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WO2003082865A1 - Composition médicinale antitumorale - Google Patents

Composition médicinale antitumorale Download PDF

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Publication number
WO2003082865A1
WO2003082865A1 PCT/JP2003/003881 JP0303881W WO03082865A1 WO 2003082865 A1 WO2003082865 A1 WO 2003082865A1 JP 0303881 W JP0303881 W JP 0303881W WO 03082865 A1 WO03082865 A1 WO 03082865A1
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Prior art keywords
group
substituted
substituent
groups
pharmaceutical composition
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PCT/JP2003/003881
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English (en)
Japanese (ja)
Inventor
Shinichi Kurakata
Naomi Shimazaki
Tomoyuki Shibata
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Sankyo Company, Limited
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Priority to AU2003220855A priority Critical patent/AU2003220855A1/en
Publication of WO2003082865A1 publication Critical patent/WO2003082865A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition, a cell growth inhibitor or an antitumor agent comprising, as active ingredients, a condensed heterocyclic compound having P PAR ⁇ activation ability and a fluorouracil-based antimetabolite or a platinum complex.
  • the present invention relates to a pharmaceutical composition containing a compound having PPARr activation activity and a fluorouracil-based antimetabolite or a platinum complex as active ingredients.
  • the compound having the ability to activate P PAR r which is one of the active ingredients of the pharmaceutical composition of the present invention, has the following general formula (I)
  • X represents a benzimidazole ring group (optionally substituted with 1 to 5 groups selected from a substituent group ⁇ 1);
  • Y 1 represents an oxygen atom or a sulfur atom
  • R is a hydrogen atom, a CI-6 alkyl group, a C1-6 alkoxy group, a halogen atom, a hydroxy group, a nitro group, an amino group (substituted by one or two groups selected from substituent group ⁇ 2; Or a C7-11 aralkyl group (which may be substituted with a group selected from the substituent group ⁇ 3).
  • n an integer of 1 to 5.
  • the “substituent group ⁇ 1” includes a ⁇ 116 alkyl group, a C 1 alkoxy group, a C7-11 aralkyloxy group, a halogen atom, a hydroxy group, a C 111 aliphatic acyloxy group, C 16 alkylthio group, halogenated C 16 alkyl group, nitro group, amino group (may be substituted with one or two groups selected from substituent group ⁇ 2), C 6- 10 aryl groups (1 to 5 groups may be substituted with a group selected from substituent group ⁇ 3) and C 7-11 aralkyl group (1 to 5 groups selected from substituent group ⁇ 3) A group of substituents consisting of
  • Substituent group 2 includes C 1-6 alkyl groups, C 7-11 aralkyl groups, C 6-10 aryl groups, C 11-11 aliphatic acyl groups, and C 7-11 aralkyl radicals.
  • a group of substituents consisting of a methyl group and a C7-11 aromatic acyl group,
  • Substituent group ⁇ 3 includes C 16 alkyl group, C 16 alkoxy group, halogen atom, hydroxy group, nitro group, C 6-10 aryl group, and halogenated C 1-6 alkyl group. And an amino group (one or two substituents may be substituted with a group selected from the substituent group ⁇ 2).
  • R 4 represents a phenyl group (substituted with 1 to 5 substituents selected from a substituent group / 31) or a pyridyl group (substituent group) 1 to 4 with a group selected from 31; May be replaced).
  • R 5 is a hydrogen atom, a halogen atom, hydroxy group, C 1-6 alkyl group, halogen of C 1-6 alkyl group, C 1 one 6 alkoxy group, C 1 one 6 Arukiruchio 'group, amino group (substituted Group] may be substituted with a group selected from 33), C 3-10 cycloalkyl group (may be substituted with 1 to 3 groups selected from a group selected from substituent group j32), C 6-10 aryl group (1 to 3 substituents may be substituted with a group selected from the substituent group / 32), C 7—C 16 aralkyl group (a group selected from the substituent group i32 1 to 3 may be substituted), C 6 -C 10 aryloxy group (1 to 3 may be substituted with a group selected from substituent group ⁇ 2), C 7-16 arylalkyloxy group ( Substituent group] may be substituted with 1 to 3 groups selected from 32), C 6-10 arylthio group
  • R 6 is a hydrogen atom, a C 16 alkyl group, a C 6-10 aryl group (1 to 3 substituents selected from the substituent group ⁇ 2 or a C 7-16 aralkyl A group (1 to 3 may be substituted with a group selected from the substitution group 132);
  • ⁇ 4 represents an oxygen atom or a sulfur atom
  • R 2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C 16 alkyl group, a halogenated C 16 alkyl group, a C 1-6 alkoxy group, or a C 16
  • An alkylthio group, an amino group may be substituted with a group selected from substituent group i33), a C 3-10 cycloalkyl group (substituent group) 1 to 3 groups selected from 32 May be substituted), C 6-10 aryl group (substituent group may be substituted by 1 to 3 groups selected from 32), C 7—C 16 aralkyl group (substituent group) May be substituted with 1 to 3 groups selected from S 2), C 6 -C 10 aryloxy group (1 to 3 groups may be substituted with a group selected from substituent group j32) ), C 7-16 ary
  • R 3 is the formula
  • ⁇ 2 represents a C 1-6 alkylene group
  • Y 3 represents an oxygen atom or a sulfur atom.
  • “Substituent group 1” includes a halogen atom, a hydroxy group, a C 16 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group, an amino group Group (may be substituted with a group selected from substituent group / 33), C 3— 10 cycloalkyl groups (1 to 3 groups may be substituted with a group selected from substituent group i32), C 6-10 aryl group (substituent group) 1 to 3 groups selected from 32 A C 7 -C 16 aralkyl group (which may be substituted with 1 to 3 groups selected from the substituent group iS 2), a C 6 -C 10 aryloxy group ( Substituent group] 1 to 3 groups may be substituted with a group selected from 32), C 7-16 aralkyloxy group (1 to 3 groups may be substituted with a group selected from substituent group ⁇ 2) Good), C6
  • the “substituent group” 3 2 is a halogen atom, a hydroxy group, a C 16 alkyl group, a halogenated C 16 alkyl group, a C 11 C 6 alkoxy group, an amino group (substituent group / 3 3 And a substituent group consisting of a C 6 -C 10 aryl group and a nitro group;
  • Substituent group j8 3 includes C 11-10 alkyl, C 6-10 aryl, C 7-16 aralkyl, C 17 aliphatic, and C 7-11 aromatic.
  • a substituent group consisting of a C.sub.8-12 araliphatic aliphatic group, a C.sub.111 cycloalkyl group and a 5- to 6-membered aromatic heterocyclic carbonyl group containing a nitrogen atom.
  • R 7 represents a carbamoyl group (which may be substituted with one or two groups selected from substituent group a 1), a thiocarbamoyl group (a group selected from substituent group a 1) May be substituted with one or two), a sulfonyl group (having one group selected from substituent group a1) or a carbonyl group (a group selected from substituent group a1 is One).
  • 18 and 19 are each independently a hydrogen atom, a C 11 alkyl group, a C 6-10 aryl group (substituted by 1 to 3 Or a C 7-16 aralkyl group (where the aryl moiety may be substituted with one to three groups selected from the substituent group r 2),
  • a 3 , A 4 and A 5 each independently represent a single bond or a C 18 alkylene group
  • ⁇ 5 , ⁇ 6 and ⁇ ⁇ 7 each independently represent an oxygen atom or a sulfur atom
  • Ar represents a benzene ring or a naphthalene ring
  • L represents 1 to 4 substituents on the Ar ring, each of which is a hydrogen atom, a C 1-6 alkyl group, a C 6-10 aryl group (a group selected from the substituent group a 2; A 3-substituted or C 7-16 aralkyl group (the aryl moiety may be substituted by 1 to 3 groups selected from the substituent group a 2);
  • substituted group a 1 means a C 1-10 alkyl group, a halogenated C 1-6 alkyl group, a C 3-10 cycloalkyl group, a C 6-10 aryl group (substituent group a 1 to 3 may be substituted with a group selected from 3), a C 7-16 aralkyl group (an aryl group may be substituted with 1 to 3 groups selected from a substituent group a 3 C 4-11 cycloalkylcarbonyl group, C 7-11 aromatic acyl group (even when 1 to 3 aryl groups are substituted with a group selected from substituent group a3) Good), C 8-17 aralkyl radical group (1 to 3 aryl groups may be substituted with a group selected from substituent group r 3), 5- or 6-membered aromatic heterocyclic group (substituted One or three groups may be substituted with a group selected from group a3), a 5- or 6-membered aromatic heterocyclic carbony
  • Substituent group T 2 j is a C 16 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen atom, a hydroxy group, a C 6-10 aryl group (substituent group a 1 to 3 may be substituted with a group selected from 4), C 7-16 aralkyl group (even when 1 to 3 aryl groups are substituted with a group selected from substituent group a) Good), a cyano group, a nitro group and an amino group (which may be substituted one or two times with a group selected from substituent group a4),
  • Substituent group a3 includes C 16 alkyl groups, halogenated C 16 alkyl groups, C 16 alkoxy groups, halogen atoms, hydroxy groups, cyano groups, nitro groups, and C 3-10 cyclo groups.
  • alkyl group a C10 aryl group (a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, or a halogen atom, which is substituted with 1 to 3 groups;
  • Aralkyl group (where the aryl moiety is a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 16 alkoxy group and a halogen atom, 1 to 3 may be substituted), C1-7 aliphatic acyl group, C1-7 aliphatic acyloxy group, amino group, diC1-6 alkylamino group and C1-4 alkylenedioxy group
  • substituents a group of substituents,
  • “Substituent group a4” includes C 11 alkyl groups, C 6-10 aryl groups (C 1-6 alkyl groups, halogenated C 16 alkyl groups, and C 16 alkoxy groups). And a group selected from halogen atoms, and may be substituted by 1 to 3), a C7-16 aralkyl group (where the aryl moiety is a C16 alkyl group, a halogenated C1-6 alkyl group) , A C1-16 alkoxy group and a group selected from a halogen atom, which may be substituted by 1 to 3), a C17 aliphatic aliphatic group, a C4-11 cycloalkylcarbonyl group, a C7 — 11 Aromatic acyl group (C 1-3 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group and one or three groups selected from octylogen atom may be substituted.
  • C 8-17 aralkylcarbonyl group (where the aryl moiety is a C 1-6 alkyl group, halogenated C 16 alkyl) 1 to 3 groups selected from a group selected from the group consisting of a C 1-6 alkoxy group and a halogen atom may be substituted, a 5- or 6-membered aromatic heterocyclic group, a luponyl group (a C 16 alkyl group, 1 to 3 may be substituted with a group selected from C 1-6 alkyl group, C 1-6 alkoxy group and halogen atom) And a group of substituents.
  • An amine derivative having the formula:
  • a fluorouracil-based antimetabolite which is one of the active ingredients of the pharmaceutical composition of the present invention, is a pyrimidine antagonist that is a drug that suppresses the growth of cancer cells by antagonizing DNA synthase.
  • 5-fluorouracil (5-Fu) 5-fluorouracil
  • doxofluridine 5'-DFUR
  • FT tegafur
  • the platinum complex which is one of the active ingredients of the pharmaceutical composition of the present invention, refers to a platinum-containing drug that forms a bridge with I-stranded DNA, thereby inhibiting DNA synthesis and suppressing cancer cell growth.
  • a platinum-containing drug that forms a bridge with I-stranded DNA, thereby inhibiting DNA synthesis and suppressing cancer cell growth.
  • CDDP cisplatin
  • CBDCA carpoplatin
  • nedaplatin nedaplatin.
  • C 1-6 alkyl group or “C 1-10 alkyl group” means a linear or branched alkyl having 1 to 6 or 1 to 10 carbon atoms, respectively. It is a group.
  • C 16 alkyl group examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl 1, 1-ethylpropyl, n-hexyl, 'isohexyl, 4-methylpentyl, 3-methylpentyl, 2-.methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 1-
  • C 1-10 alkyl group examples include, for example, the groups mentioned as examples of the aforementioned “C 1-6 alkyl group” or nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1 -Propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl., 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl or 7,7-dimethyloctyl And is preferably a linear or branched alkyl group having 1 to 4 carbon atoms.
  • halogenated C 1-6 alkyl group refers to the “C 1-6 alkyl group” substituted with a halogen atom, and includes, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl , Fluoromethyl, 2,2,2-Trifluoroethyl, 2,2,2-Trichloroethyl, 2-Bromoethyl, 2-Chloroethyl, 2-Fluoroethyl, 2-Fluoroethyl, 3-Chloropropyl, 4-Fluorobutyl And 6-odohexyl or 2,2-dibumoethyl group.
  • C 3-10 cycloalkyl group refers to a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. And a cyclononanyl or cyclodecanyl group, and is preferably a 5- to 10-membered saturated cyclic hydrocarbon group.
  • C 1-4 alkylene group means 1 to 4 carbon atoms, 1 to 6 carbon atoms, or 1 to 8 carbon atoms, respectively. Is a linear or branched alkylene group.
  • C 1-4 alkylene group for example, a methylene, methylmethylene, ethylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene or 3-methyltrimethylene group can be mentioned.
  • Examples of the “C 1-6 alkylene group” include the groups mentioned above as examples of the “C 1-4 alkylene group” or pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4 -Methyltetramethylene, 5-methyltetra Examples include methylene, 1-ethyltrimethylene, 21-ethyltrimethylene, 31-ethyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene or hexamethylene. it can.
  • Examples of the “C 18 alkylene group” include the groups mentioned above as examples of the “C 18 alkylene group”, and a heptamethylene or octamethylene group.
  • the “C 1-4 alkylenedioxy group” is a group in which the above “C 1-4 alkylene group” is bonded via oxygen atoms at both ends, for example, methylenedioxy, methylmethylenedioxy, ethylenedioxy , Trimethylenedioxy, 1-methyltrimethylenedioxy, 2-methyltrimethylenedioxy, 3-methyltrimethylenedioxy and tetramethylenedioxy groups.
  • C 6-10 aryl group refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl and naphthyl group, and a phenyl group is preferable.
  • C 7-11 aralkyl group means 7 to 11 carbon atoms and 7 to 14 carbon atoms, respectively. Alternatively, it is a group in which the above “aryl group” having 7 to 16 carbon atoms is bonded to the above “alkyl group”.
  • C 7-11 aralkyl group examples include benzyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, 1-phenyl, 2-phenyl, 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl or 5-phenylpentyl group
  • the phenyl group is preferably an aralkyl group bonded to a C14 alkyl group, and more preferably a benzyl group.
  • C 7-14 aralkyl group examples include, for example, the groups mentioned above as examples of the “C 7-11 aralkyl group” or diphenylmethyl, 1-naphthylethyl, 2-naphthylethyl, 1-naphthylpropyl, 2 1-naphthylpropyl, 3-naphthylpropyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl or 6-phenylhexyl
  • the phenyl group is an aralkyl group bonded to a C14 alkyl group, more preferably, a benzyl group.
  • C 7-16 aralkyl group examples include, for example, the groups exemplified as the above “C 7-11 aralkyl group” or the above “C 7-14 aralkyl group”, or 5-naphthylpentyl or 6-aralkyl group.
  • a naphthylhexyl group may be mentioned, preferably a phenyl group is an aralkyl group bonded to a C14 alkyl group, and more preferably a benzyl group.
  • Halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom.
  • the “C 1-6 alkoxy group” is a group to which the “C 1-6 alkyl group” is bonded via an oxygen atom.
  • C 1-6 alkoxy group examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy , 2-methylbutoxy, neopentyloxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3 , 3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,3-dimethylbutoxy or 2,3-dimethylbutoxy groups, preferably straight-chain or branched alkoxy having 1 to 4 carbon atoms. Group.
  • C 6-10 aryloxy group refers to a group in which the above “C 6-10 aryl group” is bonded via an oxygen atom, and includes, for example, a phenoxy, indenyloxy or naphthyloxy group. And a phenoxy group.
  • C 7-11 aralkyloxy group” or “C 7-16 aralkyloxy group” means that the above “C 7-11 aralkyl group” or “C 7-16 aralkyl group” is bonded via an oxygen atom, respectively. Group.
  • C 7-11 aralkyloxy group examples include benzyloxy, ⁇ -na Phthylmethoxy, ⁇ -naphthylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-phenylpropoxy, 2-phenyl:! Lupropoxy, 3-phenylpropoxy, 1-phenylbutoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4 —Phenylphenyloxy, 1-phenylpentyloxy, 2-phenylpentyloxy, 3-phenylpentyloxy, 4-phenylpentyloxy or 5-phenylpentyloxy.
  • C7-16-aralkyloxy group examples include, for example, the above-mentioned “C7-11aralkyloxy group J” or diphenylmethoxy, 11-naphthylethoxy, 2-naphthylethoxy, 1-naphthylpropo.
  • Xy 2-naphthylpropoxy, 3-naphthylpropoxy, 1-naphthylbutoxy, 2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3 Preferred is a 1-phenylhexyloxy, 4-phenylhexyloxy, 5-phenylhexyloxy, 6-phenylhexyloxy, 5-naphthylpentyloxy or 6-naphthylhexyloxy group, which is preferred.
  • the “C 1-6 alkylthio group” is a group to which the above “C 1-6 alkyl group” is bonded via a sulfur atom, and includes, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n —Butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, 2-methylpentylthio, neopentylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, List the 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutyl
  • the “C 6-10 arylthio group” is a group to which the “C 6-10 arylthio group” is bonded via a sulfur atom, and includes, for example, a phenylthio, indenylthio or naphthylthio group. be able to.
  • C 18 alkylcarbonyl group means that the above “C 1-8 alkyl group” is A group linked through a benzyl group, for example, an acetyl, propionyl, butyryl, isoptyryl, bivaloyl, pareryl, isovaleryl, hexanoyl, heptanyl or octanoyl group.
  • C 17 aliphatic aliphatic group” or “C 11 aliphatic aliphatic group” means a linear or branched, saturated, C 1-7 or C 1-11 carbon group, respectively. Or an unsaturated aliphatic acyl group.
  • C 17 aliphatic acryl group examples include, for example, an alkyl-powered luponyl group such as formyl, acetyl, propionyl, butyryl, isoptyryl, bivaloyl, valeryl, isovaleryl or hexanoyl group; (E) -12-methyl-2 Alkenylcarbonyl groups such as 1-butynyl group; or alkenylcarbonyl groups such as 3-butynyl group can be mentioned. .
  • C 11 aliphatic aliphatic group examples include, for example, the groups mentioned as examples of the above “C 1-7 aliphatic acyl group” or octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, Alkyl carboxyl groups such as 8-methyl nonyl carbonyl, 3-ethyl octyl carbonyl and 3,7-dimethyl octyl carbonyl groups can be mentioned.
  • C 1-7 aliphatic acyloxy group or “C 1-11 aliphatic acyloxy group” is, respectively, the above “C 1-7 aliphatic acyl group” or “C 11-11 aliphatic acyl machine”. A group bonded through an oxygen atom.
  • C 17 aliphatic aliphaticoxy group examples include, for example, an alkylcarbonyl group such as a formyloxy, acetyloxy, propionyloxy, petyriloxy, isoptyryloxy, vivaloyloxy, valeryloxy, isovaleryloxy or hexanoyloxy group Alkenyl groups such as (E) -2-methyl-2-butenoyloxy group; and alkynylcarboxy groups such as 3-butynyloxy group.
  • alkylcarbonyl group such as a formyloxy, acetyloxy, propionyloxy, petyriloxy, isoptyryloxy, vivaloyloxy, valeryloxy, isovaleryloxy or hexanoyloxy group
  • Alkenyl groups such as (E) -2-methyl-2-butenoyloxy group
  • alkynylcarboxy groups such as 3-butynyloxy group.
  • C11 aliphatic aliphaticoxy group examples include, for example, the groups mentioned as examples of the above “C11 aliphatic aliphaticoxy group” or octanoyloxy, nonylcarpoxyloxy, decylcarpoxyloxy, 3- Methyl nonyl carbonyloxy, 8 Examples thereof include alkyl-capable carbonyl groups such as 3-methylnonyl carbonyloxy, 3-ethyloctyl carboxy or 3,7-dimethyl octyl carboxy.
  • C 4-11 cycloalkylcarbonyl group refers to a group in which the above “C 3-10 cycloalkyl group” is bonded via a propyl group, for example, cyclopropyl propylonyl, Examples thereof include a cyclobutylcarbonyl, a cyclopentylcarbonyl, a cyclohexylcarbonyl and a cycloheptylcarbonyl group, and a C 6-8 cycloalkylcarbonyl group is preferred.
  • C 7-11 aromatic acyl group refers to a group in which the above “C 1-6 aryl group” is bonded via a carboxylic acid group, such as benzoyl, a-naphthoyl or / 3-naphthoyl groups can be mentioned.
  • the “C 7-11 aralkyl carbonyl group” is a group obtained by substituting the above “C 7-11 aralkyl group” with a carbonyl group, and examples thereof include a benzylcarbonyl group. it can.
  • the “C 8-12 aralkyl carbonyl group” is a group to which the above “C 7-11 aralkyl group” is bonded via a carbonyl group, for example, a benzylcarbonyl group. Can be.
  • C8-12 araliphatic acyl group refers to a group consisting of a straight-chain or branched saturated or unsaturated hydrocarbon group to which an araliphatic group is bonded via a propyl group.
  • a benzylcarpoxyl group can be mentioned.
  • C 1-6 alkylsulfonyl group refers to a group in which the above “C 1-6 alkyl group” is bonded via a sulfonyl group, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, Sopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentyl Sulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 3-dimethylbutylsulf
  • C 6-10 arylsulfonyl group refers to a group in which the aforementioned “C 16 arylyl group” is bonded via a sulfonyl group, for example, phenylsulfonyl, indenylsulfonyl Or a naphthylsulfonyl group.
  • C 7-16 aralkylsulfonyl group refers to a group in which the above “C 7 -16 aralkyl group” is bonded via a sulfonyl group, such as benzylsulfonyl, ⁇ -naphthylmethyl Sulfonyl, ⁇ -naphthylmethylsulfonyl, 1-phenylethylsulfonyl, 2-phenylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenyl 2-butylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-phenylpentylsulfonyl, 2-phenylpentylsulf
  • “Di C 1-6 alkylamino group” refers to an amino group substituted by two with the above “C 1-6 alkyl group”, and these substituents may be the same or different.
  • Such groups include, for example, dimethylamino, ethylmethylamino, getylamino, methylpropylamino, methylisopropylamino, butylmethylamino, t-butylmethylamino, methylpentylamino or hexylmethyl. Amino groups can be mentioned.
  • 5- or 6-membered aromatic heterocyclic group means a sulfur atom, an oxygen atom and / or a nitrogen atom.
  • 5- or 6-membered aromatic heterocyclic group containing 1 to 3 atoms for example, furyl, phenyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isotizazolyl, 1,2,3 — Oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, vilanyl, pyridyl, pyridazinyl, pyrimidinyl or vilazinyl groups.
  • 3- to 10-membered aliphatic heterocyclic group refers to a 3- to 10-membered aliphatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms, or nitrogen and nitrogen atoms, and is morpholinyl, thiomorpholinyl , Pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, vilazolidinyl, vilazolinyl, piperidyl and piperazinyl groups.
  • 4- to 7-membered saturated heterocyclic group containing a nitrogen atom refers to a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom.
  • Examples thereof include morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, vilazolidinyl, pyrazolinyl, piperidyl and piperazinyl groups.
  • a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom refers to a 5- or 6-membered aromatic heterocyclic group containing at least one nitrogen atom and optionally containing an oxygen atom or a sulfur atom.
  • the “5- or 6-membered aromatic heterocyclic group” refers to a group in which the “5- or 6-membered aromatic heterocyclic group” is bonded via an oxygen atom, and is, for example, furyloxy, cheloxy, pyrrolyloxy.
  • the “5- or 6-membered aromatic heterocyclic carbonyl group” is a group in which the above “5- or 6-membered aromatic heterocyclic group” is bonded via a carbonyl group.
  • “Substituent group ⁇ 1” includes C 1-6 alkyl group, C 1-6 alkoxy group, C 7-11 aralkyloxy group, halogen atom, hydroxy group, C 11-11 aliphatic acyloxy group, C 1 C 1-6 alkylthio group, halogenated C 1-6 alkyl group, nitro group, amino group (optionally substituted with one or two groups selected from substituent group 2), C 6-10 A aryl group (1 to 5 substituents may be substituted with a group selected from substituent group 0; 3) and a C7-11 aralkyl group (a group selected from substituent group ⁇ 3; To 5 may be substituted).
  • Substituent group 2 includes C 1-6 alkyl groups, C 7-11 aralkyl groups, C 6-10 aryl groups, C 11-11 aliphatic acyl groups, and C 7-11 aralkyl radicals. A group of substituents consisting of a methyl group and a C7-11 aromatic group.
  • Substituent group a 3 includes C 1-6 alkyl groups, C 16 alkoxy groups, halogen atoms, hydroxy groups, nitro groups, C 6-10 aryl groups, and halogenated C 16 groups.
  • a substituent group consisting of an alkyl group and an amino group (which may be substituted one or two times with a group selected from the substituent group ⁇ 2).
  • the “substituent group 31” includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, a halogenated C 16 alkyl group, a C 16 alkoxy group, a C 16 alkylthio group, Amino group (may be substituted with a group selected from substituent group 3), C 3-10 cycloalkyl group (may be substituted with 1 to 3 groups selected from a group selected from substituent group 32) C6-10 aryl group (may be substituted with 1 to 3 groups selected from substituent group i32), C7-C16 aralkyl group (selected from substituent group jS2) May be substituted by 1 to 3 groups), C 6—C 10 aryloxy group (1 to 3 groups may be substituted by a group selected from substituent group 02), C 7- 16 aralkyloxy group (1 to 3 groups may be substituted with a group selected from substituent group ⁇ 2), C 6-10 arylylthio group (1 to
  • i3 or 3 may be substituted with a group selected from 3), a 4- to 7-membered saturated heterocyclic group containing a nitrogen atom and a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom Substituent group j8 11.
  • Substituent group 02 includes octylogen atom, hydroxy group, C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group, amino group (substituent group 33 Which may be substituted with a group selected from the following), a C 6 -C 10 aryl group and a nitro group.
  • “Substituent group ⁇ 83” is a C 11-10 alkyl group, a C 6-10 aryl group, a C 7-16 aralkyl group, a C 17 aliphatic aliphatic group, a C 7-11 aromatic acyl group.
  • a substituent group consisting of a C.sub.8-12 araliphatic aliphatic group, a C.sub.111 cycloalkyl group and a 5- to 6-membered aromatic heterocyclic carbonyl group containing a nitrogen atom.
  • the “substituent group a 1” includes a C 1-10 alkyl group, a halogenated C 16 alkyl group, a C 3-10 cycloalkyl group, a C 6-10 aryl group (the substituent group a 1 to 3 may be substituted with a group selected from 3), a C 7-16 aralkyl group (an aryl group may be substituted with 1 to 3 groups selected from a substituent group a 3 Good), C 4-11 cycloalkylcarbonyl group, C 7-11 aromatic acyl group (one to three aryl groups may be substituted with a group selected from substituent group a3) , C 8-17 aralkyl carbonyl group (1 to 3 aryl groups may be substituted with a group selected from substituent group a3), 5- or 6-membered aromatic heterocyclic group (substituent group from r 3 1 to 3 groups may be substituted with a selected group), 5- or 6-membered aromatic heterocyclic sul
  • “Substituent group a 2” includes C 16 alkyl groups, halogenated C 1-6 alkyl groups, C 16 alkoxy groups, halogen atoms, hydroxy groups, C 6-10 aryl groups (substituent group a A C 7 -16 aralkyl group (where the aryl moiety is substituted with 1 to 3 groups selected from the substituent group a 4, which may be substituted with 1 to 3 groups selected from 4). ), A cyano group, a nitro group and an amino group (which may be substituted one or two times with a group selected from Substituent Group a4).
  • Substituent group a3 includes a C 16 alkyl group, a halogenated C 16 alkyl group, a C 16 alkoxy group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a C 3-10 cyclo group.
  • Alkyl group C 6-10 aryl group (C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 1-6 alkoxy group and halogen atom, and 1 to 3 C 7-16 aralkyl group (optionally substituted), wherein the aryl moiety is selected from a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group and a halogen atom May be substituted with 1 to 3 groups), a C 1-7 aliphatic acyl group, a C 17 aliphatic acyloxy group, an amino group, a di C 1-6 alkylamino group and a C 1-4 alkyl. It is a group of substituents consisting of a dioxy group.
  • “Substituent group a4” includes a C 1-10 alkyl group, a C 6-10 aryl group (a C 1-6 alkyl group, a halogenated C 16 alkyl group, a C 16 alkoxy group and a halogen atom
  • a C 7-16 alkyl group (where the aryl moiety is a C 1-6 alkyl group, a halogenated C 16 alkyl group, a C 1-16 alkyl group, 1 to 3 alkoxy groups and a group selected from a halogen atom may be substituted by 1 to 3), a C 17 aliphatic acyl group, a C 4 11 cycloalkylcarbonyl group, C 7-11 aromatic sacyl group (C 1-6 alkyl group, norogenated C 1-6 alkyl group, C 1-6 alkoxy group and 1 to 3 substituted with a group selected from halogen atoms) C 8-17 aralkyl radical group (where the aryl moiety is
  • Substituent group ⁇ refers to a halogen atom, a hydroxy group, a C 1-6 alkoxy group, an amino group (which may be substituted by one or two C 1-6 alkyl groups), a C 3 -10 cycle A substituent group consisting of an alkyl group, a C 6-10 aryl group, a C 6-10 aryloxy group, a 5- or 6-membered aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic oxy group.
  • (1) X is preferably one of the active ingredients of the pharmaceutical composition of the present invention.
  • W 1 and W 2 each independently represent a hydrogen atom or a group selected from substituent group a; 1).
  • R 1 is the following formula
  • R 4 is a phenyl group (substituent group / 31 is substituted with 1 to 5 groups selected from 11) or a pyridyl group (substituent group) 31 is a group selected from 311 1 to 4 A compound which may be optionally substituted),
  • Y 3 is an oxygen atom compound
  • R 3 is the following formula
  • R 7 is a sulfonyl group (C 16 alkyl group, halogenated C 16 alkyl group and C 6-10 aryl group (1 to 3 substituents selected from a substituent group r 3; Which is substituted with a group selected from:
  • fluorouracil-based antimetabolite which is one of the active ingredients of the pharmaceutical composition of the present invention
  • tegafur or 5-fluorouracil is used, and more preferably, 5-fluorouracil is used.
  • platinum complex which is one of the active ingredients of the pharmaceutical composition of the present invention
  • examples thereof include ratin and cisbratin, and more preferably cisplatin.
  • 5- (4- (6-hydroxy-2,5,7,8-tetramethyl-chroman-12-ylmethoxy) -1-benzyl) monothiazolidine-1,2,4-dione hereinafter referred to as "trodary Zon) is described in Japanese Patent Application Laid-Open No. 6-51189, and has the following structural formula
  • mouth diglitazone 5-(4-(2-(methyl-pyridine- 1-2-yl-amino) 1-ethoxy) 1-benzyl) 1-thiazolidine-1, 2,4-dione
  • salts with acids include, for example, salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, fumarate, and maleate Salts of carboxylic acids such as oxalate, malonate, malonate, succinate, citrate and malate; sulfones such as methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate Salts of acids; salts of amino acids such as glutamate and aspartate; and salts with bases; for example, salts with alkali metal such as lithium, sodium and potassium salts; Salts with alkaline earth metals such as calcium and magnesium salts; or ammonium salts, triethylamine salts, diisopropylamine salts, and cyclohexylamine salts.
  • inorganic acids such as hydrochloride, hydrobromide, s
  • the compound (I), compound (III), compound (I ⁇ ), fluorouracil antimetabolite or platinum complex which is an active ingredient of the pharmaceutical composition of the present invention, has stereoisomers and ⁇ or geometric isomers, respectively. However, each of them or a mixture thereof is included in the present invention.
  • Compound (I), compound (111), compound (I ⁇ ), a fluorouracil-based antimetabolite, a platinum complex, torodarizone, rosiglitazone or pioglitazone, which are the active ingredients of the pharmaceutical composition of the present invention, are respectively , Or hydrate or solvate, each of which or a mixture thereof is included in the present invention.
  • “simultaneous administration” is not particularly limited as long as it is an administration form that can be administered at about the same time, but administration as a single composition is preferred.
  • the term “separate administration at a later time” is not particularly limited as long as it can be administered separately at different times, but, for example, a fluorouracil antimetabolite or a platinum complex is administered first. Then, administration of the compound (1), the compound (III) or the compound (IV) after a determined time has elapsed.
  • a fluorouracil antimetabolite or a platinum complex is administered first. Then, administration of the compound (1), the compound (III) or the compound (IV) after a determined time has elapsed.
  • Compound (I) which is one of the active ingredients of the pharmaceutical composition of the present invention, is disclosed in JP-A-2000-001487 (WO 00/18081), and compound (III) is disclosed in JP-A-11-193276.
  • Compound (IV) can be easily produced according to the method described in Japanese Patent Publication No. 2000-351779 (WO 00/61581).
  • 5-fluorouracil is from Kyowa Enzyme Co., Ltd.
  • Doxofluridine is from Nippon Roche Co., Ltd.
  • Tegafur is Taiho Pharmaceutical Co., Ltd. Co., Ltd.).
  • Compound (1), compound (III) or compound which is an active ingredient of the pharmaceutical composition of the present invention (IV) and the fluorouracil antimetabolite or platinum complex can each be adjusted individually into separate unit dosage forms, or mixed together to form a physically single dosage form.
  • the pharmaceutical composition of the present invention in such a single unit dosage form or a mixed single dosage form is used as a prophylactic or therapeutic drug for the above-mentioned diseases
  • the pharmaceutical composition of the present invention Compound (1), compound (III) or compound ( ⁇ ), which is an active ingredient, and Z or a fluorouracil-based antimetabolite or a platinum complex are each used as such or an appropriate pharmacologically acceptable activator. It can be administered with tablets, capsules, granules, powders, syrups and the like orally, or by parenteral injections and suppositories etc. after mixing with excipients and diluents.
  • These preparations may contain excipients (eg, lactose, sucrose, dextrose, saccharide derivatives such as mannitol, sorbitol; corn starch, potato starch, ⁇ -starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose).
  • excipients eg, lactose, sucrose, dextrose, saccharide derivatives such as mannitol, sorbitol; corn starch, potato starch, ⁇ -starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose).
  • Silicic acids such as silicic anhydride, silicic acid hydrate; and the above-mentioned starch derivatives; binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and The same compounds as excipients can be mentioned), disintegrants (for example, cellulose such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, internally crosslinked carboxymethylcellulose sodium) Derivatives; Cal Po carboxymethyl starch, sodium carboxymethyl starch, chemically modified, such as crosslinked polyvinyl pyrrolidone Starch and celluloses), emulsifiers (eg, colloidal clays such as bentonite and pea gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; sodium lauryl sulfate, calcium stearate and the like) Anionic surfactants; cationic surfactants such as benzalkonium chloride;
  • Benzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol and cresol Phenols; thimerosal; dehydro'acetic acid; and sorbic acid), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), diluents It is manufactured by a well-known method using additives such as an agent.
  • the dose and the ratio of the compound (1), compound (III) or compound (IV), which is the active ingredient of the pharmaceutical composition of the present invention, and the fluorouracil antimetabolite or platinum complex are determined by the activity of each drug, It may vary depending on various conditions such as symptoms, age, and weight.
  • the dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 100 Omg (preferably 50 Orag) per dose. In the case of parenteral administration, the lower limit is 0.0 lmg (preferably 0.05 mg) and the upper limit is 10 Omg (preferably 5 Omg) per dose, 1 to 6 times daily for adults. It can be administered simultaneously or separately at intervals depending on the condition.
  • the compound (1), the compound (III) or the compound (IV) is more suitable for the prevention or treatment of arteriosclerosis in the present invention than in the dose as a bovine hyperlipidemia which is an original use. In some cases, these dosages may be lower and the dosage may be further reduced due to the superior effects of the combined use with fluorouracil antimetabolites or platinum complexes. In addition, the ratio of the compound (1), compound (III) or compound (IV), which is the active ingredient of the pharmaceutical composition of the present invention, to the dose of the fluorouracil-based antimetabolite or the platinum complex can also vary greatly.
  • the dose ratio of the compound (1), the compound (III) or the compound (IV) and the fluorouracil-based antimetabolite or the platinum complex is expressed as a weight ratio, 1: 500 to 500: 1.
  • the present inventors have found a combination of drugs having excellent cell growth inhibitory activity and provide a useful cell growth inhibitor or anticancer agent.
  • N- (5- (3-aminophenoxy) _2-ditrophenyl) 1-N-methylcarbamic acid t-butyl ester 2. Add 5.45 g of 3-aminophenol to 80 ml of a suspension of anhydrous N, N-dimethylformamide containing 18 g of sodium hydride (55% by weight), and add at room temperature. Stirred for 20 minutes. Then, 14.3 g of N- (5-chloro-2--2-nitrophenyl) -N-methylcarbamic acid t-butyl ester (JP-A-11-1933276) was added little by little, and 10 The mixture was stirred at 0 ° C for 6 hours.
  • the reaction mixture was concentrated, water was added, and neutralized using 3N hydrochloric acid and sodium bicarbonate powder.
  • the precipitated insoluble product was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (16.6 g, yield 92%).
  • Tumor pieces (5 mm X 5 marshals) of human colon cancer cell line C0L-2-JCK were implanted subcutaneously into 10 BALB / c nude mice (female, 6 weeks old) per group.
  • the test compound of Production Example 1 (hereinafter referred to as Compound A), which was a test compound, was suspended in a 5% saline solution containing 2.5% dimethylacetamide. 5-Fu (manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in a sterilized saline solution. After engraftment, tumors were grouped on day 7 after transplantation so that there was no difference in tumor size.
  • Compound A was administered at 50 mg / kg on days 7 to 11 and days 14 to 18, Oral administration was performed from day 25 to day 28, day 28 to day 32, and day 35 to day 39 (total 25 times), and 90 mg / kg of 5-Fu was intravenously administered once on day 7 of transplantation.
  • the minor axis (mm) and major axis (mm) of the tumor were measured with an electronic digital caliper, and the tumor volume was determined by the following formula: 1/2 x [tumor major axis] X [tumor minor axis] 2 .
  • the effect was determined by comparing the average tumor volume of each group on day 42 after transplantation.
  • One group of 10 mice of the CDF1 mice (female, 7 weeks old) subcutaneously and lxl0 6 cells transplanted mouse colon cancer Colon 26 cells in culture.
  • the test compound of Preparation Example 1 (hereinafter referred to as Compound A) was orally administered at a dose of 50 mg / kg from the day after transplantation to the 4th, 7th to 11th, and the Uth to 16th days.
  • Compound A received 10 mg / kg intravenously once a day after transplantation.
  • the minor axis (mm) and major axis (mm) of the tumor were measured with an electronic digital caliper, and the tumor volume was calculated as in Example 1. The effect was determined by comparing the average tumor volume of each group on day ⁇ after transplantation.
  • the compound (1), the compound (III) or the compound (IV) of the present invention and the fluorouracil-based antimetabolite or the platinum complex were used alone by combining them. Compared to the case, the effect was excellent.
  • the compound of Production Example 1 (30.Omg), 5-FU (30.011 ⁇ ), lactose (408.Omg), corn starch (50.Omg) and magnesium stearate (2.Omg) were mixed, Tablet with a tableting machine to make 50 Omg tablets.
  • the tablets can be coated (preferably sugar-coated) as needed.
  • the pharmaceutical composition containing the compound (1), the compound (III) or the compound (IV) of the present invention and a fluorouracil antimetabolite or a platinum complex as active ingredients has excellent cell growth inhibitory activity. Because of its low toxicity, medicines (especially stomach cancer, lung cancer, breast cancer, colon cancer, It is useful as a prophylactic or therapeutic agent for cancers such as prostate cancer, hepatocellular carcinoma, liver cancer, leukemia, head and neck cancer, and liposarcoma, or a cytostatic agent.
  • a pharmaceutical composition comprising troglitazone, piodarizinzone or rosiglitazone of the present invention, and a fluorouracil-based antimetabolite or a platinum complex as active ingredients has excellent cell growth inhibitory activity and low toxicity.
  • Medicines especially, cancer preventive or therapeutic agents or cell growth inhibitors such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, kidney cancer, liver cancer, leukemia, head and neck cancer, liposarcoma
  • cancer preventive or therapeutic agents or cell growth inhibitors such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, kidney cancer, liver cancer, leukemia, head and neck cancer, liposarcoma

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Abstract

L'invention concerne une composition médicinale qui comprend en tant qu'ingrédient actif un composé représenté par la formule générale (I) suivante : (I) (dans laquelle X représente un cycle benzimidazole etc., Y1 représente l'oxygène ou le soufre, Z représente un groupe thiazolidinedione etc., R représente l'hydrogène, alkyle C1-6 etc., et m est un nombre entier compris entre 1 à et 5 etc.), et un antimétabolite fluorouracil ou un complexe de platine. Cette composition présente une activité cytostatique élevée.
PCT/JP2003/003881 2002-04-01 2003-03-27 Composition médicinale antitumorale WO2003082865A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108741A1 (fr) * 2007-03-07 2008-09-12 S*Bio Pte Ltd Combinaison d'un agent anticancéreux à base de benzimidazole et d'un second agent anticancéreux
US8263631B2 (en) 2006-02-09 2012-09-11 Daiichi Sankyo Company, Limited Anti-cancer pharmaceutical compositions and methods for treating patients with cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998025598A2 (fr) * 1996-12-11 1998-06-18 Dana-Farber Cancer Institute Procedes et compositions pharmaceutiques inhibant la proliferation de cellules tumorales
WO1999030739A1 (fr) * 1997-12-16 1999-06-24 Sankyo Company, Limited Remede contre la leucemie
WO2001034200A1 (fr) * 1999-11-10 2001-05-17 Takeda Chemical Industries, Ltd Inhibiteurs de prise de poids
EP1167366A1 (fr) * 1999-04-07 2002-01-02 Sankyo Company, Limited Derives amine
EP1180519A1 (fr) * 1999-05-24 2002-02-20 Sankyo Company, Limited Chlorhydrate de compose heterocyclique fusionne

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998025598A2 (fr) * 1996-12-11 1998-06-18 Dana-Farber Cancer Institute Procedes et compositions pharmaceutiques inhibant la proliferation de cellules tumorales
WO1999030739A1 (fr) * 1997-12-16 1999-06-24 Sankyo Company, Limited Remede contre la leucemie
EP1167366A1 (fr) * 1999-04-07 2002-01-02 Sankyo Company, Limited Derives amine
EP1180519A1 (fr) * 1999-05-24 2002-02-20 Sankyo Company, Limited Chlorhydrate de compose heterocyclique fusionne
WO2001034200A1 (fr) * 1999-11-10 2001-05-17 Takeda Chemical Industries, Ltd Inhibiteurs de prise de poids

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263631B2 (en) 2006-02-09 2012-09-11 Daiichi Sankyo Company, Limited Anti-cancer pharmaceutical compositions and methods for treating patients with cancer
WO2008108741A1 (fr) * 2007-03-07 2008-09-12 S*Bio Pte Ltd Combinaison d'un agent anticancéreux à base de benzimidazole et d'un second agent anticancéreux

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