 (m, 2H, CH2N), 2.73 (m, 2H, CH2N), 2.50 (m, 1H,
CHCOOH), 1.91 (m, 2H, CH2CHCOOH), 1.64 (m, 2H, CH2CHCOOH).
Step 2: M-BOC-4-piperidinemethanol
To a solution of the acid from step 1 (0.11 g, 0.48 mmol) in dry THF (4.8 ml), under argon, at 0°C, was added dropwise BH3-THF 1.0 M/THF (0.72 ml, 1.5 eq). The solution was atirred at 0°C for 30 minutes and at room temperature for 15 hours. Methanol (10 ml) was then carefully added to destroy the excess BH3 and the solvents were evaporated. The reaidue was poured in CH2Cl2/sat. aq. NaHCO3 and the phases were separated. The aqueous layer was extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the aolvent evaporated to give the titled alcohol aa a clear oil (0.092 g, 89%).
1H NMR (CDCl3): δ 4.09 (m, 2H, CH2N), 3.44 (d, 2H, CH2OH), 2.67 (m, 2H, CH2N), 2.08 (bs, 1H, OH), 1.73-1.52 (m, 2H, CH2-CH2N), 1.48 (s, 9H, BOC), 1.22-1.01 (m, 2H, CH2-CH2N).
Step 3: 1-O-[N-BOC-4-piperidinemethanol]-3-acetyl-5,8-dimethoxy
isochroman racemic
The titled compound was obtained via DDQ induced coupling of the alcohol from step 2 herein with 3-aceto-5,8-dimethoxy isochroman. Purification: flash chromatography (silica gel, 2:1 Hex/EtOAc).
1H NMR (CDCl3): δ 6.76 (d, 1H, J = 8.8, ArH), 6.70 (d, 1H, J = 8.8,ArH), 5.77 (s, 1H, H-1), 4.59 (dd, 1H, J = 4.2, 12.2, H-3), 4.08 (m, 2H, CH2N), 3.78 (s, 3H,Ar OMe), 3.77 (8, 3H, ArOMe), 3.72 (dd, 1H, J = 6.4, 9.7, H-1'), 3.57 (dd, 1H, J = 6.4, 9.7, H-1'), 3.04 (dd, 1H, J = 4.2,
17.6, H-4), 2.70 (m, 2H, CH2N), 2.53 (dd, 1H, J = 12.2, 17.6, H-4), 2.33 (s, 3H, COCH3), 1.76 (m, 3H, CH2CH-CH2O), 1.21 (m, 2H, CH2CHCH2O).
Step 4: Methyl-(1-O-[2'-piperidinemethanol]-5,10-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, racemic, hydrochloride (BCH-2069)
The titled compound was obtained from the precursor from step 3 herein as per previously described procedure.
1H NMR (DMSO): δ 8.05-7.80 (m, 4H, ArH), 5.69 (s, 1H, H-1), 4.48 (m, 1H, H-3), 3.88 (m, 4H, CH2N and NH2Cl), 3.74 (m, 1H, H-1'), 3.60 (m, 1H, H-1'), 3.25 (m, 1H, H-4+H2O), 2.82 (m, 3H, CH2N and H-4), 2.31 (8, 3H, COCH3), 2.01-1.70 (m, 3H, CH2CH-CH2O), 1.57-1.38 (m, 2H, CH2CHCH2O). Example 69 Diamino -sugar substituted naphthoquinone derivative
Figure imgf000220_0001
Step 1: (2R,4S,5S,6S)-2-tert-butyldimethylsilyloxy-4- trifluoroacetamido-5-hydrox-6-methyl-tetrahydropyran
To a solution of the hemiacetal (0.51 g, 2.08 mmol) in dry CH2Cl2 (20 ml), under argon, at room temperature, were added successively imidazole (0.28 g, 2 eq) and t-BuMe2SiCl (0.34 g, 1.1 eq). The solution was stirred at room temperature for 15 hours after which it was poured in sat. aq. NaHCO3. The phases were separated and the aqueous layer was extracted with CH2Cl2 (2x). The combined organic extracts were dried over MgSO4, the solids were filtered and the solvent evaporated to give 0.72 g (97%) of the titled silyloxy-sugar as a white solid.
1H NMR (CDCl3): δ 6.82 (bd, 1H, NH), 4.78 (dd, 1H, J = 2.2, 9.2, H-1), 4.09 (m, 1H, H-3), 3.62 (q, 1H, J = 6.6, H-5), 3.48 (d, 1H, J = 2.6, H- 4), 2.44 (bs, 1H, OH), 2.08 (dd, 1H, J = 5.0, 13.0, H-2), 1.55 (ddd, 1H, J = 9.2, 13.0, 13.0, H-2), 1.29 (d, 3H, J = 6.6, H-6), 0.89 (s, 9H, t- Bu), 0.12 (s, 3H, SiMe), 0.11 (s, 3H, SiMe). Step 2: (2R,4S,5R,6S)-2-tert-butyldimethylsilyloxy-4- trifluoroacetamido-5-azido-6-methyl-tetrahydropyran To a solution of the alcohol (0.40 g, 1.11 mmol) in dry CH2Cl2 (11.1 ml), under argon, at -30°C were added successively pyridine (0.45 ml, 5 eq) and Tf2O (0.37 ml, 2 eq) and the solution was stirred at -10°C for 1 hour. It was then poured in sat. aq. NaHCO3 and the phases were separated. The aqueoua layer was extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the solvents were evaporated to dryness. The red oil obtained was dissolved in dry DMF (11.1 ml), under argon, at room temperature, and NaN3 (0.36 g, 5 eq) was added. The suspension was stirred for 5 hours after which it was poured in EtOAc. This organic phase was washed with water (3x) and brine. It was then dried over MgSO4, the solids were filtered and the solvent evaporated to give the titled azido-trifluoroacetamide as a clear oil (0.27 g, 68%).
1H NMR (CDCl3): δ 6.44 (bd, 1H, J = 8.6, NH), 4.82 (dd, 1H, J = 2.1, 8.8, H-1), 4.09 (ddd, 1H, J = 4.7, 9.7, 12.8, H-3), 3.41 (dq, 1H, J = 6.1, 9.2, H-5), 2.97 (dd, 1H, J = 9.7, 9.7, H-4), 2.21 (ddd, 1H, J =
2.1, 4.7, 12.8, H-2), 1.67 (ddd, 1H, J = 8.8, 12.8, 12.8, H-2), 1.39 (d, 3H, J = 6.1, H-6), 0.89 (s, 9H, tBu), 0.12 (s, 3H, SiMe), 0.10 (s, 3H, SiMe). step 3: (2R,4S,5R,68)-2-tert-butyldimethylsilyloxy-4,5-bis- trifluoroacetamido-6-methyl-tetrahydro-pyran
The azido aaccharide from step 2 was reduced as per standard
contiditons. Purification: flash chromatography (silica gel, 85:15 Hexanes/EtOAc).
1H NMR (CDCl3): δ 7.85 (bd, 1H, J = 9.4, NH), 7.48 (bd, 1H, J = 9.7, NH), 4.84 (d, 1H, J = 7.8, H-1), 4.38 (m, 1H, H-3), 3.96 (m, 1H, H-4), 3.56 (dq, 1H, J = 6.1, 9.6, H-5), 2.19 (m, 1H, H-2), 1.78 (m, 1H, H-2), 1.29 (d, 3H, J = 6.1, H-6), 0.89 (s, 9H, t-Bu), 0.12 (s, 3H, SiMe), 0.11 (s, 3H, SiMe).
Step 4: (1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'- tetradeoxy-3',4'-bis-trifluoroacetamido-L- arabinohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104 and BCH-2102)
To a solution of the hydroxyquinone (72 mg, 0.33 mmole) and di- trifluoroacetamido sugar from step 3 herein (162 mg, 1.1 eq) in 6.5 mL of a 9:1 mixture of anhydrous CH2Cl2/Acetone, under argon, at -30 °C, were added activated 4A M.S. (200 mg) and TMSOTf (94 mL). The solution was atirred at -30 °C for 4 hr and 5% NaHCO3 (5mL) was added. The biphasic solution was stirred for 15 min while the temperature was allowed to go back to r.t. It was then filtered through Celite and poured in water. The phases were separated and the aqueous layer was extracted with CH2Cl2 (2x). The combined organic extracta were dried over MgSO4, The solida ware filtered and the solvants evaporated. The pale brown solid obtained was dissolved in dry toluene (6.5 mL) and 1- acetoxybutadiene (0.19 mL, 5 eq) was added. The aolution was stirred at r.t. , under argon for 15 hr. Silica gel was added and air was bubbled through the solution. This suspension was then placed on top of a silica gel column and the column was eluted with hexanes (1 reaervoir). When the hexanes was all gone , it was replaced with 2:1 hexanea/ethyl acetate and themixture of isomers was collected. This mixture was further purified by chromatography (10% acetone/toluene) to give 58 mg (30%) of the titled separated isomers.
The faster running fraction had: 33 mg, m.p.: 180-195 °C dec.
1H NMR (Acetone-d6) : d 8.47 (d, 1H, J= 9.1, NH), 8.36 (d, 1H, J= 9.4, NH), 8.11-8.04 (m, 2H,Ar H), 7.92-7.85 (m, 2H, ArH), 6.03 (s, 1H, H- 1), 5.65 (s, 1H, H-1'), 4.68 (dd, 1H, J= 4.1, 11.6, H-3), 4.58-4.36 (m, 2H, H-3' and H-4'), 3.85 (q, 1H, J= 10.1, H-5'), 3.02 (dd, 1H, J= 4.1, 19.6, H-4), 2.51 (dd, 1H, J= 11.6, 19.6, H-4), 2.32 (a, 3H, COMe), 2.28-2.09 (m, 2H, H-2'), 1.28 (d, 3H, J= 6.3, H-6').
The slower running fraction had: 25 mg, m.p.: 143-153 dec.
1H NMR (CDCl3) : d 8.55 (d, 1H, J= 9.2, NH), 8.46 (d, 1H, J= 9.1, NH), 8.13-8.07 (m, 2H, ArH), 7.95-7.88 (m, 2H, ArH), 6.17 (a, 1H, H-1), 5.63 (t, 1H, J= 2.5, H-1'), 4.71 (dd, 1H, J= 4.3, 11.6, H-3), 4.61- 4.34 (m, 2H, H-3' and H-4'), 3.86 (q, 1H, J= 10.2, H-5'), 2.99 (dd, 1H, J= 4.3, 19.7, H-4), 2.58 (dd, 1H, J= 11.6, 19.7, H-4), 2.32 (s, 3H, COMe), 2.28-2.13 (m, 2H, H-2'), 1.37 (d, 3H, J= 6.2, H-6').
Example 70: 4'-iododaunosamine substituted naphtoquinone
derivative
Figure imgf000223_0001
Step 1: (2S,4S,5S,6S)-2-(2,-methoxy-2'-propanoxy)-4-asido-5-bromo-6- methyl-tetrahydropyran
To a solution of the triflate (1.06 g, 2.80 mmol) in a 1:1 mixture of CH2Cl2/toluene (15 ml), under argon, at room temperature, was added nBu4NBr (1.34 g, 1.5 eq) and the solution was stirred for 3 hours. It was then poured in sat. aq. NaHCO3 and the phases were separated. The aqueous layer was extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the solvents evaporated to give a crude oil that was purified by flash chromatogrphy (silica gel, 85:15 Hexanes/EtOAc). The titled bromo-azide was obtained in 66% yield (0.57 g).
1H NMR (CDCl3): δ 5.34 (d, 1H, J = 3.4, H-1), 4.27 (s, 1H, H-4), 4.02 (q, 1H, J = 6.2, H-5), 3.96 (m, 1H, H-3), 3.20 (s, 3H, OMe), 2.23 (ddd, 1H, J = 3.4, 12.5, 12.5, H-2), 1.74 (dd, 1H, J = 4.26, 12.5, H-2), 1.40 (s, 3H, gemdimethyl), 1.35 (s, 3H, gemdimethyl), 1.25 (d, 3H, J = 6.2, H-6).
Step 2: (2R,4S,5S,6S)-2-tert-butyldimethylsilyloxy-4-asido-5-bromo- 6-methyl-tetrahydropyran
To a aolution of the bromo-azide from step 1 (0.57 g, 1.84 mmol) in dry CH2Cl2 (9.0 ml), under argon, at 0°C, was added alowly CF3COOH (7 μl, 0.05 eq) and the solution was stirred for 60 minutes. The solvent and reagent were then evaporated to dryness and the crude hemiacetal was dissolved in a dry mixture (15:1) of CH2Cl2/DMF (9.2 ml). Imidazole (0.25 g, 2 eq) was then added followed by t-BuMe2SiCl (0.31 g, 1.1 eq). The solution was stirred at room temperature for 15 hours after which it was poured in sat. aq. NaHCO3. The phases were separated, the aqueous layer was extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the solvent evaporated to give the titled TBDMS protected bromo-azide (0.30 g, 46%) as a clear oil.
1H NMR (CDCl3): δ 4.80 (dd, 1H, J = 2.5, 8.7, H-1), 4.15 (dd, 1H, J = 1.2, 3.3, H-4), 3.57 (ddd, 1H, J = 3.3, 4.4, 11.8, H-3), 3.44 (dq, 1H, J = 1.2, 6.1, H-5), 2.11-1.88 (m, 2H, H-2), 1.33 (d, 3H, J = 6.1, H-6), 0.90 (s, 9H, t-Bu), 0.14 (8, 3H, SiMe), 0.11 (s, 3H, SiMe).
Step 3: (2R,4S,5S,6S)-2-tert-butyldimethylsilyloxy-4- trifluoroacetamido-5-bromo-6-methyl-tetrahydropyran
To a solution of the azide from step 2 herein (0.30 g, 0.84 mmol) in a 19:1 mixture of THF/H2O (8.4 ml) was added Ph3P (0.33 g, 1.5 eq) and the solution was heated at 50°C for 3 hours. It was then poured in sat. aq. NaHCO3 and the aqueous phase was extracted with CH2Cl2 (3x). The combined organic extracts were dried over MgSO4. The solids were filtered and the solvent evaporated to dryness to give a crude amine that was dissolved in dry CH2Cl2 (8.4 ml). To this solution, under argon, at -30°C, were added successively dry pyridine (0.14 ml, 2 eq) and TFA2O (0.13 ml, 1.1 eq). The solution was stirred for 90 minutes at -30°C and was then poured in eat. aq. NaHCO3. The phases were
separated, the aqueous layer was extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgSO4. The solids were filtered and the solvent was evaporated to give the titled crude bromo- trifluoroacetamide in 72% yield (0.26 g).
1H NMR (CDCI3): δ 6.67 (bd, 1H, J = 7.3, NH), 4.84 (dd, 1H, J = 5.4, 6.5, H-1), 4.28-4.17 (m, 2H, H-3 and H-4), 3.58 (q, 1H, J = 6.1, H-5), 1.89-1.83 (m, 2H, H-2), 1.32 (d, 3H, J = 6.1, H-6), 0.88 (s, 9H, t-Bu), 0.12 (s, 3H, SiMe), 0.10 (s, 3H, SiMe).
Step 4: (1R,3S,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3'- trifluoroacetamido-4'-bromo-L-lyxohexopyranose]-5,10-dioxo- 3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone
The titled compound was obtained as per previous procedures from the sugar of step 3 and the isochromandione. Purification: flash
chromatography (silica gel, toluene/acetone 95:5). The two isomers are separable by chromatography.
1H NMR (CDCI3): δ 8.15-8.07 (m, 2H, ArH), 7.81 -7.76 (m, 2H, ArH), 6.46 (bd, 1H, J = 8.4, NH), 6.01 (a, 1H, H-1), 5.62 (d, 1H, J = 3.2, H-1'), 4.54 (dd, 1H, J = 4.0, 11.7, H-3), 4.42 (m, 1H, H-3'), 4.37 (s, 1H, H- 4'), 4.11 (q, 1H, J = 6.5, H-5'), 3.11 (dd, 1H, J = 4.0, 19.7, H-4), 2.53 (dd, 1H, J = 11.7, 19.7, H-4), 2.35 (s, 3H, COMe), 2.14 (td, 1H, J = 3.2, 12.9, H-2'), 1.91 (dd, 1H, J = 4.5, 12.9, H-2'), 1.32 (d, 3H, J = 6.5, H-6').
The (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido- 4'-bromo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno- [2,3-c] pyran-3-yl) ketone (BCH-2047) had:
1H NMR (CDCl3): δ 8.15-8.08 (m, 2H,Ar H), 7.82-7.74 (m, 2H,Ar H), 6.50 (bd, 1H, J = 8.5, NH), 6.18 (a, 1H, H-1), 5.49 (d, 1H, J = 3.4, H-1'), 4.58 (q, 1H, J = 6.4, H-5'), 4.48 (dd, 1H, J = 4.2, 11.6, H-3), 4.40 (s, 1H, H-4'), 4.40 (m, 1H, H-3'), 3.08 (dd, 1H, J = 4.2, 19.7, H-4), 2.57 (dd, 1H, J = 11.6, 19.7, H-4), 2.32 (s, 3H, COMe), 2.18 (td, 1H, J = 3.4, 13.0, H-2'), 1.79 (dd, 1H, J = 4.4, 13.0, H-2'), 1.49 (d, 3H, J = 6.4, H-6').
Example 71: Cyclic amine substituted naphthoquinone derivative
Figure imgf000226_0001
Step 1: N-BOC-3-piperidinemethanol The titled compound obtained following protection with BOC had:
1H NMR (CDCl3): δ 3.90-3.65 (m, 2H), 3.48 (d, 2H, CH2OH), 3.25-2.75 (m, 2H), 2.28 (bs, 1H, OH), 1.86-1.54 (m, 4H), 1.25 (m, 1H).
Step 2: 1-O-[N-BOC-3-piperidinemethanol]-3-acetyl-5,8-dimethoxy
isochroman, mixture of isomers
The titled compound was obtained from the precursor of step 1 herein and 5,8-dimethoxy-3-acetoisochroman as per procedure described earlier.
Purification: flash chromatography (silica gel, 2:1 Hexanes/EtOAc). The isomers were not separable by flash chromatography.
1H NMR (CDCl3): δ 6.75-6.65 (m, 2H, ArH), 5.74+5.73 (2s, 1H, H-1), 4.60 (m, 1H, H-3), 4.05-3.56 (m, 4H, H-1' and CH2N), 3.04 (dd, 1H, H-4), 2.86-2.62 (m, 2H, CH2N), 2.53 (dd, 1H, H-4), 2.33 (s, 3H, COCH3), 1.94- 1.79 (m, 2H), 1.68 (m, 1H), 1.48 (s, 9H, BOC), 1.37-1.24 (m,2 H). Step 3: Methyl-(1-O-[N-BOC-3-piperidinemethanol]-5,6-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-c) pyran-3-yl) ketone, mixture of isomers (BCH-2060) The titled compound was obtained from the product from step 2 herein, following previoualy described procedures. Purification: flash chromatography (silica gel, 2:1 Hexanes/EtOAc). The isomers were not separable by flash chromatography.
1H NMR (CDCl3): δ 8.12-8.03 (m, 2H, ArH), 7.78-7.67 (m, 2H, ArH), 6.72 (s, 1H, H-1), 4.54 (m, 1H, H-3), 4.10-3.55 (m, 4H, H-1' and CH2N), 3.04 (dd, 1H, H-4), 2.90-2.60 (m, 2H, CH2N), 2.51 (dd, 1H, H-4), 2.30 (a, 3H, COCH3), 1.97-1.72 (m, 2H), 1.61 (m, 1H), 1.48 (s, 9H, BOC), 1.34-1.15 (m, 2H). Step 4: Methyl-(1-O-[3-piperidinemethanol]-5,10-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone hydrochloride salt, mixture of isomers (BCH-2061)
The titled compound was obtained from the tricyclic product from step 3 herein following acidic hydrolysis.
1H NMR (DMSO-d6): δ 8.23-7.84 (m, 4H, ArH), 5.68+5.67 (2s, 1H, H-1), 4.48 (m, 1H, H-3), 3.83-3.57 (m, 2H, H-1'), 3.29-3.15 (m, 2H, CH2N), 2.84 (dd, 1H, H-4), 2.66 (m, 2H, CH2N), 2.43 (m, 1H, H-4), 2.29 (s, 3H, COCH3), 1.74-1.72 (m, 4H), 1.25 (m, 1H).

Claims

We claim: 1. A compound of the formula:
Figure imgf000228_0001
wherein
X1 and X2 are independently selected from the group consisting of
O, S, and N(R), wherein R is selected from the group consisting of hydrogen, hydroxyl, C1- 16 alkyl,
C1-16 acyl and C1-16 alkylamine:
X3 is selected from the group consisting of O, S, SO, SO2, and NR, wherein R is selected from the group consisting of hydroxyl:
C1-16 acyl C1-16 alky C1-16 aryl C1-16 haloacyl, and hydrogen.
X4 is selected from the group consisting of C-Q, nitrogen, and NO:
R1, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C1-16 alkoxyl, C3-8 cycloalkyl, tosyl, mesylate, acetate optionally substituted with a C1-8 alkyl, triflate, trifluoroacotate, halogen, nitro, cyano, C1-16 acyl, C1-16 arylacyl, aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH wherein n and m are independently 1 to 4, aminoalkylaminoalkylhalide of formula NH(CH2)nNH(CH2)mX wherein n and m are independently 1 to 4 and X is a halogen, amino, which may be unsubstituted or mono or
di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl and C6-18 aryl; C2-8 alkenyl, and C2-8 alkynyl,
haloalkylnitrosoureido of the formula NH(CO)N(NO) (CH2)n CH2X, wherein n is 0 to 4 and X is a halogen, and
-NH(CH2)n N R* R** wherein n is 1 to 6, R* and R** are independently selected from hydrogen, C1-8 alkyl, C6-18 aryl, C7-18 aralkyl, C1-8 acyl, and trifluoroacyl,
a group of the formula -O-C(R)=O wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-12 alkoxyalkyl, C7-18 aralkyl, C7-18 araloxyalkyl, C7-18 aryloxyalkyl and C6-18 aryl:
Z is one of C-R6 or C-R7:
R6 is selected from the group consisting of C1-16 hydroxime, C6-18 hydrazone, C1-16 hydroxyalkyl, hydrogen, C6-18 aryl, C7-18 aryloxyalkyl, C7-18 araloxyalkyl, phenyl, C1-16 alkyl, acetoxy, C1-16 dihydroxyalkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, squaric acid, C1-16 alkyl squarate, amino, cyano, dimethylphosphonato, phenyl sulfone, C1-8 aryl sulfone, and
C1-8 acetyl, agroup of the formula -C(R) = X* wherein X is selected from the group consisting of two hydrogens, one hydrogen and R* is selected from a C1-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and O, or its dioxolane or dioxane or dialkoxy C1-8 ketal, and wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C1-8 thioalkyl, C3-8 cycloalkyl, C6-18 aryl, C7-18 aralkyl, fluoromethyl, difluoromethyl, C1-8 hydroxyalkyl, C2-16 alkene, squaric acid, C2-16 alkyne, C1-8 thioalkyl, C6-18 thioaryl, C1-4 alkyl squarate, C2-8 alkoxyalkyl, C6-18 araloxyalkyl, C2-16 acyloxyalkyl, C1-8 alkoxy, hydroxy, acetoxy methyl, bromomethyl, C1-8 aceto, amino which may be unsubstituted or mono- or di- substituted by hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7- 18 aralkyl, C6-18 aryl,
a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of C1-8 alkyl, hydrogen, PO (OR)2 wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, and
a group of the formula -(CH2)n Z* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, pyrolone, and a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl;
said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, C1-16 alkoxy, C1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
amino, which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy, Z* can also be a group of the formula -NR* R** wherein R* and R** are independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 acyl, C6-18 aryl, C7-18 aralkyl, C1-8 haloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C1-8 acyloxyalkyl, C6-12 araloxyalkyl, and a group of formula -CO(CH2)n C(PO(OR)2)2 wherein n is 1 to 4 and R is hydrogen or C1-8 alkyl; and a naturally occurring amino acid;
a group of the formula -C(OR) =0, where R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C1-8 alkoxyalkyl, C7-18 aryloxyalkyl, C6-18 araloxyalkyl, C6-18 aryl and C7-18 aralkyl;
a group of the formula -(CH2)n C(R)=O, wherein n is 1 to 6 and wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl,
C1-8 alkoxy, C7-18 aryloxyalkyl, C7-18 araloxyalkyl, C6-18 aryl, C7-18 aralkyl,
amino which may be unsubstituted, mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, C2-12 aralkyl, C6-12 aryl, a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N,
SO, SO2, P, PO, and NR wherein R is
selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C1-4 alkyl and aryl, said heterocycle being optionally substituted with one or more halogens, C6-18 arylsulfone, hydroxy, C1-16 alkoxy, nitro, C1-16 alkyl, C1-16 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C1-8 alkyl, C3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; C2-8 alkenyl, C2-8 alkynyl and hydroxy:
R7 is selected from the group consisting of hydrogen, C1-16 alkyl, halogen, amino, hydroxy, C1-16 alkoxy, thiol, cyano, sulfide, acyl of the formula -C(R)=O wherein R is selected from
the group consisting of hydrogen, C1-16 alkyl, C1-16 alkoxy, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C7-18 araloxyalkyl, C2-8 alkoxyalkyl, C2-8 acyloxyalkyl, C6-12 aryloxyalkyl, squaric acid or squarate, amino which may be unsubstituted or mono- or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, cyano, trifluoroacyl, C7-18 aralkyl or C6-12 aryl, and a naturally occuring amino acid;
a group of the formula -C(OR) =O wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 aryloxyalkyl, C7-12 araloxyalkyl,
C6-12 aryl, C7-12 aralkyl and C1-16 alkenyl:
R5 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, C1-16 alkoxyl, C1-16 alkyl, C2-16 acetylenyl, a group of the formula -(CH2)n -NR*R** wherein n is 1 to 6, and R* and R** are independently selected from a group consisting of C1-8 alkyl, C1-4 acyl, C3-8 cycloalkyl, hydrogen, C2-8 carboalkoxy, C2-8 alkene, C2-8 alkyne, C6-12 aryl, and
(OCH2CH(PO(OR)2)2
wherein R is a hydrogen or a C1-8 alkyl and wherein n is 0 to 5;
C3-8 cycloalkyl, C2-16 alkenyl, C1-16 alkoxyalkylamino, cyano;
a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C3-8 cycloalkyl, C2-8 alkoxyalkyl, and C6- 12 aryl;
an acyl of the formula -C(R)=O, wherein R is selected from the group consisting of hydrogen, thiol, C1- 16 thioalkyl, C1-16 alkyl, C3-8 cycloalkyl, C1-8 hydroxyalkyl, C2-8 alkoxyalkyl, C7-12 araloxyalkyl, C2-8 acyloxyalkyl, amino which may be unsubstituted or mono- or di-substituted, and a naturally occurring amino acid or a synthetic amino acid;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl and C3-8 cycloalkyl, acosamine, glucosamine, N-chloroethyl-nitrosoureidoglucosamine, 2,6- dideoxyrhamn ose, thioglucose, thiodaunosamine, thiol, C1-12 thioalkyl, a naturally occuring amino acid or di- and tri-peptitles thereof, a group of the formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH2, NR** wherein R** is from the group consisting of hydrogen, C1-8 alkyl, C2-8 acyl or C6-12 aryl,
R and R* are independently selected from the group consisting of hydrogen, C1-12 alkyl, C6-12 aryl, C2-8 dihydroxyalkyl, C1-8 alkene, C2-8 alkyne, C1-8 alkoxy, C1-8 alkylamino, C3-8 cycloalkyl, C2-8 carboalkoxy, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO2, P, PO, and NR
wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1- 4 alkyl and C6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy; mono or oligosaccharides of the formula:
Figure imgf000231_0001
wherein Y is selected from the group consisting of oxygen, sulfur, sulfoxide, sulfone, CR*R**, wherein R* and R** are independently selected from the group consisting of hydrogen, C1-8 alkyl, and NR wherein R is selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 acyl:
R9 and R10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C1-16 alkoxy, C1-16 alkyl, C3-8 cycloalkyl, thiol , amino, trifluoroacetamido, chloroethylnitrosoureido, and chloroethylureido:
R11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl, t-butylacyl, C1-8 alkoxy, t- butyloxycarbonyl, trifluoroacyl, C7-12 aralkyl, C6- 12 aryl, and a naturally occuring or synthetic amino acid; memo or dibenzylated amino, azido, acylated amino, trifluoroacylated amino, morpholino, cyano substituted morpholino, memo-, di-, tri- or tetra-methoxy substituted morpholino, mono-, di-, tri- or tetra-acetoxy substituted morpholino, hydroxyl, hydrogen, halogen, acetoxy, C1-16 alkoxyl, C3-8 cycloalkyl, thiol, sulfide; a group of the formula NH(CH2)nCH(OR)2 wherein R is selected from the group consisting of C1-16 alkyl, C1-16 acyl and C7-16 aroyl and wherein n is 0 to 5.
chloroalkylnitrosoureido of the formula NH(CO)N(NOXCH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)2 OCH2CH(OAc)2:
R12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, mono or oligosaccharides, C1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C1-16 alkoxy, C3-8 cycloalkyl, C2-8 haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, one of the group consisting of p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitro-soureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, and NH(CH2)2 OCH2CH(OAc)2.
R5 and R8 can also be independently selected from a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO2, P, PO and NR wherein R is selected from the group consisting of hydrogen, hydroxyl, C1-8 acyl, C1-4 alkyl and C6-12 aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, C6-18 aryl sulfone, cyano, C1-16 alkoxy, C1-16 alkyl, nitro, C1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl, trifluoroacyl, C7-18 aralkyl, C6-18 aryl, C2-8 alkenyl, C2-8 alkynyl and hydroxy.
2. A compound according to claim 1 wherein
X1 and X2 are independently selected from the group consisting of
O,
S, and
NH;
X3 is selected from the group consisting of
O,
S,
C,
SO,
SO2,
NH,
NO, and NOH
X4 is selected from the group consisting of
CQ,
N, and
NO,
R1, R2, R3, and Q are independently selected from the group consisting of
hydrogen,
hydroxyl,
C1-4 alkoxyl,
tosyl,
triflate,
fluorine,
chlorine,
amino,
aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)mOH wherein n and m are independeatly 1 to 3,
aminoalkylaminoalkylchloride of formula NH(CH2)nNH(CH2) mCl wherein n and m are independently 1 to 3, chloroalkylnitrosoureido of the formula NH(CO)N(NO)CH2)n CH2 Cl, a group of the formula -O-C(R)=O, wherein n is 0 to 4, and wherein and wherein R is selected from the group consisting of
hydrogen,
C1-8 alkyl,
and C6-12 aryl;
Z is one of C-R6, or C-R7;
R6 is selected from the group consisting of
hydrogen,
C1-8 hydroxyalkyl,
C1-8 dihydroxyalkyl,
squaric acid,
C1-16 alkyl squarate,
C1-4 alkyl,
acyl of the formula -C(R)=O, wherein R is selected from the group consisting of
hydrogen,
C1-8 alkyl,
C1-8 hydroxyalkyl,
squaric acid
C1-4 alkyl squarate,
C2-8 alkoxyalkyl,
C2-12 acyloxyalkyl and
amino which may be unsubstituted or mono- or di-substituted with C1-8
alkyl, C3-8 cycloalkyl, C1-8 acyl,
C1-8 trifluroacyl, C7-12 aralkyl or C6-12 aryl;
a group of the formula -C(OR)=O, wherein R is selected from the group consisting of hydrogen,
C1-8 alkyl,
C6-12 aryl ,
C7-12 aralkyl; and
a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of
hydrogen,
straight or branched C1-8 alkyl, and
amino which may be unsubstituted
or mono- or di-substituted with
C1-8 alkyl, C3-8 cycloalkyl, C1-8 acyl,
trifluoroacyl, C7-12 aralkyl or C6-12 aryl; A 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NO, and NH; said heterocycle being optionally substituted with one or more halogens, hydroxy, C1-8 alkoxy, C1-8 alkyl, C1-8 hydroxyalkyl, amino, which may be unsubstituted or mono- or disubstituted by C1-4 alkyl, C3-5 cycloalkyl, C1-8 acyl, trifluoroacyl, C6-12 aryl, and hydroxy;
R7 is selected from the group consisting of
hydrogen,
fluorine,
C1-4 alkyl
C1-4 alkoxy,
cyano,
acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen,
C1-8 alkyl,
C1-8 hydroxyalkyl,
C2-8 acyloxyalkyl,
amino,
cyano,
a group of the formula -C(OR)=0, wherein R is selected from the group consisting of
hydrogen,
C1-8 alkyl,
C6-12 aryl,
C1-8 alkenyl;
R5 and R8 are independently selected from the group consisting of
hydrogen,
halogen,
hydroxyl,
C1-8 alkoxy,
C2-8 acetylenyl,
C2-8 alkenyl,
cyano,
a group of the formula -O-C(R)=O, wherein R is selected from the group consisting of hydrogen, and
C1-8 alkyl;
acyl of the formula -C(R)=0, wherein R is selected from the group consisting of
hydrogen,
thiol, C1-8 alkyl,
C1-8 hydroxyalkyl,
amino;
a group of the formula -C(OR)= O, wherein R is selected from the group consisting of hydrogen, glucosamine,and
C1-8alkyl,
and a saccharide of formula
Figure imgf000235_0001
wherein
R9 and R10 are independently selected from the group consisting of
hydrogen,
fluorine,
chlorine,
hydroxyl,
amino, and
trifluoroacetamido; R11 is selected from the group consisting of
amino which may be unsubstituted or mono-or di-substituted with C1-8
acetoxy, C1-8 alkyl, C3-8 cycloalkyl, C2-8 acyl,
trifluoroacyl, C7-12 aralkyl or C6-12 aryl;
morpholino,
cyano substituted morpholino,
mono-, di-, tri-, or tetra-methoxy substituted
morpholino,
hydroxyl,
mono or dialkylated amino with 1 to 16 carbons,
C1-8 alkoxyl,
a group of the formula NH(CH2)nCH(OR)2 wherein R is independently selected from the group consisting of C1-8 alkyl, C1-8 acyl or C7-12 aroyl and wherein n is 1 to 5; chloroalkylnitrosoureido of the formula
NH(CO)N(NO)CH2)nCH2Cl wherein n is 0 to 4,
NH(CH2)2 OCH2(OAc)2,
fluorine; and R12 is selected from the group consisting of
hydroxyl or its tetrahydropyranyl ether,
halogen,
mono or oligosaccharide selected from the group consisting of from rhodosamine, cinerulose-B, L-cinerulose, D-cineiυlose, cinerulose A, amicetose, aculose, rednose, ifaodinose, 2-deoxyfucose, daunosamine;
and
trifluoroacetyldaunosamine,
amino,
trifluoroacetamido,
mono or dimethylated amino,
C1-8 alkoxy,
benzoate,
p-nitrobenzoate,
chloroalkylnitrosσurea,
acetoxy and
trifluoroacetoxy.
3. A compound of the formula
Figure imgf000236_0001
X1 and X2 are independently selected from the group consisting of
0, and
NH;
X3 is selected from the group consisting of
0,
s,
SO, and
NO;
X4 is selected from the group ccmsisting of CQ, N, and NO, R1, R2, R3, and Q are independently selected from the group consisting of
hydrogen,
hydroxy,
methoxy,
aminoethylaminoethanol
aminoethylaminoethylchloride
chloroalkylnitrosoureido of the formula
NH(CO)N(NO)(CH2)n CH2Cl, wherein n is 0 to 2,
amino, and
fluorine;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of
C1-4 alkyl,
C1-4 hydroxyalkyl,
C1-4 dihydroxyalkyl,
acyl of the formula -C(R)=0, wherein R is selected from the group consisting of
methyl,
hydroxymethyl,
acyloxymethyl and
amino;
a group of the formula -C(OR)=O, wherein R is selected firom the group consisting of hydrogen,
methyl and
ethyl;
a group of the formula -CH2C(OR)=O, wherein R is selected from the group consisting of
hydrogen,
methyl and
ethyl;
A 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O.S, N, NO, and NH said heterocycle being optionally substituted with one or more halogens, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by methyl, cyclopropyl, C2-8 acyl, and hydroxy;
R7 is selected from the group consisting of
hydrogen,
fluorine, methyl,
methoxy,
cyano,
acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen,
C1-5 alkyl,
C1-8 hydroxyalkyl,
amino,
cyano,
a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen,
C1-5 alkyl,
C6-12 aryl,
C1-4 alkenyl;
R4 and R8 are independently selected from the group consisting of
hydrogen,
halogen,
hydroxy,
methoxy,
cyano, acetyl and
a saccharide of formula
Figure imgf000238_0001
wherein
R9 and R10 are independently selected from the group consisting of
hydrogen,
fluorine, and
iodine
R11 is selected from the group consisting of
hydroxyl,
acetoxy,
amino, dimethylamino,
trifluoroacetamido,
morpholino,
cyano substituted moipholino,
mono-, di-, tri-, or tetra-methoxy substituted
morpholino,
a group of the formula NH(CH2)nCH(OR)2 wherein R is selected from the group consisting of C1-4 alkyl C1-4 acyl or C7-8 aroyl and wherein n is 2 to 5,
chloroalkylnitrosoureido of the formula NH(CO)N(NOXCH2)nCH2Cl, wherein n is 0 to 4,
NH(CO2)OCH2)CH2CH(OAc)2; and
R12 is selected from the group consisting of
hydroxyl or its tetrahydropyranyl ether,
benzoate,
acetoxy,
p-nitrobenzoste,
amino,
trifluoroacetamido,
chloroethylnitrosoureido,
fluorine, and
iodine.
4. A compound according to claim 1, wherein
X1 and X2 are both oxygen;
X3 is
0, or
S;
X4 is selected from the group consisting of N, NO, or CQ;
R1, R2, R3 and Q are each independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of
methyl,
ethyl,
hydroxymethyl,
1,2 dihydroxyethyl, acyl of the formula -C(R)=O, wherein R is selected from the group consisting of methyl, fluoromethyl, difluoromethyl,
hydroxymethyl,
acetoxymethyl, and
bromomethyl;
A 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, NH, said heterocycle being optionally substituted with one or more fluorine, hydroxy, methoxy, methyl, hydroxymethyl, amino and acylamino groups.
R7 is selected from the group consisting of
hydrogen,
fluorine,
methyl, and
cyano,
R5 and R8 are independently selected from the group consisting of
hydrogen,
hydroxyl,
bromine,
chlorine,
cyano,
acetate,
acetyl, and
a saccharide of the formula
Figure imgf000240_0001
wherein
R9 and R10 are independently selected from the group consisting of
hydrogen,
fluorine, and
iodine R11 is selected from the group consisting of
amino, hydroxy,
dimethylamino,
acetoxy,
trifluoroacetamido,
morpholino,
cyano substituted morpholino,
methoxymoipholino and
a group of the formula NH(CH2)nCH(OR)2 wherein R is selected from a group consisting of methyl, C1-8 acyl or benzoyl and wherein n is 3 to 5, chloroalkylmtrosoureido of the formula NH(CO)N(NO)(CH2) nCH2Cl, wherein n is 0 to 4, and NH(CH2)OCH2CH(OAc)2
R12 is hydroxyl or iodine.
5. A compound according to claim 1 wherein :
X1 and X2 are both oxygen;
X3 is O, or S;
X4 is CQ;
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected firom the group consisting of
ethyl,
hydroxymethyl,
1,2-dihydroxyethyl,
acyl of the formula -C(R)=0, wherein R is selected from the group ccmsisting of
methyl, fluoromethyl, difluoromethyl,
hydroxymediyl;
R7 is hydrogen;
R5 and R8 are independently aelected from the group consisting of
hydrogen,
hydroxyl and
acetyl.
6. A compound according to claim 1 wherein :
X1 and X2 are both oxygen;
X3 is O, or S; X4 is CQ,
R2 and R3 are both hydrogen;
R1 and Q are independently selected from the group consisting of hydrogen, fluorine, and hydroxyl;
Z is one of C-R6 or C-R7;
R6 is selected from the group consisting of
ethyl,
hydroxymethyl,
1,2-dihydroxyethyl,
carbonyl squarate, and
acyl of the formula -C(R)=0, wherein R is aelected from the group consisting of
mediyl,
fluoromethyl,
difluoromethyl, and
hydroxymethyl;
R7 is aelected from the group consisting of
hydrogen,
methyl,
or fluorine,
R5 and R8 are independently selected firom the group consisting of
hydrogen,
hydroxyl,
bromine,
chlorine,
cyano,
acetate,
acetyl and
a saccharide of the formula
Figure imgf000242_0001
wherein
R9 and R10 are independently selected from the group consisting of
hydrogen,
fluorine, and
iodine
R 1 1 is selected from the group consisting of
hydroxyl, acetoxy,
amino,
dimethylamino,
trifluoroacetamido,
morpholino,
cyano substituted morpholino,
methoxymorpholino,
R12 is selected from the group consisting of
acetoxy,
hydroxyl,
hydrogen, and
iodine,
with the proviso that at least one of R5 and R8 is saccharide;
7. A compound according to Claim 5 wherein R5 is hydrogen;
8. A compound according to Claim 5 wherein R5 is hydroxyl;
9. A compound according to Claim 4 wherein both R5 and R8 are independently a saccharide of the formula:
Figure imgf000243_0001
wherein
R9 and R10 are independendy selected from
hydrogen, fluorine, and
iodine;
R11 is selected from
amino,
dimethylamino
ammonium chloride,
trifluoroacetamido,
morpholino,
cyano substituted morpholino,
methoxy møipbolino, and
R12 is selected from the group consisting of
hydrogen,
hydroxyl,
iodine, and
acetoxy;
10. A compound according to claim 6 wherein cme of R5 and R8 is
saccharide.
11. A compound according to claim 9 wherein R11 is selected from the group consisting of hydroxyl, amino, and trifluoroacetamido;
12. A compound according to claim 10 wherein R11 is selected from the group consisting of hydroxyl, amino, and trifluoroacetamido;
13. A compound according to claim 3 wherein X3 is oxygen;
14. A compound according to claim 3 wherein X3 is sulfur;
15. A compound according to Claim 13 wherein both R5 and R8 are independently saccharide;
16. A compound according to claim 13 wherein one of R5 and R8 is
saccharide.
17. A compound according to Claim 14 wherein both R5 and R8 are independently saccharide;
18. A compound according to claim 10 wherein one of R5 and R8 is
saccharide.
19. A compound according to claim 12 wherein R8 is hydrogen.
20. A compound according to claim 13 wherein R8 is hydrogen.
21. A compound according to claim 14wherein R8 is hydrogen.
22. A compound according to claim 15 wherein R8 is hydrogen.
23. A compound according to claim 16 wherein R8 is hydrogen.
24. A compound according to claim 17 wherein R8 is hydrogen.
25. A compound according to claim 18 wherein R8 is hydrogen.
26. A compound according to claim 1, wherein X3 is 0 or 5; and
Z is one of C-R6 or C-R7.
27. A compound according to claim 26, wherein X3 is O; and R5 is methoxy or 3- (tetraethyl-3,3-bis phosphoric ester) propriamido- 2-yl ethoxy.
28. A compound according to claim 3 wherein X3 is O or S; and Z is one of C-R6 or C-R7.
29. A compound according to claim 28 wherein X3 is O; and R5 is methoxy or 3- (tetraethyl-3,3-bis phosphoric eater) propriamido-2-yl ethoxy.
30. A compound according to claim 1 selected from the group consisting of Methyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone (BCH-
1125);
Methyl (7-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
(BCH-1129);
Methyl (6-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
Bromomethyl (5, 10-dioxo-5,10-dihydronaphtho [2,3-C] pyran-3-yl) ketone;
2-[4,-Hydroxy-1',2',-dioxo-3'- cyclobutenoxy] mediyl (5,10- dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
Trans-3-aceto-1-methoxy-1 ,2,3 ,4-tetrahydro-(2-thia)anthracene-5,10-dione and cis-3- aceto-1-medιoxy-1,2,3,4-tetrahydro-(2-thia)anthracene-5,10-dione;
cis-3-aceto-1-methoxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione and trans-3-aceto-1-methoxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-3 '-amino-L-lyxobexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-amino -L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran
Methyl (1-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
(BCH-1148);
trans-3-aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione and cis-3- aceto-1-hydroxy-l,2,3,4-tetrahydro-(2-thia) anthracene-5, 10-dione;
1'S,1S,3R methyl (5,8-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10- tetrahydrobenzo [2,3-C] pyran-3-yI) ketone;
1'S,1R,3S methyl (5,8-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) mediyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3'4'-diacetoxy-L-
Lyxohexo-pyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl);
(1'S,1R,3S) methyl (5,8-dimethoxy-1 -(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L- Lyxohexopyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl);
(1'S,1S,3R) methyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-
L-lyxohexopyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl) ketone;
(1'S,1R,3S) methyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-
L-lyxohexopyranose)-3,4,5,8, tetrahydrobenzo [2,3-C] thiopyran-3-yl) ketone; 1'S, 1S, 3R- Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S- Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluorocetamido-4'O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-7-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1S, 3R Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1S,3R)-Bromomethyl (5,10-dιoxo-1-(2',3',6'-trideoxy-4'-O-P-nitrobenzoyl-3'- trifluoroacetamido-L-lyxohexopyranose)-(3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3- yl) ketone;
(1'S,1R,3S)-Bromomethyl (5,10 -dioxo-1-(2',3',6'-trideoxy-4'-O-P-nitrobenzoyl-3'- trifluoroacetamido-L-lyxohexopyranose)-(3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3- yl) ketone;
(1'S,1S,3R) -2-[4'-hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10-dioxo-1- [2",3",6" -trideoxy-4"-O-p-ritrobenzoyl-3'-trifluoroacetamido-L-lyxohexopyranose]-
3,4,5,10-tetrahydronaphtho [2,3,C] pyran-3-yl) ketone;
(1'S,1R,3S) -2-[4'-hydroxy-1',2'-dioxo-S'-cyclobutenoxy] methyl (5,10-dioxo-1-
[2",3",6"-trideoxy-4"-O-p-nitrobenzoyl-3 '-trifluoroacetamido-L-lyxohexopyranose]-
3,4,5,10-tetrahydronaphtho [2,3,C] pyran-3-yl) ketone;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifiuoroacetamido-L- lyxohexopyran ose)-3-(2-brom oacetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-C]-pyran;
(1'S, 1R, 3S)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-(2,3-C)-pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-(2-aza-3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-C]-pyran;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoro-acetamido-L- lyxohexopyranose)-3-(2-bromoacetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-
C] pyran;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-acetamido)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-C]-pyran; (1'S,1R,3S) methyl ( 1-2[',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-C] pyran-3-yl ketone;
(1'S,1S,3R) methyl (1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-C] pyran-3-yl ketone;
(1'S,1R,3S)-methyl-1-(2',6'-dideoxy-3',4'-di-O-p-nitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R)-methyl-1-(2',6'-dideoxy-3',4'-di-O-p-nitrobenzoyl-L-lyxohexopyranose)-
5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1R, 3R)-5,1 0-dioxo -3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S,1S,3R) methyl (5,8-dioxo- 1-2(',3', 4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxobexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] thiopyran-3-yl) ketone;
(1'S,1R,3S) methyl (5,8-dioxo-1-(2',3', 4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] thiopyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-
L-lyxohexopyranose)-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,1 0-dioxo -1-(2',3',6'-trideoxy-3'-amino-4'-hydroxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1S, 3R Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-Trifluoroacetamido-4'- hydroxy-L-lyxohexoρyranose)- 3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; 1'S, 1S, 3R Methyl (5, 10-dιoxo-1-(2',3',6'-trideoxy-3 '-amino-4' -hydroxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'- amino-L-lyxohexopyranose)-7- hydroxy-3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'- amino-L-lyxohexopyranose)-7- hydroxy- 3,4,5,10- tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza- 3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3 '-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza- 3-acetamidothiazol)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran; (1'S, 1S,3R)-1-(2',3',6'-trideoxy-3 '-trifluoroaceta mido-L-lyxohexopyranose)-3-(2-aza- 3-acetamido- thiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C]-pyran; (1'S,1S,3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-
3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C]-pyran;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-a mino-L-lyxohexopyranose)-5,10-dioxo-
3,4,5, 10-tetrahydro-7-methyl-9-azanaphtho-[2,3-C]-pynn-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino--L-lyxohexopyranose)-5,10-dioxo-
3,4,5,10-tetrahydro-7-methyl-9-azanaphtho-[2,3-C]-pyran-3-yl) ketone;
(1'S,1R,3S) methyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-4ιydroxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-7- methyl-9-aza naphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl( 1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L- lyxohexoρyranose)-5,10-dioxo-3,4,5,10-tetrahydro-7- methyl-9-aza naphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3R) -1-(2',6'-dideoxy-L-lyxohexopyranose)-5,10- dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',6'-didcoxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10- tetrahydrooaphtho [2,3-C] pyran;
(1'S, 1R,3R) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-3-ethyl- 3,4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-3-ethyl-
3,4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) - 1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9- hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9- hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9- dihydroxy -3-ethyl-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9- dihydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'- amino-2'-iodo-L-lyxcdιexopyranose)-5,10-dioxo-6 or 9-hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'- amino-2'-iodo-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy -3-ethyl-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S, 1S,3S) -1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-5, 10- dioxo-6 or 9-hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3S) Methyl( 1-(2',3',6'-trideoxy-3'-amino-2'-iodo-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-2'-iodo-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9-dihydroxy-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6,
9-dihydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1R,3S) Methyl( 1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S, 1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1R,3S) Methyl(1-(2',3',6'-trideoxy-3 '-trifluoroacetamido-L-lyxohexopyianose)- 5,10-dioxo-6, 9-dihydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6, 9-dihydroxy-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1R,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-3'-amino -L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran
31. A compound according to claim 1 selected from the group consisting of
Methyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone (BCH- 1125); Methyl (7-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone (BCH-1129);
Methyl (6-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; Brornoinediyl (5,10-dioxo-5,10-dihydronaphtho [2,3-C] pyran-3-yl) ketone;
2-[4,-Hydroxy-1',2',-dioxo-3'- cyclobutenoxy] methyl (5,10- dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
Trans-3-sceto-1-methoxy-1,2,3,4-tetrahydro-(2-thia)anthracene-5, 10-dione and cis-3- aceto-1-methoxy-1,2,3,4-tetrahydro-(2-thia)anthracene-5,10-dione;
cis-3-aceto-1-methoxy-l,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione and trans-3-aceto-1-methoxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3-(2-aza-3- aminodιiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran
32. A compound according to claim 1 aelected from the group consisting of
Methyl (1-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone (BCH-1148);
trans-3-aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione and cis-3- aceto-1-hydroxy-1,2,3,4-tetrahydro-(2-thia) anthracene-5,10-dione;
33. A compound according to claim 1 selected firom the group consisting of
1'S,1S,3R methyl (5,8-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10- tetrahydrobenzo [2,3-C] pyran-3-yl) ketone;
1'S,1R,3S methyl (5,8-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydrobenzo [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3'4'- diacetoxy-L- Lyxohaxo-pyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl);
(1'S,1R,3S) methyl (5,8-dimethoxy-1-(2',3',4',6' -tetradeoxy-3',4'-diacetoxy-L- Lyxohexopyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl);
(1'S,1S,3R) methyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy- L-lyxohexopyranose)-3,4,-dihydrobenzo [2,3-C] thiopyran-3-yl) ketone;
(1'S,1R,3S) methyl (5,8-dimethoxy-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-
L-lyxohexopyranose)-3,4,5,8, tetrahydrobenzo [2,3-C] thiopyran-3-yl) ketone;
34. A compound according to claim 1 selected from the group consisting of
1'S, 1S, 3R- Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S- Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-7-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1S, 3R Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4 '-O-p- nitrobenzoyl-L-lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydronaphtho [2,3-C] ρyran-3-yl) ketone;
(1'S,1S,3R)-Bromomethyl (5,10-dioxo-1-(2',3',6'-trideoxy-4'-O-P-nitrobenzoyl-3'- trifluoroscetamido-L-lyxohexopyranose)-(3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3- yl) ketone;
(1'S,1R,3S)-Bromomethyl (5,10-dioxo-1-(2',3',6'-trideoxy-4'-O-P-nitrobenzoyl-3'- trifluoroarotamido-L-lyxohexopyranose)-(3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3- yl) ketone;
(1'S,1S,3R) -2-[4'-hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10-dioxo-1-
[2",3",6"-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L-lyxohexopyranose]- 3,4,5, 10-tetrahydronaphtho [2,3,C] pynn-3-yl) ketone;
(1'S,1R,3S) -2-{4'-hydroxy-1',2'-dioxo-3'-cyclobutenoxy] methyl (5,10-dioxo-1-
[2",3",6" -trideoxy-4"-O-p-nitrobenzoyl-3'-trifluoroacetamido-L-lyxohexopyranose]-
3,4,5,10-tetrahydronaphtho [2,3,C] pyran-3-yl) ketone;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3 '-trifluoroacetamido-L- lyxohexopyranose)-3-(2-bromoacetyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-C]-pynn;
(1'S, 1R, 3S)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-(2,3-C)-pyran;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-(2-aza-3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-C]-pyran;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-4'-p-nitroben zoyl-3'-trifluoro-acetamido-L- lyxohexopyranose)-3-(2-bromoacetyl)-5,10-dioxo-3,4,5, 10-tetrahydro-1H-naphtho [2,3- C] pyran;
(1'S,1S,3R)-1-(2',3',6'-trideoxy-4'-O-p-nitrobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranose)-3-(2-aza-3-aceta mido)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-
[2,3-C]-pyran;
(1'S,1R,3S) methyl (1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphdio [2,3-C] pyran-3-yl ketone;
(1'S,1S,3R) methyl (1-[2',3',6'-trideoxy-3'-trifiuoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranoee]-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-C] pyran-3-yl ketone;
(1'S,1R,3S)-methyl-1-(2',6'-dideoxy-3',4'-di-O-p-ritrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1S,3R)-methyl-1-(2',6'-dideoxy-3',4'-di-O-p-nitrobenzoyl-L-lyxohexopyranose)- 5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1R, 3R)-5,10-dfoxo-3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1*S,1S,3R) methyl (5,8-dioxo-1-(2',3', 4',6'-tetradeoxy-3\4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] thiopyran-3-yl) ketone;
(1'S,1R,3S) methyl (5,8-dioxo-1-(2',3', 4',6'-tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] thiopyran-3-yl) ketone;
35. A compound according to claim 1 selected from the group consisting of
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-
L-lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10 -dioxo -1-(2',3',6'-trideoxy-3'-amino -4'-hydroxy-L- lyxobexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1S, 3R Methyl (5,10-dioxo-1 -(2 ',3',6'-trideoxy-3'-Trifluoroacetamido-4'- hydroxy-L-lyxohexopyranose)- 3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; 1'S, 1S, 3R Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-amino-4'-hydroxy-L- lyxohexopyranose)-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
1'S, 1R, 3S Methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'- amino-L-lyxohexopyranose)-7- hydroxy-3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'-trifiuoroacetamido-L- lyxohexopyranose)-7-hydroxy - 3,4,5,10-tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl (5,10-dioxo-1-(2',3',6'-trideoxy-3'- amino-L-lyxohexopyranose)-7- hydroxy- 3,4,5,10- tetrahydro [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-
3-acetamidothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran; (1'S, 1R,3S)-1-(2',3',6'-trideoxy-3 '-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-
3-acetamidothiazol)-5, 10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S, 1S,3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranosey-3-(2-aza-
3-acetamido- thiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C]-pyran; (1'S,1S,3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(2-aza-
3-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C]-pyran;
(1'S,1R,3S) Methy (1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-
3,4,5,10-tetrahydro-7-methyl-9-azanaphtho-[2,3-C]-pyran-3-yl) ketone;
(1'S,1S,3R) Methy (1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo- 3,4,5,10-tetrahydro -7-methyl-9-azanaphtho-[2,3-C]-pyιan-3-yl) ketone;
(1'S,1R,3S) methyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido -4'-hydroxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphdio [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) methyl(1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-7-methyl-9-aza naphtho [2,3-C] pyran-3-yl) ketone;
36. A compound according to claim 1 aelected from the group consisting of
(1 'S, 1R,3R) -1-(2',6'-dideoxy-L-lyxohexopyranose)-5, 10-dioxo-3,4,5, 10- tetrahydronaphdio [2,3-C] pyran;
(1'S,1S,3S) -1 -(2',6'-dideoxy-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran;
(1'S, 1R,3R) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-3-ethyl-
3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-3-ethyl-
3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1 -(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9- hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1 -(2',3'6,'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9- hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9- dihydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9- dihydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'- amino-2'-iodo-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S, 1S,3S) -1 -(2',3',6'-trideoxy-3'- amino-2'-iodo-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy -3-ethyl-3 ,4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3R) -1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy -3-ethyl-3, 4,5, 10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1S,3S) -1-(2',3',6'-trideoxy-3'-trifluoroacetam ido-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy -3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino-2'-iodo-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-2'-iodo-L-lyxohexopyranose)-5,10- dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-aιrino-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9-dihydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-5,10-dioxo-6, 9-dihydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6 or 9-hydroxy-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1R,3S) Methyl(1-(2',3',6' -trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-
5,10-dioxo-6, 9-dihydroxy-3 ,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-trifiuoroacetamido-L-lyxohexopyranose)- 5,10-dioxo-6, 9-dihydroxy-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1R,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone; (1'S,1R,3R) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-5,10-dioxo-3-ethyl-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S,1S,3S) Methyl(1-(2',3',6'-trideoxy-3'-amino or trifluoroacetamido-2'-iodo-L- lyxohexopynnose)-5,10-dioxo-3-ethyl-3,4,5, 10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone;
(1'S, 1S,3R)-1-(2',3',6'-trideoxy-3 '-amino-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
(1'S, 1R,3S)-1-(2',3',6'-trideoxy-3'-amino-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-C] pyran;
37. A compound according to Claim 1 selected firom the group consisting of: 1184 (1 'S, 1S, 3R)-methyl-(1-[2 ' ,3 ' , 6 ' -trideoxy-3 ' - trifluoro-acetamido-4 ' -hydroxy-L-lyxohexo-pyranose]- 3,4, 5, 10-tstrahydro-naphtho[2,3-C]pyran-3-yl)ketone 1620 (1'S,1-R,3-S)- methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3-yl)ketone
1648 (1'-S,1-S,3-R)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-arabino-hexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3- yl)ketone
1649 (1'-S,1-R,3-S)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-arabino-hexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3- yl)ketone
1666 (1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetyl-2'-iodo-L- lyxohexopyranose]-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1667 (1'S, 1S, 3R)-methyl-(1[2',6'-dideoxy-3',4'-diacetyl-2'-iodo-L- lyxohexopyranose]-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1673 (1'-S,1-S,3-R) and (1'-S,1-R,3-S)-methyl-(1-[2',3',4',6'-tetradeoxy-4'- trifluoroacetamido-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C ]pyran-3-yl)ketone
1998 (1S,3S,2'S,5'S)-methyl-(1-O-[N-Boc-serine-leucine-me ester]-5,10-dioxo- 3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl)ketome
2000 (1S,3S,2'S,5'S)-methyl-(1-O-[serine-leucine- me ester]-5,10-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-C]pyran-3-yl)ketone hydrochloride
2019 (1R,3S, 1'S0- methyl-(1-[2',3',4',6'-tetradeoxy-3 -trifluoroacetamido-4'-bromo-
L-lyxohexopyranose]-5,10-rioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3- yl)ketone
2022 (1'S,1S,3R)-methyl-(1-[2',3',6'-trideoxy-4'-hydroxy-2'-iodo-3'- trifluoroacetamido-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho[2,3,-C
]pyran-3-yl)ketone 2041 phenyl-(trans-1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-C]- pyran)-3-carboxamide
2046 (1R,3S, 1'S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-bromo- L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3- yl)ketone
2047 (1S,3R,1'S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-bromo- L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetranaphthaleno-[2,3-C]pyran-3-yl)ketone
2051 3-dimethylaminopropyla(1-medιoxy-5,10-dihydro-1H-naphtho-[2,3-C]-pyran)- 3-carboxamide
2061 (1S,2'S,3R) and (1R,2'S,3S)-methyl-(1-O-[3-pipecolinemethanol]-5,10-dioxo- 3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl) ketone hydrochloride racemic mixture
2069 methyl-(1-O-[4-pipecolinemethanol]-5,10-dioxo-3,4,5,10- tetrahydronaphthaleno-[2,3-C]pyran-3-yl)ketone hydrochloride racemic mixture
2070 (1 '-S,1-R,3S)-methyl-( 1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O- methanesulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C] pyran-3-yl)ketone 2071 (1'-S,1-S,3-4)-methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-dimethoxy-L - lyxohexopyranose)-5,10-DIOXO-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3-yl) ketone (Tentative assignment)
2072 (1'-S,1-R,3-R)-methyl-1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'O- methanesulfonyl-L-lyxobexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-2,3-C]- pyran-3-yl-ketone
2079 (1S,1'S,3RO-methyl-(1-[2',3',4',6'-tetradeoxy-4'-trifluoroacetamido-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C)pyran-3- yl)ketone
2087 (1R,3S,1'S) and (1S,3R,1'S)-METHYL-(1-[2',3',4',6',-tetradeoxy-3',4' - bistrifluoroacetamido-lyxo-hexopyranose]-5,10-dioxo-3,4,5,10-tetrahydro-naphthaleno-
[2,3-C]pyran-3-yl)ketone 2095 (1'-S,1-S,3-R) and (1'S,1-R,3-S)-methyl-(1 -[2',3',4',6'-tetradeoxy-3'- trifluoroacetamido-4'-O-methaneslfonyl-L-lyxopyranose)-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-C)pyran-3-yl)ketone
2102 (1S,3R, 1'S)- methyl-(1-[2',3',4',6-tetradeoxy-3',4'-bistrifluoroacetamido-lyxo- hexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl)ketone
2104 (1R,3S,1'S)-methyl-(1-[2',3',4',6-tetradeoxy-3',4'-bistrifluoroacetamido-lyxo- hexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl) ketone
2105 (1'-S,1-S,3-R)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-O- (2-brorno-acetyl)-L-lyxopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C] pyran-3-yl) ketone
2112 (1'S,1R,3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-NAPHTO[2,3-C]-pyranyl]ketone
2113 A 4:1 Misture of (1'S,1R,2S)-methyl-(1-[2',3' ,6'-trideoxy-3'- trifluoroacetamido-4-iodo-L-arabino-hexopyranose)-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-C]pyran-3-yl)ketone and (1'S,1S,3R)-methy -(1-[2',3',6'- trideoxy-3'-trifluoroacetamido-4'-iodo -beta-L-arabino-hexopyranose)-5,10-dioxo-
3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3-yl) ketone 2117 (1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho[2,3-C]-pyran-3-yl) ketone
2118 (1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
2121 (1'S,1S,3R)-5,10-rioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho[2,3-C]-pyran
38. A compound according to Claim 1 selected from the group consisting of:
1184 (1'S, 1S, 3R)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-lyxohexopyranose]-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1620 (1'S, 1-R,3-S)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-iodo-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3yl) ketone
1648 (1'-S,1-S,S-R)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy- L-arabino-hexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3-yl) ketone
1169 (1'S, 1R, 3S) AND (1'S, 1S, 3R)-methy -(1-[2',3',6'-trideoxy-3'- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranose]-7-hydroxy-3,4,5,10- tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1666 (1'S, 1R,3S)-methy -(1-[2',6 '-dideoxy-3',4'-diacetyl-2'-iodo-L- lyxohexopyranose]-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1667 (1'S, 1S, 3R)-methy-(1[2',6'-dideoxy-3',4'-diacetyl-2'-iodo-L- lyxohexopyranose]-3,4,5,10-tetrahydronaphtho[2,3-C]pyran-3-yl) ketone
1673 (1'-S,1-S,3-R) and (1'-S,1-R,3-S)-methyl-(1-[2',3',4',6'-tetradeoxy-4'- trifluoroacetamido-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C ]pyran-3-yl) ketone
2019 (1R,3S,1'S0-metoyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-bromo- L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydro-naphthaleno-[2,3-C]pyran-3-yl) ketone 2046 (1R,3S,1'S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-bromo-
L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl) ketone
2047 (1S,3R,1'S)- methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-bromo- L-lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetranaphthaleno-[2,3-C]pyran-3-yl) ketone
2051 3-dimethylaminopropyla(1- methoxy-5, 10-dihydro-1H-naphtho-[2,3-C]-pyran)- 3-carboxamide 2061 (1S,2'S,3R) and (1R,2'S,3S)-methyl-(1-O-[3-pipecolinemethanol]-5,10-dioxo-
3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yl) ketone hydrochloride racemic mixture
2070 (1'-S,1-R,3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3 '-methoxy-4'-O- methanesulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C] pyran-3-yl) ketone
2071 (1'-S,1-S,3-4)-methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-dimethoxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C]pyran-3-yl) ketone
(TENTATIVE ASSIGNMENT)
2079 (1S,1'S,3RO-methyl-(1-[2',3',4',6'-tetradeoxy-4'-trifluoroacetamido-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-C]pyran-3-yI) ketone
2087 (1R,3S,1'S) and (1S,3R,1'S)-Inethyl-(1-[2',3',4',6',-tetradeoxy-3',4'- bistrifluoroacetamido-lyxo-hexopyranose]-5,10-dioxo-3,4,5,10-tetιahydro-naphthaleno- [2,3-C]pyran-3-yl) ketone
2105 (1'-S,1-S,3-R)- methyl-(1-[2',3',4',6'-tetradeoxy-3'-trifluoroacetamido-4'-O- (2-bromo-acetyl)-L-lyxopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C] pyran-3-yl) ketone 2117 (1'S,1S,3R) and (1'S,1R,3S)- methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-L- lyxohexo-pyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho[2,3-C]-pyran-3- yl) ketone
39. A process for the preparation of a compound of formula ,
Figure imgf000260_0001
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected from the group consisting NR, 0, or S, R6 is methyl ketone or is as defined in claim 1; and R1, R2, R3, R5, R6, R7, R8, X1, X2 and X4 are as defined in claim 1
selected from the group of processes consisting of
I. 1) selecting a precurser isochroman compound of formula
Figure imgf000261_0001
wherein R5, R6, R7 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula
Figure imgf000261_0002
2) and cycle-adding said quinone with a diene of formula
Figure imgf000261_0003
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen, C1-16 alkyl, C1-16 acyl, C1-16 aryl, C1-16 alkylsilane and dimethylamino, wherein R1, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula
Figure imgf000261_0004
and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is -OH, to a saccharide of formula
Figure imgf000262_0001
wherein R9, R10, R11 and R12 are defined as in claim 1 and L is as defined above; to yield a tricyclic saccharide of formula
Figure imgf000262_0002
II. a) coupling the isochroman (14) of reaction I,1, above, wherein R5 is H, with a saccharide of formula
Figure imgf000262_0003
wherein R9, R10, R11 and R12 are defined as in claim 1 to yield a bicyclic saccharide of formula
Figure imgf000262_0004
b) oxidatively demethylating the medioxy groups from formula (21) to yield a bicyclic quinone saccharide of formula
Figure imgf000263_0001
c) and cyclo-adding said chemical (19) with said diene (16) of reaction (I)(2) to yield the tricyclic saccharide
Figure imgf000263_0002
III. 1) coupling the quinone of formula 15,
Figure imgf000263_0003
of step (I) (1), wherein R5 is -OH, with a saccharide of the formula
Figure imgf000263_0004
of step (I) (2) to yield a bicyclic quinone sacharide of the formula
Figure imgf000264_0001
2) and cycloadding said quinone saccharide with the said diene of formula
Figure imgf000264_0002
to yield a tricyclic saccharide of formula
Figure imgf000264_0003
IV. a) selecting a precurser benzoate compound of formula
Figure imgf000264_0004
and condensing it with a dihalomethyl dimethoxybenzene wherein said halogens are indepently selected from the group consisting of Cl, Br and I, and X3 is selected from the group consisting of O,S, and N;
Figure imgf000265_0001
to yield a dimethoxyisochroman of formria,
Figure imgf000265_0002
b) oxidatively demethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman;
the resulting dioxoisochroman is cyclically coupled with the diene of formula
Figure imgf000265_0003
A is NR wherein R is selected from the group consiting of H, C1-16 alkyl, C7-18 aryl and L is a leaving group as defined in 1.2)
to yield an anthracenedione of formula
Figure imgf000265_0004
the resritant compound may optionally be converted to the hydroxyl form of formula
Figure imgf000266_0001
and may be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula
Figure imgf000266_0002
may be optionally coupled with a saccharide of formula
Figure imgf000266_0003
1) to yield a dimethoxybicydic saccharide of formula
Figure imgf000266_0004
2) oxidatively demethylating the methoxy groups to yield a dioxobicyclic isochroman of formula
Figure imgf000267_0001
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29
Figure imgf000267_0002
to yield a thiotricyclic saccharide of formula.
Figure imgf000267_0003
40. Process according to claim 39 comprising the further preliminaiy steps of a: a) reacting
Figure imgf000267_0004
or b)
Figure imgf000268_0001
c) to yield product:
Figure imgf000268_0002
d) and further reacting said product: with /
to yield:
Figure imgf000268_0003
41. A process, according to claim 39, for the preparation of a compound of formula,
Figure imgf000269_0001
and pharmaceutically acceptable acid addition salts thereof,
wherein X3 is selected from the group consisting of N, S, or 0, R6 is methyl ketone or is as defined in claim 4 and R1, R2, R3, R5, R6, R7, R8, and X4 are as defined in claim 4 which comprises the steps of
I. 1) selecting a precurser isochroman compound of formula,
Figure imgf000269_0002
wherein R5, R6, R7 and R8 are defined as above; oxidatively demethylating said isochroman with an oxidant to give a quinone compound of formula,
Figure imgf000269_0003
2) and cyclo-adding said quinone with a diene of formula,
Figure imgf000269_0004
wherein L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p- nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen C1- 16 alkyl, C1-16 acyl, and C1-16 aryl, C1-16 alkyl silane and dimethylamino; wherein R1, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula,
Figure imgf000270_0001
and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is OH, to a saccharide of formula,
Figure imgf000270_0002
wherein R9, R10, R11 and R12 are defined as in claim 4 and L is a leaving group selected from the group consisting of halogen, benzoyl, tosyl, p-nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of C1-16 alkyl, C1-16 acyl, C1-16 aryl, and C1- 16 trialkylsilane,
to yield a tricyclic saccharide of formula,
Figure imgf000270_0003
42. A process according to claim 39 for the preparation of a compound of formula,
Figure imgf000271_0001
and pharmaceutically acceptable acid addition salts thereof, wherein X3 is selected from the group consisting of S, or 0, R6 is methyl ketone or is as defined in claim 4, R5 is saccharide as defined in claim 4, and X4, R1, R2, R3, R7, R8, R9, R10, R11 and R12 are defined as in claim 4, which comprises the steps of
1) coupling an isochroman
Figure imgf000271_0002
wherein R5 is H and R6, R7 and R8 are defined as above with a saccharide of formula,
Figure imgf000271_0003
wherein R9, R10, R11 and R12 are defined as above to yield a bicycbc saccharide of formula,
Figure imgf000271_0004
2) oxidatively demethylating the methoxy groups of formula (21) to yield a bicyclic quinone saccharide of formula,
Figure imgf000272_0001
3) cycle-adding said bicyclic quinone saccharide a diene of formula,
Figure imgf000272_0002
wherein L is a bving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen C1-16 alkyl, C1-16 acyl, C1-16
aryl, C1-16 alkylsilane and dimethylamino, to yield a compound of formula
Figure imgf000272_0003
43. A process, according to claim 39, for the preparation of a compound of formula,
Figure imgf000273_0003
and phaimaceutically acceptable acid addition salts thereof, wherein X3 is selected from the group ccmsisting of NR, S, or 0, R6 is methyl ketone or is as defined in claim 4, R5 is saccharide as defined in claim 4, and R1, R2, R3, R7, R8, R9, R10, R11, R12, and X4 are defined as in claim 4; which comprises the steps of
1) coupling the quinone of formula,
Figure imgf000273_0001
wherein R5 is OH with a saccharide of formula,
Figure imgf000273_0002
wherein L is a leaving group selected firom the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen C1-16 alkyl, C1-16 acyl, C1-16
aryl, C1-16 alkylsilane and dimethylamino, to yield a bicyclic quinone saccharide of the formula,
Figure imgf000274_0001
2) and cycbcally coupling said quinone saccharide with the diene of formula, wherein L is defined as above
Figure imgf000274_0002
to yield a tricyclic saccharide of formula,
Figure imgf000274_0003
44. A process according to claim 39, for the preparation of a compound of formula,
Figure imgf000274_0004
and pharmaceutically acceptable acid addition salts thereof, wherein X3 is selected from the group consisting of N, O, or S, X1 and X2 are 0, R5 is hydroxyl and R1, R2, R3, R6, R7, R8, and X4 are defined as in claim 4, which comprises the steps of 1) selecting a precurser benzoate compound of formula,
Figure imgf000275_0001
and condensing it with a dihalomethyl dimethoxybenzene,
Figure imgf000275_0002
wherein said halogens are independently selected firom the group consisting of Cl, Br and I and X3 is selected firom the group consisting of O, S, and N to yield a dimethoxyisochroman of formula,
Figure imgf000275_0003
2) oxidatively demethylating the methoxy groups to yield a bicyclic dioxoisothiochroman; the resulting dioxoisothiochroman is cycbcally coupled with the diene of formula,
Figure imgf000275_0004
wherein A is NR and R is selected from die group consisting of H, C1-16 alkyl, and C7-16 aryl, and L is a bving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR or -SR, wherein R is selected from the group consisting of hydrogen C1-16 alkyl, C1-16 acyl, C1-16 aryl, C1-16 alkylsilane and dimethylamino, to yield an anthracenedione of the formula,
Figure imgf000276_0001
the resultant compound may optionally be converted to the hydroxyl-form yielding a compound of formula,
Figure imgf000276_0002
the resultant compound may be optionally coupled with a saccharide of formula,
Figure imgf000276_0003
wherein R9, R10, R11 and R12 are defined as in claim 4, to yield a tricyclic saccharide of formula,
Figure imgf000276_0004
45. A process according to claim 39, for the preparation of a compound of formula, and pharmaceutically acceptable acid addition salts thereof, wherein R1, R2, R3, R7, R8, R9, R10, R11, R12, and X4 are defined as in claim 4; which comprises the steps of
1) selecting a dimethoxythioisochroman of formula,
Figure imgf000277_0002
and coupling it with a saccharide of formula,
Figure imgf000277_0003
2) to yield a dimethoxybicyclic saccharide of formula,
Figure imgf000277_0004
3) oxidatively demethylating the methoxy groups to yield a dioxobicyclic thioisochroman or formula,
Figure imgf000278_0001
4) cycloadding said dioxobicyclic isochroman with a diene of formula,
Figure imgf000278_0002
to yield a thiotncycbc saccharide of formula,
Figure imgf000278_0003
46. A process according to claim 39 which comprises a further preliminary step of
1) selecting a precurser compound of formula
Figure imgf000278_0004
wherein R6, and R7 are electron withdrawing groups as defined in claim 4, X3 is O or S, and Pg is a protecting group selected from the group consisting of
acyl,
trifluoracyl,
benzoyl,
P-nitrobenzyl, C1-16 alkylsilane,
C1-16 alyl,
C1-16 acyl,
C1-16 aryl,
and condensing said precursor compound with a dihalomethyl dimethoxybenzene of formula
Figure imgf000279_0001
wherein X11 and X12 are independently selected from the group consisting of Cl, Br, and I, to yield a dimethoxy bicyclic precursor chemical of formula
Figure imgf000279_0002
47. A process according to claim 39 which comprises a further step of attaching a protecting group to at least one of the moieties at positions R1, R2, R3, R6, R7 and R8 and positions R9, R10, R11, and R12 of the saccharide prior to glycosylation and then removing said protecting group or groups.
48. A process according to claim 47 wherein said protected positions are at R1, R2 and R3;
49. A process according to claim 39 wherein X3 is O or S;
50. A process according to claim 41 wherein X3 is O or S;
51. A process according to claim 42 wherein X3 is O or S;
52. A process according to claim 43 wherein X3 is O or S;
53. A process according to claim 44 wherein X3 is O or S;
54. A process according to claim 39 wherein X3 is O;
55. A process according to claim 41 wherein X3 is O;
56. A process according to claim 42 wherein X3 is O;
57. A process according to claim 43 wherein X3 is O;
58. A process according to claim 44 wherein X3 is O;
59. A process according to claim 45 wherein X3 is O;
60. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 1 and a pharmaceutical acceptable carrier.
61. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 3 and a pharmaceutical acceptable carrier.
62. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least cme compound according to claim 4 and a pharmaceutical acceptable carrier.
63. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 5 and a pharmaceutical acceptable carrier.
64. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least cme compound according to claim 6 and a pharmaceutical acceptable carrier.
65. A pharmaceutical composition possessing antitumor activity, comprising an effective amount of at least one compound according to claim 7 and a pharmaceutical acceptable carrier.
66. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 8 and a pharmaceutical acceptable carrier.
67. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 13 and a pharmaceutical acceptable carrier.
68. A pharmaceutical composition possessing anti-tumor activity, comprising an effective amount of at least one compound according to claim 14 and a pharmaceutical acceptable carrier.
69. A pharmaceutical composition according to claim 1, wherein said compound is combined with an agent facilitating targeting of said combination to tumor or cancer cells.
70. A pharmaceutical composition according to claim 3, wherein said compound is combined with an agent facilitating targetting of said combination to tumor or cancer cells.
71. A compound according to claim 1 selected from the group consisting of:
(1'-S, 1'S, 3-R)-medιyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O- methanesulfonyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone
BCH-2072
1-Methoxy-5,10-dioxo-5, 10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino- propyl)carboxamide] (BCH-2167)
1-Methoxy-5,10-dioxo-5, 10-dihydro-1H-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino- propyl)carboxamide] hydrochloride monohydrate (BCH-2051)
(1S,2'S,3S,5'S)-Methyl-(1-O-[N-BOC-Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H- naphtho [2,3-c] pyran-3-yl) ketone (BCH-1998)
(1S,2'S,3S,5'S)-Methyl-(1-O-[Serine-Leucine-Me ester]-5,10-dioxo-3,4,5,10-tetrahydro-1-H-naphth o
[2,3-c] pyran-3-yl) ketone hydrochloride (BCH-2000)
(1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-serine methyl ester]-5,10-dioxo-3,4,5,10- tetrahydronaphtaleno [2,3-C] pyran-3-yl) ketone hydrochloride. (BCH-1654)
(1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC -prolinol]-5,1 0-dioxo-3,4,5,10-tetrahydro-1-H- naphtho [2,3-C] pyran-3-yl) ketone BCH-2067
(1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-prolinol]-3,4,5,12-tetrahydronaphto-[2,3-C] pyran-3-yl) ketone hydrochloride salt (BCH-1658)
(1'-S, 1-R, 3-S) and (1'-S, 1-S, S-R)-3-cyano-1-[2',3',6'-trideoxy-3'-trifluoroaceta mido-4'-hydroxy-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-C] pyran-3-yl (BCH-
1688)
(1'-S, 1-S, 3-R) and (1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetamido-4'-O- methane-sulfonyl-L-lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2095
(1'-S, 1-S, 3-R)-methyl-(1-[2',3',4',6' tetradeoxy-3'-trifluoroacetamido-4'-O-(2-bromo-acetyl)-L- lyxopyranose]-5, 10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-
2105
(1'-S, 1-R, 3-S)-methyl-(1-[2',3',4',6' tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone
BCH-2070
(1-S, 3-R) and (1-R, 3-S)-methyl-(1-(1-ιnethoxy-4-oxocyclohexyloxy)-5,10-dioxo-
3,4,5,10 tetrahydronaphto-[2,3-c] pyran-3-yl) ketone BCH-2096 (1R, 3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-
5, 10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran BCH-2144 (1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroaceta mido-4'-hydroxy-1,5-dihydro-L-lyxohexopyranose-2-yl)-
5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran BCH-2145 (1'S, 1R, 3S)-5,10-dioxo-3-methoxymethyl-1-(2',3 ',6'-trideoxy-3'-trifluoroacetamido -L- lyxohexopyranose)-3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-1691) (1'S, 1S, 3R)-5,10-dioxo-3-metboxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5, 10-tetrahydro-1H-naphtho [2,3-c] pyran (BCH-1693) (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 3,4,5,10-tetnhydro-1H-naphtho-[2,3-c] pyran (BCH-2026)
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2020)
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-am ino-L-lyxohexopyranose)-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2021)
Trans-5,10-dioxo-1-aceta mido-3-ethyl-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2027)
3-ethyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphto-[2,3-c] pyran (BCH-2154)
(1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyιan (BCH-2053)
(1'S, 1S, 3R)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2052)
(trans)-5, 10-dioxo-3-isopropenyl-1-methoxy-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2148) (1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5, 10-tetrahydro-1H-naphto-[2,3-c]-pyran (BCH-2153)
(1'S, 1S, 3R)-5,10-dioxo-3-isopropenyl-1-(2',3',6' -trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)- 3,4,5,10-tetrahydro-1H-naphto-[2,3-c]-pynn (BCH-2152)
(1'S, 1R, 3S)-5,10-dioxo-3-methoxycarbonyl-1-(2',3',6',trideoxy-3'-trifluoroacetamido-L- lyxomexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyrano (BCH-2128) (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranos)-5,10-dioxo- 3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyranyl]-ketone (BCH-2112) (1'S, 1R, 3S)-5,10-dioxo-3-isopropoxycarbonyl-1-( 2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2122) (1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2121) (1 'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-isochroman (BCH-1697)
(1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphth o-[2,3-c] pyran (BCH-2091)
(1'S, 1R, 3S)-5,10-dioxo -3-phenyloxymethyl-1-{2',3',6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (BCH-2032) (1'S,1S,3S) and (1'S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L- lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene
(BCH-2031)
(1 'S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranoee]-5,10-dioxo- 3,4,5, 10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene (BCH-2163)
(1'-S, 1-R,3-S)-3-([2',3',6'-trideoxy-3 '-trifluoroacetamido-4'-hydroxy-L-lyhohexopyranose]-5,10-dioxo-
3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1649) (1'S,1S,3R) and (1'-S,1-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L- lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (BCH-1648)
(1'-S, 1-R,3-S,4a-S, 10a-S)-methyl-(1-[2',3',4',6'-tetradeoxy-3'-methoxy-4'-O-methanesulfonyl-L- lyxohexopyranose)-4a,10a-epoxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c] pyran-
3-yl) ketone (BCH-2141)
(1'-S,1-S,3-R,4a-R,10a-R)-methyl-(1-[2',3',4',6'-tetradeoxy-3 '-m ethoxy-4'-O- methanesulfonyl-L- lyhohexopyranose)-4a,10a-epoxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c] pyran-
3-yl) ketone (BCH-2149)
(1S,3R,1'S,5'S,6'S) and (1R,3S,1'S,5'S,6'S)-methyl-(1-[4'trifluoroacetamido-5'- methyltetrahydropyranyl]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3- yl) ketone (BCH-1673)
(1'S,1S,3R)-3 (oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran BCH-2101
(1'S, 1R,3S)-3(oximoethyl)-5,10-dioxo-1 (2,3,6-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran BCH-2115
(1's, 1S,3R)-3-(trifluoroacetamidoethyl)(-5,10-dioxo-1-(2',3 ','-trideoxy-3',4'-dihydroxy-L- lyxo hexopyranose)=-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2018)
(1'R, 1R,3S)-3-aceto-5,10-dioxo-1-(2-deoxy-2-chloroethyl-nitrosoureido-D-glucopyranose)-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]pyran (BCH-2038)
3-Aceto-5,10-dioxo-1-methoxy-5,19-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2129)
(1R,3S) and (1S,3R)-3-aceto-5,10-dioxo-1 (4-chloroethylnitrosoureido cyclohexyl-oxy)- 3,4,5,10tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2114)
1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2044) 1-methoxy-3-(3-N-pyrrobdinomylpropylaminocarbonyl)-5, 10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- yran (BCH-2166)
(3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3- carboxamide (BCH-2157)
3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2003)
3-(5'-tosyloxazolyl)-5,10-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran (BCH-2155)
(1'S, 1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3- methoxycarbonyl-3- methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2076) Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-3-yl) formate (BCH-2043) 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid (BCH-2161)
(1,3-trans)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2045)
(1,3-cis)-1-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho -[2,3-c]-pyran (BCH-2119) (1,3-trans)-1-methoxy-3-N-anilinylcarbonyl-5, 10-dioxo-3,4,5, 10-tetrahydro-1H-naphtho-[2,3c]-pyran
(BCH-2041)
(1 ,3-cis)-1-methoxy-3-N-anilinylcarbonyl-5, 10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
(BCH-2042)
(1'S, 1R,3S)-2',3',6'-trideoxy-3'-triflu oroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5,10- dioxo-3,4,5,10-tetrahydro-1H-naphth -[2,3-c]-pyran (BCH-2150)
(1'S,1S,3R)-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose-3-[5'-tosyloxazolyl]-5, 10- dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (BCH-2151)
(1,3-trans)-1-methoxy-3-(3'-aminothiazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
(BCH-1616)
(1,3-trans)-1- methoxy-3-dimethoxyphosphonoacetyl-5, 10-dioxo-3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]- pyran (BCH-1674)
(1'S,1R,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-5, 10-dioxo-4,5, 10-trihydro-
1H-naphtho-[2,3-c]-pyran (BCH-2077)
(1'S,1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl- 3,4,5,10-tetrahydro-5,10-dioxo-naphtho -[2,3-c]-pyran (BCH-2082)
(1'S, 1S,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3- dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran
(BCH-1690)
(1'S,1S,3SH-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-methoxy-carbonyl-3- methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-2081)
(1'S,1S,3S)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-bexopyranose)-3- dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5, 10-dioxo--naphtho-[2,3-c]-thiopyran
(BCH-2037.001)
(1'S,1R,3R)-1-(3'-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyιanose)-3- dimethoxyphosphonoacetyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran
(BCH-2127)
(1'S,1S,3S)-1-(3'-trifiuoroacetamido-2',3',6'-trideoxy-lyxo-L-hexopyranose)-3-acetyl-3-methyl-3,4,5, 10- tetrahydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran (BCH-2090)
(1'S, 1R,3S)-1-(3 '-trifluoroacetamido-2',3',6'-trideoxy-lyxo-L hexopyranose)3-diιnethylphosphonoacetyl- 3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c]-pyran (BCH-1689)
(1 'S, 1R,3S)- methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5, 10-dioxo-
3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-2015)
(1'S, 1R,3S)-methyl-(1-[2',6'-dideoxy-3'-4'-diacetoxy-2'-iodo-L-lyxohexopyranose]-5, 10-dioxo-
3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1666) (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'iodo-L-lyxobexopyranose]-5,10-dioxo-
3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH-1667) (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-dihydroxy-2'-iodo-L-lyxohexopyranose]-5,10-dioxo- 3,4,5,10-tetrahydronaphtho [2,3-c]-pyran-3-yl)-ketone (BCH-2014) (1'S,1R,3S)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bro
3,4,5, 10-tetrahydronaphtho -[2,3-c]-pyran-3-yl) ketone (BCH-2100) (1'S, 1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose]-5,10-dioxo-
3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2099) (1'S, 1R,3S)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'-trifiuoroacetamido-4'-hydroxy-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaρhtho -[2,3-c]-pyran-3-yl) ketone
(BCH-2023)
(1'S,1S,3R)-methyl-(1-[2',3',6'-trideoxy-2'-iodo-3'-trifluoroaceta mido-4'-hydroxy-L- lyxohexopyranose]-5, 10-dioxo-3 ,4,5, 10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2022)
(1'S, 1R, 1S) and (1'S,1S,3R)-methyl-(1-[2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-arabino-hexopyranose]- 5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2065) (1'S, 1S,3R) and (1'S, 1R,3S)-methyl-(1-[dideoxy-2',6'-dihydroxy-3',4'-L-lyxohexopyranose]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2117)
(1'S,1S,3R) and (1'S,1R,3S)-methyl-(1-[dideoxy-2',6'-diacetoxy-3',4'-L-lyxohexopyranose]-5,10-dioxo- 3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2118)
(1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-hydroxy-L- lyxohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl-ketone (BCH-2078)
Methyl-(1-O-[2'-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone, racemic, hydrochloride (BCH-2069)
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L- arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104 and BCH-2102)
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L- arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2047)
Methyl-(1-O-[N-BOC-3-piperidinemethanol]-5,6-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3- yl) ketone, mixture of isomers (BCH-2060)
Methyl-(1-O-[3-piperidinemethanol]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone hydrochloride salt, mixture of isomers (BCH-2061)
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L- arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104)
(1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifiuoroacetamido-L-arabinohexopyranose]- 5,10-draxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2102)
72. A compound according to Claim 1 selected from the group consisting of:
(1'S, 1R, 3S)-5,1 0-dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran. Methyl (1,5,8-trimethoxy-isochroman-3-yl) formate
Methyl (1-Methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate
(1S,2'S,3R,5'S) and (1R,2'S,3S,5'S)-HC-N-BOC-Serine-Leucine-Me ester]-3-aceto-5,8-dimethoxy- isochroman
(1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-serine methyl ester]-3-aceto-5,8-dimethoxy isochroman.
(1S, 2'S, 3R) and (1R, 2'S, 3S)-1-[O-NNBOC-prolinol]-3-acetyl-5,8-dimethoxy isochroman
1-hydroxy-3-cyano-5,8-dimethoxy isochroman
1-hydroxy-3-cyano-5,8-dioxo-5,8-dihydroisochroman
(1'S, 1S, 3R) and (1'S, 1R, 3S)-5,10-dioxo-3-cyano-1-(2',3',6',-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1-H-naphtho-[2,3-c pyran 5,8-Dimethoxy-3-(propane-2-one -1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-isochroman
5,8-Dioxo-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-isochroman
(1R, 3S) and (1-S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5-dihydro-L- lyxohexo-pyranose-2-yl)-5,8-dimemoxy-3-acetoisochroman
(1R, 3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,8-dioxoisochroman
(1S, 3R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,8-dioxoisochroman
(1'S, 1R, 3S)-5,8-dioxo-3-methoxymethyl-1-{2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-5,8-dihydroisochroman
(1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-
4'-O-p-nitrobenzoyl-L-lyxohexo-pyranose)-5,8-dihydroisochroman
(1'S, 1R, 3R)-5,8-dimetho xy-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-isochroman
(1'S, 1R, 3R)-5,8-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-isochroman
(1'S, 1S, 3S)-5,8-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-5,8-dihydro-isochroman
(trans)-1-acetamido-5,8-dioxo-3-ethyl-5,8-dihydro-isochroman (1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8-dioxo-3-iaopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro-isochroman (40:60) (1'S, 1S, 3R)-5,8-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-5,8-dihydro-isochroman (40:60)
(1'S, 1S, 3R)-5,8-dimethoxy-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose) isochroman.
(1'S, 1R, 3S)-5,8-dimethoxy-3-isopropeoyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose) isochroman.
(1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dimethoxy-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'- trifluoroacetamido-4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-isochroman.
(1'S, 1R, 3S) and (1'S, 1S, 3R)-5,8 dioxo-3-methoxycarbonyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-
4'-O-p-nitrobenzoyl-L-lyxohexopyranose)-5,8-dihydro-isochroman.
isopropyl-(5,8-dimethoxy-isochroman-3-yl)-ketone
5,8-dimethoxy-3-isopropoxycarbonyl-isochroman
5,8-dimethoxy-3,3 bis (dimethoxymethyl)-isochroman
(1'S, 1S)-5,8-dimethtoxy-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
(1'S, 1S)-5,8-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
(1'S, 1R, 4R)-5,8-dimethoxy-4-ethyl-1-(2',3',6'-trideoxy-3'-trifiuoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-isochroman
(1'S, 1S, 4S)-5,8-dimethoxy-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-isochroman
(1'S, 1R, 4R)-5,8-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-isochroman
(1'S, 1R, 3S)-5,8-dimethoxy-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
(1'S, 1R, 3S)-5,8-dioxo-3-phenyloxymethyl-1-(2',3',6'-tideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-isochroman
5,8-dimethoxy-3-(2-propenyl)-isochroman
(1'S,1S,3S) and (1'S,1-R,3-R)-1-(2',3',6',-trideoxy-3'-trifluoroacetamido-4'-O-paranitrobenzoyl-L- lyxohexopyranose)-5,8-dimethoxy-3-(2-propenyl)-iochroman
(1'S,1-R,3-R)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-paranitrobenzoyl-L-lyxohexopyranose)- 5,8-dimethoxy-3-(2-propenyl)-isochroman
(1S,3R-3(oximoethyl)-1 (2,3,6-trideoxy-3-trifluoroacetamido -4-p-nitrobenzoyl-L-lyxohexopyranose)- 5,89-dimethosy-isochroman
(1R,3S)-3-(oximoethyl)-1 (2,3,6-trideoxy-3-trifluoroacetamido-4-p-nitrobenzoyl-L-lyxohexopyranose)-
5,8-dimethoxy-isochroman
3-(Trifluoroacetamido-ethyl)-5,8-dimethoxy isochroman (1S',1S,3R)-3-(trifluoproacetamidoethyl)-5,8-dimethoxy-1-(2',3',5'-trideoxy-3',4'-dihydroxy-L- lyxohexopyranose)-isochroman
(1'R, 1R,3S)-3-aceto-5,8-dimethoxy-1(2-deoxy-2-chloroethylureido-3,4,6-triacetyl-D-glucopyranose)- isochroman
(1'R, 1R,3S)-3-aceto-5,8-dimethoxy-1(2-deoxy-2-chloroethylureido-4,6-benzylidene-D-glucopyranose)- isochroman
(1R,3S) and (1S,3R)-3-Aceto-1 (4-crioroethylureido-cyclohexyloxy)-5,8-dimethoxy-isochroman 3-ethylthiocarbonyl-5,8-dimethoxy-isochroman
3-ethylthiocarbonyl-5,8-dioxo-1,3,4,5,8-penta-1H-benzo-[2,3-c]-pyran
3-(5'-tosyloxazolyl)-5,8-dimethoxy iaochroman
3-(5'-tosyloxazolyl)-5,8-dioxo-1,3,4,5,8-pentahydrobenzo-[2,3-c]-pyran
(1'S, 1S, 3R)-1-(2',3',6'-trideoxy-I,3'-trifiuoroacetamido-4'-p-nitrobenzoyl-L-lyxohexopyranose)-5,8- dimethoxy-3-aceto-3-methyl isochroman
(1's,1S,3R)-1(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3-methyl-5,8-dioxo-4,5,8-trihydro-1H-benzo-[2,3-c]-pyran
3-(5'-tosyloxazolyl)-5,8-dimethoxy isochroman
(1'S, 1R,3S)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,8-dimethoxy isochroman
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,8-dimethoxy isochroman
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'-trifluoroacetamido-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,8-dioxo-3,4,5,8-tetrahydrobenzo-[2,3-c]-pyran
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'-trifluoroacetamino-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,8-dimethoxy isochroman
(1'S,1S,3RH-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3'-trifluoroacetamino-L-lyxohexopyranose)-3-(5"- tosytoxazolyl)-5,8-dioxo-3,4,5,8-tetrahydrobenzo-[2,3-c]-pyran
(1'S, 1S,3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3- methoxy- carbonyl-3-methyl-5,8-dimethoxy-isochroman
(1'S,1R,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3- methoxy-carbonyl-3- methyl-5,8-dimethoxy-isochroman
(1'S,1R,3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3- methoxy-carbonyl-3-methyl-5,8-dimethoxy-isochroman
(1'S,1R,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3- methoxy-carbonyl-3-methyl-5,8-dimethoxy-isochroman
(1'S,1R,3S)-1-(4'-p-nitrobenzoyl -3'-trifiuoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3-methyl-5,8-dioxo-4,5,8-trihydro-1H-benzo-[2,3-c]-pyran
(1'S, 1S,3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3- methyl-5,8-dioxo-4,5,8-trihydro-1H-benzo-[2,3-c]-pyran
(1'S,1S,3S) and (1'S,1R,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L- - lyxohexopyranose)-3-acetyl-5,8-dimethoxy-thioisochroman
(1'S, 1S,3S) and (1'S, 1R,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-5,8-dioxo-4,5,8-trihydro-1H-benzo-[2,3-c]-pyran (1'S,1S,3S) and (1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifiuoroacetamido-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-3- methyl-5,8-dimethoxy-isochroman
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3-acetyl-
3-methyl-5,8-dimethoxy-isochro man
(1'S,1S,3S) and (1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy- lyxohexopyranose)-3-acetyl-3-methyl-5,8-dioxo-4,5,8-trihydro-1H-benzo-[2,3-c]-pyran (1'S,1S,3R)[1'S,1R,3S]-5,8-dimethoxy 1(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-dimethylphosphon oacetyl isochroman
(1'S,1S,3R)[1'S,1R,3S]-1-(2',3',6'-trideoxy-3'-trifluoro-acetamido-4'-p-nitrobenzoyl-L- lyxohexopyranose)-3-dimethylphosphonoacetyl-3,4,5,8-tetrahydronaphthaleno-[2,3-c]- pyran
(1'S,1S,3R) - 2,5-Dimethoxy-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose)-3- acetoisochroman
(1'S, 1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-2'-iodo-L-lyxohexopyranose)-isochroman (1'S,1R,3S)-3-aceto-1-(2',6'-dideoxy-2'-iodo-L-lyxohexopyranose)-5,8-dioxo-5,8-dihydroisochroman (1'S,1R,3S)- 5,8-Dioxo-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose)-5,8- dihydroisochroman
(1'S,1S,3R)-5,8-Dioxo-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-lyxohexopyranose)-5,8- dihydroisochroman
(1'S, 1S,3R)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-2'-iodo-L-lyxohexopyranose)-isochroman (1'S,1S,3R)-3-aceto-1-(2',6'-dideoxy-2'-iodo-L-lyxohexopyranose)-5,8-dioxo-5,8-dihydroisochroman (1'S,1R,3S) and (1'S,1S,3R)-2,5-Dimethoxy-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L- lyxohexopyranose)-3-acetoisochroman
(1'S, 1S,3R)-2,5-Dimethoxy-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose)-3- acetoisochroman
(1'S, 1R,3S)-5,8-dioxo-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose)-5,8- dihydroisochroman
(1'S, 1R,3S)-5,8-dioxo-3-aceto-1-(2',6'-didepxy-3',4'-diacetoxy-2'-bromo-L-lyxohexopyranose)-5,8- dihydroisochroman
(1'S,1R,3S) and (1'S,1S,3R)-2,5-Dimethoxy-3-aceto-1-(2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-
4'-O-scetyl-L-lyxchexopyranose)-isochroman
(1'S,1S,3R)-2,5-Dimethoxy-3-aceto-1-(2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-O-acetyl-L- lyxohexopyranose)-isochroman
(1'S,1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-2'-iodo-L- lyxohexopyranose)-isochroman
(1'S,1R,3S)-3-aceto-1-(2',3',6'-trideoxy -2'-iodo-3'-trifluoroacetamido-L-lyxohexopyranose)-5,8-dioxo- 5,8-dihydroiaochroman
(1'S,1S,3R)-3-aceto-1-(2',3',6'-trideoxy-2'-iodo-3'-trifluoroacetamido -L-lyxohexopyranose)-5,8-dioxo-
5,8-dihydroisochroman
(1'S,1S,3R) and (1'S,1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L- arabinohexopyranose) isochroman
(1'S, 1R,3S)-5,8-Dimethoxy-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-2'-iodo-L-arabinohexopyranose) isochroman
(1'S,1R,3S) and (1'S,1S,3R)-3-aceto-1-(2',6'-dideoxy-2'-iodo-L-arabinohexopyranose)-5,8-dioxo-5,8- dihydroisochroman
(1'S,1S,3R) and (1'S,1R,3S)-5,8-di methoxy-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-L- lyxohexopyranose) isochroman
(1'S,1S,3R) and (1'S,1R,3S)-5,8-dimethoxy-3-aceto-1-(2',6'-dideoxy-L-lyxohexopyranose) isochroman (1'S,1S,3R) and (1'S,1R,3S)-5,8-dioxo-3-aceto-1-(2',6'-dideoxy-L-lyxohexopyranose)-5,8- dihydroisochroman
(1'S,1S,3R) and (1'S,1R,3S)-5,8-dioxo-3-aceto-1-(2',6'-dideoxy-3',4'-diacetoxy-L-lyxohexopyranose) isochroman
3-aceto-5,8-dioxo-3,4,5,8-tetrahydro-1H-benzo-[2,3-c]-pyran
1-O-[N-BOC -4-piperidinemethanol]-3-acetyl-5,8-dimethoxy isochroman racemic
(1R,3S,1'S) and (1S,3R,1'S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3',4'-bis-trifluoroacetamido-L- arabinohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone
1-O-[N-BOC -3-piperidinemethanol]-3-acetyl-5,8-dimethoxy isochroman, mixture of isomers
(1'S,1R,3S) and (1'S,1S,3R) - 2,5-Dimethoxy-1-(2',6'-dideoxy-3',4'- diacetoxy-2'-iodo-L- lyxohexopyranose)-3-acetoisochroman
73. A compound according to claim 1 selected from the group consisting of :
Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho[2,3-c]pyran-3-yl) formate
Mediyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-yl) formate
1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]pyran-3-carboxylic acid
(1S, 2'S, 3R) and (1R, 2'S, 3S)-methyl-(1-[O-N-BOC-serine methyl ster]-5,10-dioxo-3,4,5,10- tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone.
3,3 bis (methoxycarbonyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
(1R.3S) and (1S,3R)-3-Aceto-5, 10-dioxo-l (4-chloroethylureido cyclohexyl-oxy)-3,4,5,10-tetrahydro-
1H-nahtho-[2,3-c]-pyran
(3-N-imidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-carboxamide (1's, 1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',5'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3-methyl-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (1'S,1R,3S)-1-(4'-p-nitrobenzoyl-3-trifluoroacetamido-2',3',6'-trdeoxy-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphdιo-[2,3-c]-pyran
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3-(5"- tosyloxazolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-napbtho-[2,3-c]-pyran
1-methoxy-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
3-brornoacethyl-1- methoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
Methyl-(6-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone and methyl-(9- hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaph tho-[2,3-c]-pyran-3-yl) ketone (BCH-
2062)
3-aceto-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
3-bromoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
3-(3'-aminothiazolyl)-5,10-dioxo-1,3,4,5,10-pentahydro-naphtho-[2,3-c]-pyran
74. A compound according to claim 1 selected from the group consisting of:
5,10-Dioxo-3-(propane-2-one)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (1R, 3S)-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzyloxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho [2,3-c] pyran
(1S, 3RH-(2',3',6'-trideoxy-3'-trifluoroacetanudo-4'-O-p-nitrobenzyloxy-1,5-dihydro-L- lyxohexopyranose-2-yl)-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (1'S, 1R, 3S)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-3,4,5,10-tetrahydr o-1H-naphtho-[2,3-c]-pyran (1'S, 1S, 3R)-5,10-dioxo-3-methoxymethyl-1-(2',3',6'-trideoxy-3'-trifiuoroaceta mido-4'-O-p- nitrobenzoyl-L-lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (1'S, 1R, 3R)-5,10-dioxo-3-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran
(1'S, 1S, 3S)-5,10-dioxo-3-ethyl-1-(2', 3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5, 10-tetrahydro-1H-naphto-[2,3-c]-pyran
(1'S, 1S, 3R)-5,10 -dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifiuoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo-pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
(1'S, 1R, 3S)-5,10-dioxo-3-isopropyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
(1'S, 1R, 3S)-5,10-dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifiuoιoacetaιmdo-4'-O-p-nitrobenzoyl-
L-lyxohexo-pyranose) 3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran (1'S, 1S, 3R)-5,10 -dioxo-3-isopropenyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-
L-lyxohexo-pyranose) 3,4,5, 10-tetrahydro-1H-naphtho-[2,3-c]-pyran (1'S, 1R, 3S)-isopropyl-[1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydro-1H-nsphtho-2,3-c]-pyranyl]-ketone (1'S, 1R, 3S), and (1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy- 3 ',triflu oroacetamindo -4'-O-p-nitrob enzoyl-L -lyxohexopyranose)-3,4.5, 10-tetrahydro-
1H-naphtho-{2,3-c]-pyran
(1'S, 1S, 3R)-5,10-dioxo-3-isopropoxycarbonyl-1-(2',3',6'-trideoxy-3',trifluoroacetamido-4'-O-p- nitrobenzoyl-L -lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (1'S, 1S)-5,10-dioxo-3,3-dimethoxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- mtrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c] pyran (1'S, 1R, 4R)-5,10-dioxo-4-ethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p-nitrobenzoyl-L- lyxohexo pyranose)-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran
(1'S, 1R, 3S)-5,10 -dioxo-3-phenyloxymethyl-1-(2',3',6'-trideoxy-3'-trifluoroacetamido-4'-O-p- nitrobenzoyl-L-lyxohexopyranose)-3,4,5,10-tetιahydro-1H-naphtho-[2,3-c] pyran (1'S,1S,3S) and (1'-S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-trifluoroaceta midoo-4'-paramitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (1'-S,1-R,3-R)-3-([2',3',6'-trideoxy-3'-triflu oroacetamidoo-4'-paramitrobenzoyl-L-lyxohexopyranose)-
5,10-dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-propene (1'-S,1-R,3-S)-methyl-(1-[2',3',6'-trideoxy-3'-trifluoroacetamido-4'-iodo-L-lyxohexopyranose]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl)-ketone (BCH-1620)
(1'S,1S,3R) and (1'S,1-R ,3-R)-3-([2',3',6'-trideoxy-3'-trifiιιoroacetaιrido-4'-hydroxy-L- lyhohexopyranose]-5,10-dioxo-3,4,5,10-tetrahydronaphto-[2,3-c]-pyran-3-yl)-propene
(1'R, 1R,3S)(-3-aceto-5, 10-dioxo-1-(2-deoxy-2-crioroethylureid o-4,6-benzylidene-D-glucopyranose)-
3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]pyran
(1'S,1R,3S)-1-4'-p-nitrobenzoyI-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3-methyl-5,10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (1'S,1S,3S)-1-(4'-p-ritrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy- carbonyl-3-methyl-5, 10-dioxo-4,5,10-trihydro-1H-naphtho-[2,3-c]-pyran (1'S,1S,3S)-1-(4'-p-mtrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-L-lyxohexopyranose)-3-acetyl-
5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-thiopyran
(1'S,1R,3R) and (1'S,1S,3S)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamino-2',3',6'-trideoxy-L- lyxohexopyranose)-3-acetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]- thiopyran
(1'S,1S,3S) and (1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy- lyxohexopyranose)-3-acetyl-3-ιnethyl-5,10-dioxo-4,5, 10-trihydro-1H-naphtho-[2,3-c]- pyran
(1'S,1S,3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranose)-3-acetyl-3- methyl-5,10-dioxo-4,5, 10-trihydro-1H-naphtho-[2,3-c]-pyran
(1'S,1R,3S)-1-(2',3',6'-trideoxy-4'-p-nitrobenzoyl-3'-trifluoro-acetamido-L-lyxohexo pyranose)3- dimethyl-phosphonoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3-c]-pyran (1'S,1S,3R) and (1'S, 1R,3S)-1-(2',3 ',6'-trideoxy-4'-p-mtiobenzoyl-3'-trifluoro-acetamido-L-lyxohexo pyranose)3-dimethylphosphonoacetyl-5,10-dioxo-3,4,5,10-tetrahydro-1H-naphtho-[2,3- c]-pyran
(1'S,1S,3R)-methyl-(6 and 9-hydroxy-1-(2',3 ',6'-trideoxy-3'-trifluoroaceta mido-4'-O-p-nitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahyd ro-1H-naphtho-[2,3-c]-pyran-3-yl) ketone
75. A pharmaceutical composition according to claim 4 wherein said compound is combined with an agent facilitating targetting of said combination to tumor or cancer cells.
76. A pharmaceutical composition according to claim 69, wherein said agent is selected from the group consisting of monoclonal antibodies, polyclonal antibodies, proteins, and liposomes.
77. A pharmaceutical composition according to claim 71, wherein said agent is selected from the group consisting of monoclonal antibodies, polyclonal antibodies, proteins, and liposomes.
78. A method of treatment of tumors or cancer said method comprising the step of administering to an animal, a therapeutically effective amount of at least one compound according to claim 1.
79. A method for the treatment of tumors or cancer said method comprising the step of administering to an animal, a tiierapeutically effective amount of at least one compound or combination of clinically defective antitumor agents according to claim 2.
80. A method according to claim 79, wherein said animal is a mammal.
81. A method according to claim 80, wherein said mammal is a human.
PCT/CA1993/000463 1992-11-09 1993-11-05 Antineoplastic heteronaphthoquinones WO1994011382A1 (en)

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