EP0659190A1 - Antineoplastic heteronaphthoquinones - Google Patents

Antineoplastic heteronaphthoquinones

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Publication number
EP0659190A1
EP0659190A1 EP93924460A EP93924460A EP0659190A1 EP 0659190 A1 EP0659190 A1 EP 0659190A1 EP 93924460 A EP93924460 A EP 93924460A EP 93924460 A EP93924460 A EP 93924460A EP 0659190 A1 EP0659190 A1 EP 0659190A1
Authority
EP
European Patent Office
Prior art keywords
dioxo
pyran
lyxohexopyranose
trideoxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93924460A
Other languages
German (de)
French (fr)
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 200 Boulevard Dudomaine Barbeau
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire Canada Inc
Original Assignee
IAF BioChem International Inc
Biochem Pharma Inc
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Filing date
Publication date
Application filed by IAF BioChem International Inc, Biochem Pharma Inc filed Critical IAF BioChem International Inc
Publication of EP0659190A1 publication Critical patent/EP0659190A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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., Saro ⁇ y, 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 analogs with either an improved therapeutic index or with reduced cross-resistance.
  • anthracycline derivatives have been obtained either from streptomyces biosynthesis or via the semisynthetic modification of known natural anthracycline antibiotics (Arcamone, F., Doxombicin, Academic Press, N.Y. 1980; Thomson, R.H., Naturally Occurring Quinones m: Recent Advances, Chapman and Hall, New York 1987; Anthncyclines: Current Status and New Developments, Academic Press, New York, 1980; Brown, J.R.
  • Tricyclic variants of daunonibicin have been reported to possess antitumor activity (EPA 91202015.3)
  • R is COCH3 or C_CH or C_C-Si(CH 3 )3
  • R 3 is H or COCF3
  • nanaomycin A (___) and kalafungin ⁇ 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., ___%, 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 doxorabic ⁇ n-re ⁇ istant tumor cells, and are more potent in some cases than the corresponding tetracyclic heteroanthracycline compound.
  • X j and X2 are independently selected from the groi ⁇ consisting of
  • R is selected from the groi ⁇ consisting of hydrogen, hydroxyl, C ⁇ . j g alkyl, C ⁇ _i acyl and C j . j g 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,
  • TIT TE SHEET c l-16 ⁇ y 1 ' c l-16 - ⁇ - ⁇ -> c l-16 "y 1 ' c l-16 haloacyl, and hydrogen. is selected from the group consisting of C-Q, nitrogen, and NO.
  • R j , R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, Cj_ g alkyl, C . g alkoxyl, C _ cycloalkyl, tosyl, mesylate, acetate optionally substituted with a C j _ g alkyl, triflate, trifiuoroacetate, halogen, nitro, cyano, C j .
  • acyl C j . g arylacyl, aminoalkylaminoalcohol of formula NH(CH2) n NH(CH2)
  • n and m are independently 1 to 4 and X is a halogen, amino, which may be unsubstituted or mono or di- ⁇ ubstituted by C _g alkyl, C3_g cycloalkyl, C j _g acyl, trifluoroacyl, C . ⁇ g aralkyl and C$_ g aryl; C2_g alkenyl, and C ⁇ . alkynyl, haloalkylnitrosoureido of the formula NH(CO)N(NO) (CH ⁇ CH 2 X, wherein n is 0 to 4 and X is a halogen, and
  • Z is one of C-Rg or C-R7.
  • Rg is selected from the group consisting of C j . g hydroxime, Cg_ g hydraztme, C j . j g hydroxyalkyl, hydrogen, Cg_ 18 aryl, C7_ 18 aryloxyalkyl, C ⁇ . j araloxyalkyl, phenyl, C j . j g alkyl, acetoxy, C j . j g dihydroxyalkyl, C ⁇ . alkenyl, C j . alkynyl, C _ cycloalkyl, squaric acid, C j . j g alkyl squarate, amino, cyano, dimethylpbosphonato, phenyl sulfone, C _g aryl sulfone, and
  • C j .g 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 Cl-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and O, or its dioxolane or dioxane or dialkoxy Cl-8 ketal, and wherein R is selected from the group consisting of hydrogen, C j . j g alkyl, C j .g thioalkyl, C3_ cycloalkyl, Cg_ j g aryl, C .
  • j aralkyl, fluoromethyl, difluoromethyl, C j .g hydroxyalkyl, C2.16 alkene, squaric acid, C ⁇ . j g alkyne, C j .g thioalkyl, Cg_ g thioaryl, C j _4 alkyl squarate, C2_g alkoxyalkyl, Cg.
  • n O to 7 and Z* is from the group consisting of hydrogen, C .g acyl, Cg_ j g aryl, C . g 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 groi ⁇ consisting of
  • aralkyl amino which may be unsubstituted, mono- or di-substituted by C j .g alkyl, C 3 .g cycloalkyl, acyl, trifluoroacyl, C2-12 aralkyl, C2.12 *-7-> a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the groi ⁇ consisting of O, S, N, SO, SO2, P, PO, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C j _4 alkyl and aryl, said heterocycle being optionally substituted with one or more halogens, Cg_ g arylsulfone, hydroxy, C j .
  • C3_ 8 cycloalkyl C j .g hydroxyalkyl, C-.. ⁇ araloxyalkyl, C ⁇ .g alkoxyalkyl, ⁇ .g acyloxyalkyl, C _ j 2 aryloxyalkyl, squaric acid or squarate, amino which may be unsubstituted or mono- or di-substituted by C j .g alkyl, C3_g cycloalkyl, C j .g acyl, cyano, trifluoroacyl, C 7 . j g aralkyl or Cg.
  • R is selected from the groi ⁇ consisting of hydrogen, C j . j g alkyl, C3.g cycloalkyl, C j .g hydroxyalkyl, Cr j .g alkoxyalkyl, C7. 2 aryloxyalkyl, C7.J2 araloxyalkyl, C . j 2 aryl, C . j g aralkyl and C j . j g alkenyl.
  • R5 and Rg are independently selected from the groi ⁇ consisting of hydrogen, halogen, hydroxyl, C j . j g alkoxyl, C j . j g alkyl, ⁇ . j acetylenyl, a groi ⁇ 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 C j .g alkyl, C .4 acyl, C3_ cycloalkyl, hydrogen, C2.g carboalkoxy, C2_ alk ⁇ e, C ⁇ . alkyne, Cg. 2 aryl, and
  • j g alkyl and C3_g cycloalkyl aco ⁇ amine, glucosamine, N-chloroethyl-nitrosoureidoglucosamine, 2,6- dideoxyrhamnose, thioglucose, thiodaunosamine, thiol, C j . j 2 thioalkyl, a naturally occuring amino acid or di- and tri-peptides thereof, a group ofthe formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH2, NR** wherein R** is from the groi ⁇ consisting of hydrogen, Cj.g alkyl, C ⁇ . acyl or Cg. 12 aiyl,
  • R and R* are independently selected from the groi ⁇ consisting of hydrogen, C j . j 2 alkyl, C . j 2 aryl, C ⁇ .g dihydroxyalkyl, C ⁇ .g alkene, C2-g alkyne, C j .g alkoxy, C j .g alkylamino, C3_g cycloalkyl, ⁇ .g carboalkoxy, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the groi ⁇ consisting of O, S, N, SO, SO2, P, PO.
  • R is selected from the groi ⁇ consisting of hydrogen, hydroxyl, C j .g acyl, C j . 4 alkyl and C _ j 2 -- ⁇ -. -*-- heterocycle being optionally substituted with one or more halogens, hydroxy, Cg_ j g aryl sulfone, cyano C j . j g alkoxy, C j . j g alkyl, nitro, C j .
  • j g hydroxyalkyl amino, which may be unsubstituted or mono-or di-substituted by C .g alkyl, C3_g cycloalkyl, C j .g acyl, trifluoroacyl, C 7 . ⁇ g aralkyl, Cg. j g aryl, C2. alkenyl, ⁇ . alkynyl and hydroxy; mono or oligosaccharides of the formula:
  • Y is selected from the groi ⁇ consisting of oxygen, sulfur, sulfoxide, sulfone, CR*R**, wherein R* and R** are independently selected from the group consisting of hydrogen, C .g alkyl, and NR wherein R is selected from the groi ⁇ consisting of hydrogen, C j .g alkyl, and C j .g acyl.
  • R and R j g are independently selected from the group consisting of hydrogen, halogen, hydroxy,
  • Rj is selected from the groi ⁇ consisting of hydrogen, amino which may be unsubstituted or mono or di-substituted by C .g alkyl, C3_g cycloalkyl, C2. acyl, t-butylacyl, C j .g alkoxy, t- butyloxycarbonyl, trifluoroacyl, C7.J2 aralkyl, C _j2 ***• > and a n»turally 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 j .
  • R ⁇ is selected from the groi ⁇ consisting of hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, memo or bligosaccharides, C j .g alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C j .
  • 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 groi ⁇ consisting of hydrogen, hydroxyl, C j .g acyl, C _4 alkyl and C . j aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, Cg_ j g aryl sulfone, cyano, C j . j g alkoxy, C j . j g alkyl, nitro, C j .
  • j g hydroxyalkyl, amino which may be unsubstituted or mono-or di-substituted by C .g alkyl, C3_g cycloalkyl,. C .g acyl, trifluoroacyl, C ⁇ . j g aralkyl, Cg_ j g aryl, C ⁇ . alkenyl, ⁇ . alkynyl and hydroxy.
  • Preferred compounds of formula (12) are those wherein
  • Xj and X2 are independently selected from the groi ⁇ 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 groi ⁇ consisting of CQ, N, and NO.
  • Rj, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C .4 alkoxyl, tosyl, triflate, fluorine, chlorine, amino, aminoalkylaminoalcohol of formula NH(CH2) jj NH(CH2) m OH wherein n and m are independently 1 to 3, aminoalkylaminoalkylchloride of formula NH(CH2)nNH(CH2) m Cl where n and m are independently 1 to 3, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2) classroom CH 2 Cl, wherein n is 0 to 4, and a groi ⁇ of the formula -O-
  • R is selected from the group consisting of hydrogen, C j _g alkyl, and aryl;
  • Z is one of C-Rg or C-R7.
  • Y is selected firom the group consisting of oxygen, sulfur, and CHR wherein R is hydrogen or C j __4 alkyl,
  • R and RJQ are independently selected from the groi ⁇ consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl;
  • RJJ is selected from the group consisting of amino which may be unsubstituted or m mo- or di- substituted with C .g acetoxy alkyl, C .g 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 j .g alkoxyl, a group of the formula NH(CH2)nCH(OR)2 wherein R is independently selected from a group consisting of C j .g alkyl, Cj.g acyl and C7.J2 aroyl and wherein n
  • More preferred compounds of formula (12) are those wherein X ⁇ 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.
  • Rj, 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 ⁇ CC NfNO ⁇ CI ⁇ CI ⁇ Cl wherein n is 0 to 2; amino, and fluorine.
  • Z is one of C-Rg or C-R7.
  • alkene a groi ⁇ of the formula -(C ⁇ NR*,R** wherein n is 1 to 4 and R* and R** are independently selected from the group consisting of hydrogen, C j .5 alkyl, C _4 acyl; acosamine, 2,6-dideoxy ⁇ hamnose, thiodaiinosamine, C .5 thioalkyl, a naturally occurring amino acid or dipeptides thereof, a groi ⁇ 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, C .4 alkyl and C .
  • R and R* are independently selected firom the group consisting of hydrogen, C j .4 alkyl, C2.4 alkene, C j .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, C j _4 alkyl, and C j _4 acyl, said heterocycle being optionally substituted by C j .4 alkyl, C _4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-substituted by C .4 alkyl, C j _4 acyl and trifluoroacyl; methoxy, cyano, C j .4 acetate, C .4 acetyl and a groi ⁇ of the formula
  • Y is selected firom the groi ⁇ consisting of oxygen, sulfur, and CH2 :
  • R and RJQ are independently selected from the groi ⁇ consisting of hydrogen, fluorine, and iodine.
  • Rjl is selected firom 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)JJCH(OR)2 wherein R is selected from the group consisting of C j _4 alkyl, C j _4 acyl or C7 radicalg aroyl and wherein n is 2 to 5, chloroalkylnitrosoureido of the formula NH(CO)N(NO)(CH2) n CH2Cl wherein n is 0 to 4, NH(CH2) CH(OAc)
  • 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 _4 alkyl, and C j _4 acyl, said heterocycle being optionally substituted by C j _4 alkyl, C j _4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di- ⁇ ub ⁇ tituted by C j .4 alkyl, C j .4 acyl and trifluoroacyl.
  • a still further preferred compound of formula (12) are those wherein Xj and X2 are both oxygen; X is 0, S or SO;
  • X4 is selected from the groi ⁇ consisting of N, or CQ;
  • Rj, R2, R3 and Q are each independently selected from the groi ⁇ consisting of hydrogen, fluorine, and hydroxyl, and methoxy.
  • Z is one of C-Rg or C-R7.
  • R7 is selected from the group consisting of hydrogen, fluorine, methyl, and cyano;
  • R5 and Rg are independently selected from the groi ⁇ consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl, and a saccharide ofthe formula
  • SUBSTIT EET wherein Y is selected from oxygen and CH2, and wherein R9 and RJQ are independently selected firom the groi ⁇ consisting of hydrogen, fluorine, and iodine.
  • Rjl 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 groi ⁇ consisting of methyl, acyl or benzoyl and wherein n is 3 to 5, chloroalkylnitrosoureido of the formula NH CO)N(NO)(CH2) Q CH2C1 wherein n is 0 to 4, and NH(CH 2 )OCH 2 CH(OA c )2
  • R 2 ⁇ s hydroxyl,iodine, or bromine.
  • Still further preferred compounds of formula (12) are those wherein
  • X and X2 are both oxygen.
  • X3 is O or S.
  • X 4 is CQ.
  • R2 and R3 are both hydrogen.
  • R j and Q are independently selected firom the group consisting of hydrogen, fluorine, and hydroxyl.
  • Z is one of C-Rg or C-R7.
  • Rg is selected from the groi ⁇ consisting of ethyl, hydroxymethyl,
  • R7 is selected firom the group consisting of hydrogen, methyl, or fluorine
  • R5 and Rg are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and a saccharide of the formula
  • R and RJQ are independently selected from the groi ⁇ consisting of hydrogen, fluorine, and iodine.
  • Rjj is selected firom the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino;
  • R]2 is selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine, with the proviso that at least one of R5 and Rg is saccharide.
  • the invention also seeks to provide a process for the preparation of a compound of formula ,
  • X3 is selected firom the groi ⁇ consisting NR, 0, or S, Rg is methyl ketone or is as defined in claim 1; and R , R2, R3, R5, Rg, R7, Rg, X , 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
  • L is a leaving group selected firom the groi ⁇ consisting of halogen, tosyl, benzoyl, p- nitrobenzoyl and -OR or -SR, wherein R is selected firom the groi ⁇ consisting of hydrogen, C j . g alkyl, Cl-16 "c l* Ci-16 "y-' ⁇ 3-16 alkyh ⁇ h e* Cg.jg alkylaryl silane and dimethylamino, wherein R j , R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula
  • step (I) (1) wherein R5 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, ⁇ 1-16 " ⁇ ⁇ ⁇ 7-16 " ⁇ and L is defined as above; to yield a tricyclic saccharide of formula
  • 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;
  • A is NR wherein R is selected from the group consisting of H, C j . j g alkyl, C7. 6 aryl, and L is a leaving group as defined in (I)(2): to yield an anthracenedione of formula
  • the resultant compound may optionally be converted to the hydroxyl form of formula
  • the quinones at positions X and X2 may be converted to other moities such as, for exa ⁇ le,
  • the compound may further be optionally coupled with a saccharide of formula 20 to yield the
  • 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 groi ⁇ s 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.
  • halo substituent such
  • cycloalkyl as used herein means a cycloalkyl groi ⁇ 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 _4 alkyl, halogen, C _4 alkoxy, hydroxy or nitro.
  • halogen as used herein means chlorine, bromine, fluorine or iodine.
  • aralkyl refers to alkyl groi ⁇ s as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and triphenylmethyl.
  • aroyl refers to a groi ⁇ of the formula -COAr wherein Ar denotes an "aryl” group as defined above.
  • alkoxy or "a alkoxy” 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 exan ⁇ le methoxymethyl.
  • aryloxyalkyl as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for exan ⁇ le 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 j .g acyl group linked to an alkyl groi ⁇ 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 groi ⁇ as discussed above, for example, hydroxymethyl.
  • This invention also includes all the possible isomers and mixtures thereof, including diastereoi8omeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centos, when pertinent, at C j , 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.
  • new or known isochromans of formula _ __ where R5 is not a saccharide (PCT CA 9100208)
  • an oxidant such as eerie ammonium nitrate or- silver oxide in an adequate solvent mixture such as acetonitrile-water
  • isochromandiones of formula 15 Cycloaddition of this latter quinone with diene ⁇ of general formula J6 in a solvent such as toluene can give the tricyclic heteronaphthoquinone of formula 2.
  • two independent synthetic routes (A2 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 exa ⁇ le a C j . j g alkyl groi ⁇ such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as a C j . j g acyl groi ⁇ such.
  • R is an unsubstituted or substituted aryl groi ⁇ or R is a C3 to CJQ trialkyl silyl such as trimethylsilyl or dimethyl-t-butylsilyl.
  • Such sugars are obtained by derivatizing known saccharides of the family of
  • TITUTE SHEET. of formula _19 can be obtained via route B2 by reacting isochromans of formula J4 with a saccharide of formula 2Q 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.
  • 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 groi ⁇ s such as benzyl may be cleaved, for example, by treatment with BF3tetherate and acetic anhydride followed by removal of acetate groi ⁇ s.
  • 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 die final product or by stereo ⁇ pecific 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.
  • the invention therefore provides pharmaceutical compositions primarily suitable for use as antitumor and anticancer agents, co ⁇ rising 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 HC1 and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
  • 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
  • N-alkyl-N-nitrosoureas e.g. ca ⁇ nustine, 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 pho ⁇ phoramide mustards (e.g. cyclophosphamide); urethane and hydantoin mustards
  • Antimetabolite ⁇ 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;
  • Intercalators such as: bleomycins and related glycoproteins; anthracylines (e.g. doxombicin, daunorubicin, epir ⁇ bicin, esorubicin, idambicin,
  • acridities e.g. m-AMSA
  • hycanthones e.g. hycanthones
  • ellipticines e.g. 9-hydroxyellipticine
  • 5 actinomycins e.g. actinocin
  • anth aquinones e.g. l,4-bis[(aminoalkyl)- amino]-9,10-anthracenediones
  • anthracene derivatives e.g. pseudourea and bisanthrene
  • phleomycins 10 aureolic acids (e.g. mithramycin and olivomycin);
  • Ca ⁇ tothecins e.g. topotecan
  • Mitotic inhibitors such as: dimeric catharanthus alkaloids
  • etoposide and teniposide maytansinoids (e.g. maytansine and colubrinol); terpenes (e.g. helenalin, tripdiolide and taxol); 2.0 steroids (e.g. 4 ⁇ -hyroxywithanolide E); quassiniods (e.g. bniceantin); pipobroman; methylglyoxals (e.g. methylglyoxalbis-(thiosemicarbazone);
  • maytansinoids e.g. maytansine and colubrinol
  • terpenes e.g. helenalin, tripdiolide and taxol
  • 2.0 steroids e.g. 4 ⁇ -hyroxywithanolide E
  • quassiniods e.g. bniceantin
  • pipobroman methylglyoxals (e.g. methylglyoxalbis-(
  • Hormones e.g. estrogens, androgens, tamoxifen, nafoxidine, progesterone, 25 glucocorticoids, mitotane, prolactin;
  • Drug-resistance reversal compounds such as P-glycoprotein inhibitors, for exan ⁇ le Verapamil, cyclosporin-c, fujimycin;
  • Cytotoxic cells such as lymphol ⁇ ne activated killer -cells or T-cells, 13) Other tmm ⁇ n_ ⁇ __rim ⁇ i_ ⁇ h 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 co ⁇ ound 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 carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol for exa ⁇ le, chremc ⁇ hor-EL, tween
  • glycerol dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils.
  • DMSO dimethyl sulfoxide
  • propylene glycol propylene glycol
  • 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
  • SUBSTITUTE SHEET required other ingredients from those enumerated above.
  • 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.
  • 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 sub ⁇ tances 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 the ⁇ eutic 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 cm (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 do ⁇ ages, 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
  • 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 g., 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 the ⁇ eutic 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.
  • Step l Monob ⁇ imomeihyl (5,8-dimetlMxy-3,4-dihydrobenzo [2 ⁇ -C] pyran-3-yl) ketone
  • Example 4 Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphto[2,3-C] pyran-3-yl) ketone.
  • TMSOTf trimethyl silyl triflate
  • Step 5 (1'S,1S,3R)-Methyl (5,10-dioxo-l-(2 , ⁇ 6 , -trideoxy-3 , -trifluoroacetamido-4'- hydroxy-L-iyxohexopyranose)-3,4 ⁇ , 10-tetrahydronaphtho [23-C] pyran-3-yl) ketone BCH-1146
  • the titled compound was prepared in 62% yield by cyclocondensing the l'S, IR, 3S-quinone glycoside from step 1 of this exa ⁇ le with l-methoxy-3-trimethylsilyloxybutadiene. The same procedure as described in step 2, in this example, was used.
  • the titled co ⁇ ound was prepared by applying the same procedure as described in step 8 on the l'S, IS, 3R, quinone glycoside of step 1 of this example.
  • Step 9 (1'S,1S R)-Methyl (5,l ⁇ -dioxo-l-(2 , 3 ⁇ 6 , -trideoxy-3 , -trifluoroac£tamido-L- lyxohexopyrano6e)-7-hydroxy-3,4,5, 10-tetrahydro [2,3-C] pyran-3-yl) ketone BCH-1180
  • Example 6 Tricyclic pyranyinap thoquinones with a squaric acid moiety.
  • Step 3 2-[4 , -Hydroxy-l , 3 , -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 (l'-S, 1-R, 3-S)-l-(2'-3'-6 , -trideoxy-4 ⁇ p-nitrobe_n ⁇
  • Step 2 (l'S,l-R S)-l-(2 , ⁇ 6 , -trickoxy ⁇ *-p-nitrobenzoyI-3'-trinuoroa_»t ⁇ 5 lyxohexopyraiM)_%)-3-(2-aza-3-aminot_ ⁇ naphtho-(2 -c)p ran
  • 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 (l'S,l-R3-S)-l-(2 , ,3S6 ⁇ -trideoxy-3 t -tiifliion ⁇ lyxong»opyranose)-3-(2-aza-3-arrtamidotl__iazo ⁇ lH-naphtho-[2,3-c]-pyran
  • 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 (l'-S,l-R3-S)-l-(2 , ,3 6 l -tride ⁇ xy-3 l -trifluoro acetamido-L-lyxohexopyra ⁇ ose)-3-(2-aza-3- aceta ⁇ o thiazDlyl)-5,10-di ⁇ xo-3,4,5,10-tetrahy
  • 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 (l'-Sjl-R ⁇ -H ⁇ ' ⁇ '. ⁇ '-trideoxy-S'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5, 0-dioxo-3,4 ⁇ ,10-tet_rahydro-lH-naphtho-[2 -C] pyran
  • a sample of PNB-derivative (2.5 mg, 3.5 ⁇ mol) from step 2 dissolved in a tri-solvent system containing water (85.7 ⁇ l), methanol (370 ⁇ l) and methylene chloride (138 ⁇ l), at 0°C, was added a solution of sodium bicarbonate (0.66 mg, 7.0 ⁇ mol, in 30 ⁇ l of water).
  • 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 (r-S.l-S ⁇ RH- ⁇ ' ⁇ '- ⁇ '-tri eoxy- ⁇ - -mtrxibe ⁇ lyxohexopy ⁇ uM ⁇ e)-3-(2-bromoacetyl)-5,10-t ⁇ [2,3-c]-pyran
  • Step 2 (l , -S,l-S -R)-l-(2 , '-6'-trideoxy ⁇ , -0-p-nitrobenzoyl-3 , -trin ⁇ MOacetamid - ⁇ lyxohexopyranose)-3-(2-aza-3-acetamido)-5,10-dioxo-3,4,5,l( ⁇ tet ⁇ A naphtho-[2,3-c]-pyran
  • Step 3 (l , -S,l-S -R)-l-(2 , ⁇ , ,6 , -trideoxy-3'-trifluoro ac*tamido-L-lyxohexopyranose)-3-(2-a_a-3- accta____ ⁇ do-tl ⁇ a_raiy0-5,10-di ⁇ xo-3,4 ,10 ⁇
  • 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).
  • Step 2 (1'S,1S,3R) and (1'S,1R S) methyl (l- ⁇ ' ⁇ f'-trideoxy ⁇ '-tifflimroacet ⁇ trobe__ ⁇ _ ⁇ yl-L-lyxohexo-pyranose]-5,10- ⁇ naphtho [2,3-c] pyran-3-yl ketone
  • Step 3 (1'S,1S,3R) and (1'S,1R,3S) methyl-l-(2 , ⁇ 6'-trit oxy-3 , -trinuoroac ⁇ ta ⁇ dt l'-h.vdroxy- L-lyxohexopyra__ ⁇ ose)-5,10-dkno-3,4,5,10-tet_r ⁇ [2,3- c] pyran-3-yl ketone
  • Step 3 3-Ethyl-l-hydroxy-isofhroman-5,8-dione.
  • the first one (48 mg, 14% overall) contained a 2:1 mixture favoring die (l'S, lS,3S)-5,10-dioxo-3-ed ⁇ yl-l-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-___ ⁇ lyoxobexopy ⁇ anose)-3,4,5,10-tetrahydro-lH ___ ⁇ htho [2,3-C] pyran over its (l'S, IR, 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.
  • a 2:1 mixture favoring die (l'S, lS,3S)-5,10-dioxo-3-ed ⁇ yl-l-(2',3',4',6'- tetradeoxy-3',4'-di
  • Step 2 Trans-3-aceto-l,5,8-trimethoxythioisoc__ ⁇ _ro ⁇ an and cis-3-ace ⁇ o-l ⁇ ,8-tri ⁇ etlH>xythioisochro ⁇ __an
  • Step 4 T ⁇ uB-3-aceto-l-methoxy-l,2,3,4-tetrahydro-(2-su__fur)m ⁇ and ds-3- aceto-l-methoxy-l ⁇ ,4-tetrahydro-(2-s ⁇ dfur)anthrace ⁇ e-5,10-d ⁇
  • Trans-3-aceto-l-methoxy-5,8-dioxoisothiochroman (0.66 mmole) was dissolved in dry toluene (14ml), followed by the addition of die diene (120.0 mg, 1.07 mmole). The resulting mixture was stirred at room temperature overnight. Solvent was removed and die crude obtained was flash chromatographed using pure toluene to give the tided compounds in a ratio of about 1:1, in 48% yield.
  • Step 5 cis-3-aceto-l-methoxy-5,8-dioxoisot__ ⁇ ochroman
  • Step 6 ⁇ s-3-aceto-l-methoxy-l,2,3,4-tet__ ⁇ ydro-(2- ⁇ _lfur) anthracene-5,10-dione and trans-3- aceto-l-metboxy-1 ⁇ > 4-tetrahydro-(2-sulfur) anthracene-S,10-dione
  • Step 7 tra ⁇ __s-3-aceto-l-hydroxy-l ⁇ r ⁇ » 4-tet_rahyd_ro-(2-sulfur) anthracene-5,10-dione and cis-3- aceto-l-hydroxy-1 ⁇ ,4-tetrahydro-(2-su__f ⁇ r) anthracene-5,10-dione
  • the mixture of compounds obtained from step 6 (exa ⁇ le 13) (30.8 mg, 0.102 mmole) was dissolved in
  • Step 3 (l'S,U S) and (1'S,1S,3R) methyl 4',6'-tetradeoxy-3',4'- diacetoxy-I ⁇ yxohexopyranose)-3,4 ⁇ ,10-tetrahydronaphtho [2,3-c] thiopyran-3-yl) ketone
  • step 1 The procedure for the preparation of the tided compound is as described previously in step 1 (example 1).
  • 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 con ⁇ ounds towards tumor cells is measured in vitro using die 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 fo ⁇ nazan product.
  • tissue Culture (Irvine Scientific Catalog)
  • T47D Ductal carcinoma of breast
  • ATCC catalog ft HTB-133.
  • HT 29 Cold 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;
  • SHEET MTT 2 mg/ml in phosphate buffered saline (stable at 4°C in dark for 1 week).
  • Sorensen's buffer 0. IM glycine/NaOH, pH 10.5, containing 0. IM NaCl.
  • Test co ⁇ ounds 20 mM in DMSO and diluted to a final concentration of 200 ⁇ M in culture medium before use.
  • die assay metiiod The following is the generic description of die assay metiiod. - It should be noted that although die conditions described work well with die cells listed above, the initial plating density and die MTT concentration used should be verified for each new cell line used to test compounds.
  • 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 die following manner
  • the assays are carried out in 96-well (8 well x 12 well) microtiter plates. Serial dilutions of die compound are tested along the length of die plate. A 1:3 serial dilution of co ⁇ ound 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 aftw which die co ⁇ ound 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 die 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 die 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 die 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 multid ⁇ ig resistant cell line SKVLB. In breast cancer, MCF- 7, BCH-1146 is less potent than adriamycin but nearly as effective in die sensitive and adriamycin resistant cell line. These results suggest that tricyclic derivatives such as BCH-1184 and 1146 should be
  • Step l Methyl (l,5,8-trimethoxyisoch ⁇ )n ⁇ 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 die filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml).
  • Step 2 Methyl (l-Metlr ⁇ xy-5,8-diox ⁇ -5,8-dihyd ⁇ >-isochronuu ⁇ -3-yl) formate
  • Step 3 Methyl (l-n__ethoxy-5,10-dioxcH3,4 ⁇ ,10-tet_rahydro-m-naphthot2 -c]p formate
  • Methyl (l-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, die 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 (l-metlwxy-5,10-dioxo-5,10-dihydro-lH-naphtho[2 ⁇ -c]pvran-3-yl) formate
  • Step 5 Methyl (l-methoxy-5,10-dioxo-5,10 ⁇ hydro-_LH-naphtho[2 -c]pyran-3-yl)formate.
  • the reaction mixture was poured onto water (200 ml) and ethyl acetate(800 ml), then neutralized witii acetic acid.
  • the oiganic layer was separated, the water layer was extracted witii ethyl acetate (3x30 ml).
  • the combined organic layers were dried (MgSO ⁇ and concentrated to dryness.
  • dichlorometane(120 ml) and saturated sodium bicaibonate solution (40 ml) was added, stirred for 5 minutes. After separation die organic layer was dried (MgS0 ) and concentrated to diyness to give die tide product (8.98 g, 59.4 ).
  • Step 6 l-MetlMxy-5,10-dioxo-5,10-dihyd_r >-lH-napht_M ⁇ add
  • the crystals formed were filtered and washed with water.
  • the filtrate was extracted with ethyl acetate (4x40 ml). All the oiganic fractions - including die previous extractions as well - were combined, dried (MgSO ⁇ and concentrated to dryness.
  • the residue was combined witii 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 l-Methoxy-5,10-diox(H5,l(l-dihydro-lH-naphtbo[2 -c]pyran-3-IN-(3- d ⁇ n_ethylan__ino-propyl)carboxamide]
  • Step 8 l-Methoxy-5,10-dioxo-5,10-dihydro-m-naphtho[23-c]pyran-3- ⁇ N-(3- dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
  • Step 2 (1S ⁇ 'S3R,5'S) and (lR ⁇ 'S ⁇ S.S'Sl-l-fO-N-BOC-Serine-Leucine-Me ester]-3- aceto-5,8-dime ⁇ )xy-isochroman
  • Step 3 (lS ⁇ 'S ⁇ S ⁇ 'Sl-Methyl ⁇ l-O-IN-BOC-Serine-I ⁇ ucine-Me esterl-SJO-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 die 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 2 (IS, 2'S, 3R) and (IR, 2'S, 3S)-H -serine methyl ester]-3-aceto-5,8-dimethoxy isochroman.
  • step 2 The tided 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 (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyI-(l-[0-N-BOC- ⁇ e_rine methyl ester]-5,10- dioxo-3,4,5,10-tetrahydro-l-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 (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyl-(H - ⁇ eri ⁇ e methyl ester]-5,10-dioxo-
  • Step 2 (IS, 2'S, 3R) and (IR, 2'S, 3S)-HO-N-BOC-prolinol]-3-acetyl-5,8-dimethoxy isochroman
  • Step 3 (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyHl-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10- tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone BCH-2067
  • Step 4 (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyl-(HO-prolinol]-3,4,5,12-tetrahydronaphti ⁇ >-
  • step 2 To a stirred solution of AICI3 (1.39 g, 10.4 mmol) and TMS-CN (1.4 ml, 10.4 mmol) in CH 2 C1 2 (40 ml) at -78°C under argon was added die pyranylsulfone from step 1 (example 2) (1.16 g, 3.5 mmol) then the temperature was slowly raised to -20°C. After 4 hours, die reaction mixture was worked up in methylene chloride and water. The organic layer was washed with brine and dried over MgS0 4 . The solvent was evaporated and die residue was purified by flash chromatography (hexanes/AcOEt 3/1) to give the tided compound (596 mg, 78 %).
  • Step 3 l-hydroxy-3-cyano-5,8-dimetboxy isochroman
  • Step 4 l-hydraxy-3-cyan ⁇ >-5,8-dioxo-5,8-dihydroisochroman
  • the tided 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 (l'S, IS, 3R) and (l'S, IR, 3S)-5,10-dioxo-3-cyano-l-(2 , ',6',- trideoxy-3'-trifluoroacrtamido-4'-Q-p-nitrobenzoyl-L- lyxohexopyranose)-3,4 ⁇ ,10-tetrahydro-l-H-naphtho-[2 ⁇ -c] pyran
  • the tided compounds were obtained in 27 % yield by following die procedure described in step 4, example 12, on die precursor of step 4 of this example.
  • Step 7 (l'-S, 1-R, 3-S) and (l'-S, 1-S, 3-R)-3 ⁇ cyano-l-[2 , ⁇ ',6 , -trideoxy-3'- trifluoroaceta ⁇ __tido-4 , -hyd_n_ ⁇ y-I_f-l ⁇ tetrahydronaphtho-[2 -C] pyran-3-yl BCH-1688
  • Step 1 3,4-dimethoxy-L-fucal, and 3-methoxy-L-fucal
  • Step 3 1-t-Butyl dimc ⁇ ylsUyk>xy-3-trifluo ⁇ arrtamido-4-n_ «tha ⁇ _ ⁇ ulfonyl-2 ⁇ ,6 ⁇ trideoxy-
  • Step 4 1-t-Butyl dimethylsUyioxy-3-trifluoroacetamido-4-0-bromoac ⁇ l-2 > 6-trideoxy- ⁇ lyxohexopyranose
  • Step l (l'-S, 1-S, 3-R) and (l'-S, 1-R, 3-S)-methyl-(l-[2' ⁇ ',4 , ,6 l tetradeoxy-3'- t_rifluoroarrtamido-4'-Q-methane-s ⁇ _Jfonyl-L-lyxohexopyra__ ⁇ 3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2095
  • the tided 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).
  • Step 2 (l'-S, 1-S, tetra ⁇ eoxy-3 , -trifliMroacetamido-4'-0-(2- bromo-acetyl)-L-lyxopyranose]-5, lO-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2105
  • Step 3 (l'-S, 1-R, 3-S)-methyMl-[2',3',4',6' tetradeoxy-3'-methoxy-4'-0- methanesu__fonyl-Lr4yxobexopyranose)-5,10-dioxo-3 > 4 ⁇ ,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 exa ⁇ le 3 and die glycal from step 2, example 21. Purification was carried out by flash chromatography (toluene/acetone:95/5) M.P. 85-89°C.
  • Step 3 (l'-S, l'S, 3-R)-methyl-(l-[2' ⁇ ',4',6 l tetradeoxy-3'-methoxy-
  • Step 3 5,tM>imet mxy-3-(propane-2-o ⁇ _e)-l-(2',3',6 ⁇ nitrobenzoyl-L-lyxohexopyronose)-isoc__ ⁇ roman
  • 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-Dk>xo-3-(propane-2s)ne)-l-(2' ⁇ ',6 l -trideoxy-3 , -trifl ⁇ oroaceta ⁇ nid mtrobenzoyl-L4vxohexopy ⁇ anose)-isochroman
  • Step 5 5,10-Dioxo-3-(p ⁇ a__ ⁇ e-2-one)-l-(2',3',6'-tri ⁇ mtrobenzoyl-L-lyxohexopy ⁇ uM)se)-3,4 ,10-t ⁇
  • the tided 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.
  • Step 6 (l'-S, 1-S, 3-R) and (l'-S, 1-R, 3-S)-l- ⁇ 6-h dro -l-(2 , ⁇ , , , -trideox -3 , - trifluoroa « ⁇ amido,4-hydroxy-Lr-lyxopyranose)-5,10-dioxo-3,4 ⁇ ,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) propane-2-one BCH-2098
  • the tided compound was obtained following deprotection of die glyco ⁇ ide from step 5 herein as per procedure described in step 6, example 34.
  • Step l (IR, 3S) and (1-S, 3R)-l-(2' ⁇ ',6'-trideoxy-3'-trifluoroacetamid ⁇ H4 , -0-p- nitrobenzyk>xy-l,5-dihyd ⁇ >-L-l ⁇ acetoisochroman
  • Step 2 dihydro-Lr-lyxohexopyraiMi8e-2-yl)-S,8-dioxoisochroman
  • Step 3 (IR, 3S)-l-(2' ⁇ 6'-trideoxy-3 , -trifluoroac*tan ⁇ do-4 , -0-p-nitroben_ ⁇ dihydro- -lyx(>l_-exopyranos 2-yl)-5,lQ ⁇ [2,3-c] pyran
  • the quinone firom step 2 herein was cycloadded with 1 -acetoxybutadiene as per procedure from step 4, exa ⁇ le 12.
  • the product had:
  • Step 4 (IR, 3S)-l-(2 , r 3S6 , -tricteo. ⁇ y-3 , -t_rifl ⁇ _ ⁇ oroace u ⁇ lyxobcxopyrano6e-2-yl)-5,10-dioxo-3,4,5,10 ⁇ etrah ⁇ pyran
  • Step 6 (IS, 3R)-l-(2' r 3 '-trid_». ⁇ y-3 , -trifluoroace ⁇ dihydro-L-lyxob£xopyrano6e-2-yl)-5,10-dioxo ⁇
  • Step 7 (IS, SRH-P' ⁇ C'-trideox ⁇ '-trifluoroa eta ⁇ lyxohexopy ⁇ uM6e-2-yl)-5,10-dioxo-3,4,5,lQ-tet ⁇
  • Example 25 Preparation of 3 -bis-(methoxycari ⁇ myl)-5,10-dioxo-3,4 ,10-tetrahydro- lH-naphtho-[2,3-c]-pyran (BCH-1665)
  • Step 2 5,8-dioxo-3,3 bis ( ⁇ m4__Mxycarhonyl)-5,8-dihydro-isod ⁇ ron ⁇ an
  • Step 3 (l'S, IR, 3S)-5,8-dk ⁇ o-3-me-thoxy ⁇ H ⁇ yl ⁇ trifluoroacetamido- ⁇ -O-p-mtroben ⁇ yl-U dihydroisochroman and its (l'S, IS, 3R) diastereomer
  • the second diastereomer: (l'S, IS, 3R)-5,10-dioxo-3-m ⁇ _ ⁇ hoxymethyl-l- ⁇ 2 3 ⁇ 6 , -trideoxy-3 , -trifluoro ⁇ cetamido-4'-0 ⁇ mtrobenzoyl-_Wyxohexo-pynux>ee)-3,4,5,10-*etr ⁇ pyran was obtained in 19% yield and had:
  • Step 5 (l'S, IR, 3S)-5,10-d »xo-3-roetl »xy ⁇ ethyl-l-(2 , 6 , -t_rideoxy-3 l - trifluoroacetamido-L-lyxohexopyra__ ⁇ ose)-3,4,5,l( pyran (BCH-1691)
  • Step 6 (l'S, IS, 3R)-5,10-doxo-3- ⁇ nedM ⁇ m_ ⁇ yl-l-(2 , 3 6 , -trideox -3 , - pyran (BCH-1693)
  • 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 CH 2 C1 . The combined organic layers were dried over Na 2 S0 4 , filtered and the solvent was removed. The crude material was purified by flash chromatog ⁇ hy with hexanes- ethyl acetate (9: 1) then (8:2) as the eluent. The isolated titled compound was a white solid (11.4 g, 75%).
  • Step 3 (l'S, IR, 3R)-5,8-dimethoxy-3-e_ l-l-(2',3',6'-tri 0-p-nitrobenzoyl-L-lyxohexopyra )se)-isochroman
  • step 3 Application of the first part of die procedure described in step 3, example 26, on the isochroman precursor from step 2 herein resulted witii die tided compound as a yellow solid; 62%.
  • Step 5 (l'S, IR, 3R)-5,10-dioxo-3- €thyl-l-(2',3',6'-trideoxy-3'-trffluora mtroben ⁇ yl-_---4] ⁇ cohecopyra__ ⁇
  • 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 (l'S, IR, 3R)-5,10-dioxo-3-ethyl-l-(2 , ⁇ 6 , -trideoxy-3 , -trinuoroacetamido-L- lyxohexopyranc ⁇ e)-3,4 ⁇ ,10 ⁇ etrahydro-lH- ⁇ __apht__ ⁇ o-[2 ⁇ -c] pyran (BCH-2026)
  • the titled compound was in 64 % yield from the glycoside of step 5 of this exa ⁇ le as per procedure described in step 5 of exa ⁇ le 26.
  • Step 8 (l'S, IS, 3S)-5,10-dio ⁇ t H3-ethyl-l-(2 , ⁇ 6'-trid_»xy ⁇ mtroben ⁇ yl-L-lyxobrao-pyrano6e)-3,4,5,10-te ⁇
  • Step 9 (l'S, IS, 3S)-5,10-dioxo-3He yl-l-(2',3',6'-tride ⁇ lyxob «opyrano6e)-3,4 ,10-tetrahyd ⁇ m4iapht__ ⁇ o-[2 ]-pyran (BCH-2020)
  • Step 10 (l'S, IS, 3S)-5,10-dioxo-3-emyl-l-(2' ⁇ ',6'-trio ⁇ oxy-3'-a ⁇ m ⁇ o-Uyxohexopyra ⁇
  • Example 28 Preparation of tra ⁇ -5,10 d ⁇ xo-l-acetamido-3-ethyl-3,4 ⁇ ,10-tetrahydro- lH-naphtho-[2 -c]-pyran: (BCH-2027) and 3-ethyl-5,10-dioxo-3,4,5,10- tetrahydro-lH-naphtho-[23-c] ⁇ *yran: (BCH-2154)
  • Step 1 (trans)-l-acetamidc-5,8-dtoxo-3-ethyl-5,8-dihydn>-is ⁇
  • Step 4 3-eUiyI-5,10-dioxo-3,4 ⁇ ,l( etrahydn>-lH-naphtho- ⁇ 2 -c] pyran
  • step 3 the starting quinone from step 3 herein (250 g; 1.30 mmol) and l-acetoxy-l,3-butadiene (876 ⁇ l; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2 % ethyl acetate in toluene the tide compound (62 mg; 20 %) along with mixed fractions containing a lot of desired tided product (230 mg), M.P.: 98-101°C.
  • Step l 3-isopropyl-5,8-dunetboxy-isochn_a__an
  • Step 2 (l'S, IR, 3S) and (l'S, IS, 3R)-5,8-dioxo-3-isopropyl-l-(2 , ⁇ , ,6 , -trideoxy-3'- trifluoroacetamido ⁇ '-O-p-nitrobenzoyl-Lrlyxohex 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 witii CAN as described in step 3, example 26, to afford a diastereomeric tide quinones mixture (450 mg; 59 %) in a ratio of (40:60) favoring the l'S, IS, 3R isomer which were used as such for the next reactions.
  • Step 3 (l'S, IS, 3R)-5,10 ⁇ oxo-3-i propyI-l-(2 , r 3 ⁇ 6 , -trideoxy-3 , -t ⁇
  • step 2 the starting quinone mixture from step 2 herein (100 mg; .167 mmol) was treated with l-acetoxy-l,3-butadiene (112 ⁇ l; 1 mmol) in 5 ml of toluene to afford the tide compound (34 mg pure + 9 mg of 1:1 mixture of diastereomers).
  • Step 4 (l'S, IR, 3S)-5,10-clk ⁇ o-3-i_»propyl-l-(2',3 , ,6'-tf ⁇
  • 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 con ⁇ ound (5 mg; 59%), M.P.: 180-185°C.
  • Step 5 (l'S, IS, 3R)-5,10-dr ⁇ xo-3-isopropyl-l-(2' ⁇ 6'-trideo. ⁇ lyxc»l_ «opyranose)-3,4 ⁇ ,10-tetrahydro-m-naph__ho-[2 -c]-pyran (BCH-2052)
  • step 5 the starting protected alcohol from step 3 herein (32 g; .0495 mmol) afforded after flash chromatography using 7% acetone in benzene as eluent, a gummy product which was dissolved in dichloromethane and precipitated witii pentane yielding the title product

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

ANT1 EOPLASΗC 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., Saroβy, 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).
(1) daunorubicin R = H
(2) doxombicin R = OH
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 m: Recent Advances, Chapman and Hall, New York 1987; Anthncyclines: 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:
FIG. l
Tricyclic variants ) of daunonibicin have been reported to possess antitumor activity (EPA 91202015.3)
3 2 R is COCH3 or C_CH or C_C-Si(CH3)3 R3 is H or COCF3
Pynnonaphthoquinones such as nanaomycin A (___) and kalafungin © 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., ___%, 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).
11
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 doxorabicϊn-reβistant 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):
12
wherein
X j and X2 are independently selected from the groiφ consisting of
O, S, and N(R), wherein R is selected from the groiφ consisting of hydrogen, hydroxyl, C^.jg alkyl, Cι_i acyl and Cj.jg 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,
TIT TE SHEET cl-16 ∞y1' cl-16 -~-Υ-> cl-16 "y1' cl-16 haloacyl, and hydrogen. is selected from the group consisting of C-Q, nitrogen, and NO. Rj, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, Cj_ g alkyl, C . g alkoxyl, C _ cycloalkyl, tosyl, mesylate, acetate optionally substituted with a Cj_ g alkyl, triflate, trifiuoroacetate, halogen, nitro, cyano, Cj. g acyl, Cj. g arylacyl, aminoalkylaminoalcohol of formula NH(CH2)nNH(CH2)|nOH wherein n and m are independently 1 to 4, aminnaHrylnminn_ιHrylha1iA». 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-βubstituted by C _g alkyl, C3_g cycloalkyl, Cj_g acyl, trifluoroacyl, C .^g aralkyl and C$_ g aryl; C2_g alkenyl, and C^. alkynyl, haloalkylnitrosoureido of the formula NH(CO)N(NO) (CH^ 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, C _g alkyl, Cg.jg aryl, C/.j aralkyl, Cj.g acyl, and trifluoroacyl, a groiφ of the formula -0-C(R)=0 wherein R is selected from the group consisting of hydrogen, Cj. g alkyl, C3. cycloalkyl, C2.12 alkoxyalkyl, C .j aralkyl, C7.jg araloxyalkyl, C7_j aryloxyalkyl and
Cδ-iβ «y
Z is one of C-Rg or C-R7. Rg is selected from the group consisting of Cj. g hydroxime, Cg_ g hydraztme, Cj.jg hydroxyalkyl, hydrogen, Cg_18 aryl, C7_18 aryloxyalkyl, C^.j araloxyalkyl, phenyl, Cj.jg alkyl, acetoxy, Cj.jg dihydroxyalkyl, C^. alkenyl, Cj. alkynyl, C _ cycloalkyl, squaric acid, Cj.jg alkyl squarate, amino, cyano, dimethylpbosphonato, phenyl sulfone, C _g aryl sulfone, and
Cj.g 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 Cl-8 alkyl, C2-8 alkenyl, C7-18 aralkyl, and O, or its dioxolane or dioxane or dialkoxy Cl-8 ketal, and wherein R is selected from the group consisting of hydrogen, Cj.jg alkyl, Cj.g thioalkyl, C3_ cycloalkyl, Cg_jg aryl, C .j aralkyl, fluoromethyl, difluoromethyl, Cj.g hydroxyalkyl, C2.16 alkene, squaric acid, C^.jg alkyne, Cj.g thioalkyl, Cg_ g thioaryl, Cj_4 alkyl squarate, C2_g alkoxyalkyl, Cg.|g araloxyalkyl, C2_j acyloxyalkyl, Cj.g alkoxy, hydroxy, acetoxy methyl, bromomethyl, Cj.g aceto, amino which may be unsubstituted or mono- or di- substituted by hydrogen, Cj.g alkyl, C3_g cycloalkyl, Cj.g acyl, trifluoroacyl, C .- - aralkyl, Cg_ g aryl, a group of the formula -CHR* R**, wherein R* and R** are independently selected from the group consisting of Cj.g alkyl, hydrogen, PO (OR>2 wherein R is selected from the group consisting of hydrogen, Cj.g alkyl, Cj.g acyl, Cg. g aryl, Gy.jg aralkyl, and a group of the formula -(CΑ^Z* wherein n is O to 7 and Z* is from the group consisting of hydrogen, C .g acyl, Cg_jg aryl, C . g 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 groiφ consisting of
5
SUBSTIT SHEET hydrogen, hydroxyl, C .g acyl, C ^ alkyl and Cg_j2 aryl; said heterocycle being optionally substituted with one or more halogens, hydroxy, Cg_jg aryl sulfone, Cj.jg alkoxy, Cj.jg alkyl, nitro, Cj.jg hydroxyalkyl, amino, which may be unsubstituted or mono- or di-substituted by C .g alkyl, C3_ cycloalkyl, C .g acyl, trifluoroacyl, Oj.is aralkyl, C . atyl, C2. alkenyl, C2. alkynyl and hydroxy.
Z* can also be a groiφ of the formula -NR* R** wherein R* and R** are independently selected from the group consisting of hydrogen, Cj.g alkyl, Cj.g acyl, Cg„18 aryl, Oy.jg aralkyl, C .g haloalkyl, Cj.g hydroxyalkyl, Cj.g alkoxyalkyl, Cj.g acyloxyalkyl, C _j2 araloxyalkyl, and a group of formula -COiCΑ^ C(PO(OR)2)2 wherein n is 1 to 4 and R is hydrogen or Cj.g alkyl; ami a naturally occurring amino acid; a group of the formula -C(OR)=0, where R is selected from the groiφ consisting of hydrogen, Cj.jg alkyl, C3_ cycloalkyl, C .g hydroxyalkyl, Cj.g alkoxyalkyl, C7_ aryloxyalkyl, Cg_ g araloxyalkyl, Cg_18 aryl and C7.jg aralkyl; a groiφ of the formula -(CΑ^ C(R)=0, wherein n is 1 to 6 and wherein R is selected from the groiφ consisting of hydrogen, hydroxyl, Cj.jg alkyl, C3. cycloalkyl, C .g hydroxyalkyl, ^.g alkoxyalkyl, Cj.g alkoxy, C7.18 aryloxyalkyl, C7.18 araloxyalkyl, Cg_18 aryl, C7.18 aralkyl, amino which may be unsubstituted, mono- or di-substituted by Cj.g alkyl, C3.g cycloalkyl, acyl, trifluoroacyl, C2-12 aralkyl, C2.12 *-7-> a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms selected from the groiφ consisting of O, S, N, SO, SO2, P, PO, and NR wherein R is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, Cj_4 alkyl and aryl, said heterocycle being optionally substituted with one or more halogens, Cg_ g arylsulfone, hydroxy, Cj.jg alkoxy, nitro, Cj.jg alkyl, Cj.jg hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by Cj.g alkyl, C3. cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; C^.g alkenyl, ^. alkynyl and hydroxy..
R7 is selected from the groiφ consisting of hydrogen, Cj.jg alkyl, halogen, amino, hydroxy, Cj.jg alkoxy, thiol, cyano, sulfide, acyl of the formula -C(R)=0 wherein R is selected from the groiφ consisting of hydrogen, Cj.jg alkyl, Cj.jg alkoxy, C3_8 cycloalkyl, Cj.g hydroxyalkyl, C-..^ araloxyalkyl, C^.g alkoxyalkyl, ^.g acyloxyalkyl, C _j2 aryloxyalkyl, squaric acid or squarate, amino which may be unsubstituted or mono- or di-substituted by Cj.g alkyl, C3_g cycloalkyl, Cj.g acyl, cyano, trifluoroacyl, C7.jg aralkyl or Cg. 2 aryl, and a naturally occuring amino acid; a group of the formula -C(OR)=0 wherein R is selected from the groiφ consisting of hydrogen, Cj.jg alkyl, C3.g cycloalkyl, Cj.g hydroxyalkyl, Crj.g alkoxyalkyl, C7. 2 aryloxyalkyl, C7.J2 araloxyalkyl, C .j2 aryl, C .jg aralkyl and Cj.jg alkenyl.
R5 and Rg are independently selected from the groiφ consisting of hydrogen, halogen, hydroxyl, Cj.jg alkoxyl, Cj.jg alkyl, ^.j acetylenyl, a groiφ 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 Cj.g alkyl, C .4 acyl, C3_ cycloalkyl, hydrogen, C2.g carboalkoxy, C2_ alk∞e, C^. alkyne, Cg. 2 aryl, and
SUBSTITUTE SHEET (OCH2CH(PO(OR)2)2 wherein R is a hydrogen or a C .g alkyl and wherein n is 0 to 5; C3_g cycloalkyl, C2_j alkenyl, Cj.jg alkoxyalkylamino, cyano; a groiφ of the formula -0-C(R)=0, wherein R is selected from the groiφ consisting of hydrogen, C j. g alkyl, C3_g cycloalkyl, C2. alkoxyalkyl, and C .j2 aryl; an acyl of the formula -C(R)=0, wherein R is selected from the groiφ consisting of hydrogen, thiol, C . g thioalkyl, Cj.jg alkyl, C3_g cycloalkyl, Cj.g hydroxyalkyl, ^ g alkoxyalkyl, C .J2 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 groiφ of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, Cj.jg alkyl and C3_g cycloalkyl, acoβamine, glucosamine, N-chloroethyl-nitrosoureidoglucosamine, 2,6- dideoxyrhamnose, thioglucose, thiodaunosamine, thiol, Cj. j2 thioalkyl, a naturally occuring amino acid or di- and tri-peptides thereof, a group ofthe formula -Z*-CHRR* wherein Z* is selected from the group consisting of O, CH2, NR** wherein R** is from the groiφ consisting of hydrogen, Cj.g alkyl, C^. acyl or Cg.12 aiyl,
R and R* are independently selected from the groiφ consisting of hydrogen, Cj.j2 alkyl, C .j2 aryl, C^.g dihydroxyalkyl, C^.g alkene, C2-g alkyne, Cj.g alkoxy, Cj.g alkylamino, C3_g cycloalkyl, ^.g carboalkoxy, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the groiφ consisting of O, S, N, SO, SO2, P, PO. and NR wherein R is selected from the groiφ consisting of hydrogen, hydroxyl, Cj.g acyl, Cj. 4 alkyl and C _j2 --Υ-. -*-- heterocycle being optionally substituted with one or more halogens, hydroxy, Cg_jg aryl sulfone, cyano Cj.jg alkoxy, Cj.jg alkyl, nitro, Cj.jg hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C .g alkyl, C3_g cycloalkyl, Cj.g acyl, trifluoroacyl, C7.ιg aralkyl, Cg.jg aryl, C2. alkenyl, ^. alkynyl and hydroxy; mono or oligosaccharides of the formula:
wherein Y is selected from the groiφ consisting of oxygen, sulfur, sulfoxide, sulfone, CR*R**, wherein R* and R** are independently selected from the group consisting of hydrogen, C .g alkyl, and NR wherein R is selected from the groiφ consisting of hydrogen, Cj.g alkyl, and Cj.g acyl. R and Rjg are independently selected from the group consisting of hydrogen, halogen, hydroxy,
IT TE SHEET acetoxy, Cj.jg alkoxy, Cj.jg alkyl, C . cycloalkyl, thiol, amino, trifluoroacetamido, chloroethylnitrosoureido, and chloroethylureido.
Rj is selected from the groiφ consisting of hydrogen, amino which may be unsubstituted or mono or di-substituted by C .g alkyl, C3_g cycloalkyl, C2. acyl, t-butylacyl, Cj.g alkoxy, t- butyloxycarbonyl, trifluoroacyl, C7.J2 aralkyl, C _j2 ***•> and a n»turally 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, Cj.jg alkoxyl, C3.g cycloalkyl, thiol, sulfide; a group of the formula NH(CH2)nCH(OR>2 wherein R is selected from the group consisting of Cj.jg alkyl, Cj.jg acyl and C7.jg aroyl and wherein n is 0 to 5. chloroalkylnitroβoureido of the formula NH(CO)N(NθχCH2)nCH2Cl wherein n is 0 to 4, and
NH(CH2)2 OCH2CH(OAc)2.
R^ is selected from the groiφ consisting of hydrogen, hydroxyl or its tetrahydropropyl ether (-OTHP), mesylate, tosylate, halogen, memo or bligosaccharides, Cj.g alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, Cj.jg alkoxy, C3_ cycloalkyl, C^.g haloalkylacetate, benzoate which may be unsubstituted or substituted with nitro, one of the groiφ consisting of p-nitrobenzoate, acetoxy, trifluoroacetoxy, chloroalkylnitro-βoureido of the formula NH(CO)N(NO)(CH2)nCH2Cl wherein n is 0 to 4, and NHiCHJ 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 groiφ consisting of hydrogen, hydroxyl, Cj.g acyl, C _4 alkyl and C .j aryl, said heterocycle being optionally substituted with one or more halogens, hydroxy, Cg_jg aryl sulfone, cyano, Cj.jg alkoxy, Cj.jg alkyl, nitro, Cj.jg hydroxyalkyl, amino, which may be unsubstituted or mono-or di-substituted by C .g alkyl, C3_g cycloalkyl,. C .g acyl, trifluoroacyl, C^.jg aralkyl, Cg_jg aryl, C^. alkenyl, ^. alkynyl and hydroxy.
Preferred compounds of formula (12) are those wherein
Xj and X2 are independently selected from the groiφ 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 groiφ consisting of CQ, N, and NO.
Rj, R2, R3, and Q are independently selected from the group consisting of hydrogen, hydroxyl, C .4 alkoxyl, tosyl, triflate, fluorine, chlorine, amino, aminoalkylaminoalcohol of formula NH(CH2)jjNH(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)„ CH2 Cl, wherein n is 0 to 4, and a groiφ of the formula -O-
C(R)=0, wherein R is selected from the group consisting of hydrogen, Cj_g alkyl, and aryl;
Z is one of C-Rg or C-R7.
8
SUBSTITUTE SHEET ^ is selected from the groiφ consisting of hydrogen, Cj.g hydroxyalkyl, Cj.g dihydroxyalkyl, squaric acid, Cj.jg alkylsquarate, Cj^ alkyl, acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen, Cj.g alkyl, Cj.g hydroxylalkyl, squaric acid, Cj_4 alkyl squarate, alkoxyalkyl, aminoacetaldehyde diethyl acetal, -m nna~*'i'.W'- -'Λ* diacetoxy acetal, aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl and amino which may be unsubstituted or mono- or di-substituted with Cj.g alkyl, C3_g cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl; a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, Cj.g alkyl, aryl, aralkyl; and a groiφ of the formula -CH2C(0R)=0, wherein R is selected from the groiφ consisting of hydrogen, straight or branched C .g alkyl, and amino which may be unsubstituted or mono- or di-substituted with Cj.g alkyl, C3_ 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, Cj.g alkoxy, Cj.g alkyl, C .g hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C _4 alkyl, C3.5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy;
R7 is selected from the group consisting of hydrogen, fluorine, C _4 alkyl, Cj_ alkoxy, cyano acyl of the formula -C(R)=0 where R is selected from the group consisting of hydrogen, Cj.g alkyl, hydroxyalkyl, acyloxyalkyl, amino, cyano, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, Cj.g alkyl, aryl, Cj.g alkenyl;
R5 and Rg are independently selected firom the group consisting of hydrogen, halogen, hydroxyl, Cj.g alkoxy, ^.g acetylenyl, ^.g alkenyl, cyano, a groiφ of the formula -0-C(R)=0, wherein R is selected from the groiφ consisting of hydrogen and Cj.g alkyl; acyl of the formula -C(R)=0, wherein R is selected from the group consisting of hydrogen, thiol, Cj.g alkyl, hydroxyalkyl, amino; a groiφ of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen and C .g alkyl, glucosamine, and a saccharide of formula:
wherein Y is selected firom the group consisting of oxygen, sulfur, and CHR wherein R is hydrogen or Cj__4 alkyl,
R and RJQ are independently selected from the groiφ consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl; RJJ is selected from the group consisting of amino which may be unsubstituted or m mo- or di- substituted with C .g acetoxy alkyl, C .g 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, Cj.g alkoxyl, a group of the formula NH(CH2)nCH(OR)2 wherein R is independently selected from a group consisting of Cj.g alkyl, Cj.g acyl and C7.J2 aroyl and wherein n is 1 to 5; chloroalkylnitrosoureido of the formula NH(CO)N(NθχCH2)nCH2Cl wherein n is 0 to 4, NΑiCrl^ OCH2CH(OAc)2.fluorine; 2 is selected from the groiφ consisting of hydroxyl or its tetrahydropynnyl ether, halogen, mono or oligosaccharide Bfflttrtfd from the groiφ consisting of rhodoβamine, cineraloβe-B, L-cineiulose, D- cineralose, cinemlose A, amicetoβe, aculoβe, rednose, rhodinose, 2-deoxyfucose, daunosamine, trifluoroacetyl-daunoβamine, amino, trifluoroacetamido, mono or dimethylated amino, C .g alkoxy, benzoate, p-nitrobenzoate, chloroalkyl-nitrosourea, acetoxy and trifluoroacetoxy.
More preferred compounds of formula (12) are those wherein X} 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. Rj, 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^CC NfNOχCI^CI^Cl wherein n is 0 to 2; amino, and fluorine.
Z is one of C-Rg or C-R7.
R<j is selected from the group consisting of Cj_ hydroxime, Cg_jo hydrazone, Cj_4 alkyl, Cj_4 hydroxyalkyl, phenyl, Cj_4 dihydroxyalkyl, a groiφ 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 Cj_4 alkyl, hydroxymethyl, hydrogen, acyloxymethyl, C2. alkenyl, C2. actylyl, Cj_4 alkoxy, hydroxy, Cj_4 aceto, amino which may be unsubstituted or mono- or di-substituted by hydrogen, Cj_4 alkyl, C _4 acyl, trifluoroacyl, and a group of the formula -CHR*R** wherein R* and R** are independently selected firom a groiφ consisting of C _ alkyl, hydrogen, Cj_4 acyl, a groiφ of the formula -(CΑ^Z* wherein n is 0 to 3 and Z* is a hydrogen, or Cj_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, Cj_4 alkoxy, Cj.4 alkyl, and amino which may be unsubstituted, mono-or di-substituted by a C .4 alkyl, C _4 acyl, trifluoroacyl and (^.4 alkynyl, Z* can also be a group of the formula -NR*R** wherein R* and R** are independently selected from the groiφ consisting of hydrogen, Cj_4 alkyl, and C _4 acyl; a group of the formula -C(OR)=0, wherein R is selected from the groiφ consisting of hydrogen, Cj_4 alkyl; a groiφ of the formula - CH2)nC(R)= O, wherein n is 1 to 3 and R is selected from the group consisting of hydrogen, hydroxy, Cj_4 alkoxy, Cj.4 alkyl, Cj.4 hydroxyalkyl, amino, dimethylamino; a
10 BSTITUTE SHEET 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, Cj_4 alkoxy, Cj_4 alkyl, Cj_4 hydroxyalkyl, amino which may be unsubstituted or mono-or disubstituted by methyl, cyclopropyl, acyl, and hydroxy. R7 is selected from the groiφ consisting of hydrogen, fluorine, methyl, methoxy, cyano, acyl of the formula -C(R)=0, wherein R is selected from the groiφ consisting of hydrogen, Cj.5 alkyl, C _4 hydroxyalkyl, amino, cyano, a group of the formula -C(OR)=0, wherein R is selected from the group consisting of hydrogen, Cj.5 alkyl, aryl, and Cj_4 alkenyl: R5 and Rg are independently selected firom the group consisting of hydrogen, halogen, hydroxy, Cj.4 alkoxy, Cj_g alkyl, C2. alkene,a groiφ of the formula -(CΑ^ NR*,R** wherein n is 1 to 4 and R* and R** are independently selected from the group consisting of hydrogen, Cj.5 alkyl, C _4 acyl; acosamine, 2,6-dideoxyιhamnose, thiodaiinosamine, C .5 thioalkyl, a naturally occurring amino acid or dipeptides thereof, a groiφ 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, C .4 alkyl and C . 4 acyl, and wherein R and R* are independently selected firom the group consisting of hydrogen, Cj.4 alkyl, C2.4 alkene, Cj.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, Cj_4 alkyl, and Cj_4 acyl, said heterocycle being optionally substituted by Cj.4 alkyl, C _4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-substituted by C .4 alkyl, C j_4 acyl and trifluoroacyl; methoxy, cyano, Cj.4 acetate, C .4 acetyl and a groiφ of the formula
wherein Y is selected firom the groiφ consisting of oxygen, sulfur, and CH2: R and RJQ are independently selected from the groiφ consisting of hydrogen, fluorine, and iodine. Rjl is selected firom 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)JJCH(OR)2 wherein R is selected from the group consisting of Cj_4 alkyl, Cj_4 acyl or C7„g 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) CH(OAc)2, NH(CH2)2θCH2CH(OAc)2> and NH(Cθ2)OCH2)CH2CH(OAC)2: Rj2 ιs selected firom the group consisting of hydroxyl or its tetrahydropyranyl ether, benzoate, acetoxy, p-nitrobenzoate, amino, trifluoroacetamido, chloroethylnitroβσureido, fluorine, and
11
SUBSTITUTE SHEET 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 _4 alkyl, and C j_4 acyl, said heterocycle being optionally substituted by Cj_4 alkyl, Cj_4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di-βubβtituted by Cj.4 alkyl, Cj.4 acyl and trifluoroacyl.
A still further preferred compound of formula (12) are those wherein Xj and X2 are both oxygen; X is 0, S or SO;
X4 is selected from the groiφ consisting of N, or CQ;
Rj, R2, R3 and Q are each independently selected from the groiφ consisting of hydrogen, fluorine, and hydroxyl, and methoxy.
Z is one of C-Rg or C-R7. Rg is selected from the groiφ consisting of Cj.3 hydroxime, methyl, ethyl, C .3 alkyl, hydroxymethyl, 1,2 dihydroxymethyl, a group of the formula -C(R)= X, wherein X is selected from the groiφ of hydrogen and oxygen, and wherein R is selected from the group consisting of methyl, fluoromethyl, difluoromethyl, hydroxymethyl, acetoxymethyl, bromomethyl and Cj.4 alkoxy, C2.3 alkenyl, Cj.3 aceto, amino which may be unsubstituted or mono-or di-substituted by hydrogen, Cj.3 alkyl, C2.3 acyl or a groiφ of the formula -CHR*R** wherein R* and R** are independently selected from a hydrogen, C j_3 alkyl, a group of the formula -{Cii^Z* wherein n is 0 to 2 and Z* is a C j.3 alkyl, and a groiφ of the formula -NR*R** wherein R* and R** are independently selected firom hydrogen, C .3 alkyl and Cj.3 acyl, Z* can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the groiφ consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, Cj.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 Rg are independently selected from the groiφ consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl, and a saccharide ofthe formula
12
SUBSTIT EET wherein Y is selected from oxygen and CH2, and wherein R9 and RJQ are independently selected firom the groiφ consisting of hydrogen, fluorine, and iodine.
Rjl 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 groiφ consisting of methyl, acyl or benzoyl and wherein n is 3 to 5, chloroalkylnitrosoureido of the formula NH CO)N(NO)(CH2)QCH2C1 wherein n is 0 to 4, and NH(CH2)OCH2CH(OAc)2
R 2 ύs hydroxyl,iodine, or bromine.
Still further preferred compounds of formula (12) are those wherein
X and X2 are both oxygen.
X3 is O or S.
X4 is CQ. R2 and R3 are both hydrogen.
Rj and Q are independently selected firom the group consisting of hydrogen, fluorine, and hydroxyl.
Z is one of C-Rg or C-R7.
Rg is selected from the groiφ consisting of ethyl, hydroxymethyl,
1,2-dihydroxyethyl, carbonyl, squarate, acyl of the formula -C(R)=0 wherein R is selected from the groiφ consisting of methyl, fiuoromethyl, difluoromethyl, hydroxymethyl.
R7 is selected firom the group consisting of hydrogen, methyl, or fluorine;
R5 and Rg are independently selected from the group consisting of hydrogen, hydroxyl, bromine, chlorine, cyano, acetate, acetyl and a saccharide of the formula
wherein R and RJQ are independently selected from the groiφ consisting of hydrogen, fluorine, and iodine.
Rjj is selected firom the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino; R]2 is selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine, with the proviso that at least one of R5 and Rg is saccharide.
The invention also seeks to provide a process for the preparation of a compound of formula ,
13
12
and pharmaceutically acceptable acid addition salts thereof wherein X3 is selected firom the groiφ consisting NR, 0, or S, Rg is methyl ketone or is as defined in claim 1; and R , R2, R3, R5, Rg, R7, Rg, X , 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
14
wherein R5, Rg, R7 and Rg are defined as above, oxidatively demethylating said coπφound with an oxidant to give a quinone coπφound of formula
15
2) and cyclo-adding said quinone with a diene of formula
14
SUBSTITUTE SHEET
16
wherein L is a leaving group selected firom the groiφ consisting of halogen, tosyl, benzoyl, p- nitrobenzoyl and -OR or -SR, wherein R is selected firom the groiφ consisting of hydrogen, C j. g alkyl, Cl-16 "c l* Ci-16 "y-' ^3-16 alkyhύh e* Cg.jg alkylaryl silane and dimethylamino, wherein Rj, R2, R3 and X4 are as defined as above; to yield a tricyclic heteronaphthoquinone of formula
17
and 3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is -OH, to a saccharide of formula
18a 18b
wherein R9, RJQ, RJ J and Rj2 are defined as in claim 1 and L is as defined above; to yield a tricyclic saccharide of formula
15 π. a) coupling the isochroman (14) of reaction (iχi), above, wherein R5 is H, with a saccharide of formula
20
wherein R9, RJQ. Rn and R 2 are as defined in claim 1 to yield a bicyclic saccharide of formula
21
b) oxidatively demethylating the methoxy groups from formula (21) to yield a bicyclic quinone saccharide of formula
16
19
c) and cycloadding said chemical (19) with said diene (16) of reaction (I)(2) to yield the tricyclic saccharide
m. 1) coupling the quinone of formula 15,
15
of step (I) (1), wherein R5 is -OH, with a saccharide of the formula
17 ITUTE SHEET
of step (I) (2) to yield a bicyclic quinone sacharide of the formula
19
2) and cycloadding said quinone saccharide with the said diene of formula
A is NR wherein R is selected from the group consisting of H, ^1-16 "^ ^ ^7-16 "^ and L is defined as above; to yield a tricyclic saccharide of formula
18
SUBSTITUTE SHEET
IV. a) selecting a precursor benzoate compound of formula
R7 *<
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 firom the group consisting of O, S, and N;
to yield a dimethoxyisochroman of formula,
14
19
SUBSTITUTE SHEET b) oxidatively demethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman; the resulting dioxoisochroman is cyclically coupled with the diene of formula
16
A is NR wherein R is selected from the group consisting of H, Cj.jg alkyl, C7. 6 aryl, and L is a leaving group as defined in (I)(2): to yield an anthracenedione of formula
the resultant compound may optionally be converted to the hydroxyl form of formula
The quinones at positions X and X2 may be converted to other moities such as, for exaπφle,
OH, S, NR, where R is hydrocarbon, and others. Such conversions are carried out using known methodology by chemists skilled in the art. For exanφle, these conversions are taught in "The chemistry of the quinonoid Couπφonds" 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
20
SUB tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula
may be optionally coupled with a saccharide of formula
20
1) to yield a dimethoxybicyclic saccharide of formula
2) oxidatively demethylating the methoxy groiφs to yield a dioxobicyclic isochroman of formula
21
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29
to yield a thiotricyclic saccharide of formula
Compounds of formula:
One obtained by treatmg a compound of formula:
22
SUBSTITUTE SHEET
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 groiφs 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 groiφ 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 C _4 alkyl, halogen, C _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 groiφs 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 groiφ of the formula -COAr wherein Ar denotes an "aryl" group as defined above.
The term "alkoxy" or "a alkoxy" 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 exanφle 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 exanφle 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 Cj.g acyl group linked to an alkyl groiφ as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
23
SUBSTITUTE SHEET The term "hydroxyalkyl" as used herein means an alkyl group as discussed above bonded to a hydroxyl groiφ as discussed above, for example, hydroxymethyl.
It will be appreciated by those skilled in the art that when R* = R4 = hydroxyl and X =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.
42 43
(X1=X2 = 0, R, = OH = C-OH)
This invention also includes all the possible isomers and mixtures thereof, including diastereoi8omeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centos, when pertinent, at Cj, 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 _ __ where R5 is not a saccharide (PCT CA 9100208), are oxydatively demethylated with an oxidant such as eerie 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 dieneβ of general formula J6 in a solvent such as toluene can give the tricyclic heteronaphthoquinone of formula 2. In the case when R5 is a saccharide, two independent synthetic routes (A2 or B) may be employed.
With respect to route A2, glycosideβ of formula 12 (R5 = Saccharide, Xj = X2 = O) are obtained by reacting appropriate aglycones of general structure 12, in which R5 is an hydroxy, with known sugar derivatives of formula 18 in which R9 to *2 are as defined herein and L is a displaceable atom or groiφ.
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 exaπφle a Cj.jg alkyl groiφ such as methyl, ethyl or butyl, or R is an unsubstituted or substituted acyl group such as a Cj.jg acyl groiφ such. as acetyl, or R is an unsubstituted or substituted aryl groiφ or R is a C3 to CJQ trialkyl silyl such as trimethylsilyl or dimethyl-t-butylsilyl. Such sugars are obtained by derivatizing known saccharides of the family of
24
SUBSTITUTE SHEET 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 12. is typically reacted with the appropriate sugar derivative of formula
18 in a conφatible solvent such as methylene chloride using a Lewis acid such as titanium tetrachloride, stannic chloride, of trimethylsilyltrifluoromethane-βulfonate. Alternatively, as it is known in the art of anthracycline chemistry, when the leaving groiφ of the sugar moiety is a halogen, the Koenigs-Knorr glycosidation or its modification may be used. Alternatively glycosidation of 2 caa he effected with known sugar derivates of formula 18b under protic catalysis to yield 12 (R5 — Saccharide, X = X2 = 0).
In the event that the glycosidation of aglycone 12 is impractical then route B j or B2 can be used to prepare glycoβideβ of formula 12 (R5 = saccharide, X = X2 = 0). With reference to route B , 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, X j = X2 — 0). Alternatively, glycosidated isochromandiones
25
SUBSTITUTE SHEET Scheme I
21 12 ( R5 - Saccharide, XI - X2 - O )
26
SUBSTITUTE SHEET Scheme 2
27
TITUTE SHEET. of formula _19 can be obtained via route B2 by reacting isochromans of formula J4 with a saccharide of formula 2Q 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 groiφs, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groiφs 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 groiφs may be protected using any conventional hydroxyl protecting groiφ, for example, as described in "Protective Groiφs 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 groiφs such as benzyl may be cleaved, for example, by treatment with BF3tetherate and acetic anhydride followed by removal of acetate groiφs.
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 die final product or by stereoβpecific 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, coπφrising 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 HC1 and tartaric acid salts of the compounds useful as antitumor agents in mammals, including humans, are included in this invention.
28
SUBSTITUTE SHEET 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. caπnustine, 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; phoβphoramide mustards (e.g. cyclophosphamide); urethane and hydantoin mustards
2) Antimetaboliteβ 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,
29 f~~ * . <C 1 STI m i ft *- ! aclacinomycin A); acridities (e.g. m-AMSA); hycanthones; ellipticines (e.g. 9-hydroxyellipticine); 5 actinomycins (e.g. actinocin); anth aquinones (e.g. l,4-bis[(aminoalkyl)- amino]-9,10-anthracenediones); anthracene derivatives (e.g. pseudourea and bisanthrene); phleomycins; 10 aureolic acids (e.g. mithramycin and olivomycin);
Caπφtothecins (e.g. topotecan);
4) Mitotic inhibitors such as: dimeric catharanthus alkaloids
(e.g. vincristine, vinblastine and vindesine); 15 colchicine derivatives (e.g. trimethylcolchicinic acid) epipodophyllotoxins and podcφhylotoxins
(e.g. etoposide and teniposide); maytansinoids (e.g. maytansine and colubrinol); terpenes (e.g. helenalin, tripdiolide and taxol); 2.0 steroids (e.g. 4β-hyroxywithanolide E); quassiniods (e.g. bniceantin); pipobroman; methylglyoxals (e.g. methylglyoxalbis-(thiosemicarbazone);
5) Hormones (e.g. estrogens, androgens, tamoxifen, nafoxidine, progesterone, 25 glucocorticoids, mitotane, prolactin);
6) Immunostimulants
(e.g. human interferons, levamisole and tilorane);
7) Monoclonal and polyclonal antibodies; 0 8) Radiosensitiziiig and radkφrotecting compounds
(e.g. metronidazole and miβonidazole);
9) Other misodlaneous cytotoxic agents such as: camptothecins; 5 quinolinequinones
(e.g. streptonigrin and isopropylidene azastreptonigrin); citφlatin, cisrhodium and related platinum series complexes; tricothecenes (e.g. tnchodermol or vermicarin A); cephalotoxines (e.g. harringtonine); 10)Cardioprotecting compounds, such as (±)-l,2-bis(3,5-dioxopiperazin-l-yl)
30
SUBSTITUTE SHEET propane, commonly known as ICRF-187, and ICRF-198;
11) Drug-resistance reversal compounds such as P-glycoprotein inhibitors, for exanφle Verapamil, cyclosporin-c, fujimycin;
12) Cytotoxic cells such as lympholάne activated killer -cells or T-cells, 13) Other tmmιιn_ι__rimιιi_ιιιh such as interleukin factors or antigens.
14) Polynuc otides 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 coπφound 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 exaπφle, chremcφhor-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
^denotes trademark
31
SUBSTITUTE SHEET 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 subβtances 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 theπφeutic 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 cm (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 doβages, 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
32
SUBSTITUTE SHEE1 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 g., 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 theπφeutic 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^,10-tetndiydronaphtbo [2 - 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 L 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 (2*5 mL). The organic layer was then washed with water (3x50 mL) and dried over MgSO 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,lH,J= 18.0, 10.3,3.6 and 1.8Hz,HCHa-CH), 2.97 (dm,lH,J»=19 and 3.0Hz,HCHe-CH=), 4.05 (dd, 1H,J= 10.3 and 3.9Hz, CH2-CH), 4.58 (dt,lH,J= 18.7 and 3.6Hz,HCHa-0), 4.92 (dd,lH,J= 18.7 and 1.8Hz,HCHe-0), 7.72 (m,2H,Ar-H), 8.04 (m,2H,Ar-H).
CMR _(CDC13,75.44 MHz): 24.42 (CH2-CH), 26,57 (COCH3), 63.97(CH2-0-), 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),
33
SUBSTITUTE SHEET 183.51 and 183.63 (C=0 quinone), 207.25 (CO-CH3).
EXAMPLE 1
EXAMPLE 2
Methyl (7-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-CJ pyran-3-yl) ketone BCH-1129
A mixture of l-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 fwinntog 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. HC1 solution. The combined organic layers were then washed with water and dried over MgSO Flash chromatography (toluene: ethyl acetate; 95%:5%) of the residue gave 180 mg (65% yield) of the titled coπφound (MP: 169-170°C). PMR (DMSO-d6, 250 MHz): 2.24 (β,3H,CH3), 2.45 (m,lH,HCHa-CH=), 2.77 (dd,lH,J=19 and 3.0Hz,HCHe-CH),4.20 (dd,lH,J=9.8 and 3.9Hz,CH2-CH), 4.55 (d overlapped, IH, J=22 Hz,HCHa-
O-), 4.78 (d overlapped, IH, J= 18.0Hz,HCβe-O), 7.15 (dd,lH,J=8.5 and 2.4Hz,Ar-H), 7.30 (2d,
IH, J=2.5Hz,Ar-H), 7.88 (2d,lH,J=9.1Hz,Ar-H), 10.96 (s,lH,Ar-OH). EXAMPLE 2
EXAMPLE
34
SUB ^ i 1 m I Methyl (l-hydroxy-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone BCH-1148
A mixture of methyl (l-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 dg, 250 MHz): 2.26 (s,3H,COCH3), 2,50 (dd,lH =11.6, 19.5Hz,HCHa-CH), 2.89 (dd,lH,J=4.2,19.5Hz,HCHe-CH), 4.71 (dd,lH, J=4.2,11.6 Hz,CH-CH2); 6.12 (broad s,lH,CHOH); 7.87 (m,2H,ArH); 8.07 (m,2H, ArH).
EXAMPLE 3
EXAMPLE 4 - Monofluoromethyl (5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-
3-yl) ketone
Step l: Monobπimomeihyl (5,8-dimetlMxy-3,4-dihydrobenzo [2^-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-bromoβuccinamide (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 coπφound was obtained following flash chromatography (hexanes:ethyl acetate, 9:1) of the crude product. *H NMR (benzene-dg, 250 MHz) _: 2.68 (dd, lH,HCHa), 3.16 (dd,lH,HCHe), 3.28 (s,3H,OCH3), 3.32 (s,3H,OCH3), 3.73
35
SUBSTITUTE SHEET (dd,lH,J=4.0,11.5Hz,CH), 3.81 (dd,2H,CH2Br), 4.51 (d,lH, J= 15.8Hz, HCHaO), 5.05 (d,lH,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.
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 IM 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 NaSθ and solvent evaporation, the residue was flash chromatographed (Toluene: Ethyl acetate; 9.5:0.5) to give a 50% yield of pure titled coπφound. -H NMR (250 MHz, CDCI3): 2.61 (dd,lH,HCHa), 3.11 (dd,lH,HCHe), 4.27 (dd,lH,CH), 4.63 (d,lH,HCHaO), 4.99 (d,lH,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 MgSO^ The titled quinone was obtained (67 mg) following evaporation of solvent.
-H NMR (250 MHz, CDCI3): -U NMR (250 MHz, CDCI3) _: 2.46
36
ET (dddd,lH,J=3.0,4.0,10.4,18.9Hz,HCHa), 2.91 (dt, IH, 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 coπφound was isolated after two flash chromatography (2% EtOAc in toluene).
PMR (Acetone-dβ, 250 MHz): 2.62 (dddd,lH,HCHa), 2.94 (dt,lH,HCHe), 4.46 (dd,lH,CH), 4.62 (dt,lH,HCHa), 4.84 (dd,lH,HCHe), 5.43 (d, 2H, CH2F), 7.83 (m,2H,ArH), 8.03 (m,2H,ArH).
EXAMPLE S
Ste l. (1'S,1R^S) and (1'S,1S,3R)-Methyl (5,8-dioxo-l-(2'^', 6'- trideoxy-3'- trifluoroacetamido-4'-0-p-mtrobenzøyl-L^ 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 (l-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 NaHCθ3 solution. The organic layer was washed with water and dried (Na2S04). Flash chromatography of the residue gave 917 mg (69 % yield) of the mixture of titled stereoisomers.
37
S BSTIT T T Example 5: Glycosidated derivatives of pyranonaphtoquinoneβ with a methyl ketone side chain.
Rj = OPNB R2*NHCOCF3
OH R 2 βNHCOCF3
A second flash chromatography seperated the individual diastereomers.
The 1'S,1S,3R tided diastereomer had *H NMR (250 MHz, acetone-dg) _: 1.28 (d.3H,J=6.4Hz,CH3), 2.05 (hidden m, 1H,2,-CH2), 2.30 (s,lH, COCH3), 2.42-2.49 (m,2H,2'-CH2 overlapped with HCHa), 2.84 (dd,lH,HCHe.) 4.53-4.65 (broad m,lH,3*-CH), 4.635 (dd,2H,J=4.2, 11.6Hz,0-CH-COCH3), 4.76 (broad q,lH,5'-CH), 5.50 (broad s.lH^'-CH), 5.69 (broad s,lH,l'-CH), 6.02 (s,lH,0-CH-O), 6.90 (dd,2H,2X C= CH), 8.37 (m,4H,ArH), 8.68 (broad d,lH,NH).
38
SUBSTITUTE SHEET The 1'S,1R,3S titled diastereomer had *H NMR (250 MHz, acetone-dg) _: 1.19 (d,3H,J=6.6Hz,CH3), 1.89 (dd,lH,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,lH, J=4.1Hz,HCHe). 4.60 (m,2H,3*-CH overlapped with 5*-CH), 4.71 (dd,lH, J=4.1,11.5Hz,0-CH-COCH3), 5.48 (broad s, 1H,4'-CH), 5.64 (broad s, 1H,1'-CH), 5.89 (s.lH.O- CH-O), 6.87 (dd,2H,2XC=CH), 8.37 (dd,4H, ArH), 8.69 (broad d, IH, NH).
Step 2.
(1'S,1R S)-Methyl (5,10-dioxo-l-(2, \6'-trideoxy-3,-triflικ)roacetamid^4,-O-p- nitrobenzoyl-_Wyxohexo-pyraικ)6e)-3,4^,10-tet__^ydVonaphtbo [2,3-C] pyran-3-yl) ketone
To a stirred solution of l'S, IR, IS -diastereomer, from step 1 (Exaπφle 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 chromatogπφhed (toluene:ethyl acetate; 90%: 10%) to give 244 mg (82% yield) of the pure titled compound. lH NMR (250 MHz, acetone-άg): 1.22 (d,3H^=6.4Hz,CH3), 1.94 (dd,lH,J=4.7,13.1Hz,2,-CH2), 2.35 (s,3H,COCH3), 2.42 (m,lH,2,-CH2), 2.52 (dd,lH,J=11.6,19.8Hz,HCHa), 3.04 (dd,lH,J=3.9,19.6 Hz, HCHs), 4.55-4.68 (overlapped m,2H,3'-CH and 5'-CH), 4.79 (dd,lH,J=4.0,11.5 Hz,0-CH-COCH3), 5.49 (broad s,lH,4'-CH), 5.75 (broad s,lH,r-CH), 6.07 (s,lH,0-CH-0), 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,lH,NH).
Step 3. (1'S,1R S)-Methyl (S^C &oxo-l^'^Sβ'-trid∞xy-S'-trifluoroacetamido^'- hydroxy-Lrlyxohexopyrano6e)-3,4,5, 10-tetrahydronaphtho [23-C] pyran-3-yl) ketone BCH-1184
To a stirred solution of the glycoside from step 2, (30 mg, 4.65x10"' mmol) in 4 mL of dry methanol and 1 mL of anhydrous THF at 0°C and undo- argcm, was added llμl (4.66xl0"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 coπφound. lH NMR (250 MHz, Acetone-dg): 1.25 (d,3H =6.5Hz,CH3), 1.76 (dd,lH, J=4.5,12.9Hz,2,-CH2), 2.16 (m,lH,2,-CH2), 2.32 (s,3H,COCH3), 2.48(dd, J=11.6,19.5Hz,HCHa), 2.99 (dd,lH,J=4.1,19.5 Hz,HQJe), 3.68 (broad s.lH^'-CH), 4.17-4.41 (ov^apped m,2H,3'-CH and 5*-CH), 4.69 (dd, lH,J=4.0,11.0Hz,O-CH-COCH3), 5.53 (broad s,lH,l'-CH), 5.97 (s,lH,0-CH-0), 7.82-7.90 (m,2H,ArH), 8.01-8.05 (m,2H,ArH), 8.13 (broad d, 1H,NH).
39
ET Step 4:
(1'S,1S R)-Methyl (5,10-d >xo-l-(2,^\6l-trid∞xy-3,-trifluoroacetaιmdo-4,-O^ mtrobenzoyl-Lr-lyxohexti-pyraii06e)-3,4,5,l( etrahydronaph^ [2,3-C] pyran-3-yl) ketone
Application of the procedure described in step 2 of the present example on the l'S, IS, 3R quinone glycoβide from stop 1 gave the titled compound which had:
-U NMR (250 MHz, Acetone-dg): 1.33 (d,3H^=6.6Hz,CH3),1.94 to 2.08 (m,lH,2,-CH2), 2.33 (s,3H,COCH3), 2.49 3.01 (dd,lH,J«4.1,19.7Hz,HCHs), 4.53-4.65 (m, iH,3'-CH), 4.71 (dd,lH,J-=4.1,11.5 Hz,0-CH-COCH3), 4.90 (broad q.lH, 5'-CH), 5.53 (broad s,lH,4'-CH), 5.75 (broad s,lH,l'-CH), 6.21 (s, lH.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-l-(2,^ 6,-trideoxy-3,-trifluoroacetamido-4'- hydroxy-L-iyxohexopyranose)-3,4^, 10-tetrahydronaphtho [23-C] pyran-3-yl) ketone BCH-1146
Treatment of the glycoβide obtained firom step 5 with sodium methoxide as described in step 3 of this exaπφle yielded the titled compound, which had: NMR (250 MHz, Acetone-dg) 1.35 (d,3H,J=6.4Hz,CH3), 1.77(dd,lH, J=4.5,12.9Hz,2'-CH2), 2.17 (dt,lH,J= 3.7,12.9Hz,2,-CH2), 2.30 (s,3H, COCH3), 2.56 (dd,lH,J=10.7,19.6Hz,HCHa), 2.98 (dd,lH,J=4.2,19.8 Hz, HCHs),3.70 (broad s,lH,4--CH), 4.2-4.4 (m,lH,3'- CH), 4.60 (broad quartet,lH,5,-CH), 4.66 (dd,lHJ=4.2,11.5Hz,0-CH-COCH3), 5.52 (broad d,lH,r-CH), 6.15 (s,lH,0-CH-0), 7.86-7.92 (m,2H,ArH), 8.07-8.11 (m,2H,ArH), 8.15 (broad d,lH,NH). .
Step 6:
(l'S,lI S)-Methyl (5,10-dioxtHl-(2'^\6,-trideoxy-3,-trinuoroacetamido-4,-O-p- mtroben_myl-L-lyxohexo-pyrano6e)-7-hyd_ro^ [2 -C] pyran-3-yI) ketone
The titled compound was prepared in 62% yield by cyclocondensing the l'S, IR, 3S-quinone glycoside from step 1 of this exaπφle with l-methoxy-3-trimethylsilyloxybutadiene. The same procedure as described in step 2, in this example, was used. -H NMR (250 MHz, Acetonwφ: 1.21 (d,3H,J=6.6Hz,CH3), 1.93 (m,lH, T-CΗ^. 2.34 (s,3H,COCH3), 2.49 (dd,lH,J=11.6,19.5Hz,HCHa), 3.00 (dd,lH,J=4.1,19.5Hz,HCHe), 4.57-4.69 (overhqφed multiplets, 2H,3'-CH and 5'-CH),4.76 (dd,lH,J=4.0,11.5Hz,0-CE-COCH3), 5.49 (broad s, 1H,4'-CH), 5.73 (broad d,lH,l'-CH), 6.04 (s.lH.O-CH-O), 7.25 (dd, lH,J=2.5,8.5Hz,ArH), 7.46 (d,lH,J=2.5Hz,ArH), 7.98 (d,lH,J= 8.6Hz, ArH), 8.38 (m,4H,ArH), 8.58 (broad d,lH,NH) 10.23
SUBSTITUTE SHEET (broad s,lH, ArOH).
Step 7:
(1'S,1R3S)-Methyl (S.lO-dioxo-l- '^ ^'-trickoxy '-trinuoroacetamido-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 l'S, IR, 3S tricyclic glycoside of step 8 resulted in the removal of the p-nitrobenzoyl protecting group. The titled compound had:
-H NMR (250 MHz, Acetone-dg): 1.63 (d,3HJ=6.4Hz,CH3), 2.14 (m,lH, T-CH^ 2.53 (m,lH,2'- CH2), 2.70 (s,3H,COCH3), 2.87 (dd,lH,J=11.7, 19.4Hz,HCfia), 3.35 (dd,lH,J«=4.1,19.4Hz,HCHe), 4.07 (broad s,lH,4'-CH), 4.65 (overlapped m,2H,3'-CH and 5'-CH), 5.07 (dd,lH,J=4.1,11.7 Hz,0- CE-COCH3), 5.91 (broad d,lH,l'-CH), 6.35 (s,lH,0-CH-0), 7.64 (dd,lH,J=2.5,8.5Hz,ArH), 7.84 (d,lH,J=2.5Hz,ArH), 8.35 (d,lH,J= 8.5 Hz,ArH), 8.48 (broad d,lH,NH), 10.23 (broad s,lH,ArOH). Step 8:
(1'S,1S3R)-Methyl (5,10-dioxo-l-(2, \(>,-trideoxy-3,-t_rmuoraaceta__ do^ lύtroben∞yl-L-lyxohexo-pyπuMβe^^ [2,3-C] pyran-3-yl) ketone
The titled coπφound was prepared by applying the same procedure as described in step 8 on the l'S, IS, 3R, quinone glycoside of step 1 of this example.
-H NMR (250 MHz, Acetone-dβ): 1.32 (d,3H,J=6.4Hz,CH3),2.08 (m,lH, 2,-CH2), 2.51 (m,lH,2'- CH2) 2.55 (dd,lH,J=11.5,19.5Hz,HCHa), 2.96 (dd,lH,J=4.2,19.6Hz,HCHs), 4.51-4.62 (m,lH,3'- CH), 4.68 (dd,lH = 4.2,U.5Hz,0-QΪ-COCH3), 5.52 (broad s,lH,4'-CH), 5.73 (broad s,lH, l'-CH), 6.18 (s.lH,0-CH-0), 7.28 (dd,lH,J=2.6,8.5Hz,ArH), 7.47 (dd, lH,J=2.6,8.5Hz,ArH), 8.03 (d,lH,J=8.5Hz,ArH), 8.38 (m,4H,ArH), 8.68 (broad d,lH,NH), 9.85 (broad s,lH,ArOH).
Step 9: (1'S,1S R)-Methyl (5,lϋ-dioxo-l-(2,3\6,-trideoxy-3,-trifluoroac£tamido-L- lyxohexopyrano6e)-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 l'S, IS, 3R tricyclic glycoside of step 11 resulted in the removal of the p-nitrobenzoyl protecting group. The titled compound had: l NMR (250 MHz, Acetone-i ) 1.73 (d,3H,J=6.6Hz,CH3), 2.17 (m,lH, 2.58 (m,lH,2'- CH2), 2.68 (s,3H,COCH3), 2.90 (dd,lH,J=11.6, 19.7Hz,HCHa), 3.33 (dd,lH,J=4.3,19.8Hz,HCHe), 4.09 (broad s,lH,4'-CH), 4.63 (m,lH,3'-CH), 4.95-5.06 (overlapped m,2H,5'-CH, and OCH-COCH3),
41
SUBSTITUTE SHEET 5.91 (broad d,lH,l'-CH), 6.51 (s,lH,0-CH-0), 7.65 (dd,lH, J=2.6,8.5Hz,ArH), 7.85 (d,lH,J=2.6 Hz,ArH), 8.38 (d,H,J=8.5Hz, ArH), 8.52 (broad d,lH,NH), 10.18 (broad s,lH,ArOH).
EXAMPLE 6 2-[4,-Hydroxy-l'3'H__ioxo-3l-cyclobutenoxy] nκthyl-(5,10~dioxo-3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yI) ketone
Example 6: Tricyclic pyranyinap thoquinones with a squaric acid moiety.
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,l.lmmol) 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 MgSθ4 and then evaporated to yield 263 mg of pure titled compound.
-H NMR (250 MHz,CDCl3): 2.43-2.69 (m,lH,CH2), 2.82-3.07 (m,lH,CH2), 4.24 (dd,2H,CH2Br), 4.4-4.6 (m,2H,CH20 and CHCOCH2Br), 4.52 (d,lH, CH20), 6.74 (dd,2H,HC=CH).
Step 2: Bromomethyl (5,10-dioxo-5,10-dihydronaphtho [2 -C] pyran-3-yl) Ketone
To a solution containing one equivalent of isochromandione (263mg, 0.92mmol) from ste ] (^nmrle 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:l). The titled orange compound was isolated (192mg) in 62% yield. -H NMR (250 MHz,CDCl3): 2.4-2.6 (m,lH,CH2), 2.7-3.2 (m,lH,CH2), 4.3-4.4 (m,2H,CH2Br), 4.45
42
SUBSTITUTE SHEET (m,lH,CH-0), 4.6-4.7 (m,lH,CH20), 4.9-5.05 (m,lH,CH20), 7.6 (m,2H,ArH), 8.1 (m,2H,ArH).
Step 3: 2-[4,-Hydroxy-l,3,-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 CsCC<3 (0.9mmol) were diaolved in 10ml of dry dimethyl foπnamide (DMF) (non homogeneous solution). To this solution was added one equivalent (0.45mmol) of the pyranonaphthoquinone from step 3 (exaπφle 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 coπφound was obtained in 30% yield. 1H NMR (250 MHz.AcetoiKHlg): 2.5-2.6 (m.lH.O^. 2.8-3.0 (rn.lH, CH2 , 4.4 (m,lH,CH-0), 4.6 (overlapped m,2H,COCH20), 4.8-5.0 (m,2H, CH20), 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.
+ 1,3-diepimer + 1,3-diepimer + 1,3-diepimer
Ste l: (l'S.U S) and (l'S,lS,3R)-Bromoπιethyl (5,10-dioxo-l-(2, ϊ,,6,-trideoxy^,-O-P- nitrobauoyl-3'-trifluoro acetanήdo-L-lyxob_αopyra__κ>6e)-(3,4,5,10- tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
At room teπφerature, under N2, to one equivalent (0.482 mmol) of a 1:1 mixture starting quinone glycosides firom steps 3 and 6 (example 1) dissolved in 6 ml dry tetra hydro fiiran (THF) was added 1.1 equivalent of pyridinium hydrobromide perbromide. After two hours, to the solution was added 7 ml 5% NaHCθ3 solution and extracted wiύi 3 x 10 ml EtOAc. After drying over Na2Sθ4 and evaporation, die residue was chromatograpbed using 95% toluene -5% EtOAc solvent Two major fractions were isolated corresponding to die 2 isomers (yield 40% of pure compounds, ratio # 1/1 isomer). PMRs of the separated isomers are described in step 1 (exaπφle 8) and step 1 (example 9).
43
SUBSTITUTE SHEET Step 2:
(1'S,1R S) and (l,S,lS R)-2-[4,-hydroxy-l' 2,-dioxo-3'-cyclobutenoxy] methyl (5,10-αraxo-l-β" ",<S"-trideoxy^"-Oφ^t_robeιιzoyl-3" lyxobexopyπuM6e]-3,4^,lQ-tetrahytJ_ronaphtho [2,3,c] pyran-3-yl) ketone
The title compounds were obtained by applying the procedure described in step 4 (exanφle 6) to the tricyclic glycosides from step 1 (example 7). -K NMR (250 MHz, CD3OD): 1.2 (d,3H,5"-CH3), 1.9 (dd,lH,2"-CH2), 2.42 (m,lH,2"-CH2), 4.6 (m,2H,CO-CH2-0), 4.8 (m,lH,OCH-CO), 5.5 (m, 1H,4"-CH), 5.8 (m,lH,r-CH), 6.1 (m,lH.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,lH,C4-H), 2.6 (m,lH,C4-H), 4.6-4.2 (overiapped m, 2H, 3"-CH and 5"-CH).
EXAMPLE 8
Step l: (l'-S, 1-R, 3-S)-l-(2'-3'-6,-trideoxy-4^p-nitrobe_n^
Iyxohexopyπuιose)-3-(2-broι__ιo-acetyl)-5,10-diox^
(2,3-c)-pyran
Example 8 ,
This exanφle exemplifies interconversion of functional groups wherein a methyl ketone; at Rg is eventually converted to a substituted thiazole ring.
44
SUBSTITUTE SHEET Step l
To a solution of (l'-S,l-R,3-S)-l-(2',3',6'-trideoxy-4,-p^tro-benzoyl-3,-trifluoroacetamido-L- lyxc^exopyranose)-3-a∞tyl-5,10-dioxo-3,4,5,10-tetrahydro-lH^uφhtho-(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 5 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
1.0 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 -ifi— «»< ««. starting material (< 66% mol) was also obtained.
M.P. (Electrothermal IA-9100): 125-130°C; decomposed at 175°C. -H NMR (250MHz, acetone^): 1.25 (d,3H,J=6.5Hz,6'-CH3), 1.97 (dd, lH,J=4.8Hz,13.7Hz,2'-
15 HCHa), 2.48 (dt,lH,J«4.2Hz,13.7Hz,2'-HCHe), 2.64 (dd,lH,J=11.6Hz,25.6Hz,4-HQHa), 3.14 (dd,lH,J=5.7Hz,25.6Hz,4-HCHe). 4.66 (S,2H,COCH2Br), 4.71 (qua,lH,J«=6.5Hz,5'-CH), 4.83 (overlapped m,lH,3'-CH), 5.08 (dd, IH, J=5.7Hz,11.6Hz,3-CH), 5.52 (bs,lH,4'-CH), 5.79 (bd,lH,J=3.0Hz,l'-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 ). 8.41 (d,2H,J=7.4.H^PNB-NC^C(CH)2), 8.75 (d,lH,J=7.7Hz,3*- 0 NHCOCF3).
IR(Nicc4et 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: (l'S,l-R S)-l-(2,^\6,-trickoxy^*-p-nitrobenzoyI-3'-trinuoroa_»t^ 5 lyxohexopyraiM)_%)-3-(2-aza-3-aminot_^ naphtho-(2 -c)p ran
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 die previous step in methylene chloride (1 ml). The reaction 0 mixture was stirred at room te perature 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 5 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). *H NMR (250 MHz, acetone-dg), δ: 1.13 (d,3H,J=6.7Hz,6'-CH3), 1.92 (dd,lH,J=5.4Hz, 12.8Hz,2'-HCHa), 2.42 (dt,lH,J=3.4Hz,12.8Hz,2'- HCHe), 2.71 (dd,lH, J=12.2Hz,20.3Hz,4-HCHa), 3.12 (dd,lH,J=3.4Hz,20.3Hz,4-HCHe), 4.65
45 (m,lH,3'-CH), 4.67 (qua,lH,J=6.7Hz,5'-CH), 5.18 (dd,lH,J=3.4Hz, 12.2Hz.3-CH), 5.50 (bs,lH,4'- CH), 5.68 (d,lH,J=2.7Hz,l'-CH), 5.99 (s,lH,l-CH), 6.67 (S,lH,thiazole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.35 (d,2H,J=9.4Hz,PNB-COC(CH2), 8.42 (d,2H,J=9.4 Hz, PNB- Nθ2C(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: (l'S,l-R3-S)-l-(2,,3S6<-trideoxy-3t-tiifliion^^ lyxong»opyranose)-3-(2-aza-3-arrtamidotl__iazo^ lH-naphtho-[2,3-c]-pyran
A solution of bromomethyl ketone (lOmg, 8mmol), from step 1 (example 8), in methylene chloride (0.5 ml) was added to an ether solution (2 ml) of 1-methylthiourea (l.lmg, 1.0 mmol). The reaction mixture was stirred for 3 hours at room tenφerature then 3 hours at 40°C. Solvent was evaporated and the crude product was analyzed by *H 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, chlorofoπn: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.
-n NMR (250 MHz, acetone-dg), δ: 1.09 (d,3H^=7.4Hz,6'-CH3), 1.92 (dd, 1H,J= 4.7Hz, 12. lHz,2'- HCHa), 2.42 (dt,lH,J=2.3Hz,12.1Hz,2'-HCHe), 2.75 (dd,lH,J=11.7Hz,19.5Hz,4-HCEa), 3.14 (dd,lH,J=2.3Hz,
19.5Hz,4-HCHe), 4.62 (qua,lH,J-7.4Hz,5'-CH), 4.64 (m,lH,3'-CH), 5.31
(dd,lH,J=2.3Hz,11.7Hz,3-CH), 5.47 (bβ,lH,4'-CH), 5.68 (bs,lH, l'-CH), 6.00 (s,lH,l-CH), 7.20 (s,lH,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:N02-C-(CH)2), 8.72 (d,lH,J=7.4Hz, 3'-NHCOCF3), 11.08 (S,lH,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: (l'-S,l-R3-S)-l-(2,,3 6l-trideαxy-3l-trifluoro acetamido-L-lyxohexopyraιιose)-3-(2-aza-3- acetaπύάo thiazDlyl)-5,10-diαxo-3,4,5,10-tetrahy
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
46 solution (20 μl) of sodium bicarbonate (0.51 mg, 6.11 mmol). The reaction mixture was then stirred at room tenφerature for 1 hour. When die 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 die 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): 160-165βC, decomposed at 195 °C.
-K NMR (250 MHz, acetone-ά^), δ: 1.12 (d,3H,J=7.9Hz,6'-CH3), 1.24 (dd,lH =6.7Hz,15.0Hz,2'- HCHa), 2.14 (dt,lH,J«=4.2Hz,15.0Hz,2'-HCHe), 2.25 (s,3H,COCH3), 2.64 (dd,lH,J=12.5Hz,20.9Hz,4-HCHa), 3.13 (dd,lH =4.2Hz,20.9Hz,4-HCHe), 3.63 (bs,lH,4'-CH), 4.21 (qua,lH, J=7.9Hz, S'-CH), 4.30 (m,lH,3'-CH), 5.26 (dd,lH,J=4.2Hz,12.5Hz,3'-CH), 5.50 (d,lH =2.4HZ,l'-CH), 5.97 (s,lH,l-CH), 7.12 (s, IH, thiazole-CH), 7.90 (m,2H,7.8,ArH), 8.10 (m,2H,6.9,ArH), 11.07 (s,lH,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: (l'-Sjl-R^^-H∑'^'.β'-trideoxy-S'-trifluoro acetamido-L-lyxohexopyranose)-3-(2-aza-3- aminothiazolyl)-5, 0-dioxo-3,4^,10-tet_rahydro-lH-naphtho-[2 -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.
*H NMR (250 MHz, acetone-dg), 6: 1.14 (d,lH,J=5.9Hz,6'-CH3), 1.74 (dd,lH,J=12.5Hz,4.8Hz,2'- HCHa), 2.11 (m,lH,2'-HCHe), 2.62 (dd,lH, J=11.8Hz,18.4Hz,4'-HCHa), 3.12 (dd,lH,J=4.2Hz,18.4Hz,4-HCHe), 3.65 (bβ,lH,4'-CH), 4.24 (qua,lH,J=5.9Hz,5'-CH), 4.33 (m,lH,3'-CH), 5.11 (dd,lHJ=4.2Hz,11.8Hz,3-CH), 5.48 (bd,lH,J=3.0Hz,l'-CH), 5.92 (s, 1H.1- CH), 6.57 (s,lH,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
47
SUBSTITUTE SHEET Exaapit y
Step 1: (r-S.l-S^RH-α'^'-δ'-tri eoxy-^- -mtrxibe^ lyxohexopyπuMβe)-3-(2-bromoacetyl)-5,10-tø [2,3-c]-pyran
To a solution of (l'-S,l-S,3-R)-l-(2',3',6,-trideoxy-4'-p^trobenzoyl-3'-trifluoroacetamido-L- lyxohexopyranoβe)-3-acetyl-5,10Htioxo-3,4,5,10-tetrahydro-rø (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) firom which, via flash chromatography (eluent in volume ratio, toluene:ethyl acetate' 10:3), a pure sample ofthe tided substance (27 mg) was obtained as a light yellow solid. Unreacted starting material (10 mg) was also obtained.
-H NMR (250 MHz.acetone-ctø, δ: 1.33 (d,3H *=6.8Hz,6'-CH3), 2.02 (dd, 1H,J -4.9Hz, 13.5Hz,2'- HCfia), 2.48 (dt,lH,J=5.8Hz,13.5Hz,2'-H £e), 2.78 (dd,lH,J=12.1Hz,20.3_Hz,4-HCfia), 3.12 (dd,lH, J=4.0Hz, J=20.3 Hz,4-HCfie), 4.29 (m,lH,3*-CH), 4.52 (d,lH,J«=13.8Hz,BrHCHre), 4.67 (d,lH,J=13.8Hz,BrHCHsi), 4.88 (qua,lH,J=6.8Hz,5'-CH), 5.04 (dd,lH, J=4.0Hz,12.1Hz,3-CH), 5.53 (bβ,lH,4'-CH), 5.85 (bd,lH =3.4Hz,l'-CH), 6.24 (s,lH,l-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,lH,J=7.4Hz,3,-NHCOCF3).
Step 2: (l,-S,l-S -R)-l-(2, '-6'-trideoxy^,-0-p-nitrobenzoyl-3,-trinικMOacetamid -^ lyxohexopyranose)-3-(2-aza-3-acetamido)-5,10-dioxo-3,4,5,l(^tetπA naphtho-[2,3-c]-pyran
48
SUBSTITUTE SHEET A sample of 1-acetylthiourea (1.06 g, 9.0 mmol) in ether (2 ml) was stirred at room temperature while a solution of bromomethyl ketone (9 mg, βmmol), 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 chlorofbπ methanor 100:7, with 1 drop of pyridine added), to yield a product, which was further purified by recrystallization from C^C^/ exane. he titled substance was obtained as an off-white solid (4mg). *H NMR (250 MHz, aoetone-dβ), δ: 1.33 (d,3H^=7.5Hz,6'-CH3), 1.96 (dd,lH,J=5.8Hz,15.2Hz,2'- HQfr), 2.28 (β,3H,COCH3), 2.49 (dt,lH, J«= 3.8Hz,15.2Hz,2'-HCHe), 2.76 (dd,lH,J=12.5Hz,20.0Hz,4-HCHa), 3.15 (dd,lH,J=4.2Hz,20.0Hz,4-HCΗe), 4.60 (m,lH,3'-CH), 4.92 (qua,lH, J=7.5Hz,5'-CH), 5.24 (dd,lH,J=4.2Hz,12.5Hz,3-CH), 5.55 (bs,lH,4'-CH), 5.68 (bd,lH,J=3.0Hz,l'-CH), 6.16 (s,lH,l-CH), 7.18 (s,lH, 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-N02C(CH)2), 8.74 (bd, lH =7.9Hz, 3'-NHCOCF3), 11.07 (s,lH,thiazole-NHAC).
Step 3: (l,-S,l-S -R)-l-(2,^,,6,-trideoxy-3'-trifluoro ac*tamido-L-lyxohexopyranose)-3-(2-a_a-3- accta____ύdo-tlύa_raiy0-5,10-diαxo-3,4 ,10^^
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 recryβtalized firom dichloromethane hexane to yield die titled substance as a light-colored solid. M.P. (Electrodie mal IA-9100): Decomposed at 195°C. *H NMR (250 MHz, acetone-dg), 6: 1.35 (d,3H F=7.5Hz,6,-CH3), 1.76 (dd,lH,J=5.8Hz,14.2Hz,2'- HCHa), 2.16 (dt,lH,J-=4.2Hz,14.2Hz,2,-HCHe). 2.75 (dd,lH,J«12.1Hz,20.2Hz,4-HCHa), 3.12 (dd,lH,J= 4.0Hz, 20.2Hz,4-HCHe), 3.72 (bs,lH,4'-CH), 4.28 (m,lH,3'-CH), 4.58 (qua,lH, J=7.5Hz,5'-CH), 5.18 (dd,lH -=4.0Hz,12.1Hz,3-CH), 5.48 (bd,lH, J=2.9Hz,l'-CH), 6.10 (s,lH,l- CH), 7.16 (s,lH,thia2ole-CH), 7.90 (m,2H,7,8-ArH), 8.11 (m,2H,6,9-ArH), 8.17 (d,lH,overlapped,3'- NHCOCF3), 11.07 (s,lH,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).
49
SUBSTITUTE SHEET EXAMPLE 10
Example 10
Step 1: Methacrolein-N,N-dimethylhydrazone
Under N2, at room tenφerature, was mixed 3g (50mM) of dimethylhydrazine in sodium phosphate solution 7. Ig (SOmM) 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 Et2
50
SUBSTITUTE SHEET (3x40 ml), dried over MgSθ4, and evaporated. The residue was flash chromatograpbed using CH2CI2 as eluent; 5. Ig of colorless oil was isolated.
-H NMR (250 MHz, CDCl3)δ: 2.13 (s,3H,CH3), 3.04 (s,6H,N(CH3)2), 5.23 (broad s,lH,C=CH2), 5.32 (broad s,lH,C=CH2), 7.25 (s,lH,C=CH).
Step 2: (1'S,1S,3R) and (1'S,1R S) methyl (l-β'^f'-trideoxy^'-tifflimroacet^ trobe__ι_∞yl-L-lyxohexo-pyranose]-5,10-ώ^ naphtho [2,3-c] pyran-3-yl ketone
Under N2 at room tenφerature, to 235 g (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 (exaπφle 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, die residue was flash chromatographed [EtOAc 1: toluene 3] to give 95.1 mg of titled compound (40% yield).
-H NMR (250 MHz, CDCl3)δ: 1.22 (d,3H,5'-CH3), 1.75 (dd,lH,2'-CH2), 2-18 (m.UW-CI , 2.32 (s,3H,COCH3), 2.59 (s,3H,C7-CH3), 2.62 (overlapped m,lH,H-C -H), 3.1-3.3 (m,lH,HC4H), 4.32 (m,lH,5'-CH), 4.53 (m,lH,CHCOCH3), 5.4 (m,lH,3'-CH); 5.5 (m,lH,4'-CH), 5.7 (m,lH, l'-CH),
6.2 (s,lH,C H); 6.4 (m, broad, 1H,NH), 8.2 (overlapped m, lH.Cg-H-arom), 8.2-8.4 (m,4H,p- nitobenzoyl), 8.2 (m,lH,Cg-H arom).
Step 3: (1'S,1S,3R) and (1'S,1R,3S) methyl-l-(2, \6'-trit oxy-3,-trinuoroacεtaπύdt l'-h.vdroxy- L-lyxohexopyra__ιose)-5,10-dkno-3,4,5,10-tet_r^ [2,3- c] pyran-3-yl ketone
To 80 mg (0.121 mM) of azaquinone firom step 2 (exaπφle 10), dissolved in 13 ml MeOH and 3.2 ml H2O, was added 10.4 mg (0.121 mM) of NaHCC^. 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 tided coπφounds (50% yield).
- NMR (250 MHz, CDCl3)δ: 1.24 (d,3H^=6.5Hz,CH3), 1.76 (dd,lH,2'-CH2), 2.16 (m,lH,2'- CH2), 2.30 (s,3H,COCH3), 2.58 (s,3H,C7-CH3), 4.3 (m,lH;5'-CH), 4.52 (m,lH,CH-COCH3), 5.3 (dd,lH,3'-CH), 5.5 (dd,lH, 4'-CH), 5.6 (m,lH, l'-CH), 6.1 (s,lH,CrH), 6.4 (m, broad, 1H,NH), 8.2 (m,lH,Cg-H arom), 8.9 (m,lH, Cg-H arom).
EXAMPLE 11
51 su Upm3 \ ^rϊEET Example 11 Preparation of naphto[2,3-C] pyran glycosides of 2-deoxyfucose.
Ste l: 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 @° ""^ *nd was ed with water, NaHCC^ 10%, and then brine. The tided product was purified by flash chromatogπφhy (hexanes/acyl acetate (AcOet 5:1)) (MP: 130-132°C) (210mg, 90%).
-H NMR (250 MHz, CD2Cl2)δ: 1.40 (d,3H,-CH3), 4.40 (q,lH,H-5), 4.85 (m,lH,H-2), 5.65 (m,lH,H-4), 5.90 (m,lH,H-3), 6.6 (m,lH,H-l).
52
SUBSTITUTE SHEET Step 2:
(1'S,1S R) and l,S,lR S)-methyl-l-(2\6,-dideoxy-3\4'-di-0-p-nitrobenzoyl-L- lyxohexopyranose)-5,10-dioxo-3,4,5,10-tetrahydronaphtho [2,3-C] pyran-3-yl) ketone
To a mixture of methyl (l-hydroxy-5,8-dioxo-5,8-dihydroisochromaa-3-yl) ketone (698 mg, 3.1 mmol), l,5-anhydro-3,4-di-0-paraHiitrobenzoyl-2,6-dideoxy-L-lyxohex-l-enitol (1.58g, 3.7 mmol), and molecular sieves 4 °A (3.8g) in CH2C12 (150 ml), at -60°C, was added triethylamine (0.24 ml, 1.7 mmol), and trimethylsilyl trifluoromethanesulfcmate (0.64 ml, 3.3 mmol), subsequently. After stirring for 40 minutes, die reaction was quenched by adding aqueous NaHCC«3 (50 ml) at -60°C and gradually wa med up to room temperature. Insolubles were filtered off and the filtrate was extracted into CH2CI2. The organic phase was washed with aqueous HC1 (0. IN), 100ml, water and brine, dried over MgSθ4 and the solvent evaporated to give 2.36 g of crude isochromandione glycoside. This was used without any further purification. To a solution of die 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 die reaction mixture was stirred for 18 hours. Silica gel (1.0 g) was then added and air was bubbled through die suspension. After 15 minutes, die 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. -H NMR (CDCl3)δ: 8.34-7.73 (m,12H), 6.23+6.06 (2s,lH), 5.82+5.72 (2d,lH,J=2.8), 5.62-5.52 (m,2H), 4.88+4.43 (2q,lH,J=6.5), 4.62+4.58 (2dd,lH,J=4.1,11.5), 3.10+3.02 (2dd,lH,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
53
SUBSTITUTE SHEET
BCH-K07 Step l: 2^Dimethoxy-6-(2-hydπιxybutyl)-bm?aloVhydedioxanf acetal
To a cooled (-15°C) solution of 2,5-dimeUκ>xybenzaldehydedioxane 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 -78 βC, treated with boron trifluoride etherate (21.8 ml; 177 mmol), and 1,2 epoxybutane (10.2 ml; 119 mmol). After stiπing at -78°C for 60 minutes the reaction mixture was quendied witii a saturated solution of bicaibonate and tiien extracted with ether. The organic
54
SUBSTITUTE SHEET layers were combined, washed witii water, and brine, and were dried over MgSθ4> 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. *H NMR (250 MHz, CDCl3)δ: 0.95 (t,J=7.3 Hz,3H,-CH2CH3), 1.35 (IH, dm,J=13.6Hz,-CH2- CHHβq-CH2), 1.55 (2H,m,-CH2-CH3)» 2.18 (lH,m,-CH2-CHHax-CH2.) 2.98 (lH,dd,J=2.7 and 13.7 Hz,=C-CH2-CH-0-). 3.36 (lH,dd, J=10.3 and 13.6 Hz=C-CH.2-CH-0) 3.65 (3H,s,-OCH3), 3.66 (3H,s,-OCH3), 3.60 - 4.10 (4H,m,-CHHβq-0-,-CH-OH), 4.16 (2H,m,-CHβax-0-), 6.16 (IH, 8,-O-CE- O-), 6.61 (lH,d,J=9.0 Hz,Ar-H), 6.70 (lH,d,J=9.0 Hz,Ar-H).
Step 2: 5,8-Dimethoxy-3-e_thyl-l-hydroxy-isochroπιan
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 IN 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 MgSθ4. Evaporation of the solvent gave pure 5,8-dimethoxy-3-ethyl-l-hydroxy- isochroman (4.1 g; 98%) which could be recryβtalized in dichloromethane/hexane to give white crystals (M.P.: 108.9-110. lβC).
*H NMR (250 MHz, CgDg^: 1.02 (3H,t,J=7.4 Hz,CH2-CH.3), 1.60 (lH,m,
-CHH-CH3), 1.76 (lH,m,-CHH-CH3), 2.48 (lH,dd,J=11.6 and 17.3 Hz, Ar-CH-Hj,-.-), 2.88 (lH,ddJ=3.3 and 17.3 Hz, Ar-CH-fleq), 2.98 (lH,d =3.9 Hz,-OH), 3.34 and 3.38 (6H,2S,-0-CH3), 4.28 (lH,m,-CH-CH2-CH3), 6.40 (2H,m,ArH and -O-CH-O-), 6.46 (lH,d,J=8.8 Hz,ArH).
Step 3: 3-Ethyl-l-hydroxy-isofhroman-5,8-dione.
To a stirred solution of 5,8-dimethoxy-3-ethyl-l-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 die combined organic layer was washed with water, brine, and dried ova- MgSθ4. Evaporation of solvent gave a crude quinone which was suitably pure to undergo further reactions (600 mg; 90 %). *H NMR (CDCl3)δ: 1.02 (3H, =7.4 Hz,-CH2-CE3), 1-70 (2H,m,-CH2-CH3), 2.15 (lH,ddd,J= 1.1,12.4 and 19.5 Hz^-CH-H^-), 2.60 (lH,ddJ=3.2 and 19.5 Hz.Ar-CH-Hβq-), 3.20 (lH,br 8,-OH), 4.08 (lH,m,-CH.-CH2-CH3), 5.91 (lH,s,-0-CE-0-)» 6.76 (2H, 2 parts of an AB system, Ar-H).
55
SUBSTITUTE SHEET Step 4: (l'S, IS, 3S) and (l'S, IR, 3R)-5,10-dk»o-3-ethyI-l-(2,^,,4',6'-tetraά^eoxy-3,,4'-diacetoxy- L-lyxobexo-pyrano6e)-3,4^,10-tet_rahydro-lH-ι__aphtho [2,3-C] pyran
To a cooled solution (-60°C) of 3-ethyl-l-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 die combined organic layers with IN HC1, brine, and then drying over MgS04> Following evaporation, 407 mg of die resulting crude thick oil was dissolved in 20 ml of toluene. To this solution was added 1- acetoxy-l,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 die (l'S, lS,3S)-5,10-dioxo-3-edιyl-l-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-___Λlyoxobexopyτanose)-3,4,5,10-tetrahydro-lH ___φhtho [2,3-C] pyran over its (l'S, IR, 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.
*H NMR (1'S,1S,3S isomer, CL^Cl^. 1 00 (3H,t,J=7.3Hz,-CH2-CH3), 1.23 (3H,d =6.4Hz,6'- CH3), 1.55-2.20 (4H,m,-CH2-CH3 and H-2'), 1.89 and 2.12 (6H,2s,0=C-CH3)» 2.27 (lH,dd,J=11.3 and 19.3Hz,H„-4), 2.74 (lH,dd,J=3.3 and 19.51^11^-4), 3.95 (lH,m,H-3), 4.58 (IH, q,J= 6.5 Hz,H-5'), 5.10 (2H,m,H-3'and H-4'), 5.46 (lH,dJ=3.5Hz,H-l'), 5.95 (lH,s,H-l), 7.75 and 8.05 (4H,2m,Ar-H).
JH NMR (1'S,1R,3R isomer, CLt^Cl^B: 1.01 (3H,t,J=7.3Hz,-CH2-CH.3), 1.11 (3H,d,J=6.5Hz,6'- CH3), 1.55-2.35 (5H,m,-CH2-CH3,H-2' and H^-4), 1.89 and 2.12 (6H,2s,0=C-Cfi3), 2.74 (lH,dd,J=3.3 and 19.5Hz, Hβq-4), 4.00 (lH,m,H-3), 4.22 (lH,q,J=6.5Hz,H-5')f 5.10 (2H,m,H-3' and H-4'), 5.54 (lH,dJ-=3.0Hz,H-l'), 5.79 (lH,s,H-l), 7.75 and 8.05 (4H,2m,Ar-H). The (1'S,1S,3S) diastereoisomer was obtained pure by recrystalization.
EXAMPLE 13
56
SUBSTITUTE SHEET Example 13 Preparation of naphto[2,3-C] thiopyran aglycones.
Step 1: 3-Ae^o-5,8-d methoxythioisochroman
57
SUBSTITUTE SHEET l-Thiobenzoate-propan-2-one (10.083g,51.97mmole) was dissolved in MeOH (100ml), cooled to 0°C, followed by die 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-l,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 MgSθ4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed to give -die tided compound (2.08g,8.25mmol) in 41 % yield.
-H NMR (250MHz, CD3COCD3)δ: 2.31 (s,3H,CH3),2.83(dd,lH,J=1.06, 8.55 Hz, HCHaCH-S), 2.99 (dd,lH,J=2.44,6.17Hz, HCHgCH-S), 3.44 (m,lH, 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=0.
Step 2: Trans-3-aceto-l,5,8-trimethoxythioisoc__ι_roπιan and cis-3-aceέo-l^,8-triπιetlH>xythioisochroπ__an
The thioisochroman from step 1 (Example 13) (100.0mg,0.40 mmmol) was dissolved in CH2CI2 (12ml) and MeOH (4ml) followed by die 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 MgSθ4, filtered and concentrated in vacuum. The crude obtained was flash chromatographed using toluene: ethylacetate (95:5) to give the trans tided compound (65.0mg,0.23mmol) in 58% yield (MP: 84°C). lH NMR (250MHz,CDCl3)δ: 2.34 (s,3H,CH3CO), 2.91 (dd,lH, J=11.73,17.78Hz,HCHaCHC-S), 3.27 (dd,lH,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,lH, 4.13,11.79Hz,CH-S), 5.69 (s,lH,0-CH-S), 6.75 (dd,2H,J=8.96, 14.36 Hz,ArH). IR (cm"1): 2925: CH, 1705.7: C=0. Cis-3-aceto-i,5,8-trimethoxydιioisochroman (32.4mg,0.11mmol) was obtained in 30% yield (MP: 129 °C).
*H NMR (250MHz,CDCl3)δ: 2.34 (s,3H,CH3), 3.25 (d,2H,J=6.58Hz, H^CHeCHC-S), 3.46 (s,3H,OCH3), 3.59 (dd,lH,J=6.75,13.55Hz,CH-S), 3.79 (2s,6H,OCH3), 5.73 (s,lH.O-CH-S), 6.76 (dd,2H,J=9.50,21.30Hz, ArH).
Step 3: Trans-3-aceto-l-methoxy-5,8-dioxoisot__ύochroman
The thioisochroman derivative from step 2 (example 13) ■ (178.2 mg, 0.63 mmole) was dissolved in acetonitrile (10 ml) and H20 (10 ml), followed by die addition of NaHC03 (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 die mixture was extracted with CH2CI2. The combined organic phases were washed with H2O, dried over MgSO^ filtered and concentrated in vacuum. The crude obtained was found to be pure tided compound by *NMR and was used in die following step (>95% yield).
58
SUBSTITUTE SHEET -H NMR (250 MHz, CDCl3)δ: 1.73 (s,3H,COCH3), 2.62 (dd.lH, J=11.32, 19.81Hz,HCHaCH-S), 2.87 (dd,lH,J=4.28, 20.20Hz,HCHeCH-S), 3.21 (s, 3H,OCH3), 3.61 (dd,lH,J=4.31, 11.42Hz,CHS); 5.97 (m,2H,HC=CH).
Step 4: TπuB-3-aceto-l-methoxy-l,2,3,4-tetrahydro-(2-su__fur)m^ and ds-3- aceto-l-methoxy-l^^,4-tetrahydro-(2-sιdfur)anthraceιιe-5,10-d^
Trans-3-aceto-l-methoxy-5,8-dioxoisothiochroman (0.66 mmole) was dissolved in dry toluene (14ml), followed by the addition of die diene (120.0 mg, 1.07 mmole). The resulting mixture was stirred at room temperature overnight. Solvent was removed and die crude obtained was flash chromatographed using pure toluene to give the tided compounds in a ratio of about 1:1, in 48% yield.
XH NMR (250MHz, CDCl3)δ: 2.37, 2.39 (2s,6H,CH3, cis and/or trans), 2.75 (dd,lH,J=6.42,19.81Hz,HCfiaCH-S, cis or trans), 2.90 (dd,lH, J=11.79, 20.08 Hz,HCHa-CH-S, cis or trans), 3.27 (dd,lH,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,lH,J=3.92,11.80Hz,CH-S, cis or trans), 5.30 (s,lH,OCH-S, cis or trans), 5.49 (s,lH,OCH-S, cis or trans), 7.74 (m, 4H,ArH, cis and trans), 8.10 (m,4H,ArH, cis and trans). IR (cm'1): 29O0.CH; 1709.4:C=O; 1668.1, 1631.9:C=0 quinone.
Step 5: cis-3-aceto-l-methoxy-5,8-dioxoisot__ύochroman
Oxidative demethylation, by using the procedure from step 3 (example 13), of cis-3-aceto-l,5,8- trimethoxythioisochroman gave the tided coπφound in 98% yield.
Hj NMR (250 MHz, CDCl3)δ: 2.04 (s,3H,CH3), 2.23 (dd,lH,J=4.88, 19.49Hz, HCHaCH-S), 2.54 (d,lH,J=5.68Hz,HCHeCH-S), 3.56 (dd, IH, J=2.10, 19.23Hz,HCHa,e-S), 5.09 (s,lH,CH-S), 5.96 (dd,2H,J= 10.30, 12.20Hz,ArH).
Step 6: άs-3-aceto-l-methoxy-l,2,3,4-tet__^ydro-(2-βιι_lfur) anthracene-5,10-dione and trans-3- aceto-l-metboxy-1^ >4-tetrahydro-(2-sulfur) anthracene-S,10-dione
Application of the procedure described for step 4 (example 13) to trans-3-aceto-l-methoxy-5,8- dioxoisothiochroman gave pure tided compounds.
-K NMR (250 MHz, CDCl3)δ: 2.37 (s,3H,CH3), 2.75 (dd,lH,J=6.42, 19.81Hz,HCHaCH-S), 3.58
(s,3H,OCH3), 3.64 (m,2H,CH-S,HCHeCH-S), 5.49 (s,lH,0-CH-S), 7.74 (m,2H,ArH), 8.10 (m,2H,ArH). IR (cm.!): 2900:CH; 1707.8:C=O; 1660.0, 1630.2, 1594.4:C=0 quinone.
Step 7: traι__s-3-aceto-l-hydroxy-l^r}»4-tet_rahyd_ro-(2-sulfur) anthracene-5,10-dione and cis-3- aceto-l-hydroxy-1^ ,4-tetrahydro-(2-su__fιιr) anthracene-5,10-dione The mixture of compounds obtained from step 6 (exaπφle 13) (30.8 mg, 0.102 mmole) was dissolved in
59
SUBSTITUTE SHEET CH3COOH:H2θ (2:0,4 ml) at 0°C. The resulting mixture was stirred at 0°C for about 2 hours. NaHCθ3 (5 %) was added and it was extracted with CH2CI2. The combined organic phases were washed with H2O, dried over MgSθ4, filtered and concentrated in vacuum. The crude product obtained was flash chromatographed using hexanes:ethyl acetate (7:3) to give the tided compounds in 7% yield. According to NMR one isomer is major:
*H NMR (250 MHz, CDCl3)δ: 2.74 (s,3H,CH3), 3.00 (dd,lH, J= 11.99, 20.74Hz,HCHaCH-S), 3.26 (dd,lH,J=3.96, 20.61Hz,HCfleCH-S), 4.37 (dd, lH =3.99,12.0Hz,CH-S), 6.67 (s,lH.O-CH-S), 7.73 (m,2H,ArH), 8.08 (m,2H,ArH).
60
SUBSTITUTE S EET EXAMPLE 14 - Thiopyranylnaphthoquinone glycosides
Example 14 Preparation of naphto[2,3-C] thiopyran glycosides.
Step 2
/
Step 3
Step l:
(1'S,1I S) and (1'S,1S,3R) methyl (5,8-dimethoxy-l-(2, ,,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-0-acetyl-2,6-dideoxy-L-lyxohexopyranose (_-
61
SUBSTITUTE SHEET 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 NaHCC^ solution (5%) and 10 ml of H20, the products were extracted with CH2CI2 (25 ml x 4). The combined organic phase was washed with H2O (15 ml), dried over MgSθ4, filtered and tiien concentrated. The residue was purified by flash chromatography (hexanes/C^C^/ethyl acetate, 2=1 = 1) to provide a mixture of tided conφounds (2=1, 116.9 mg, 0.24 mmol) in 64% yield along with recovered sugar (48 mg, 0.21 mmol).
*H NMR (CDCI3), 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,lH, J=16.5Hz,10.5Hz), 3.28 (dd,lH,J=16.5Hz,5.1Hz), 3.80 (s,6H), 4.14 (dd,lH,J=10.5Hz,5.1Hz), 4.42 (q,lH,J=6.3Hz), J6.3Hz), 5.10-5.25 (m, 2H), 5.65 (d,lH,J=3.2Hz), 6.27 (s,lH), 6.72 (d,lH =9.8Hz), 6.81 (d,lH,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,lH,J=16.5Hz, 10.5Hz), 3.30 (dd,lH,J= 16.5Hz,5.1Hz), 3.81 (s,6H), 4.22 (dd,lH, J=10.5Hz,5.1Hz), 4.42 (q,lH,J=6.3Hz), 5.10-5.25 (m,2H), 5.50 (d,lH, J=3.2Hz), 6.03 (s.lH), 6.70 (d,lH,J=9.8Hz, 6.79 (d,lH,J=9.8Hz).
Step 2:
(1'S,1I S) and (1'S,1S,3R) methyl (5,8-dioxo-l-(2'^', 4',6'-tetradeoxy-3,,4l- diacetoxy-L-Iyxohexo-pyπuιoβe)-3,4^,8-tetrahydrobenzo [2,3-c] thiopyran-3-yI) ketone
To a stirred solution of die thioisochroman glycosides from step 1 (example 14) (106.0 mg, 0.22 mmol) in 5 ml of CH3CN was added a solution of NaHCC«3 (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 MgS04, filtered and then concentrated. The residue (94.3 mg, 0.21 mmol) was found to be the tide coπφounds (2: 1) by 1H NMR. The yield was 95 % .
-H NMR (C CI3), 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,lH,J=18.8Hz,11.0Hz), 3.14 (dd,lH,J=18.8Hz,4.8Hz), 4.00 (dd,lH,J=11.0Hz,4.8Hz), 4.24 (q,lH,J=7.6Hz), 4.95-5.20 (m,2H), 5.56Hz (d,lH,J=3.2Hz), 6.00 (s,lH), 6.19 (d,lH,J= 11.0Hz), 6.85 (d,lH,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,lH,J=19.0Hz,10.5Hz) 3.15 (dd,lH,J=19.0Hz,4.8Hz), 4.07 (dd,lH,J=10.5Hz,4.8Hz), 4.33 (q,lH,J=7.5Hz), 4.95-5.20 (m,2H), 5.52 (d,lH,J=3.2Hz), 5.77 (s,lH), 6.70 (d,lH,J=11.0Hz), 6.78 (d,lH,J=11.0Hz).
Step 3: (l'S,U S) and (1'S,1S,3R) methyl 4',6'-tetradeoxy-3',4'- diacetoxy-I^yxohexopyranose)-3,4^,10-tetrahydronaphtho [2,3-c] thiopyran-3-yl) ketone
The procedure for the preparation of the tided compound is as described previously in step 1 (example 1).
62
SUBSTITUTE SHEET Thus, die 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 tided compounds 2:1 (74.2 mg, 0.15 mmol) in 70% yield after flash chromatography.
-H NMR (CDC13), 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,lH, J=20.0Hz,11.9Hz), 3.30 (dd,lH,J=19.9Hz,4.2Hz), 4.06 (dd,lH, J=12.0Hz,4.1Hz), 4.38 (m,lH), 5.05-5.22 (m,2H), 5.61 (d,lH, J=3.8Hz), 6.23 (s,lH), 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,lH,J= 20.0Hz, 12.0Hz), 3.32 (dd,lH,J=20.0Hz,4.1Hz), 4.15 (dd,lH,J=12.0Hz,4.1Hz), 4.38 (m, IH), 5.05-5.22 (m,2H), 5.63 (d,lH,J=3.8Hz), 6.00 (s,lH), 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.!-
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 conφounds towards tumor cells is measured in vitro using die 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 foπnazan product.
The following reagents were used for : tissue Culture, (Irvine Scientific Catalog)
-MEM containing nucleosides (Catalog tf 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 firom 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 ft 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;
63
SHEET MTT: 2 mg/ml in phosphate buffered saline (stable at 4°C in dark for 1 week). Sorensen's buffer: 0. IM glycine/NaOH, pH 10.5, containing 0. IM NaCl.
Test coπφounds: 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 die assay metiiod. - It should be noted that although die conditions described work well with die cells listed above, the initial plating density and die 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 die following manner
The assays are carried out in 96-well (8 well x 12 well) microtiter plates. Serial dilutions of die compound are tested along the length of die plate. A 1:3 serial dilution of coπφound 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 aftw which die coπφound 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 die 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 die 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 die 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 multidπig resistant cell line SKVLB. In breast cancer, MCF- 7, BCH-1146 is less potent than adriamycin but nearly as effective in die sensitive and adriamycin resistant cell line. These results suggest that tricyclic derivatives such as BCH-1184 and 1146 should be
64 usefid in die 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.
65
SUBSTITUTE SHEET EXAMPLE 15
BIOLOGICAL RESULTS
TABLE 1 IC50 μM
66
SUBSTITUTE SHEET
67
SUBSTITUTE SHEET
68
SUBSTITUTE SHEET
69 UBSTITUTE SH EET BCH2163 BCH2164
XλBLB 2 IC50 (UM
70
SUBSTITUTE SHEET Example 16: Preparation of naphthop ran derivatives
BCH-M51
Step l: Methyl (l,5,8-trimethoxyisochπ)nιan-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 die 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 (MgSO^ and evaporated under reduced pressure. The residue was recrystallized from methanol to give the tide product (white crystals, 14.34 g, 85.1 %). -NMR (250 MHz, Biucker, CDC13), d: 2.70 (IH, dd, J= 11.8 and 17.1 Hz, 4-HM), 3.08 (IH, dd, J=4.2 and 17.1 Hz, 4-Hβq), 3.57 (3H, s, 1-MeO), 3.77 (3H, s, Ar-O s), 3.80 (3H, s, Ar-QMe), 3.83 (3H, s, COOMe), 4.79 (IH, dd, J=4.2 and 11.8 Hz, 3-HM), 5.70 (IH, s, 1-H), 6.68 (IH, d, J=8 Hz, Ar-H), 6.74 (2H, d, J=8 Hz, Ar-H).
Step 2: Methyl (l-Metlrøxy-5,8-dioxυ-5,8-dihydπ>-isochronuuι-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 (l,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 oiganic phases were
71
SUBSTITUTE SHEET washed with brine (200 ml), dried (MgS04) 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. *H-NMR (250 MHz, Brucker, CDC13), d: 2.52 (IH, dd, J=11.4 and 19.4 Hz, 4-H„), 2.83 (IH, dd, J=4.2 and 19.4, 4-Hβq), 3.56 (IH, s, 1-MeO), 3.82 (IH, s, COOMe), 4.66 (IH, dd, J=4.2 and 11.4 Hz, 3-H„), 5.48 (IH, s, 1-H), 6.62 (IH, d, CHCO), 6.78 (IH, d, CHCO).
Step 3: Methyl (l-n__ethoxy-5,10-dioxcH3,4^,10-tet_rahydro-m-naphthot2 -c]p formate
Methyl (l-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, die 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 die clean fraction from flash chromatography were combined to give 9.07 g, (59.6 %) tide product.
*H-NMR (250 MHz, Biucker, CDCI3), d: 2.68 (IH, dd, J— 11.1 and 19.9 Hz, 4-H„), 3.07 (IH, dd, J=4.4 and 19.9 Hz, 4-Hgq), 3.62 (IH, s, 1-MeO), 3.83 (IH, s, COOMe), 4.72 (IH, dd, J=4.4 and 11.1 Hz, 3-H„), 5.70 (IH, s, 1-H), 7.75 (2H, m, Ar-H), 8.08 (2H, m Ar-H).
Step 4: Methyl (l-metlwxy-5,10-dioxo-5,10-dihydro-lH-naphtho[2^-c]pvran-3-yl) formate
Mediyl (l-methoxy-5, 10-dioxo-3,4,5,10-tetrahydro-ΪH-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 witii acetic acid. The oiganic layer was separated, the water layer was extracted witii ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO^ 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 (MgS04) 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 %). *H-NMR (250 MHz, Brucker, CDCI3), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, s, COOMe), 6.38 (IH, 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 (l-methoxy-5,10-dioxo-5,10^hydro-_LH-naphtho[2 -c]pyran-3-yl)formate.
72
SUBSTITUTE SHEET Methyl (l-methoxy-5,8-dioxo-5,8-dihydro-i8θchroman-3-yl) formate (12.70 g, 50.35 mmol), 1- acetoxybutadiene (30.00 g, 267. SS mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, die 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 witii acetic acid. The oiganic layer was separated, the water layer was extracted witii ethyl acetate (3x30 ml). The combined organic layers were dried (MgSO^ and concentrated to dryness. To the residue dichlorometane(120 ml) and saturated sodium bicaibonate solution (40 ml) was added, stirred for 5 minutes. After separation die organic layer was dried (MgS0 ) and concentrated to diyness to give die tide product (8.98 g, 59.4 ). -NMR (250 MHz, Brucker, CDC13), d: 3.63 (3H, s, 1-MeO), 3.92 (3H, S, COOMe), 6.38 (IH, s, 1- H), 7.33 (1-H, s, 4-H), 7.75 (2H, m, Ar-H), 8.13 (2H, m, Ar-H).
Step 6: l-MetlMxy-5,10-dioxo-5,10-dihyd_r >-lH-napht_Mβ add
Methyl (l-medιoxy-5,10-άιoxc)-5,10-dihydro-lH-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 die previous extractions as well - were combined, dried (MgSO^ and concentrated to dryness. The residue was combined witii 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-dg), d: 3.50 (3H, s, 1-MeO), 6.37 (IH, s, 1-H), 7.02 (IH, s, 4- H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 7: l-Methoxy-5,10-diox(H5,l(l-dihydro-lH-naphtbo[2 -c]pyran-3-IN-(3- dύn_ethylan__ino-propyl)carboxamide]
l-Methoxy-5,10-dioxo-5,10-dihydπ>-lH-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
73
SUBSTITUTE S'πEET were dried (MgS04) 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 witii ether to give the title product (4.15 g, 69.6 %). iH-NMR (250 MHz, Brucker, CDC13), d: 1.74 (2H, quint., CH2), 2.29 (6H, s, NMe^, 2.47 (2H, m, CH2), 3.35 - 3.65 (2H, m, O , 3.63 (3H, s, 1-MeO), 6.37 (IH, s, 1-H), 7.33 (IH, s, 4-H), 7.75 (2H, m, Ar-H), 8.15 (2H, m, Ar-H), 8.70 (IH, broad, NH).
Step 8: l-Methoxy-5,10-dioxo-5,10-dihydro-m-naphtho[23-c]pyran-3-{N-(3- dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
l-Methoxy-5, 10-dioxo-5, 10-dihydro-lH-naphtho[2,3-c]pyran-3-[N-(3-dimethylamino- propyl)caιboxamide] (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
%).
*H-NMR (250 MHz, Brucker, DMSO-ctø, d: 1.90 (2H, m, T-CΑj). 2.72 (6H, s, NMe^, 3.00 (2H, m, 3'-CH2>, 3.30 (2H, m, l'-CH^, 3.60 (3H, s,MeO), 6.35 (IH, s, 1-H), 7.00 (IH, s, 4-H), 7.90 (2H, m, Ar-H), 8.05 (2H, m, Ar-H), 8.92 (IH, t, CONH), 10.53 (IH, broad, NH+).
13C-NMR (250 MHz, Brucker, DMSO- g), 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
74
SUBSTITUTE SHEET NH30C __M,a
+1 - Sepin_er
BCH-2017
Ste l: 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 chlorofoπn (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 die solvent was evaporated. The residue was taken up in EtOAc and washed with 5% HC1 (2x), sat. aq. NaHCθ3 and brine. The oiganic phase was dried over Na2S04, the solids filtered and die solvant evaporated to give 0.71 g (87 %) of N-Boc-Ser-Leu-OMe as a clear oil that was used without further purification. -U NMR (CDC13): δ 7.30 (bs, IH, NH), 5.72 (bs, IH, NH), 4.51 (m, IH), 4.19 (m, IH), 3.90 (m, IH), 3.68 (s, 3H), 3.62 (m, 2H), 1.55 (m, 3H), 1.34 (s, 9H), 0.79 (m, 6H).
Step 2: (1S^'S3R,5'S) and (lR^'S^S.S'Sl-l-fO-N-BOC-Serine-Leucine-Me ester]-3- aceto-5,8-dimeϋκ)xy-isochroman
75 m f«
SUBST ι L» SHEET To a solution of 5,8-dimethoxy-3-aceto-isochroman (0.46g, 1.93 mmole), the peptide from step 1 (exanφle 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. NaHCC^ and die phases were separated. The aqueous phase was extracted with CH2CI2 (2x) and die combined oiganic extracts were dried over MgS04. The solids were filtered and die 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 (CDCI3): δ 7.00 (bs, IH, NH), 6.74 (d, IH, J = 9.0, ArH), 6.68 (d, IH, J - 9.0, ArH), 5.81 (s, IH, H-l), 5.64 (bs, IH, NH), 4.52 (m, 2H), 4.29 (m, IH), 4.05 (m, IH), 3.88 (dd, IH, J *= 7.4, 10.6), 3.81 (s, 3H, AiOMe), 3.73 (s, 3H, ArOMe), 3.57 (s, 3H, COjMe), 3.00 (dd, IH, J - 4.1, 17.6, H-4), 2.47 (dd, IH, J = 12.3, 17.6, H-t), 2.29 (s, 3H, COMe), 1.57-1.46 (m, 3H, CH -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 %), Η NMR (CDCI3): δ 6.79 (m, 3H, 2ArH +NH), 6.10 (bs, IH, NH), 5.74 (s, IH, H-l), (4.62-4.33 (m, 3H), 3.91 (m, 2H), 3.77 (s, 6H, 2 ArOMe), 3.68 (s, 3H, CC^Me), 3.01 (dd, IH, J - 4.0, 17.6, H-4), 2.50 (dd, IH, 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: (lS^'S^S^'Sl-Methyl^l-O-IN-BOC-Serine-I^ucine-Me esterl-SJO-dioxo-
3,4 ,10-tetrahydro-l-H-naphtho [2,3-c] pyran-3-yl) ketone
To a solution of die peptido-isochroman from step 2 (exaπφle 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 NaHCC^ (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. NaHCθ3> The aqueous layer was then extracted with CH2CI2 (3*) «nd die combined organic extracts were dried over MgS04. The solids were filtered and die 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 die 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. -U NMR (CDCI3): δ 8.12-8.02 (m, 2H, ArH), 7.76-7.73 (m, 2H, ArH), 4.91 (bs, IH, NH), 5.92 (s, IH, H-l), 5.52 (bs, IH, NH), 4.62-4.47 (m, 3H, H-2' + H-5' + H-3), 4.17 (dd, IH, J = 4.4, 10.9, H- 1'), 3.83 (dd, IH, J = 8.6, 10.9, H-l'), 3.56 (s, 3H, CC^Me), 3.02 (dd, IH, J = 4.0, 19.9, H-4), 2.51 (dd, IH, 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).
76
SUBSTITUTE SHEET Step 4: (lS^,S^S,5,S)-Methyl-(l-O4Seriι^Leu ne-Me ester]-5,10-diox(>-3,4,5,10- tetrahydτo-1-H-naphtho [2,3K.] pyran-3-yI) ketone hydrochloride BCH-2000
A solution of die 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 HC1. The aqueous phase was washed with CH2CI2 (2x) and die water was evaporated. The tided compound was obtained as a yellow oil was dried under high vacuum for 18 hours after which it had crystallized: 40 mg (83 %).
-U NMR (DMSO-dg): δ 8.98 (bs, IH, NH amide), 8.42 (bs, 3H, NH3CI), 8.06-7.98 (m, 2H, ArH), 7.93-7.87 (m, 2H, ArH), 5.82 (s, IH, H-l), 4.61 (dd, IH, J = 3.9, 11.4), 4.34-4.23 (m, 2H), 4.13 (m, IH), 4.02 (dd, IH, J = 5.7, 9.8), 3.61 (s, 3H, CC^Me), 2.88 (dd, IH, J - 3.9, 19.6, H-4), 2.47 (m, IH, H-4 hidden under die 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
NHjCI
" ^Ns OjMe
BCH-1654 +l,3- ieptmer
Ste l: 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 (BO 2O (0.19 g, 1.1 eq.) and die soluticm was stirred for 60 minutes. It was then poured in cold 2% HC1 and the
77
SUBSTITUTE SHEET aqueous layer was extracted with CH2CI2 (3x). The combined organic extracts were dried over MgS0 , the solids were filtered and die solvents evaporated to give 0.17 g (100 %) of the titled compound as a clear oil.
*H NMR (CDCI3): δ 5.56 (bs, IH, NH), 4.34 (m, IH, CJI-CC^Me), 3.88 (m, 2H, £H2-OH), 3.75 (s, 3H, CC^Me), 2.96 (bs, IH, OH), 1.44 (s, 9H, BOC).
Step 2: (IS, 2'S, 3R) and (IR, 2'S, 3S)-H -serine methyl ester]-3-aceto-5,8-dimethoxy isochroman.
The tided 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.
-H NMR (CDCI3): δ 6.73 (m, 2H, ArH), 6.07+5.78 (2d, IH, NH), 5.72+5.70 (2s, IH, H-l), 4.56- 4.35 (m, 3H, H-l' and H-2'), 3.98 (m, IH, H-3), 3.90+3.81+3.78+3.77+3.76+3.67 (6s, 18H [6x3H], Ar-OMe and CC^Me), 3.04 (2dd, IH, H-4), 2.50 (2dd, IH, H-4), 2.32 (d, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 3: (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyI-(l-[0-N-BOC-βe_rine methyl ester]-5,10- dioxo-3,4,5,10-tetrahydro-l-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.
*H NMR (CDCI3): δ 8.05 (m, 2H, ArH), 7.73 (m, 2H, ArH), 5.90+5.52 (2d, IH, NH), 5.73+5.72 (2s, IH, H-l), 4.60-4.05 (m, 4H, H-3, H-l' and H-2'), 3.81+3.70 (2s, 3H, CO2CH3), 3.01 (2m, IH,
H-4), 2.48 (m, IH, H-4), 2.35 (2β, 3H, COCH3), 1.47+1.43 (2s, 9H, BOC).
Step 4: (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyl-(H -βeriιιe methyl ester]-5,10-dioxo-
3,4^,10-tetrahydronaphtaleno [2,3-C] pyran-3-yl) ketone hydrochloride.
The titled compounds were obtained as per procedure described in step 4, example 17. -U NMR (DMSO): δ 8.05-7.82 (m, 4H, ArH), 5.83+5.78 (2s, IH, H-l), 4.69-4.40 (m, 2H, H-l'), 4.27 (m, IH, H-3), 4.16 (m, IH, H-2'), 3.79+3.73 (2s, 3H, CC^Me), 2.91+2.87 (2m, IH, H-4), 2.50 (m, IH, H-4), 2.31+2.29 (2s, 3H, COCH3).
Example 19: Amino akobol substituted naphthoquinone derivative
78 UB^ ϋ . c πEE l
+lf3^-MpMMT
BCH-1658 BCH-2067
Step l: N-BOC-Prolinol
The tided coπφound was obtained as per procedure described in step 1, example 18.
-K NMR (CDC13): δ 4.19 (bs, IH, OH), 3.95 (m, IH, H-2), 3.59 (m, 2H, fiFfc-OH), 3.42 (m, IH, H- 5), 3.30 (m, IH, H-5), 2.01 (m, IH, H-3), 1.83 (m, 2H, H-4), 1.60 (m, IH, H-3), 1.45 (s, 9H, BOC).
Step 2: (IS, 2'S, 3R) and (IR, 2'S, 3S)-HO-N-BOC-prolinol]-3-acetyl-5,8-dimethoxy isochroman
The tided 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 chromatogπφhy. -K NMR (CDCI3): δ 6.72 (m, 2H, ArH). 5.82+5.77 (2s, IH, H-l), 4.54 (m, IH, H-3), 4.18-3.20 (m, 5H, H-l', H-2' and H-5'), 3.82+3.79 (2s, 6H, ArOMe), 3.05 (2m, IH, H-4), 2.53 (m, IH, 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: (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyHl-[O-N-BOC-prolinol]-5,10-dioxo-3,4,5,10- tetrahydro-1-H-naphtho [2,3-C] pyran-3-yl) ketone BCH-2067
79
SUBSTITUTE SHEET 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 hexaneβ/ethyl acetate). -H NMR (CDC13): δ 8.02 (m, 2H, ArH), 7.70 (m, 2H, ArH), 5.75+5.73 (2s, IH, H-l), 4.47 (m, IH, H-3), 4.15-3.18 (m, 5H, H-l', H-2' and H-5'), 2.97 (2m, IH, H-4), 2.5 (m, IH, 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: (IS, 2'S, 3R) and (IR, 2'S, 3S)-methyl-(HO-prolinol]-3,4,5,12-tetrahydronaphtiκ>-
[2,3-C] pyran-3-yI) ketone hydrochloride salt
The tided conφounds were obtained as per procedure described in step 4, exaπφle 17. JH NMR (DMSO): δ 8.02 (m, 2H, ArH), 7.88 (m, 2H, ArH), 5.73+5.71 (2s, IH, H-l), 4.68 (m, IH, H-3), 4.19-3.48 (m, 3H, H-2' and H-l'), 3.10 (m, 2H, H-5'), 2.39 (dd, IH, H-4), 2.35 (m, IH, 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- ] pyran derivative with a cyano side chain
80
SUBSTITUTE SHEET
7 r-R-PN ' l»R- H
BCH-1688
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 MgS04 and evaporated. The tided compound was purified by trituration in ether (11 g, 60%), m.p.: 118-119°C.
-H NMR (250 MHz, CgD^, 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, IH, H-l), 4.53 (d, J = 15.5 Hz, IH, H-l), 4.40 (dd, J = 4.7 and 9.2 Hz, IH, H-3), 3.40 (dd, J - 4.7 and 17.0 Hz, IH, H-4), 3.28 (s, 3H, -OCH3), 3.27 (dd, 9.2 and 17.0 Hz, IH, H-4), 3.19 (s, 3H, -OCH3).
81
SUBSTITUTE SHEET 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 CH2C12 (40 ml) at -78°C under argon was added die pyranylsulfone from step 1 (example 2) (1.16 g, 3.5 mmol) then the temperature was slowly raised to -20°C. After 4 hours, die reaction mixture was worked up in methylene chloride and water. The organic layer was washed with brine and dried over MgS04. The solvent was evaporated and die residue was purified by flash chromatography (hexanes/AcOEt 3/1) to give the tided compound (596 mg, 78 %).
-H NMR (250 MHz, CDCI3), δ: 6.30 (2d, J «= 8.2 Hz, 2H, Ar-H), 5.08 (d, J - 16.3 Hz, IH, H-l), 4.78 (d, J = 16.3 Hz, IH, H-l), 4.03 (t, J - 5.1 Hz, IH, H-3), 3.27 (s, 3H, -OCH3), 3.18 (s, 3H, - OCH3), 2 8° (**. J = 5.1 and 17.2 Hz, IH, H-4), 2.66 (dd, J = 5.1 and 17.2 Hz, IH, H-4).
Step 3: l-hydroxy-3-cyano-5,8-dimetboxy isochroman
To a stirred solution of 2,5-dimethoxy-3-cyano isochroman (670 mg, 3.06 mmol) in CC14 (60 ml) were added N-bromoβuccinimide (653 mg, 3.67 mmol) and a catalytic amount of AIBN. The mixture was heated to reflux and after 45 minutes, die solvent was evaporated and tetrahydrofurane (40 ml) and water (40 ml) were added. After 1 hour, die reaction mixture was worked up in ether. The organic layer was washed witii brine and dried over MgS04. The solvent was evaporated and die residue purified by trituration in a small amount of ether to give the tided compound (453 mg, 63 %). JH NMR (250 MHz, acetone D6): 6.90 (2d, J = 9.0 Hz, 2H, Ar-H), 6.06 (2d, J = 5.2 Hz, 2H, H-l , - OH), 5.27 (dd, J - 4.1 and 12.1 Hz, IH, H-3), 3.81 (β, 3H, -OCH3), 3.78 (s, 3H, -OCH3), 3.09 (dd, J - 4.1 and 17.1 Hz, IH, H-4), 2.82 (dd, J = 12.1 and 17.1 Hz, IH, H-4).
Step 4: l-hydraxy-3-cyanι>-5,8-dioxo-5,8-dihydroisochroman
The tided 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.
-H NMR (250 MHz, acetone D6) δ: 6.86 (2d, J - 10.1 Hz, 2H, -CH=CH-), 6.61 (d, J = 5.7 Hz, IH, H-l), 5.88 (d, J = 5.7 Hz, IH, -OH), 5.20 (dd, J - 3.8 and 11.6 Hz, IH, H-3), 2.98 (dd, J = 3.8 and 18.9 Hz, IH, H-4), 2.73 (dd, J = 11.6 and 18.9 Hz, IH, H-4).
Step 5 and 6: (l'S, IS, 3R) and (l'S, IR, 3S)-5,10-dioxo-3-cyano-l-(2, ',6',- trideoxy-3'-trifluoroacrtamido-4'-Q-p-nitrobenzoyl-L- lyxohexopyranose)-3,4^,10-tetrahydro-l-H-naphtho-[2^-c] pyran
The tided compounds were obtained in 27 % yield by following die procedure described in step 4, example 12, on die precursor of step 4 of this example.
JH 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, IH, -NH), 6.15 and 5.95 (2s, IH, H-l), 5.70 (m, IH, H-4'), 5.60 and 5.55 (m, IH, H-l'), 5.10 (m,
82
SUBSTITUTE SHEET IH, 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: (l'-S, 1-R, 3-S) and (l'-S, 1-S, 3-R)-3^cyano-l-[2,^',6,-trideoxy-3'- trifluoroacetaι__tido-4,-hyd_n_κy-I_f-l^ tetrahydronaphtho-[2 -C] pyran-3-yl BCH-1688
The tided coπφounds were obtained in 63% yield by following die procedure described in step 3, example 5, cm the precursor from step 6 of this exanφle. -H NMR (250 MHz, CD2C12) δ: 8.07 (m, 2H, Ar-H), 7.79 (m, 2H, Ar-H), 6.80 (m, IH, N-H), 6.09 and 5.92 (2s, IH, H-l), 5.52 and 5.42 (2d, IH, H-l'), 5.04 (lm, IH, H-3), 4.40-4.05 (m, 2H, H-3', H- 5'), 3.70 (m, IH, H-4'), 3.20-3.05 (lm, IH, H-4), 3.00-2.80 (lm, IH, H-4), 2.30-2.00 (m, 3H, -OH, H-2'), 1.38 and 1.29 (2d, J = 6.7 Hz, 3H, H-6').
83
SUBSTITUTE SHEET Example 21: Preparation of some sugar derivatives
OMc OKfc
Me
TBDMSCV/^^-^ - NHT A TBDMSOr/,, .*-. VNHIFA
Me Me
\
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 MgS04. The solvent was evaporated. The products were separated by flash chromatography (hexanes/AcOEt 2/1) to give dimethoxy fucal (79 mg, 16 %).
JH NMR (250 MHz, CDC13) δ: 6.29 (dd, J = 1.3 and 6.2 Hz, IH, H-l), 4.72 (m, IH, H-2), 4.05 (m, 2H, H-5, H-4), 3.57 (s, 3H, -OCH3), 3.44 (m, IH, 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:
*H NMR (250 MHz, CDCI3) δ: 6.36 (dd, J = 1.2 and 6.2 Hz, IH, H-l), 4.60 (m, IH, 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, IH, -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.
84
SUBSTITUTE SHEET ln NMR (250 MHz, CDCI3) δ: 6.34 (dd, J = 2.1 and 6.5 Hz, IH, H-l), 4.95 (m, IH, H-2), 4.73 (m, IH, 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 dimc^ylsUyk>xy-3-trifluoπιarrtamido-4-n_«thaι_^ulfonyl-2^,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 CH2C12 (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 witii CH2Cl2 and HCl 0.1 N. The oiganic layer was washed with a solution of NaHCC^ and brine then dried over MgS04. The solvent was evaporated to give 1-t-butyl dimethyl silyloxy, 3- trifluoroacetamido-2,3,6 trideoxy-4 methanesulfonyl-L-lyxohexopyranose (604 mg, 98%). 'K NMR (250 MHz, CDCI3) δ: 7.28 (d, J = 7.7 Hz, IH, N-H), 4.83 (dd, J = 2.1 and 9.1 Hz, IH, H- 1), 4.71 (d, J = 2.2 Hz, IH, H-4), 4.25 (m, IH, H-3), 3.75 (q, J - 6.4 Hz, IH, H-5), 3.18 (s, 3H, - SO2-CH3), 2.0 (m, IH, H-2), 1.75 (m, IH, 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-4-0-bromoac^l-2 >6-trideoxy-^ lyxohexopyranose
To a stirred solution of 1-t-butyl diinethylsUyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L- lyxohexopyranose (81 mg, 0.18 mmol) in CH2C12 (2 ml) at 0°C were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, die reaction mixture was worked up with CH2C12 and water. The organic layer was washed with brine and dried over MgS0 . The solvent was evaporated to give the tided compound (76 mg, 74%).
JH NMR (250 MHz, CDCI3) δ: 6.47 (d, J - 8 Hz, IH, N-H), 5.03 (d, J = 3.0 Hz, IH, H-4), 4.84 (dd, J = 2.3 and 9.0 Hz, IH, H-l), 4.35 (m, IH, 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, IH, 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
85
SUBSTITUTE SHEET
BCH-2072
Step l: (l'-S, 1-S, 3-R) and (l'-S, 1-R, 3-S)-methyl-(l-[2'^',4,,6l tetradeoxy-3'- t_rifluoroarrtamido-4'-Q-methane-sι_Jfonyl-L-lyxohexopyra__^^ 3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2095
The tided 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).
-H NMR (250 MHz, CDC13) δ: 8.10 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H), 7.15 (2d, J = 8.0 Hz, IH, N-H), 6.16 and 6.00 (2s, IH, H-l), 5.62 and 5.50 (2d, J = 1.5 Hz, IH, H-l'), 4-89 and 4.84 (2 broad s, IH, 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, IH, H-4), 2.55 (m, IH, 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: (l'-S, 1-S, tetraαeoxy-3,-trifliMroacetamido-4'-0-(2- bromo-acetyl)-L-lyxopyranose]-5, lO-dioxo-3,4,5,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) ketone BCH-2105
86
SUBSTITUTE To a stirred solution of die aglycone from example 3 (30 mg, 0.11 mmol), 4-bromoacetyl-l-t-butyl dimethylsilyloxy-3-trifiuoro-acetamido daunoβamine derivative (76 mg, 0.13 mmol) molecular sieves A (62 mg) in CH2C12 (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 NaHC03 10% and CH2C12. The organic layer was washed with brine and dried over MgS0 , the residue was purified by flash chromatography (hexanes/AcOEt 2:1) to give the tided coπφound (8 mg, 12%). lH NMR (250 MHz, CDCI3) δ: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 6.33 (d, J = 8.1 Hz, IH, N-H), 6.00 (s, IH, H-l), 5.67 (s, IH, H-l'), 5.16 (s, IH, H-4'), 4.53 (dd, J = 3.9 and 11.6 Hz, IH, H-3), 4.53 (m, IH, H-3'), 4.23 (q, J = 6.7 Hz, IH, H-5'), 3.90 (2d, J = 10.9 Hz, 2H, -CH2-Br), 3.08 (dd, J = 3.9 and 19.8 Hz, IH, H-4), 2.53 (dd, J = 11.6 and 19.8 Hz, IH, 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: (l'-S, 1-R, 3-S)-methyMl-[2',3',4',6' tetradeoxy-3'-methoxy-4'-0- methanesu__fonyl-Lr4yxobexopyranose)-5,10-dioxo-3>4^,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 exaπφle 3 and die glycal from step 2, example 21. Purification was carried out by flash chromatography (toluene/acetone:95/5) M.P. 85-89°C.
-K NMR (250 MHz, CDCI3) δ: 8.11 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 5.98 (s, IH, H-l), 5.62 (d, J = 2.8 Hz, IH, H-l'), 4.85 (s, IH, H-4'), 4.46 (dd, J = 4.0 and 11.6 Hz, IH, H-3), 4.04 (q, J - 6.5 Hz, IH, H-5'), 3.62 (m, IH, H-3'), 3.39 (s, 3H, -OCH3), 3.14 (s, 3H, -SO2-CH3), 3.05 (dd, J = 4.0 and 19.5 Hz, IH, H-4), 2.50 (dd, J = 11.6 and 19.5 Hz, IH, 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): (l'-S, l'S, 3-R)-methyl-(l-[2'^',4',6l tetradeoxy-3'-methoxy-
4'-O-π_^hanesu__fonyI-___^yxolκxopyranose)-5,10-dioxo- 3,4,5,10 tetrahydronaphtho-[23 ] pyran-3-yl) ketone BCH- 2072
The tided compound was obtained in 11% yield by using die procedure described in step 3 of this example but using the 1,3-diepimeric aglycone. M.P. 139-141°C. lH NMR (250 MHz, CDCI3) δ: 8.12 (m, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 6.15 (s, IH, H-l), 5.52 (d, J = 1.5 Hz, IH, H-l'), 4.95 (d, J = 1.5 Hz, IH, H-4'), 4.59 (q, J - 6.5 Hz, IH, H-5'), 4.49 (dd, J = 4.1 and 11.6 Hz, IH, H-3), 3.60 (m, IH, H-3'), 3.38 (s, 3H, -SO2CH3), 3.15 (s, 3H, -OCH3), 3.07 (dd, J = 4.1 and 19.9 Hz, IH, H-4), 2.55 (dd, J = 11.6 and 19.9 Hz, IH, H-4), 2.33 (s, 3H, -CO-CH3), 1.95 (m, 2H, H-2'), 1.50 (d, J = 6.5 Hz, 3H, H-6').
87
SUBSTITUTE SHEET Step 4: (1-S, 3-R) and (1-R, 3-S)-methyl-(l-(l-πιethoxy-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 tetrahydrofiirane (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 CH2C12 and NaHCθ3 5 % . The organic layer was washed with brine and dried over MgS04. The solvent was evaporated to give the tided compound (10 mg, 96%).
-H NMR (250 MHz, CDC13) δ: 8.10 (m, 2H, Ar-H), 7.70 (m, 2H, Ar-H), 6.34 (s, IH, H-l), 4.66 (dd, J - 4.3 and 11.6 Hz, IH, 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, IH, H-4), 2.52 (dd, J = 11.6 and 19.0 Hz, IH, H-4), 2.30 (s, 3H, -CO- CH3), 2.20-1.85 (m, 4H, -CH2-C-CH2-).
88
SUBSTITUTE SHEET Example 23: Preparation of naphtho-[2,3,-c] pyran derivative with a homo methyl ketone side chain
BCK2098
Ste l: 5,8-Dimetboxy-3-(t-butyl acetoacetato) isochroman
To a stirred soluticm of pyranosulfcme from step 1, example 20, (1.12 g, 3.35 mmol) in CH2C12 (40 ml) at -78°C were added a solution of silyl enol ether of t-butyl acetoacetato (10 mmol) in CH2C12 (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 CH2C12 and HC10.1 N. The oiganic was washed with brine and dried over MgS04. The solvent was evaporated to give the title β-ketoester (519 mg, 43 %)_ -ϋ NMR (250 MHz, CDCI3), δ: 6.63 (m, 2H, Ar-H), 4.91 and 4.85 (2d, J = 9.8 Hz, IH, H-l), 4.60 and 4.53 (2d, J = 7.9 Hz, IH, H-l), 4.20 (m, IH, H-3), 3.76-3.74 (3s, 6H, -OCH3), 3.62 (t, J = 9.5
89
SUBSTITUTE SHEET Hz, IH), 2.90 (m, IH, H-4), 2.45 (m, IH, 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 exaπφle was decaiboxylated, in 91 % yield, witii concentrated aqueous
HBr in acetone. lH NMR (250 MHz, CDCI3) δ: 6.63 (2d, J = 9.0 Hz, 2H, Ar-H), 4.88 (d, J = 15.9 Hz, IH, H-4),
4.58 (d, J = 15.9 Hz, IH, H^»), 4.06 (m, IH, 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, IH, H-4), 2.40 (dd, J «= 10.9 and 16.5 Hz, IH, H-4), 2.24
(s, 3H, -CO-CH3).
Step 3: 5,tM>imet mxy-3-(propane-2-oι_e)-l-(2',3',6^ nitrobenzoyl-L-lyxohexopyronose)-isoc__ιroman
The isochroman from 2 herein was glycosidated as per procedure described in step 3, example 34. The title compound was obtained in 97% yield.
-H NMR (250 MHz, CDCI3) 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, IH, -NH), 6.02 and 5.88 (2s, IH, H-l), 5.59 (s, IH, H-l'), 5.49 and 5.46 (2s, IH, 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-Dk>xo-3-(propane-2s)ne)-l-(2'^',6l-trideoxy-3,-triflιιoroacetaιnid mtrobenzoyl-L4vxohexopyιanose)-isochroman
The tided conφound was obtained in 94% yield via oxidative demethylation of the isochroman obtained from step 3 herein as per procedure described in step 4, exaπφle 34.
JH NMR (250 MHz, CDCI3), 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, IH, N-H), 5.81 and 5.70 (2s, IH, H-l), 5.59 and 5.54 (2s, IH, H-l'), 5.45 (2d, J = 1.5 Hz, IH, H-4'), 4.80-4.40 (m, 3H, H-3', H-5', H-3), 2.90 (m, IH, 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-(pπφa__ιe-2-one)-l-(2',3',6'-triα^ mtrobenzoyl-L-lyxohexopyπuM)se)-3,4 ,10-t^
The tided 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.
90 CT 3 I D f " ~~^" z f- • * - .- ' , » «*■ ■_-> -*» JH NMR (250 MHz, CDCI3), 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, IH, N-H), 5.99 and 5.88 (2s, IH, H-l), 5.71 and 5.60 (2s, IH, H- 1'), 5.48 (Is, IH, 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: (l'-S, 1-S, 3-R) and (l'-S, 1-R, 3-S)-l-{6-h dro -l-(2,^,, ,-trideox -3,- trifluoroa«^amido,4-hydroxy-Lr-lyxopyranose)-5,10-dioxo-3,4^,10 tetrahydronaphtho-[2,3-c] pyran-3-yl) propane-2-one BCH-2098
The tided compound was obtained following deprotection of die glycoβide from step 5 herein as per procedure described in step 6, example 34.
-H NMR (250 MHz, CDCI3) δ: 8.10 (m, 2H, Ar-H), 7.75 (m, 2H, Ar-H), 6.73 (d, J = 7.5 Hz, IH,
N-H), 5.93 and 5.81 (2s, IH, H-l), 5.52 and 5.41 (2d, J = 2.7 Hz, IH, H-l'), 4.80-4.20 (m, 3H, H-3, H-3', H-5'), 3.70 (m, IH, 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 lin age
91
SUBSTITUTE oκfc m
/
4 |-R -PN ? ΓR-PN
BCH-21 4 BCH-214S
Step l: (IR, 3S) and (1-S, 3R)-l-(2'^',6'-trideoxy-3'-trifluoroacetamid<H4,-0-p- nitrobenzyk>xy-l,5-dihydπ>-L-l^^ acetoisochroman
2,5-Dimethoxy-l-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). -H 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, IH, H-l'), 5.84 (d, J = 3.6 Hz, IH, H-4'), 5.62 (s, IH, H-l), 5.30 (m, IH, H-3'), 4.45 (m, 2H, H-3, H-5'), 3.81 (Is, 3H, - CH3), 3.76 (Is, 3H, -OCH3), 3.11 (dd, J = 3.9 Hz and 17.3 Hz, IH, H-4), 2.61 (dd, J = 12.1 and 17.3 Hz, IH, H-4), 1.95 (s, 3H, -COCH3), 1.28 (d, J - 6.6 Hz, 3H, H-6'). The second diastereomer had:
92
SU -H NMR (250 MHz, CDCI3) δ: 8.28 (2d, J - 9.0 Hz, 4H, Ar-H), 6.90 (d, J = 7.8 Hz, IH, N-H), 6.70 (2d, J - 9.0 Hz, 2H, Ar-H), 6.18 (d, J = 1.5 Hz, IH, H-l'), 5.75 (d, J = 4.8 Hz, IH, H-4'), 5.55 (s, IH, H-l), 5.30 (m, IH, 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, IH, H-4), 2.57 (dd, J = 11.6 and 17.6 Hz, IH, H-4), 2.29 (s, 3H, -CO-CH3), 1.29 (d, J - 6.6 Hz, 3H, H-6').
Step 2: dihydro-Lr-lyxohexopyraiMi8e-2-yl)-S,8-dioxoisochroman
The (IR, 3S) product from step 1 herein was oxidatively demethylatod as per procedure in step 3, example 12. lH NMR (250 MHz, CDCI3) 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, IH, N-H), 6.75 (2d, J = 10.3 Hz, 2H, Ar-H), 6.28 (d, J = 1.4 Hz, IH, H-l),
5.78 (d, J = 3.8 Hz, IH, H-4'), 5.37 (s, IH, H-l'), 5.21 (m, IH, H-3'), 4.43 (q, J = 6.5 Hz, IH, H- 5'), 4.24 (dd, J = 3.8 and 11.2 Hz, IH, H-3), 2.90 (dd, J = 3.8 and 19.5 Hz, IH, H-4), 2.40 (ddd, J =
1.6, 11.2 and 19.5 Hz, IH, H-4), 1.88 (s, 3H, -COCH3), 1.26 (d, J - 6.5 Hz, 3H, H-6').
Step 3: (IR, 3S)-l-(2'^ 6'-trideoxy-3,-trifluoroac*tanύdo-4,-0-p-nitroben_^ dihydro- -lyx(>l_-exopyranos 2-yl)-5,lQ^ [2,3-c] pyran
The quinone firom step 2 herein was cycloadded with 1 -acetoxybutadiene as per procedure from step 4, exaπφle 12. The product had:
-U NMR (250 MHz, CDCI3) 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, IH, H-l), 5.86 (d, J = 3.9 Hz, IH, H-4'), 5.60 (s, IH, H-l'), 5.31 (m, IH, H-3'), 4.49 (q, J - 6.6 Hz, IH, H-5'), 4.35 (dd, J = 3.9 Hz, and 11.4 Hz, IH, H-3), 3.12 (dd, J
= 3.9 Hz and 19.4 Hz, IH. H-4), 2.62 (ddd, J - 1.9, 11.4 Hz, 19.4 Hz, IH, H-4), 1.98 (s, 3H, -CO-
CH3), 1.31 (d, J « 6.6 Hz, 3H, H-6').
Step 4: (IR, 3S)-l-(2, r3S6,-tricteo.<y-3,-t_riflι_ιoroace uιύ lyxobcxopyrano6e-2-yl)-5,10-dioxo-3,4,5,10^etrah^ pyran
BCH-2144
The tricyclic product from step 3 herein was deprotected as per procedure from step 3, example 5. The title product had: *H NMR (250 MHz, CDCI3) δ: 8.20 (m, 2H, Ar-H), 7.75 (m, 3H, N-H, Ar-H), 6.25 (d, J = 1.7 Hz, IH, H-l), 5.55 (s, IH, H-l'), 5.11 (m, IH, H-3'), 4.32 (dd, J - 4.0 Hz and 11.1 Hz, IH, H-3), 4.23 (q, J = 6.5 Hz, IH, H-5'), 4.05 (d, J = 3.7 Hz, IH, H-4'), 3.00 (dd, J = 4.0 and 19.8 Hz, IH, H-4), 2.59 (ddd, J = 1.7, 11.1 and 19.8 Hz, IH, H-4), 2.28 (s, 3H, -CO-CH3), 1.70 (broad s, IH, -OH), 1.34 (d, J = 6.5 Hz, 3H, H- ').
93
SUBSTITUTE SHEET Step 5: (IS, 3R)-l-(2, \6,-trideoxy-3^trinuoroacetamido^'-0-p-nitrobenzyloxy-l,5- dihydro-L^yxohexopyranose-2-yl)-5,8-dioxoiso hroιnan
The (IS, 3R) product from step 1 herein was oxidatively demethylated as per procedure in step 3, example 12.
-K NMR (250 MHz, CDCI3) 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, IH, N-H), 6.80 (2d, J - 10.1 Hz, 2H, Ar-H), 6.46 (d, J - 1.3 Hz, IH, H-l), 5.73 (d, J - 4.8 Hz, IH, H-4'), 5.33 (d, J = 1.9 Hz, IH, H-l'), 5.25 (m, IH, H-3'), 4.35 (q, J - 6.6 Hz, IH, H-5'), 4.20 (dd, J - 4.1 Hz and 10.5 Hz, IH, H-3),.2.88 (dd, J - 4.1 and 19.9 Hz, IH, H-4), 2.40 (ddd, J «= 1.9, 10.5 and 19.9 Hz, IH, H-4), 2.27 (β, 3H, -COCH3), 1.32 (d, J = 6.6 Hz, 3H, H- 6').
Step 6: (IS, 3R)-l-(2'r3 '-trid_».<y-3,-trifluoroace^ dihydro-L-lyxob£xopyrano6e-2-yl)-5,10-dioxo^
[2,3-c] pyran
The quinone from step 5 herein was cycloadded with 1 -acetoxybutadiene as per procedure from step 4, exanφle 12. The tided product had: -H NMR (250 MHz, CDCI3) δ: 8.30 (d, J = 8.9 Hz, 2H, Ar-H), 8.22 (d, J - 8.9 Hz, 2H, Ar-H), 8.20 (m, IH, Ar-H), 8.00 (m, 2H, N-H, Ar-H), 7.86 (m, 2H, Ar-H), 6.53 (s, IH, H-l), 5.77 (d, J ~= 4.7 Hz, IH, H-4'), 5.50 (s, IH, H-l'), 5.30 (m, IH, H-3'), 4.37 (q, J « 6.6 Hz, IH, H-5'), 4.27 (dd, J = 4.0 and 10.7 Hz, IH, H-3), 3.08 (dd, J = 4.0 and 19.8 Hz, IH, H-4), 2.55 (ddd, J = 1.0, 10.7 and 19.8 Hz, IH, H-4), 2.31 (s, 3H, -CO-CH3), 1.31 (d, J - 6.6 Hz, 3H, H-6'). Step 7: (IS, SRH-P'^C'-trideox ^'-trifluoroa etaπύ^ lyxohexopyπuM6e-2-yl)-5,10-dioxo-3,4,5,lQ-tetι^^
BCH-2145
The tricyclic product from step 6 herein was deprotected as per procedure from step 3, example 5. The tided product had:
-H NMR (250 MHz, CDCI3) δ: 8.19 (d, J = 8.9 Hz, IH, N-H), 8.10 (d, J - 7.3 Hz, IH, Ar-H), 7.90 (d, J = 7.3 Hz, IH, Ar-H), 7.70 (m, 2H, Ar-H), 6.26 (s, IH, H-l), 5.47 (s, IH, H-l'), 5.10 (m, IH, H-3'), 4.20 (m, 2H, H-3, H-5'), 3.97 (d, J = 4.0 Hz, IH, H-4'), 3.00 (dd, J = 4.0 and 20.0 Hz, IH, H-4), 2.55 (dd, J - 10.8 Hz, and 20.0 Hz, IH, H-4), 2.32 (s, 3H, -CO-CH3), 1.70 (broad s, IH, -OH), 1.36 (d, J = 6.4 Hz, 3H, H-6').
Example 25: Preparation of 3 -bis-(methoxycariκmyl)-5,10-dioxo-3,4 ,10-tetrahydro- lH-naphtho-[2,3-c]-pyran (BCH-1665)
94
- r — »« __ ->
SUBSTITb 1 c -Dr eπ I
BOfclBi
Step 1: 5,8-dimethoxy-3,3 bis (methoxycarbonyl)-isochroman
To a solution of 2,3 bis (b_romomethyl)-l,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 die 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 HC1 and extracted with dichloromethane. The combined organic layers were washed with brine and dried over MgS0 . The crude product was purified by column chromatography on silica gel using 10-25% ethyl acetate in hexane to afford die tide compound (452 mg; 36% overall): -H NMR (250 MHz; CDCI3) δ: 3.25 (2H, a, H-4), 3.72, 3.78, 3.79 (12H, 3β, 4xOCH3), 4.88 (2H, s, H-l), 6.59 and 6.65 (2H, AB doublets, Ar-H).
Step 2: 5,8-dioxo-3,3 bis (ιm4__Mxycarhonyl)-5,8-dihydro-isodιronιan
To a aolution of5,8-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 die combined oiganic layers were washed witii brine and dried over MgS0 . Evaporation afforded the crude quinone (60 mg; 95 %) which was used without further purification: *H NMR (CDCI3, 250 MHz) δ: 3.03 (2H, t, J = 3Hz, H-4), 3.81 (6H, s, OCH3), 4-67 (2H« *> J - 3Hz, H-l), 6.70 and 6.77 (2H, AB doublets, Ar-H).
95
SUBSTITUTE Step 3: 3 bis (metiMκycarbonyI)-5,10-dMno-3,4^,10-tetπ^ pyran
To a solution of 5,8-dioxo-3,3 bis (medκ>xycaιbonyl)-5,8-dihydιoi8θchroman (50 mg; 0.17 mmol) in toluene (4 ml) at room temperature was added l-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 g; 34%) as a yellow solid; m.p.: 210-222°C (dec): -H NMR (250 MHz, CDC13) 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-l), 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.
96
SUBSTITUT Example 26: Preparation of (l'S, IR, 3S) and (l'S, IS, 3R)-5,10-dioxo-3- ιm<lmxymemyl-l-0' ',6'-trideoxy-3'-trifluoroarrtamido-L- lyxohexopyranoβe)-3,4^,l(Metrahydro-lH-naphtbo-[2 -c]-pyran (BCH- 1691) and BCH-1693)
PNBOfNfIΠmFiA pNB -OtNfHmTTiA
BOfclffil BCH-lrø
Ste l: 5,8-dύnethoxy-3-hydroxyιn€thyl-isochron__an
To a solution of 5,8-dimethoxy-3-metiιoxycarbonyl-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 """"ft*" and was quenched witi 1 N HQ. The product was extracted with ether and the combined organic layers were washed witii brine and dried over MgS0 affording crude tide alcohol (246 mg; 90%) used as such for subsequent steps:
97
SUBSTITUTE SHEET - NMR (250 MHz, CDQ3) δ: 2.42 (IH, 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, β, -OCH3), 4.62 (IH, br d, J -= 16.0 Hz, H-l), 4.97 (IH, d, J = 16.0 Hz, H-l), 6.61 and 6.65 (2H, AB doublets, ArH).
Step 2: 5,8^1iπMt__ιoxy-3-metiιoxyn_«thylisoduOman
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-iβochroman (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) waa added. The mixture was then stirred at room temperature for 30 minutes. Since die 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 witii dichloromethane. The combined organic layers were washed witii brine and dried over MgS04. The crude was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford the title compound (301 mg; 86%):
*H NMR (250 MHz, CDCI3) δ: 2.45 (IH, br dd, J - 11.0 and 17 Hz, H-4 ax), 2.69 (IH, dm, J = 17.0 Hz, H-4 eq), 3.44 (3H, s, CH2-0-CH3), 3.55 (2H, d, J *= 5.5 Hz, -CH2-0), 3.75 (3H, s, OCH3), 3.77 (3H, s, OCH3), 4.63 (IH, br d, J - 16.0 Hz, H-l), 4.97 (IH, d, J = 16.0 Hz, H-l), 6.61 and 6.64 (2H, AB doublets, Ar-H). Step 3: (l'S, IR, 3S)-5,8-dkκo-3-me-thoxyπH^yl ^ trifluoroacetamido-^-O-p-mtroben∞yl-U dihydroisochroman and its (l'S, IS, 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-trifluo_roacetamido-4-0^>-ιύtrobenzoyl-α-L- lyxohexopynnoβe (555 mg; 1.42 mmol), 4A 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 tenφerature for 14 hours. It was quenched witii saturated NaHCθ3 aolution and extracted witii dichloromethane. The combined oiganic layers were washed with saturated NaHCC^, brine and were dried ova Na2S04 affording, after evaporation, 671 mg of a crude adduct which was dissolved in acetonitrile (20 ml) at 0°C. A aolution of eerie 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 die isochroman solution. After the addition, tiie mixture was stirred at 0°C for 20 minutes, quenched with saturated NaHCC<3 aolution and extracted with dichloromethane. The combined oiganic layers were washed witii brine and dried over Na2S04 to afford after evaporation a crude quinone which was recrystallized from dichloromethane:pentane yielding 225 mg of a diastereomeric quinone mixture favoring die tide conφound (2: 1):
-H NMR (250 MHz, CDQ3): 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 (IH,
98
SUBSTITUTE SHEET br s, H-l'), 5.60 (IH, br s, H-4'), 5.78 (IH, s, H-l), 6.30 (IH, m, NH), 6.65-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB): signals for minor (l'S, IS, 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, CH2-0-CH3 and H-3'), 4.15-4.70 (2H, m, H-3 and H-5'), 5.40 (IH, br s, H-l'), 5.59 (IH. br s. H-4'), 5.91 (IH, s, H-l), 6.40 (IH, m, NH), 6.65-6.90 (2H, m, Ar-H), 8.30 (2H, m, Ar-H).
trifluoroacetaιmdo-4'-0-p-mt_robe___αoyl-Lr4 lH-naphtho-[2,3-c]-pyran
To a solution of die quinone mixture from step 3 of this example, (100 mg; 0.17 mmol) in 6 ml of toluene at room temperature was added l-acetoxy-l,3-butadiene (113 μl; 1 mmol). The rest ofthe procedure is identical to step 2, exanφle 5, affording the tide coπφound (42 mg; 40%): -K NMR (CD2Cl2. 250 MHz) δ: 1.17 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.20 (2H, , H-2'), 2.37 (IH, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.70 (IH, dd, J - 3.5 and 19.5 Hz, H-4 eq), 3.38 (3H, s, O-CH3), 3.55 (2H, m, -CH2- CH3), 4.25-4.70 (3H, m, H-3, H-3' and H-5'), 5.41 (IH, br s, H-l'), 5.65 (IH, br s, H-4'), 5.90 (IH, s, H-l), 6.44 (IH, br d, J = 7 Hz, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar¬ il), 8.27 (4H, m, PNB). The second diastereomer: (l'S, IS, 3R)-5,10-dioxo-3-mι_<hoxymethyl-l-{2 3\6,-trideoxy-3,-trifluoroβcetamido-4'-0^ mtrobenzoyl-_Wyxohexo-pynux>ee)-3,4,5,10-*etr^ pyran was obtained in 19% yield and had:
-U NMR (250 MHz, 0^02) δ: 1.30 (3H, d, J = 6.5 Hz, H-6'), 1.90-2.30 (2H, m, H-2'), 2.47 (IH, dd, J = 11 and 19.5 Hz, H-4 ax), 2.71 (IH, dd, J - 4 and 19.5 Hz, H-4 eq), 3.89 (3H, β, -OCH3), 3.57 (2H, d, J = 5 Hz, CH2-OCH3), 4.27 (IH, m, H-3), 4.52 (IH, m, H-3'), 4.75 (IH, q, J - 6.5 Hz, H-5'), 5.41 (IH br a, H-l'), 5.56 (IH, br β, H-4'), 6.03 (IH, s, H-l), 6.46 (IH, 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: (l'S, IR, 3S)-5,10-d »xo-3-roetl »xyπιethyl-l-(2, 6,-t_rideoxy-3l- trifluoroacetamido-L-lyxohexopyra__ιose)-3,4,5,l( pyran (BCH-1691)
To a solution of (l'S, IR, 3S)-5,10-dioxo-3-m_4hoxymethyl-l-(2',3',6,-trideoxy-3'-trifiucm)acet_unido- 4'-0-p-nit_ro-ben2oyl-___^lyxohexopyn__K>ee)-3,4,5,^ pyran (19 mg; .029 mmol) in medianol (.4 ml) and tetrahydrofuran (1.5 πd) at 0°C was added .86 μl (.1 eq) of a 4.37 M solution of sodium methoxyde in medianol. The resulting mixture was stirred at 0°C for 20 minutes and was quenched with saturated NH4Q. Extraction with dichloromethane followed by washing of the combined organic layers with brine and drying with Na2S04 furnished a crude product which was purified by column chromatography cm silica gel using 5-10% acetone in benzene as eluent yielding the
99
«_• ■ f B_k , -» «-p» <_ • -* % f «-T~ *» /"» V * ~-~ ~~~ ~~^
SUBSTh ϋ i c - niiET title compound (14 mg; 96%) which was recrystallized from dichloromethane:etheπpentane to give yellow crystals: M.P.: 140-159°C; IR (neat): 3500, 3422, 3320, 2938, 1715, 1667, 1597, 1295, 1178 and 980 cm'1:
*H NMR (250 MHz, CD2CI2) δ: 1.21 (3H, d, J = 7.6 Hz, H-6'), 1.52 (IH, br s , O-H), 1.70-2.20 (2H, m, H-2'), 2.35 (IH, dd, J - 11.7 and 19.3 Hz, H-4 ax), 2.68 (IH, dd, J - 3.4 and 19.3 Hz, H-4 eq), 3.56 (3H, s, OCH3), 3.52 (2H, d, J - 4.8 Hz, CE2-OCH3). 3.58 (IH, br a, H-4'), 4.15-4.40 (3H, m, H-3, H-3', H-5'), 5.46 (IH, br s, H-l'), 5.83 (IH, β, H-l), 6.73 (IH, br d, J - 7 Hz, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 6: (l'S, IS, 3R)-5,10-doxo-3-^nedM τm_^yl-l-(2,3 6,-trideox -3,- pyran (BCH-1693)
The starting protected alcohol from step 4 of this exaπφle (18 mg; 0.028 mmol) in .4 ml medianol and 1.5 ml of tetrahydrofuran was treated witii .83 μl of a 4.37 M solution of sodium methoxide in methanol following the procedure from step 5 herein to afford the tide coπφound (12.5 mg; 90%): m.p.: 92-102° C; IR (neat): 3485, 3424, 3323, 2937, 1715, 1666, 1595, 1296, 1175, 1117, 980 cm'1. *H NMR (CD2Q2. 250 MHz) δ: 1.35 (3H, d, J - 6.5 Hz, H-6'), 1.85 (2H, m, H-2'), 2.01 (IH, br d, J = 7 Hz, O-H), 2.46 (IH, dd, J - 11.5 and 20 Hz, H-4 ax), 2.69 (IH, dd, J = 3.7 and 20 Hz, H-4 eq), 3.36 (3H, β, OCH3), 3.54 (2H, d, J « 4.7 Hz, CH2-OCH3), 3.60 (IH, m, H-4'), 4.15-4.40 (2H, m, H-3' and H-3), 4.55 (IH, q, J - 6.5 Hz, H-5'), 5.39 (IH, br β, H-l'), 5.98 (IH, s, H-l), 6.78 (IH, br d, J - 7 Hz, -NH), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
100
SUBSTITUTE Example 27: Preparation of (l'S,Uc_ S) and l'S,lSr3S)-5,10-dioxo-3-ethyl-l-(2'r3\6'- trideoxy-3'triflι__oroacetamido-L-lyxohexopyι^^ lH-naphtho-[2,3-c]-pyπu: (BCH-2026) and BCH-2020) and (1'S,1S S)- S.lO-dioxo-S-ethyl-M∑'^'jβ'-trideoxy-S'-ainiiKHWyxohexopyπuwse)- 3,4,5,10-tetndιydro-lH-naphth(>-I2-3-c]-pyπuι hydrochloride: (BCH-2021)
o o o o
NBONHIFA PNBONHTFA
o o o o
HO HTFA n&nm
Step 1: l-(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 CH2C1 . The combined organic layers were dried over Na2S04, filtered and the solvent was removed. The crude material was purified by flash chromatogπφhy 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 -H (250 MHz) (CDC13; ppm): 6.75 (3H, m, aromatics), 3.79 (3H, s, OCH3), 3.77 (IH, m, H2-)» 3.76 (3H, s, OCH3), 2.85 (IH, dd, Jγ = 3.8 Hz, J2 = 13.5 Hz, Hr>), 2.65 (IH, dd, Jj - 8.1 Hz, J2 - 13.5 Hz, Hlb), 2.16 (IH, d, J = 3.7 Hz, OH), 1.52 (2H, m, H3-) 0.99 (3H, dd, Iχ = J2 = 7.4 Hz, -CH3).
Step 2: 5,8-dimethoxy-3-ethyl-isochroman
Under argon atmosphere, the starting material from step 1 of this exaπφle, 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 stiπing was left overnight. The reaction was then quenched using aqueous NaHCC^. Extractions were done using ether and die combined organic extracts were dried over Na2S04, 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 -K (250 MHz) (CDQ3; ppm): 6.63 (2H, d, J = 3.4 Hz, aromatics), 4.93 (IH, d, J = 15.9 Hz, Hla), 4.57 (IH, d, J = 15.9 Hz, Hlb), 3.78 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.47 (IH, m, H3), 2.74 (IH, ddd, H^, 2.38 (IH, dd, H^, 1.68 (2H, m, -CH2- side chain) 1.03 (3H, dd, Jj = J2 = 7.4 Hz, -CH3).
Step 3: (l'S, IR, 3R)-5,8-dimethoxy-3-e_ l-l-(2',3',6'-tri 0-p-nitrobenzoyl-L-lyxohexopyra )se)-isochroman
Application of the first part of die procedure described in step 3, example 26, on the isochroman precursor from step 2 herein resulted witii die tided compound as a yellow solid; 62%.
NMR !H (250 MHz) (C^Dg; ppm): 7.72 (4H, m, aromatics), 6.48 (2H, d, J = 4.7 Hz, aromatics), 6.17 (IH, s, Hj), 5.95 (IH, m, NH), 5.67 (IH, d, H4 , 5.29 (IH, d, H^), 4.67 (IH, m, H3.), 4.26 (IH, q, H5.), 4.20 (IH, m, H3), 3.49 (3H, s, OCH3), 3.40 (3H, s, OCH3), 3.01 (IH, dd, H4a), 2.52 (IH, dd, H4b), 1.90 (IH, m, -CH2 side chain), 1.75 (IH, 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=0), 1707 (C=0), 1603 (C-=C), 1532 (C- N), 1259 and 1175 (C-O).
102
SUBSTITUTE SHEET Step 4: (l'S, IR, 3R)-5,8-d ) o-3-ethyl- (2, 6•- rideox -3,-tI^nuo^oacetami <>-4,-0-p- nit_robenzoyl-___^yxohexopyraικ)se)-i_wchroιnan
Application of the second part of the procedure (CAN) described in step 3, example 26, on die glycosylated isochroman precursor from die previous step resulted in an 87% yield of die titled compound.
NMR -U (250 MHz) (CgD^ ppm): 7.80 (4H, m, aromatics), 6.92 (IH, st,^, NH), 6.08 (2H, m, quinone ring), 5.72 (IH, s, Hj), 5.54 (IH, β, H4.), 5.53 (IH, s, Hr), 4.74 (IH, m, H3.), 4.36 (IH, m, H5.), 3.68 (IH, m, H3), 2.28 (IH, dd, J1 = 3.2 Hz, J = 19.3 Hz, H^, 1.88 (2H, m, -CH2- sugar), 1.80 (IH, dd, H^, 1.49 (2H, m, -CH2- aide chain), 1.15 (3H, d, J = 6.5 Hz, CH3 sugar), 0.89 (3H, dd, Jj = J2 = 7.4 Hz, -CH3 aide chain).
Step 5: (l'S, IR, 3R)-5,10-dioxo-3-€thyl-l-(2',3',6'-trideoxy-3'-trffluora mtroben∞yl-_---4]πcohecopyra__ι
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 *H (250 MHz) (CD2Q2; ppm): 8.28 (4H, d, J = 4.3 Hz, aromatics), 8.05 (2H, m, aromatics), 7.73 (2H, m, aromatics), 6.31 (IH, d, NH), 5.87 (IH, s, Hx), 5.67 (IH, s, H4 , 5.42 (IH, s, Hr), 4.58 (IH, m, H3.), 4.42 (IH, q, J = 6.3 Hz, H5 , 4.05 (IH, m, H3), 2.78 (IH, dd, Iχ = 3.4 Hz, J2 = 19.5 Hz, H4.), 2.24 (IH, dd, Jj = 11.3 Hz, J2 = 19.0 Hz, H4b), 2.05 (2H, m, -CH2- sugar), 1.70 (2H, m, -CH2- aide chain), 1.18 (3H, d, J = 6.5 Hz, -CH3 sugar), 1.05 (3H, dd, Jl = J2 = 7.4 Hz, - CH3 side chain).
IR (film) (cm"1): 3332 (NH), 2955 and 2929 (CH aliphatic), 1740 (C-O), 1669 (C= , 1529 (C-N), 1279 and 1180 (C-O).
Step 6: (l'S, IR, 3R)-5,10-dioxo-3-ethyl-l-(2, \6,-trideoxy-3,-trinuoroacetamido-L- lyxohexopyrancιβe)-3,4^,10^etrahydro-lH-ι__apht__ιo-[2^-c] pyran (BCH-2026)
The titled compound was in 64 % yield from the glycoside of step 5 of this exaπφle as per procedure described in step 5 of exaπφle 26.
NMR *H (250 MHz) (CD2 2; ppm): 8.03 (2H, m, aromatics), 7.71 (2H, m, aromatics), 6.77 (IH, d, NH), 5.81 (IH, s, Hj), 5.50 (IH, d, J = 2.8 Hz, Hr), 4.26 (IH, m, H3 , 4.22 (IH, m, H5.), 4.05 (IH, m, H3), 3.58 (IH, d, J = 2.2 Hz, H4 , 2.76 (IH, dd, Jj = 3.5 Hz, J2 = 19.5 Hz, H^, 2.21 (IH, ddd, Jj = 0.9 Hz, J2 = 11.0 Hz, J3 = 19.5 Hz, H4b), 2.07 (IH, 8(1^^), 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).
103
SUBSTITUTE SHEET Step 7: (l'S, IS, 3S)-5,8-dioxo-3^thyI-l-(2l^',6,-trideoxy-3'-trifluoroacetamido-4'-0-p- nitroben_Eoyl-L-lyxohexo-pyranose)-5,8-dihydro-isodιronιan
To a solution of (l'S, IS, 3S)-5,8-diιnethoxy-3-edιyl-l-(2',3',6'-trideoxy-3'-trifluoroacetamidc^ nitro-benzoyl-L-lyxohexopyranoβe)-i8θchroman (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 witii saturated bicaibonate solution. The product was extracted with dichloromethane and die combined organic layers were washed witii brine and dried over Na2S0 to give after evaporation the crude title compound:
(360 mg; 100%): -H NMR (250 MHz; CDC13) 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, CS,2-C1.3). 1.80-2.30 (3H, m, H-2' and H-4 ax), 2.60 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.89 (IH, m, H-3), 4.50-4.80 (2H, m, H-3' and H-5'), 5.41 (IH, br s, H-l') 5.55 (IH, br s, H-4'), 5.87 (IH, s, H-l), 6.58 (IH, br d, J = 7.5 Hz, NH), 6.75 and 6.81 (2H, AB doublets, ArH), 8.28 (4H, br s, PNB).
Step 8: (l'S, IS, 3S)-5,10-dioχtH3-ethyl-l-(2, \6'-trid_»xy^ mtroben∞yl-L-lyxobrao-pyrano6e)-3,4,5,10-te^
Using the procedure described in step 4, exaπφle 26, the starting quinone from step 7 herein (330 mg;
0.57 mmol) was treated witii l-acetoxy-l,3-butadiene (379 μl; 3.4 mmol) in 20 ml of toluene to afford after chromatography the title conφound (165 mg; 46%).
*H NMR (250 MHz, CD2Q2) δ: 1.03 (3H, d, J = 7.5 Hz, CH2-CH.3), 1.30 (3H, d, J - 6.5 Hz, H- 6'), 1.68 (2H, qn, J = 7.5 Hz, CH2-CH3). I 05 IH, m, H-2 eq), 2.12 (IH, td, J = 13 and 3-5 Hz, H-
2' ax), 2.29 (IH, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.76 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.97
(IH, m, H-3), 4.55 (IH, m, H-3'), 4.78 (IH, q, J - 6.5 Hz, H-5'), 5.41 (IH, br s, H-l'), 5.57 (IH, d,
J = 6.5 Hz, H-4'), 6.01 (IH, s, H-l), 6.51 (IH, br d, J = 7.5 Hz, -NH), 7.75 (2H, m, ArH), 8.07 (2H, m, Ar-H), 8.27 (4H, β, PNB).
Step 9: (l'S, IS, 3S)-5,10-dioxo-3He yl-l-(2',3',6'-trideα^ lyxob«opyrano6e)-3,4 ,10-tetrahydι^m4iapht__ιo-[2 ]-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 die 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.
104
SUBSTITUTE SHEET -U NMR (250 MHz, CD2CI2): 1.00 (3H, t, J - 7.5 Hz, CH2-CH.3), 1.35 (3H, d, J = 6.5 Hz, H-6*), 1.66 (2H, qn, J = 7.5 Hz, CE2-CH3). 1.80-2.20 (3H, m, H-2' and O-H), 2.27 (IH, dd, J = 11.0 and 19.5 Hz, H-4 ax), 2.75 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.61 (IH, br s, H-4*), 3.% (IH, m, H- 3), 4.25 (IH, m, H-3*), 4.58 (IH, q, J = 6.5 Hz, H-5'), 5.40 (IH, t, J = 2.0 Hz, H-l'), 5.97 (IH, s, H-l), 6.77 (IH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Step 10: (l'S, IS, 3S)-5,10-dioxo-3-emyl-l-(2'^',6'-trio^oxy-3'-aιm^ιo-Uyxohexopyraι^
3,4^,l»-tetnιhydro-lH-naphth_ {23-c]-pyπm (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 HQ 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 die organic extract were added 1.5 ml of .1 N HQ, 5 ml of methanol and 25 ml of ether and die mixture was evaporated partially in order to induce crystallization. Since no crystallization occured, the solvents were evaporated completely and die residue was dissolved in methanol (1 ml) and 200 μl of .1 N HQ were added followed by 25 ml of ether. A precipitate formed which was filtered and washed with ether yielding die crude tide compound (3.8 mg; 13 %). *H NMR (250 MHz, DMSO-D6), δ: 0.97 (3H, t, J = 7.0 Hz, CH2-CH.3), 1.23 (3H, d, J - 6.5 Hz, H-6'), 1.50-1.80 (3H, m, CH2-CH3 *» H-2' eq). 1.97 (IH, m, H-2' ax), 2.23 (IH, dd, J = 11.0 and 19.5 Hz, H-4 ax), 2.72 (IH, dd, J = 3.0 and 19.5 Hz, H-4 eq), 3.63 (IH, m, H-4*), 3.87 (IH, m, H-3), 4.33 (IH, m, H-5*), 5.29 (IH, br s, H-l*), 5.53 (IH, m, H-3*), 5.82 (IH, s, H-l), 7.85 (2H, m, Ar-H), 8.05 (5H, m, Ar-H and N-H).
105 Example 28: Preparation of traιβ-5,10 dκιxo-l-acetamido-3-ethyl-3,4^,10-tetrahydro- lH-naphtho-[2 -c]-pyran: (BCH-2027) and 3-ethyl-5,10-dioxo-3,4,5,10- tetrahydro-lH-naphtho-[23-c]^*yran: (BCH-2154)
\> I*
BOfc222Z
BOfc215_t
Step 1: (trans)-l-acetamidc-5,8-dtoxo-3-ethyl-5,8-dihydn>-is^
To a solution of 5,8-dimethoxy-3-ethyl-isochroman (1.0 g; 4.5 mmol) in dichloromethane (30 ml) at room teπφerature 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 NaHCC<3 aolution. It was extracted with dichloromethane and die combined organic layere were washed with bicaibonate, brine and then dried over Na2S04 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 witii 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 teπφerature for 15 minutes and was quenched with saturated NaHCC«3 solution followed by extraction witii dichloromethane. The combined organic extracts were washed with brine and dried over Na2S0 to afford die tided compound as a yellow solid (125 mg; 42% overall). *H NMR (250 MHz, CDC13) δ: 0.99 (3H, t, J = 7.5 Hz, CE3-CH2), 1.65 (2H, m, -Cfi2-CH3), 2.02 (3H, s, -CH3), 2.20 (IH, m, H-4 ax ), 2.60 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.70 (IH, m, H-3), 6.12 (2H, br s, H-l and N-H), 6.73 and 6.78 (2H, AB system, Ar-H).
106
SUBST Step 2: Trans-5,10-dioxo-l-acetamido-3^thyl-3,4,5,10-tetrahydro-lH-naphtho-[2^-c]- pyran
To a solution of the starting quinone from step 1 herein (56 mg; .22 mmol) in toluene (50 ml) was added l-acetoxy-l,3-butadiene (30 μl; 11 eq). The mixture was stirred overnight at room temperature and w waas thai 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 tide compound as a yellow solid (10 mg; 15 %). -H NMR (250 MHz, DMSO-D6), δ: 0.90 (3H, t, J = 7.5 Hz, CH3-CH2). 1.58 (2H, m, Cfi2-CH3), 1.82 (3H, s, CH3-C=0), 2.20 (IH, m, H-4 ax), 2.64 (IH, br d, J - 16.0 Hz, H-4 eq), 3.71 (IH, m, H-3), 6.17 (IH, d, J = 8.0 Hz, H-l), 7.88 (2H, m, Ar-H), 8.01 (2H, m, Ar-H), 8.78 (IH, d, J = 8.0 Hz, N-H).
Step 3: 5,8-dioxo-3-ethyl-5,cMihydro-isochπnιan
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 bicaibonate solution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over Na2S04 affording die crude tide coπφound (251 mg; 97 %) which was used as such for subsequent steps.
-H NMR (250 MHz, CDCI3) δ: 0.97 (3H, t, J = 7.5 Hz, CH2-CH.3), 1.60 (2H, m, -Cfi2-CH3), 2.10 (IH, m, H-4), 2.52 (IH, m, H-4), 3.35 (IH, m, H-3), 4.30 (IH, m, H-l), 4.62 (IH, br d, J = 16 Hz, H-l), 6.68 (2H, m, Ar-H).
Step 4: 3-eUiyI-5,10-dioxo-3,4^,l( etrahydn>-lH-naphtho-{2 -c] pyran
Following the procedure described in step 4, exanφle 26, the starting quinone from step 3 herein (250 g; 1.30 mmol) and l-acetoxy-l,3-butadiene (876 μl; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2 % ethyl acetate in toluene the tide compound (62 mg; 20 %) along with mixed fractions containing a lot of desired tided product (230 mg), M.P.: 98-101°C. IR (neat): 2963, 2938, 2876, 1658, 1636, 1593, 1337, 1299, 1176 and 698 cm'1. *H NMR (250 MHz, CDCI3) δ: 1.04 (3H, t, J = 7.5 Hz, CH3-), 1.70 (2H, m, CM2-CH3), 2.30 (IH, m, H-4 ax), 2.75 (IH, br d, J - 19.0 Hz, H-4 eq), 3.45 (IH, m, H-3), 4.50 (IH, dt, J = 4.0 and 18.5 Hz, H-l), 4.86 (IH, dd, J = 2.5 and 18.5 Hz, H-l), 7.72 (2H, m, Ar-H), 8.18 (2H, m, Ar-H).
107
SUBSTITUTE SHEET Example 29: Preparation of (1'S,1R^S) and (l'S,lS,3R)-5,10-dioxo-3-isopropyl-l- (2' ',6'-trideoxy-3'-triflικM >arrtamido-Lr4yxohexopyranose)-3,4,5,10- tetrahydro-lH-ιιaphtho-[2^-c]-pyran: (BCH-2053) and (BCH-2052)
PNBONHΠ'A
HONHΠ?A
Step l: 3-isopropyl-5,8-dunetboxy-isochn_a__an
To a solution of die 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 teπφerature 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 MgS04 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 teπφerature for 20 hours and was then quenched with saturated sodium bicaibonate solution. It was then extracted with ether and the combined organic layers were washed with brine and dried over MgS04. The crude product was then
108
SUBSTITUTE SHEET 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).
-H NMR (CDC13) δ: 1.00 and 1.05 (6H, 2d, J= 7 Hz, -CH^CH^. 1-84 (IH, sept., J = 7 Hz, CH- (CH3)2), 2.42 (IH, dd, J = 11 and 17 Hz, H-4 ax), 2.74 (IH, dm, J = 17 Hz, H-4 eq), 3.22 (IH, m, H-3), 3.76 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.56 (IH, dm, J = 16 Hz, H-l), 4.95 (IH, d, J = 16 Hz, H-l), 6.63 (2H, AB system, Ar-H).
Step 2: (l'S, IR, 3S) and (l'S, IS, 3R)-5,8-dioxo-3-isopropyl-l-(2,^,,6,-trideoxy-3'- trifluoroacetamido^'-O-p-nitrobenzoyl-Lrlyxohex isochroman (40:60)
Using the procedure described in step 3, exaπφle 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 witii CAN as described in step 3, example 26, to afford a diastereomeric tide quinones mixture (450 mg; 59 %) in a ratio of (40:60) favoring the l'S, IS, 3R isomer which were used as such for the next reactions.
For minor isomer: *H NMR (250 MHz, CDCI3) δ: 0.90-1.40 (9H, m, H-6' and -CH(-CH3)2), l °- 2.35 (4H, m, H-2', H-4 ax and Cfi-CH3), 2.62 (IH, m, H-4 eq), 3.80 (IH, m, H-3), 4.42 (IH, q, J = 6.5 Hz, H-5'), 4.5&4.70 (IH, m, H-3'), 5.44 (IH, br s, H-l'), 5.63 (IH, br s, H-4'), 5.74 (IH, s, H- 1), 6.32 (IH, m, N-H), 6.70-6.90 (2H, m, A -H), 8.30 (4H, m, PNB).
For major isomer: 0.90-1.40 (9H, m, H-6' and 1.70-2.35 (4H, m, H-2', H-4 ax and Cβ- CH3), 2.62 (IH, m, H-4 eq), 3.69 (IH, m, H-3), 4.50-4.75 (2H, m, H-3' and H-5'), 5.42 (IH, br s, H- 1'), 5.56 (IH, d, J = 3 Hz, H-4*), 5.88 (IH, s, H-l), 6.43 (IH, br d, J = 7.5 Hz, N-H), 6.70-6.90 (2H, m, Ar-H), 8.30 (4H, m, PNB).
Step 3: (l'S, IS, 3R)-5,10^oxo-3-i propyI-l-(2, r3\6,-trideoxy-3,-tι^
0-p- trobenzoyl-L-lyxohexo-pyranose)-3,4,5,l(^ pyran
Using die procedure described in step 4, example 26, the starting quinone mixture from step 2 herein (100 mg; .167 mmol) was treated with l-acetoxy-l,3-butadiene (112 μl; 1 mmol) in 5 ml of toluene to afford the tide compound (34 mg pure + 9 mg of 1:1 mixture of diastereomers). - NMR (250 MHz, CD2CI2) δ: 1.01 and 1.04 (6H, 2d, J = 6.5 Hz, -CH-(CΑ.3)2), 1.31 (3H, d, J = 6.5 Hz, H-6*), 1.70-2.02 (2H, m, H-2* and QHC^^, 2.13 (IH, t d, J = 3.5 and 13 Hz, H-2*), 2.34 (IH, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.78 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.76 (IH, m, H- 3), 4.55 (IH, m, H-3'), 4.80 (IH, q, J - 6.5 Hz, H-5'), 5.42 (IH, d, J = 2.5 Hz, H-l'), 5.58 (IH, d, J = 3 Hz, H-4'), 6.03 (IH, s, H-l), 6.52 (IH, 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:
109
C l f F* ^*"V" . m?m- _»-!_•• _r_. * I ■ •_. _._. UB > ι f l u έ c ^HEET (l'S, IR, 3S)-5,10-dioxo-3-iscφr(_φyl-l-(2*,3\6,-trideoxy-3'-trifluoroacetaπιido-4'-Oι ^t^^ lyxcAexo-pyranose)-3,4,5,10-tetrahydπ)-lHMiajΛtho-[2,3-c]-pyran, obtained in 16% yield, had 1H NMR (250 MHz, CD2α2) δ: 0.90-1.10 (6H, m, CH-(CIi3)2). l-W (3H» d» 3 = 6-5 Hz, H"6')' 1-70-2.40 (4H, m, H-2', CH-(CH3)2) and H-4), 2.60-2.90 (IH, m, H-4), 3.87 (IH, m, H-3), 4.44 (IH, q, J = 6.5 Hz, H-5'), 4.58 (IH, , H-3'), 5.42 (IH, br s, H-l'), 5.69 (IH, br β, H-4'), 5.89 (IH, s, H-l), 6.40 (IH, 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: (l'S, IR, 3S)-5,10-clkαo-3-i_»propyl-l-(2',3,,6'-tf ^
Ivxoh«opyranose)-3,4,5,l(M-3trahydπ^ (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 conφound (5 mg; 59%), M.P.: 180-185°C. IR (neat): 3491, 3423, 3325, 2962, 2938, 1721, 1670, 1596, 1293, 1179, 982 cm"1. -H NMR (250 MHz, CD2CI2): 1.00 and 1.01 (6H, 2d, J = 6.5 Hz, 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.60-2.00 (4H, m, 11.0 and 19.5 Hz, H-4 ax), 2.74 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.58 (IH, d, J - 2.5 Hz, H-4'), 3.85 (IH, m, H- 3), 4.25 (2H, m, H-3' and H-5'), 5.52 (IH, d, J = 3.0 Hz, H-l'), 5.82 (IH, s, H-l), 6.75 (IH, m, NH), 7.74 (2H, m, Ar-H), 8.03 (2H, m, Ar-H).
Step 5: (l'S, IS, 3R)-5,10-drøxo-3-isopropyl-l-(2' \6'-trideo.^ lyxc»l_«opyranose)-3,4^,10-tetrahydro-m-naph__ho-[2 -c]-pyran (BCH-2052)
Using the procedure described in step 5, example 26, the starting protected alcohol from step 3 herein (32 g; .0495 mmol) afforded after flash chromatography using 7% acetone in benzene as eluent, a gummy product which was dissolved in dichloromethane and precipitated witii pentane yielding the title product
(16 mg; 65%), M.P.: 212-213°C.
IR(neat): 3509, 3421, 3333, 2961,2944, 1718, 1667, 1592, 1292, 1166and979cm'1.
-HNMR(250MHz, CL^Clf): 0.98and 1.00(6H, 2d,J - 6.7Hz, - H(CH3>2), 1.36(3H, d,J = 6.5 Hz,H-6'), 1.70-2.00(4H, m, -CE(CH3)2, H-2' and-OH), 2.32(IH, dd,J = 11.5and 19.5Hz, H-4 ax), 2.76(IH, dd,J - 3.5and 19.5Hz, H-4eq), 3.61 (IH, brs, H-4'), 3.74(IH,ddd,J = 3.5, 6.5 and 11.5Hz, H-3), 4.24(IH, m,H-3'), 4.59 (IH, q, J - 6.5HzH-5*), 5.39(IH, t, J = 2.0Hz, H-l'),
5.97 (IH, s, H-l), 6.77 (IH, m, NH), 7.72(2H, m, A -H), 8.05 (2H, m, Ar-H).
110
SUBSTITUTE SHEET Example 30: Preparation of (1'S,1R S) and (l'S,lS^R)-5,10-dioxo-3-isopropenyl-l- (2'^',6'-trideoxy-3'-triflιιoι narrtamido-Lrlyxol_«xopyranose)-3,4^,l^ tet__^ydro-lH-naphtbo-[2 -c]-pyran: (BCH-2153) and (BCH-2152) and trans-5,10-dioκo-3-isopropenyM-__netlMxy^ naphtho-[2 -c]-Pjran: (BCH-2148)
B£K214£
I' I,
- -
BQfcZlϊl BOL2152
Step l: 5,8-dύnethoxy-3-isopropenyl-i_Mκ_hroman
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-(l-acethyl)- isochroman (1.0 g; 4.2 mmol) was then added to die yellow-orange mixture and die resulting solution was stirred at room temperature for 3 hours. The mixture was then quenched with NH4Q (sat.) and extracted with ether. The combined oiganic layers were washed witii brine and dried ova- Na2S04. 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 %).
Ill
SUBSTITUTE SHEET -H NMR (250 MHz, CDC13) δ: 1.86 (3H, s, =C-CH3), 2.58 (IH, br dd, J = 11 and 17 Hz, H-4 ax), 2.85 (IH, ddd, J - 1.5, 3.5 and 17 Hz, H-4 eq), 3.77 and 3.79 (6H, 2s, -O-CH3), 4.00 (IH, dd, J = 3.5 and U Hz, H-3), 4.66 (IH, br d, J = 16 Hz, H-l), 4.93 (IH, br s, =CH^), 4.99 (IH, d, J = 16Hz, H-l), 5.09 (IH, br s, --CHj), 6.62 and 6.67 (2H, 2d (AB), J = 9 Hz, Ar-H).
Step 2: (trans)-5,10- __ioxo-3-isopropenyl-l-methoxy-3 A 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-l,3-butadiene as described in step 4, exaπφle 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). -H NMR (CDCI3, 250 MHz) δ: 1.87 (3H, s, =C-CH3 > 2.49 (IH, dd, J = 11.5 and 19.5Hz, H-4 ax), 2.84 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.61 (3H, s, -OCH3), 4.50 (IH, dd, J « 3.5 and 11.5 Hz, H-3), 5.00 (IH, s, =CH), 5.15 (IH, s, =CH), 5.63 (IH, s, H-l), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H).
Step 3: (l'S, IS, 3R)-5,8-dimethoxy-3-i_Mpropenyl-l-(2^ trifluoroacxtanudo^'-O-p-nitrobenzoyl-L-Iyxobexo-pyi ^ isochroman.
Following the procedure described in the first part of step 3, exaπφle 26, the starting isochroman from step 1 herein (250 mg; 1.07 mmol) was treated witii α-2,3,6-trideoxy-3-trifiuoroacetamido-4-0-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 tide compound as a mixture with its (l'S, IR, 3S) diastereomer (1:1; 310 mg). Another fraction gave pure tided conφound (131 mg; 19%). -H NMR (250 MHz, CD2CI2) δ: 1.22 (3H, d, J -= 6.5 Hz, H-6'), 1.83 (3H, s, -C-Qfe), 1.75-2.20 (2H, m, H-2'), 2.48 (IH, dd, J - 12 and 17.5 Hz, H-4 ax), 2.89 (IH, 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 (IH, q, J - 6.5 Hz, H-5*), 4.92 (IH, β, -CH), 5.09 (IH, s, =CH), 5.42 (IH, br s, H-l*), 5.57 (IH, d, J = 3 Hz, H- 4*), 6.12 (IH, s, H-l), 6.31 (IH, br d, J - 6 Hz, N-H), 6.73 and 6.79 (2H, AB doublets, Ar-H), 8.27 (4H, m, PNB). The (l'S, IR, 3S)-5,8-dimetirøxy-3-i.xφropenyl-l-(2*,3,,6'-trideoxy nitrobenzoyl-L-lyxohexo-pyranose) isochroman had -H NMR (CD^l^ 250 MHz) δ: 1.10 (3H, d, J = 6.5 Hz, H-6*), 1.83 (3H, s, =C-CE3), 1.90-2.20 (2H, m, H-2'), 2.39 (IH, dd, J = 12 and 17.5 Hz, H- 4 ax), 2.89 (IH, dd, J = 3.5 and 17.5 Hz, H-4 eq), 3.76 (3H, s, OCH3), 3.77 (3H, s, OCH3), 4.35 (IH, q, J = 6.5 Hz, H-5'), 4.50-4.70 (2H, m, H-3 and H-3*), 4.90 (IH, br s, =CH), 5.10 (IH, br s,
112
SUBSTITUTE SHEET -CH), 5.38 (IH, br β, H-l'), 5.54 (IH, br β, H-4'), 5.94 (IH, s, H-l), 6.31 (IH, m, N-H), 6.71 and 6.77 (2H, AB system, Ar-H), 8.27 (4H, m, PNB).
Step 4: (l'S, IR, 3S)-5,10-dioxo-3-isopropenyl-l-(2'^6'-t^^ 4'-O-p-nitrobenzoyl-L-lyxohex(>-pyrai__06e) 3,4,5,10-tetrahyd_rt>-lH-naphtho-[2,3-c]- pyran
Using the same procedure as described in step 6 of this exanφle, die 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. -H NMR (250 MHz, CDQ3) 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 (IH, m, H-4 ax), 2.90 (IH, m, H-4 eq), 4.34 (IH, q, J = 6.5 Hz, H-5'), 4.5C .75 (2H, m, H-3 and H-3'), 5.00 (IH, s, -C-H), 5.17 (IH, s, =C-H), 5.44 (IH, br s, H-l'), 5.72 (IH, s, H-4'), 5.99 (IH, s, H-l), 6.40 (IH, br d, J - 7.5 Hz, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, , Ar-H), 8.28 (4H, m, PNB).
Step 5: (l'S, IR, 3S)-5,10-dioxo-3πsιφropenyl-l-(2' ',6'-trideoxy-3,-trifluoroacetamido-
Uyxohexopyrano∞)-3,4,5,10-tetrahyd_ HlH-_^
Using the procedure described in step 3, exaπφle 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. lH NMR (250 MHz, CDQ3) 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 (IH, dd, J = 11.5 and 19.5 Hz, H-4 ax), 2.89 (IH, dd, J = 3.5 and 19.5 Hz, H-4 eq), 3.59 (IH, m, H-4'), 4.16 (IH, q, J = 6.5 Hz, H-5'), 4.35 (IH, m, H-3'), 4.52 (IH, dd, J - 3.5 and 11.5 Hz, H-3), 4.96 (IH, s, -CH), 5.13 (IH, s, =CH), 5.54 (IH, d, J = 3.5 Hz, H-l'), 5.93 (IH, s, H-l), 6.71 (IH, br d, J - 8.5 Hz, -NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, ArH).
Step 6: (l'S, IS, 3R)-5,10-draxo-3-isopropenyl-l-(2,,3',6'-ti^ 4'-0-p-mtrobenzoyl-L-lyxohexo-pyraiiose) 3,4,5,10-tetrahydro-lH-naphtho-[23-c]- pyran
To a solution of die 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 Na2S04 to yield a crude quinone (112 mg) which was dissolved in toluene (5 ml) and reacted with l-acetoxy-l,3-butadiene (113 μl; 1 mmol) at room temperature for 15 hours. After this
113
SUBSTITUTE SHEET 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 %).
-H NMR (250 MHz, CDQ3) δ: 1.36 (3H, d, J = 6.5 Hz, H-6'), 1.86 (3H, s, =C-CH3), 1.99 (IH, br dd, J - 5 and 12.5 Hz, H-2' eq), 2.13 (IH, td, J - 3.5 and 12.5 Hz, H-2' ax), 2.52 (IH, dd, J = 11.5 and 19 Hz, H-4 ax), 2.91 IH, dd, J = 3.5 and 19 Hz, H-4 eq), 4.48 (IH, br d, J = 11.5 Hz, H-3), 4.62 (IH, m, H-3'), 4.84 (IH, q, J - 6.5 Hz, H-5'), 5.00 (IH, br s, -CH), 5.14 (IH, br s, -C-H), 5.47 (IH, br s, H-l'), 5.62 (IH, d, J = 2.5 Hz, H-4'), 6.13 (IH, β, H-l), 6.47 (IH, 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: (l'S, IS, 3R)-5,l(M__ioxo-3 sopropenyl-l-&',3',6'^
Wyxohexopyranose)-3,4^,10-tetπdιydro- -naphUii>-[2 -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.
-H NMR (250 MHz, CDCI3) 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 (IH, d, J = 8.0 Hz, -OH), 2.51 (IH, dd, J - 11.5 and 19.5 Hz, H-4 ax), 2.89 (IH, dd, J = 3.5 and 19.5 Hz, H- eq), 3.65 (IH, m, H-4'), 4.35 (IH, m, H-3'), 4.46 (IH, dd, J = 3.5 and 11.5 Hz, H-3), 4.63 (IH, q, J - 6.5 Hz, H-5'), 4.98 (IH, s, -CH), 5.12 (IH, s -CH), 5.43 (IH, br s, H-l'), 6.07 (IH, s, H-l), 6.72 (IH, m, -NH), 7.75 (2H, m, Ar-H), 8.12 (2H, m, Ar-H).
Example 31: Preparation of (l,S,H S)-5,10-dioxo-3-metboxycarbonyl-l-(2'^,,6'- trideoxy-3'-trifluoπ)afrtamido-L-lyxohexopynuιose)-3>4,5,10-tetι^ydι^ lH-naphtbo-[23-c]-pyran: (BCH-2128)
114
SUBSTITUTE SHEET OCH,
Ste l: trideoxy-3'-4rifliH>roacetamido-4'-0-p-ιύt_robenzoyI-L^ 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 tide compounds (490 mg; 40% (-1:1)). *H NMR (250 MHz, CD2C-2) δ: (foτ rS' 1R' 3S>: 1 15 <3H« d- J " 6'5 ^ H-5'^ 1-70-2J5 (2H, m, H-2'), 2.65 (IH, m, H-4 ax), 3.10 (IH, m, H-4 eq), 3.76-3.78 (9H, superimposed singlets, OCH3), 4.38 (IH, q, J - 6.5 Hz, H-5'), 4.45-4.85 (2H, m, H-3 and H-3'), 5.41 (IH, m, H-l'), 5.57 (IH, m, H-4'), 5.97 (IH, s, H-l), 6.45 (IH, br d, J - 7.5 Hz, -NH), 6.65-6.85 (2H, m, Ar-H), 8.26 (4H, m, PNB); δ (for l'S, IS, 3R): 1.22 (3H, d, J = 6.5 Hz, H-6'), 1.70-2.20 (2H, , H-2'), 2.66 (IH, m, H- 4 ax), 3.10 (IH, m, H-4 eq), 3.76-3.78 (9H, superimposed singlets, OCH3), 4.45-4.85 (3H, m, H-3, H-
115
SUBSTITUTE SHEET 3" and H-5'), 5.42 (IH, m, H-l'), 5.57 (IH, m, H-4'), 6.16 (IH, s, H-l), 6.45 (IH, br d, J = 7.5 Hz, - N-H), 6.65-6.85 (2H, m, Ar-H), 8.26 (4H, m, PNB).
Step 2: (l'S, IR, 3S) and (l'S, IS, 3R)-5,8 dioxo-3-methαxycarbonyl-l-(2'^',6'-trideoxy- 3'-triπuoroacetamido-4'-0-p-mtrobenzoyl-L^ 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 Na2S04 giving a erode mixture of the title quinones (422 mg; 93 %) used as such for the next reaction. -H NMR (250 MHz, 0^2) & 1.15 (3H, d, J = 6.5 Hz, H-6', Δ*), 1-27 (3H, d, J = 6.5 Hz, H-6', 1), 1.70 -2.25 (2H, m, H-2', Δ and 2H, m, H-2', ©, 2.55 (IH, m, H-4 ax, Δ and IH, m, H-4 ax, E), 2.85 (IH. m, H-4 eq, Δ and IH, m, H-4 eq, £), 3.76 (3H, s, OCH3, £), 3.77 (3H, s, OCH3, Δ), 4.34 (IH, q, J = 6.5 Hz, H-5', Δ), 4.40-4.70 (2H, m, H-3' and H-3, Δ end 3H, m, H-3', H-3 and H-5', β), 5.39 (IH, m, H-l*. Δ and IH, m, H-l*. B), 5.54 (IH, d, J -3H, H-4', fi), 5.57 (IH, d, J = 3Hz, H-4', Δ). 5.80 (IH, s, H-l, Δ). 5.95 (IH, s, H-l, £). 6.60 (IH, m, NH, Δ and IH, m, NH, £), 6.80 (2H, m, Ar-H, Δ and 2H, m, Ar-H, £), 8.26 (4H, m, PNB, Δ and 4H, m, PNB, £). * A is (l'S, IR, 3S) diastereomer and B is (l'S, IS, 3R) diastereomer.
Step 3: (l'S, IR, 3S)-5,10-diox<H3-methoxycarbonyl-l-(2'^',6,-trideoxy-3'- trifliMroacetamido-4'-0-p-mtroben2»y^ lH-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 ofa 1:1 mix of l'S, IR, 3S and l'S, IS, 3R) afforded pure tide product (13 mg) along with a -1:1 mixture of (l'S, IR, 3S) and (l'S, IS, 3R) isomers (275 mg). -H NMR (250 MHz, CΪ^ l^ δ: 1.18 (3H, d, J - 6.5 Hz, H-6'), 1.90-2.20 (2H, m, H-2'), 2.68 (IH, dd, J - 11.5 and 19 Hz, H-4 ax), 3.08 (IH, dd, J = 4 and 19 Hz, H-4 eq), 3.80 (3H, s, OCH3), 4.38 (IH, q, J = 6.5 Hz, H-5'), 4.57 (IH, m, H-3'), 4.75 (IH, dd, J = 4 and 11.5 Hz, H-3), 5.42 (IH, br s, H-l'), 5.69 (IH, br s, H-4'), 5.99 (IH, s, H-l), 6.42 (IH, 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: (l'S, lR, 3S)-5,10-dMxo-3-methoxycarbony trifluoroacetaπύdo-Lr4yxobexopyra__ιose)-3,4,5,lθ- pyrano (BCH-2128)
116
SUBSTITUTE SHEET 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 chromatogπφhy (10% acetone in dichloromethane), the title conφound (5 mg; 54%) as a yellow solid. M.P. 92-105°C. lH NMR (250 MHz, d^Q^ & 1-22 (3H, d, J = 6.5 Hz, H-6'), 1.55 (IH, br s, OH), 1.70-2.00 (2H, m, H-2'), 2.66 (IH, dd, J - 12.0 and 19.0 Hz, H-4 ax), 3.06 (IH, dd, J - 4.0 and 19.0 Hz, H-4 eq), 3.59 (IH, br s, H-4'), 3.79 (3H, s, -CO2CH3), 4.17 (IH, q, J = 6.5 Hz, H-5'), 4.28 (IH, m, H-3'), 4.73 (IH, dd, J = 4.0 and 11.5 Hz, H-3), 5.52 (IH, br s, H-l'), 5.92 (IH, s, H-l), 6.75 (IH, m, -NH), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
117
SUBSTITUTE SHEET Example 32: Preparation of (l,S,lR^S)- sopropyl-[5,10-dioxo-l-(2'^',6,-trideoxy-3l- trifluoroac^amido--_^yxohexopyrai_»se)-3,4,5,10^et_rahydro-lH-naphtho- [2 -c]-pyranyl]- etone: (BCH-2112)
BCH-2112
Step 1: isopropyl-(5,8-dimetlMixy-4soc__ιroman-3-yI)-ketoιιe
To a solution of die 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 tenφerature for 1 hour. It was then quenched witii saturated ammonium chloride solution and extracted with dichloromethane. The combined oiganic layers were washed with brine and dried over
MgS0 to afford after evaporation, die title coπφound (240 mg; 23 % (40% based on S.M. recovered)).
*H NMR (250 MHz, CDC13) δ: 1.13 (3H, d, J = 6.5 Hz, CE3-CH), 1.16 (3H, d, J = 6.5 Hz, Cfi3- CH), 2.59 (IH, br dd, J - 11.5 and 17 Hz, H-4 ax), 3.04 (IH, dm, J = 17 Hz, H-4 eq), 3.17 (IH, m,
CE-CH3), 3.76 (3H, s, OCH3), 3.78 (6H, s, OCH3), 4.17 (IH, dd, J = 3.5 and 11.5 Hz, H-3), 4.64
(IH, br d, J = 16 Hz, H-l), 5.03 (IH, d, J = 16 Hz, H-l), 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. *H NMR (250 MHz, CDCI3) δ: 1.29 (3H, d, J = 6Hz, CH3-CH), 1.30 (3H, d, J = 6 Hz, CH3-CH),
2.74 (IH, br dd, J = 11 and 17 Hz, H-4 ax), 3.05 (IH, dm, J = 17 Hz, H-4 eq), 3.75 (3H, s, OCH3),
118
SUBSTITUTE SHEET 3.78 (3H, β, OCH3), 4.19 (IH, dd, J - 4 and 11 Hz, H-3), 4.65 (IH, br d, J - 16 Hz, H-l), 5.04 (IH, d, J = 16 Hz, H-l), 5.15 (IH, βept., J - 6 Hz, CH-CH3), 6.64 (2H, AB system, Ar-H).
Step 2: (l'S, IR, 3SM∞pπ»yHM2',3',6'-trideoκy-3'-trinu^ troben∞yl-Lrlyxohαopyranose)-5,10-^^
[2 -c]-pyranyI]- etone
To a solution of α-2 3,,6'-trideoxy-3'-trifluoroacetamido ,-0-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 4λ molecular sieves (400 g) 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 Na2S04 to afford a crude adduct (590 mg) which was dissolved in acetonitrile (20 ml) at 0°C and treated dropwise witii a solution of eerie ammonium nitrate (3.15 g; 5.7 mmol) in water (10 ml) containing sodium bicaibonate (847 mg). After the addition, die mixture was stirred at 0°C for 15 minutes and was quenched witii saturated NaHCC«3 and extracted witii dichloromethane. The combined organic layers were washed with brine and dried over Na2S04 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-l,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 tide compound (20 mg) slightly contaminated by its (IS, 3R) diastereomer (-3:1). lH NMR (250 MHz, CDCI3) δ: 1.00-1.30 (9H, m, H-6' and CH-iCQ^, 1.60-2.40 (2H, m, H-2'), 2.52 (IH, m, H-4 ax), 3.00-3.35 (2H, m, H-4 eq and QHQ^, 4.32 (IH, q, J = 6.5 Hz, H-5'), 4.50-4.90 (2H, m, H-3 and H-3'), 5.44 (IH, br s, H-l'), 5.75 (IH, br β, H-4'), 6.06 (IH, s, H-l), 6.49 (IH, 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 (IS, 3R) diastereomer are: 6.22 (IH, s, H-l) and 6.58 (IH, br d, J - 7.5 Hz, NH).
Step 3: (l'S, IR, SSJ-iMpropyKl^'^ ^'-trideoxy-S'-triflucjroacetamido-L- lyxohexopyranose)-5,10-dH»xo-3,4,5,10-tetrahydro-lH^ 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 witii saturated NH4Q solution and was extracted with dichloromethane. The combined organic layers were washed with brine and dried over Na2S04 to afford a crude residue which was purified by column chromatogπφhy on silica gel using 10% acetone in benzene yielding the titled compound (6.4 mg; 63%).
119
SUBSTITUTE SHEET *H NMR (CD2Q 2. 250 MHz), δ: 1.11 (6H, d, J = 6.5 Hz, - H-(C_i3)2), I-20 (3H- d- J = 6-5 z> H-6'), 1.65 (IH, s, OH), 1.75-2.05 (2H, m, H-2'), 2.48 (IH, dd, J = 11.5 and 19.5 Hz, H-4 ax), 3.01 (IH, dd, J = 4.0 and 19.5 Hz, H^t eq), 3.15 (IH, sept., J ~- 6.5 Hz, PH-CCH^, 3.58 (IH, d, J = 2.5 Hz, H-4'), 4.10 (IH, q, J = 7.0 Hz, H-5'), 4.28 (IH, m, H-3'), 4.68 (IH, dd, J = 4.0 and 11.5 Hz, H-3), 5.55 (IH, d, J = 3.5 Hz, H-l'), 5.97 (IH, s, H-l), 6.72 (IH, m, N-H), 7.75 (2H, m, Ar-H), 8.05 (2H, m, Ar-H).
Example 33: Preparation of (1'S,1S,3R) and (l'S,Ut_ S)-5,10-dioxo-3- isopropoxycarbonyl-l-(2' \6'-t"deoxy-3'-trifluorowrrtamido-L- lyxohexopyranose)-3,4,5,10-tetrahydπ>-_UI^ (BCH-2122) and (BCH-2121)
l UUTCl
HO .NHIFA
Step 1: (l'S, IR, 3S), and (l'S, IS, 3R)-5,10-o oxo-3-isopropoxycarbonyl-l-(2'^',6'- trideoxy-3' ,trifluoτoac^amido-4'-O-p-ιutroben_royl-L>-lyxohexopyranose)-3,4,5,10- tetrahydro-lH-naphtho-[2,3-c]-pyran
Using the procedure described in step 2, exanφle 32, the starting isochroman from step 1, example 32, (300 mg; 1.07 mmol) afforded a crude glycosylated adduct (417 mg) which was treated witii CAN to give a crude quinone mixture (355 mg) of which 250 mg were reacted with acetoxybutadiene. This reaction
120
SUBSTITUTE SHEET yielded a slightly impure mixture of the title compounds (113 mg; 15 % overall) (-55:45) favoring the (l'S, IR, 3S) isomer.
*H NMR (250 MHz, CDQ3) δ: (for l'S, IR, 3S): 1.15-1.42 (9H, m, H-6' and CH-(CH3)2), 1.90- 2.20 (2H, m, H-2'), 2.68 (IH, dd, J = 12 and 19 Hz, H-4 ax), 3.i2 (IH, m, H-4 eq), 4.40 (IH, q, J = 6.5 Hz, H-5'), 4.50-4.80 (2H, m, H-3 and H-3'), 5.18 (IH, m, 5.44 (IH, br s, H-l'), 5.74 (IH, br s, H-4'), 6.03 (IH, s, H-l), 6.55 (IH, 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 l'S, IS, 3R): 1,15-1.42 (9H, m, H-6* and CH(C li)_j). 1.90- 2.20 (2H, m, H-2*), 2.69 (IH, dd, J = 12 and 19 Hz, H-4 ax), 3.12 (IH, m, H-4 eq), 4.50-4.80 (3H, m, H-3, H-3* and H-5*), 5.18 (IH, m, CH(CH3)2), 5.45 (IH, br s, H-l'), 5.65 (IH, d, J = 3 Hz, H- 3*), 6.18 (IH, s, H-l), 6.61 (IH, 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: (l'S, IR, 3S)-5,l(Wwxo-3-i*>propoxyαu ny^ trifluoroacetanύdo-L-Jyxohexop^ pyran (BCH-2122)
Using the procedure described in step 3, exaπφle 32, die 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. lH NMR (CDQ3) δ: 1.29 and 1.33 (6H, 2d, J = 6.5 Hz, -C -iCH^, 1.33 (3H, d, J = 6.5 Hz, H- 6'), 1.70-2.10 (3H, m, H-2' and O-H), 2.68 (IH, dd, J - 11.5 and 19.5 Hz, H-4 ax), 3.11 (IH, dd, J = 4.0 and 19.5 Hz, H-4 eq), 3.65 (IH, m, H-4'), 4.21 (IH, q, J = 6.5 Hz, H-5'), 4.38 (IH, m, H-3'), 4.66 (IH, dd, J = 4.0 and 11.5 Hz, H-3), 5.18 (IH, sept., J = 6.5 Hz, OHO^, 5.56 (IH, br s, H- 1*), 5.98 (IH, s, H-l), 6.72 (IH, m, NH), 7.75 (2H, m, Ar-H), 8.10 (2H, m, Ar-H). (l'S, IS, 3R)-5,10-dioxo-3-isopπφoxycaιb∞yl-l-(2\3\6,-trideoxy-3,-trifluoroa_»tamido-L- lyxob_exopyranoβe)-3,4,5,10-tetnhydro-lH-naphtho-[2,3-c]-pyran (BCH-2121) was isolated after multiple chromatographic separations (5 mg; 6%). M.P.: 155°C (dec).
JH NMR (CDQ3) δ: 1.32 (6H, d, J - 6.5 Hz, 1.41 (3H, d, J - 6.5 Hz, H-6'), 1.87 (2H, m, H-2'), 2.05 (IH, m, OH), 2.70 (IH, dd, J - 12.0 and 19.5 Hz, H-4 ax), 3.10 (IH, dd, J - 4.0 and 19.5 Hz, H-4 eq), 3.63 (IH, m, H-4*), 4.32 (IH, m, H-3*), 4.55 (IH, q, J = 6.5 Hz, H-5*), 4.62 (IH, dd, J = 4.0 and 12.0 Hz, H-3), 5.16 (IH, sept., J = 6.5 Hz, COiC j)?). 5.47 (IH, br s, H-l*), 6.14 (IH, s, H-l), 6.75 (IH, m, N-H), 7.75 (2H, m, Ar-H), 8.12 (2H, m, A -H).
121
SUBSTITUTE SHEET Example 34: Preparation of (l'S,lS)-5,10-diαxo-3,3-dime_UMxymethyl^ trideoxy-3'-trifluoroacrtamido-4'-0-p-mtrobeιιzoyl-L-lyxohexopyranose)- isochroman (BCH-1697)
BOfclfiZZ
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 teπφerature, and stiπing was continued for 3 hours. After that time, another 160 mg (4.22 mmol) of LAH was then added and die 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 HQ. Extractions of the aqueous
122
SUBSTITUTE SHEET layer are done using CH2C12. The combined organic layers are dried over Na2S04, filtered, and the solvent is removed. The isolated titled compound is used without further purification (0.333 g; 90%). NMR *H (250 MHz) (CDCl3:ppm): 6.64 (2H, 2d, aromatics); 4.80 (2H, s, Hla- Hlb); 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 (dimethoxymethylHsochroinan
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 die reaction which was completed after another hour of stirring. Aqueous HQ (0.1 N) was then added and extractions were done using CH2C12. The combined oiganic extracts were washed witii an aqueous solution of sodium bicaibonate, dried over Na2S04, filtered, and die solvent was removed. The obtained tided compound was used for next step without further purification. Isolated product (0.470 g; >99%).
NMR *H (250 MHz) (CDC^ppm): 7.26 (2H, 2d, aromatics); 4.74 (2H, s, Hlβ-Hlb); 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, H^-I^b). IR (film) (cm'1) 2925 (CH aliphatic), 1580 (C-Q, 1475 (CH^, 1450 and 1360 (CH3), 1100 and 1248 (C-O).
Step 3: (l'S, lS)-5,8-dimetboxy-33-dimethoχymeihy^ t__τπι__oroacetamido-4'-Q-p- trobenroyl-I yxohCT^
Under argon atmosphere, the following reagents: product from step 2 herein, 0.477 g (1.70. mmol),
2,3,6-trideoxy-3-trifluoroacetaιmdo-4-0-p-mtrobeu 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 teπφerature for a period of 16 hours. After that time, an excess of DDQ was then added to the reaction mixture and stiπing was left for another hour. The reaction mixture was then quenched with aquous NH4Cl and extractions of the aqueous layer was done using CH2C1 . The combined organic layers were dried over Na2S04, filtered and die solvent was removed. The crude material was purified by flash chromatography; eluentihexanes-ethyl acetate (70:30) then (60:40). The obtained titled compound was a pale yellow solid (0.434 g; 39%). NMR -H (250 MHz) (C D6; ppm): 7.89 (2H, m, aromatics), 7.68 (2H, m, aromatics), 6.53 (2H, m, aromatics), 6.52 (IH, NH), 6.08 (IH, s, Hx), 5.62 (IH, s, Hr). 4.70 (IH, m, H5>), 4.60 (IH, m, H3 , 3.82 (2H, m, CH2-OMe), 3.74 (IH, m, H4-), 3.55 (2H, m, CH2-OMe), 3.48 and 3.42 (6H, 2s, 2xOCH3), 3.40 (2H, m, H2-a and H2>\_), 3.18 and 3.11 (6H, 2s, 2xOCH3), 2.13 (IH, m, H^, 1.86 (IH, m, H^), 1.21 (3H, d, J = 6.2 Hz, CH3 sugar).
123
SUBSTITUTE SH Step 4: (l'S, lS)-5,8-d no-3 -dimetl_oxymethyl-l-(2'^,,6,-trideoxy-3,-trifl
4'-0-p-mt_robenzoyI-_ -iyxoiιexopyra]_M_βe)-isodιron__an
The starting material from step 3 herein, 0.430 g (0.65 mmol), was dissolved in acetonitrile at 0°C. A solution of NaHCC«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 die reaction mixture in a dropwise manner. The reaction was complete after 10 minutes. A very diluted solution of NaHCC<3 in water was then added to die reaction mixture. Extractions of die reaction mixture were done using CH2Q2- The combined organic layere are dried over Na2S04, filtered and the solvent was removed. The titied coπφound was used for next step without further purification, (0.387 g; 95%).
NMR *H (250 MHz) (C Ω -, ppm): 7.94 (2H, d, J = 7.5 Hz, aromatics), 7.75 (2H, d, J = 7.5 Hz, aromatics), 7.42 (IH, m, NH), 6.20 (2H, m, quinone ring), 5.98 (IH, s, H^, 5.92 (IH, s, Hr), 5.41 (IH, s, H4.), 4.90 (IH, q, H5 , 4.67 (IH, m, H3 , 3.47 (2H, CH2-OMe), 3.29 (2H, CH2-OMe), 3.16 (3H, s, OCH3), 3.11 (3H, β, OCH3), 2.50 (2H, 2d, H2«a, H2'b). 2.22 (IH, m, H^, 1.97 (IH, m, H4b), 1.27 (3H, d, J - 6.3 Hz, -CH3 sugar).
Step 5: (l'S, lS)-5,l()-dioxo-3 -di ethoxymethyl-l-(2'^',6,-triα » trifluoroafrtamido-4'-Q-p-nitrobenzoyl-L-lyxohexopyraiM__s^ lH-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 l-acetoxy-l,3-butadiene. The reaction mixture was left stiπing 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 of silica gel column and toluene waa used as die first eluent. Toluene-ethyl acetate (1:1) was then used to elute the desired compound. The tided compound was isolated (0.06 g, 32%) as a yellow solid. NMR XH (250 MHz) (CE^C^; ppm): 8.29 (4H, m, aromatics), 8.07 (2H, m, aromatics), 7.76 (2H, m, aromatics), 6.45 (IH, d, NH), 6.05 (IH, s, Ht), 5.70 (IH, s, Hr), 5.43 (IH, s, H3-), 4.82 (IH, m, H5.), 4.52 (IH, , H4 , 3.27-3.52 (4H, m, 2x-CH2- aide 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: (l'S, lS)-5,M-dioxo-3,3-dimethoxymethyl-l-(2^^ trifluoroacetaπύdo-^-O-p-mtrobenzoyl-L^ (BCH-
1697)
124 s UBSTΪTUTE SHEET Undo' argcm 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 NH4Q. Extractions of the aqueous layer was done using dichloromethane. The combined oiganic layers were dried over Na2S04, filtered and the solvent was removed. The cnide material was then purified by flash chromatography, eluentiethyl acetate-dichloromethane (35:75). The isolated titled conφound was a yellow solid (0.03 g, 67%).
NMR -H (250 MHz) (CDQ3; ppm): 8.05 (2H, m, aromatics), 7.74 (2H, m, aromatics), 6.81 (IH, d, NH), 6.00 (IH, s, Hj), 5.49 (IH, d, J = 2.8 Hz, Hr), 4.58 (IH, q, H5 , 4.23 (IH, m, H4 , 3.60 (IH, 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^ and H4b), 2.09 (IH, broad)8' 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).
125
SUBSTITUTE SHEET Example 35: Preparation of (l'S,lR,4R)-5,10-diαxo-4-ethyl-l-(2',3',6,-ti^ trifluoroacetaπύdo-L-lyxohexopyπuM)se)-3,4,5,10-tetrahyd [2,3-c] pyran (BCH-2091)
BQfcHfil
Step l: methyl-2-(2l,5l-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 die ester 5.00 g (23.78 mmol), 208-186-01 in 65 ml of THF was then added dropwise. After die 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
126
SUBSTITUTE SHEET 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 teπφerature and the reaction was monitored by TLC. The reaction mixture was left stiπing at room temperature for 15 hours. The reaction mixture was then quenched by adding aqueous NH4Q and extracting with ether. The combined oiganic layers were washed witii brine, dried over N^S04, filtered and die solvent was removed. The crude was purified by flash chromatography using hexaneβ-ethyl acetate as eluent; 3.36 g of pure titled compound as a white solid were obtained.
NMR lH (250 MHz) (CDC13; ppm): 6.84 (IH, m, aromatic), 6.76 (2H, m, aromatics), 3.90 (IH, t, J = 7.6 Hz, H3), 3.77 (3H, β, OCH3), 3.75 (3H, s, OCH3), 3.64 (3H, s, (Cθ2 CH3), 2.03 (IH, m, H3a), 1.72 (IH, m, H3 ), 0.88 (3H, t, J = 7.3 Hz, -CH3 terminal). Step 2: 2-(2',5'-dimethoxyphenyl)-l-butaιιol
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 HQ IN was then added to the reaction mixture and extractions were done using dichloromethane. The combined oiganic layers were dried over Na2S04, filtered, and die solvent was removed. The isolated titied compound was used for next step without fuihtor purification.
NMR -H (250 MHz) (CDQ3; ppm): 6.76 (3H, m, aromatics), 3.77 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.75 (2H, m, Hla and Hlb), 3.19 (IH, m, H2), 1.74 (2H, m, H3a and H3 ), 1.51 (IH, 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 NaHCC<3 and extractions were done using ether. The combined oiganic extracts were dried over Na2S04, filtered, and die solvent was removed. The residue was purified by flash chromatography using hexaneβ-ethyl acetate (80:20) and (70:30) as eluent. The isolated tided product was a white solid (1.56 g; 54%).
NMR -H (250 MHz) (CDQ3; ppm): 6.64 (2H, m, aromatics), 4.85 (IH, d, J - 16.1 Hz, Hla), 4.55 (IH, d, J = 16.0 Hz, Hlb), 4.09 (IH, d, J - 11.3 Hz, H3a), 3.79 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.58 (IH, dd, Jj = 2.7 Hz, J2 = 11.4 Hz, H3b), 2.62 (IH, m, H4), 1.67 (2H, m, -CH2- ethyl), 1.01 (3H, t, J = 7.5 Hz, -CH3).
Step 4: (l'S, IR, 4R)-5,8-dimethoxy-4-ethyl-l-(2',3',6,-trideoxy^
Oφ-mtrobenzoyI-Lr4yxohexo-pyraiMse)HSθchroman
127
SUBSTITUTE SHEET The titled compound was obtained by applying the procedure from step 3, example 34, to the isochroman from step 3 herein.
NMR -H (250 MHz) (CgD6; ppm): 7.81 (2H, d, J = 8.8 Hz, aromatics), 7.65 (2H, d, J = 8.9 Hz, aromatics), 6.48 (2H, dd, Jχ= 9.0 Hz, J2 - 18.1 Hz, aromatics), 6.35 (IH, s, Hj), 6.26 (IH, d, J = 6.9 Hz, NH), 5.81 (IH, s, Hv), 5.52 (IH, s, H3 , 4.75 (IH, q, H5 , 4.58 (IH, m, H4 , 4.24 (IH, dd, Jj - 2.9 Hz, J2 = 11.4 Hz, H3a), 3.88 (IH, d, J = 11..4 Hz, H3b), 3.38 (3H, s, OCH3), 3.37 (3H, s, OCH3), 2.84 (IH, m, H4), 1.89 (2H, m, -CH2- sugar), 1.85-1.55 (2H, m, -CH - side chain), 1.18 (3H, d, J - 6.6 Hz, -CH3 sugar), 1.05 (3H, t, J = 7.3 Hz, -CH3 aide chain). (l'S, IS, 4S 5,8-dύ_tιedιoxy-4-etiιyl-H2',3',6'-trideoxy-3'-trifluora lyxohexo-pynnoseHsochroman was also obtained.
NMR *H (250 MHz) (CgDg; 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 (IH, NH), 6.09 (IH, s, Hx), 5.69 (IH, s, Hχ . 5.45 (IH, s, H3 , 4.72 (IH, m, H4 , 4.32 (IH, m, H5.), 4.26 (IH, dd, Jj = 2.9 Hz, J2 = 11.4 Hz, H3a), 3.89 (IH, d, J = 11.2 Hz, H3 ), 3.45 (3H, s, OCH3), 3.39 (3H, s, OCH3), 2.80 (IH, m, H^, 1.88 (2H, m, -CH2- sugar), 1.82 (2H, m, -CH - aide chain), 1.12 (3H, d, J - 6.4 Hz, CH3 sugar), 1.04 (3H, t, J = 7.4 Hz, -CH3 side chain).
Step 5: (l'S, IR, 4R)-5,8-dioxo^-ethyl-l-(2, \6'-trickoxy-3,-triflι )roacetamido-4,-0-p- nitrobenzoyl-I^yxohexopyraιιose) sochroman
The (1'S,1R,4R) glycoβide from step 4 herein was oxidatively demethylated as per procedure described in step 4, example 34. The titled coπφound had:
NMR -H (250 MHz) (C^Dg; ppm): 7.80 (2H, d, J = 8.9 Hz, aromatics), 7.62 (2H, d, J = 8.8 Hz, aromatics), 6.89 (IH, d, J - 6.9 Hz, NH), 6.04 (2H, dd, Jj = 10.1 Hz, J2 = 18.3 Hz, quinone ring),
5.87 (IH, s, Hx), 5.63 (IH, 8, Hr), 5.16 (IH, s, H3-), 4.80 (IH, q, J - 6.5 Hz, H5>), 4.56 (IH, m
H4 , 3.75 (IH, dd, Jj - 3.0 Hz, J2 = 11.6 Hz, H3a), 3.54 (IH, d, J = 11.5 Hz, H3b), 2.25 (IH, 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 aide chain).
Step 6: (l'S, IR, 4R)-5,10-tioxo-4-ethyl-l-(2',3',6'-tri nitrobe_u»yI-L lyxohexopyranose)-3,4,5,10-tetrah^
The titied coπφound 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 *H (250 MHz) (C D6; 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 (IH, d, NH), 6.11 (IH, s, Hx), 5.67 (IH, d, Hr), 4.97 (IH, s, H3 , 4.95 (IH, m, H4-), 4.49 (IH, m, H5.), 3.83 (IH, dd, H3a), 3.60
128
SUBSTiT ! ~V te-
«? HEET (IH, d, J - 11.4 Hz, H3b), 2.50 (IH, 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: (l'S, IR, 4R)-5,10-4Uαxo~4-ethy!-l-(2',3',6,-trid^ lyxohexopyranose)-3,4^,10-tetrahydro-lH-naphtho-[2 -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, exaπφle 34.
NMR -U (250 MHz) (CDQ3; ppm): 8.10 (2H, m, aromatics), 7.75 (2H, m, aromatics), 6.72 (IH, d, NH), 5.91 (IH, s, Hj), 5.41 (IH, β, Hr), 4.59 (IH, q, J = 6.6 Hz, H5 . 4.46 (IH, m, H4-), 4.32
(IH, m, H3.), 4.03 (IH, dd, Jj = 3.0 Hz, J2 = 11.6 Hz, H3a), 3.85 (IH, d, J = 11.6 Hz, H3b), 3.64
(IH, m, OH), 2.66 (IH, m, H4), 1.99 (IH, d, J - 8.3 Hz, -CH2- side chain), 1.86 (2H, m, H2-a and -
CH2- side chain), 1.65 (IH, 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 aUphatic), 1710 (C-O), 1668 (C-Q, 1299 and 1165 (C-O).
129
~ ~ -y **-
SUBSTIT _____ ς » «:cτ Example 36: Preparation of (l'S,lR S)-5,lu-diιιxo-3-plιenyloxymethyl-l-(2'^',6l- trideoxy-3'-trifluoroacetamido-L-lyxoi__exo^ lH-naphtho-[2^-c] pyran
Step l: α-phenoxymethyI-2^-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 teπφerature 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 NaHCC^ soluticm and extracted with
130
SUBSTITUTE SHEET dichloromethane. The combined organic layers were washed with bicaibonate, brine and were dried over MgS04. The crude residue was purified by column chromatogπφhy on silica gel using 25 % ethyl acetate in hexane to yield the title product (2.4 g; 64%).
*H NMR (250 MHz, CDC13) δ: 2.75 (IH, 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, Cfi2-0), 4.29 (IH, m, -CH-O), 6.70-7.00 (6H, m, Ar¬ il), 7.28 (2H, m, Ar-H).
Step 2: 5,8-din_«thoxy-3-phenoxynwthyI-isodιπ__π__an
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). Hie rest of the procedure is identical to the second part, step 1, example 29, to yield the title product (715 mg; 33%). -H NMR (250 MHz, CDCI3) 5: 2.65 (IH, dd, J = 11 and 17 Hz, H-4 ax), 2.89 (IH, 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-j-OPh and H-3), 4.73 (IH, d, J - 16 Hz, H-l), 5.07 (IH, d, J - 16 Hz, H-l), 6.68 (2H, AB doublets, Ar-H), 7.01 (3H, m, Ar-H), 7.33 (2H, m, Ar-H).
Step 3: (l'S, IR, 3S)-5,δ^liπletlM) -3-phCT lo meth l-l-(2,^,, ,-trideox - ,- triflι_»τoar-rtamid<>-4'-0-p-mtrobenzoyl-L-Jyx^
The isochroman from step 3 herein was glycosydated in 57% yield as per procedure described in step 3, exaπφle 34.
NMR XH (250 MHz) (CDQ3; ppm): 8.31 (4H, m, aromatics), 7.31 (2H, m, aromatics), 6.97 (3H, m, aromatics), 6.76 (2H, m, aromatics). 6.22 (IH, d, NH), 6.02 (IH, s, Hj), 5.63 (IH, s, Hr), 5.42 (IH, s, H3 , 4.67 (IH, m, H4 , 4.66 (IH, m, H5>), 4.57 (IH, m, H3), 4.18 (2H, m, -CH2- side chain), 3.82 (3H, s, OCH3), 3.81 (3H, β, OCH3), 2.90 (IH, dd, 1^, 2.56 (IH, dd, H^, 2.00-2.18 (2H, m, -CH2- sugar), 1.16 (3H, d, J - 6.5 Hz, -CH3 sugar).
Step 4: (l'S, IR, 3S)-5,8-dioxo-3-phαιylo.<ym^ trifluoroacetaπύdo-4'-0--p--Utrobe__ιm^
The (1'S,1R,3S) glycoβide from step 3 herein was oxidatively demethylated as per procedure described in step 4, example 34. NMR -H (250 MHz) (CgDg; ppm): 7.73 (4H, dd, aromatics), 7.17 (2H, m, aromatics), 6.90 (3H, d, aromatics), 6.71 (IH, d, NH), 6.08 (2H, d, quinone ring), 5.80 (IH, s, Hj), 5.76 (IH, s, Hr), 5.50 (IH, s, H3 , 4.70 (IH, m, H4<), 4.62 (IH, m, H5.), 4.22 (IH, m, H3), 3.85 (IH, m, CH2 s e chain), 3.66 (IH, dd, CH2 side chain), 2.27 (IH, dd, H4a), 1.94 (IH, dd, H4b), 1.85 (2H, m, -CH2 side chain), 1.34 (2H, m, -CH2- sugar), 1.18 (3H, d, -CH3 sugar).
131
SUBSTITUTE SHEET Step 5: (l'S, IR, 3S)-5,10-dioxo-3-phenytoxymeωyl-l-(2',3',6'-trideo^ triflι__oroacetamido-4'-0-p-_ritro^^ lH-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 lii (250 MHz) (CDC13; 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 (IH, d, J = 7.5 Hz, NH), 6.01 (IH, s, Hx), 5.75 (IH, s, Hr), 5.43 (IH, s, H3 , 4.63 (IH, m, H4 . 4.61 (IH, m, H3), 4.60 (IH, m, H5 , 4.20 (2H, m, -CH2- side chain), 2.89 (IH, dd, Iχ - 3.4 Hz, J2 - 19.3 Hz, H+J, 2.57 (IH, dd, Iχ = 11.5 Hz, J2 = 19.4 Hz, H^, 2.07 (2H, dd, -CH2- sugar), 1.19 (3H, d, J - 6.5 Hz, -CH3 sugar).
Step 6: (l'S, lR, 3S)-5,10-dioxo-3-phe_nyloxymethyl-l-(2, ,,6,-trideoxy-3'- trifluαroacetaπudo-L-lyxohexopyra_ιose)-3,4,5,10-te^ pyran (BCH-2032)
The glycoβide from step 5 herein was deprotected as per procedure described in step 6, exaπφle 34, to afford the tided coπφound in 81 % yield.
NMR -H (250 MHz) CDCI3; ppm): 8.11 (2H, m, aromatics), 7.78 (2H, m, aromatics), 7.33 (2H, m, aromatics), 6.98 (IH, m, aromatic), 6.91 (2H, d, J - 8.3 Hz, aromatics), 6.69 (IH, d, NH), 5.95 (IH, s, Hj), 5.55 (IH, d, Hχ . 4.61 (IH, m, I ), 4.41 (IH, m, H5 , 4.38 (IH, m, H3), 4.16 (2H, m, - CH2- side chain), 3.64 (IH, m, OH), 2.89 (IH, dd, H4J, 2.57 (IH, dd, H^, 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).
132
SUBSTITUT Example 37: Preparation of naphtho-[2,3-c] pyran derivatives with an allyl side chain
BCH-2163
Step l: 5,8-din__ethoxy-3-(2-propenyl)-isochronιan
To a stirred solution of pyranosulfcme (670 mg, 2.0 mmol) in CH2Q2 (20 ml) at -78°C were added allyltri ethylsilane (636 μl, 4.0 mmol) and AIQ3 (533 mg, 4.0 mmol). Temperature was then raised to -35°C few minutes, then HQ (0.1 N, 10 ml) was added. The reaction mixture was worked up with CH2C12 and water. The organic layer was washed with brine and dried over MgS04. The solvent was evaporated to give the allyl isochroman (450 mg, 96%).
133
SUBSTITUTE SHEET lH NMR (250 MHz, CDCI3) δ: 6.63 (2d, J = 8.9 Hz, 2H, A -H , 5.96 (m, IH, -CH-C), 5.17 (d, J = 17 Hz, IH, -CH-CU2), 5.10 (d, J - 9.9 Hz, IH, -CH-CU2). 4-93 (d> J = 16 ° -**- 1H' H_1)' 4.58 (d, J = 16.0 Hz, IH, H-l), 3.78 and 3.75 (2s, 6H, 2xOCH3), 3.65 (m, IH, H-3), 2.75 (broad d, J = 17.0 Hz, IH, H-4), 2.45 (m, 3H, H-4, -Qfe-CH-C).
Step 2: (1'S,1S,3S) and (l'S,l-R R)-l-(2,^',6',-trideoxy-3'-trinuoroacetamido-4'-0- paramt_robenzoyl-Lr4yxohexopyranose)-5,8-dimrthoxy-3-(
To a mixture of 5,8-dimethoxy-3-(2-propenyl)-i∞ hroπιan (400 mg, 1.72 mmol), 2',3',6'-trideoxy-3- trifluoroacrtamido-4-Oj aranitrobenzoyl-l-α,β-hydroxy-lyxohexopyranose 2 (1.2 eq., 810 mg, 2.06 mmol) and MS4A (500 mg) in CH2Q2 (17 ml) at room temperature waa 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 NaHCC<3 sat. solution. Evaporation of the solvent and purifying by FC (CH2Cl2:Hex:Et0Ac 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. lH NMR (250 MHz, acetone^) δ (ppm): 8.65 (bd,lH,NH), 8.4 (d,8.9Hz,2H,PNB-H), 8.34 (d,8.9Hz,2H, PNB-H), 6.86 (d,8.8Hz,lH,Ar-H), 6.8 (d,8.8Hz,lH,Ar-H), 6.0 (m,lH,C=CH-C), 5.88 (s,lH,H-l), 5.56 (bs, 1H.H-1*), 5.47 (bs,lH,H-4*), 5.14 (bm,2H,C=CH2), 4.6 (m,2H,H-3',H-5'), 4.3 (m,lH,H-3), 3.8 (s,3H,ACOCH3), 3.78 (s,3H,Ar-OCH3), 2.75 (m.lH.H-4), 2.47 (m,2H,C=C-CH2), 2.4 (m,lH,H-4), 2.3 (m,lH,H-2*), 1.9 (m,lH,H-2*), 1.16 (d,6.4Hz,3H,H-6*).
Step 3: (±)-Methyl ketone hydroxy-l-isochroπian 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
NaHC03 (7.19g, 85.6 mmol) in water. The reaction mixture was then droped in a mixture of 200 ml of CH2C12 and 200 ml of water and extracted with CH2C12 and back extracted witii Ethyl Acetate. Combined organic layers were washed with water (3x300 ml)and then dried (Na2S04). Recristallisation of the residu gave 2.237 g (85 % yield) of the pure methyl ketone hydroxy-1 isochromane quinone. PMR (CDCI3, 300MHz)δ: 2.30 (s, 3H, COCH3), 2.39 (ddd, IH, J = 20.0 Hz, 12.0 Hz and 1.2 Hz, CHaCHCO), 2.88 (dd, IH, J - 19.5 Hz and 3.9 Hz, CHeCHCO), 3.42 (broad m, IH, OH-1), 4.64 (dd, IH, J - 11.7 Hz and 4 Hz, H-3), 6.03 (broad s, IH, H-l), 6.78 (2xd, 2H, quinone-H).
Step 4: (1'S,1S3S) and (l'-S.l-R^RVS^ '^'^'-trideoxy-S'-trinuoroacetamidoo^'- paraιωt_robe∞oyI-L-lyxohexopyra__ιose)-5,10-dioxo-3,4,5,10
[2,3-c]-pyran-3-yl)-propene
To a solution of (l,-S,l-R,3-R)-l-(2',3',6'-trideoxy-3'-trifluoroa__«tamiA_^'^jaranitrobenzoyl-L- lyxohexopyranose)- 5,8-dioxo-3-propenyl-l,4,5,8-tetrahyd_robenzo-[2,3-c]-pyran (205 mg, .34 mmol) in
134
SUBSTITUTE SHEET toluene (10 ml) at room temperature was added l-acetoxy-l,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 (l'S, 1S.3S) diastereomer was prepared the same way.
-H 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,lH,NH), 5.95 (1H,C=CH-C), 5.9 (s,lH,H-l), 5.7 (s,lH,H-l'), 5.43 (bs,lH,H-4') , 5.25 (m,2H,C-CH2), 4.6 (m,lH,H-3*), 4.43 (q,6.4Hz,lH,H-5*), 4.21 (m,lH,H-3), 2.8 (dd,19.4Hz,3.2Hz,lH,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,l-R^-R)-3-([2•^ 6 rid€o -3,-trinuoro cet_^mic t,- hydroxy-L-lybohexopyraι__ose]-5,10-dioxo-3,4,5,10^tetrahydronaphtho-[2^- :]- pyran-3-yl)-propene (BCH-2031)
To a solution of (l'-S,l-R,3-R)-3-([2\3\6'-trid^xy-3,-trifluoroacetamido-4' )aranitrobenzoyl-L- lyx(^xopyranose)-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 (4.37 in MeOH, 60μl, .26 mmol) and stirred for 15 minutes. The reaction was quenched by adding NH4C1 sat. and extracted with QI2C12. The organic phase was then dried over MgS04, 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.
JH-NMR (250MHz,CD2Cl2) δ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, 1H.C-CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), 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,lH,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 naphtbo-[2,3-c] pyran derivatives with a methyl ketone side chain from a bicyclic quinone aglycal
135
SUBSTITUTE SHEET
R-I BCH-1620 R - I BCH-1621 c R-PNB,«pi R-PNB, epi R - OR epi BCH-16 9 ■c R -0H, ep BCH-1648
Step l and 2: (l,-S,l-R -S)-methyl-(l-[2' \6'-trid_»xy-3,-trinuoroacetamido- 4'-iodo-L-lyxohexopyranose]-5,10-dioxo-3,4,5,10- tetrahydronaphthH2 -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 odo-2,3,6-trideoxy-α, β-L-lyxohexopyranose (478 mg, 1.02 mmol) and 3-acetyl- 5,8-dioxo-l-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. NaHCC<3 5 % and warmed up to room temperature. After filtering off solids, the filtrate was extracted with CH2C12. The oiganic phase was then washed with brine and dried over MgS04. 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 l.-acetoxy-l,3-butadiene (98 μl, .82 mmol) in toluene (10 ml) for overnight at room teπφerature and under argon. Silica gel was next added and air was bubbled into the reaction mixture and stiπing for 2 hours. The crude product was recovered by filtering and washing of
136
SUBSTIT TE SHEET 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 die same method. -H NMR (250 MHz, acetone) δ (ppm): 8.43 (bd,lH,N-H), 8.0 (m,2H,ArH), 7.9 (m,2H,Ar-H), 6.0 (s,lH, H-l), 5.6 (bd, 5.4Hz, 1H,H-1'), 4.89 (bβ,lH,H-3'), 4.75 (dd,11.6Hz,4.0Hz,lH,H-3), 3.75 (m,lH,H-4*), 3.7 (q,6.1Hz,lH,H-5*), 3.0 (dd,19.6Hz,4Hz,lH,H-4), 2.55 (dd, 19.6Hz, 11.6Hz, 1H,H- 4), 2.3 (s,3H,COCH3), 2.26 (m,lH,H-2*), 1.8 (m,lH,H-2'), 1.25 (d,6.1Hz,3H,H-6*).
Step 3: (l'-S,l-R S)-3-([2'^',<'-trideo_ry-3l-4riflιιoroacetaιnido-4'4ydro_^ lyi_-θhexopyranose]-5,10-dkιxo-3,4,5,10-tetraty propene (BCH-1649)
To a soluticm of (l'-S,l-R,3-S)-3-([2',3',6'-trideoxy-3'-trifluoroacetamido-4'-pannitrobenzoyI-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 NH Q sat. and extracted witii CH2Q2. The organic phase was then dried over MgS04, evaporated to give 64 mg crude. Purifying by preparative TLC (tol: EtOAc 6:1) gave 25 mg (25%) of die desired product. The (1'S,1S,3R), BCH-1648, diastereomer was obtained using the same method.
-H NMR (250MHz,CD2Cl2) δ (ppm): 8.05 (m,2H,Ar-H), 7.75 (m,2H,Ar-H), 6.25 (bd,lH,NH), 5.95 (m, 1H.C-CH), 5.84 (s,lH,H-l), 5.51 (bd,lH,H-l'), 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,lH,H-4), 2.44 (m,2H,C=C-CH2), 2.3 (dd,19.4Hz,HHz,lH,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
BCH-2143
AΛi_fc__.OOMM_e_
BCH-2141 BCH-2149
Step 1: (l'-S^-I -S^-S^Oa-Sj-methyl-d-P'^'^'^'-tetradeoxy-S'-methoxy^'-O- methanesulfonyI-L-lyxol_«xopyraiM)se)-4a,10a-epoxy-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2 -c] pyran-3-yl) ketone (BCH-2141)
137
SUBSTITUTE SHEET To a solution of (l'-S,l-R,3-S)-methyl-(l-[2',3',4,,6,-tetn_deoxy-3,-methoxy-4'-0-methansulfonyl-L- lyxohexopyranoβe 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 ^C^ (30% aq. solution , 5.2 μl, 46 μmol). After 10 minutes, NaOH (.IN, .364 ml) was added and the reaction mixture was stirred at 0βC for 30 minutes. Workiφ was carried out by adding brine to the mixture, extracting with CH2C12 and drying die organic phase over MgS04. The crude obtained after evaporation of the solvent was purifying by recrystalization to give 8 mg (50%) of the pure tided product. The (l'S,lS,3R,4aR,10aR), BCH-2149, diastereomer was obtained using the same method l NMR (250MHz, CDC13) δ (ppm): 8.05 and 7.8 (m,4H.ArH), 6.15 (s,lH,H-l), 5.55 (bd,lH,H-l*), 4.86 (bβ,lH,H-4'), 4.3 (dd,9Hz,3Hz,lH,H-3), 4.05 (q,6.6Hz,lH,H-5*), 3.65 (m,lH,H-3*), 3.45 (s,3H,S02CH3), 3.15 (s,3H,OMe), 2.75 (dd,12.3Hz,3Hz,lH,H-4), 2.35 (m,lH,H-4), 2.3 (s,3H,COCH3), 1.9-2.2 (m,2H,H-2'), 1.25 (d,6.6Hz,3H,H-6*).
138
SUB Example 40: Monoaminoβugar substituted naphthoquinone derivative
+1 -ϋepi_ner
+1 -diepi_ner BCH-1673
Ste l: (2R,4R^S,6S) and (2R,4S^,t)S)-2-tert-butyldimethyl_dlyloxy-4-thioac_etoxy-5- acetoxy-6-methyl-tetrahydropyran
A solution of ihamnal diacetate (0.514 g, 2.4 mmols) in H20 (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 NaHCθ3 (1.2 g, 6 eq.) is added to neutralize the excess CH3COSH. The water is evaporated and the residue is dissolved in CH2C12 and dried over MgS04. The solids are filtered and die solvent evaporated. A solution of the oil obtained after evaporation in CH2C12 (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 teπφerature, under argon, for 18 hours. It is poured in sat. aq. NaHCC«3 and die phases are separated. The aqueous layer is extracted with CH2C12 (2x) and the combined oiganic extracts are dried over MgS04. The solids are filtered and the solvents evaporated.
139
S ____. .U . _B_-_S_•(- ____m__• * -»"u •• -τi~-> »Eα: r~ 1h • ^£ ?E___ TT The oil obtained is purified by flash chromatogπφhy (silica gel, 9: 1 bexanes/EtOAc) to give a 1 : 1 mixture of titled isomers: 0.50 g (60 %) as a clear oil.
-H NMR (CDC13): δ 4.90+4.85 (2dd, IH, H-l), 4.73+4.62 (2dd, IH, H-4), 4.30+3.75 (q+m, IH,
H-5), 3.71+3.55 (2ddd, IH, H-3), 2.36+2.30 (2s, 3H, SAc), 2.19 (m, IH, H-2), 2.03+1.99 (2s, 3H, OAc), 1.77 (m, IH, H-2), 1.22+1.18 (2d, 3H, H-6), 0.88 (s, 9H, t-Bu), 0.09+0.10 (2s, 6H, SiMe^.
Step 2: (2R,5R,6S)-2-tert-butyldimemy_^yloxy-5-acetoxy- -α__ethyl-tetr^
A solution of the duo-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 conφound as a clear oil. lH NMR (CDCI3): δ 4.74 (dd, IH, J = 2.0, 8.6, H-l), 4.42 (ddd, IH, J - 4.7, 10.5, 10.5, H-4), 3.98 (dq, IH, J = 6.16, 9.23, H-5) 2.10 (m, IH, 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 R,6S)-2-tert-butyldimethylsUyloxy-5-hydroxy-i-methyl-tetrahydropyra^
To a solution of the acetate from step 2 herein (36 mg, 0.13 mmol) in dry MeOH (1.3 ml), at room teπφerature, was added 1 N NaOH (0.14 ml, 1.1 eq.) and the solution was stirred for 45 minutes. It was then poured in H20 and die aqueous phase was extracted 3x with CH2Q2. The combined organic extracts were dried over MgS0 , the solids were filtered and the solvent evaporated to give 30 mg (96 %) of the pure tided alcohol.
JH NMR (CDCI3): δ 4.72 (dd, IH, J = 1.9, 8.7, H-l), 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^S,6S)-2-tert-butyldimethyl_άlyk>xy-5-arido-6-methyl-tetrahydropyra_^
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 PI13P (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.
*H NMR (CDQ3): δ 4.71 (dd, IH, J = 3.0, 7.9, H-l), 3.64 (dq, IH, J = 1.7, 6.3, H-5), 3.33 (m, IH, 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^S,6^-2-tert-butyldimcΛyl_άlyloxy-5-trifluoroacetamido-6-methyI- tetrahydropyran
140
S r. p i . <■» «- " T ' "w i- ~ ~ ~-~ TmmTm ' f 4 i _. I 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 die black suspension was placed under a H atmosphere for 3 hours. The catalyst was then filtered dirough Celite and die solvent was evaporated to diyness. The erode amine (0.18 g, 0.72 mmol) was dissolved in dry CH2Q2 (7.2 ml) and Et3N (0.20 ml, 2 eq.) was added. The solution was cooled to 0°C and TFA20 (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. NaHC03. The phases were separated and the aqueous layer was extracted witii CH2C12 (2x). The combined organic extracts were dried over MgS04, the solids filtered and die solvent evaporated to give 0.17 g (71 %) of the crude titied trifluoroacetamide that was used as such. lH NMR (CDC13): δ 6.70 (be, IH, NH), 4.75 (dd. IH, H-l), 3.92 (m, IH, H-4), 3.73 (dq, IH, 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 R,1'S^'S,6'S) and (U S,l,S,5,S,6,S)-methyl-(H4,trifluoroacetamido-5'- methyltetrahydropyranyl]-5,10-dmxo-3,4,5,10-tetrahydn^ pyran-3-yl) ketone (BCH-1673)
The tided coπφounds were obtained in 30% yield by following the fnocedure described in step 4, example 12, on the precursor of step 5 herein. The tided compounds were purified via flash chromatography (silica gel, 3: 1 hexanes/EtOAc). The mixture of isomers was not separable by chromatography.
JH NMR (CDCI3): δ 8.14-8.07 (m, 2H, ArH), 7.79-7.73 (m, 2H, ArH), 6.17+5.99 (2s, IH, H-l), 5.50+5.39 (2bs, IH, H-l*), 4.68+4.24 (2q, IH, J = 6.5, H-5'), 4.56+4.49 (2dd, IH, J = 4.2, 11.8, H-3), 4.05 (m, IH, H-4'), 3.08+3.07 (2dd, IH, J = 4.2, 19.9, H-4), 2.57 (dd, IH, 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').
141
SUBSTITUTE SHEET Bxaaple 41: (1'8,18,3R)-3-(oxi___o«thyl)-5,10-di.oxo-l<2,3,6- trid*oxy-3-trifluoroaceta_aido-_L-lyxohexopyranoae)- 3,4,5,10-tetrahydro-lH-naphtho [2,3-c] pyran (BCH- 2101) and l,3-diepi_ser (BCH-2115)
BCH-210I
BCH-2115
Step It (lS,3R)-3 <oxiaoethyl)-l (2,3,6-trideoxy-3- trifluoroacetaa__ido-4-p-nitxO_bensoyl-Xι-lyxohexopyranose)-5,8- diaethoxy-isochxαauui
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 CH2C12 (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 oxi e (63 mg; 67%).
142
SUBSTITUTE SHEET NMR (acetone-d6; δ) : 1.26 (3H, d, J « 6.8 Hz; -CH3 ) , 1.26 (3H, d, J *~ 8.3 Hz; -CH3) , 1.89 ( H, dd, J - 4.4, 13.2 Hz; H-2 of the sugar) , 1.96 (3H, β, CH3 of the side chain) , 2.47 (IH, dt, J - 3.6, 13.1 Hz; H-2 ) , 3.81, 3.88 (3H, s each; Ar-OCH3) , 4.60-4.66 (IH, m; βugar-H) , 4.72 (IH, t, J « 7.8 Hz; H-3 ) , 4.83 (IH, q; J ■ 6.5 Hz; H-5 of the sugar) , 5.51 (IH, br singlet; H-l of the sugar) , 5.61 (IH, d, J ■ 2.9 Hz; H-4 of the sugar) , 6.15 (IH, s; H-l) , 6.87, 6.90 (IH, 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 (IH, d, J -~ 8.0 Hz; -NHTFA) , 10.02 (IH, s; «NOH) .
Step 2: (l 'S, lS,3R)-3 (oxiaoethyl)-5, 10-dioxo-l (2,3,6-trideoxy-3- triflttoroacatamido- -lyxohexopyranose)-3,4,5,10-tetrahydro- lH-naphtho-[2,3-c] pyran (BCH-2101)
Acetylation was done on the oxime from step 1 herein (33mg; 0.051 mmole) in CH2C12 (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 CH2C12 (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 CH2Cl2t MeOH«9:l as eluents) pure tricyclic glycoβide (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 CH2C12 (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 CH2 C12 aβ eluent) and preparative TLC (CH2C1 : MeOH«9:l) yielding pure titled oxime (3.7 mg; 14% in 4 steps), m.p.-125-27βC.
NMR (acetone-dg) δ: 1.35 (3H,d,J=6.6Hz; CH3 of the sugar), 1.75 (lH,dd,J«4.6,13.0Hz;H-2 of the sugar), 1.95 (3H,s,CH3 of the side- chain), 3.71 (IH, br.signal; H-4 of the sugar), 4.27 (2H,m;sugar-H), 4.57 (lH,q,J«6.6Hz;H-5 of the sugax), 4.70 (lH,t,J=7.5Hz;H-3) , 5.44
143
SUBSTITUTE SHEET (lH,d,J-3.3Hz;H-l of the sugar) , 6.07 (1H,S;H-1) , 7.87-7.90 (2H,m;Ar-H) , 8.08-8.12 (2H,m;λr-H) , 10.15 (lH,bit br. ainglet;*NOH) .
Step 3i (lR,38)-3-(oxiaoethyl)-l (2,3,6-trideoxy-3- trifluoroacetaa .do-4-p-nitrobensoyl-L-lyxohexopyranose)-5,8- dimethoxy-isochroawn
Oxime was prepared from 3-acetyl isochroman glycoside (60 mg; .096 mmol) using hydroxylamine hydrochloride (39 mg; 0.56 mmole) in KtOH (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 (IH, dt, J ■ 3.6, 12.9 Hz; H-4), 3.81 (6H, s; Ar-OCH3), 4.63-4.73 (IH, m; H-3 of sugar), 5.45 ( H, br signal; H-l of sugar; same of the other diastereomer overlapped), 5.56 (IH, br signal; H-4 of the sugar; same of the other diastereomer overlapped), 5.95 (IH, s, H-l), 6.81-6.95 (m; Ar-H), 8.30-8.43 (m; λ-H of PNB group), 8.66 (IH, br d, J - 5.9 Hz; NHTFA), 10.05 (IH, 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: (l'S, IR, 38)-3 (oxi__κethyl)-5,10-dioxo-l (2,3,6-trideoxy-3- trifluoroacetaaido-Zi-lyxohexop ranose)-3, ,5,10-tetrahydro- lH-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 CH2C12 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
144
SUBSTITUTE SHEET through two columns of silica gel (1% and 2% methanol in CH2C12 as eluentβ) yielding the oxime in 12.5% yield (5 mg) (contaminated with the other diastereomer in 5.6:1 ratio).
NMR (acetone-dg; δ): 1.18 (3H,d,J-6.4Hz;CH of the sugar), 1.76 (lH,dd,J«4.8,12.9Hz;H-2 of the sugar), 1.98 (3H,a,CH3 of the side chain), 2.18 (IH, dd,J-3.7,12.9Hz,H-4), 3.67 (lH,br.d,J-3.9Hz;βugar-H), 4.21-4.29 (2H,m,sugar-H), 4.77 (lH,dd,J«5.4, 9.6Hz;H-3), 5.48 (lH,d,J=3.2; H-l of the sugar), 5.91 (lH,β,H-l), 7.86-7.92 (2H,m;Ar-H), 8.06-8.10 (2H,m;Ar-H), 10.14 (lH,β,-N-OH) , (there were small signals due to the other diastereomer present in the spectrum which were not detailed).
Example 42: Pre aration of (l'S,lS,3R)-3
(trifluoroacetaad.doethyl)-5,10-dioxo-l (2,3,6- trideoxy-3,4-dihydroxy-L-lyxohβxopyranosβ)-3,4,5,10- tetrahydro-lH-naphtho [2,3-c] pyran (BCH-2018)
BCH-2018
Step 1: 3-(Trifluoroacetaa .do-ethyl)-5,8-di_aethoxy isochroamn
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
145
mj J i-imJ H i ϋ « > _. ■ __- _____ I dissolved in small volume of water (10 ml), extracted with CH2C12 (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 CH2C1 (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 CH2C12 (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 (CDC13; δ) : 1.29 (3H, d, J « 6.8 Hz; -CH3), 2.52 (IH, dd, J - 11.3, 16.9 Hz; H-4), 2.69 (IH, dd, J * 2.2, 16.4 Hz; H'-4), 3.65 (IH, ddd, J * 3.2, 6.3, 11.2 Hz; H-3), 3.75, 3.78 (3H, s each, Ar-OCH3), 4.24 ( H, m; -CH(NHCOCF3)CH3), 4.58 (IH, d, J - 15.8 Hz; H-l), 4.97 (IH, d, J « 15.8 Hz; H'-l), 6.62, 6.67 (IH, d each, J * 8.9 Hz; Ar-H).
step 2: (IS',18,3R)-3-(trifluoroacataaidoathyl)-5,8-di—thoxy-1- (2' ,3',6'-trideoxy-3•,4•-dihydroxy-Xi- yxohexopyranoae)- isochroaum
Coupling with sugar was done using DDQ in CH2C12 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 CH CN (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 CH2C12 (3x100 ml), washed with water (20 ml), dried and evaporated. The crude product was chromatographed over silica gel
146
SUBSTITUTE SHEET (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 (IH, dd,
J - 5.1,12.6 Hz; H-2 of the sugar), 1.91 (IH, dt, J - 3.8, 12.3 Hz; H-2 of the sugar), 2.41 (IH, dd, J ■ 11.6, 17.4 Hz,- H-4), 2.79 (IH, dd, J « 3.4, 17.6 Hz; H'-4), 3.42 (IH, d, J - 4.4, sugar-H), 3.55 (IH, br signal; H-4 of the sugar), 3.64 (IH, 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 (IH, q, J ■ 6.5 Hz; H-5 of sugar), 5.36 (IH, d, J ■ 3.3 Hz; H-l of the sugar), 6.04 (IH, s, H-l), 6.79, 6.88 (IH, d each, J - 8.9Hz; Ar-H), 8.50 (IH, br d, J - 7.0; NfiTFA). 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 (IH, dd, J - 6.1, 11.3 Hz; H-4), 2.80 (IH, dd, J - 3.3, 17.3 Hz; H'-4), 3.45 (IH, d, J - 4.8 Hz; βugar- H), 3.53 (IH, br signal; sugar-H), 3.66 (IH, d, J - 6.9 Hz; sugar-H), 3.78, 3.81 (3H, s each; Ar-OCH3), 4.08 (IH, q, J - 6.7 Hz; H-5 of the sugar), 4.16-4.29 (2H, m; CH(NHTFA)CH3 and sugar-H), 5.36 (IH, br singlet, H-l of sugar), 5.85 (IH, s; H-l), 6.78-6.89 (2H, m; λ-H), (There were few signals due to the other diastereomer which are not detailed.).
Step 3: (l'S,lS,3R)-3-(trifluoroaceta_aidoethyl)-5,10-dioxo-l- (2*,3' ,6'-trideoxy-3• , •-dihydroxy-L-lyxohexopyranose)-
3,4,5,10-tβtrahydro-lH-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: CH2C12: MeOH«9:l) (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 (lH,dd,J«4.7,12.6Hz;H-2 of the sugar), 1.92 (lH,dd,J=3.7,12.2Hz;H-2 of the sugar), 2.47 (lH,dd,J*10.2,19.0Hz;H-4), 2.82
(lH,dd,J=2.9,19.0Hz;H*-4), 3.49 (lH,d,J=4.3Hz;-OH of the sugar), 3.59 (lH,br.signal which became sharp on 0 O-exchange;H-4 of sugar), 3.68
147
SUBSTITUTE S EET (lH,d,J«6.7Hz;-OH of the sugar), 3.82 (lH,m;H-3), 4.19-4.30 (2H,m,overlapping-CBCH3(NHTFλ) and sugar-proton), 4.42 (lH,q, J=6.5Hz,H-5 of the sugar), 5.36 (lH,d,J-3.5Hz,H-l of the sugar), 6.0 (lH,s,H-l), 7.86-7.90 (2H,m;λr-H), 8.05-8.10 (2H,m;Ar-H), 8.56 (lH,br. signal;- NHTFλ) . (Stereochemistry of NHTFA is not yet determined).
Example 43: Preparation of (l'R,lR,3S)-3-acato-5,10-dioxo-l-(2- deoxy-2-chloroethylnitroBθuraido-D-glucopyranose)- 3,4,5,10-tetrahydro-lH-naphtho [2,3-c] pyran (BCH- 2038)
BCH-2038
Step 1: ( 'R, R, 3S)-3-acβto-5,8-dijBβthoxy-l(2-deoxy-2- chloroethylureido-3 , 4 , 6-tr acetyl-D-glucopyranose ) - isochroman .
148
SUBST; ■* »-T"ι r f T t 'mm-? I - Jl t "ΛEΓ _.C" 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. r 1£, 104 (1975)). This compound was coupled with 3-acβto-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-dς; δ) of the title compound: 1.91, 1.95, 2.00 (3H, β each; acetyl groups) 2.32 (3H, β, keto-methy1), 2.50 (IH, dd, J - 12.3, 17.6 Hz; H-4), 3.01 (IH, 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-C1 group); 3.83, 3.88 (3H, s each; λr-OCH3), 4.14 (4H, m; H-5, H-2, H-6 and H-6 of the sugar overlapping), 4.60 (IH, 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 (IH, d, J = 3.5 Hz; H-l of the sugar), 5.49 (IH, broad s; -NH-CO-), 6.02 (IH, s; H- 1), 6.15 (IH, br signal; CONH-CH2), 6.87, 6.96 (IH, d each, J - 9.0 Hz; λr-H).
NMR (acetone-dg; δ) of the 1,3-diepimer: 1.92, 2.00, 2.06 (3H, s each; acetate-groups), 2.28 (3H, s; keto-methy1), 2.48 (IH, dd, J ~~ 12.0, 17.8 Hz; H-4), 2.91 (IH, dd, J - 4.2, 11.7 Hz; H'-4), 3.26-3.51 (2 multiplets, IH each; -HN-CH2-), 3.56 (2H, t, J ■ 6.2 Hz; -CH2C1), 3.84 (6H, s; λr-OCH3), 4.14-4.23 (2H, m; sugar-H), 4.34 (IH, 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 (IH, d, J ~~ 3.7 Hz; H-l of the sugar), 5.81 (IH, d, J ■ 9.6 Hz; -NH-CO), 5.98 (IH, br, triplet; -NH-CH2), 6.16 (IH, s; H-l), 6.91, 6.99 (IH, d each, J - 9.0 Hz; λr-H).
Step 2: (l'R, IR, 38)-3-aceto-5,8-di_aethoxy-l(2-deoxy-2- chloroeth lureido-4,6-bena lidene-D-glucopyranoae)- isochroman
To a cold solution of triacetyl derivative (120 mg; .19 mmol) in CH CN was added .I 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% NaHC03-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
149 | IP r' UT"": c ET 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 CH C12 (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-methy1), 2.50 (IH, dd, J - 12.2, 17.6 Hz; H-4), 2.99 (IH, dd, J - 4.1, 17.6 Hz; H'-4), 3.49 (2H, t, J - 5.8 Hz; -CH2-C1), 3.63 (2H, m, -NH-CH2-), 3.82, 3.91 (3H, a, Ar-OCH3), 4.19 (IH, dd, J ■ 4.5, 9.6 Hz; βugar-H), 4.62 (IH, dd, J - 4.1, 12.2 Hz; H-3), 5.46 (IH, d, J - 3.8 Hz; H-l of the augar), 5.62 (IH, β, -CH Ph), 5.68 (IH, d, J - 8.5 Hz; -NH-), 6.00 (IH, β, H-l), 6.18 (IH, br β, -NH CH2-), 6.87, 6.95 (IH, d each, J - 8.9 Hz; Ar-H), 7.34 (3H, m; Ar-H), 7.46 (2H, m; Ar-H).
Step 3 (l'R, R, 3S)-3-aceto-5,10-dioxo-l-(2-deoxy-2- ch oroethylureido-4,6-benaylidene-D-glucopyranose)-3,4,5,10- tetrahydro-lH-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 CH2C12 (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 acetoxy¬ butadiene (1.2 ml) was added. The mixture waβ stirred at room temperature for 16 hours. The solution was not quite homogeneous and TLC showed some starting material. λcetoxy-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 CH Cl :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 (IH, dd, J = 11.4, 19.7 Hz; H-4), 3.01 (IH, dd, J - 3.9, 19.6 Hz; H'-4) 3.55, 3.67 (m each, HN Cfi2-£H2C1), 4.22 (IH, dd, J = 4.6, 9.7 Hz; sugar-H), 4.65 (IH, d, J =
150
Cl . Ω ~ " r~ ~ - T** r"**"T"
- _. S . km, m-. I 3.9 Hz; -OH) , 4.73 (IH, dd, J - 4.0, 11.4 Hz; H-3) , 5.52 (IH, d, J = 3.8 Hz; H-l of the sugar) , 5.63 (2H, br s; CH-Ph and -Nϋ-CO) , 5.94 (IH, t, J ■ 5.7 Hz; -NH-CH2 ) , 6.04 (IH, s; H-l) , 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: ( 'R, IR, 3S)-3-acβto-5, 10-dioxo-l-(2-d#oxy-2-chloroethyl- nitroaoureido-D-glucopyranoae)-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 waa added NaN02 (10 mg) in two portions. The reaction was complete in 2 minutes. It was diluted with water (5 ml), extracted with CH C12 (3x25 ml), washed with water (10 ml; 15 ml), dried over Na2S04 and evaporated. The crude product (4.5 mg) waa paβaed through a small column of silica gel (eluent:EtOAc and 10% methanol in CH2C12) yielding pure titled product (yield - .9 mg; 17%) (HPLC:92%) NMR (acetone-d6; δ): 2.35 (3H, a, keto-methyl), 2.51 (IH, dd, J - 12.9, 19.2 Hz; H-4), 2.98 (IH, dd, J - 4.1, 19.6 Hz; H'-4), 3.52-3.89 (two multiplets; some of the sugar protons, and overlapping A2B system due to -HN(CH2)2C1), 4.08 (H, dd, J ■ 3.5, 6.0 Hz; sugar-H), 4.26 (IH, dd, J - 6.6, 11.3 Hz; sugar-H), 4.43 (IH, dd, J - 4.7, 7.5 Hz; sugar-H), 4.66 (IH, dd, J « 4.0, 11.5 Hz; H-3), 5.66 (IH, d, J ■ 3.6; H-l of the sugar), 5.99 (IH, s, H-l), 7.59 (IH, d, J ■ 8.6 Hz; NH-CO), 7.88, 8.08 (two multiplets, Ar-H).
kple 44: Preparation of 3-aceto-5,10-dioxo-l-methoxy-5,10- dihydro-lH-naphtho [2,3-c] pyran (BCH-2129)
BCH-2129
Step 1: 3-λeeto-5,10-dioxo-l-_aβthoxy-5,10-dihydro-lH-naphtho-(2,3- c)-pyran (BCH-2129)
To a solution of 3-acetyl-5,10-dioxo-l-methoxy-3,4-5,10-tetrahydro-1H- naphtho (2,3-c) pyran (50 mg, .175 mmole) in CH CN (8 ml) and THF (4 ml)
151
SUBSTIT at 0°C waa 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 NH C1 (5 ml) was added and the mixture waa extracted with CH2C12 (3x50 ml), waahed with water (10 ml), dried and evaporated. The crude titled product was subjected to preparative TLC (eluent: toluene:EtOλc-96: ) 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,β,-OCH3), 6.42 (lH,s,H-l), 7.11 (lH,s;H-4), 7.92 (2H,m;λr-H), 8.14 (2H,m;λr-H).
Example 45: Preparation of (1R,3S) and (lS,3R)-3-aceto-5,10-dioxo- 1 (4-chloroethylnitrosoureido cyclohexyl-oxy)- 3,4,5,10-tetrahydro-lH-naphtho [2,3-c] pyran (BCH- 2114)
BCH-2114
Step 1: (1R,3S) and (lS,3R)-3-Acβto-l (4-chloroethylureido- eyclohex ox )-5,8-d ■ethoxy-iaochroman
3-λcetyl 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, . Med. Chem. r 14., 600 (1971)) using DDQ following the general procedure (step 1, example 14).
Enantiomeric mixture of the titled products was isolated from the crude
152
SUB iS I i s ϋ 1 *___.___. I reaction mixture by column chromatography over silica gel (eluent: 50% and 80% EtOAc in hexane) yield=100mg (52%).
NMR (acetone-dg;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 (IH, dd, J «= 12.1, 17.8 Hz; H-4), 2.90 (IH, dd, J - 4.2, 17.7 Hz; H'-4), 3.42 (2H, m; -HNCH2C1), 3.59 (2H, t, J - 6.0 Hz; -CH2- Cl), 3.78, 3.79 (3H, s each, λr-OCH3), 3.86 (IH, m; H-l of the cyclohexyl ring), 4.61 (IH, dd, J - 4.2, 12.0 Hz; H-3), 5.51 (IH, d, J » 7.4 Hz; -NH-CO-), 5.67 (IH, br signal; -CONHCH2-), 5.90 (IH, a, H- 1), 6.79, 6.87 (IH, d each, J - 8.9 Hz; λr-H).
Step 2: (1R,3S) and (lS,3R)-3-λceto-5,10-dioxo-l (4- chloroethylureido cyclohβxyl-ox )-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) waa diaβolved in dry toluene (3 ml) and acetoxybutadiene (0.5 ml) waβ added. The mixture was stirred at room temperature for 18 hours. Silica gel (500 mg) waa 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 CH C12: MeOH«19:l 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 (IH, dd, J - 11.6, 19.5 Hz; H-4), 3.42 (2H, m; -NHCfi2-CH2Cl), 3.60 (2H, t, J - 6.2 Hz; -CH2C1), 3.95 (IH, m, H- 1 of the cyclohexyl ring), 4.64 (IH, dd, J - 4.2, 11.5 Hz; H-3), 5.54 (IH, br d, J * 6.9 Hz; NHCO-), 5.69 (IH, br signal; -CONH-CH2-), 5.92 (IH, s; H-l), 7.86-7.91 (2H, m; λr-H), 8.06-8.10 (2H, m; λrH) .
Step 3: (1R,3S) and (lS,3R)-3-acβto-5,10-dioxo-l (4- chloroethylnitroaoureido cyclohexy1-ox )-3,4,5,10- tetrahydro-lH-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
153
*8 R" diluted with water (10 ml), extracted with CH2C12 (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»58-63eC (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 (lH,dd,J-11.6, 19.6Hz;H-4), 2.93
(lH,dd,J«4.3,19.7Hz;H'-4), 3.60 (2H,t,J«6.5Hz;-CH2-Cl), 3.76-4.05 (m,H-l and H-4 of the cyclohexyl group), 4.16 (2H,t,J«6.6Hz;-N(NO)CH2-) . 4.66 (lH,dd,J«4.3,11.4Hz;H-3), 5.97 (lH,β,H-l), 7.77 (lH,br.d, J«7.8Hz;-NHCO- ), 7.87-7.90 (2H,m;λr-H), 8.07-8.11 (2H,m;λr-H).
Example 46: Using the aaate carboxylic acid as deacribed in Example 16, l-mβthoxy-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-c]-pyran-3-carboxamides were prepared
BCH-2044
R-C6H5
Step 1: l-methoxy-3-M-anilinylcarbonyl-5,10-dioxo-5,10-dihydro-lH- 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, waβ converted to the titled compound. dec. 140°C; m.p. 200°C.
154
SUBST TUTE SHEET H NMR (CDCI3, 250 MHz, Bruker) : δ, 3.68 (3H, s, OCH3 ) , 6.48 (IH, s, 1- CH) , 7.18 (IH, tr, J - 7.6 Hz, p-λni-H) , 7.49 (2H, tr, J ■ 8.0 Hz, m- λni-H) , 7.50 (IH, s, 4-CH) , 7.66 (2H, d, J -= 7.8 Hz, O-λni-H) , 7.79 (2H, m, 7, 8-λrH) , 8.15 (2H, m, 6, 9-λrH) , 8.40 (IH, β, 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: l-a»thoxy-3-(3-M-pyrrolidJ_noaylpropylaari_nocarbonyl)-5 , 10- dioxo-5, 10-dihydro-lH-naphtho-[2,3-c]-pyran (BCH-2166)
60 mg of the acid from atep 6, example 16, waβ diββolved 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 waβ again dissolved into dry THF. The solution was cooled to - 10°C. 29.3 μl of triethylamine and 19.90 μl of l-(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 waβ 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 (CDC13 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, CONHCfi2), 3.36-3.55 (4H, m, CH2-pyrr, 5'- pyrr-CH2), 3.74 (3H, β, -OCH3), 6.43 (s, IH, 4-CH), 7.32 (β, IH, 1-CH), 7.70-7.78 (2H, m, 6, 9-λrH), 8.08-8.16 (3H, m, 7, 8-λrH, 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-i_aidasolylpropyl)-l-methoxy-5,10-dioxo-5,10-dihydro-lH- naphtho-[2,3-c]-pyran-3-carboxaaύ.de
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). λfter stirring at 0°C for one hour, and at room
155
SUBSTITUTE SHEET 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 l-(3-amminopropyl)- imidazole (8.39 μl, 0.20 mmol) dissolved in 1 ml of THF waa added dropwiae. The mixture waβ allowed to βtir for one hour at which time it waβ 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. *H 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 (β, IH, 4-CH), 6.96 (β, IH, 4-CH (imidazol)), 7.16 (β, IH, 1-CH), 7.18 (β, IH, 5-CH (imidazol)), 7.70 (β, IH, 2-CH (imidazol)), 7.90 (m, 2H, 6, 9- λrH), 8.12 (m, 2H, 7, 8-λrH), 8.29 (m, IH, 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)-l-aethoxy-5,10-dioxo-5,10- dihydro-lH-naphtho-[2,3-c]-pyran-3-carboxa_aide (BCH-2157)
6 mg of product from βtep 3 herein waβ dissolved in 2 ml of ether. To this waβ added 6 μl of IM HCl/ether aolution (from λldrich) . The mixture waβ stirred, and then the solvent evaporated to give 6.7 mg of the HCl salt.
XH NMR (acetone-d6, 250 MHz, Bruker) for salt, δ: 2.29 (m, 2H, CH - imidazol), 3.53 (m, 2H, C-CH2-C), 3.62 (s, 3H, OCH3), 4.50 (m, 2H, CH2NHCO), 6.33 (β, IH, 4-CH), 7.14 (β, IH, 1-CH), 7.55 (β, IH, 5- CH(imi)), 7.76 (s, IH, 4-CH(imi)), 7.88 (m, 2H, 7, 8-λrH), 8.05 (m, 2H, 6, 9-λrH), 8.64 (m, IH, NH), 9.285 (e, IH, 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-βthylthiocarbon l-l,3,4,5,10- pentahydro-5,10-dioxo-naphtho-[2,3-c] pyran (BCH-2003) and 3-(5'-tosyloxasoly1)-1,3, ,5,lO-pentahydro-5,10- dioxo-naphtho-[2,3-c]-pyran (BCH-2155)
156
SUBSTITUTE SHEET
Step 1: 3-ethylthiocarbonyl-5,β-dimethoxy-iaochzMaan
5,8-dimethoxy-3-carboxyiaochroman (300 mg, 1.26 mmol) in THF (6 ml) was stirred with 1, '-carbonyldiimidazole (225 mg, 1.386 mmol) at room temperature for 30 minutes. More THF (6 ml) waβ added to dilute the forming βuβpenβion. λfter one hour, ethanethiol (103 μl, 1.40 mmol) was added and the mixture waa stirred for 18 hours at room temperature. Solvent waa 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).
X NMR (CDC13, 250 MHz, Bruker): δ, 1.28 (3H, tr, J * 7.6 Hz, CH3), 2.68 (IH, dd, J - 17.6 Hz, 11.2 Hz, 4-HCHa), 2.92 (IH, qua, J = 7.6 Hz, -CH2-) , 3.12 (IH, dd, J «= 11.2 Hz, 3.5 Hz, 4-HCHe) , 3.76 (3H, s, OCH3) , 3.78 (3H, s, OCH3) , 4.24 (IH, dd, J « 11.2 Hz, 3.0 Hz, 3-CH) , 4.70 (IH, d, J * 15.3 Hz, l-HCHa) , 5.06 (IH, d, J - 15.3 Hz, l-HCHe) , 6.64 (IH, d, J = 8.0 Hz, ArH) , 6.67 (IH, 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-l,3,4,5,8-oenta-lH-benso-[2,3- c] -pyran
157
SUBSTITUTE SHEET 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 waβ followed by addition of a aolution of ammonium cerium nitrate (583 mg, .0063 mmol) in 2 ml. of water. The reaction mixture waβ allowed stirred for 5 minutes at 0°C. TLC showed completion of the reaction. It waa poured to water and extracted with methylene chloride. The organic layer was dried over Na2S04 and evaporated to give a crude titled product (83 mg). *H NMR (CDC13, 250 MHz, Bruker): δ, 1.24 (3H, tr, J - 7.6 Hz, CH3), 2.51 (IH, dd tr, J ~~ 17.6 Hz, 9.2 Hz, 3 Hz, 4-HCHa), 2.85 (IH, d, J - 17.6 Hz, 4-HCHβ), 2.88 (IH, qua, J ■ 7.6 Hz, -CH2-), 4.18 (IH, dd, J - 9.2 Hz, 3 Hz, 3-CH), 4.47 (IH, d tr, J - 17.5 Hz, 3 Hz, l-HCHa), 4.81 (IH, br d, J « 17.6 Hz, l-HCHβ), 6.71 (IH, d, J - 9.7 Hz, Quin-H), 6.76 (IH, 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-l,3,4,5,10-pentahydro-ι__aphtho- [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-l,3-butadiene (119 μl, 1.0 mmol) at 60°C for 22 hours. Solvent was evaporated and the crude product was chromatographed (toluene/EtOλc ~~ 100/15) to give desired titled product
(41 mg) as a aolid (m.p. 95.4-96.5°C).
XH NMR (CDCI3, 250 MHz, Bruker): δ, 1.26 (3H, tr, J = 7.6 Hz, CH3),
2.65 (IH, dd tr, J * 19.4 Hz, 9.4 Hz, 3 Hz, 4-HCHa), 2.91 (2H, qua, J = 7.6 Hz, CH2), 3.04 (IH, d tr, J - 19.4 Hz, 3 Hz, 4-HCHe), 4.25 (IH, dd,
J - 9.4 Hz, 3 Hz, 3-CH), 4.61 (IH, d tr, J » 18.2 Hz, 3 Hz, l-HCHa),
4.97 (IH, dd, J - 18.2 Hz, 1.8 Hz, l-HCHe), 7.71 (2H, m, 7, 8-λrH), 8.04
(2H, m, 6, 9-λrH).
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-di_methoxy iaochroaan
158
SUBSTITUTE SHEET To 5,8-dimethoxy-3-carboxyiβochroman (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 waβ atirred for 20 minutes then at room temperature for 20 minutes. The reaction mixture waβ evaporated to dryness to give deβired acid chloride. It waβ rediasolved in THF (4 ml) and cooled to -78°C. λ aolution of toβylmethyl isocyamide anion (made from the treatment of toβylmethyl 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 waa atirred for 24 hours aβ it warmed to room tempeture. Then, it waβ poured to NH4CI (sat.) and extracted with methylene chloride. The organic layer waβ dried (over Na2S04) 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, β, tosy-CH3), 2.99 (2H, d, J ■= 7.4 Hz, 4-CH2), 3.76 (6H, s, 2xCH3), 4.85 (IH, d, J « 17.5 Hz, 1- HCHa), 4.03 (IH, d, J « 17.5 Hz, l-HeCH) , 5.54 (IH, tr, J = 7.4 Hz, 3- CH), 6.67 (2H, br β, 6, 7-ArH), 7.33 (2H, d, J « 8.2 Hz, 3', 5', tosyl- H), 7.82 (IH, β, oxa-H), 7.92 (2H, J » 8.2 Hz, 2, 6-toβyl-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'-tosyloxaaolyl)-5,8-dioxo-l,3,4,5,8-pentahydrobenso- [2,3-c]-pyran
The compound from step 4 herein (10 mg, 0.024 mmol) waβ diaaolved in acetonitrile (2 ml) and cooled to 0°C. λ aolution of ammonium cerium nitrate (39.5 mg, 0.072 mmol) in 0.5 ml of water waβ added dropwise. The reaction mixture waa stirred at 0°C for 5 minutes, then poured to water and extracted with dichloromethane. The organic layer waβ waahed with brine, dried and evaporated to give the titled compound as a white aolid (9 mg, dec. 150°C; m.p. 177°C). λ NMR (CDCI3, 250 MHz, Bruker): δ, 2.42 (3H, β, toβyl-CH3), 2.82 (2H, m, 4-CH ), 4.65 (IH, d tr, J ■ 17.6 Hz, 4.1 Hz, l-HCHa) , 4.82 (IH, d tr, J = 17.6 Hz, 1.8 Hz, l-HCHe) , 5.52 (IH, tr, J * 7.0 Hz, 3-CH), 6.75 (IH, d, J - 9.1 Hz, quin-H), 6.81 (IH, d, J « 9.1 Hz, quin-H) , 7.35 (2H, d, J « 8.2 Hz, 3', 5'-tθβyl-H), 7.83 (IH, β, oxa-H), 7.90 (2H, d, J » 8.2 Hz, 2', 6*-tosyl-H).
159
SUBSTITUTESHEET Step 6: 3-(5'-toβyloxasolyl)-5,10-dioxo-l,3,4,5,10-pβntahydro- naphtho-[2,3-c]-pyran (BCH-2155)
λ aolution of toayloxazolyl pyranoquinone from atep 5 herein in 4 ml of toluene and 0.5 ml of tetrahydrofuran (9 mg, 0.023 mmol) waa heated with 1-acetoxy 1,3-butadiene (55 μl, 0.47 mmol) at 50°C for 20 hourβ. Solvent waβ evaporated to drynesβ and the crude product waa purified by means of chromatography (Tol:EtOλc-100:15) to give deβired titled product aa a light colored aolid (6.6 mg obtained). M.P. >240°C. H NMR (CDC13, 250 MHz, Bruker): δ, 2.43 (3H, β, λrCH3), 2.99 (2H, m, 4-CH2), 4.78 (IH, d tr, J - 18.8 Hz, 3.3 Hz, l-HCHa), 4.96 (IH, d, J ~~ 18.8 Hz, l-HCHe), 5.57 (IH, dd, J - 8.9 Hz, 5.0 Hz, 3-CH), 7.36 (2H, d, J - 8.2 Hz, 3', δ'-toβyl-H), 7.75 (2H, m, 7, 8-ArH), 7.85 (IH, s, oxa- H), 7.92 (2H, d, J « 8.2 Hz, 2', 6'-tozyl-H), 8.11 (2H, m, 6, 9-λrH) . 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 (l * S, lS,3R)-l-(3 ' -trifluoroacβtamido-
2 ' , 3 ' , 6 ' -trideoxy- yxo-L-hexopyranoae) -3- aMthoxycarbonyl-3-methyl-3 ,4,5 , 10-tetrahydro-5 , 10- dioxo-naphtho- [2,3-c] pyran (BCH-2076)
160
SUBSTITUTE HEET
BCH-2076
Step 1: (l'S, IS, 3R)-l-(4'-p-nitrobenaoyl-3,-trifluoroacβta_aido- 2',3' , 6'-trideoxy-lyxohβxopyranoββ)-3-methoxy-carbonyl-3- mathyl-5,8-dioxo-4,5,8-trihydro-lH-benso-[2,3-c]-pyran
(1'S,IS,3R) 1-(2',3' ,6'-trideoxy-3-trifluoroacetamido-4•-O-p- nitrobenzoyl-L-lyxohexopyranoae-5,8-dimethoxy-3-aceto-3-methyliaochroman (62 mg, 0.0945 mmol) in acetonitrile (3 ml) waβ 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), waa added dropwise. The solution waβ stirred for 5 minutes at 0°C then poured to water and extracted with dichloromethane. The organic layer waβ dried and evaporated to give deβired titled product (40 mg, 0.064 mmol). *H NMR (CDC13 25° MΑz- Bruker): δ, 1.27 (3H, d, J ■ 6.5 Hz, 6'-CH3), 1.57 (3H, β, 3-CCH3), 1.91 (IH, dd, J - 11.8 Hz, 4.7 Hz, 2'-CH), 2.10 (IH, d tr, J « 11.8 Hz, 3.6 Hz, 2'-CH), 2.72 (IH, d, J = 17.9 Hz, 4-CH), 2.94 (IH, dd, J ■ 17.9 Hz, 0.9 Hz, 4-CH), 3.75 (3H, β, OCH3), 4.54 (IH, m, 3'-CH), 4.64 (IH, qua, J - 6.5 Hz, 5'-CH), 5.40 (IH, a, 4'-CH), 5.65 (IH, d, J ■ 2.4 Hz, l'-CH), 6.06 (IH, a, 1-CH), 6.52 (IH, d, J - 8.2 Hz, NHCOCF3), 6.77 (IH, d, J « 10 Hz, Quin-H), 6.83 (IH, d, J = 10Hz, Quin- H), 8.27 (4H, m, PNB).
161
SUBSTITUTE SHEET 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: (l'S, IS, 3R)-l-(4<-p-nitrobensoyl-3'-trifluoroacetaa__ido- 2' ,3' ,6'-trideoxy-lyxohexopyranoae)-3-a»thoxy-earbonyl-3- methyl-5,10-dioxo-4,5,10-trihydro-lH-naphtho-[2,3-c]-pyran
The titled compound was obtained aa per procedure described in βtep 2, example 5, but using the quinone from atep 1 herein.
XH NMR (CDC13 250 MHz, Bruker): δ, 1.32 (3H, d, J - 6.6 Hz, 6'-CH3), 1.95 (IH, dd, J « 12.4 Hz, 5.0 Hz, 2*-CH), 2.10 (IH, d tr, J ■ 12.4 Hz, 3.5 Hz, 2'-CH), 2.88 (IH, d, J - 18.2 Hz, 4-CH), 3.13 (IH, dd, J - 18.2 Hz, 1.0 Hz, 4-CH), 3.75 (3H, s, OCH3), 4.56 (IH, m, 3'-CH), 4.76 (IH, qua, J « 6.6 Hz, 5'-CH), 5.45 (IH, β, 4'-CH), 5.72 (IH, d, J ■= 2.0 Hz, l'-CH), 6.26 (IH, S, 1-CH), 6.45 (IH, d, J - 7.1 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-λrH), 8.12 (2H, m, 6, 9-λrH), 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: (l'S, IS, 3R)-l-(3'-trifluoroacetamido-2' ,3' ,6'-tridβoxy-L- lyxohexopyranose)-5,10-dioxo-4,5,10-trihydro-lH-naphtho- [2,3-c]-pyran (BCH-2076)
The titled compound was obtained from the glycoβide from step 2 herein via baβe hydrolysis as per procedure described in step 3, example 5. NMR (CDC13, 250 MHz, Bruker): δ, 1.38 (3H, d, J ■ 6.0 Hz, 6'-CH3), 1.60 (3H, s, 3-CCH3), 1.85 (IH, d, J « 6.8 Hz, 4'-OH), 1.85 (IH, dd, J = 9.4 Hz, 2.6 Hz, 2'-HCHa), 1.96 (IH, d, J « 9.4 Hz, 2'-HCHe), 2.87 (IH, d, J - 18.8 Hz, 4-HCHa), 3.12 (IH, dd, J - 18.8 Hz, 0.6 Hz, 4-HCHe), 3.63 (IH, br d, J - 6.8 Hz, 4'-CH), 3.75 (3H, s, OCH3), 4.28 (IH, qua, J « 8.8 Hz, 3'-CH), 4.55 (IH, qua, J - 6.0 Hz, 5'-CH), 5.54 (IH, s, l'- CH), 6.21 (IH, s, 1-CH), 6.71 (IH, br d, J « 9.4 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-λrH), 8.11 (2H, m, 6, 9-λrH),
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.
162
SUBSTITUTE SHEET Example 49: ( 1 , 3-trana ) -anline- ( l-methoxy-5 , 10-dioxo-3 , 4,5, 10- tetrahydro- lH-naphtho- [2,3-c] -p ran ) -3-earboxaauLde (BCH-2041) and (l,3-ciβ)-anlin*-(l-*βthoxy-5, 10-dioxo- 3,4,5, 10-tetrahydro- lH-naphtho-£2 , 3-c ] -pyran) -3- earboxa ide (BCH-2042)
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 waβ then added alowly. After 10 minutes, the brown solution waβ 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 waβ dried and evaporated to give a mixture of 3 productβ (18 mg). Chromatography (CHCl3/MeOH/HOAc = 100:15:2) allowed separation of the 3 compounds. One of the products waβ the same as the one obtained in atep 6, example 16, and had: XH NMR (CD3COCD3, 250 MHz, Bruker): δ, 3.58 (3H, 8, OCH3), 6.36 (IH, s, 1-CH), 7.22 (IH, s, 4-CH), 7.91 (2H, m, 7, 8-λrH), 8.12 (2H, m, 6, 9- ArH).
163
SUBSTITUTES The second product ( l, 3-tranβ )-l-methoxy-3-carboxyl-5 , 10-dioxo-3 , 4 , 5 , 10- tetrahydro-lH-naphtho- ( 2 , 3-c ] -pyran, BCH-2045 had :
XH NMR (CD3SOCD3 250 MHz, Bruker) : δ, 2.55 ( IH, dd, J = 18.5 Hz, 12.4 Hz, 4-HCHa) , 2.88 ( IH, dd, J ■ 18.5 Hz, 3.5 Hz , 4-HCHβ) , 3.47 (3H, β, OCH3 ) , 4.49 ( IH, dd, J - 12.4 Hz, 3.5 Hz, 3-CH) , 5.55 ( IH, 8, 1-CH) ,
7.88 (2H, m, 7 , 8-λrH) , 8.00 (2H, m, 6, 9-λrH) .
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: (l,3-ciβ)-l-methoxy-3-carboxyl-5,10-dioxo-3,4,5,10- tetrahydro-lH-naphtho-[2,3-c]-pyran, (BCH-2119), had:
2H NMR (CD3SOCD3 250 MHz, Bruker): δ, 1.28 (IH, dd, J - 15.3 Hz, 11.5 Hz, 4-HCHa), 2.58 (IH, dd, J - 11.5 Hz, 2.9 Hz, 4-HCHe), 3.45 (3H, 8, OCH3), 4.17 (IH, dd, J ■ 11.5 Hz, 2.9 Hz, 3-CH), 5.62 (IH, a, 1-CH),
7.89 (4H, m, 6, 7, 8, 9-λrH).
Step 2: (l,3-trana)-l-methoxy-3-N-anilinylcarbonyl-5,10-dioxo- 3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-pyran, BCH-2041:
λ aolution of acid from atep 1 herein (20 mg, 0.069 mmol) in THF (4 ml) was cooled to 0°C. To the solution.waβ 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 redisβolved in methylene chloride and then evaporated. The reaidue was dissolved again in methylene chloride (4 ml) and half of the volume waa taken for coupling with aniline (4 μl, 0.044 mmol) aβ follows: To the ice-cold solution of the acid chloride waβ added aniline (1 eq.) in 1 ml of methylene chloride. The reaction mixture waβ stirred for 10 minutes. It was poured to water and extracted with methylene chloride. The organic layer waa dried and evaporated to give a crude product which was purified by recryβtallization from methylene chloride and hexane. The deβired titled product was obtained (11 mg) as a light yellow solid.
M.P. 183-184°C. λH NMR (CDC13, 250 MHz, Bruker): δ, 2.63 (IH, dd, J = 19.4 Hz, 12.5 Hz, l-HCHa), 3.30 (IH, dd, J - 19.3 Hz, 4.2 Hz, 1-HCHe), 3-67 <3H* B' °∞3)» 4.74 (IH, dd, J * 12.5 Hz, 4.5 Hz, 3-CH), 5.77 (IH, s, 1-CH), 7.16 (IH, tr, J - 8.5 Hz, 4'-λni-H), 7.47 (2H, tr, J - 8.5 Hz, 3', 5'-λni-H), 7.52 (2H, d, J - 8.5 Hz, 2', 6'-λni-H), 7.75 (2H, m, 7, 8-λrH), 8.10 (2H, m, 6, 9-λrH), 8.31 (IH, s, NHCO) .
SUBSTITUTE SHEET 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-ci ) -l-»ethoxy-3-M-anilinylcarbonyl-5 , 10-dioxo-
3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-pyran, BCH-204 ,
λ similar to the procedure deβcribed previously in step 2, the cis acid from step 1 herein waa converted to the titled product. M.P. 217-219°C. λH NMR (CDC13, 250 MHz, Bruker): 6, 2.49 (IH, dd, J - 15.6 Hz, 11.2 Hz, 4-HCHa), 3.08 (IH, dd, J « 15.6 Hz, 3.2 Hz, 4-HCHe), 3.65 (3H, β, OCH3), 4.50 (IH, dd, J - 11.2 Hz, 3.2 H, 3-CH), 5.94 (IH, s, 1-CH), 7.14 (IH, tr, J = 7.6 Hz, p-λni-H), 7.35 (2H, tr, J ~~ 7.6 Hz, m-λni-H), 7.56 (2H, d, J = 7.6 Hz, O-λni-H), 7.78 (2H, m, 7, 8-λrH), 8.00 (2H, m, 6, 9-λrH), 8.21 (IH, 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 (l'S,lR,3S)-l-(3'-trifluoroacatamido-
2',3',6'-trideoxy-lyxohexpyranoβe)-3-(5"- tosyloxazolyl)-3,4,5,10-tetrahydro-5, 0-dioxo-naphtho- [2,3-c] pyran (BCH-2150)
165
BCH-2150 Step 1: (1•S, IS, 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-lyxohexopyranoβe (49 mg, 0.125 mmol) waβ added l,2-dichloro-4,5-dicyano-benzoquinone (35.6 mg, 0.157 mmol). The resulting mixture was stirred for 18 hours at 40°C. Solvent waβ 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: -H NMR (acetone-d6, 250 MHz, Bruker): δ, 1.27 (3H, d, J = 5.9 Hz, 6'- CH3), 2.14-2.30 (2H, m, 2'-CH ), 2.44 (3H, s, tosyl-CH3), 3.01 (2H, d, J
166
SUBSTITUTESHEET * 6.5 Hz, 4-CH2 ) , 3.82 (3H, β, OCH3 ) , 3.92 (3H, s, OCH3 ) , 4.65 ( IH, m, 3 '-CH) , 4.86 (IH, qua, J ~~ 5.9 Hz, 5 ' -CH) , 5.71 ( IH, d, J ■ 2.4 Hz, 4- CH) , 6.17 (IH, tr, J « 6.5 Hz, 3-CH) , 6.24 (IH, s, 1-CH) , 6.95 (2H, m, 6, 7-λrH) , 7.48 (2H, d, J = 7.4 Hz, 3" , 5"-toβyl-H) , 7.95 (2H, d, J = 7.4 Hz, 2 " , 6"-tosyl-H) , 8.38 (4H, , PNB) , 8.37 ( IH, β, oxa-H) , 8.66 ( IH, d, J - 7.4 Hz, NHCOCF3 ) .
The (l'S, IR, 3S)-1-(4'-p-nitrobenzoyl-2',3',6'-trideoxy-3*- trifluoroacetamido-L-lyxohexopyranose)-3-(5"-toβyloxa-zolyl)-5,8- dimethoxy isochroman had: *H NMR (acetone-d6, 250 MHz, Bruker): δ, 0.80 (3H, d, J ■ 6.8 Hz, 6'- CH3), 2.19 (IH, m, 2'-HCHa), 2.48 (IH, d tr, J » 11.8 Hz, 4.1 Hz, 2'- HCHe), 2.46 (3H, β, toβyl-CH3), 2.88 (IH, dd, J ~~ 17.6 Hz, 11.8 Hz, 4- HCHa), 3.04 (IH, dd, J * 17.6 Hz, 4.4 Hz, 4-HCHe), 3.83 (3H, β, OCH3), 3.86 (3H, s, OCH3), 4.42 (IH, qua, J « 6.8 Hz, 5'-CH), 4.84 (IH, m, 3'- CH), 5.48 (IH, a, 4.'-CH), 5.58 (IH, d, J ■ 3.5 Hz, l'-CH), 6.01 (IH, 8, 1-CH), 6.92 (IH, d, J - 6.5 Hz, λrH), 6.96 (IH, d, J - 6.5 Hz, ArH), 7.54 (2H, d, J ■ 9.1 Hz, 3", 5"-toβyl-H), 8.06 (2H, d, J - 9.1 Hz, 2", 6"-toβyl-H), 8.35 (IH, s, oxa-H), 8.49 (4H, m, PNB), 8.62 (IH, d, J « 6.8 Hz, NHCOCF3).
Step 2: (l'S, IS, 3R)-l-(4'-p-nitrobansoyl-2' ,3' ,6'-trideoxy-3'- trifluoroaceta_aido-L-lyxohexopyranoae)-3-(5"-toβyloxaaolyl)- 5,8-dioxo-3,4,5,8-tetrahydrobenso-[2,3-c]-pyran.
The compound from atep 1 herein (17 mg, 0.021 mmol) in acetonitrile (2 ml) waβ cooled to 0°C and ammonium cerium nitrate (35.5 mg, 0.0648 mmol, pretreated with sodium bicarbonate, 3.6 mg, 0.042 mmol) waa added dropwise. The reaction mixture waa stirred for 15 minutes at 0°C then poured to water. It was extracted with dichloromethane. The organic phase waβ washed with brine, dried (over sodium sulfate) and evaporated to give a crude product which waβ purified on silica gel (hexane/EtOAc = 2:1) to give the desired titled product (7 mg).
XH 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, toβyl-CH3), 2.80-2.93 (2H, m, 4-CH2), 4.55 (IH, qua, J - 6.5 Hz, 5'-CH), 4.86 (IH, m, 3'-CH), 5.49 (IH, s, 4'-CH), 5.61 (IH, d, J « 2.1 Hz, l'-CH), 5.85 (IH, s, 1-CH), 6.12 (IH, dd, J * 10.6 Hz, 4.7 Hz, 3-CH), 6.80 (IH, d, J = 10.6 Hz, Quin-H), 6.85 (IH, d, J = 10.6 Hz, Quin-H), 7.48 (2H, d, J - 8.8 Hz, 3",
167
SUBSTITUTESHEET 5"-tosyl-H) , 7.88 ( IH, β, oxa-H) , 7.94 (2H, d, J = 8.8 Hz, 2" , 6"-toβyl- H) , 8.28 (4H, m, PNB) .
Step 3: (l'S, IR, 3S)-l-(4'-p-nitrobensoyl-3-trifluoroacetaad.do- 2' ,3' ,6,-tridβoxy-L-lyxohβxopyranoββ)-3-(5"-toβyl-oxaaolyl)-
5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-pyran
The compound from step 2 herein (9 mg, 0.012 mmol) was stirred with 1- acetoxy-l,3-butadiene (28 μl, 0.236 mmol) in toluene (4 ml) and THF (0.5 ml) at 50°C for 18 houra. Solvent waa evaporated and the crude product was chromatographed (toluene/ethyl acetate - 5/1) to give the deβired titled product (4.8 mg).
2H NMR (CDC13 250 MHz, Bruker): δ, 1.06 (3H, d, J « 6.2 Hz, 6'-CH3), 2.00 (IH, d tr, J ■ 11.5 Hz, 2.9 Hz, 2'-HCHa), 2.25 (IH, dd, J - 11.5 Hz, 4.4 Hz, 2'-HCHe), 2.44 (3H, 8, tθβyl-CH3), 2.98 (IH, d, J - 5.6 Hz, 4-CH), 2.99 (IH, d, J « 11.0 Hz, 4-CH), 4.60 (IH, qua, J - 6.2 Hz, 5'- CH), 4.87 (IH, m, 3'-CH), 5.40 (IH, 8, 4'-CH), 5.72 (IH, d, J - 2.0 Hz, l'-CH), 6.05 (IH, 8, 1-CH), 6.19 (IH, 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-λrH), 7.90 (IH, 8, oxa-H), 7.95 (2H, d, J - 8.8 Hz, 2", 6"-toayl-H), 8.13 (2H, m, 6, 9-λrH), 8.31 (4H, m, PNB).
Step 4: (l'S, IR, 3S)-2' ,3' ,6'-trideoxy-3'-trifluoroacetamido-L- lyxohexopyranoae-3-[5'-toβyloxasoly1)-5,10-dioxo-3,4,5,10- tetrahydro-lH-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 waa added aodium methoxide (4.37 M,1.4 μl, 5.92 mmol). λfter 5 minutes, the reaction waβ quenched with dilute hydrochloride acid and extracted with methylene chloride. The organic layer waa dried (over Na2S04) and evaporated to give a crude product which waa purified on TLC (CHCl3:MeOH ■ 100:7) to give deβired titled product aβ 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 (IH, tr d, J = 11.2 Hz, 2'-HCHa), 2.05 (IH, m, 2'-HCHe, due to solvent overlap, this is an estimation), 2.43 (3H, s, tol-CH3), 2.92 (IH, d, J = 5.9 Hz, 4-HCHa), 2.94 (IH, d, J = 10.5 Hz, 4-HCHe), 3.71 (IH, m, 4'-OH), 4.20 (IH, dd, J - 5.9 Hz, 3-2 Hz, 4'-OH), 4.47 (IH, qua,
168
SUBSTITUTE SHEET J « 6.5 Hz, 5'-CH3), 4.58 (IH, m, 3'-CH), 5.55 (IH, d, J « 3.0 Hz, l'- CH), 5.99 (IH, β, 1-CH), 6.16 (IH, dd, J ~~ 10.6 Hz, 5.9 Hz, 3-CH), 6.77 (IH, d, J * 10.6 Hz, NHCOCF3), 7.36 (2H, d, J ~~ 8.8 Hz, toβyl-H), 7.79 (2H, m, 7, 8-λrH), 7.90 (IH, β,. oxa-H), 7.91 (2H, d, J = 8.8 Hz, toβyl- H), 8.11 (2H, m, 6, 9-λrH) .
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 (l'S,18,3R)-l-(3'trifluoroaceta_aido- 2' ,3' ,6'-trideoxy-lyxc—L-hβxopyranoβe)-3-(5"- tosyloxasolyl)-3,4,5,10-tetrahydro-5, 0-dioxo-naphtho- [2,3-c] pyran (BCH-215 )
■top 2
BCH-2131
Step 1: (l'S, IS, 3R)-l-(4'-p-nitrobensoyl-2*,3' ,6•-trideoxy-3'- trifluoroacetaaido-L-lyxohexopyranose)-3-(5"-tosyloxasolyl)- 5,8-dioxo-3,4,5,8-tβtrahydrobβnao-[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 (ainmonium cerium nitrate, 25 mg, 0.046 mmol; NaHC0 , 2.55 mg, 0.0304 mmol; acetonitrile, 1.5 ml; H20, 0.4 ml) and following the same procedures as deβcribed in atep 2, example 50, the deβired titled product waβ obtained (9 mg).
169
SUBSTITUTE SHEET -H 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, toβyl-CH3) , 2.95 ( IH, d, J = 6.8 Hz, 4-CH) , 2.95 (IH, d, J - 8.8 Hz, 4-CH) , 4.56 (IH, m, 3 '-CH) , 4.74 (IH, qua, J = 6.6 Hz, 5 - -CH) , 5.53 (IH, s, 4 '-Cfi) , 5.68 ( IH, d, J = 2.9 Hz, l '-CH) , 6.01 (IH, s, 1-CH) , 6.09 (IH, dd, J - 8.8 Hz, 6.8 Hz, 3-CH) , 6.93 (IH, d, J = 11.8 Hz, Quin-H) , 6.96 (IH, d, J * 11.8 Hz, Quin-H) , 7.49 (2H, d, J « 8.8 Hz, 3" , 5"-toβyl-H) , 7.93 (2H, d, J ■ 8.8 Hz, 2" , 6"-tosyl-H) , 8.36 (IH, β, oxa-H) , 8.39 (4H, m, PNB) , 8.68 (IH, d, J = 8.8 Hz, NHCOCF3) .
Step 2 : (l ' S, IS, 3R)-l-(4 ' -p-nitrobβnaoyl-3-trifluoroacβtamido-
2' ,3',6'-tridβoxy-L-lyxohβxopyranoβe)-3-(5M-toβyl-oxaaolyl)- 5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-pyran
The compound from atep 2 herein (7 mg, 0.009 mmol) waβ reacted with 1- acetoxy-l,3-butadiene (21 μl, 0.184 mmol) in toluene (3 ml) at 50°C for 18 hours. The solvent waa evaporated to give a crude product, λfter chromatography (toluene/ethyl acetate « 5:1) deaired titled product was obtained (6.4 mg). -H NMR (CDCI3 250 MHz, Bruker): δ, 1.34 (3H, d, J - 7.1 Hz, 6'-CH3), 2.15 (IH, d tr, J « 12.9 Hz, 4.1 Hz, 2'-HCHa), 2.32 (IH, dd, J - 12.9 Hz, 4.1 Hz, 2'-HCHe), 2.45 (3H, a, toβyl-CH3), 2.96 (IH, dd, J « 18.2 Hz, 4.1 Hz, 4-HCHa), 3.13 (IH, dd, J *~ 18.2 Hz, 11.2 Hz, 4-HCHe), 4.64 (IH, m, 3'-CH), 4.77 (IH, qua, J - 7.1 Hz, 5*-CH), 5.52 (IH, s, 4'-CH), 5.76 (IH, d, J « 2.0 Hz, l'-CH), 6.08 (IH, dd, J ~- 11.2 Hz, 4.1 Hz, 3- CH), 6.20 (IH, 8, 1-CH), 6.21 (IH, m, HNCOCF3), 7.37 (2H, d, J - 8.2 Hz, 3", 5"-tθβyl-H), 7.71 (2H, m, 7, 8-λrH), 7.89 (2H, d, J « 8.2 Hz, 2", 6"-tosyl-H), 7.90 (IH, s, oxa-H), 8.15 (IH, m, 6, 9-λrH), 8.31 (4H, m, PNB).
Step 3: (l'S, IS, 3R)-2',3',6'-trideoxy-3'-trifluoroaceta_aido-L- lyxohexop ranose-3-[5'-tosyloxasolyl))-5,10-dioxo-3,4,5,10- tetrahydro-lH-naphtho-[2,3-C]-pyran (BCH-2151)
To PNB derivative from βtep 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). λfter 5 minutes, the pink solution waβ quenched with dilute HCl. The product waβ extracted with methylene chloride. The organic layer waβ dried and evaporated to give
170
SUBSTITUTESHEET a crude product which waβ purified by thin-layer-chromatography
(CHCl3:MβOH ~~ 100:7) to desired titled product aa an off-white aolid
(0.8 mg) .
M.P. 100-105°C. NMR (CDC13, 250 MHz, Bruker): δ, 1.41 (3H, d, J - 5.9 Hz, 6'-CH3),
1.92 (IH, tr d, J - 11 Hz, 3.5 Hz, 2'-HCHa, aβtimation), 2.20 (IH, m,
2'-HCHe, estimation), 2.44 (3H, s, tol-CH3), 2.95 (IH, dd, J - 18.5 Hz,
4.7 Hz, 4-HCHe), 3.12 (IH, dd, J - 18.5 Hz, 11.2 Hz, 4-HCHa), 4.00 (IH, m, 4'-CH), 4.37 (m, IH, 3'-CH), 4.60 (IH, qua, J - 5.9 Hz, 5'-CH), 5.10
(IH, br 8, 4'-OH, estimation), 5.58 (IH, d, J - 3.5 Hz, l'-CH), 6.05
(IH, dd, J * 11.2 Hz, 4.7 Hz, 3-CH), 6.15 (IH, s, 1-CH), 6.66 (IH, m,
NHCOCF3), 7.36 (2H, d, J « 8.8 Hz, toβyl-H), 7.78 (2H, m, 7, 8-λrH),
7.87 (IH, s, oxa-H), 7.88 (2H, d, J - 8.8 Hz, toβyl-H), 8.12 (2H, m, 6,
9-λrH).
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 (l,3-tra_nβ)-l-mβthoxy-3-(3'- aminothiaaolyl)-5,10-dioxo-3,4,5,10-tetrahydro-1H- naphtho [2,3-c]-pyran (BCH-1616) and (l,3-tranβ)-l- BMthoxy-3-di_aethoxyphosphonoacetyl-5,10-dioxo- 3,4,5,10-tetrahydro-lH-naphtho [2,3-c]-pyran (BCH- 1674)
171
SUBSTITUTE SHEET Step 1: l-mβthoxy-3-acβty1-5,8-dioxo-3,4,5,8-tetrahydrobenso-[2,3- c]-pyran
λ sample of 5,8-dimethoxy-l-hydroxy-3-acetoiβochroman (200 mg, 0.79 mmol) in MeOH (10 ml) waa stirred at room temperature while a solution of CAN (2.16 g, 3.95 mmol) in water (9 ml) waa added dropwiae. λfter 5 minutes, the reaction mixture waβ poured to water and then extracted with methylene chloride. The organic layer waβ dried (over sodium sulfate), and evaporated to give a yellow sticky aolid (157 mg). B NMR ahowed that deβired titled product was obtained with 89% purity. XH NMR (CDC13, 250 MHz Bruker), δ: 2.28 (s, 3H, COCH3), 2.35 (dd, IH, J « 20.5 Hz, 12.1 Hz, 4-Ha) , 2.78 (dd, IH, J * 20.5 Hz, 4.3 Hz, 4-He), 3.56 (s, 3H, OCH3), 4.44 (dd, IH, J - 12.1 Hz, 4.3 Hz, 3-H), 5.46 (s, IH, 1-H), 6.73 (m, 2H, 6.7-quinone) .
Step : l-methoxy-3-acetyl-5, 0-dioxo-3,4,5,10-tetrahydro-1H- naphtho-[2,3-c]-pyran
The bicyclic quinone from atep 1 herein (157 mg, 0.66 mmol) was atirred with l-acetoxy-l,3-butadiene (632 μl, 5.32 mmol) in toluene (20 ml) at 40°C for 16 hours. Solvent waβ evaporated and the crude product waβ chromatographed (toluene:EtOAc «= 100:25) to give deβired titled tricyclic quinone as a yellow solid (190 mg) . M.P. 169.8-170.8°C.
2H NMR (CDC13, 250 MHz Bruker), δ: 2.34 (s, 3H, COCH3), 2.53 (dd, IH, J - 20.7 Hz, 10.7 Hz, 4-Ha), 3.00 (dd, IH, J - 10.7 Hz, 4.3 Hz, 4-He), 3.63 (s, 3H, OCH3), 4.54 (dd, IH, J « 10.7 Hz, 4.3 Hz, 3-H), 5.66 (s, IH, 1-H), 7.73 (m, 2H, 7.8-λrH), 8.06 (m, 2H, 6.8-λrH). 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-l-aethoxy-5, 0-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 waβ stirred for 45 minutes at room
172
SUBSTITUTESHEET temperature. It waβ poured to water and extracted with methylene chloride. The organic layer waβ 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. H NMR (CDC13, 250 MHz Bruker), δ: 2.53 (dd, IH, J - 20.3 Hz, 11.0 Hz, 4-Ha), 3.02 (dd, IH, J ■ 20.3 Hz, 4.1 Hz, 4-He), 3.64 (8, 3H, OCH3), 4.15 (d, IH, J - 12.7 Hz, BrCHAH), 4.35 (d, lH, J « 12.7 Hz, Br CHHB), 4.84 (dd, IH, J - 11.0 Hz, 4.1 Hz, 3-H), 5.65 (β, IH, 1-H), 7.72 (m, 2H, 7.8-λrH), 8.02 (m, 2H, 6.9-λrH).
Step 4: (1,3-tranβ)-l-methoxy-3-(3•-a inothiasol 1)-5,10-dioxo- 3,4,5,10-tetrahydro-lH-naphtho [2,3-c] pyran (BCH-1616)
Bromomethyl ketone from atep 3 herein (20 mg, 0.054 mmol) waa atirred with thiourea at room temperature for 3.5 hours in ether (2 ml) and dichloromethane (2 ml). It waβ poured to sat. aodium bicarbonate and extracted with dichloromethane. The organic layer waa evaporated to give crude product which waβ chromatographed (MeOH:CHCl3:HOλc ■ 4:100:1) to give desired titled product (5.3 mg). λ polar by-product waβ also obtained (8 mg).
XH NMR (CDCI3, 250 MHz Bruker), δ: 2.77 (IH, dd, J - 18.8 Hz, 11.8 Hz, 4-HCHa), 3.00 (IH, dd, J = 18.8 Hz, 5.2 Hz, 4-HCHe), 3.63 (3H, s, OCH3), 5.03 (IH, dd, J * 11.8 Hz, 5.2 Hz, 3-CH), 5.67 (IH, B, 1-CH), 6.53 (IH, β, thia-H), 7.73 (2H, m, 6, 9-λrH), 8.08 (2H, m, 7, 8-λrH).
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: l-methoxy-3-dimethyl phosphonoacetyl-5,10-dioxo-3,4,5,10- tetrahydro-lH-naphtho-[ ,3-c]-pyran (BCH-1674)
λ solution of bromomethylketone from step 3 herein (10 mg, 0.027 mmol) waβ refluxed with trimethylphoβphite (3.54 μl, 0.03 mmol) and aodium iodide (0.2 mg, 0.05 mmol) in THF at 70°C overnight. Solvent waβ evaporated and the brown residue was chromatographed (CHCl3:MeOH 50:1) to give desired titled product as a light-colored βolid (2 mg). 2H NMR (CDCI3, 250 MHz, Bruker): δ, 2.60 (IH, dd, J - 19.8 Hz, 11.6 Hz 4-HCHa), 2.94 (IH, dd, J = 19.8 Hz, 3.5 Hz, 4-HeCH), 3.62 (3H, β, 1-
173
SUBSTITUTESHEET OCH3 ) , 3.85 (3H, β, POCH3 ) , 3.88 (3H, 8, POCH3 ) , 4.59 ( IH, dd, J - 11.6 Hz, 3.5 Hz, 3-CH) , 5.02 (IH, br β, CHP) , 5.15 (IH, br s, CHP) , 5.62 (IH, s, 1-CH) , 7.73 (2H, m, 6, 9 -ArH) , 8.08 (2H, m, 7, 8 -ArH) .
Example 53 : Preparation of ( 1 ' S , IR, 38 ) -1- ( 3 ' -trif luoroacetamido- 2 ' , 3 ' , 6 • -tridβoxy-L-lyxohβxopyranoaβ ) -3- awthoxycarbonyl-3 a.athyl-3 ,4,5 , 10-tβtrahydro-5 , 10- dioxo-lH-naphtho- [ , 3-c] pyran (BCH-2077)
Step 1: ■thoxycarbonyl-3-awthyl-5,8-diawthoxy isochroman
λ aolution 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) waβ added, λfter stirred for 30 minutes at 0°C, the
174
SUBSTITUTESHEET solution was further cooled to -78°C. A solution of 5,8-dimethoxy-3- methoxycarbonyliaochroman (1.0 g, 3.97 mmol) in THF (10 ml), pre- degaβsed, waa added slowly. The resulting yellow solution was stirred for 1 hour at -78°C before the addition of methyliodide (1.01 ml, 16 mmol). λfter atirred further for 45 minutes, sat. NH4C1 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:EtOλc * 3:1) to give the desired product aa 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
XH NMR (CDC13 250 MHz, Bruker): δ, 1.50 (3H, β, 3-CCH3), 2.58 (IH, d, J « 17.1 Hz, 4-CH), 3.25 (IH, d, J ■ 17.1 Hz, 4-CH), 3.64 (3H, s, OCH3), 3.68 (3H, β, OCH3), 3.72 (3H, 8, OCH3), 4.76 (IH, d, J - 17.1 Hz, 1-CH), 4.84 (IH, d, J « 17.1 H, 1-CH), 6.53 (IH, d, J «= 7.1 Hz, ArH), 6.59 (IH, d, J - 7.1 Hz, λrH).
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: (l'S, IR, 3S)-l-(4'-p-nitrobensoyl-3'-trifluoroacataaido-
2 ' , 3 ' , 6 ' -trideoxy-Llyxohexopyranose) -3-methoxy-carbonhyl-3- ■ethyl-5 , 8-dimathoxy-iaochroa__an .
The compound from atep 1 herein (133 mg, 0.5 mmol) was reacted with DDQ (136 mg, 0.6 mmol) and 5'-p-nitrobenzoy1-3*,4*,7•-trideoxy-3•- trifluoroacetamido-L-lyxohexopyranoae (196 mg, 0.5 mmol) at 45°C for 16 hourβ, the aame way aa deβcribed in step 2, example 13. λfter chromatography (hexane:EtOAc *= 2.5:1), four iaomerβ were obtained: C, 49 mg; B, 24 mg; D, 73 mg; A, 56 mg.
For C, 1H NMR (CDC13 250 MHz, Bruker): 5, 1.22 (3H, d, J « 6.1 Hz, 6'- CH3), 1.45 (3H, a, 3-CCH3), 1.89 (IH, dd, J - 11.8 Hz, 4.7 Hz, 2'-CH), 2.05 (IH, d, tr, J = 11.8 Hz, 3.0 Hz, 2'-CH), 2.77 (IH, d, J - 17.1 Hz, 4-CH), 3.82 (IH, d, J - 17.1 Hz, 4-CH), 3.64 (3H, a, OCH3), 3.78 (3H, β, OCH3), 3.81 (3H, 8, OCH3), 4.52 (IH, m, 3*-CH), 4.60 (IH, qua, J ~~ 6.1 Hz, 5'-CH), 5.42 (IH, 8, 4'-CH), 5.74 (IH, d, J = 1.7 Hz, l'-CH), 6.22 (IH, β, 1-CH), 6.36 (IH, d, J - 8.2 Hz, NHCOCF3), 6.71 (IH, d, J = 8.8 Hz, ArH), 6.80 (IH, d, J « 8.8 Hz, ArH), 8.28 (4H, m, PNB).
175
SUBSTITUTE SHEET 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 (l'S, IS, 3S)-l-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2',3',6'- trideoxylyxohexopyranoβe)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- iβochroman had:
XH NMR (CDC13 250 MHz, Bruker): δ, 1.16 (3H, d, J - 7.3 Hz, 6'-CH3), 1.63 (3H, β, 3-CCH3), 2.02 (2H, m, 2'-CH2), 2.86 (IH, d, J - 15.9 Hz, 4- CH), 3.21 (IH, d, J - 15.9 Hz, 4-CH), 3.65 (3H, 8, OCH3), 3.76 (6H, β, 2xOCH3), 4.10 (IH, qua, J - 7.2 Hz, 5'-CH), 4.61 (IH, m, 3'-CH), 5.45 (IH, β, 4'-CH), 5.55 (IH, β, l'-CH), 6.24 (IH, a, 1-CH), 6.68 (IH, d, J - 9.4 Hz, λrH), 6.76 (IH, d, J - 9.4 Hz, λrH), 6.23 (IH, 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 (l'S, IS, 3R)-1-( •-p-nitrobenzoyl-3■-trifluoroacetamido-2',3',6•- trideoxy-L-lyxohexopyranoβe)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- iaochroman had: -*-H NMR (CDC13 250 MHz, Bruker): δ, 1.19 (3H, d, J ■ 6.1 Hz, 6'-CH3), 1.60 (3H, a, 3-CCH3), 1.87 (IH, dd, J « 12.4 Hz, 4.7 Hz, 2*-CH), 2.11
(IH, d tr, J * 12.4 Hz, 3.0 Hz, 2'-CH), 2.86 (IH, d, J ■ 16.5 Hz, 4-CH), 3.33 (IH, d, J > 16.5 Hz, 4-CH), 3.62 (3H, a,OCH3), 3.78 (6H, s, 2xOCH3), 4.54 (IH, qua, J * 6.1 Hz, 5'-CH), 4.57 (IH, m, 3'-CH), 5.41 (IH, β, 4'-CH), 5.69 (IH, d, J ~~ 2.9 Hz, l'-CH), 6.40 (IH, 8, 1-CH), 6.45 (IH, d, J - 7.6 Hz, NHCOCF3), 6.71 (IH, d, J ■ 8.9 Hz, λrH), 6.81 (IH, d, J « 8.9 Hz, λrH), 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 (l'S, IR, 3R)-1-(4'-p-nitrobenzoyl-3'-trifluoroacetamido-2*,3' ,6'- trideoxy-L-lyxohexopyranoae)-3-methoxy-carbonyl-3-methyl-5,8-dimethoxy- iβochroman had:
2H NMR (CDCI3 250 MHz, Bruker): δ, 1.20 (3H, d, J ■ 6.0 Hz, 6'-CH3), 1.53 (3H, s, 3-CCH3), 1.93 (IH, dd, J = 11.8 Hz, 2.9 Hz, 2'-CH), 2.05 (IH, m, 2'-CH), 2.60 (IH, d, J - 16.5 Hz, 4-CH), 3.39 (IH, d, J » 16.5 Hz, 4-CH), 3.73 (3H, 8, OCH3), 3.76 (3H, 8, OCH3), 3.80 (3H, s, OCH3), 4.71 (IH, m, 3'-CH), 4.86 (IH, qua, J - 6.0 Hz, 5'-CH), 5.45 (IH, β, 4--CH), 5.55 (IH, d, J = 1.74 Hz, l'-CH), 6.01 (IH, s, 1-CH), 6.49 (IH,
176
SU * _. fc > * * " " Ϊ .I -—-7 d, J « 6.8 Hz, NHCOCF3 ) , 6.24 (IH, d, J » 10.2 Hz, λrH) , 6.82 ( IH, d, J ~~ 10.2 Hz, λrH) , 8.29 (4H, s , PNB) .
Step 3: (l'S, IR, 3S)-l-(4'-p-nitrobensoyl-3'-trifluoroacetamido- 2',3' ,6•-trideoxy-lyxohexopyranoae)-3-methoxycarbonyl-3-
■ethyl-5,8-dioxo-4,5,8-trihydro-lH-bβnso-[2,3-c]-pyran
The titled compound waa obtained via CAN oxidation (atep 3, example 13) of the (1'S,1R,3S) precursor from step 2 herein. H 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 (IH, d, J - 20 Hz, 4-CH), 3.31 (IH, d, J « 20 Hz, 4-CH), 3.67 (3H, β, OCH3), 4.46 (IH, m, 3'-CH), 4.66 (IH, qua, J - 6.5 Hz, 5'-CH), 5.36 (IH, s, 4'-CH), 5.62 (IH, B, l'-CH), 5.93 (IH, 8, 1-CH), 6.56 (IH, d, J - 7.1 Hz, NHCOCF3), 6.77 (IH, d, J « 9.7 Hz, Quin-H). 6.85 (IH, 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: (l'S, IR, 3S)-l-(4'-p-nitrobenzoyl-3•-trifluoroacetamido- 2',3', '-trideoxy-lyxohexopyranoae)-3-mβthoxy-carbonyl-3- methyl-5,10-dioxo-4,5,10-trihydro-lH-naphtho-[ ,3-c]-pyran
The titled compound waa obtained following cycloaddition between 1- acetoxybutadiene and the precursor from step 3 herein as per previoualy deacribed procedure. αH NMR (CDC13 250 MHz, Bruker): δ, 1.34 (3H, d, J ■ 6.5 Hz, 6'-CH3),
1.59 (3H, β, 3-CCH3), 1.90-2.10 (2H, m, 2'-CH2), 2.50 (IH, d, J * 19.4
Hz, 4-CH), 3.49 (IH, d, J « 19.4 Hz, 4-CH), 3.65 (3H, a, OCH3), 4.46 (IH, m, 3'-CH), 4.79 (IH, qua, J - 6.5 Hz, 5'-CH), 5.40 (IH, br a, 4'-
CH), 5.65 (IH, d, J * 2.5 Hz, l'-CH), 6.10 (IH, a, 1-CH), 6.51 (IH, d,
J - 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-λrH), 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.
177
SUBSTITUTE SHEET Step 5: (l'S, IR, 38)-1-(3•-trifluoroacetamido- ' ,3' ,6'-tridβoxy-L- lyxohexopyranoae)-5,10-dioxo- ,5,10-trihydro-lH-naphtho- [2,3-c]-pyran (BCH-2077)
The titled compound was obtained following methanolysis of the precursor from step 4.
1H NMR (CDC13, 250 MHz, Bruker): δ, 1.39 (3H, d,- J - 6.0 Hz, 6'-CH3), 1.58 (3H, β, 3-CCH3), 1.77 (IH, dd, J - 12.0 Hz, 4.1 Hz, 2'-HCHa), 1.84 (IH, dd, J - 12.1 Hz, 5.9 Hz, 2'-HCHa), 1.96 (IH, d, J - 8.7 Hz, 4'-OH), 2.48 (IH, d, J - 19.5 Hz, 4-HCHa), 3.47 (IH, d, J - 19.5 Hz, 4-HCHβ), 3.60 (IH, d, J - 8.7 Hz, 4'-CH), 3.64 (3H, β, OCH3), 4.17 (IH, m, 3'- CH), 3.56 (IH, qua, J - 6.0 Hz, 5'-CH), 5.46 (IH, d, J * 2.9 Hz, l'-CH), 6.05 (IH, s, 1-CH), 6.71 (IH, d, J ■ 8.8 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-λrH), 8.10 (2H, m, 6, 9-λrH). 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 (l,S,lS,3R)-l-(3*-trifluoroacβtaa do- 2',3*,6'-trideoxy-lyxo-L-hexopyranoae)-3-acetyl-3- methyl-3,4,5,10-tetrahydro-5,10-dioxo-naphtho-[2,3-c] pyran (BCH-2082)
BCH-2082
Step 1: (l'S, IS, 3R)-1-(3'-trifluoroacetamido-2',3' ,6•-trideoxy-L- lyxohexopyranoae)-3-acetyl-3-avethyl-5,10-dioxo-4,5,10- trihydro-lH-naphtho-[2,3-c)-pyran (BCH-2082)
Methanolysis of the p-nitrobenzoylated precuraor yielded the titled product.
•-n NMR (CDCI3, 250 MHz, Bruker): δ, 1.31 (IH, d, J « 6.6 Hz, 6'-CH3), 1.45 (3H, s, 3-CCH3), 1.80 (IH, d, J = 8.8 Hz, 2'-CH), 1.81 (IH, d, J ■■
178
SUBSTITUTESHEET 10 Hz, 2'-CH), 2.24 (3H, S, COCH3), 2.52 (IH, d, J ~~ 18.5 Hz, 4-HCHa) , 3.38 (IH, d, J « 18.5 Hz, 4-HCHe), 3.60 (IH, br 8, 4'-CH), 4.19 (IH, br qua, J « 10 Hz, 3'-CH), 4.41 (IH, qua, J « 6.6 Hz, 5'-CH), 5.45 (IH, a, l'-CH), 6.13 (IH, β, 1-CH), 6.63 (IH, d, J = 10 Hz), 7.75 (2H, m, 7, 8- λrH), 8.09 (2H, m, 6, 9-λrH).
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 (l'S,lS,3R)-l-(3'-trifluoroacβtamido- 2',3' ,6'-trideoxy-lyxo-L-hβxop ranosβ)-3- dimathoxyphθBphonoacetyl-3,4,5,10-tβtrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH-1690)
BCH-1690
Step 1: (1'S,1S,3R)-1-(2*,3',6'-trideoxy-3'-trifluoroacβtaa do-L- lyxohexopyranoae)-3-diaethylphoaphonoacet l-5,10-dioxo- 3,4,5-10-tetrahydro-lH-naphtho-[2,3-c)-pyran (BCH-1690)
The p-nitrobenzoyl precuraor waa hydrolyzed with catalytic aodium methoxide in methanol aa per previously described procedure. The titled compound had:
M.P. 91-93°C,
1H NMR (CDC13, 250 MHz, Bruker): δ, 1.40 (3H, d, J = 7.6 Hz, 6'-CH3), 1.89 (2H, m, 2'-CH2), 2.62 (IH, dd, J « 18.2 Hz, 11.8 Hz, 4-HCHa), 3.00 (IH, dd, J - 18.2 Hz, 4.1 Hz, 4-HCHe), 3.65 (IH, br β, 4-CH), 3.83 (3H, β, POCH3), 3.87 (3H, 8, POCH3), 4.32 (IH, qua, J = 7.6 Hz, 5'-CH), 4.56 (IH, m, 3-CH), 4.99 (IH, br s CHP), 5.13 (IH, br s, CHP), 5.44 (IH, s, l'-CH), 6.09 (IH, β, 1-CH), 6.83 (IH, br d, J ~~ 7.6 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-λrH), 8.09 (2H, m, 6, 9-λrH).
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.
179
SUBSTITUTE SHEET Example 56 : Preparation of ( • 8, lS,38)-l-(3 ' -trifluoroacetamido- 2 ' ,3 ' ,6 '-trideoxy-lyxo-L-hexopyranose)-3- aMthoxycarbonyl-3-methyl-3 ,4,5, lO-tetrahydro-5 , 10- dioxo-naphtho- [2, 3-c] pyran (BCH-2081)
BCH-2081
Step 1: (l'S, IS, 3S)-l-( '-p-nitrobenzoyl-3•-trifluoroacβtamido- 2',3',6'-trideoxy-lyxohexopyranose)-3-methoxy-carbonyl-3- methyl-5,8-dioxo- ,5,8-trihydro-lH-bβnao-[2,3-c]-pyran.
CAN oxidation of the (1'S,1R,3S)' precuraor from atep 2, example 53, yielded the titled compound.
XH NMR (CDC13 250 MHz, Bruker): δ, 1.14 (3H, d, J ■ 6.0 Hz, 6'-CH3), 1.61 (3H, 8, 3-CCH3), 1.96 (IH, d tr, J ~~ 11.7 Hz, 4.1 Hz, 2'-CH), 2.10 (IH, dd, J * 11.7 Hz, 2.9 Hz, 2'-CH), 2.58 (IH, d, J - 18.2 Hz, 4-CH), 3.00 (IH, d, J •__ 18.2 Hz, 4-CH), 3.71 (3H, 8, OCH3) 4.50 (IH, qua, J = 6.0 Hz, 5'-CH), 4.60 (IH, m, 3'-CH), 5.42 (IH, β, 4'-CH), 5.56 (IH, s, l'-CH), 6.03 (IH, B, 1-CH), 6.58 (IH, d, J = 7.4 Hz, NHCOCF3), 6 * 72 <1H' d, J « 8.8 Hz, Quin-H), 6.78 (IH, 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.
su Lm- mz* . I ϋTΞ SHEET Step 2 : (l ' S, IS, 3S)-l-(4 '-p-nitrobensoyl-3 ' -trifluoroaeatamido-
2 ' ,3 ' ,6 '-trideoxy-lyxohexopyranoae )-3-awthoxy-carbonyl-3- methyl-5 , 10-dioxo- , 5 , 10-trihydro-lH-naphtho- [ 2 , 3-c ] -pyran
The titled compound waa obtained following cycloaddition between 1- acetoxybutadiene and the quinone from atep 1 herein. H NMR (CDC13 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 (IH, dd, J « 17.6 Hz, 0.6 Hz, 4-HCHa), 3.22 (IH, dd, J - 17.6 Hz, 1.8 Hz, 4-HCHe), 3*73 <3H' a, OCH3), 4.57 (IH, qua, J - 6.0 Hz, 5'-CH), 4.64 (IH, m, 3'-CH), 5.45 (IH, d, J •__ 2.ι Hz, 4'-CH), 5.67 (IH, a, l'-CH), 6.22 (IH, s, 1-CH), 6.34 (IH, d, J - 8.2 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-λrH), 8.08 (2H, m,
6, 9-λrH), 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: (l'S, IS, 38)-1-(3'-tri luoroacetamido-2*,3',6•-trideoxy- lyxohexopyranoae)-3-mathoxycarbonyl-3■ athyl-5,10-dioxo-
4,5,10-trihydro-lH-naphtho-[2,3-c]-pyran (BCH-2081)
The precuraor from atep 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 (IH, d tr, J - 12.9 Hz, 3.8 Hz, 2'-HCHa), 1.88 (IH, dd, J - 13.0 Hz, 4.7 Hz, -2'-HCHβ), 1.94 (IH, d, J » 7.6 Hz, 2'- OH), 2.74 (IH, d, J « 18.8 Hz, 4-HCHa), 3.17 (IH, d, J - 18.8 Hz, 4- HCHe), 3.61 (IH, d, J - 7.8 Hz, 4'-CH), 3.71 (3H, β, OCH3), 4.32 (IH, m, 3'-CH), 4.40 (IH, qua, J - 6.1 Hz, 5'-CH), 5.50 (IH, d, J « 3.5 Hz, l'- CH), 6.15 (IH, a, 1-CH), 6.67 (IH, d, J « 8.8 Hz, NHCOCF3), 7.74 (2H, m,
7, 8-λrH),8.07 (2H, m, 6,9-λrH).
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)-l-(3'-trifluoroaceta ido-
2',3' ,6'-tridβoxy-lyxo-L-hβxopyranoββ)-3-
181
SU - >mJ i i _ fc- ET dimethoxyphosphonoacetyl-3 , 4 , 5 , 10-tetrahydro-5 , 10- dioxo-naphtho- [2 , 3-c) thiopyran (BCH-2037 .001 )
BCH-2037.001
Example 1
Step It Preparation of (l'S,IS,38) and (l'S,lR,3R)-l-(3'- trifluoroacetaad.do-2•,3',6'-trideoxy-L-lyxohexopyranoae)-3- acetyl-5,8-di■ethoxy-thioisochroman
The compound from step 1, example 13, and daunoaamine precursor (259 mg, 0.66 mmole) were dissolved in CH2C12 (25 ml) and left stirring in presence of molecular sieve for 30 minutes before DDQ (150 mg, 0.66 mmole) waβ added. The resulting mixture waa stirred for 2 1/2 hours. NaHC0 (5% solution) waa added and the aqueous layer waa extracted with CH2C12. The combined organic phases were waahed with H20, dried over MgS04, 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.
182
SU -.-> i I < Step 2: Preparation of (l'S,IS,38) and (l'S,lR,3R)-l-(4'-p- nitrobensoyl-3'-trifluoroacetamido-2' ,3' ,6'-tridβoxy-L- lyxohexopyranose)-3-acβtyl-5,8-dioxo-4,5,8-trihydro-lH- benso-[ ,3-c]-pyran
The compound from step 1 herein (112.7 mg, 0.18 mmole) waa diaaolved in acetonitrile (5 ml), cooled to 0°C, followed by the addition of NaHC03 (29 mg, 0.34 mmole) and some H20. The resulting mixture was stirred for 5 minutes before CAN (296 mg, 0.54 mmole) waa added, λfter all CAN was added, the reaction mixture waa atirred 10 minutea extra 0°C, then warmed to room temperature. H20 waa added and it waβ extracted with CH2C12. The combined organic phaaeβ were waahed with H20, dried over MgSO^, filtered and concentrated in vacuo. The crude containing a mixture of two titled diaatereoiβomerβ waβ uβed in the following βtep.
Step 3: (1'S,lS,3S)-l-(4'-p-nitrobβnaoy1-3'-trifluoroacetamido-
2',3' ,6'-trideoxy-L-lyxohβxopyranoββ)-3-acβtyl-5,10-dioxo- 3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-thiopyran
Following the example 1, atep 1, a mixture of the two titled adducta waβ obtained which could be aeperated via flash chromatography. The firβt eluent had: H 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 (IH, dd, J - 17.8 Hz, 11.8 Hz, 4-HCHa), 3.36 (IH, dd, J - 17.8 Hz, 4.1 Hz, 4'-HCHe), 4.53 (IH, dd, J - 11.8 Hz, 4.1 Hz, 3-CH), 4.60 (IH, m, 3'-CH), 4.75 (IH, qua, J - 5.6 Hz, 5'-CH), 5.53 (IH, a, 4'-CH), 5.70 (IH, d, J « 2.3 Hz, l'-CH), 6.13 (IH, a, 1-CH), 7.90 (2H, m, 7, 8-λrH), 8.12 (2H, m, 6, 9- λrH), 8.39 (4H, m, PNB), 8.65 (IH, d, J - 5.8 Hz, NHCOCF3). The aecond eluent had:
1H NMR (acetonβ-d6, 250 MHz, Bruker) : δ, 1.32 (3H, d, J - 6.8 Hz, 6 ' - CH3) , 2.39 (3H, a, COCH3 ) , 1.94 (IH, dd, J - 12.3 Hz, 4.1 Hz, 2 ' -HCHa) , 2.50 (IH, tr d, J > 12.3 Hz, 2.9 Hz, 2 ' -HCHe) , 2.89 (IH, dd, J = 18.2 Hz, 11.2 Hz, 4-HCHa) , 3.35 (IH, dd, J = 18.2 Hz, 3.5 Hz, 4-HCHe) , 4.41 (IH, dd, J - 11.2 Hz, 3.5 Hz, 3-CH) , 4.52 (IH, m, 3 '-CH) , 4.66 (IH, qua, J « 6.8 Hz, 5 ' -CH) , 5.47 (IH, 8, 4 '-CH) , 5.74 (IH, d, J = 2.9 Hz, l ' - CH) , 6.31 (IH, β, 1-CH) , 7.91 (2H, m, 7, 8-λrH) , 8.14 (2H, m, 6, 9-λrH) , 8.38 (4H, m, PNB) , 8.68 (IH, d, J = 7.1 Hz, NHCOCF3) .
183
SU V\ ~ t _. - « ϊ ' - "■-. "-" tm a> 8
+-< . . m im, Step 4: (1'8,18,3S)-l-(3'-trifluoroacetamido-2' ,3' ,6•-tridβoxy-L- lyxohexopyranoae)-5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho- [2,3-c]-thiopyran (BCB-2037.001)
--H NMR (CDC13 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 (IH, dd, J - 17.8 Hz, 12 Hz, 4- HCHa), 3.32 (IH, dd, J « 17.8 Hz, 4.1 Hz, 4-HCHe), 3 ' 61 <1H' br B' '~ CH), 4.07 (IH, dd, J - 12.0 Hz, J - 4.1 Hz, 3-CH), 5.53 (IH, s, l'-CH), 6.21 (IH, s, 1-CH), 6.74 (IH, d, J - 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-λrH), 8.12 (2H, m, 6, 9-λrH) .
Example 58: Preparation of (l'S,lR,3R)-l-(3'trifluoroacβtamido- ' ,3',6'-tridβoxy-lyxo-L-hβxopyranoββ)-3- diMthoxyphoaphonoacety1-3,4,5,10-tβtrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH- 127)
BCH-2127
Step 1: (l'S, IR, 3R)-l-(3'-trifluoroacetamido-2* ,3',6•-tridaoxy-L- lyxohexopyranoae)-3-acβty1-5,10-dioxo-3,4,5,10-tetrahydro- lH-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: -H NMR (CDC13 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, β, COCH3), 2.91 (IH, dd, J - 18.3 Hz, 11.8 Hz, 4-HCHa), 3.33 (IH, dd, J = 18.3 Hz, 4.7 Hz, 4-HCHe) , 3.60 (IH, br 8, 4-CH), 4.07 (IH, dd, J *~ 11.8 Hz, 4.7 Hz, 3-CH), 4.25 (IH, m, 3'-CH), 4.35 (IH, qua, J ~~ 6.5 Hz, 5'-CH), 5.53 (IH, d, J « 2.4 Hz, 1'- CH), 6.21 (IH, 8, 1-CH), 6.74 (IH, d, J « 7.6 Hz, NHCOCF3), 7.76 (IH, m, 7, 8-λrH), 8.14 (2H, m, 6, 9-λrH) .
Example 59: Preparation of (l'S,lS,3S)-l-(3'-trifluoroacetamido-
2' ,3' ,6'-tridβoxy-lyxo-L-hβxopyranoae)-3-acetyl-3- 184 ύϋlij' 1 i 1 i rict I methyl-3 ,4,5, 10-tetrahydro-5 , 10-dioxo-lH-naphtho- [2,3- c] pyran (BCH-2090)
BCH-2090
Step I: 3-acetyl-3-mβthyl-5 ,8-dimethoxy isochroman
The compound from atep 1, example 53, (126.5 mg, 0.474 mmol) waβ diβsolved in ether and then cooled to -78°C. Methyllithium (1.4 M in ether (0.71 ml, 0.995 mmol) waβ added, λfter 10 minutea methanol waa added. The reaction mixture waβ acidified with HCl (0.5 N) and extracted with ethyl acetate. The organic layer waβ dried over aodium sulfate and then evaporated to give a crude product (121 mg). 1H NMR ahowed that it waa a mixture of starting material and product in 1:1 ratio. Chromatography allowed iaolution of the deβired titled product as a gel.
1H NMR (CDC13 250 MHz, Bruker): δ, 1.37 (3H, β, 3-CCH3), 2.24 (3H, β, COCH3), 2«59 (1H» d, J - 17.6 Hz, 4-CH), 2.99 (IH, d, J - 17.6 Hz, 4-
185
SUPt ' r - . ' i Lm m i ϊ EET CH), 3.74 (3H, β, OCH3), 3.76 (3H, 8, OCH3), 4.77 <2H, β, 1-CH ), 6.57 (IH, d, J ■ 9.4 Hz, λrH), 6.62 (IH, d, J - 9.4 Hz, λrH).
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*8,18,38) and (l'S,18,3R)-l-(4'- -nitrobβnsoyl-3'- trifluoroacetamido-2',3',6•-trideoxy-L-lyxohexop ranoae)-3- acβtyl-3-mβthyl-5,β-dimethoxy-iaochroman
The compound from atep 1 herein (67 mg, 0.268 mmol) waβ stirred with DDQ (91.3 mg, 0.422 mmol) and 4',5'-protected daunoβa ine (157 mg, 0.402 mmol) in methylene chloride at 40°C for 24 hourβ. The solvent was evaporated. The crude product waβ chromatographed (hextEtOλc * 10:4) to give the titled compounds (88 mg containing two isomers in 2:1 ratio inseparable) . U NMR (CDC13250 MHz, Bruker): δ, 1.23 (3H, d, J « 6.0 Hz, λ-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 (IH, m, λ-2'-CH), 1.84 (IH, m, B-2--CH), 2.14 (IH, m, λ-2'-CH), 2.15 (IH, m, B-2'-CH), 2.80 (IH, d, J = 15.9 Hz, A-4-CH), 3.02 (2H, s, B-4-CH2), 3.14 (IH, d, J - 15.9 Hz, λ-4- CH), 3.77 (6H, s, B-OCH3), 3.80 (6H, β, A-OCH3), 4.41 (IH, qua, J - 6.0 Hz, B-5'-CH), 4.47 (IH, m, B-3'-CH), 4.56 (IH, qua, J - 6.0 Hz, A-5'- CH), 4.61 (IH, m, λ-3'-CH), 5.40 (IH, 8, B-4'-CH), 5.44 (IH, 8, λ-4'- CH), 5.61 (IH, d, J « 2.5 Hz, B-l'-CH), 5.70 (IH, d, J * 2.2 Hz, λ-1'- CH) , 6.35 (IH, 8, B-l-CH) , 6.37 (IH, 8, λ-l-CH) , 6.41 (IH, d, J ~~ 7.6 Hz, B-NHCOCF3) , 6.46 (IH, d, J ~~ 7.8 Hz, A-NHCOCF3) , 6.76 (2H, m, B- ArH) , 6.81 (2H, m, A-λrH) , 8.25 (8H, br a, λ-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) waβ (l'S, IR, 3S)-l-(4'-p- nitrobenzoy1-3'-trifluoroacetamido-2',3',6'-trideoxylyxohexopyranoae)-3- acetyl-3-methyl-5,8-dimethoxy-iBochroman which had: H NMR (CDCI3 250 MHz, Bruker): δ, 1.18 (3H, d, J = 7.6 Hz, 6'-CH3), 1.51 (3H, β, 3-CCH3), 2.00-2.10 (2H, m, 2*-CH ), 2.84 (IH, d, J = 17.1 Hz, 4-CH), 2.96 (IH, d, J - 17.1 Hz, 4-CH), 3.77 (3H, β, OCH3), 3.78 (3H, 8, OCH3), 4.54 (IH, qua, J « 7.6 Hz, 5'-CH), 4.62 (IH, m, 3'-CH), 5.46 (IH, d, J « 2.1 Hz, 4'-CH), 5.56 (IH, β, l'-CH), 6.14 (IH, β,
186
SUG5T. UTΞ SHEET 1-CH), 6.41 (IH, d, J « 7.6 Hz, NHCOCF3), 6.70 (IH, d, J « 8.8 Hz, λrH), 6.76 (IH, d, J * 8.8 Hz, λrH), 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: (l'S,IS,38) and (l'S, IS, 3R)-l-(4'-p-nitrobβnsoyl-3'- trifluoroacetaa .do-2',3',6'-trideoxy-lyxohexopyranoae)-3- acetyl-3-methyl-5,8-dioxo-4,5,8-trihydro-lH-bβnao-[2,3-c]- pyran
CAN oxidation of the producta from atep 2 herein gave the titled quinoneβ (as per procedure step 2, example 14) .
XH NMR (CDC13 250 MHz, Bruker): δ, 1.30 (3H, d, J ■ 6.0 Hz, λ-6*-CH3), 1.27 (3H, d, J ■ 6.1 Hz, B-6'-CH3), 1.44 (3H, 8, λ-3-CCH3), 1.44 (3H, s, B-3-CCH3), 1.80-2.30 (4H, m, λ-2'-CH2, B-2'-CH ), 2.62 (IH, d, J -
18.1 Hz, λ-4-HCHa), 2.72 (IH, d, J - 18.1 Hz, λ-4-HCHβ), 2.70 (IH, d, J * 18.0 Hz, B-4-CH), 3.25 (IH, d, J « 18 Hz, B-4'-CH), 4.41 (IH, m, B-3'- CH), 4.56 (IH, m, λ-3'-CH), 4.57 (IH, qua, J ■ 6 Hz, B-5'-CH), 4.72 (IH, qua, J - 6 Hz, λ-5'-CH), 5.38 (IH, β, B-4'-CH), 5.42 (IH, s, λ-4'-CH), 5.58 (IH, d, J « 2.4 Hz, B-l'-CH), 5.66 (IH, d, J - 2.9 Hz, λ-l'-CH), 5.98 (IH, s, B-l-CH), 6.02 (IH, 8, λ-l-CH), 6.45 (IH, d, J - 8.1 Hz, B-NHCOCF3), 6.55 (IH, d, J « 8 Hz, λ-NHCOCF3), 6.70-6.87 (4H, m, λ-6, 7- Quin, B-6, 7-Quin), 8.28 (8H, m, λ-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 4ι (1'8,1S,3S) and (l'S, IS, 3R)-l-(4'-p-nitrobensoyl-3'- trifluoroacetamido-2',3',6'-trideoxy-lyxohexopyranoae)-3- acβtyl-3-methyl-5,10-dioxo-4,5,10-trihydro-lH-naphtho-[2,3- c)-pyran
The quinone from step 3 herein waβ 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, a, 3-CCH3), 1.95 (IH, dd, J = 12.6 Hz, 4.7 Hz, 2'-CH), 2.12 (IH, d tr, J * 12.6 Hz, 2.9 Hz, 2'-CH), 2.71 (IH, d, J = 18.2 Hz, 4-CH), 2.89 (IH, d, J * 18.2 Hz, 4-CH), 4.60 (IH, m, 3'-CH), 4.85 (IH, qua, J =
187
C £ ϊ ""__* ■'"* "*lf" " ***** * ■" **" " ■*** *** * * ~*m ~-~ -*-* oU j i . . & i £' irict ϋ. 5.9 Hz, 5'-CH), 5.47 (IH, br s, 4'-CH), 5.71 (IH, d, J « 2 Hz, l'-CH), 6.21 (IH, d, J - 1.2 Hz, 1-CH), 6.42 (IH, d, J - 7.6 Hz, NHCOCF3), 7.78 (2H, m, 7, 8-λrH), 8.14 (2H, m, 6, 9-λrH), 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) diaatereomer had: λE NMR (CDCI3 250 MHz, Bruker): δ, 1.31 (3H, d, J - 5.9 Hz, 6'-CH3), 1.47 (3H, a, 3-CCH3), 1.89 (IH, dd, J - 11.8 Hz, 5.3 Hz, 2'-HCHa), 2.06 (IH, d tr, J - 11.8 Hz, 4.1 Hz, 2'-HCHe), 2.55 (IH, d, J - 17.8 Hz, 4- HCHa), 3.40 (IH, d, J - 17.8 Hz, 4-HCHe), *45 <1H* m* 3''CH)' 4-66 <1H' qua, J - 5.9 Hz, 5'-CH), 5.43 (IH, S, 4'-CH), 5.63 (IH, d, J - 2.3 Hz, l'-CH), 6.17 (IH, a, 1-CH), 6.30 (IH, d, J - 11.8 Hz, NHCOCF3), 7.77 (2H, m, 7, 8-λrH), 8.13 (2H, m, 6, 9-λrH), 3.30 (4H, m, PNB).
Step 5: (l'S, IS, 3S)-1-(3'-trifluoroacetamido-2' ,3' ,6'-trideoxy-L- lyxohexopyranoae)-3-acβty1-3-mβthy1-5,10-dioxo-4,5,10- trihydro-lH-naphtho-[2,3-c)-p ran (BCH-2090)
Hydrolysis of the (1'S,1S,3S) precursor from step 4 herein gave the titled compound.
M.P. 95°C. λH 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'-CH ), 2.27 (3H, a, COCH3), 2.84 (2H, d, J - 5.9 Hz, 4-CH2), 3.65 (IH, β, 4'-CH), 4.31 (IH, m, 3'-CH),
4.64 (IH, qua, J * 6.0 Hz, 5'-CH), 5.53 (IH, br a, l'-CH), 6.15 (IH, a,
1-CH),-6.71 (IH, br d, J ■ 8.8 Hz, NHCOCF3), 7.75 (2H, m, 7, 8-λrH),
8.11 (2H, m, 6, 9-λrH).
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 (l,S,lR,3S)-l-(3'-trifluoroacβtamido-
2',3' ,6'-trideoxy-lyxo-L-hβxopyranosβ)-3- Λ j et oxyphosphonoacety1-3,4,5,10-tetrahydro-5,10- dioxo-naphtho-[2,3-c] pyran (BCH-1689)
188 su T5 c i* ?. **- * -~~r--~- r- - i^rv
Step 1 : 3-bromoacetyl-5,8-dimethoxy-iaochrcamn
The titled compound waβ prepared by using 5,8-dimethoxy-3- acetoiaochroman and the procedure from atep 1, example 8. B NMR (CDC13, 250 MHz, Bruker): 2.59 (IH, dd, J « 15.9 Hz, 11.8 Hz, 4- HCHa), 3.03 (IH, dd, J - 15.9 Hz, 2.9 Hz, 4-HCHβ) • 3-74 (3H» ■• OCH3), 3.75 (3H, B, OCH3), 4.23 (IH, dd, J - 11.8 Hz, 2.9 Hz), 4.27 (IH, d, J « 13.5 Hz, CHBr), 4.34 (IH, d, J - 13.5 Hz, CHBr), 4.63 (IH, d, J « 15.9 Hz, l-HCHa), 4.96 (IH, d, J > 15.9 Hz, l-HCHβ), 6.63 (2H, m, λrH).
Step 2: 3-dimethoxy phosphinoacety1-5,8-dimethoxy-isoch:
The titled compound waa obtained following treatment of the product from βtep 1 herein with P(OCH3)3.
1HNMR (CDC13, 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) ,
189
- - w (T- i _\ m" 'f
*< mj Q"^ k lm m-. M . --< -m i 3.71 (s, 3 H, λrOCH3), 3.72 (e, 3 H, λrOCH3), 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 - λrH). 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) (l'8,lR,3S)-5,8-dimethoxyl(2' ,3', '-trideoxy-3'- trifluoroacetamido-4'-p-nitrobβnsoyl-L-lyxohβxopyranoββ)-3- dimethylphoaphonoacetyl isochroman
To a stirred solution of the phosphonate from atep 2 herein (199 mg, 0.58 mmole) with 4 - PNB - 3 - TFλ - daunoβamine (270 mg, 0.69 mmole) in dichloromethane (60 ml) waa added 4 peleta of molecular sieves (4λ~). This waa followed by addition of dichlorodiβyanoquinone (DDQ, 170 mg,.
0.75 mmole) in one portion. The reaulting green liquid waβ atirred at 40 °c (controlled by an Ikamag-Ret-G-Heating-Stirring aystem) 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 (HexiEλ ~~ 1:1.5) to yield the deβired titled glycoβideβ
(diaatereomeric mixture λ and B, aa light-colored glaaβy 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 H§, .4.6 Hz, 2' - HCHBa), 2.07 (dt,
1 H, J « 12.3 Hz, 3.5 Hz, 2' - HCHAβ), 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 - HCHAβ), 3.03 (dd, 1 H, J « 11.1 Hz, 3.3 Hz, 4 - HCHge), 3.74 - 3.87 (8x8, 24 H, 2 x ArOCH3A, 2 x λrOCH3B, 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 (β, 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 COλrHAN02, 4 x COλrHBN02).
190
'' I5' I (>" m mtm
S I *4 f' *r* . & _ < . - -- I Step 4: [(l'S,18,3R) and (l'S,lR,3S)-l-(2',3,6'-tridβoxy-3'- trifluoroacetamido- '-p-nitrobβnsoyl-L-lyxohβxopyranoββ)-3- imethylphosphonoaceth 1-3,4,5,8-tetrahydronaphthaleno-[2,3- e]-pyran
To a aolution of glycoaide from atep 3 herein (98 mg, 0.13 mmole) in 8 ml of acetonitrile cooled to 0°C waβ added aodium bicarbonate powder (22 mg, 0.27 mmole). Thia was followed by dropwise addition of aqueous cerium ammonium nitrate (CAN, 298 mg, 0.54 mmole in 3.0 ml of water). λfter 10 minutea at 0°C, the reaction mixture waa poured to water (20 ml) and extracted with dichloromethane (4 x 10 ml). The organic layer was dried (over aodium sulfate) and evaporated to give the titled quinonea aa a glaββy mixture (85 mg).
XHNMR (CDC13, 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 - HCHAβ, 2 - HCHβe), 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 - HCHAβ), 2.85 (dd, 1 H, J « 16.8 Hz, 5.0 Hz, 4 - HCH ), 3.79 (B, 3 H, POCH3A), 3.84 (B, 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 (β, 2 H, 4', CHA, 4' - CHB), 5.55 (β, 1 H, 1'- CHA), 5.61 (β, 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 - λrHB), 6.82 (m, 2 H, 6.7 - λrHA), 8.27 (8, 8 H, 4 x COλrHλN02, 4 x COλrHBN02).
Step 5: (l'S,lR,3S)-l-(2' ,3',6'-tridβoxy-4'-p-niprobenaoyl-3'- trifluoroacetaa_ido-L-lyxohexo pyranoae)-3-dimethyl phoβphonoacetyl-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-l,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:EtOλc: HOMe: acetone:HOAc ~~ 240:75:10:10:1) to give the (1'S,1R,3S) isomer (21 mg) and the (1'S,1S,3R) iβomer (18 mg). The titled compound had:
191
- m ~- p ψm wm
JU -*J I 3-H NMR (CDCI3, 250 MHz, Bruker): δ, 1.19 (3H, d, J « 7.0 Hz, 6'-CH3), 2.03 (IH, m, 2-HCHa), 2.07 (IH, m, 2-HCHe), 2.56 (IH, dd, J * 18.2 Hz, 11.8 Hz, 4-HCHa), 3.05 (IH, 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 (IH, qua, J - 7.0 Hz, 5'-CH), 4.60 (IH, m, 3'-CH), 4.65 (IH, dd, J - 11.8 Hz, 4.7 Hz), 5.04 (IH, br s, CHP), 5.17 (IH, tr, J - 2.0 Hz, CHP), 5.42 (IH, β, 4'-CH), 5.71 (IH, B, l'-CH), 6.00 (IH, B, 1-CH), 6.48 (IH, d, J - 7.6 Hz, NHCOCF3), 7.76 (2H, m, 7, 8-λrH), 8.10 (2H, m, 6, 9-λrH), 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,IS,3R)-1-(2',3' ,6■-tridβoxy-4'-p-niprobenzoy1- 3•-trifluoroacetamido-L-lyxohexo pyranoβe)-3-dimβthyl phoaphonoacetyl- 5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho[2,3-c]-pyran had: M.P. 135-137°C. αH NMR (CDC13, 250 MHz, Bruker): δ, 1.33 (3H, d, J - 6.4 Hz, 6'-CH3),
2.01 (IH, br tr, J - 11.8 Hz, 3'-HCHa), 2.15 (IH, br tr, J - 11.8 Hz, 3'-HCHe), 2.62 (IH, dd, J - 18.8 Hz, 12.1 Hz, 4-HCHa), 3,01 (IH, dd, J = 18.8 Hz, 4.4 Hz, 4-HCHe), 3*81 <3H* ■* POCH3), 3.86 (3H, 8, POCH3), 4.58 (IH, m, 4'-CH), 4.60 (IH, dd, J - 12.1 Hz, 4.4 Hz, 3-CH), 4.79 (IH, qua, J - 6.4 Hz, 6-CH), 5.02 (IH, br a, PCH), 5.13 (IH, br a, PCH), 5.46 (IH, 8, 5'-CH ), 5.62 (IH, 8, l'-CH), 6.14 (IH, 8, 1-CH), 6.63 (IH, d, J =
8.2 Hz, NHCOCF3), 7.79 (2H, m, 7, 8-λrH), 8.16 (2H, m, 6, 9-λrH), 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: (l'S,lR,3S)-l-(2',3',6'-trideoxy-3'-trifluoroacβtamido-L- lyxohexo yranoae)-3-dimethylphoaphonoacatyl-5,10-dioxo- 3,4,5-10-tetrahydro-lH-naphtho-[2,3-c]-pyran (BCH-1689)
The PNB-protβctβd ketophosphonate from βtep 5 herein (21 mg, 0.028 mmol) waa diaaolved in THF-MeOH (3 ml of each) and cooled to 0°C. Sodium methoxide (4.3 m, 6.5 μl) waa added, λfter βtirred for 5 minutes at 0° C, the crude mixture (pink) waβ 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 waa recrystallized
192 m-» * ■ 9-S «■*» ~~~~ ' ~~~~- ' ' "■"*" ■"* *"* * ' "*" "^ T
SUE . L . U . :: iπcc l from methylene chloride and hexane to give the desired product (10 mg) as an off-white solid. M.P. 95-97βC.
2H NMR (CDCI3, 250 MHz, Bruker): δ, 1.25 (3H, d, J - 8.2 Hz, 6'-CH3), 1.83-1.98 (2H, m, 2'-CH ), 2.53 (IH, dd, J - 17.6, 11.8 Hz, 4-HCHa),
3.00 (IH, dd, J - 17.6 Hz, 3.5 Hz, 4-HCHβ), 3.62 (IH, br s, 4'-CH), 3.82 (3H, B, POCH3), 3.86 (3H, B, POCH3), 4.16 (IH, qua, J - 8.2 Hz, 5'-CH), 4.34 (IH, m, 3'-CH), 4.62 (IH, dd, J - 11.8 Hz, 3.5 Hz, 3-CH), 5.01 (IH, 8, CHP), 5.12 (IH, 8, CHP), 5.54 (IH, S, l'-CH), 5.94 (IH, 8, 1-CH), 6.82 (IH, d, J « 7.1 Hz, NHCOCF3), 7.74 (2H, m, 7, 8-λrH), 8.06 (2H, m, 6, 9-λrH).
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.
193
SUBSTITUTE SHEET Kxample 61 : Various C-2 ' axialy iodinated pyran Itiaphthoφi i none glycosides
BCH-2015 BCH-1666 BCH-1667 BCH-2014
Step 1: 3,4-Di-0-acetyl-2-iodo-2,6-dideoxyfucose
To a mixture of di-C—acetyl fucal (3.029 g, 14.140 mmol) in 180 ml of acetonitrile and 18 ml of water waa added portionwiae the NIS (3.590 g, 15.554 mmol). λfter stirring for 30 minutea the mixture waa extracted with CH2C12 (2x) and the combined organic extracta were waahed with 10% aodium thioβulfate aolution, water and finally dried (Na2S04) 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, 2XOλc), 4.36 (d, Is, J=5.1Hz, H-2), 4.48 (q, IH,
J*6.6Hz, H-5), 4.98 (unresolved dd, IH, H-3), 5.18 (broad β,lH, H-4),
5.59 (broad β, IH, H-l), 5.94 (d, IH, OH).
194
Cf Fr f** ■"*** *-r -~- *• . t».--___— Step 2: (1'8,1R,38) and (1*S,1S,3R) - 2,5-Dimethoxy-l-(2',«'- dideoxy-3' ,4•-diacetoxy-2'-iodo-L-lyxohβxopyranoae)-3- acetoiaochroman
To a mixture of augar from atep 1 herein (910 mg, 2.539 mmol) and methyl ketone isochroman (500 mg, 2.116 mmol) in dry CH C12 under argon atmoaphere and room temperature waa added aome - molecular aieve (4λ). λfter stirring for 20 minutes DDQ (577 mg, 2.539 mmol) waβ added, λfter Btirring for 72 hours, while additiona of 0.5 equivalent of augar and 0.5 equivalent of DDQ were done after 24 and 48 houra, the reaction waa worked up by addition of 100 ml of NaHC03 5% and water mixture (1x3). Extractions with CH C1 (3x100 ml) following by washing with the same aqueous mixture and drying (Na S0 ). 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, 2XOλc), 2.30 (β,3H,COCH3), 2.50 (dd, IH, J«17.8Hz and 12.1Hz, CHaCHO), 2.95 (dd, IH, J-17.8 and 4.3Hz, CHeCHO), 3.80 and 3.83 (2s, 2X3H, 2XOCH3), 5.52 (d, IH, J-5.0HZ, H-2'), 4.75 (m, 3H, H-3, H-3' and H-5'), 5.24 (broad a, IH, H-4'), 5.89 (a, IH, H-l'), 6.15 (8, IH, H-l), 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 (β, 3H, COCH3), 2.45 (dd, IH, J-17.6Hz and 12.2Hz, CHaCHO), 2.96 (dd, H, J-17.6HZ and 4.1Hz, CHeCHO), 3.80 and 3.82 (2s, 2X3H, 2XOCH3), 4.48 (d, IH, J*5.0Hz, H-2'), 4.54 (m, 2H, H-3, H-5'), 4.83 (unresolved dd, IH, H-3'), 5.20 (broad s, IH, H-4'), 5.86 (s, IH, H-l'), 6.03 (a, IH, H-l), 6.88 (2d, 2H, λr-H).
Step 3: (1'S,IR,38)-5,8-Dimβthoxy-3-acβto-l-(2•, '-dideoxy-2•-iodo- L-lyxohexopyranose)-iβochroa_an
To mixture of the compound from atep 2 herein (500 mg, 0.844 mmol) in 90 ml of dry THF maintained at 0°C and under argon atmoaphere were added 90 ml of NaOH 0.5N. λfter stirring for 1 hour the reaction mixture was neutralized with 160 ml of NH4CI sat.:NaHC03 eat. (4:1) and extracted with CH2C12 (3x200 ml). The combined organic layere were dried over MgS04. 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 (β, 3H, COCH3), 2.44 (dd, IH, J=17.5Hz and 12.2Hz, CHaCH0), 2.93 (dd, IH, J=17.7Hz and 4.1Hz, CHeCHO), 3.16 (d, IH, J-6.0HZ, OH), 3.49 (m, IH, H- 3'), 3.77 (m, IH, H-4'), 3.79 and 3.84 (2Xβ, 2X3H, OCH3), 4.09 (d, IH, J=7.4Hz, OH), 4.25 (q, IH, J-6.6HZ, H-5'), 4.37-(d, IH, J-δ.OHz, H-2'), 4.54 (dd, IH, J«12.2Hz, 4.1Hz, H-3), 5.84 (β, IH, H-l'), 5.99 (8, IH, H- 1), 6.88 (2Xd, 2XH, λrH)
Step 4ι (l'8,lR,3S)-3-acβto-l-(2',6'-dideoxy-2'-iodo-L- lyxohexopyranoae)-5,8-dioxo-5,8-dihydroiaochroman
The titled compound waa obtained following CAN oxidation of the product from atep 3 herein aa per previous procedure.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J«6.6Hz, CH3-6'), 1.86 (large d, IH, OH), 2.33 (a, 3H, COCH3), 2.39 (dd, IH, J-19.9 and 11.9Hz, CHa-CHO), 2.81 (large a, IH, OH), 2.90 (dd, IH, J*19.7Hz and 3.9Hz, CHe-CHO), 3.32 (large s, IH, H-3'), 3.78 (large unreaolved d, IH, H-4'), 4.17 (broad q, IH, J-5.0HZ, H-5'), 4.39 (m, 2H, H-3 and H-2'), 6.81 (a, IH, H-l'), 6.89 (β, IH, H-l), 6.81 (2Xd, 2H, quinone ring-H). IR (film) Vnaxt 3486, 3400, 2937, 1711, 1657, 1307, 968 cm'1.
Step 5: (1'S,1R,38)- mβthyl-(l-[2',6•-dideoxy-3' ,4'-dihydroxy-2'- iodo-Zi-lyxohexop ranoae]-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 atep 4 herein and 1 ml of 1-acetoxybutadiene, the procedure described in atep 2, example 5, haa been followed, λfter purification, 15.8 mg (29% yield) of pure titled compound waβ iaolated.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J«6.7Hz, CH3-6'), 1.91 (large d, IH, J=11.0Hz, OH), 2.36 (β, 3H, COCH3), 2.53 (dd, IH, J*19.5Hz, 11.4Hz, CHaCHO), 2.81 (large d, IH, J-10.4Hz, OH), 3.08 (dd, IH, J-19.9Hz and 4.1Hz, CHeCHO), 3.34 (m, IH, H-3'), 3.80 (m, IH, H-4'), 4.17 (broad q, IH, 6.9Hz, H-5'), 4.45 (m, 2H, H-3 and H-4'), 5.98 (2Xa, 2X1H, H-l and H-l'), 7.78 and 8.11 (2Xm, 2X2H, λrH). IR (film) Vmaχ: 3477 broad, 2928, 1722, 1670, 1298, 961, 732 cm'1.
196
SUr <■* ? ? "_-* tK"tj. : 1 . ΞT Step 6: (1'8,1R,3S)- 5,8-Dioxo-3-acato-l-(2' ,6'-dideoxy-3' ,4'- diacetoxy- '-iodo-L-lyxohβxopyranose)-5,8-dihydroiβoch
CAN oxidation of the (1'S,1R,3S) diastereomeric product from step 2, example 61, yielded the titled compound.
PMR (CDC13, 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, IH, J-2 .1Hz, 11.8Hz, CHaCHO), 2.92 (dd, IH, J«19.7Hz and 3.9Hz, CHeCHO), 4.29 (q, IH, J-6.5 Hz, H-5'), 4.36 (d, IH, J-5.1HZ, H-2'), 4.41 (dd, IH, J-11.2HZ and 4.0Hz, H-3), 4.78 (dd, IH, J-4.0HZ, H-3'), 5.23 (broad a, IH, H-4'),
5.82 (lβ, IH, H-l'), 5.87 (la, IH, H-l), 6.81 (2d, 2H, quinone ring-H).
Step 7: (l'S,lR,3S)-mβthyl-(l-[2',6,-didβoxy-3'-4'-diacβtoxy-2'- iodo-L-lyxohexopyranoae]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c]-pyran-3-yl) ketone (BCH- 666)
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, waβ added 1- acetoxybutadiene (66 mg, 0.587 mmol). λfter 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 (CD2C12, 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, IH, J-19.5HZ and 11.5Hz, HCϋaCHC«0), 3.16 (dd, IH, J-19.5HZ, 4.0Hz, HCHeCHC-0), 4.45 (broad q, IH, J-6.6HZ, H-5'), 4.51 (d, IH, J«5.0Hz, H-2'), 4.62.
(unresolved dd, IH, J«11.7Hz and 4.0Hz, H-3), 4.88 (dd, IH, J-4.0Hz, H- 3'), 5.32 (broad a, IH, H-4'), 6.06 (a, IH, H-l'), 6.16 (a, IH, H-l), 7.71 and 8.22 (2Xm, 2X2H, λrH). IR (film) Vgnx'. 2991, 2935, 1746, 1668, 1238, 970, 730 cm-1.
Step 8: (l'S,lS,3R)-5,8-Dioxo-3-aceto-l-(2',6'-dideoxy-3',4<- diacetoxy-2'-iodo-L-lyxohexopyranoae)-5,8-dihydroisochroman
CAN oxidation of the (1'S,1S,3R) glycoβide 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, 2XOλc), 2.32 (s, 3H, COCH3), 2.46 (dd, IH, J-20.3 Hz and 11.7 Hz, CHaCHO), 2.90 (dd, IH, J«19.7Hz and 4.1Hz, CHeCHO), 4.25 (d, IH, J=5.2Hz, H-2'), 4.43 (dd, IH, J=11.6Hz and 4.1Hz, H-3), 4.61 (q, IH,
197
C? I C " m?~* --*"••- < ~ i ^T J=6.2Hz, H-5'), 4.75 (dd, IH, J-3.6 Hz, H-3'), 5.26 (broad s, IH, H- 4'), 5.82 (β, IH, H-l'), 5.97 (β, IH, H-l), 6.81 (2d, 2H, quinone ring- H).
IR (film) Vmax: 2945, 1747 broad, 1663, 1237, 969 cm'1.
Step 9: (l'S,lS,3R)-methyl-(l-[2',6'-didβoxy-3',4'-diacetoxy-2'- iodo-L-lyxohexopyranoae]-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 atep 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 (CDC13, 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, IH, J-20.0 and
12.4Hz, HCϋaCHCO), 3.07 (dd, IH, J>20.0Hz and 4.2Hz, HCHeCHC«0), 4.27 (d, IH, J-S.OHz, H-2'), 4.49 (dd, IH, J-11.6, 4.2 Hz, H-3), 4.75 (m, 2H, H-3' and H-5'), 5.28 (large a, IH, H-4'), 5.86 (a, IH, H-l'), 6.14 (a, IH, H-l), 7.77 and 8.11 (2m, 2X2H, ArH). IR (film) V^: 2945, 1743 broad, 1668, 1236 broad, 958, 734 cm'1.
Step 10: (l'S,lS,3R)-5,8-Dimethoxy-3-aceto-l-(2',6'-dideoxy-2'-iodo- Xι-lyxohexopyranoae)-isochroman
The titled compound waa obtained via base hydrolyaia of the (1'S,1S,1R) precuraor from atep 2 herein aa per procedure from atep 3 herein. PMR (acetonβ-d6, 250 MHz) δ: 1.35 (d, 3H, J-6.6HZ, CH3-6'), 2.30 (a, 3H, COCH3), 2.50 (dd, IH, J-17.6 and 11.5 Hz, CHaCHO), 2.94 (dd, IH, J-17.9 and 4.3Hz, CHeCHO), 3.20 (d, IH, OH), 4.44 (m, IH, H-3'), 3.80 (large a, 7H, 2XOCH3 and H-4'), 4.12 (d, IH, OH), 4.41 (d, IH, J=5.0Hz, H-2'), 4.55 (q, IH, J»6.4Hz, H-5'), 4.70 (dd, IH, J=12.1 Hz and 4.5 Hz, H-3), 5.87 (IS, IH, H-l'), 6.14 (Is, IH, H-l), 6.88 (2d, 2H, ArH).
Step 11: (l'S,lS,3R)-3-aceto-l-(2' , '-dideoxy-2'-iodo-L- lyxohexopyranoae)-5,8-dioxo-5,8-dihydroisochroa_an
The titled compound was obtained following CAN oxidation of the product from atep 10 herein as per previous procedure.
198
SU t l___-> «*_ i J l * rmi. γm y I
+-* . ϊt L km PMR (CDC13, 250 MHz) δx 1.45 (d, 3H, J-6.6HZ, CH3-6'), 1.90 (broad s, IH, OH), 2.31 (β, 3H, COCH3), 2.43 (dd, IH, J«20.1Hz and 11.8 Hz, CHaCHO), 2.80 (m, la, OH), 2.88 (dd, IH, J*19.8Hz and 4.1Hz, CHeCHO), 3.32 (m, IH, H-3'), 3.84 (m, IH, H-4'), 4.24 (d, IH, J-4.4HZ, H-2'), 4.42 (dd, IH, J«11.8Hz and 4.2Hz, H-3), 5.82 (a, IH, H-l'), 5.95 (a, IH, H-l), 6.79 (2Xd, 2H, quinone ring-H).
Step 12: (l'S,lS,3R)-methyl-(l-[2' ,6'-dideoxy-3',4'-dihydroxy-2'- iodo-L-lyxohexopyranoae]-5,10-dioxo-3,4,5,10- tetrahydronaphtho [2,3-c)-pyran-3-yl)-kβtone (BCH-2014)
A mixture of compound from atep 11 herein (1 ml) and 1-acetoxy-butadiene (96 mg, 0.201 mmol) in 2 ml of dry toluene waβ atirred for 18 hours under argon atmoaphere and then flash chromatographed (Toluene:Ethyl acetate; 8:2) to give .42 mg (40% yield) of pure titled compound.
PMR (CDC13, 250 MHz) δ: 1.52 (d, 3H, CH3-6'), 2.36 (a, 3H, COCH3), 2.58 (dd, IH, J-19.7HZ and 11.4Hz, HCHaCHCO), 2.78 (broad m, IH, OH), 3.09 (dd, IH, J-20.0HZ and 4.2Hz, HCHeCHCO), 3.34 (m, IH, H-3'), 3.89 (m, IH, H-4'), 4.27 (d, IH, J-4.5HZ, H-2'), 4.49 (dd, IH, J-11.7HZ and 4.2Hz, H- 3), 4.66 (broad q, IH, J-6.4HZ, H-5'), 5.30 (s, IH, H-l'), 5.89 (8, IH, H-l), 7.53 and 8.13 (2m, 2X2H, λr-H). IR (film) ___ax'. 3434 broad, 2934 broad, 1720, 1669, 1292, 995, 955 cm'1.
199
SU ~m~. im w*" : m*-' - ..«-*•■"-
BS I H ϋ i mj t fei-i- Example 62 : Various C-2 ' axialy brominated pyranylnaphthoquinone glycosides
Step 1: 3,4-Di-0-acetyl-2-bromo-2,6-dideoxyfucoae
Following the procedure deβcribed in atep 1, example 61, we obtained after work-up 89% yield of a mixture of four compounds. Probably axial and equatorial bromo βugarβ and α and β iaomera of each.
Step 2: (1 ' 8, 1R,3S) and (l * S, lS,3R)-2,5-Dimethoxy-l-(2 ' ,6 ' -dideoxy-
3 ' , 4 ' -diacetoxy- ' -bromo-L-lyxohexopy ranoae) -3- acetoiaochroman
Following the procedure deβcribed in step 2, example 61, we obtained after purification (DichloromethanexHexanexEthyl acetate; 12:7:1) 35% yield of a separable (1'S,1R,3S and 1'S,1S,3R) 1:1 mixture of titled diaatereoiβomers.
200
SUBSTITUTE SHEET (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, 2XOλc), 2.29 (β, 3H, COCH3), 2.50 (dd, IH, J=17.7Hz and 12.1Hz, CHaCHO), 2.96 (dd, IH, J-17.8 and 4.2Hz, CHeCHO), 3.80 and 3.84 (2Xa, 2X3H, 2XOCH3), 4.42 (d, IH, J-4.2Hz, H- 2'), 4.71 (dd, IH, J*12.2Hz and 4.2 Hz,H-3), 4.81 (q, IH, J-6.4Hz, H- 5'), 5.22 (m, 2H, H-3' and H-4'), 5.74 <β,lH, H-l'), 6.17 (8, IH, H-l), 6.90 (2Xd, 2H, λr-H).
IR (film) Vg^x'. 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 (2Xβ, 2X3H, 2XOλc), 2.30 (s, 3H, COCH3), 2.45 (dd, IH, J-17.6HZ and 12.2Hz, CHaCHO), 2.97 (dd, IH, J«17.6Hz and 4.0Hz, CHeCHO), 3.80 and 3.82 (2Xβ, 2X3H, 2XOCH3), 4.38 (d, IH, J«4.6Hz, H-2'), 4.53 (q, IH, J-6.4HZ, H-5'), 5.16 (broad s, IH, H-4'), 5.27 (dd, IH, J-4.2HZ, H- 3'), 5.71 (s, IH, H-l'), 6.05 (s, IH, H-l), 6.89 (2Xd, 2H, λr-H).
Step 3: (l'S,lR,3S)-5,8-dioxo-l-(2',6'-dideoxy-3',4'-diacetoxy-2'- bromo-L-lyxohexopyranoae)-5,8-dihydroisochroman
CAN oxidation of the compound from step 2 herein yielded the titled compound.
PMR (CDC13, 250 MHz) δ: 1.19 (d, 3H, J-6.6HZ, CH3-6'), 2.04 and 2.16 (2Xβ, 2X3H, 2XOAC), 2.29 (s, 3H, COCH3), 2.38 (dd, IH, J«19.9Hz and 11.6Hz, CHaCHO), 2.88 (dd, IH, J=19.8Hz and 3.9Hz, CHeCHO), 4.25 (m, 2H, H-2' and H-5'), 4.39 (dd, IH, J-11.6Hz and 3.8Hz, H-3), 5.16 (broad β, IH, H-4'), 5.19 (dd, IH, J*4.0Hz, H-3'), 5.71 (β, IH, H-l'), 5.81 (β, 1H,H-1), 6.79 (2Xd, 2H, λr-H).
Step : (1'S,IR,38)-methyl-(1-[2',6'-dideoxy-3',4'-diacβtoxy-2•- bromo-L-lyxohexopyranoβe]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2100)
The titled compound waa obtained following the procedure deβcribed in step 2, example 5, from the compound from step 3 herein. HPLC purification gave 9% of deaired (1'S,1R,3S) natural titled glycoβide. PMR (CDC13, 250 MHz) δ: 1.23 (d, 3H, J«6.4Hz, CH3-6'), 2.06 and 2.19 (2β,2X3H, 2XOAC), 2.35 (β, 3H, COCH3), 2.54 (dd, IH, J=19.7Hz and 11.7Hz, CHaCHO), 3.09 (dd, IH, J=19.8Hz and 4.0Hz, CHeCHO), 4.29 (m, 2H, H-2* and H-5'), 4.47 (dd, IH, J=11.7Hz and 4.0Hz, H-3), 5.18 (broad s,
su If"*^"*T*r"***"» ~ ~~ J m ~,tι ,-._»^ 4» IH, H-4'), 5.23 (unresolved dd, IH, H-3'), 5.83 (s, IH, H-l'), 6.01 (β,
IH, H-l), 7.77 and 8.11 (2m, 2X2H, λr-H).
IR (film) V,,,^: 2991 and 2943, 1748,1665, 1241, 975 cm"1.
Step 5: (l*S,lR,3S)-5,8-dioxo-3-acβto-l-(2' ,6'-dideoxy-3',4'- diacetoxy-2'-bromo-L-lyxohβxopyranoββ)-5,8-dihydroiaochroman
CλN oxidation of the (1'S,1R,3S) diaatereomer from atep 2 herein yielded the titled product. IR (film) VmajjX 2939, 1743, 1674, 1241, 968 cm'1.
Step 6: (l'S,18,3R)-methyl-(l-[2',6'-dideoxy-3',4'-diacetoxy-2'- bromo-L-lyxobaxopyranoae]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c)-pyran-3-yl) ketone (BCH-2099)
The titled compound waβ obtained following the procedure deβcribed in atep 2, example 5, from the quinone from atep 5 herein. Flaah chromatography (Toluene:Ethyl acetate; 9:1) gave 30% of deβired titled compound. PMR (CDC13, 250 MHz) δ: 1.41 (d, 3H, J«6.4Hz, CH3-6'), 2.05 and 2.21 (2β, 2X3H, 2XOλc), 2.34 (β, 3H, COCH3), 2.58 (dd, IH, J«20.1Hz and 11.6Hz, CHaCHO), 3.08 (dd, IH, J«20.0Hz and 4.2Hz, CHeCHO), 4.16 (d, IH, J«4.5Hz, H-2'), 4.48 (dd, IH, J=11.6Hz and 4.1Hz, H-3), 4.76 (q, IH, J-5.9HZ, H-5'), 5.20 (unresolved dd, IH, H-3'), 5.25 (broad a, IH, H- 4'), 5.72 (la, IH, H-l'), 6.17 (lβ, IH, H-l), 7.78 and 8.12 (2m, 2X2H, Ar-H). IR (film) Vjnajj: 2937, 1750, 1672, 1243, 964.cm'1.
Example 63: C-2'-axialy iodinated daunosaminyl pyranylnaphtho iinone glycosides
202
SUBSTITUTESHEET
BCH-M23 BCH-2i22
Step 1: 2* ,3',6'-trideoxy-2'-iodo-3•-trifluoroacetamido- •-o-acetyl- L-lyxohexopyranoβe
Following the procedure described in βtep 1, example 61, we obtained after work-up 94% yield of a non-aeparable 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, Oλc-4), 4.47 (m, IH, H-3), 4.53 (d, IH, J-4.3Hz, H-2), 4.56 (broad q, IH, J=5.2Hz, H-5), 5.17 (broad s, IH, H-4), 5.65 (d, IH, J=3.8Hz, H-l), 6.04 (d, IH, J-3.8HZ, OH).
Step 2: (1'S,1R,3S) and (l'S,lS,3R)-2,5-Dimethoxy-3-aceto-l- (2',3' ,6•-trideoxy-2'-iodo-3'-trifluoroacetamido-4'-O- acetyl-L-lyxohexopyranoae)-iaochrcHaan
203
SUBSTITUTESHEET Following the same procedure as described in βtep 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 diaβtβreoiβomerβ (1:1).
The natural (1'S,1R,3S) glycoβide: PMR (acetone-d6, 250 MHz) δ: 1.16 (d, 3H, J=6.6Hz, CH3-6'), 2.15 (s, 3H, λcO-4'), 2.30 (β, 3H, COCH3), 2.41 (unresolved dd, IH, CHaCHCO), 2.97 (dd, IH, J«17.7Hz and 3.89Hz, CHeCHO), 3.80 and 3.84 (2xβ, 2x3H, 2xOCH3), 4.36 (m, IH, H-3'), 4.63 (m, 3H, H-3, H-2' and H-5'), 5.19 (broad a, IH, H-4'), 5.90 (β, IH, H-l'), 6.06 (a, IH, H-l), 6.87 (2xd, 2H, λr-H), 7.95 (broad β, IH, NHCOCF3). The non-natural glycoside (1'S,1S,3R): PMR (acetone-dς, 250 MHz) δ: 1.23 (a, 3H, J-6.5HZ, CH3-6'), 2.16 (β, 3H, λcO-4'), 2.30 (β, 3H, COCH3), 2.51 (dd, IH, J-18.2HZ and 12.0Hz, CHaCHO), 2.97 (dd, IH, J=17.8Hz and 4.3Hz, CHeCHθ), 3.80 and 3.83 (2Xs, 2X3H, 2XOCH3), 4.30 (m, IH, H-3'), 4.69 (d, IH, J«4.72Hz, H-2'), 4.74 (dd, IH, J=12.1Hz and 4.3Hz, H-3), 4.88 (q, IH, J-5.0HZ, H-5'), 5.24 (broad a, IH, H-4'), 5.92 (s, IH, H-l'), 6.18 (β, IH, H-l), 6.90 (2Xd, 2X1H, λr-H), 7.95 (broad a, IH, NHCOCF3).
Step 3: (l'S,lR,3S)-5,8-Dimethoxy-3-aceto-l-(2',3' ,6'-trideoxy-3'- trifluoroacetamido-2'-iodo-L-lyxohexopyranoae)-iaochroman
Baae hydrolyaia of the compound from atep 2 herein aa per procedure from atep 3, example 61, yielded the titled compound. PMR (acetone-dg, 250 MHz) δ: 1.28 (d, 3H, J«6.6Hz, CH3-6'), 2.30 (a, 3H, COCH3), 2.45 (dd, IH, J-17.6Hz and 12.2Hz, CHaCHO), 2.95 (dd, IH, 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, IH, J-6.4HZ, H-5'), 4.58 (m, 2H, H-3 and H-2'), 5.89 (β, IH, H-l'), 6.04 (β, IH, H-l), 6.89 (2d, 2XH, λr-H), 7.65 (broad 8, IH, NHCOCF3).
IR (film) Vmaχ: 3539 and 3414, 2941 and 2844, 1728, 1488, 1260, 1175, 970 cm'1.
Step 4: (l'S,lR,3S)-3-acβto-l-(2',3* ,6'-trideoxy -2'-iodo-3•- trifluoroacetaiaido-L-lyxohaxopyranoae)-5,8-dioxo-5,8- dihydroiaochroaum
204
SUBSTITUTE SHEET CAN oxidation of the product from atep 3 herein yielded the titled product.
PMR (CDCI3, 250 MHz) δ: 1.32 (d, 3H, J«6.6Hz, CH3-6'), 2.06 (broad d, IH, OH-4'), 2.32 (β, 3H, COCH3), 2.41 (dd, IH, J«20.4Hz and 11.7Hz, CHaCHO), 2.93 (dd, IH, J-19.6 and 3.9Hz, CHeCHO), 3.75 (broad d, IH, H- 4'), 3.96 (m, IH, H-3'), 4.28 (q, IH, J-6.7HZ, H-5'), 4.42 (m, 2H, H-3 and H-2'), 5.82 (8, IH, H-l'), 5.90 (β, IH, H-l), 6.82 (2xd, 2H, Ar-H), 7.06 (broad d, IH, NHCOCF3).
IR (film) Vnax'. 3541 and 3417, 2992 and 2944, 1729, 1664, 1174, 967 cm' 1.
Step 5: (l'S,lR,3S)-methyl-(l-[2',3',6'-trideoxy-2'-iodo-3'- trifluoroacetamido-4'-hydroxy-L-lyxohβxopyranoae]-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2023)
The titled compound waa obtained aa per procedure described in step 2, example 5, but using the product from atep 4 herein. Purification waβ effected by flaah chromatography (Toluene:Ethyl acetate; 8:2). PMR (CDCI3, 250 MHz) δ: 1.34 (d, 3H, J-6.6HZ, CH3-6'), 2.35 (β, 3H, COCH3), 2.53 (dd, IH, J«19.6Hz and 11.5Hz, CHaCHO), 3.11 (dd, IH, J=19.6Hz and 4.1Hz, CHeCHO), 3.76 (broad β, IH, H-4'), 3.97 (m, IH, H- 3'), 4.30 (q, IH, J-6.6HZ, H-5'), 4.49 (dd+d, 2H, H-3 and H-2'), 6.00 (Is, 2H, H-l and H-l'), 7.01 (broad d, IH, 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: (l'S,18,3R)-5,8-dimothoxy-3-acato-l-(2',3',6'-trideoxy-3'- trifluoroacetamido-2'-iodo-L-lyxohexopyranoae) iaochroman
To a mixture of (1'S,1S,3R) glycoaide from atep 2 herein (103 mg, 0.16 mmol) in 15 ml of anhydrous methanol was added, at 0°C and under argon atmoaphere, 2 dropβ of NaOCH3, 4.37M (cat.). After stirring for 45 minutes, the reaction waa worked up by adding 10 ml of a mixture NH4CI aat.:NaHC0 sat. (8:3) and extracted with CH2C12 (2x30 ml). The combined organic layers were waahed with the aame aqueous mixture (30 ml) and dried (MgS04). Flaah chromatography (Toluene:Ethyl acetate; 9:1) gave 70 mg of pure titled glycoβide (73% yield).
205
SUBSTITUTE SHEET PMR (acetone-d6, 250 MHz) δ: 1.38 (d, 3H, J=6.5Hz, CH3-6<), 2.30 (s, 3H, COCH3), 2.50 (dd, IH, 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, IH, J-4.8HZ, H-2'), 4.74 (m, 2H, H-3 and H-5'), 5.92 (Is, IH, H-l'), 6.18 (Is, IH, H-l), 6.88 (2Xd, 2H, Ar-H), 7.65 (broad s, IH, NHCOCF3).
IR (film) V^jj: 3530, 3410, 2942 and 2837, 1723 broad, 1491, 1263, 1175, 958 cm'1.
Step 7: (l'S,18,3R)-3-acβto-l-(2' ,3' ,6'-trideoxy-2'-iodo-3'- tri luoroacβtamido-L-lyxohβxopyranosβ)-5,8-dioxo-5,8- dihydroiaochroman
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, IH, OH-4'), 2.32 (la, 3H, COCH3), 2.46 (dd, IH, J«19.6Hz and 11.7Hz, CHaCHO), 2.92 (dd, IH, J«19.9Hz and 4.2Hz), 3.78 (broad d, IH, H-4'), 3.91 (m, IH, H-3'), 4.37 (d, H, J«4.8Hz, H-2'), 4.43 (dd, IH, J=11.7Hz and 4.1Hz, H-3), 4.64 (q, IH, J-6.3HZ, H-5'), 5.84 (β, IH, H-l'), 5.97 (β, IH, H-l), 6.82 (2xd, 2H, λr-H), 7.06 (broad d, IH, NHCOCF3). IR (film) V,^: 3531 and 3406, 2929, 1726, 1663, 1181 broad, 960 cm'1.
Step 81 (1'S,IS,3R)-mβthyl-(l-[2',3',6'-trideoxy-2'-iodo-3•- trifluoroacetamido-4'-hydroxy-L-lyxohexopyranoae}-5,10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2022)
The titled compound waa obtained aa per procedure described in step 2, example 5, but uaing the product from atep 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,
IH, OH-4'), 2.34 (a, 3H, COCH3), 2.58 (dd, IH, J=19.4Hz and 11.6Hz,
CHaCHO), 3.10 (dd, IH, J=19.8Hz and 4.1Hz, CHeCHO), 3.82 (broad d, IH, H-4'), 3.92 (dd, IH, J=11.6Hz and 4.1Hz, H-3), 4.79 (q, IH, J=6.5Hz, H-
5'), 5.88 (s, IH, H-l'), 6.14 (s, IH, H-l), 7.07 (broad d, IH, NHCOCF3),
7.78 and 8.11 (2Xm, 2X2H, λr-H).
IR (film) Vmax: 3539 and 3414, 2946, 1731, 1666, 1293, 1174, 961 cm'1.
206
SUBSTITUTESHEET Example 64:
o δ o o
AcO--- ~~l AcO—* ~~f (|i J.i.nii)
OAc I OAc I "•■' * '
BCH-M65
Step 1 : 2 ' , 6 ' -didβoxy-3 ' , 4 ' -diacetoxy-2 ' -iodo-L-arabinohexopyranoae
Following the procedure deβcribed in atep 1, example 61, we obtained after work-up a quantitative yield of the deβired compound which waa used in the next βtep without purification: PMR (Benzβnβ-d6, 250 MHz) δ: 1.17 (d, 3H, J*6.2Hz, CH3-6), 4.04 (m, IH, H-5), 4.48 (d, IH, J*4.2Hz, H-2), 4.84 (dd, IH, J-9.5HZ and 4.2Hz, H-3), 5.01 (large s, IH, H-l), 5.51 (dd, IH, J=9.7Hz, H-4).
Step 2: (1'S,1S,3R) and (l'S,lR,3S)-5,8-Dimethoxy-3-aceto-l-(2' ,6'- dideoxy-3 ' , 4 ' -diacetoxy-2 ' -iodo-L-arabinohexopyranoae ) isochroman
207
SUBSTITUTE SHEET Following the same procedure as deβcribed in βtep 2, example 61, we obtained after flash chromatography (Toluene:Ethyl acetate; 9:1) a mixture of the titled atereoiaomers (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 (4β, 4X3H, 4X0λc), 1.95 and 2.12 (2a, 2X3H, 2XOCH3), 2.76 (m, 2XH, 2XCHaCH0), 3.20 ( , 2H, 2XCHβCHO), 2.30, 2.31 and 2.32 (3s, 4X3H, 4XOCH3), 4.18 (m, IH, 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, IH, H-l), 6.33 (m, 5H, 2X2 λr-H and H-l).
Step 3: (1'S,1R,3S) and (l'S,18,3R)-3-acato-l-(2' ,6•-dideoxy-2'- iodo-Xi-arabinohexopyranoae)-5,8-dioxo-5,8-dihydroiaochroa_an
The titled compounds were obtained following CAN oxidation of the productβ from step 2 herein as per previous procedures. PMR (CDC13, 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, 2XCHaCH0), 2.90 (dd, 2H, J-19.7HZ and 3.8Hz, 2XCHeCH0), 4.02 (m, IH, 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, 4Xλr-H) .
Step 4x (1'S,1R,1S) and (l'S,18,3R)-methyl-(l-[2' ,6•-dideoxy-3' ,4'- diacetoxy-2'-iodo-L-arabino-hexopyranose)-5,10-dioxo-
3,4,5,10-tβtrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH- 2065)
Following the reported procedure in atep 2, example 5, and atarting from the tvrø atereoiaomers from atep 3 herein, titled compoundβ (9%) were isolated after flaah 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, IH, J«19.5Hz and
11.7Hz, CHaCHO), 3.09 (dd, IH, J«19.8Hz and 4.2Hz, CHeCHO) , 4.46 (m, 4H, H-3, H-2', H-3' and H-5'), 5.21 (dd, IH, J-9.5HZ, H-4"), 5.67 (s, IH, H-
1'), 6.14 (s, IH, H-l), 7.78 and 8.13 (2m, 2X2H, λr-H).
IR (film) Vjuajj: 2941, 1750 and 1739, 1665, 1298, 1236 large, 971 cm"1.
Example 65: C-2' deoxyfucoaβ pyranylnaphthoquinone glycoaides
208 su r LrmJ I . i J TE SHEET
Step 1: (1'8,1S,3R) and (l'S,lR,3S)-5,8-dimethoxy-3-aceto-l-(2' ,6'- dideoxy-3',4'-diacβtoxy-L-lyxohβxopyranoae) iaochroman
The procedure described in step 2, example 61, waa applied to 5,8- dimethoxy-3-acetoisochroman and 3,4-diacetoxy-2,6-dideoxy fucoae. Flaah chromatography (dichloromethane:Hexane:Ethyl acetate; 6:3:1) gave a 50% yield of the two non-aeparable titled atereoiβomera 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, 4xOλc), 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, IH, 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 β, 2H, 2XH-1'), 5.97 and 6.16 (2s, 2H,H-1), 6.88 (m, 2X2H, 2Xλr- H).
Step 2: (1'S,1S,3R) and (l'S,lR,3S)-5,8-dimβthoxy-3-acβto-l-(2*,6'- dideoxy-L-lyxohexopyranoae) iaochroman
209
SUBSTITUTE SHEET The same procedure described in step 3, example 61, waβ applied to the products from βtep 1 herein. Flash chromatography of the crude (Toluene:Ethyl acetate; 6:4) gave 39% yield of non-aeparable titled diaβtereoisomerβ (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 (β, 2X3H, 2XCOCH3), 2.45 (unresolved dd, 2H, CHaCH0), 2.87 (dd, 2H, CHeCHO), 3.37 (8, IH, 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 (2β, 2H, 2XH-1), 6.83 (2X2d, 4H, λr-H).
Step 3: (1'S,1S,3R) and (l'S,lR,3S)-5,8-dioxo-3-acβto-l-(2' ,6'- dideoxy-L-lyxohexopyranoae)-5,8-dihydroisochroman
The titled producta were obtained following CAN oxidation of the producta from atep 2 herein.
PMR (CDC13, 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 (2β, 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, IH, H-5'), 4.36 (q, IH, J*6.8Hz, H-5'), 4.43 (2 overlapping, 2H, 2XH-3), 5.41 and 5.49 (2 broad β, 2H, 2XH-1'), 5.81 and 5.98 (2β, 2H, 2xH-l), 6.79 (2X2d, 4H, Ar-H).
Step 4: (1'8,18,3R) and (l'S,lR,3S)-methyl-(l-[dideoxy-2' ,6'- dihydroxy-3', '-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 uaing the products from atep 3 herein. Flaah 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 ( , 2H, 2XCHaCHO), 2.86 (2 overlapping dd, 2H, CHeCHO), 3.73 (m, 2H, 2XH-3'), 3.89 (q, IH, J=6.5Hz, H-5'), 4.28 (q, IH, J=6.3Hz, H-5'), 4.38 (broad s, IH, H-4'), 4.52 (2X unresolved dd, 2H, 2XH-3), 4.54 (broad s, IH, H-4'),
210
SUBSTITUTE SHEET 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, λr-H).
Step 5: (1'S,1S,3R) and (l'8,lR,3S)-5,8-dioxo-3-acβto-l-(2',6'- dideoxy-3' ,4'-diacetoxy-L-lyxohexopyranose) isochroman
The titled compounds were obtained following CλN oxidation of the producta obtained from atep 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,
4XOλc), 2.23 and 2.25 (2β, 2X3H, 2XCOCH3), 2.39 (2 overlapping dd, 2H, 2XCHaCHO), 2.80 (2 overlapping dd, 2H, 2XCHeCHO), 4.10 (q, IH, 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, λr-H).
Step 6: (l'S,18,3R) and (l'S,lR,3S)-methyl-(l-[dideoxy-2' ,6'- diacetoxy-3',4'-L-lyxohβxopyranoββ]-5,10-dioxo-3,4,5,10- tetrahydronaphtho-[2,3-c]-pyran-3-yl) ketone (BCH-2118)
The titled compoundβ were obtained in 51% yield by following the procedure deacribed in atep 2, example 5, and uaing the products from step 5 herein, λromatization by flaah chromatography (Toluene:Ethyl acetate; 8:2). Final purification by preparative TLC (aame aolvent conditions).
PMR (CDC13, 250 MHz) δ: 1.17 and 1.33 (2d, 2X3H, J-6.6HZ, 2XCH3-6'), 1.88 (m, 2H, 2XH-2'), 1.96 (β, 2X3H, 2XOAc), 2.16 (large m, 2H, 2XH-2'), 2.18 and 2.19 (2β, 2X3H, 2XOλc), 2.32 and 2.34 (2s, 2X3H, 2XCOCH3), 2.54 (2X overlapping dd, 2H, 2XCfiaCHO), 3.07 (2X overlapping dd, 2H, 2XCHeCHO), 4.17 (q, IH, J«6.7Hz, H-5'), 4.51 (2X aoverlapping dd, 2H, 2X H-3), 4.63 (q, IH, 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).
211
SUBSTITUTESHEET Example 66 : Phenolic pyranylnaphthoφii nono glycosides
+ Hydroxy C-10
+ Hydroxy C-10
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 uaing 1-acetoxybutadiene and 3-acetoiaochroman-5,8- dione.
PMR (CDC13, 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-l), 4.95 (m, 2H, H-l), 7.26 (m, 2H, λr-H), 7.62 (m, 2X2H, λr-H), 11.84 and 11.96 (2s, 2H, OH-5 and OH-8).
Step 2: (l'S,18,3R)-methyl-(6 and 9-hydroxy-l-(2* ,3' ,6'-trideoxy-3'- trifluoroacetaaido- '-O-p-nitrobensoyl-L-lyxohexopyranose)- 5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]-pyran-3- yl) ketone
212 su B^ i i i . li ϋ Ϊ i 1 - 1. * ■ *- •*■ ■ To a mixture of (1'S,1S,3R) glycoaide from step 1, example 5, (200 mg, 0.335 mmol) in dry toluene (2.5 ml) under argon atmoaphere, waa added dropwiae the l-trimethylailyloxy-l,3-butadiene. λfter stirring for 18 hourβ at room temperature, the solvent waβ removed in vacuo. The reaidue waa dried over vacuum for 10 minutes, dissolved in 5 ml of THF and cooled to 0C. λddition of HCl IN (5 ml) gave after 30 minutes stirring a complete cleavage of the ailyl group. Extractions were done with CH2C1 (3x30 ml) and the combined organic layera were dried with Na2S04 and then evaporated. The reaidue waa diββolved with 10 ml of dry CH2C12, at room temperature and under argon, and treated with 200 mg of PCC. λfter 30 minutea atirring, the reaction mixture was dropped on Si02 and flaah chromatographed (Toluene:Ethyl acetate; 8:2) to give 162 mg (72% yield) of a non-aeparable titled regioiaomerβ (1:1). PMR (CDC13, 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 unreβolved dd, 2X1H, H-3), 4.61 (2Xm, 2X1H, H-3'), 4.77 (2X unreaolved q, 2X1H, H-5'), 5.45 (broad β, 2X1H, H-4'), 5.63 (broad a, 2XH, H-l'), 6.19 and 6.21 (2B, 2H, H-l), 6.46 (broad a, 2H, NHCOCF3), 7.32 (m, 2H, λr-H), 7.67 (m, 2X2H, λr-H), 8.32 (m, 2X2H, λr- H), 11.89 and 11.90 (2a, 2H, OH-5 and OH-8).
Step 3: (l'S,lS,3R)-mβthyl-(6 and 9-hydroxy-l-[2',3' ,6'-trideoxy-3'- trifluoroacetamido- '-hydroxy-L-lyxohexopyranoae]-5(10- dioxo-3,4,5,10-tetrahydronaphtho-[2,3-c]-pyran-3-y1-kβtonβ (BCH-2078)
Hydrolyaia of the glycosides from atep 2 herein with catalytic aodium 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 regioiaomera 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-l'), 6.13 and 6.15 (2S, 2H, H-l), 6.74 (broad d, 2H, NHCOCF3), 7.30 (m, 2H, λr-H), 7.65 (m, 2X2H, λr-H), 11.89 and 11.91 (2β, 2H, OH-5 and OH-8).
213
SU BS'i i 1 . Example 67: 3-(3'-aminothiasolyl)-5,10-dioxo-1,3,4,5,10- ρantahydro-naphtho-[2,3-c]-pyran (BCH)
Step 1: 3-aceto-5,8-dioxo-3,4,5,8-tetrahydro-lH-benso-[2,3-c]-pyran
CAN oxidation of 5,8-Dimethoxy-3-acetoiβochroman yielded the titled compound. αH NMR (CDC13, 250 MHz, Bruker) δ: 2.23 (3H, β, COCH3), 2.36 (IH, dd tr, J=17.8Hz, ll.OHz, 2.9Hz, 4-HCHa), 2.75 (IH, d tr, J-17.8HZ, 2.9Hz, 4- HCHβ), 3.96 (IH, dd, J«llHz, 5.3Hz, 3-CH), 4.41 (IH, d tr, J=17.8Hz, 3.5Hz, l-HCHa), 4.72 (IH, d tr, J=17.5Hz, 1Hz, l-HCHβ), 6.71 (2H, m, λrH).
Step 2: 3-aceto-5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho-[2,3-c]- pyran
The titled compound waa obtained by following the procedure described in step 2, example 5, and using the product from βtep 1 herein. XH NMR: (CDCI3, 250 MHz, Bruker) δ: 2.30 (3H, s, COCH3), 2.56 (IH, dd tr, J=18Hz, 11.2Hz, 2.9Hz, 4-HCHa), 3.01 (IH, d, J*18.0Hz, 4-HCHe), 4.05 (IH, dd, J=11.2Hz, 3.8Hz, 3-CH), 4.60 (IH, d tr, J=17.8Hz, 4.1Hz, 1- HCHa), 4.95 (IH, d m, J=17.8Hz, l-HCHe), 7.73 (2H, m, 7, 8-λrH), 8.08 (2H, m, ArH).
214
SUBSTi £ . mJ .1_*- I Step 3: 3-bromoacβtyl-5,10-dioxo-3,4,5,10-tetrahydro-lH-naphtho- [2,3-c]-pyran
The titled compound waa obtained by following the procedure described in step 1, example 7, and uaing the product from atep 2 herein. NMR (CDC13, 250 MHz, Bruker) δ: 2.57 (IH, dd tr, J«18.8Hz, 11.2Hz, 3Hz, 4-HCHa), 3.02 (IH, d m, J-lβ.βHz, 4-HCHβ), 4.21 (IH, d, J«=12.9Hz, CHBr), 4.30 (IH, d, J«12.9Hz, CHBr), 4.34 (IH, dd, J-11.2HZ, 4.7Hz, 3- CH), 4.58 (IH, d tr, J-lβ.OHz, 3.0Hz, l-HCHa), 4.90 (IH, d m, J«18.0Hz, 1-HCHe), 7.70 (2H, m, 7, 8-λrH), 8.04 (2H> m, 6, 9-λrH).
Step 4: 3-(3'-ami_nothiasolyl)-5,10-dioxo-l,3,4,5,10-pentahydro- naphtho-[2,3-c]-pyran
Bromomethyl ketone from atep 3 herein (270 mg, 0.81 mmol) waa 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 βieves were used to take up water. Solvent waa evaporated to give a white aolid. The crude product waa waahed with chloroform/ether (8:1) firβt, then baaified with potaaβium carbonate. It waa extracted with chloroform. The organic phase was evaporated to give a crude product which waa chromatographed to give desired titled product.
dec. 130°C.
XH NMR (CDC13, 250 MHz, Bruker) , 2.80 (IH, m, 4-HCHa) , 3.09 ( IH, br d, J = 18.2 Hz, 4-HCHβ) , 4.58 ( IH, dd, J * 10.0 Hz, 3.5 Hz, 3-CH) , 4.68 (IH, d tr, J - 18.8, 2.9 Hz, l-HCHa) , 4.95 (IH, dd, J ~~ 18.8 Hz, 2.3 Hz, l-HCHβ) , 5.54 ( IH, br 8, NH) , 6.54 ( IH, s, thia-H) , 7.73 ( IH, m, λrH) , 8.08 ( IH, m, λrH) .
215
5 f --_■■ r"~r "*- . i ---- --- tr t i r" "*"*
«__^ > I fi » ijl - k- i i Sm m Example 68 x Cyclic aauLne substituted napht hoφi i none derivative
step 1: M-BOC-iaonipecotic acid
The titled compound waa obtained following standard conditionβ.
1H NMR (CDC13): δ 4.02 (m, 2H, CH2N), 2.73 (m, 2H, CH2N), 2.50 (m, IH,
CHCOOH), 1.91 (m, 2H, £H2CHCOOH), 1.64 ( , 2H, £H2CHCOOH).
Step 2: -BOC-4-piperidineaethanol
To a aolution of the acid from atep 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 waa atirred at 0°C for 30 minutes and at room temperature for 15 hours. Methanol (10 ml) waβ then carefully
216
SUBSTITUTE SHEET added to destroy the excess BH3 and the solvents were evaporated. The reaidue waa poured in CH Cl2/aat. aq. NaHC03 and the phases were separated. The aqueous layer waβ extracted with CH2C12 (2x) and the combined organic extracts were dried over MgSθ4« The solids were filtered and the aolvent evaporated to give the titled alcohol aa a clear oil (0.092 g, 89%).
2H NMR (CDC13): δ 4.09 (m, 2H, CH2N), 3.44 (d, 2H, £H20H), 2.67 (m, 2H, CH2N), 2.08 (bs, IH, OH), 1.73-1.52 (m, 2H, £H2-CH2N), 1.48 (s, 9H, BOC), 1.22-1.01 (m, 2H, £H2-CH2N).
Step 3: l-O-[M-BOC-4-piperidinemethanol]-3-acetyl-5,8-dimethoxy isochroman racemic
The titled compound waa obtained via DDQ induced coupling of the alcohol from βtep 2 herein with 3-aceto-5,8-dimethoxy iaochroman. Purification: flaah chromatography (βilica gel, 2:1 Hex/EtOAc).
^■H NMR (CDC13): δ 6.76 (d, IH, J - 8.8, ArH), 6.70 (d, IH, J - 8.8, λrH), 5.77 (8, IH, H-l), 4.59 (dd, IH, J - 4.2, 12.2, H-3), 4.08 (m, 2H, CH2N), 3.78 (β, 3H, λrOMe), 3.77 (8, 3H, ArOMe), 3.72 (dd, IH, J - 6.4, 9.7, H-l'), 3.57 (dd, IH, J » 6.4, 9.7, H-l'), 3.04 (dd, IH, J « 4.2,
17.6, H-4), 2.70 (m, 2H, CH2N), 2.53 (dd, IH, J - 12.2, 17.6, H-4), 2.33 (8, 3H, COCH3), 1.76 (m, 3H, £H2£H-CH20), 1.21 (m, 2H, £H CHCH 0).
Step 4: Methyl-(l-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 waβ obtained from the precurβor from βtep 3 herein as per previously described procedure. NMR (DMSO): δ 8.05-7.80 (m, 4H, ArH), 5.69 (s, IH, H-l), 4.48 (m,
IH, H-3), 3.88 (m, 4H, CH N and NH2C1), 3.74 (m, IH, H-l'), 3.60 (m, IH, H-l'), 3.25 (m, IH, H-4+H20), 2.82 (m, 3H, CH2N and H-4), 2.31 (8, 3H, COCH3), 2.01-1.70 (m, 3H, £H2£H-CH20), 1.57-1.38 (m, 2H, £H2CHCH20) •
Example 69 Diajaino-βugar substituted naphthoquinone derivative
217
SUBSTITUTE SHEET */,1^ )H */ 0 xOSiXBΛfc2
HO **'
NHIFA NHIFA
NHIFA
+l,3-diepi_n__r
BCH-2104
+l,3-di_φiner
BCH-2102
Step 1: (2R,4S,5S,6S)-2-tert-butyldimethylailyloxy-4- trifluoroacetamido-5-hydrox-6-aMthyl-tetrahydropyran
To a aolution of the hemiacetal (0.51 g, 2.08 mmol) in dry CH2C12 (20 ml), under argon, at room temperature, were added successively imidazole (0.28 g, 2 eq) and t-BuMe SiCl (0.34 g, 1.1 eq). The aolution was stirred at room temperature for 15 houra after which it waa poured in sat. aq. NaHC03. The phaseβ were aeparated and the aqueoua layer was extracted with CH C12 (2x). The combined organic extracta were dried over MgS04, the aolidβ were filtered and the βolvent evaporated to give 0.72 g (97%) of the titled βilyloxy-sugar aβ a white βolid. H NMR (CDC13): δ 6.82 (bd, IH, NH), 4.78 (dd, IH, J = 2.2, 9.2, H-l), 4.09 (m, IH, H-3), 3.62 (q, IH, J * 6.6, H-5), 3.48 (d, IH, J = 2.6, H- 4), 2.44 (bs, IH, OH), 2.08 (dd, IH, J = 5.0, 13.0, H-2), 1.55 (ddd, IH, J - 9.2, 13.0, 13.0, H-2), 1.29 (d, 3H, J - 6.6, H-6), 0.89 (β, 9H, t- Bu), 0.12 (s, 3H, SiMe), 0.11 (s, 3H, SiMe).
218
SUBSTITUTE SHEET Step 2: (2R,4S,5R,6S)-2-tert-butyldimethylailyloxy-4- trifluoroacata_mido-5-azido-6-methyl-tetrahydropyran
To a aolution of the alcohol (0.40 g, 1.11 mmol) in dry CH2C1 (11.1 ml), under argon, at -30°C were added βuccessively pyridine (0.45 ml, 5 eq) and Tf20 (0.37 ml, 2 eq) and the aolution waa atirred at -10°C for 1 hour. It was then poured in aat. aq. NaHC03 and the phases were separated. The aqueoua layer waa extracted with CH2C12 (2x) and the combined organic extracts were dried over MgS04. The solids were filtered and the βolventa were evaporated to drynaaβ. The red oil obtained was dissolved in dry DMF (11.1 ml), under argon, at room temperature, and NaN3 (0.36 g, 5 eq) waa added. The suspension was βtirred for 5 hours after which it waa poured in EtOAc. This organic phase waa waahed with water (3x) and brine. It waβ then dried over MgS04, the aolida were filtered and the aolvent evaporated to give the titled azido-trifluoroacetamide aa a clear oil (0.27 g, 68%). H NMR (CDC13): δ 6.44 (bd, IH, J - 8.6, NH), 4.82 (dd, IH, J - 2.1, 8.8, H-l), 4.09 (ddd, IH, J - 4.7, 9.7, 12.8, H-3), 3.41 (dq, IH, J = 6.1, 9.2, H-5), 2.97 (dd, IH, J - 9.7, 9.7, H-4), 2.21 (ddd, IH, J *
2.1, 4.7, 12.8, H-2), 1.67 (ddd, IH, J * 8.8, 12.8, 12.8, H-2), 1.39 (d, 3H, J * 6.1, H-6), 0.89 (β, 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 βtep 2 waβ reduced as per standard contiditons. Purification: flash chromatography (silica gel, 85:15 Hexanes/EtOAc).
1H NMR (CDC13): δ 7.85 (bd, IH, J « 9.4, NH), 7.48 (bd, IH, J - 9.7, NH), 4.84 (d, IH, J - 7.8, H-l), 4.38 (m, IH, H-3), 3.96 (m, IH, H-4), 3.56 (dq, IH, J « 6.1, 9.6, H-5), 2.19 (m, IH, H-2), 1.78 (m, IH, H-2), 1.29 (d, 3H, J - 6.1, H-6), 0.89 (β, 9H, t-Bu), 0.12 (β, 3H, SiMe), 0.11 (s, 3H, SiMe).
Step 4: (1R,3S,1'S) and (lS,3R,l'S)-Methyl-(l-[2',3',4',6'- tetradeoxy-3' ,4'-biβ-trifluoroacβtamido-L- arabinohexopyranoae]-5,10-dioxo-3,4,5,10-
219
SUBSTITUTE SHEET tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone (BCH-2104 and BCH-2102)
To a aolution of the hydroxyquinone (72 mg, 0.33 mmole) and di- trifluoroacetamido augar from atep 3 herein (162 mg, 1.1 eq) in 6.5 mL of a 9:1 mixture of anhydrous CH2C1 /Acetone, under argon, at -30 °C, were added activated 4A M.S. (200 mg) and TMSOTf (94 mL) . The solution waa atirred at -30 °C for 4 hr and 5% NaHC03 (5mL) waa added. The biphaβic aolution waβ stirred for 15 min while the temperature was allowed to go back to r.t. It waβ then filtered through Celite and poured in water. The phaβeβ were aaparated and the aqueoua layer was extracted with CH2C12 (2x). The combined organic extracta were dried over MgS04, The aolida ware filtered and the aolvanta evaporated. The pale brown βolid obtained waa diaaolved in dry toluene (6.5 mL) and 1- acetoxybutadiene (0.19 mL, 5 eq) waa added. The aolution waβ stirred at r.t. , under argon for 15 hr. Silica gel waa added and air waβ bubbled through the aolution. Thia suspension waβ then placed on top of a βilica gel column and the column waβ eluted with hexaneβ (1 reaervoir). When the hexaneβ waβ all gone , it waa replaced with 2:1 hexanea/ethyl acetate and themixture of iaomerβ waβ collected. Thiβ mixture waβ further purified by chromatography (10% acetone/toluene) to give 58 mg (30%) of the titled aeparated iaomerβ. The faater running fraction had: 33 mg, m.p.: 180-195 °C dec. 2H NMR (Acetone-d6) : d 8.47 (d, IH, J- 9.1, NH), 8.36 (d, IH, J« 9.4, NH), 8.11-8.04 (m, 2H, λrH), 7.92-7.85 (m, 2H, λrH), 6.03 (β, IH, H- 1), 5.65 (s, IH, H-l'), 4.68 (dd, IH, J- 4.1, 11.6, H-3), 4.58-4.36 (m, 2H, H-3' and H-4'), 3.85 (q, IH, J- 10.1, H-5'), 3.02 (dd, IH, J- 4.1, 19.6, H-4), 2.51 (dd, IH, 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 alower running fraction had: 25 mg, m.p.: 143-153 dec. λH NMR (CDC13) : d 8.55 (d, IH, J- 9.2, NH), 8.46 (d, IH, J- 9.1, NH) , 8.13-8.07 (m, 2H, λrH), 7.95-7.88 (m, 2H, λrH), 6.17 (a, IH, H-l), 5.63 (t, IH, J» 2.5, H-l'), 4.71 (dd, IH, J« 4.3, 11.6, H-3), 4.61- 4.34 (m, 2H, H-3' and H-4'), 3.86 (q, IH, J* 10.2, H-5'), 2.99 (dd, IH, J- 4.3, 19.7, H-4), 2.58 (dd, IH, J- 11.6, 19.7, H-4), 2.32 (β, 3H, COMe), 2.28-2.13 (m, 2H, H-2'), 1.37 (d, 3H, J= 6.2, H-6').
Example 70: 4'-iododaunoaaatine substituted naphtoquinone derivative
220
'? !" " P £ I
+l,3-d_cρimer
+l,3-dieptπ_er . BCH-20 7
Step 1: (2S,4S,5S,6S)-2-(2,-methoxy-2'-propanoxy)-4-asido-5-bromo-6- awthyl-tatrahydropyran
To a aolution of the triflate (1.06 g, 2.80 mmol) in a 1:1 mixture of CH2C12/toluene (15 ml), under argon, at room temperature, waβ added nBu4NBr (1.34 g, 1.5 eq) and the aolution waa atirred for 3 hourβ. It waβ then poured in aat. aq. NaHC03 and the phaaeβ were aeparated. The aqueous layer waa extracted with CH2C1 (2x) and the combined organic extracts were dried over MgS04. The solids were filtered and the solvents evaporated to give a crude oil that waa purified by flaah chromatogrphy (βilica gel, 85:15 Hexaneβ/EtOλc) . The titled bromo-azide waa obtained in 66% yield (0.57 g).
1H NMR (CDC13 ) : δ 5.34 (d, IH, J = 3.4, H-l) , 4.27 (β, IH, H-4) , 4.02 (q, IH, J «= 6.2, H-5) , 3.96 (m, IH, H-3 ) , 3.20 ( s, 3H, OMe) , 2.23 (ddd, IH, J = 3.4, 12.5 , 12.5 , H-2 ) , 1.74 (dd, IH, J - 4.26, 12.5 , H-2 ) , 1.40
221
SUBSTITUT" tr ~ « -— ».-— (s, 3H, gemdi ethyl) , 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-mβthyl-tβtrahydropyran
To a aolution of the bromo-azide from atep 1 (0.57 g, 1.84 mmol) in dry CH2C12 (9.0 ml), under argon, at 0°C, was added alowly CF3COOH (7 μl, 0.05 eq) and the aolution waa βtirred 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 CH2C1 /DMF (9.2 ml). Imidazole (0.25 g, 2 eq) waβ then added followed by t-BuMe2SiCl (0.31 g, 1.1 eq) . The aolution waa βtirred at room temperature for 15 hourβ after which it waβ poured in eat. aq. NaHC03. The phaaeβ were βeparated, the aqueous layer waa extracted with CH2Cl2 (2x) and the combined organic extracts were dried over MgS04. The βolids were filtered and the solvent evaporated to give the titled TBDMS protected bromo-azide (0.30 g, 46%) aa a clear oil. αH NMR (CDC13): δ 4.80 (dd, IH, J = 2.5, 8.7, H-l), 4.15 (dd, IH, J = 1.2, 3.3, H-4), 3.57 (ddd, IH, J - 3.3, 4.4, 11.8, H-3), 3.44 (dq, IH, 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 (β, 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 aolution of the azide from step 2 herein (0.30 g, 0.84 mmol) in a 19:1 mixture of THF/H20 (8.4 ml) waβ added Ph3P (0.33 g, 1.5 eq) and the aolution was heated at 50°C for 3 houra. It waβ then poured in eat. aq. NaHC03 and the aqueoua phaae waa extracted with CH2C12 (3x) . The combined organic extractβ were dried over MgS04. The aolida were filtered and the βolvent evaporated to dryness to give a crude amine that waa diaaolved in dry CH2C12 (8.4 ml). To this solution, under argon, at -30°C, were added successively dry pyridine (0.14 ml, 2 eq) and TFλ20 (0.13 ml, 1.1 eq) . The βolution waβ βtirred for 90 minutes at -30°C and waβ then poured in eat. aq. NaHC0 . The phases were separated, the aqueous layer was extracted with CH2C12 (2x) and the combined organic extractβ were dried over MgS0 . The solids were
222
<r ~ ιr-»f filtered and the solvent waβ evaporated to give the titled crude bromo- trifluoroacetamide in 72% yield (0.26 g) .
2H NMR (CDCI3): δ 6.67 (bd, IH, J - 7.3, NH), 4.84 (dd, IH, J - 5.4, 6.5, H-l), 4.28-4.17 (m, 2H, H-3 and H-4), 3.58 (q, IH, J « 6.1, H-5), 1.89-1.83 (m, 2H, H-2), 1.32 (d, 3H, J - 6.1, H-6), 0.88 (β, 9H, t-Bu), 0.12 (s, 3H, SiMe), 0.10 (8, 3H, SiMe).
Step 4: (lR,3S,l'S)-Methyl-(l-[2,,3',4,,6'-tetradeoxy-3'- trifluoroacetamido-4'-broακ>-L-lyxohexopyranose]-5,10-dioxo- 3,4,5,10-tetrahydronaphthaleno-[2,3-c] pyran-3-yl) ketone
The titled compound waa obtained as per previous procedures from the sugar of atep 3 and the isochromandione. Purification: flaβh chromatography (silica gel, toluene/acetone 95:5). The two isomers are separable by chromatography. λE NMR (CDCI3): δ 8.15-8.07 (m, 2H, ArH), 7.81 -7.76 (m, 2H, ArH), 6.46 (bd, IH, J « 8.4, NH), 6.01 (a, IH, H-l), 5.62 (d, IH, J * 3.2, H-l'), 4.54 (dd, IH, J « 4.0, 11.7, H-3), 4.42 (m, IH, H-3'), 4.37 (β, IH, H- 4'), 4.11 (q, IH, J - 6.5, H-5'), 3.11 (dd, IH, J « 4.0, 19.7, H-4), 2.53 (dd, IH, J - 11.7, 19.7, H-4), 2.35 (β, 3H, COMe), 2.14 (td, IH, J - 3.2, 12.9, H-2'), 1.91 (dd, IH, J « 4.5, 12.9, H-2'), 1.32 (d, 3H, J ~~ 6.5, H-6').
The (IS,3R,1■S)-Methyl-(1-[2',3',4',6'-tetradeoxy-3■-trifluoroacetamido- 4*-bromo-L-lyxohexopyranoae]-5,10-dioxo-3,4,5,10-tetrahydronaphthaleno- [2,3-c] pyran-3-yl) ketone (BCH-2047) had: E NMR (CDC13): δ 8.15-8.08 (m, 2H, λrH), 7.82-7.74 (m, 2H, λrH), 6.50 (bd, IH, J - 8.5, NH), 6.18 (a, IH, H-l), 5.49 (d, IH, J - 3.4, H-l'), 4.58 (q, IH, J * 6.4, H-5'), 4.48 (dd, IH, J - 4.2, 11.6, H-3), 4.40 (β, IH, H-4'), 4.40 (m, IH, H-3'), 3.08 (dd, IH, J ■ 4.2, 19.7, H-4), 2.57 (dd, IH, J - 11.6, 19.7, H-4), 2.32 (β, 3H, COMe), 2.18 (td, IH, J = 3.4, 13.0, H-2'), 1.79 (dd, IH, J - 4.4, 13.0, H-2'), 1.49 (d, 3H, J = 6.4, H-6').
Example 71: Cyclic amine substituted naphthoquinone derivative
223
SUBSTi'TϋTΞ SHEET H
BCH-2061 BCH-2060
Step 1: N-BOC-3-piperidinemethanol
The titled compound obtained following protection with BOC had:
1H NMR (CDC13): δ 3.90-3.65 (m, 2H), 3.48 (d, 2H, CH2OH), 3.25-2.75 (m, 2H), 2.28 (be, IH, OH), 1.86-1.54 (m, 4H) , 1.25 (m, IH).
Step 2: l-O-[N-BOC-3-pipβridinβmethanol]-3-acetyl-5,8-dimethoxy iaochroman, mixture of isomers
The titled compound waa obtained from the precuraor of atep 1 herein and 5,8-d___methoxy-3-acβtoiβochroman aβ per procedure deβcribed earlier. Purification: flaah chromatography (ailica gel, 2:1 Hexanes/EtOAc). The isomers were not separable by flash chromatography.
XH NMR (CDC13): δ 6.75-6.65 (m, 2H, ArH), 5.74+5.73 (2s, IH, H-l), 4.60 (m, IH, H-3), 4.05-3.56 (m, 4H, H-l' and CH2N), 3.04 (dd, IH, H-4), 2.86-2.62 (m, 2H, CH2N), 2.53 (dd, IH, H-4), 2.33 (B, 3H, COCH3), 1.94- 1.79 (m, 2H), 1.68 (m, IH), 1.48 (s, 9H, BOC), 1.37-1.24 (m,2 H) .
224
Step 3x Methyl-(l-O-[M-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 waa obtained from the product from atep 2 herein, following previoualy described procedures. Purification: flaah chromatography (ailica gel, 2:1 Hexaneβ/EtOAc) . The isomers were not separable by flaah chromatography. λE NMR (CDC13): δ 8.12-8.03 (m, 2H, ArH), 7.78-7.67 (m, 2H, ArH), 6.72 (β, IH, H-l), 4.54 (m, IH, H-3), 4.10-3.55 (m, 4H, H-l' and CH2N), 3.04 (dd, IH, H-4), 2.90-2.60 (m, 2H, CH2N), 2.51 (dd, IH, H-4), 2.30 (a, 3H, COCH3), 1.97-1.72 (m, 2H), 1.61 (m, IH), 1.48 (β, 9H, BOC), 1.34-1.15 (m, 2H).
Step 4: Mβthyl-(l-O-[3-pipβridinemβthanol]-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 waa obtained from the tricyclic product from atep 3 herein following acidic hydrolysis. λE NMR (DMSO-d6): δ 8.23-7.84 (m, 4H, ArH), 5.68+5.67 (2s, IH, H-l), 4.48 (m, IH, H-3), 3.83-3.57 (m, 2H, H-l'), 3.29-3.15 (m, 2H, CH2N), 2.84 (dd, IH, H-4), 2.66 (m, 2H, CH2N), 2.43 (m, IH, H-4), 2.29 (β, 3H, COCH3), 1.74-1.72 (m, 4H), 1.25 (m, IH).
225
SUBSTITUTE SHEET

Claims

We claim: 1. A compound of the formula:
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:
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
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
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
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
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
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:
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 ,
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 wherein R5, R6, R7 and R8 are defined as above, oxidatively demethylating said compound with an oxidant to give a quinone compound of formula
2) and cycle-adding said quinone with a diene of formula
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
and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is -OH, to a saccharide of formula
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
II. a) coupling the isochroman (14) of reaction I,1, above, wherein R5 is H, with a saccharide of formula
wherein R9, R10, R11 and R12 are defined as in claim 1 to yield a bicyclic saccharide of formula
b) oxidatively demethylating the medioxy groups from formula (21) to yield a bicyclic quinone saccharide of formula
c) and cyclo-adding said chemical (19) with said diene (16) of reaction (I)(2) to yield the tricyclic saccharide
III. 1) coupling the quinone of formula 15,
of step (I) (1), wherein R5 is -OH, with a saccharide of the formula
of step (I) (2) to yield a bicyclic quinone sacharide of the formula
2) and cycloadding said quinone saccharide with the said diene of formula
to yield a tricyclic saccharide of formula
IV. a) selecting a precurser benzoate compound of formula
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; to yield a dimethoxyisochroman of formria,
b) oxidatively demethylating the methoxy groups from formula 14 to a bicyclic dioxoisochroman;
the resulting dioxoisochroman is cyclically coupled with the diene of formula
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
the resritant compound may optionally be converted to the hydroxyl form of formula and may be optionally coupled with a saccharide of formula 20 to yield the tricyclic saccharide of formula 12;
V. a dimethoxyisothiochroman of formula
may be optionally coupled with a saccharide of formula
1) to yield a dimethoxybicydic saccharide of formula
2) oxidatively demethylating the methoxy groups to yield a dioxobicyclic isochroman of formula
3) cycloadding said dioxobicyclic isothiochroman with a diene of formula 29
to yield a thiotricyclic saccharide of formula.
40. Process according to claim 39 comprising the further preliminaiy steps of a: a) reacting
or b)
c) to yield product:
d) and further reacting said product: with /
to yield:
41. A process, according to claim 39, for the preparation of a compound of formula, 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,
wherein R5, R6, R7 and R8 are defined as above; oxidatively demethylating said isochroman with an oxidant to give a quinone compound of formula,
2) and cyclo-adding said quinone with a diene of formula,
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,
and
3) optionally coupling said tricyclic heteronaphthoquinone at R5, wherein R5 is OH, to a saccharide of formula,
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,
42. A process according to claim 39 for the preparation of a compound of formula,
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
wherein R5 is H and R6, R7 and R8 are defined as above with a saccharide of formula,
wherein R9, R10, R11 and R12 are defined as above to yield a bicycbc saccharide of formula,
2) oxidatively demethylating the methoxy groups of formula (21) to yield a bicyclic quinone saccharide of formula,
3) cycle-adding said bicyclic quinone saccharide a diene of formula,
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
43. A process, according to claim 39, for the preparation of a compound of formula, 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,
wherein R5 is OH with a saccharide of formula,
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,
2) and cycbcally coupling said quinone saccharide with the diene of formula, wherein L is defined as above
to yield a tricyclic saccharide of formula,
44. A process according to claim 39, for the preparation of a compound of formula,
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,
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 firom the group consisting of O, S, and N to yield a dimethoxyisochroman of formula,
2) oxidatively demethylating the methoxy groups to yield a bicyclic dioxoisothiochroman; the resulting dioxoisothiochroman is cycbcally coupled with the diene of formula,
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,
the resultant compound may optionally be converted to the hydroxyl-form yielding a compound of formula,
the resultant compound may be optionally coupled with a saccharide of formula,
wherein R9, R10, R11 and R12 are defined as in claim 4, to yield a tricyclic saccharide of formula,
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,
and coupling it with a saccharide of formula,
2) to yield a dimethoxybicyclic saccharide of formula,
3) oxidatively demethylating the methoxy groups to yield a dioxobicyclic thioisochroman or formula,
4) cycloadding said dioxobicyclic isochroman with a diene of formula,
to yield a thiotncycbc saccharide of formula,
46. A process according to claim 39 which comprises a further preliminary step of
1) selecting a precurser compound of formula 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
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
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.
EP93924460A 1992-11-09 1993-11-05 Antineoplastic heteronaphthoquinones Withdrawn EP0659190A1 (en)

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