WO1995012588A1 - Heteronaphtoquinones antineoplasiques - Google Patents

Heteronaphtoquinones antineoplasiques Download PDF

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Publication number
WO1995012588A1
WO1995012588A1 PCT/CA1994/000210 CA9400210W WO9512588A1 WO 1995012588 A1 WO1995012588 A1 WO 1995012588A1 CA 9400210 W CA9400210 W CA 9400210W WO 9512588 A1 WO9512588 A1 WO 9512588A1
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group
alkyl
hydrogen
formula
acyl
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PCT/CA1994/000210
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English (en)
Inventor
Giorgio Attardo
Wuyi Wang
Tibor Breining
Tiechao Li
Yves St.-Denis
Jean-Louis Kraus
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Biochem Pharma Inc.
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Priority to AU66727/94A priority Critical patent/AU6672794A/en
Publication of WO1995012588A1 publication Critical patent/WO1995012588A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • This invention relates to heterocyclic naphthoquinone derivatives, to processes, and to intermediates for
  • Anthracycline antibiotics including doxorubicin and daunorubicin are important chemotherapeutic agents in the treatment of a broad spectrum of neoplastic conditions. While daunorubicin (1) is clinically used mainly against acute childhood and adult leukemias, doxorubicin (2), also known as adriamycin, has the widest spectrum of antitumor activity of all chemotherapeutic agents (Weiss, R.B.,
  • Tricyclic variants (3) of daunorubicin have been reported to possess antitumor activity (EPA 91202015.3)
  • R is COCH 3 or C-CH or C-C-Si(CH 3 ) 3
  • R 3 is H or COCF 3
  • nanaomycin A (4) and kalafungin (5) occur naturally and show potent antibacterial as well as antifungal activity (Moore, H.W. and Czerniak, R., Medicinal Research Reviews, 1(3), 249-280, 1981 and references therein).
  • Granaticin (6) has been reported to show antitumor activity (Chang, C.J., Floss, H.G., Soong, P.l and Chang, C.T., J. Antibiot., 28, 156, 1975). More recently
  • thiopyranoanthraquinone (7) and pyranoanthraquinone ( 8 ) were found to possess antitumor activity (PCT, CA9100208).
  • 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 at carbon 1 to an alkyl, oxygen functionality, 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 very active against certain doxorubicin-resistant tumor cells.
  • X 1 and X 2 are independently selected from the group
  • R 20 is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 1-16 acyl and C 1-16 alkylamine.
  • X 3 is selected from the group consisting of O, S, SO, SO2, and
  • R 21 is selected from the group consisting of hydroxyl, C 1-16 acyl, C 1-16 alkyl, C 1-16 aryl, C 1- 16 haloacyl, and hydrogen.
  • X 4 is selected from the group consisting of C-Q, nitrogen, and NO.
  • R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen; hydroxyl; C 1-16 alkyl; C 1-16 alkoxyl; C 3-8 cycloalkyl; tosyl; mesylate; triflate;
  • aminoalkylaminoalkylhalide of formula NH(CH 2 ) n NH(CH 2 ) m X 10 wherein n and m are independently 1 to 4 and X 10 is halogen;
  • alkenyl or C 2-8 alkynyl
  • R 24 is selected from the group consisting of hydrogen, C 1-16 alkyl, C 3-8 cycloalkyl, C 2-12 alkoxyalkyl, C 7-18 aralkyl, C 7- 18 araloxyalkyl, C 7-18 aryloxyalkyl and C 6-18 aryl.
  • Z is selected from the group consisting of hydrogen;
  • Z may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, trifluoroacyl, cyano, C 7-18 aralkyl, C 6-18 aryl, a naturally occurring amino acid, a group of the formula -CHR 26 R 27 , wherein R 26 and R 27 are independently selected from the group consisting of C 1-8 alkyl, hydrogen, C 1-8 acyl, C6- 1 8 aryl, C 7-18 aralkyl, PO(OR 28 ) 2 wherein R 28 is hydrogen or C 1-8 alkyl.
  • R 26 and R 27 may also be a group of the formula - (CH 2 ) n X 15 wherein n is 0 to 7 and X 15 is selected from the group consisting of hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
  • R 29 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
  • cycloalkyl C 1-8 acyl, trifluoroacyl, C 7- 18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
  • R 25 may also be amino which may be unsubstituted or mono- or di-substituted by hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, trifluoroacyl, cyano, C 7-18 aralkyl, C 6-18 aryl, or a naturally occurring amino acid.
  • R 25 may also be an amino substituted with a group of the formula -CHR 26 R 27 , wherein R 26 and R 27 are independently selected from the group consisting of C 1-8 alkyl, hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, PO(OR 28 ) 2 wherein R 28 is hydrogen or C 1-8 alkyl,
  • n 0 to 7 and X 15 is selected from the group consisting of hydrogen, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, pyrolone, a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
  • R 29 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl. amino, which may be unsubstituted or mono- or di-substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy.
  • X 15 can also be a group of the formula - NR 30 R 31 or NOR 30 R 31 wherein R 30 , and R 31 , are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 acyl, C 6-18 aryl, C 7-18 aralkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8
  • alkoxyalkyl C 1-8 acyloxyalkyl, C 6-12 araloxyalkyl, a naturally occurring amino acid, and a group of formula
  • n 1 to 6 and wherein R 34 is selected from the group consisting of hydrogen, hydroxyl, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkoxyalkyl, C 1-8 alkoxy, C 7- 18 aryloxyalkyl, C 7-18 araloxyalkyl, C 6-18 aryl, C 7-18 aralkyl,
  • Z can also be a 5 or 6 membered aromatic or non aromatic heterocycle containing one or more heteroatoms
  • R 35 is selected from the group consisting of hydrogen, oxygen, hydroxyl, acyl, C 1-4 alkyl and C 6-12 aryl,
  • heterocycle being optionally substituted with one or more halogens, C 6-18 arylsulfone, hydroxy, C 1-16 alkoxy, nitro, C 1-16 alkyl, C 1-16 hydroxyalkyl, and amino which may be unsubstituted or mono- or
  • C 1-8 alkyl C 3-8 cycloalkyl, acyl, trifluoroacyl, C 7-12 aralkyl, C 6-12 aryl, C 2-8 alkenyl, C 2-8 alkynyl and hydroxy;
  • halogen. and R 8 are independently selected from the group
  • R 40 and R 41 are independently selected from a group consisting of C 1-8 alkyl, C 1-4 acyl, C 3-8 cycloalkyl, hydrogen, C 2-8 carboalkoxy, C 2-8 alkene, C 2-8 alkyne, C 6-12 aryl, and
  • R 46 is selected from the group consisting of hydrogen, thiol, Ci-ig thioalkyl, C 1-16 alkyl, C 3-8 cycloalkyl, C 1-8
  • R 47 is selected from the group consisting of hydrogen, C 1-16 alkyl and C 3-8 cycloalkyl,
  • acosamine glucosamine
  • N-chloroethyl- nitrosoureidoglucosamine 2,6-dideoxyrhamnose
  • thioglucose thiodaunosamine
  • thiol C 1-12 thioalkyl
  • X 16 is selected from the group consisting of O, CH 2 , and
  • R 50 is from the group consisting of
  • R 48 and R 49 are independently selected from the group consisting of hydrogen, C 1-12 alkyl, C 6- 12 aryl, C 2-8 dihydroxyalkyl, C 2-8 alkene, C 2-8 alkyne, C 1-8 alkoxy, C 1-8 alkylamino, C 3-8
  • R 48 and R 49 may also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
  • R 5 and R 8 may also be mono or oligosaccharides of the
  • Y is selected from the group consisting of
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, halogen, hydroxy, acetoxy, C 1-16 alkoxy, C 1-16 alkyl, C 3-8 cycloalkyl, thiol, amino, trifluoroacetamido,
  • R 11 is selected from the group consisting of hydrogen, amino which may be unsubstituted or mono or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 acyl, t-butylacyl, C 1-8 alkoxy, t- butyloxycarbonyl, trifluoroacyl, C 7-12 aralkyl, C 6-12 aryl, and a naturally occurring or
  • n 0 to 5 and R 55 is selected from the group consisting of C 1-16 alkyl, C 1-16 acyl and C 7-18 aroyl,
  • R 12 is selected from the group consisting of hydrogen, hydroxyl or its tetrahydropyranyl ether (-OTHP), mesylate, tosylate, halogen, mono or
  • oligosaccharides C 1-8 alkoxy, amino, mono or dialkylated amino in which each alkyl contains 1 to 16 carbon atoms, trifluoroacetamido, C 1-16 alkoxy, C 3-8 cycloalkyl, C 2-8 haloalkylacetate,
  • R 5 and R 8 can also independently be a 5 or 6 membered
  • aromatic or non-aromatic ring optionally containing one or more heteroatoms, selected from the group consisting of O, S, N, SO, SO 2 , P, PO and NR 56 wherein R 56 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2- 8 alkenyl, C 2-8 alkynyl and hydroxy.
  • R 8 and X 12 can further form a 5 or 6 membered aromatic or nonaromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
  • R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl,
  • Preferred compounds of formula (12) are those wherein: X 1 and X 2 are independently selected from the group
  • X 3 is preferably selected from the group consisting of O; S;
  • X 4 is preferably selected from the group consisting of CQ;
  • R 1 , R 2 , R 3 , and Q are preferably independently selected from the group consisting of hydrogen; hydroxy; methoxy;
  • n and m are independently 1 to 3;
  • chloroalkylnitrosoureido of the formula NH(CO)N(NO) (CH 2 ) n CH 2 CI, wherein n is 0 to 4;
  • R 24 is selected from the group consisting of hydrogen, C 1-6 alkyl, and
  • Z is preferably selected from the group consisting of
  • R 62 and R 63 are independently selected form the group consisting of C 1- 4 alkyl, hydrogen, C 1-4 acyl,
  • X 21 is a hydrogen, C 1-4 acyl, hydroxyl
  • 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, C 1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C 1-4 alkyl, C 1-4 acyl, trifluoroacyl, and C 2-4 alkynyl.
  • X 21 can also be a group of the formula NR 64 R 65 wherein R 64 and R 65 are independently selected from hydrogen, C 1-4 alkyl, C 1-4
  • chloroalkyl C 1-4 hydroxyalkyl, and C 1-4 acyl.
  • aminopropanol diacetoxy acetal aminopropanol diacetoxy acetal, aminobutanol diacetoxy acetal, aminopentanol diacetoxy acetal, acyloxyalkyl, C 2-4 alkenyl, C 2-4 acetylyl, C 1-4 alkoxy, hydroxy, C 1-4 aceto, amino which may be unsubstituted or
  • heterocycle containing one or more heteroatoms selected from the group
  • heterocycle consisting of O and N, said heterocycle being optionally substituted with one or more fluorines, hydroxy, C 1-4 alkoxy, and amino which may be unsubstituted or mono- or di- substituted by a C 1-4 alkyl, C 1-4 acyl,
  • X 21 can also be a group of the
  • C 1-4 alkyl independently selected from hydrogen, C 1-4 alkyl, C 1-4 chloroalkyl, C 1-4 hydroxyalkyl, and C 1-4 acyl.
  • R 34 is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 hydroxyalkyl, straight or branched C 1-8 alkyl, and
  • amino which may be unsubstituted or mono- or di- substituted with C 1-8 alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl, aryl, and
  • heterocycle being optionally substituted with one or more halogen, hydroxy, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, amino which may be unsubstituted or mono- or disubstituted by C 1-4 alkyl, C 3-5 cycloalkyl, acyl, trifluoroacyl, aryl, and hydroxy.
  • R 8 are independently selected from the group
  • n 1 to 4 and R 40 and R 41 are independently selected from the group consisting of hydrogen, C 1-5 alkyl, C 1-4 acyl.
  • R 5 and R 8 also include acosamine; 2,6-dideoxyrhamnose; thiodaunosamine; C 1-5 thioalkyl; a naturally occurring amino acid or dipeptides thereof.
  • Other preferred R 5 and R 8 are a group of the formula -X 16 - CHR 48 R 49 wherein X 16 is selected from the group
  • R 50 is C 1-4 alkyl or C 2-4 acyl
  • R 48 and R 49 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 2-4 alkene, C 1-5 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
  • heterocycle being optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, and amino, which may be unsubstituted or mono-or di- substituted by C 1-4 alkyl, C 1-4 acyl and
  • Y is preferably selected from the group
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, amino, fluorine, chlorine, trifluoroacetamido and hydroxyl.
  • Preferred R 11 is selected from the group consisting of amino which may be unsubstituted or mono- or di- substituted with C 1-8 acetoxy alkyl, C 3-8 cycloalkyl, acyl, trifluoroacyl, aralkyl or aryl,
  • R 12 is selected from the group consisting of hydroxyl or its tetrahydropyranyl ether, halogen,
  • amicetose aculose, rednose, rhodinose, 2- deoxyfucose, daunosamine, trifluoroacetyl- daunosamine,
  • R 5 and R 8 can also preferably be independently selected from a 5 or 6 membered aromatic or non-aromatic ring
  • heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO and
  • R 56 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, trifluoroacyl, C 7-18 aralkyl, C 6-18 aryl, C 2- 8 alkenyl, C 2-8 alkynyl and hydroxy.
  • R 8 and Z, or R 8 and X 21 can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and NR 57 wherein R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl,
  • heterocycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, and trifluoroacyl.
  • More preferred compounds of formula (12) are those wherein:
  • X 1 and X 2 are independently selected from the group
  • X 3 is more preferably selected from the group consisting of
  • X 4 is more preferably selected from the group consisting of
  • R 1 , R 2 , R 3 , and Q are independently selected from the group consisting of hydrogen; hydroxy; methoxy; halogen; aminoethylaminoethanol;
  • Z is selected from the group consisting of hydrogen; fluorine; methoxy; cyano; C 1-4 hydroxime; C 6-10 hydrazone; C 1-4 alkyl; C 1-4 hydroxyalkyl; phenyl; C 1-4 dihydroxyalkyl;
  • X 15 can also be a 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally substituted with a fluorine, a hydroxy, C 1-3 alkoxy, and cyano.
  • R 34 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, amino,
  • R 5 and R 8 are independently selected from the group consisting of hydrogen; halogen; hydroxy; C 1-4 alkoxy; C 1-6 alkyl; C 2-4 alkene; methoxy; cyano; C 1-4 acetate; C 1-4 acetyl;
  • Y is more preferably oxygen, sulfur, or CH 2 .
  • R 9 and R 10 are independently selected from the group consisting of hydrogen, fluorine, chlorine, amino, trifluoroacetamido, iodine, and hydroxyl.
  • R 11 is selected from the group
  • R 55 is selected from the group consisting of C 1-4 alkyl, C 1-4 acyl or C 7-8 aroyl and wherein n is
  • R 12 is selected from the group
  • R 5 and R 8 independently a 5 or 6
  • R 56 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 acyl,
  • cycle being optionally substituted by C 1-4 alkyl, C 1-4 alkoxy, cyano, hydroxy, and
  • R 8 and Z, or R 8 and X 21 can further form a 5 or 6 membered aromatic or non aromatic ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N, SO, SO 2 , P, PO, and
  • R 57 is selected from the group consisting of hydrogen, hydroxyl, C 1-8 acyl, C 1-4 alkyl and C 6-12 aryl. said cycle being optionally substituted with one or more halogens, hydroxy, C 6-18 aryl sulfone, cyano, C 1-16 alkoxy, C 1-16 alkyl, nitro, C 1-16 hydroxyalkyl, and amino, which may be unsubstituted or mono-or di- substituted by C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 acyl, and trifluoroacyl.
  • Still further preferred compounds of formula (12) are those wherein:
  • X 1 and X 2 are both oxygen.
  • X 3 is O; S; or SO.
  • X 4 is CQ.
  • R 1 , R 2 , R 3 and Q are each independently selected from the group consisting of hydrogen; fluorine; hydroxyl; and methoxy.
  • n 0 to 2 and X 15 is a C 1-3 alkyl or a group of the formula - NR 30 R 31 wherein R 30 and R 31 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 acyl, and
  • X 15 can also be a 5 or 6 membered aromatic or non- aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O and N, said heterocycle being optionally
  • Z can be 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.
  • R 5 and R 8 are independently selected from the group consisting of hydrogen; hydroxyl; methoxy; C 1-4 alkyl; bromine; chlorine; cyano; acetate; acetyl; and a saccharide of the formula
  • Y is further preferably oxygen or CH 2 .
  • R 9 and R 10 are independently
  • R 11 is selected from the group
  • n 3 to 5 and R 55 is selected from the group consisting of methyl, acyl or benzoyl,
  • R 12 is hydroxyl, iodine, or bromine.
  • R 5 and R 8 independently selected from 5 or 6 membered aromatic or non-aromatic heterocycle containing one or two heteroatoms selected from the group consisting of O, and N, and
  • said cycle being optionally substituted by cyano, hydroxy, amino, or dimethylamino.
  • X 1 and X 2 are both oxygen.
  • X 3 is O or S.
  • X 4 is CQ.
  • R 2 and R 3 are both hydrogen.
  • R 1 and Q are independently selected from the group
  • Z is selected from the group consisting of ethyl
  • acyl of the formula -C(R 25 ) O wherein R 25 is selected from the group consisting of methyl, fluoromethyl,
  • R 5 is selected from the group consisting of hydrogen; hydroxyl; cyano; acetate; acetyl; methoxy;
  • R 9 and R 10 are independently
  • R 11 is preferably selected from the group consisting of hydroxyl, acetoxy, amino, dimethylamino, trifluoroacetamido, morpholino, cyano, substituted morpholino, methoxymorpholino.
  • R 12 is preferably selected from the group consisting of acetoxy, hydroxyl, hydrogen, and iodine.
  • the invention also seeks to provide a process for the preparation of a compound of formula 12,
  • X 3 is selected from the group consisting NR, O, or S; and R 1 , R 2 , R 3 , R 5 , R 8 , X 1 , X 2 , X 4 , and z are as defined above, selected from the group of processes consisting of:
  • L is a leaving group selected from the group
  • L is a leaving group selected from the group consisting of halogen, tosyl, benzoyl, p-nitrobenzoyl and -OR* or -SR* wherein R* is a C 1-8 alkyl, and wherein R 1 , R 2 , R 3 and X 4 are as defined above, to yield only compounds of formula 21:
  • the quinones at positions X 1 and X 2 of formula 21 may be converted to other moieties such as, for example, OH, S, NR 120 , where R 120 is hydrocarbon, and others.
  • moieties such as, for example, OH, S, NR 120 , where R 120 is hydrocarbon, and others.
  • the compound may further be optionally coupled with a saccharide of formula 50:
  • alkyl as employed herein includes both straight and branched chain radicals of up to 16 carbons, for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, as well as such groups including one or more halo substituent, such as F, CI, Br, I or CF 3 , one or more alkoxy sustituent, one or more hydroxy, a haloaryl substituent, one or more silyl group, one or more silyloxy group, a cycloalkyl substituent or an alkylcycloalkyl substituent.
  • halo substituent such as
  • cycloalkyl as used herein means a cycloalkyl group having 3 to 8 carbons, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl and
  • aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl substituted phenyl, naphtyl, substituted phenyl or substituted naphthyl, wherein the substituent on either the phenyl or naphthyl may be for example C 1-4 alkyl, halogen, C 1-4 alkoxy, hydroxy or nitro.
  • halogen as used herein means chlorine, bromine, fluorine or iodine.
  • aralkyl refers to alkyl groups as discussed above having an aryl substituent, such as benzyl, p-nitrobenzyl, phenethyl, diphenylmethyl, and
  • aroyl refers to a group of the formula -COAr wherein Ar denotes an "aryl” group as defined above.
  • alkoxy or “aralkoxy” as used herein includes any of the above alkyl or aralkyl groups linked to an oxygen atom.
  • alkoxyalkyl as used herein means any alkyl as discussed above linked to any alkoxy as discussed above, for example methoxymethyl.
  • aryloxyalkyl as used herein means any alkyl as discussed above linked to an aryl as discussed above by an oxygen atom, for example phenoxymethyl.
  • araloxyalkyl as used herein means any aralkyl as discussed above linked to an alkyl as discussed above by an oxygen atom, for example benzyloxymethyl.
  • acyloxyalkyl as used herein means a C 1-8 acyl group linked to an alkyl group as discussed above linked to an alkyl as discussed above by an oxygen atom, for example acetoxymethyl.
  • hydroxyalkyl as used herein means an alkyl group as discussed above bonded to a hydroxyl group as discussed above, for example, hydroxymethyl.
  • dimer as used herein means two compounds of formula 12 similar (homo-) or different (heterodimer) that are linked together by a common Z moiety, Z being as defined hereinabove. It will be appreciated by those skilled in the art that when reference is made to substituents, these substituents may be directly or indirectly linked to the tricyclic compound via a heteroatom or a carbon chain.
  • R 5 and R 8 may independently be -X 101 -X 102 wherein X 101 may be O, OCH 2 , or CH 2 , and X 102 may be selected from the group consisting of a 5 or 6 membered aromatic or non-aromatic ring.
  • This invention also includes all the possible dimers, epimers, salts, and isomers and mixtures thereof, including diastereoisomeric mixtures and racemic mixtures, resulting from the possible combination of R or S stereochemical centers, when pertinent, at C 1 , C 2 and C 3 as well as in all the other chiral centers.
  • This invention also comprises novel compounds which are prepared as intermediates or precursors of compounds of formulas (42) and (43). Such intermediate compounds are described hereinafter in connection with processes of preparing compounds of formulas (42) and (43).
  • Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in "Protective Groups in Organic Chemistry", Ed. J.F.W. McOmie (Plenum Press, 1973) or “Protective Groups in Organic Synthesis” by Theodora W. Greene (John Wiley and Sons, 1981, 1991).
  • suitable hydroxyl protecting groups include groups selected from alkyl (e.g. methyl, t-butyl or methoxymethyl), aralkyl (e.g. benzyl,
  • heterocyclic groups such as tetrahydropyranyl, acyl (e.g. acetyl or benzoyl), and silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • acyl e.g. acetyl or benzoyl
  • silyl groups such as trialkylsilyl (e.g. t-butyldimethylsilyl).
  • alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g. by hydrolysis under acidic or basic
  • Aralkyl groups such as triphenylmethyl may be similarly removed by solvolysis, e.g. by hydrolysis under acidic conditions.
  • Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups.
  • Heteronaphthoquinones of general formula (12) are prepared as illustrated in Scheme I.
  • new or known isochromans of formula (14) are oxidatively demethylated with an oxidant such as eerie ammonium nitrate or silver oxide in an adequate solvent mixture such as acetonitrile-water, to give key
  • heteronaphthoquinone of general formula (16) are air-oxidized in the presence of an inorganic base such as sodium hydroxide or an organic base such as triethylamine or 1,4-diaza-bicyclo-[2,2,2]-octane or a fluoride salt such as tetrabutylammonium fluoride to form a mixture of compounds of general formula 21 and 19.
  • an inorganic base such as sodium hydroxide or an organic base such as triethylamine or 1,4-diaza-bicyclo-[2,2,2]-octane or a fluoride salt such as tetrabutylammonium fluoride
  • compounds of general formula 19 can be deoxygenated to compounds of general formula 21 by using a reducing agent such as triphenylphosphine.
  • An alternative method of preparing compounds of general formula 12 is by route B designated through the sequence consisting of steps B1-B3.
  • the isochromans of formula 14 are first oxidized via an oxidative sequence consisting of an enolate addition to a selenylating agent such as
  • organometallic reagents to the aldehydes 30 or addition of metalated 31 to epoxides 32 as shown in step A or B.
  • step C position with a nucleophile such as an ester enolate 34, as seen in step C, can also lead to the formation of 35.
  • the ring closure step C can be effected using an aldehyde or its acetal form under the influence of a Lewis acid such as borontrifluoride etherate.
  • a Lewis acid such as borontrifluoride etherate.
  • Compounds of general formula 14 may be prepared through the process described in Scheme 2. However, when Z is a group consisting of electron-withdrawing functional group such as methylester group, the ring closure step (step C, scheme 2) does not proceed with certain R 5 substituents. In this case, reduction of the carboxylate group is required. After the ring cyclization, the carboxylate functionality can be re-installed by an oxidative reactive step.
  • compounds of formula 14 where R 5 is OCH 3 can serve as a precursor for other compounds of formula 14 where R 5 is not OCH 3 .
  • a compound of formula 14 where R 5 is an alkyl can be obtained through the steps involving a Lewis acid treatment of the compound of formula 14 where R 5 is OCH 3 in the presence
  • the diastereoisomers may be separated by conventional chromatography or fractional crystallization techniques.
  • the racemic mixture whose enantiomic excess can be determined by the technique such as HPLC using a chiral column or NMR experiments using a chiral shifting agent known in the art. It is therefore appreciated that each enantiomer of the mixture is included within the scope of the invention.
  • 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), “Tables of Resolving Agents", by S.H. Wilen and
  • the compounds of the formula (12) and (13) possess anti-cancer and anti-tumor activity. It is also believed that they are active against tumor cell lines for ex vivo treatments. While it is possible to administer one or more of the compounds of the invention as a raw chemical, it is preferred to administer the active ingredient(s) as a pharmaceutical composition.
  • the invention therefore provides
  • compositions primarily suitable for use as antitumor and anticancer agents comprising an effective amount of at least one compound of the invention or a pharmaceutically acceptable derivative thereof in
  • 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.
  • composition of this invention can be used in association with one or more of the therapeutic agents belonging to any of the following groups:
  • Hormones e.g. estrogens, androgens, tamoxifen,
  • nafoxidine nafoxidine, progesterone, glucocorticoids, mitotane, prolactin);
  • Cardioprotecting compounds such as ( ⁇ )-1,2- bis(3,5-dioxopiperazin-1-yl) propane, commonly
  • Drug-resistance reversal compounds such as P- glycoprotein inhibitors, for example Verapamil, cyclosporin-c, fujimycin;
  • Cytotoxic cells such as lymphokine activated killer - cells or T-cells
  • Other Immunostimulants 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
  • formulations may be conveniently presented in discrete dosage units and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the pharmaceutical composition forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the
  • the carrier can be a solvent or
  • dispersion medium containing, for example, water, ethanol.
  • polyol for example, chremophor-EL, Tween 80 1 , glycerol, dimethyl sulfoxide (DMSO), propylene glycol, and liquid polyethylene glycol, and the like suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • 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
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the preferred methods of preparation are vacuum drying and the freeze-drying
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, sachets or tablets each containing a predetermined
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
  • the expression "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except isofar as any conventional media or agent is incompatible with the active ingredient, its use in the present compositions is contemplated.
  • Supplementary active ingredients can be incorporated into the inventive compositions.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suited as unitary dosages for the animal subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification.
  • the dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condition and its severity; the particular form of the active ingredient, the potency of the active
  • a daily dose of from about 0.001 to about 100 mg/kg of body weight given singly or in divided doses of up to 5 times a day or by continuous infusion embraces the effective range for the treatment of most conditions for which the novel compounds are effective. For a 75 kg subject, this translates into between about .075 and about 7500 mg/day. If the dosage is divided for example, into three individual dosages, these will range from about .25 to about 2500 mg. of the active ingredient. The preferred range is from about 0.1 to about 50 mg/kg of body weight/day with about 0.2 to about 30 mg/kg of body weight/day being more preferred.
  • the principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.
  • a unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 1000 mg., with from about 1.0 to about 500 mg. being preferred.
  • the active ingredient is generally present in from about 0.1 to about 500 mg/ml of carrier.
  • 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
  • compositions at the effective therapeutic dosage 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 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 doxorubicin against P-170 mediated multidrug resistant cancers.
  • Preferred compounds of this invention are as follows:
  • BCH-2168 3-hydrochlorodimethylaminopropyl-(1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3-)-carboxamide.
  • BCH-2170 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
  • BCH-2171 N-morpholinopropyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide
  • BCH-2166 1-methoxy-3-(3-N-pyrrolidinonylpropylcarboxamide)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2129 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H-naphtho [2,3-C] pyran.
  • BCH-2157 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-carboxamide.
  • BCH-2160 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyranyl-3-methoxycarbonyl.
  • BCH-2161 3-carboxyl-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2186 trans-1-methoxy-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-4a,10a-epoxy-naphtho-[2,3-c]-pyran.
  • BCH-2824 1-methoxy-3-(3-bromopropylaminocarbonyl)5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2825 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2829 3-methoxycarbonyl-1-propyl-5,10-dioxo-5,10-dihydro-5a,10a-epoxy-naphtho-[2,3-c]-pyran.
  • BCH-2830 3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2831 1-methoxy-3-(3-methylthiopropylamino)carbonyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
  • BCH-2835 3-[2-(2-pyridinyl)ethlaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] hydrochloride.
  • BCH-2836 3-[2-(N-morpholino)ethylaminocarbonyl]-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
  • BCH-2837 3-(2-trimethylammoniumethylaminocarbonyl)-1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride.
  • BCH-2840 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2841 3-[(2-pyridinyl)methylaminocarbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2861 1-Methoxy-3-[(2-(N-pyrrolidinylethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH-2877 3-N-oxo-dimethylaminopropyl-(1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3)-carboxamide.
  • BCH-2878 1-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3-c]thiine-3-[N-(dimethylaminopropyl)carboxamide].
  • BCH-2880 N-Methyl-N, N'-bis ⁇ 1-methoxy-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran-3-carbonyl ⁇ -propyldiamine.
  • BCH2847 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methylamino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH2848 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH2849 1-methoxy-3-(3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • BCH2854 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran.
  • microculture tetrazolium assay was used to test in vi tro cytotoxicity. This assay is described in Plumb, J.A. et al., 1989 Cancer Research 49, 4435-4440, which is herein incorporated by reference. The cytotoxicity of compounds towards tumor cells is measured in vi tro using the assay.
  • This assay method is based upon the ability of live, but not dead cells to reduce the yellow water soluble dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to its water insoluble purple formazan product.
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • SKOV3 (Ovarian adenocarcinoma) - provided by Dr. V. Ling, Ontario Cancer Institute.
  • T47D Ductal carcinoma of breast
  • HTB-133 ATCC catalog # 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% CO 2 in air.
  • MEM minimal essential media
  • Sorensen's buffer 0.1M glycine/NaOH, pH 10.5,
  • Test compounds 20 mM in DMSO and diluted to a final concentration of 200 ⁇ M in culture medium before use.
  • doxorubicin is included as an inter-assay standard. This allows us to monitor the behaviour of the assay in general, and in particular, to check that the SKVLB line has maintained its resistant phenotype.
  • the plate layout is done in the following manner:
  • the assays are carried out in 96-well (8 well ⁇ 12 well) microtiter plates. Serial dilutions of the compound are tested along the length of the plate. A 1:3 serial dilution of compound in culture medium covers a concentration range from 100 uM to 1.7nM. Each concentration of compound is tested in quadruplet, allowing two compounds to be tested per plate. Wells containing no cells (blank) and cells with no test compound (control) are included on each plate. Cells are plated out in 100 ⁇ l of culture medium in the microtiter plates at a density of around 1,500 - 4,000 cells per well.
  • the plates are incubated overnight to allow the cells to become adherent after which the test compound is added (100 ⁇ l of appropriate dilution per well).
  • the cells are incubated with test compound at 37°C for 48h after which the compound is replaced with fresh medium. After a further 48h incubation at 37°C, 50 ⁇ l of MTT solution (2mg/ml) is added to each well.
  • the plates are incubated in the dark for 4h at 37°C after which the medium is removed.
  • the MTT formazan product is extracted from the cells by the addition of 200 ⁇ l DMSO followed by 50 ⁇ l of Sorensen's buffer.
  • the plates are shaken briefly and the absorbance at 570 nm is read using a Molecular Devices UV max plate reader. Curves are fit to the MTT assay data using a four parameter
  • Table 1 shows the antitumor activity of some of synthetic tricyclic pyranylnaphthoquinones of this invention. A range of potency is observed in this set of compounds. Most notably BCH-2051, a "sugarless" tricyclic naphthoquinone, possesses intense in vitro antitumor potency while
  • Methyl (5,8-dimethoxy-isochroman-3-yl) formate (15.00 g, 59.46 mmol) and DDQ (16.20 g, 71.35 mmol) were dissolved in dry dichloromethane (500 ml), and dry methanol (7.2 ml, 178.37 mmol) was added. The solution was stirred at ambient temperature overnight, then refluxed for 8 hours. Methanol (1.0 ml, 24.69 mmol) and DDQ (2.00 g, 8.81 mmol) was added and further refluxed for 8 hours. The reaction mixture was cooled down, filtered, and the filtrate was poured onto a saturated solution of sodium bicarbonate (200 ml).
  • Step 2 Methyl (1-Methoxy-5,8-dioxo-5,8-dihydro- isochroman-3-yl) formate
  • CAN 83.24 g, 151.84 mmol
  • sodium bicarbonate 8.50 g, 101.22 mmol
  • water 500 ml
  • methyl (1,5,8-trimethoxy-isochroman-3-yl) formate 14.34 g, 50.61 mmol
  • Step 3 Methyl (1-methoxy-5,10-dioxo-3,4,5,10-tetrahydro- 1H-naphtho[2,3-c]pyran-3-yl) formate
  • Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol)
  • 1-acetoxybutadiene (30.00 g, 267.55 mmol)
  • dry toluene 100 ml was stirred overnight at 50 C°.
  • the solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g).
  • Step 4 Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl) formate
  • Step 5 Methyl (1-methoxy-5,10-dioxo-5,10-dihydro-1H- naphtho[2,3-c]pyran-3-yl)formate.
  • Methyl (1-methoxy-5,8-dioxo-5,8-dihydro-isochroman-3-yl) formate (12.70 g, 50.35 mmol), 1-acetoxybutadiene (30.00 g, 267.55 mmol) and dry toluene (100 ml) was stirred overnight at 50 C°. The solvent was removed under reduced pressure, the residue was recrystallized from methanol to give yellow crystals (11.05 g). The product was dissolved in
  • Step 8 1-Methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho[2,3- c]pyran-3-[N-(3-dimethylamino-propyl)carboxamide] hydrochloride monohydrate BCH-2051
  • Example 3 1-methoxy-3-methoxy carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran.
  • 1 H NMR (CDCI 3 , 300 MHz, Bruker), ⁇ : 3.69 (3H, s, COOCH 3 ),
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2947, 2938, 2855, 1734, 1678, 1659, 1595, 1562, 1444, 1384, 1327, 1294, 1275, 1234, 1133, 1069, 1001, 957, 863, 799, 770, 718.
  • Step 1 3-Aceto-5,10-dioxo-1-methoxy-5,10-dihydro-1H- naphtho-(2,3-c)-pyran (BCH-2129) To a solution of 3-acetyl-5,10-dioxo-1-methoxy-3,4-5,10-tetrahydro-1H-naphtho (2, 3-c) pyran (50 mg, .175 mmole) in CH 3 CN (8 ml) and THF (4 ml) at 0°C was added 0.5N sodium hydroxide (1 equiv.). The mixture was stirred at 0°C for 15 minutes and it was allowed to come to room temperature.
  • Example 5 Using the same carboxylic acid as described in Example 2, 1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho-[2,3-c]-pyran-3- carboxamides were prepared
  • Step 1 1-methoxy-3-N-anilinylcarbonyl-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2044)
  • step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound
  • 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,
  • Step 2 1-methoxy-3-(3-N- pyrrolidinomylpropylaminocarbonyl)-5,10-dioxo- 5,10-dihydro-1H-naphtho-[2,3-c]-pyran (BCH-2166)
  • Step 4 (3-N-hydrochloroimidazolylpropyl)-1-methoxy-5,10- dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran-3- carboxamide (BCH-2157) 6 mg of product from step 3 herein was dissolved in 2 ml of ether. To this was added 6 ⁇ l of 1M HCl/ether solution (from Aldrich). The mixture was stirred, and then the solvent evaporated to give 6.7 mg of the HCl salt.
  • Step 5 1-methoxy-3-[2-(N-morpholino) ethyl amino
  • Step 6 1-methoxy-3-[2-(N-morpholine) ethyl amino
  • step 8 The title compound was prepared using similar steps as detailed in example 2, step 8. During the process, compound I was present in the amountof 33 mg, 0.081 mmol, HCl (0.25 ⁇ l in ether) in the amount of 0.4 ml, 0.103 mmol, and 30 mg, 0.068 mmol of the title compound was produced.
  • Step 7 1-methoxy-3-[2-(2-pyridinyl) ethyl amino
  • step 7 The title compound was prepared using a similar method as detailed in example 2, step 7. During the process, compound I was present in the amount of 20 mg, 0.070 mmol, oxalyl chloride was present in the amount of 9.2 ⁇ l, 0.105 mmol, THF in the amount of 4 ml, DMF in the amount of 1 ⁇ l, and 1- (2-aminoethyl)-pyrrolidine in the amount of 8.28 ⁇ l, 0.070 mmol.
  • Step 8 1-methoxy-3-[2-(2-pyridinyl) ethyl amino carbonyl]
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3324 (strong), 2926.1, 1677.6, 1651.0, 1522.6, 1274.3, 1083.6, 723.39.
  • Step 9 1-methoxy-3-[(2-pyridinyl) methyl amino carbonyl]-3-methoxy-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3360.1, 2934.7, 1675.5, 1655.5, 1595.5, 1518.4, 1292.9, 1270.0, 1084.4, 950.23, 861.04, 719.77.
  • Step 10 1-methoxy-3-[(2-pyridinyl) methyl amino
  • Step 11 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: See example 2, step 7.
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3356.7, 2960.5, 2935.8, 2797.8, 1676.5, 1651.7, 1520.8, 1276.7, 1097.4, 1083.4, 953.25, 863.58, 794.8, 722.19.
  • Step 12 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt
  • Step 12 1-methoxy-3-[2-(N-pyrrolidinyl) ethyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran hydrochloride salt
  • Step 13 1-methoxy-3-[(4-diethoxy) butyl amino carbonyl]- 5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
  • IR (Nicolet, 205FT, film on NaCl plate): cm -1 , 3337.8, 2967.7, 2932.3, 2877.2 ,1676.3, 1652.7, 1522.8, 1294.4, 1270.8, 1129.8, 1085.0, 952.02, 863.71, 798.63, 721.95.
  • Step 14 1-methoxy-3- (3-hydroxy) propyl amino carbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran Preparative details: see example 12.
  • IR (Nicolet, 205FT, film on NaCl plate): cm -1 , 3365.4, 2928.4, 1676.3, 1652.7, 1526.7, 1275.5, 1085.5, 950.95, 862.66, 795.81, 721.91.
  • EXAMPLE 6 Preparation of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho- [2,3-c]-pyran.
  • Step 1 (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8- dimethoxy-isochroman
  • step 1 500 mg, 1.773 mmol
  • allyl trimethyl silane 571 ⁇ l, 3.55 mmol
  • boron trifluoride etherate 436.12 ⁇ l, 3.55 mmol
  • the resulting liquid was stirred for 2 hours as it warmed to 20°C.
  • the crude product was diluted with dichloroform, washed with sodium bicarbonate (10%), 0.01 N hydrogen chloride and brine. The organic layer was dried and
  • step 1 The (1,3-trans)-1-allyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman described in step 1 (734 mg, 2.51 mmol) was dissolved in 40 ml of THF and subjected to hydrogenation conditions (1 at m, Pd/c-10%, 27 mg, 0.0251 mmol). After 2 hours at room temperature, the reaction mixture was
  • step 2 The 1-propyl-3-methoxy carbonyl-5,8-dimethoxy-isochroman isochroman described in step 2 (93 mg, 0.316 mmol) was dissolved in acetonitrile (8 ml) and then cooled to 0°C. A solution of ammonium cerium (IV) nitrate (519.7 mg, 0.948 mmol) in 2.0 ml of water buffered with sodium bicarbonate (53 mg, 0.632 mmol) was added dropwise. After 10 minutes the reaction mixture was poured to dichloromethane. The organic layer was washed with brine, dried and evaporated to give the titled compound (77 mg, 92%).
  • IV ammonium cerium
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2958.4, 2932.9, 2873.2, 1745.3, 1657.2, 1489.6, 1461.2, 1444.1, 1304.9, 1262.3, 1219.7, 1097.5, 1040.7, 840.8.
  • Step 4 1-propyl-3-methoxycarbonyl-3,4,5,10-tetrahydro- 5,10-dioxo-1H-naphtho-[2,3-c]-pyran.
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2959.3, 2931.1, 2877.2, 1751.1, 1663.8, 1594.6, 1461.2, 1440.7, 1330.4, 1291.9, 1284.2, 1225.2, 1179.0, 1179.0, 1104.5, 872.11, 790.4, 717.4.
  • Step 5 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10- dihydro-1H-naphtho-[2,3-c]-pyran.
  • Step 6 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H- naphtho-[2,3-c]-pyran.
  • 1-propyl-3-methoxycarbonyl-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran 63 mg, 0.201 mmol was dissolved in tetrahydrofuran (4 ml) and cooled to 0°C. A solution of sodium hydroxide (2.41 ml, 0.1 N, 0.241 mmol) was added dropwise.
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 3667-2500 (strong), 2864.6, 2927.4, 2869.6, 2634.0, 1732.9, 1712.3, 1670.9, 1654.4, 1592.4, 1567.6, 1394.0, 1332.0, 1298.9, 1265.9, 1227.6, 1071.1, 719.09.
  • step 7 this compound was prepared. During the preparation, 29 mg of 1-propyl-3-carboxyl-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran, 21.2 ⁇ l, 0.243 mm of oloxalyl chloride, and 12.5 ⁇ l, 0.99 mmol of 3-dimethyl amino propyl amine was used to produce 33.6 mg, 90% of the title compound.
  • This compound was prepared using similar steps as explained in example 2, step 8. During the process, 16 mg, 0.042 mmol of 1-propyl-3-(3-dimethyl amino propyl amino carbonyl)-5,10-dihydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran was used along with HCl in ether - 1 eq, to produce 15 mg of the title compound.
  • IR (Nicolet, 205 FT, film on NaCl) : cm -1 , 2958.9, 2926.0, 2978.4, 1736.2 1699. 6, 1644 .7, 1589. 8, 1432.4 , 1297.0, 1267.7, 1238.4, 1120.1, 764.48 , 711.07 , 632.30.
  • triphenylphosphine 308.4 mg, 1.176 mmol
  • Tricyclic carboxylic acid 25 mg, 0.084 mmol
  • CH 2 CI 2 2 ml
  • oxalyl chloride 0.1 ml of 2 M solution in CH 2 CI 2
  • Excess reagent was pumped off and the acid chloride in CH 2 CI 2 (2 ml) was treated with 1-(2-amino ethyl)-pyrrolidine (9 mg, 0.079 mmol) in CH 2 CI 2
  • Example 12 1-methoxy-3-(2-trimethyl ammonium ethyl amino carbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]- pyran chloride salt
  • Example 14 1-methoxy-3-(2-pyrrolidinoethylcarbonyl)-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c] pyran
  • step 7 the titled compound was prepared.
  • IR Nicolet 205 FT, film on NaCl plate
  • Example 16 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2937.0, 2771.1, 1676.7, 1648.2, 1595.6, 1565.9, 1300.8, 1108.7, 1054.6, 949.16, 839.44, 801.92, 722.25.
  • Example 17 1-methoxy-3-[N-(2-dimethyl amino) ethyl-N-methyl amino carbonyl]-5,10-dioxo-5,10-dihydro-1H-naphtho- [2,3-c]-pyran
  • IR (Nicolet, 205 FT, film on NaCl plate): cm -1 , 2942.4, 2768.2, 1677.5, 1643.2, 1597.5, 1571.8, 1297.7, 1109.3,
  • Example 18 1-Methoxy-3 [2- (N-pyrrolidinylethoxylcarbonyl)]-5,10-dioxo-5,10-dihydro-1H-naphtho-[2,3-c]-pyran
  • step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound.
  • IR Nicolet 205 FT, film on NaCl plate
  • cm -1 2959, 2932, 2863, 1733, 1677, 1659, 1594, 1565, 1497, 1461, 1393, 1337, 1287, 1267, 1236, 1139, 1069, 990, 860, 798, 769, 743, 720.
  • Step 1 Methyl-1-methoxy-5,10-dioxo-3,4,5,10- tetrahydro-1H-naphtho [2,3-c] thiine-3- carboxylate Methyl-1-methoxy-5,8-dioxo-5,8-dihydro-3-isothiocromane
  • Step 1 (1'S) Methyl (5,8-dimethoxy-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-1H-benzo[2,3-c]thiopyran-3- yl) ketone
  • 3-acetyl-5,8-dimetoxythioisochromane (2.52 g, 10.00 mmol)
  • 3,4-di-O-acetyl-2,6-dideoxy-L-lyxohexopyranose (sugar) (2.79 g, 12.00 mmol)
  • Step 2 (1'S) Methyl (5,8-dioxo-1-(2',3',4',6'- tetradeoxy-3',4'-diacetoxy-L- lyxohexopyranose)-5,8-dihydro-1H-benzo[2,3- c]thiopyran-3-yl) ketone
  • Step 3 ( 1 ' S ) Methyl ( 5, 10-dioxo-1- (2 ' , 3 ' , 4 ' , 6 ' - tetradeoxy-3 ' , 4 ' -diacetoxy-L- lyxohexopyranose-5,10-dihydro-1H-naphtho[2,3- c]thiopyran-3-yl) ketone
  • step 7 the carboxylic acid from step 6, example 2, was converted to the titled compound.
  • the title compound is a mixture of three isomers.
  • IR Nicolet 205 FT, film on NaCl plate
  • cm -1 3339, 2935, 2843, 1679, 1655, 1592, 1517, 1404, 1381, 1334, 1278, 1202, 1093, 954, 865, 796, 721.
  • step 7 example 2 the carboxylic acid from step 6, example 2, was converted to the titled compound.
  • the title compound is a mixture of four isomers.
  • 1 HNMR 300MHz, Bruker, CDCI 3 ) ⁇ : 1.92 (2H, m, -CH 2 -), 3.15
  • IR Nicolet 205 FT, film on NaCl plate
  • cm -1 3341, 2936, 2833, 1675, 1656, 1597, 1570, 1520, 1450, 1411, 1383, 1330, 1276, 1199, 1121, 1083, 1057, 987, 946, 915, 863, 794, 722.
  • N-Boc-propyldiamine was prepared according to a procedure described by W. S. Saari, J. E. Schwering, P. A. Lyle, S. J. Smith and E. L. Engelhardt, J. Med. Chem. 1990, 33, 97-101.
  • IR Nicolet 205 FT, film on NaCl plate
  • cm -1 3339, 2973, 2934, 1679, 1659, 1603, 1522, 1451, 1365, 1335, 1276, 1170, 1083, 950, 864, 796, 720.

Abstract

La présente invention concerne d'une part des dérivés tricycliques d'hétéronaphtoquinone à activité antinéoplasique et d'autre part les procédés de synthèse correspondants. Certains de ces composés antinéoplasiques comportent une fraction saccharide. Certains membres de ce groupe structurellement distinct font preuve d'une activité contre les cellules cancéreuses résistant à plusieurs médicaments.
PCT/CA1994/000210 1993-11-05 1994-05-06 Heteronaphtoquinones antineoplasiques WO1995012588A1 (fr)

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