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

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