WO2003082865A1 - Medicinal antitumor composition - Google Patents

Abstract

A medicinal composition which comprises as active ingredients a compound represented by the following general formula (I): (I) (wherein X represents a benzimidazole ring, etc.; Y1 represents oxygen or sulfur; Z represents a thiazolidinedione group, etc.; R represents hydrogen, C1-6 alkyl, etc.; and m is an integer of 1 to 5, etc.) and a fluorouracil antimetabolite or platinum complex. It has excellent cytostatic activity.

Description

 Description Antitumor pharmaceutical composition

(Technical field)

 TECHNICAL FIELD 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 τ activation ability and a fluorouracil-based antimetabolite or a platinum complex.

 (Background technology)

 To date, it has not been known that the combined use of a compound having the ability to activate PPAR and a fluorouracil antimetabolite or a platinum complex suppresses cell proliferation or increases the antitumor effect.

 (Disclosure of the Invention)

 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)

[Wherein, X represents a benzimidazole ring group (optionally substituted with 1 to 5 groups selected from a substituent group α1);

Y ¹ represents an oxygen atom or a sulfur atom,

Z is

Indicates'

 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 α2; Or a C7-11 aralkyl group (which may be substituted with a group selected from the substituent group << 3).

 m represents an integer of 1 to 5.

 In the above, the “substituent group α 1” includes a 〇116 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 α2), C 6- 10 aryl groups (1 to 5 groups may be substituted with a group selected from substituent group α3) and C 7-11 aralkyl group (1 to 5 groups selected from substituent group α3) 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 α 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 α2). ] A fused heterocyclic compound having —General formula (III)

[In the above formula, R ¹ is

Ν

 Eight hundred

 R 4 /

In the formula, 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 β 2), C 7-16 arylalkyloxy group ( Substituent group] may be substituted with 1 to 3 groups selected from 32), C 6-10 arylthio group (1 to 3 groups selected from substituent group 2) 3 may be substituted), a C 17 aliphatic acyloxy group, a nitrogen-containing 4- to 7-membered saturated heterocyclic group, a nitrogen-containing 5- or 6-membered aromatic heterocyclic group, a nitro group or Represents a cyano 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 β 2 or a C 7-16 aralkyl A group (1 to 3 may be substituted with a group selected from the substitution group 132);

Υ ⁴ represents an oxygen atom or a sulfur atom, E ¹ represents a = CH_ group or a nitrogen 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 arylalkyloxy group (1 to 3 groups may be substituted with a group selected from substituent group j82), C 6-10 arylthio group (substituent group) 32 1 to 3 may be substituted with a group selected from the following), C 1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5- or 6-membered aromatic containing a nitrogen atom Represents a heterocyclic group, a nitro group or a cyano group,

R ³ is the formula

A group having

Α ² represents a C 1-6 alkylene group,

Y ³ represents an oxygen atom or a sulfur atom.

In the above, “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 β 2) Good), C6-10 arylthio group (substituent group; may be substituted with 1 to 3 groups selected from 62), C1-7 aliphatic acyloxy group, containing nitrogen atom A substituent group consisting of a 4- to 7-membered saturated heterocyclic group, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, a nitro group and a cyano group,

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. A substituted fused heterocyclic compound having

 General formula (IV)

[Wherein, 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;

Υ ⁵ , Υ ⁶ and 及 び⁷ each independently represent an oxygen atom or a sulfur atom,

Ε ² represents a = CH— group or a nitrogen 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);

In the above, “substituent 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 carbonyl group (from substituent group a3) Selected from 1 to 3 substituents), a C 16 alkylsulfonyl group, a halogenated C 16 alkylsulfonyl group, a C 6-10 arylsulfonyl group (where the aryl moiety is One to three substituents may be substituted with a group selected from Substituent Group a3) and a C 7-16 aralkylsulfonyl group (a group in which the aryl moiety is selected from Substituent Group a3) 1 to 3 may be substituted). “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. An 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 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:

 5- (4- (6-Hydroxy-1,2,5,7,8-tetramethyl-chroman-1-ylmethoxy) -1-benzyl) -thiazolidine-1,2,4-dione,

 5- (4- (2- (5-ethyl-pyridine-1-yl) -1-ethoxy) benzyl) thiazolidine-1, 2-dione or

 5- (4- (2- (Methyl-pyridine-1-2-aminoamino) -1-ethoxy) -benzyl) Thiazolidine-one, 2,4-dione.

 In addition, 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. For example, 5-fluorouracil (5-Fu), doxofluridine (5'-DFUR), or tegafur (FT) can be mentioned.

 In addition, 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. For example, cisplatin (CDDP :), carpoplatin (CBDCA), or nedaplatin.

 In the above, “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.

Examples of the “C 16 alkyl group” 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-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3 -Methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1- Examples thereof include propylpentyl, 2-ethylhexyl and 5,5-dimethylhexyl groups, and are preferably straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms.

 Examples of the “C 1-10 alkyl group” 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.

 The “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.

 The “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”, “C 1-6 alkylene group” or “C 18 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.

 As the “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.

 The “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”, “C 7-14 aralkyl group” or “C 7-16 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”.

 Examples of the “C 7-11 aralkyl group” include benzyl, α-naphthylmethyl, β-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.

Examples of the “C 7-14 aralkyl group” 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 Preferably, the phenyl group is an aralkyl group bonded to a C14 alkyl group, more preferably, a benzyl group.

 Examples of the “C 7-16 aralkyl group” 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.

 Examples of the “C 1-6 alkoxy group” 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.

Examples of the “C 7-11 aralkyloxy group” include benzyloxy, α-na Phthylmethoxy, β-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.

 Examples of the “C7-16-aralkyloxy group” 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. Is an aralkyloxy group in which a phenyl group is bonded to a C 1-4 alkyl group, and more preferably a benzyl group. It is a Okishi group.

 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-dimethylbutylthio group Can be.

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.

 Examples of the “C 17 aliphatic acryl group” 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. .

 Examples of the “C 11 aliphatic aliphatic group” 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.

 The “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.

 Examples of the “C 17 aliphatic aliphaticoxy group” 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.

Examples of the "C11 aliphatic aliphaticoxy group" 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. For example, a benzylcarpoxyl group can be mentioned.

The “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-dimethylbutylsulfonyl and 2,3-dimethylbutylsulfonyl groups can be mentioned. “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, α-naphthylmethyl Sulfonyl, β-naphthylmethylsulfonyl, 1-phenylethylsulfonyl, 2-phenylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-phenylbutylsulfonyl, 2-phenyl 2-butylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-phenylpentylsulfonyl, 2-phenylpentylsulfonyl, 3-phenylpentylsulfonyl, 4-phenylpentylsulfonyl, 5 —Phenylpentylsulfonyl, diphenylmethylsulfonyl, 1-naphthyl Rusulfonyl, 2-naphthylethylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 1-phenylhexylsulfonyl, 2-phenylhexylsulfonyl, 3-phenylhexylsulfonyl, 4-phenylhexylsulfonyl, 5-phenylhexylsulfonyl, 6-phenylhexylsulfonyl, 51-phenylhexylsulfonyl Examples include naphthylpentylsulfonyl and 6-naphthylhexylsulfonyl groups.

 “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.

 The term "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. For example, pyrrolyl, azepinyl, virazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyridazinyl, pyridazinyl or pyridazinyl it can.

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. , Azepinyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy , Thiadiazolyloxy, bilanyloxy, pyridyloxy, pyridazini Roxy, pyrimidinyloxy or birazinyloxy groups can be mentioned.

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. Nilcarponyl, pyrrolylcapillonil, azepinylcarbonyl, virazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxazidiazolylcarbonyl, Examples thereof include a triazolylcarbonyl, a tetrazolylcarbonyl, a thiadiazolylcarbonyl, a 'biranylcarbonyl, a pyridylcarbonyl, a pyridazinylcarbonyl, a pyrimidinylcarbonyl or a pyrazinylcarbonyl 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 α3; 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 α2).

In the above, 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 β 2), C 6-10 arylylthio group (1 to 3 group (s) selected from substituent group i32) May be substituted), a C 1-7 aliphatic acyloxy group, a 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, a nitro group and a cyano group A halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, an amino group (substituent group). 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 ι83” 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.

In the above, 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 sulfonic group (1 to 3 groups may be substituted with a group selected from substituent group a3) Good), C 1-6 alkylsulfonyl group, octogenated C 1-6 alkylsulfonyl group, C 6-10 arylsulfonyl group (where the aryl portion is a group selected from 3 substitutions) and a C 711 aralkylsulfonyl group (where the aryl moiety may be substituted with one to three substituents selected from substituent group a3). It is a group.

 “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 selected from a C 1-6 alkyl group, a halogenated C 16 alkyl group, a C 1-6 alkoxy group and an octogen atom) Group may be substituted with 1 to 3 groups), 5- or 6-membered aromatic heterocyclic group, a luponyl group (C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and And 1 to 3 substituents selected from halogen atoms). ,

 “Substituent group δ” 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. As the compound (I) which is one of the active ingredients of the pharmaceutical composition of the present invention, (1) X is preferably

(Wherein, W ¹ and W ² each independently represent a hydrogen atom or a group selected from substituent group a; 1).

(2) The compound according to (1), wherein W ¹ is a hydrogen atom or a C 1-6 alkyl group,

(3) The compound according to (1), wherein W ¹ is a methyl group,

(4) The compound according to (1), wherein W ² is a C 16 alkoxy group or a C 7-11 aralkyloxy group,

(5) a compound wherein W ² is a benzyloxy group,

(6) a compound wherein Y ¹ is an oxygen atom,

 (7) a compound wherein m is 1;

 (8) a compound wherein R is a hydrogen atom,

(9) Z is the following formula

A compound that is a group represented by, or

 (10) Compounds obtained by appropriately combining the above (1) to (4), (5), (6), (7), (8) and (9).

 As the compound (I I I) which is one of the active ingredients of the pharmaceutical composition of the present invention,

(1 1) R ¹ is the following formula

A compound that is a group represented by

(12) a compound wherein R ⁵ is a hydrogen atom,

(13) a compound wherein R ⁶ is a methyl group,

(14) a compound wherein Y ⁴ is an oxygen atom,

(1 5) 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),

(1 6) Y ³ is an oxygen atom compound,

(17) a compound wherein R ² is a hydrogen atom,

(18) a compound wherein A ² is a methylene group,

(19) R ³ is the following formula

A compound that is a group represented by, or

 (20) Compounds obtained by appropriately combining the above (11), (12), (13), (14), (15), (16), (17), (18) and (19). Can be

 As the compound (IV) which is one of the active ingredients of the pharmaceutical composition of the present invention,

(21) The compound wherein R ⁷ is a sulfonyl group (having one group selected from substituent group a1),

(22) 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:

(23) The compound wherein R ⁷ is a sulfonyl group (substituted with a C 1-6 alkyl group),

(24) the compound, wherein R ⁸ is a hydrogen atom or a C 16 alkyl group,

(25) a compound wherein A ³ is a single bond,

(26) a compound wherein A ⁴ is a single bond,

(27) a compound wherein A ⁵ is a methylene group,

(28) the compound, wherein Y ⁵ is an oxygen atom,

(29) the compound, wherein Y ⁶ is an oxygen atom,

(30) the compound, wherein Y ⁷ is a sulfur atom,

(31) the compound wherein E ² is a = CH— group,

 (32) a compound wherein Ar is a benzene ring,

 (33) a compound wherein L is a hydrogen atom or a C1-6 alkyl group, or

 (34) The above (21) to (23), (24), (25), (26), (27), (28), (29), (30), (31), (32) and (33) ) Are appropriately combined.

 As the fluorouracil-based antimetabolite which is one of the active ingredients of the pharmaceutical composition of the present invention, preferably, tegafur or 5-fluorouracil is used, and more preferably, 5-fluorouracil is used.

As a 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. In the pharmaceutical composition of the present invention, 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

Is a compound having

 5-(4-(2-(5-Edupyridine-2-yl) 1-ethoxy) benzyl) 1-thiazolidine-1, 2, 4-dione (hereinafter referred to as "pioglitazone") is disclosed in European Patent Publication No. The following structural formula described in Japanese Patent Publication No.

Is a compound having

 5-(4-(2-(methyl-pyridine- 1-2-yl-amino) 1-ethoxy) 1-benzyl) 1-thiazolidine-1, 2,4-dione (hereinafter referred to as “mouth diglitazone”) is an international publication The following structural formula described in No. 9 1/2003

Is a compound having

 Form a salt among compound (I), compound (III), compound (Iv), a fluorouracil antimetabolite, a platinum complex, troglitazone, rosiglitazone and piodarizone which are the active ingredients of the pharmaceutical composition of the present invention. Each of these can be converted into a salt according to a conventional method, if desired, and such salts are also included in the present invention. Among such salts, 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. Such salts with organic bases can be mentioned. The compound (I), compound (III), compound (Iν), fluorouracil antimetabolite or platinum complex, which is an active ingredient of the pharmaceutical composition of the present invention, has stereoisomers and Ζ or geometric isomers, respectively. However, each of them or a mixture thereof is included in the present invention.

 Compound (I), compound (111), compound (Iν), 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.

 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. In the pharmaceutical composition of the present invention,

5- (4-(6-Methoxy-1-methyl-1H-benzoimidazo-l-l-l-methoxy) -benzyl) monothiazolidine- 2,4-dione,

 5- (4- (6-ethoxy-1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) 1-thiazolidine-1 2,4-dione,

 5- (4- (6-isopropoxy-1-methyl-1H-benzoimidazole-2-ylmethoxy) -1benzyl) thiazolidine-1 2,4-dione,

5- (4- (6-benzyloxy-1-methyl-1H-benzoimidazole-2-ylmethoxy) monobenzyl) thiazolidine-2,4-dione,

5- (4-(1-Methyl-6-pentafluorophenoxy-1H-benzoimidazo-l-2-ylmethoxy) -1benzyl) 1-thiazolidine-1, 4-dione,

5- (4-(6-1-amino-phenoxy) -1-methyl-1H-benzoimidazo-lu-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5- (4- (6- (3-Amino-phenoxy) 1-1H-Methyl-1H-Benzoimidazo-Ru-21-Myloxy) 1-Benzyl) -Thiazolidine-1 2,4-dione, 5- (4— (6— (4—Amino-1,3,5-1) Dimethyl-1-phenoxy) -1-methyl-1-H-benzoimidazo-1-yl-2-ylmethoxy) -benzyl) thiazolidine-1,2,4-dione,

 5- (4- (1-methyl-6- (pyridine-2-yloxy) -1H-benzoimidazole-2-ylmethoxy) -1benzyl) thiazolidine-1 2,4-dione, 5- (4--(6— (5 —Amino-pyridine-1-2-yloxy) 1-methyl-1-H 1-benzoimidazo-1-lu-2-ylmethoxy) -benzyl) monothiazolidine-1,2,4-dione,

 5- (4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) thiazolidine-1, 4-dione,

5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzoimidazole-2- ^ T-methoxy) -1-benzyl) -thiazolidine-1, 4-di ON, '

 5- (4- (6- (4- (ethyl-isopropylamino) -phenoxy) -1-1-methyl-1H-benzoimidazo-1-ru-2-ylmethoxy) monobenzyl) thiazolidin-2,4-dione,

 5- (4- (6- (3- (Ethyl-isopropyl-amino) -phenoxy) -1-1-Methyl-1H-Benzoimidazo-l- 2-ylmethoxy) -Benzyl) -thiazolidin-2,4-dione,

 5- (4- (6- (4- (isobutyl-methyl-amino) 1-phenoxy) — 1-methyl—1H—benzoimidazo-2-yl-methoxy) 1-benzyl) 1-thiazolidine —2,4-dione ,

 5- (4- (6- (3- (isobutyl-methyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazo-1-ru-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,

 5- (4-(6-(4-dimethylamino-phenoxy) _1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione, 5-(4 1- (6- (3-dimethylamino-1-phenoxy) — 1-methyl-1H—benzoimidazole-2-ylmethoxy) -1benzyl) —thiazolidine—2,4-dione, 5-—4— (6— (4— ( Tyl-methyl-amino) -phenoxy) 1-methyl-1- 1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1,2, dione,

 5— (4— (6— (3— (ethyl-methyl-amino) -phenoxy) -1-methyl-1-H-benzoimidazole-1-ylmethoxy) -benzyl) thiazolidine-1,

4—Zeon,

 5- (4-(6-(4- (butyl-methyl-l-amino) -phenoxy) -l-l-methyl-lH-benzoimidazole- 2-l-methoxy) -benzyl) -thiazolidine-l, 4-dione,

5- (4- (6- (3- (butyl-methyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1 4—Zeon,

 5-(4-(6-(4-acetylaminophenoxy) 1-1-methyl-1H-benzo imidazole-2-ilmethoxy)-benzyl)-thiazolidine-2, 4-dione, 5-( 4-(6-(3-Gethylamino-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,

5- (4-(6-(4- (butyl-ethyl-amino) -phenoxy) -1-1-methyl-1-H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1,2,4-dione,

 5- (4- (6- (3- (butyl-ethyl-amino) -phenoxy)-1-methyl-1H-benzoimidazo-1-ru 2-ilmethoxy) -benzyl) thiazolidine-1, 4-dione,

 5-(4- (1-Methyl-1 6- (4-Phenylamino-phenoxy)-1H-Benzimidazole-2-ylmethoxy) -benzyl) -Thiazolidine- 1,2,4-dione, 5- (4--( 1-Methyl-6- (3-phenylamino-phenoxy) -1-H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-(1-methyl-1-6) — (4-pyrrolidine- 1-ylofenoxy)-1H- benzoimidazo-l- 2-ylmethoxy) -benzyl) 1-thiazolidine- 2,4 dione,

 5- (4- (1-methyl-6- (3-pyrrolidine-1-1-ylofenoxy) -1-benzoimidazole-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione,

 5- (4- (1-methyl-1-6-(4-piperidine_1-yl-phenoxy) -1H-1benzoimidazole-2-ylmethoxy) -1benzyl) thiazolidine-2,4 dione,

 5— (4— (1-Methyl-6— (3-Pyridine-1-1-ylofenoxy)-1H-Penzoimidazole -2-2-Methoxy) -Benzyl) —Thiazolidine—2,4-dione,

5-(4-(1-Methyl-1 6- (4-Morpholine-1-4-Lifenoxy) -1H —Benzimidazole-2-ylmethoxy) —benzyl) monothiazolidine — 2,4 dione,

 5- (4- (1-Methyl-6- (3-Morpholine-1-4-ylofenoxy) -1H-1Penzoimidazo-1-Lu-2-ylmethoxy) -benzyl) 1-thiazolidine _ 2,4 dione,

 5- (4- (1-Methyl-1-6- (4-methanesulfonylamino-phenoxy) -1H-1Penzoimidazo-1-2-ylmethoxy) -1benzyl) 1-thiazolidine-2,4-dione or

 5- (4-(1-Methyl-6- (3-1-methanesulfonylamino-phenoxy) -1H-Benzoimidazo-1-Ru-2-ylmethoxy) -1Benzyl) 1-thiazolidine-2,4-dione and 5-fluorouracil or cisplatin Is a pharmaceutical composition containing as an active ingredient, more preferably,

 5- (4- (6-methoxy-1-methyl-1H-benzimidazole-2-ylmethoxy) monobenzyl) thiazolidine mono 2,4-dione,

 5- (4- (6-benzyloxy-1-methyl-1H-benzoimidazole-2-ylmethoxy) monobenzyl) thiazolidine mono 2,4 dione,

5-(4-(1 -methyl-6-pentafluorophenoxy 1H-benzimidazoyl 2- ylmethoxy) 1 benzyl) 1 thiazolidine 1, 4 dione,, 5-(4-1 (6-(4- Amino-3,5-dimethyl-phenoxy) -1-methyl-1H-benzoimidazole-1-2-ylmethoxy) monobenzyl> monothiazolidine-2,

4—Zeon,

 5-(4-(6-(4 -Isopropylamino-phenoxy)-1 -methyl-1H-Benzoimidazole-2-ylmethoxy)-1-benzyl) 1-thiazolidine-2 ', 4 dione,

 5- (4-(6-(3-isopropylamino-phenoxy) -1-1-methyl- 1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine- 1,4-dione,

5— (4-(6-(4-(Ethyl isopropylamino) phenoxy) 1 1 1 Methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidin-2,4-diene,

 5- (4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -1-1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidin-2,4-dione,

 5- (4-(6-(4- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazo-1-ru-2-ylmethoxy) -benzyl) thiazolidine-2,4-dione,

 5-(4-(6-(3-(isobutyl-methyl-l-amino) -phenoxy)-1-methyl-1H-benzoimidazo-1-2-ylmethoxy) 1-benzyl) 1-thiazolidine-1, 2, 4-dione,

 5- (4-(6- (4-Dimethylamino-phenoxy) -1-1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) -thiazolidine- 2,4-dione, 5- (4-(6- ( 3-Dimethylamino-phenoxy) 1 1-methyl-1H-Benzoimidazo-l- 2-ylmethoxy) -benzyl) -thiazolidine-2, 4-dione, 5- (4--(6-(4-Jetylamino) 1-Methyl-1H-Benzoimidazo-1-yl-2-ylmethoxy) -benzyl) 1-thiazolidine-2,4-dione, 5- (4- (6- (3-Jethylamino-phenoxy)) 1-methyl-1H- Benzoimidazole--2-1-dimethyl 1, xy)-1-benzyl)-1-thiazolidine-1, 2, 4-dione, 5-(4-(1-methyl-6-(4-pyrrolidine-1-ylenoxy)) 1 1 H-benzo Imidazole _ 2-ilmethoxy) Undil) monothiazolidine-2,4

 5-(4-(1-Methyl-6- (3-pyrrolidine- 1-ylofenoxy)-1H-Benzoimidazole-2-ylmethoxy)-benzyl) 1-thiazolidine-2,4-dione,

5— (4— (1-Methyl-1-6- (4-Morpholine-1-4-ylofenoxy) -1H-1Benzoimidazole-2-ylmethoxy) 1-benzyl) 1-thiazolidine—2,4-dione, 5- (4- (1-Methyl-6- (3-morpholine-1-4-ylofenoxy) -1H-benzimidazo-1-ru-2-ylmethoxy) -1-benzyl) -thiazolidine-2,4-dione,

 5- (4- (1-Methyl-1-6- (4-Methanesulfonylamino-phenoxy) -1H-benzimidazo-l-2-ylmethoxy) -1benzyl) -Thiazolidine-1, 4-dione, or

 5- (4-(1-Methyl-6- (3-methanesulfonylamino-phenoxy)-1H-Penzoimidazole_2-ylmethoxy) 1-benzyl) 1-thiazolidine-2,4-dione and 5-fluorouracil or cis-bratin A pharmaceutical composition containing as an active ingredient, most preferably,

 5- (4-(6-methoxy-1-methyl-1H-benzoimidazo-l-l-l-methoxy) -benzyl) 1-thiazolidine- 2,4-dione,

 5-(4- (6-I-benzyloxy 1-methyl-1H-benzoimidazole-2-ylmethoxy) -i-benzyl) -thiazolidine- 1,2,4-dione, ■

 5- (4- (1-methyl-6-pentafluorophenoxy 1H-benzoimidazo-l-2-methoxy) -1benzyl) -thiazolidine-1, 4-dione,

 5- (4-(6-1 (4-amino-3,5-dimethyl-phenoxy) -1-methyl-

1H-Benzoimidazo-1-yl-2-ylmethoxy) 1-benzyl) 1-thiazolidine

4 diones,

 5- (4- (6- (4 f-sopropylamino-phenoxy)-1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) -thiazolidine- 1,2,4-dione,

 5- (4- (6- (3-isopropylamino-phenoxy) -1-1-methyl--1H-benzoimidazole-21-fluoromethoxy) -benzyl) thiazolidine- 1,2,4-dione,

5- (4- (6- (4-(ethyl-isopropyl-amino) -phenoxy) -1-1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidin-1,2,4-dione, 5- (4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazole-21-methoxy) -benzyl) -thiazolidin-2,4-dione,

 5- (4-(6-(4-(isobutyl-methyl-amino) 1-phenoxy) 1-methyl-1H-benzoimidazoyl-2-ylmethoxy) 1-benzyl) 1-thiazolidine-2,4-dione,

 5- (4-(6- (3- (isobutyl-methyl-amino) -phenoxy) -1 1-methyl-1H-benzoimidazo-1-ru-2-ylmethoxy) -1benzyl) thiazolidine-1 2,4-dione,

 5- (4-(1-Methyl-16- (4-methanesulfonylamino-1-phenoxy) -1H-benzoimidazo-1-ru-2-ylmethoxy) -1benzyl) 1-thiazolidine-2,4-dione or

 5-(4-(1-Methyl-16- (3-methanesulfonylamino-1-phenoxy) -1H-1Benzoimidazo-1-ru-2-ylmethoxy) -1benzyl) 1-thiazolidine-2,4-dione and 5-fluorouracil or cis-bratin It is a pharmaceutical composition containing as an active ingredient.

 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).

 Among the fluorouracil-based antimetabolites, which are other active ingredients of the pharmaceutical composition of the present invention, 5-fluorouracil is from Kyowa Enzyme Co., Ltd., Doxofluridine is from Nippon Roche Co., Ltd., and Tegafur is Taiho Pharmaceutical Co., Ltd. Co., Ltd.).

 Of the platinum complexes which are another active ingredient of the pharmaceutical composition of the present invention, cisplatin is obtained from Nippon Kayaku Co., Ltd., etc., carpoplatin is obtained from Bristol Pharmaceutical Co., Ltd., etc., and nedaplatin is obtained from Shionogi Pharmaceutical Co., Ltd., etc. You can do it.

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. When 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 (ιν), 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, α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose). Arabian gum; dextran; organic excipients such as pullulan; and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium metasilicate magnesium; phosphates such as calcium hydrogen phosphate; Inorganic excipients such as carbonates such as calcium carbonate; sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, magnesium stearate, etc.) Metal stearate; talc; colloidal silica; Waxes such as beeswax, gay 蠟; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium lauryl sulfate; lauryl sulfate such as magnesium lauryl sulfate. 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; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester. 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. However, for example, 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.

(Best mode for carrying out the invention)

 (Production Example 1)

 5- (4- (6- (3-Isopropylamino-1-phenoxy) -1-methyl-1- ^ 1-benzoimidazole-2-ylmethoxy) -1-benzyl) -thiazolidine-2,4-dione dihydrochloride

0.74 g of N- (2-amino-5- (3-dipropylamino-phenoxy) -phenyl) -1-N-methylcarbamic acid t-butyl ester obtained in Reference Example 2, 0.70 g of 4- (2 , 4 dioxothiazolidine-15-ylmethyl) monophenoxyacetic acid (Japanese Patent Laid-Open No. 11-1932776), 0.41 g of getyl cyanophosphonate, 0.25 g of triethylamine and 3 A mixture of 0 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate Zn-hexane = 2/3) to obtain an intermediate. N— (5- (3-Isopropylamino-phenoxy) -1-2- (4- (2,4-dioxothiazolidine-1-ylmethyl) -phenoxyacetylamino) -phenyl) —N-methylcarbamic acid t-Butyl ester was obtained. This intermediate was dissolved in 5 Om 1 of 4N hydrochloric acid / 1,4-dioxane, allowed to stand at room temperature for 16 hours, and the precipitated product was collected by filtration, washed with ethyl acetate, and treated with the title compound (0. (76 g, yield 64%).

Ή-NMR (DMSO-d ₆ ) δ: 1.21 (6Η, d, J = 6.4 Hz), 3.11 (1H, dd, J = 14 and 9.0 Hz), 3.34 (1H, dd, J = 14 and 4.4 Hz) , 3.57-3.65 (1H, m), 3.95 (3H, s), 4.9K 1H, dd, J = 9.0 and 4.4Hz), 5.63 (2H, s), 6.70-7.20 (3H, m), 7.14 (2H , d, J = 8.7Hz), 7.25 (2H, d, J = 8.7Hz), 7.25 (1H, d, J = 3.3Hz), 7.35-7.45 (1H, m), 7.68 (1H, (d, J = 1.9Hz), 7.83 (1H, d, J = 8.9Hz), 12.05 (1H, s; disappeared by adding heavy water). (Production Example 2)

 5- (4-(6-(3- (isobutyl-methyl-l-amino) -phenoxy) -l-l-l-l-l-H-benzoimidazole-l-ylmethoxy) -l-benzyl) 1-thiazolidin--2,4-dione-2 Hydrochloride, N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid obtained in Reference Example 5 instead of N- (2 —Amino-5- (3- (isobutyl-methyl-amino) phenoxy) —phenyl) 1-N-methylcarbamic acid Using t-butyl ester, the title compound was obtained in the same manner as in Production Example 1.

Ή-NMR (DMS0-d ₆ ) δ: 0.86 (6Η, d, J = 6.7 Hz), 1.90-1.99 (1H, m), 2, 91 (3H, s), 3.08-3.14 (3H, m), 3.3 (1H, dd, J = 14 and 4.4Hz), 3.94 (3H, s), 4.91 (1H, dd, J-9.0 and .4Hz), 5.65 (2H, s), 6.21 (1H, br), 6.39 (1H, br), 6.53 (1H, br), 7.15-7.27C 6H, m), 7.62 (1H, d, J-2.1Hz), 7.80 (1H, d, J = 8.9Hz), 12.04 (1H, br; disappeared by adding heavy water).

(Production Example 3)

 5- (4-(6-(4-(isobutyl) methyl-1-amino) -phenoxy) 1-1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidin-2,4-dione'dihydrochloride Salt N- (2-amino-5- (3-isopropylamino-1-phenoxy) -phenyl) -1-N-methylcarbamic acid N- (2-methyl-5-5) obtained in Reference Example 8 in place of Production Example 1 — The title compound was obtained in the same manner as in Production Example 1 using (4- (isobutyl-methyl-amino) phenoxy) -monophenyl) methylamine.

'Η-wake R (DMS0-d ₆ ) δ: 0 · 90 (6H, d, J = 4.4 Hz), 1.75-2.05 (1H, m), 1.99 (3H, s), 2.90-3.10 (2H, m), 3.11 (1H, dd, J = 14 and 8.9Hz), 3.34 (1H, dd, J = 14 and 4.4Hz), 3.92 (3H, s), 4.91 (1H , Dd, J = 8.9 and 4.4Hz), 5.62 (2H, s), 6.65-7.20 (5H, m), 7.13 (2H, d, J = 8.7Hz), 7.25 (2H, d, J = 8.7Hz) , 7.45-7.60 (1H, m), 7.78 (1H, d, J = 8.9Hz), 12.05 (1H, s; disappeared by adding heavy water).

(Production Example 4)

 5- (4-(6-(3- (ethyl-isopropyl-amino) -phenoxy)-1-methyl-1H-benzoimidazole 2-ylmethoxy) -benzyl) -thiazolidin-1 2,4-dione

5- (4- (6- (3-isopropylamino-phenoxy) -1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) obtained in Preparation Example 1 of 62 Omg 1-thiazolidine-2,4-dione 'A mixture of dihydrochloride, 66 mg of acetoaldehyde, 90 mg of acetic acid, 318 mg of sodium triacetoxyborohydride and 15 ml of anhydrous tetrahydrofuran was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Zn-hexane == 1/1) to give the title compound (26 0 mg, 48% yield).

Ή-NR (DMS0-d ₆ ) δ 1.06 (3Η, t, J = 7.0 Hz), 1.11 (6H, d, J = 6.6 Hz), 3.05 (1H, dd, J = 14 and 9.2 Hz), 3.18 ( 2H, q, J = 7.OHz), 3.31 (1H, dd, J = 14 and 4.3Hz), 3.79 (3H, s), 3.94-4.04 (1H, m), 4.87 (1H, dd, J = 9.2 And 4.3Hz), 5.63 (2H, s), 6.11 (1H, dd, J = 7.9 and 2.OHz), 6.34 (1H, t, J = 2.2Hz), 6.46 (1H, dd, J = 8.5 and 2.3 Hz), 6.92 (1H, dd, J = 8.8 and 2.2Hz), 7.06-7.11 (3H, m), 7.19 (1H, d, J = 8.7Hz), 7.28 (1H, d, J = 2.3Hz), 7.63 (1H, d, J = 8.7Hz), 12.02 (1H, s disappeared by adding heavy water).

(Production Example 5) 5- (4- (6- (4-I-isopropylamino-phenoxy) -1-methyl-1 H-benzoimidazole 2-ylmethoxy) -benzyl) 1-thiazolidine-1 2,4-dione 4- (6- (3-Isopropylamino-phenoxy) -1-1-methyl-1H-benzoimidazoyl 21-^-methoxy) 1-benzyl) 1-thiazolidine 1,2,4-dione dihydrochloride Instead, 5- (4- (6- (4-amino-phenoxy) -1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -1benzyl) -1 thiazolidine-1,2,4-dione dihydrochloride ( 11-1 93276), and the title compound was obtained in the same manner as in Production Example 4 using acetone instead of acetoaldehyde.

'Η-wake R (DMS0-d ₆ ) δ: 1.13 (6Η, d, J = 6.3 Hz), 3.05 (1H, dd, J = 14 and 9.1 Hz), 3.3K 1H, dd, J = 14 and 4.3 Hz), 3.45-3.52 (1H, m), 3.75 (3H, s), 4.87 (1H, dd, J = 9.1 and 4.3Hz), 5.24 (1H, br; disappeared by adding heavy water), 5.34 (2H, s ), 6.56 (2H, dd, J = 12 and 3.3Hz), 6.8K 2H, d, J = 8.6Hz), 6.83 (1H, dd, J = 8.2 and 2.3Hz), 7.04-7.07 (3H, m) , 7.19 (2H, d, J-8.6Hz), 7.57 (1H, d, J = 8.8Hz), 12.02 (1H, br; disappeared by adding heavy water).

(Production Example 6)

5- (4- (4- (4-sec-butylamino-phenoxy) -11-methyl-1-H-benzoimidazole-2-ylmethoxy) -1-benzyl) thiazolidine-1,2,4-dione Production Example 4-5 — (4 -— (6- (3-Isopropylamino-phenoxy) -1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -1-benzyl) monothiazolidine —2,4-dione.In place of dihydrochloride 5— (4— (6— (4-amino-phenoxy) -1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1,2,4-dione dihydrochloride, acetate The title compound was obtained in the same manner as in Production Example 4 using methyl ethyl ketone instead of the aldehyde. Ή-NMR (DMS0-d ₆ ) δ: 0.90 (3H, t, J = 7.4 Hz), 2.17 (3H, d, J = 6.4 Hz), 1.34-1.46 (IH, m), 1.48-1.59 (IH, m), 3.06 (IH, dd, J = 1 and 9.2Hz), 3.24-3.34C 2H, m), 3.75 (3H, s), 4.87 (IH, dd, J = 9.2 and 4.3Hz), 5.23 ( 1H, br; disappeared by adding heavy water), 5.34 (2H, s), 6.57 (2H, d, J = 8.7Hz), 6.81 (2H, d, J = 8.9Hz), 6.84 (1H, dd, J = 8.8) And 2.2Hz), 7.01-7.09 (3H, m), 7.19 (2H, d, J = 8.7Hz), 7.57 (IH, d, J = 8.8Hz), 12.01 '(IH, br; disappeared by adding heavy water) .

(Production Example 7)

 5- (4-(6-(4-isobutylamino-phenoxy) -1-1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidine- 1,2,4-dione Production Example 4 5- (4- ( 6- (3-Isopropylamino- 1-phenoxy) 1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) 1-thiazolidine 1-, 4-dione dihydrochloride (4-Amino-phenoxy) 1-methyl-1H-benzimidazole 2-ylmethoxy) 1-benzyl) 1-thiazolidine-2,4-dione dihydrochloride, Production example 4 using isobutylaldehyde instead of acetoaldehyde The title compound was obtained in the same manner as described above.

'Η-丽 R (DMS0-d ₆ ) δ: 0.94 (6Η, d, J = 6.7 Hz), 1.77-1.88 (1H, m), 2.78-2.81 (2H, m), 3.05 (IH, dd, J = 14 and 9.3Hz), 3.31 (IH, dd, J = and 4.3Hz), 3.74 (3H, s), 4.86 (IH, dd, J = 9.3 and 4.3Hz), 5.34 (2H, s), 5.50 ( IH, s; disappeared by adding heavy water), 6.57 (2H, dd, J = 6.8 and 2.OHz), 6.81 (2H, d, J = 8.8Hz), 6.83 (IH, dd, J = 8.6 and 2.4Hz) , 7.04-7.07 (3H,), 7.19 (2H, d, J = 8.6 Hz), 7.56 (IH, d, J = 8.8 Hz), 12. OK IH, s; disappeared by adding heavy water.

(Reference example 1)

, 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%).

'Η - NMR (DMS0 - d 6) d: 1.23 and 1.42 (total 9H, each s), 3.18 (3H, s ), 5.38 (2H, s; disappeared by the addition of heavy water), 6.25 (1H, dd, J = 7.6 and 2.4 Hz), 6.31 (1H, s), 6.46 (1H, dd, J = 8.1 and 1.0Hz), 6.88 (1H, dd, J = 9.0 and 2.1Hz), 7.09 (1H, t, J = 8.0 Hz), 7.16 (1H, s), 8.00 (1H, d, J = 9.0 Hz).

(Reference example 2)

 N- (2-Amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester '

14.4 g of N- (5- (3-aminophenoxy) -l-nitrophenyl) -l-methylcarbamic acid t-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10. A mixture of 6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2Z3) to be an intermediate. N- (5- (3-isopropylamino-phenoxy) -l-2-trophenyl) -l-N-methylcarbamic acid t-butyl ester was obtained. This intermediate was dissolved in 20 Om 1 of methanol, added with 2.02 g of 10% palladium-carbon, and vigorously stirred at room temperature under a hydrogen atmosphere for 2.5 hours. After completion of the reaction, the catalyst was removed by filtration, the solvent was distilled off, and the title compound (12.0 g, yield Rate of 81%).

• H-NMR (DMS0-d 6) δ 1.08 (6Η, d, J = 6.4Hz), 1 · 29 (9Η, s), 2.98 (· 3Η, s), 3.40-3.47 (1Η, m), 4.78 (2H, s; disappeared by adding heavy water), 5.45 (1H, d, J = 7.8Hz; disappeared by adding heavy water), 5.96 (1H, d, J = 7.2Hz), 6.07 (1H, t, J = 2.2Hz) ), 6.20 (1H, dd, J = 8.1 and 1.9 Hz), 6.60 (1H, s), 6.71 (2H, s), 6.93 (1H, t, J = 8.1 Hz).

(Reference example 3)

 N- (5- (3-bromophenoxy) -l-nitrophenyl) -l-N-methylcarbamic acid t-butyl ester

2. Add 5.0 g of 3-bromophenol to 50 ml of anhydrous N, N-dimethylformamide suspension containing 5 g of sodium hydride (55% by weight), and add Stir for 5 minutes. Then, a solution obtained by dissolving 16.6 N- (5-chloro-2-nitrophenyl) -l-N-methylcarbamic acid t-butyl ester in 70 ml of anhydrous N, N-dimethylformamide was added dropwise. The mixture was stirred at 0 ° C for 3 hours. The reaction mixture was concentrated, added with water, neutralized with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate. 'Ethyl acetate was distilled off from the extract, and the precipitated insoluble product was washed with hexane, collected by filtration, and dried under reduced pressure to obtain the title compound (20.2 g, yield 83%). Was.

_{'H-NMR (CDC1 3)} δ: 1.24 (9Η, s), 3.19 (3H, s), 6.97 (1H, dd, J = 9.0 and 2.4Hz), 7.22 (1H, d , J = 7.9Hz), 7.29 (1H, d, J = 1.7Hz), 7.42-7.51 (3H, m), 8.03 (1H, d, J = 9.0Hz).

(Reference example 4)

 N- (5- (3- (isobutyl-methyl-amino) phenoxy) -1-nitrophenyl) -N-methylcarbamic acid t-butyl ester

7 0 0. Omg of N- (5- (3-bromophenoxy) obtained in Reference Example 3 Trophenyl) -N-methylcarbamic acid t-butyl ester, 0.24 ml of isobutylmethylamine, 15 1.Omg of tris (dibenzylideneacetone) dipalladium, 15.7 mg of 2- (dicyclohexyl) (Phosphino) pifenil and 277.7 mg of potassium t-butoxide were suspended in 4 ml of anhydrous toluene and stirred at 100 for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate n-hexane = 1Z7). Thus, the title compound (204.2 mg, yield 29%) was obtained.

_{• H-NMR (CDC1 3)} δ 0 · 80 (6Η, d, J = 6.6Hz), 1.25 (9H, s), 1.88-2.01 (1H, i), .85 (3H, s), 2.95 (2H , D, J-7.3Hz), 3.14 (3H, s), 6.20-6.27 (2H, m), 6.43 (1H, dd, J = 8.8 and 2.2Hz), 6.72-6.83 (2H, m), 7.11 ( 1H, t, J = 8.1Hz), 7.81 (1H, d, J = 9.5Hz).

(Reference example 5)

 N- (2-Amino-5- (3- (isobutyl-methyl-amino) 'phenoxy) -phenyl) N-methylcarbamic acid monobutyl ester

204. 2 mg of N- (5- (3- (isobutyl-methyl-amino) phenoxy)-2-nitrophenyl) mono-N-methylcarbamic acid t_butyl ester obtained in Reference Example 4 It was dissolved in ethanol, 100 mg of 10% palladium-carbon was added, and the mixture was vigorously stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane = lZ4 → l / 3) to give the title compound (145.4mg, yield 77%).

_{Ή-NMR (CDC1 3) δ} : 0.90 (6Η, d, J-6.6Hz), 1.57 (9H, s), 1.98- 2.09 (1H, in), 2.92 (3H, s), 3.06 (2H, d, J = 7.3 Hz), 3.13 (3H, s), 3.64 (2H, s; disappeared by adding heavy water), 6.30 (1H, t, J = 2.2Hz), 6.35 (1H, dd, J = 8.1 and 2.2Hz), 6.70-6.88 (3H, m), 7.08 (1H, t, J = 8.2Hz), 7.25-7.31 (1H, m).

(Reference example 6)

 (4- (isobutyl-methyl-amino) phenoxy) 1-t-butyldimethylsilane

5 ml of (4-bromophenoxy) -t-butyldimethylsilane, 2.9 ml of isobutylmethylamine, 4.58 Omg of palladium acetate, 1.2 g of 2— (di-t (Butylphosphino) Biphenyl and 2.9 g of sodium t-butoxide were suspended in 4 Om1 of anhydrous toluene and stirred at 100 ° C for 1.5 hours. After filtering off the catalyst, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/40). The residue was purified by 1 → 20) to give the title compound (3.83 g, yield 64%).

'H- Hokusatsu _{R (CDC1 3) δ: 0.16} (6H, s), 0.91 (6Η, d, J = 6.6Hz), 0.97 (9H, s), 1.94-2.05 (1H, m), 2.87 (3H, s), 2.98 (2H, d, J = 7.3Hz), 6.57 (2H, d, J = 8.8Hz), 6.72 (2H, d, J = 8.8Hz).

(Reference example 7)

 N- (5— (4- (isobutyl-methyl mono) phenoxy) 12-nitrophenyl) methylamine

3.83 g of (4- (isobutyl-methyl-amino) phenoxy) -t-butyldimethylsilane obtained in Reference Example 6 were dissolved in 2 Om 1 of anhydrous tetrahydrofuran, and 20 ml of 1 M fluorinated A solution of tetra-n-butylammonium in tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes. Concentrate the reaction mixture, add water and add ethyl acetate Extracted. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl ethyl acetate-hexane = 1Z5). The obtained product was dissolved in 4N hydrochloric acid-1,4-dioxane fc and stirred at room temperature for 30 minutes. After the reaction solution was concentrated and washed with getyl ether, an intermediate, 4-isobutylmethylaminophenol monohydrochloride, was obtained. 2 Om containing 500. Omg of this intermediate and 2.6 g of potassium carbonate

One anhydrous N, N-dimethylformamide suspension was stirred at room temperature for 15 minutes. Then, 664.7 mg of N- (5-chloro-1--2-nitrophenyl) -1-N-methylcarbamic acid t-butyl ester was added, and the mixture was stirred at 150 ° C. for 3 hours. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate toluene = 1/30). Title compound

(256. lmg, yield 34%).

_{Ή-NMR (CDC1 3) δ} : 0 · 96 (6Η, d, J = 6.8Hz), 2.00-2.13 (lH, m), 2.92 (3H, d, J = 5.9Hz), 2.98 (3H, s) , 3.12 (2H, d, J = 7.8Hz), 6196.23 (2Η, m), 6.68 (2H, d, J = 8.8Hz), 6.96 (2H, d, J = 8.8Hz), 8.13 ( 1H, d, J = 9.8Hz).

(Reference Example 8)

N- (2-Methyl-5- (4- (isobutyl-methyl-amino) phenoxy) -phenyl) methylamine Reference Example 5 N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl Using N- (5- (4- (isobutyl-methyl-ami) phenoxy) -2-2-trophenyl) methylamine obtained in Reference Example 7 instead of 1-N-methylcarbamic acid t_butyl ester, The title compound was obtained in the same manner.

Ή-NMR (CDCb) <3: 0.88 (6H, d, J = 6.6Hz), 1.94-2.04 (lH, m), 2.77 (3H, s), 2 .87 (3H, s), 2.99 (2H, d, J = 7.3Hz), 3.22 (2H, s), 6.16 (lH, dd, J = 8.1 and 2.5Hz), 6.33 (1H, d, J = 2.5Hz) Hz), 6.57 (lH, d, J = 8.lHz), 6.59 (2H, d, J = 8.8Hz), 6.87 (2H, d, J = 8.8Hz).

(Test Example 1)

Combination effect of a compound having the ability to activate PPARa against human colorectal cancer cell line C0L-2-JCK (compound of Preparation Example 1) and 5_fluorouracil (5-Fu)

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.

The results are summarized in Table 1.

 (Table 1) Test compound dose (mg / kg) Average tumor volume S.E.

Control 4709 ± 556 Compound A 50 4658 ± 346

5-Fu 90 31 77 ± 285 Compound A 50 1695 ± 389 *

 + 5-Fu 90

*; P 0.01 vs. 5-Fu monotherapy group As can be seen from Table 1, the combination of Compound A, which has PPARr activating ability, and 5-Fu, a fluorouracil antimetabolite, was compared with each monotherapy. As a result, it showed remarkable tumor growth inhibitory activity of human colon cancer cell lines.

(Test Example 2)

Combination effect of a compound having the ability to activate PPARa against mouse colon cancer Colon 26 (compound of Preparation Example 1) and cisplatin (CDDP)

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. Note, Nippon Kayaku Co., Ltd.) 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 後 after transplantation.

Table 2 summarizes the results.

 (Table 2) Test compound dose (mg / kg) Average tumor volume S.E.

Control * 1650 M 108 Compound A 50 2026 ± 142 CDDP 10 549 ± 62 Compound A 50 253 ± 46 "

 + CDDP 10

*; Data of 6 out of 10 animals (4 animals died by 17 days)

«; Pku 0.01 vs CDDP monotherapy group

 As is evident from Table 2, the combination of Compound A having PPARr activating ability and the platinum complex CDDP showed a remarkable tumor growth inhibitory activity of human colon cancer cell lines as compared with the administration of each drug alone.

 As described above, 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.

 (Formulation example)

 Tablets

 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.

 Injection

 1.5% by weight of the compound of Preparation Example 1 and 1.5% by weight of 5-FU were stirred in 10% by volume of propylene glycol, made up to a constant volume with water for injection, and then sterilized.

(Industrial applicability)

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.

 In addition, 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) Useful as

Claims

The scope of the claims

 1.-General formula (I)

[Wherein, X represents a benzimidazole ring group (optionally substituted with 1 to 5 groups selected from a substituent group α1);

Υ ¹ represents an oxygen atom or a sulfur atom,

 Ζ

Indicates that

 R is a hydrogen atom, a CI-6 alkyl group, a C16 alkoxy group, a halogen atom, a hydroxy group, a nitro group, an amino group (substituted by one or two groups selected from a substituent group α2; Or a C7-11 aralkyl group (which may be substituted with a group selected from the substituent group α3).

 m represents an integer of 1 to 5.

In the above, the “substituent group α 1” includes a C 1-6 alkyl group, a C 16 alkoxy group, a C 7-11 aralkyloxy group, a halogen atom, a hydroxy group, a C 11-11 aliphatic acyloxy group, C1-6 alkylthio group, halogenated C1-6 alkyl group, nitro group, amino group (may be substituted with 1 or 2 groups selected from substituent group α2 C6-10 aryl group (may be substituted with 1 to 5 groups selected from substituent group 3) and C7-11 aralkyl group (selected from substituent group α3 Which may be substituted with 1 to 5 groups).

 The “substituent group α 2” includes a C 1-6 alkyl group, a C 7-11 aralkyl group, a C 6-10 aryl group, a C 11-11 aliphatic acyl group, and a C 7-11 aralkyl group. A group of substituents consisting of a methyl group and a C7-11 aromatic acyl group,

 “Substituent group << 3” includes C 1-6 alkyl group, C 1-6 alkoxy group, halogen atom, hydroxy group, nitro group, C 6-10 aryl group, halogenated C 1-6 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 α2). A pharmaceutical composition comprising, as active ingredients, a fused heterocyclic compound having the formula: and a fluorouracil-based antimetabolite or a platinum complex.

2. In the compound represented by the general formula (I), X is

W ¹

(Wherein, W ¹ and W ² each independently represent a hydrogen atom or a group selected from substituent group α 1).

 In the above, the “substituent group α 1” is a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 7-11 aralkyloxy group, an octogen atom, a hydroxy group, a C 11-11 aliphatic acyloxy group. A C 16 alkylthio group, a halogenated C 16 alkyl group, a nitro group, an amino group (optionally substituted with one or two groups selected from the substituent group α2), C 6 — 10 aryl groups (1 to 5 groups may be substituted with a group selected from substituent group α3) and C 7-11 aralkyl group (1 to 5 groups selected from substituent group α3 5 substituents may be substituted).

3. The pharmaceutical composition according to 2, wherein W ¹ is a hydrogen atom or a C 16 alkyl group.

4. The pharmaceutical composition according to 2, wherein W ¹ is a methyl group.

5. The pharmaceutical composition according to any one of 2 to 4, wherein W ² is a C 16 alkoxy group or a C 7-11 aralkyloxy group.

6. The pharmaceutical composition according to any one of 2 to 4, wherein W ² is a benzyloxy group.

7. The pharmaceutical composition according to any one of 1 to 6, wherein in the compound represented by the general formula (I), Y ¹ is an oxygen atom. '

 8. The pharmaceutical composition according to any one of 1 to 7, wherein m is 1 in the compound represented by the general formula (I).

 9. The pharmaceutical composition according to any one of 1 to 8, wherein R is a hydrogen atom in the compound represented by the general formula (I).

 10. In the compound represented by the general formula (I), Z represents the following formula

The pharmaceutical composition _c according to any one of 1 to 9, which is a group represented by

1 1. General formula (III)

[In the above formula, R ¹ is

(In the formula, R ⁴ represents a phenyl group (1 to 5 substituents selected from a substituent group; 81) or a pyridyl group (1 to 4 substituents selected from a substituent group 31) May be substituted),

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 1-6 alkylthio group, amino A group (may be substituted with a group selected from the group of substituents / 33), a C 3-10 cycloalkyl group (1 to 3 groups may be substituted with a group selected from the group of substituents 2 ), A C 6-10 aryl group (substituent group may be substituted with 1 to 3 groups selected from 32), a C 7—C 16 aralkyl group (selected from substituent group i32) May be substituted with 1 to 3 groups), C 6—C 10 aryloxy group (substituent group) 32 may be substituted with 1 to 3 groups selected from 32), C 7−1 6 aralkyloxy group (1 to 3 groups may be substituted with a group selected from substituent group / 32), C 6-10 arylylthio group (1 to 3 group (s) selected from substituent group i32) May be substituted), C 1 -7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, nitro It represents a group or Shiano group,

R ⁶ is a hydrogen atom, a C 16 alkyl group, a C 6-10 aryl group (1 to 3 substituents may be substituted with a group selected from the substituent group ^ 82), or a C 716 An aralkyl group (which may be substituted by 1 to 3 groups selected from a group of substituents i32);

Y ⁴ represents an oxygen atom or a sulfur atom,

E ¹ represents a = CH— group or a nitrogen atom. } Represents a group represented by

R ² represents a hydrogen atom, 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 (substituent Group] may be substituted with a group selected from 33), C 3-10 cycloalkyl group (may be substituted by 1 to 3 groups selected from a group selected from substituent group j82), C 6 -10 aryl groups (1 to 3 groups may be substituted with a group selected from substituent group iS2), C7-C16 aralkyl group (1 to 3 groups selected from substituent group i32) A C 6 -C 10 aryloxy group (optionally substituted with 1 to 3 groups selected from substituent groups / 32), a C 7-16 arylalkyloxy group (substituted) 1 to 3 groups may be substituted with a group selected from group j8 2), C 6-10 arylthio group (1 to 3 with a group selected from substituent group / 32) May be substituted), C 1 -7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, nitro group or cyano group Indicates that

R ³ is the formula

A group having

A ² represents a C 1-6 alkylene group,

Y ³ represents an oxygen atom or a sulfur atom. 'In the above, “substituent group] 31 represents 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 1-6 alkylthio group. Group, amino group (may be substituted with a group selected from substituent group / 33), C 3-10 cycloalkyl group (substituted with 1 to 3 groups selected from substituent group / 82) C 6-10 aryl group (may be substituted by 1 to 3 groups selected from substituent group j82), C 7 -C 16 aralkyl group (substituent group jS 1 to 3 groups may be substituted with a group selected from 2), C 6 -C 10 aryloxy group (substituent group) 1 to 3 groups may be substituted with a group selected from 32), C 7-16 aralkyl carboxyl group (1 to 3 substituents may be substituted with a group selected from substituent group β 2), C 6-10 aryl thio group (selected from substituent group 0 2 C 1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5- or 6-membered aromatic containing a nitrogen atom A substituent group consisting of a heterocyclic group, a nitro group and a cyano group,

"Substituent group] 32" includes octylogen atom, hydroxy group, C1-6 alkyl group, halogenated C1.6 alkyl group, C1-1 C6 alkoxy group, amino group (substituent group] 3 Which may be substituted with a group selected from 3), C 6 -C 10 aryl group and a nitro group,

"Substituent group] 33" is a C1-10 alkyl group, a C6-10 aryl group, a C7-1 6 containing an aralkyl group, a C1-7 aliphatic aliphatic group, a C7-11 aromatic aromatic group, a C8-12 aromatic aliphatic acyl group, a C4-11 cycloalkyl group, and a nitrogen atom Or a substituent group consisting of a 6- to 6-membered aromatic heterocyclic carbonyl group. A pharmaceutical composition comprising, as an active ingredient, a substituted condensed heterocyclic compound having the above formula, and a fluoro / ourouracyl antimetabolite or a platinum complex.

1 2. In the compound represented by the general formula (III), R ¹ is

11. The pharmaceutical composition according to 11, which is a group represented by:

1 3. The pharmaceutical composition according to any one of 11 or 12, wherein R ⁵ is a hydrogen atom in the compound represented by the general formula (III).

14. The pharmaceutical composition according to any one of 11 to 13, wherein in the compound represented by the general formula (III), R ⁶ is a methyl group.

15. The pharmaceutical composition according to any one of 11 to 14, wherein in the compound represented by the general formula (III), Y ⁴ is an oxygen atom.

1 6. In the compound represented by the general formula (III), R ⁴ is a phenyl group (1 to 5 substituted with a group selected from a substituent group j81①) or a pyridyl group (a substituent group: 81① The pharmaceutical composition according to any one of 11 to 15, wherein 1 to 4 groups may be substituted with the selected group.

 In the above, “Substituent group ΐ①” represents a halogen atom, a C 1-6 alkyl group, a halogenated C 16 alkyl group, an amino group (one or two substituted with a group selected from the substituent group j33. ), 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.

The “substituent group jS 3” includes a C 11-10 alkyl group, a C 6-10 aryl group, a C 7-16 aralkyl group, a C 1—C 7 aliphatic acyl group, and a C 7-11 aromatic group. Aliphatic acyl group, C 8-12 araliphatic aliphatic acyl group, C 4-11 cycloalkyl radical group and nitrogen atom A group of substituents consisting of a 5- or 6-membered aromatic heterocyclic carbonyl group containing a substituent.

1 7. The pharmaceutical composition according to any one of 11 to 15, wherein in the compound represented by the general formula (III), Y ³ is an oxygen atom.

1 8. The pharmaceutical composition according to any one of 11 to 17, wherein in the compound represented by the general formula (III), R ² is a hydrogen atom.

1 9. The pharmaceutical composition according to any one of 11 to 18, wherein in the compound represented by the general formula (III), A ² is a methylene group.

20. —In the compound represented by the general formula (III), R ³ is

Is a group represented by, the pharmaceutical composition _c according to any one of 11 to 19

2 1. The compound represented by the general formula (III) is represented by the following general formula

The pharmaceutical composition _c according to any one of claims 20 to 20, which is a compound represented by:

22. General formula (IV)

[Wherein, R ⁷ represents a carbamoyl group (which may be substituted with one or two groups selected from a substituent group r 1), a thiocarbamoyl group (a group selected from a substituent group a 1 May be substituted with one or two), a sulfonyl group (having one group selected from the substituent group a1) or a sulfonyl group (a group selected from the substituent group a1) Has one).

¹⁸ and ¹⁹ are each independently a hydrogen atom, a C10-10 alkyl group, a C6-1 0 aryl group (1 to 3 groups may be substituted with a group selected from substituent group r 2) or C 7-16 aralkyl group (aryl group is 1 Or three may be substituted),

A ³ , A ⁴ and A ⁵ each independently represent a single bond or a C 1-8 alkylene group;

Υ ⁵ , Υ ⁶ and 及 び⁷ each independently represent an oxygen atom or a sulfur atom,

Ε ² represents a = CH— group or a nitrogen atom,

 Ar represents a benzene ring or a naphthalene ring,

 L is 1 to 4 substituents on the Ar ring, each of which is a hydrogen atom, a C 16 alkyl group, a C 6-10 aryl group (a group selected from the substituent group a 2; 3) may be substituted) or C 7-16 aralkyl group (the aryl moiety may be substituted by 1 to 3 groups selected from substituent group a2).

 In the above, “substituent group a 1” includes a C 11-10 alkyl group, a halogenated C 16 alkyl group, a C 3-10 cycloalkyl group, and a C 6-10 aryl group (substituent group 1). 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 r 3 C 4-11 cycloalkylcarbonyl group, C 7-11 aromatic acyl group (even when one to three aryl groups are substituted with a group selected from substituent group a3) C8-17 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 (substituted) One or three groups may be substituted with a group selected from group a3), a 5- or 6-membered aromatic heterocyclic carbonyl group (selected from substituent group a3) May be substituted with 1 to 3 selected groups), C 1-6 alkylsulfonyl group, halogenated C 1-6 alkylsulfonyl group, C 6-10 arylsulfonyl group (where aryl is a substituent 1 to 3 groups which may be substituted with a group selected from group a3) and a C 7-16 aralkylsulfonyl group (where the aryl moiety is 1 to 3 groups selected from a substituent group a3) Which may be substituted)

“Substituent group a2” includes a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, 1-6 alkoxy group, halogen atom, hydroxy group, C 6-10 aryl group (optionally substituted with 1 to 3 groups selected from substituent group a4), C 7-16 aralkyl Groups (aryl moieties may be substituted one to three times with a group selected from substituent group a4), cyano group, nitro group, and amino group (one or a group selected from substituent group a4) Two substituents may be substituted)

 “Substituent group 3 j is a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group, a halogen atom, a hydroxy group, a cyano group, a nitro group, a C 3-10 cyclo group. An 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, or a halogen atom, which is substituted with 1 to 3 groups; A C 7-16 aralkyl group (where the aryl moiety is a C 16 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group and a halogen atom, 1 to 3 may be substituted), C1-7 aliphatic acyl group, C17 aliphatic aliphaticoxy group, amino group, diC16 alkylamino group and C1-4 alkylenedioxy group A group of substituents,

The “substituent group r 4” includes a C 11-10 alkyl group, a C 6-10 aryl group (a C 16 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkoxy group and a halogen atom A group selected from the group consisting of 1 to 3 substituents), a C 7-16 aralkyl group (where the aryl moiety is a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, 1 to 3 groups may be substituted with a group selected from 17 alkoxy groups and halogen atoms), C 17 aliphatic aliphatic group, C 4-11 cycloalkylcarbonyl group, C 7-11 An aromatic acyl group (1 to 3 of which may be substituted with a group 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), C 8 -17 aralkyl radical group (where the aryl moiety is a C 16 alkyl group or a halogenated C 1 _ 6 alkyl group 1 to 3 groups selected from C 16 alkoxy groups and halogen atoms may be substituted), 5- or 6-membered aromatic heterocyclic group, luponyl group (C 16 alkyl group, halogenated C 1 1 to 3 alkyl groups, C 1-6 alkoxy groups and halogen atoms, which may be substituted by 1 to 3 groups). Amine derivative compound having the formula: A pharmaceutical composition containing an antagonist or a platinum complex as an active ingredient.

23. The pharmaceutical composition according to 22, wherein in the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (having one group selected from substituent group a1).

24. In the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (C 1-6 alkyl group, halogenated C 1-6 alkyl group and C 6-10 aryl group (substituent group a 3 23. The pharmaceutical composition according to claim 22, which is substituted with one to three groups which may be substituted with a group selected from:

25. The pharmaceutical composition according to 22, wherein in the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (substituted with a C 16 alkyl group).

26. The pharmaceutical composition according to any one of 22 to 25, wherein in the compound represented by the general formula (IV), R ⁸ is a hydrogen atom or a C 1-6 alkyl group. '

27. The pharmaceutical composition according to any one of 22 to 26, wherein in the compound represented by the general formula (IV), A ³ is a single bond.

28. The pharmaceutical composition according to any one of 22 to 27, wherein in the compound represented by the general formula (IV), A ⁴ is a single bond.

29. The pharmaceutical composition according to any one of 22 to 28, wherein in the compound represented by the general formula (IV), A ⁵ is a methylene group.

30. The pharmaceutical composition according to any one of 22 to 29, wherein in the compound represented by the general formula (IV), Y ⁵ is an oxygen atom.

31. The pharmaceutical composition according to any one of 22 to 30, wherein in the compound represented by the general formula (IV), Y ⁶ is an oxygen atom.

32. The pharmaceutical composition according to any one of 22 to 31, wherein in the compound represented by the general formula (IV), Y ⁷ is a sulfur atom.

33. The pharmaceutical composition according to any one of 22 to 32, wherein in the compound represented by the general formula (IV), E ² is a == CH_ group.

 34. The pharmaceutical composition according to any one of 22 to 33, wherein Ar is a benzene ring in the compound represented by the general formula (IV).

35. In the compound represented by the general formula (IV), L is a hydrogen atom or C 16 35. The pharmaceutical composition according to any one of 22 to 34, which is a alkyl group.

 36. The pharmaceutical composition according to any one of 1 to 35, wherein the fluorouracil antimetabolite is 5-fluorouracil, doxofluridine, or tegafur.

 37. The pharmaceutical composition according to any one of 1 to 35, wherein the fluorouracil-based antimetabolite is tegafur or 5-fluorouracil.

 38. The pharmaceutical composition according to any one of 1 to 35, wherein the fluorouracil antimetabolite is 5-fluorouracil.

 '39. The pharmaceutical composition according to any one of 1 to 35, wherein the platinum complex is cisplatin, carpoplatin, or nedaplatin.

 40. The pharmaceutical composition according to any one of 1 to 35, wherein the platinum complex is cisplatin or carpoplatin.

 41. The pharmaceutical composition according to any one of 1 to 35, wherein the platinum complex is cisplatin.

 42. 5- (4- (6-Hydroxy-1,2,5,7,8-tetramethyl-chroman-2-ylmethoxy) -1-benzyl) monothiazolidine_2,4-dione, 5- (4-

(2- (5-Ethyl-pyridine-1-2-yl) -1-ethoxy) benzyl) 1-thiazolidin-1 2,4-dione or 5- (4- (2-1 (methyl-pyridine-2-ylamino) 1-ethoxy) 1-benzyl A pharmaceutical composition comprising monothiazolidine mono 2,4-dione and 5-fluorouracil or cisplatin as active ingredients.

 43. The pharmaceutical composition according to any one of 1 to 42, for administering each active ingredient simultaneously or separately at an interval.

 44. A cell growth inhibitor comprising the pharmaceutical composition according to any one of 1 to 43.

45. An antitumor agent comprising the pharmaceutical composition according to any one of 1 to 43.