Pharmaceutical composition

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

[Technical field to which the invention belongs]

In the present invention, a fused heterocyclic compound having PPARγ activating ability or a pharmacologically acceptable salt thereof and a diphenylamine derivative having MEK inhibitory ability or a pharmacologically acceptable salt thereof are administered simultaneously or separately at intervals. The present invention relates to a pharmaceutical composition, a cell growth inhibitor or an antitumor agent.

【0002】

[Conventional technology]

A cell growth inhibitor consisting of a PPARγ activator and a MAP kinase inhibitor is disclosed (see, for example, Patent Document 1). However, the publication only predicts that the combined use of these compounds will suppress cell growth on the basis of increased fat accumulation, and the combined use of these compounds actually suppresses cell growth. It does not show that. Further, the publication specifically discloses a cell growth inhibitor using troglitazone as a PPARγ activator and PD098059 as a MAP kinase inhibitor, and cell growth obtained by a combination thereof. The inhibitory effect was not sufficient.

【0003】

[Patent Document 1]

U.S. Pat. No. 6,242,196 [0004]

[Problems to be Solved by the Invention]

As a result of diligent studies to find a combination of drugs having more excellent cell growth inhibitory activity, the inventors of the present application, etc. have found that compound (I), compound (III) or compound (IV) having PPARγ activating ability or its pharmacology. It has been found that it is more useful as a cell growth inhibitor to use a combination of an acceptable salt and a diphenylamine derivative having MEK inhibitory ability or a pharmacologically acceptable salt thereof.

【0005】

In addition, the inventors have described troglitazone, pioglitazone or rosiglitazone having PPARγ activating ability and 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy- which is a diphenylamine derivative having MEK inhibitory ability. We have also found that the combined use of 3,4-difluoro-benzamide is more useful as a cell growth inhibitor, and have completed the present invention.

【0006】

[Means for solving problems]

The present invention relates to a pharmaceutical composition containing a compound having a PPARγ activating ability and a compound having a MEK inhibitory ability.

【0007】

A compound having PPARγ activating ability, which is one of the active ingredients of the pharmaceutical composition of the present invention, has the following general formula (I). [0008]

[Chemical 15]

<img file="JP2003192592A_D0001.tif" />【0009】

[In the formula, X represents a benzimidazole ring group (1 to 5 may be substituted with a group selected from the substituent group α1), and Y¹Indicates an oxygen atom or a sulfur atom, and Z is [0010]

[Chemical 16]

<img file="JP2003192592A_D0002.tif" />【0011】

Indicates that R is a hydrogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom, a hydroxy group, a nitro group, or an amino group (one or two substituted groups selected from the substituent group α2). Or C7-11 aralkyl group (which may be substituted with a group selected from the substituent group α3), where m is an integer of 1-5.

【0012】

In the above, the "substituent group α1" refers to C1-6 alkyl group, C1-6 alkoxy group, C7-11 aralkyloxy group, halogen atom, hydroxy group, C1-11 aliphatic acyloxy group, C1-6 alkylthio group, Halogenized C1-6 alkyl group, nitro group, amino group (one or two may be substituted with a group selected from the substituent group α2), C6-10 aryl group (selected from the substituent group α3). It is a substituent group consisting of 1 to 5 substituents (may be substituted with 1 to 5 groups) and a C7-11 aralkyl group (1 to 5 groups may be substituted with a group selected from the substituent group α3). Substituent group α2 is a substituent consisting of a C1-6 alkyl group, a C7-11 aralkyl group, a C6-10 aryl group, a C1-11 aliphatic acyl group, a C7-11 aralkylcarbonyl group and a C7-11 aromatic acyl group. A group of groups, the "substituent group α3" is a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom, a hydroxy group, a nitro group, a C6-10 aryl group, a halogenated C1-6 alkyl group and an amino group. It is a substituent group consisting of (1 or 2 may be substituted with a group selected from the substituent group α2). ] Condensed heterocyclic compound, general formula (III) [0013]

[Chemical 17]

<img file="JP2003192592A_D0003.tif" />【0014】

[In the above formula, R¹Is [0015]

[Chemical 18]

<img file="JP2003192592A_D0004.tif" />【0016】

[In the formula, R⁴Is a phenyl group (1 to 5 substituted with a group selected from the substituent group β1) or a pyridyl group (1 to 4 substituted with a group selected from the substituent group β1). Show, R⁵Is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group (a group selected from the substituent group β3). Substituted), C3-10 cycloalkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-10 aryl group (group selected from the substituent group β2) 1 to 3 substituted with C7-C16 aralkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-C10 aryloxy group (substituent group β2) 1 to 3 substituted with a group selected from), C7-16 aralkyloxy group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-10 arylthio group (1 to 3 may be substituted with a group selected from the substituent group β2), C1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5 containing a nitrogen atom. Or 6-membered aromatic heterocyclic group, nitro group or cyano group, R⁶Is a hydrogen atom, a C1-6 alkyl group, a C6-10 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group β2) or a C7-16 aralkyl group (selected from the substituent group β2). 1 to 3 may be substituted with the groups to be), and Y⁴Indicates an oxygen atom or a sulfur atom, E¹Indicates = CH-group or nitrogen atom. Indicates a group represented by }, R²Is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, an amino group (a group selected from the substituent group β3). Substituted), C3-10 cycloalkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-10 aryl group (group selected from the substituent group β2) 1 to 3 substituted with C7-C16 aralkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-C10 aryloxy group (substituent group β2) 1 to 3 substituted with a group selected from), C7-16 aralkyloxy group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-10 arylthio group (1 to 3 may be substituted with a group selected from the substituent group β2), C1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, 5 containing a nitrogen atom. Or 6-membered aromatic heterocyclic group, nitro group or cyano group, R³Is an expression [0017]

[Chemical 19]

<img file="JP2003192592A_D0005.tif" />【0018】

Indicates a group having²Indicates a C1-6 alkylene group, Y³Indicates an oxygen atom or a sulfur atom.

【0019】

In the above, the "substituent group β1" refers to a halogen atom, a hydroxy group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, and an amino group (substituent group β3). C3-10 cycloalkyl group (may be substituted with 1 to 3 groups selected from substituent group β2), C6-10 aryl group (may be substituted with a group selected from), C6-10 aryl group (substituent group) 1 to 3 substituted with a group selected from β2), C7-C16 aralkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-C10 aryloxy Group (1 to 3 may be substituted with a group selected from the substituent group β2), C7-16 aralkyloxy group (1 to 3 may be substituted with a group selected from the substituent group β2) , C6-10 arylthio group (1 to 3 may be substituted with a group selected from the substituent group β2), C1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, It is a substituent group consisting of a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, a nitro group and a cyano group, and the "substituent group β2" is a halogen atom, a hydroxy group, a C1-6 alkyl group, or a halogenated group. It is a substituent group consisting of a C1-6 alkyl group, a C1-C6 alkoxy group, an amino group (which may be substituted with a group selected from the substituent group β3), a C6-C10 aryl group and a nitro group. "Substituent group β3" includes C1-10 alkyl group, C6-10 aryl group, C7-16 aralkyl group, C1-7 aliphatic acyl group, C7-11 aromatic acyl group, C8-12 aromatic aliphatic acyl group, C4-11 A group of substituents consisting of a 5- to 6-membered aromatic heterocyclic carbonyl group containing a cycloalkylcarbonyl group and a nitrogen atom. ], Substituent condensation heterocyclic compound, general formula (IV) [0020]

[Chemical 20]

<img file="JP2003192592A_D0006.tif" />【0021】

[In the formula, R⁷Is a carbamoyl group (which may be substituted with one or two groups selected from the substituent group γ1), a thiocarbamoyl group (which may be substituted with one or two groups selected from the substituent group γ1). Good), sulfonyl group (has one group selected from the substituent group γ1) or carbonyl group (has one group selected from the substituent group γ1), R⁸And R⁹Are each independently a hydrogen atom, a C1-10 alkyl group, a C6-10 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group γ2) or a C7-16 aralkyl group (which may be substituted with 1 to 3). The aryl moiety may be substituted with 1 to 3 groups selected from the substituent group γ2), and A³, A⁴And A⁵Independently indicate a single bond or C1-8 alkylene group, Y⁵, Y⁶And Y⁷Independently indicate an oxygen atom or a sulfur atom, and E²Indicates a = CH- group or nitrogen atom, Ar indicates a benzene ring or a naphthalene ring, and L is 1 to 4 substituents on the Ar ring, which are a hydrogen atom and a C1-6 alkyl group, respectively. C6-10 aryl group (1 to 3 may be substituted with a group selected from the substituent group γ2) or C7-16 aralkyl group (aryl moiety 1 to 3 with a group selected from the substituent group γ2) It may be replaced).

【0022】

A group selected from a luryl group, a C1-6 alkoxy group and a halogen atom, which may be substituted with 1 to 3 groups), a C7-16 aralkyl group (aryl moiety is a C1-6 alkyl group, halogenated C1- A group selected from 6 alkyl groups, C1-6 alkoxy groups and halogen atoms, which may be substituted 1 to 3), C1-7 aliphatic acyl group, C1-7 aliphatic acyloxy group, amino group, It is a substituent group consisting of a di-C1-6 alkylamino group and a C1-4 alkylenedioxy group, and the "substituent group γ4" is a C1-10 alkyl group and a C6-10 aryl group (C1-6 alkyl group, halogen). C1-6 alkyl group, C1-6 alkoxy group and group selected from halogen atom, which may be substituted with 1 to 3 groups, C7-16 aralkyl group (aryl moiety is C1-6 alkyl group, A group selected from a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom, which may be substituted 1 to 3), a C1-7 aliphatic acyl group, a C4-11 cycloalkylcarbonyl group. , C7-11 aromatic acyl group (1 to 3 may be substituted with a group selected from C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom), C8 -17 Aralkylcarbonyl group (aryl moiety may be substituted with 1 to 3 groups selected from C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom), 5- or 6-membered aromatic heterocyclic carbonyl group (1 to 3 may be substituted with a group selected from C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom) It is a group of substituents consisting of. ] Amine derivative, 5- (4- (6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (4- (2- (5-Ethyl-pyridin-2-yl) -ethoxy) benzyl) -thiazolidine-2,

【0023】

In addition, the compound having MEK inhibitory ability, which is one of the active ingredients of the pharmaceutical composition of the present invention, has the following general formula (II). [0024]

[Chemical 21]

<img file="JP2003192592A_D0007.tif" />【0025】

[In the formula, R^aIndicates a bromine atom or iodine atom, R^{b b}Indicates a hydrogen atom, a hydroxy group, a C1-8 alkyl group (which may be substituted with a group selected from the substituent group δ), a C1-8 alkoxy group, a halogen atom, a trifluoromethyl group or a cyano group. , R^cIs-COOR^gGroup, tetrazolyl group, -CONR^gR^hGroup, -CONHNRⁱR^jGroup, -CH₂OR^gGroup or -C (= O) -NR^kOR^lBasic {in formula, R^gAnd R^hAre independently substituted with a hydrogen atom, a C1-8 alkyl group (which may be substituted with a group selected from the substituent group δ), and a C2-8 alkenyl group (substituent with a group selected from the substituent group δ). (May be substituted), C2-8 alkynyl group (may be substituted with a group selected from the substituent group δ), C1-8 alkylcarbonyl group, C6-10aryl group, 5- or 6-membered aromatic Shows a heterocyclic group, a 3- to 10-membered aliphatic heterocyclic group or a C3-10 cycloalkyl group, or R^gAnd R^hShows a 3- to 10-membered aliphatic heterocycle with the binding nitrogen atom, RⁱAnd R^jIndependently indicate a hydrogen atom, a C1-8 alkyl group, or RⁱAnd R^jShows a 3- to 10-membered aliphatic heterocyclic group together with the nitrogen atom to which it binds, R^kIs a hydrogen atom, a C1-8 alkyl group (which may be substituted with a group selected from the substituent group δ), a C1-8 alkylcarbonyl group, a C6-10aryl group, a C7-14 aralkyl group or C3-. Shows 10 cycloalkyl groups, R^lIs a hydrogen atom, a C1-8 alkyl group (which may be substituted with a group selected from the substituent group δ), a C2-8 alkenyl group (which may be substituted with a group selected from the substituent group δ). Good), C2-8 alkynyl group (which may be substituted with a group selected from the substituent group δ), C3-10 cycloalkyl group, showing 3-10 member aliphatic heterocyclic groups}, R^d, R^eAnd R^fAre independent of hydrogen atom, hydroxy group, halogen atom, trifluoromethyl group, C1-8 alkyl group (may be substituted with a group selected from the substituent group δ), C1-8 alkoxy group. , Nitro group, cyano group or -Y²A¹R^mIndicates a group (in the formula, Y²Indicates a single bond, oxygen atom or -NH- group, A¹Indicates a single bond or C1-4 alkylene group, R^mIs a hydrogen atom, a hydroxy group, a carboxyl group or -NRⁱR^jGroup (RⁱAnd R^jHas the same meaning as above).

【0026】

In the above, the substituent group δ is a halogen atom, a hydroxy group, a C1-6 alkoxy group, an amino group (one or two may be substituted with a C1-6 alkyl group), a C3-10 cycloalkyl group, and a C6. It is a group of substituents consisting of a -10aryl group, a C6-10aryloxy group, a 5- or 6-membered aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic oxy group. ] Is a diphenylamino derivative or a pharmacologically acceptable salt thereof.

【0027】

In the above, the "C1-6 alkyl group", "C1-8 alkyl group" or "C1-10 alkyl group" means a direct group having 1 to 6, 1 to 8 or 1 to 10 carbon atoms, respectively. A chain or branched alkyl group.

【0028】

Examples of the "C1-6 alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 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 or 2-ethylbutyl group can be mentioned, preferably a linear or branched alkyl group having 1 to 4 carbon atoms. is there.

【0029】

Examples of the "C1-8 alkyl group" include the groups mentioned as examples of the "C1-6 alkyl group" or 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 or 5,5-dimethylhexyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms.

【0030】

Examples of the "C1-10 alkyl group" include the groups mentioned as examples of the "C1-8 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 group It can be mentioned, preferably a linear or branched alkyl group having 1 to 4 carbon atoms.

【0031】

The "halogenated C1-6 alkyl group" is the "C1-6 alkyl group" substituted with a halogen atom, and is, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoro. Methyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6- Iodohexyl or 2,2-dibromoethyl group can be mentioned.

【0032】

The "C3-10 cycloalkyl group" is a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl or cyclodecanyl group. It can be mentioned, preferably a 5- to 10-membered saturated cyclic hydrocarbon group.

【0033】

The "C1-4 alkylene group", "C1-6 alkylene group" or "C1-8 alkylene group" is a linear chain having 1 to 4 carbon atoms, 1 to 6 carbon atoms or 1 to 8 carbon atoms, respectively. Alternatively, it is a branched alkylene group.

【0034】

Examples of the "C1-4 alkylene group" include methylene, methylmethylene, ethylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene or 3-methyltrimethylene group.

【0035】

The "C1-6 alkylene group" includes the groups mentioned as examples of the "C1-4 alkylene group" or pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetra. Methylene, 5-methyltetramethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltriethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1,3-dimethyltrimethylene or Hexamethylene groups can be mentioned.

【0036】

Examples of the "C1-8 alkylene group" include the groups mentioned as examples of the "C1-6 alkylene group", and heptamethylene or octamethylene groups.

【0037】

The "C1-4 alkylenedioxy group" is a group to which the "C1-4 alkylene group" is bonded at both ends via an oxygen atom, and is, for example, methylenedioxy, methylmethylenedioxy, or ethylenedioxy. , Trimethylenedioxy, 1-methylethylenedioxy, 2-methyltrimethyldioxy, 3-methyltrimethyldioxy or tetramethylenedioxy groups.

【0038】

A "C2-8 alkenyl group" is a linear or branched alkenyl group having 2 to 8 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl. , 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1 -Methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl , 1-Pentenyl, 2-Pentenyl, 1-Methyl-2-Pentenyl, 2-Methyl-2-Pentenyl, 3-Pentenyl, 1-Methyl-3-Pentenyl, 2-Methyl-3-Pentenyl, 4-Pentenyl, 1 -Methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 3-heptanyl or 3-octanyl group can be mentioned.

【0039】

A "C2-8 alkynyl group" is a linear or branched alkenyl group having 2 to 8 carbon atoms, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl. -2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3 -Butynyl, 2-Methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl , 2-Methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl group. ..

【0040】

The "C6-10 aryl group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl and a naphthyl group, and a phenyl group is preferable.

【0041】

The "C7-11 arylyl group", "C7-14 arylyl group" or "C7-16 arylyl group" are the above-mentioned groups having 7 to 11 carbon atoms, 7 to 14 carbon atoms or 7 to 16 carbon atoms, respectively. An "aryl group" is a group bonded to the "alkyl group".

【0042】

Examples of the "C7-11 aralkyl group" include benzyl, α-naphthylmethyl, β-naphthylmethyl, 1-phenyl, 2-phenyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenyl. Phenyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl or 5-phenylpentyl groups can be mentioned and are preferred. Is an aralkyl group in which a phenyl group is bonded to a C1-4 alkyl group, and more preferably a benzyl group.

【0043】

Examples of the "C7-14 aralkyl group" include the groups mentioned as examples of the "C7-11 aralkyl group" or diphenylmethyl, 1-naphthylethyl, 2-naphthylethyl, 1-naphthylpropyl, 2-naphthylpropyl, and the like. 3-naphthylpropyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl or 6-Phenylhexyl group can be mentioned, preferably an aralkyl group in which a phenyl group is bonded to a C1-4 alkyl group, and more preferably a benzyl group.

【0044】

Examples of the "C7-16 aralkyl group" include the group mentioned as an example of the "C7-11 aralkyl group" or the "C7-14 aralkyl group", or a 5-naphthylpentyl or 6-naphthylhexyl group. It is possible, preferably an aralkyl group in which a phenyl group is bonded to a C1-4 alkyl group, and more preferably a benzyl group.

【0045】

The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom.

【0046】

The "C1-6 alkoxy group" or "C1-8 alkoxy group" is a group to which the "C1-6 alkyl group" or "C1-8 alkyl group" is bonded via an oxygen atom, respectively.

【0047】

Examples of the "C1-6 alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, and 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 can be mentioned, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms.

【0048】

Examples of the "C1-8 alkoxy group" include the groups mentioned as examples of the "C1-6 alkoxy group" or heptyloxy, 1-methylhexyloxy, 2-methylhexyloxy, 3-methylhexyloxy, 4-. Methylhexyloxy, 5-methylhexyloxy, 1-propylbutoxy, 4,4-dimethylpentyloxy, octyloxy, 1-methylheptyloxy, 2-methylheptyloxy, 3-methylheptyloxy, 4-methylheptyloxy, 5-Methylheptyloxy, 6-methylheptyloxy, 1-propylpentyloxy, 2-ethylhexyloxy or 5,5-dimethylhexyloxy group can be mentioned, preferably a linear or linear group having 1 to 4 carbon atoms. It is a branched alkoxy group.

【0049】

The "C6-10 aryloxy group" is a group to which the "C6-10 aryl group" is bonded via an oxygen atom, and examples thereof include a phenoxy, indenyloxy or naphthyloxy group. , Preferably a phenoxy group.

【0050】

The "C7-11 aralkyloxy group" or "C7-16 aralkyloxy group" is a group to which the "C7-11 aralkyl group" or "C7-16 aralkyl group" is bonded via an oxygen atom, respectively. ..

【0051】

Examples of the "C7-11 aralkyloxy group" include benzyloxy, α-naphthylmethoxy, β-naphthylmethoxy, 1-phenyloxy, 2-phenyloxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy. , 1-Phenyl Butoxy, 2-Phenyl Butoxy, 3-Phenyl Butoxy, 4-Phenyl Butitoxy, 1-Phenylpentyloxy, 2-Phenylpentyloxy, 3-Phenylpentyloxy, 4-Phenylpentyloxy or 5-Phenylpentyl An oxy group can be mentioned.

【0052】

Examples of the "C7-16 aralkyloxy group" include the groups mentioned as examples of the "C7-11 aralkyloxy group" or diphenylmethoxy, 1-naphthylethoxy, 2-naphthylethoxy, 1-naphthylpropoxy, 2-naphthyl. Propoxy, 3-naphthylpropoxy, 1-naphthylbutoxy, 2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3-phenylhexyloxy, 4-phenylhexyloxy , 5-Phenylhexyloxy, 6-Phenylhexyloxy, 5-naphthylpentyloxy or 6-naphthylhexyloxy group can be mentioned, preferably an aralkyloxy group in which the phenyl group is bonded to a C1-4 alkyl group. Yes, more preferably a benzyloxy group.

【0053】

The "C1-6 alkylthio group" is a group to which the "C1-6 alkyl group" is bonded via a sulfur atom, and is, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyl. Thio, s-butylthio, tert-butylthio, n-pentylthio, isopentilthio, 2-methylbutylthio, neopentylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, List 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio group be able to.

【0054】

The "C6-10 arylthio group" is a group to which the "C6-10 aryl group" is bonded via a sulfur atom, and examples thereof include a phenylthio, indenylthio or naphthylthio group.

【0055】

The "C1-8 alkylcarbonyl group" is a group to which the "C1-8 alkyl group" is bonded via a carbonyl group, and is, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl. , Heptanoyl or octanoyl groups can be mentioned.

【0056】

The "C1-7 aliphatic acyl group" or "C1-11 aliphatic acyl group" is a linear or branched saturated or unsaturated fat having 1 to 7 carbon atoms or 1 to 11 carbon atoms, respectively. It is a group acyl group.

【0057】

Examples of the "C1-7 aliphatic acyl group" include alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl or hexanoyl groups; (E) -2-methyl-2-butenoyl. Alkenylcarbonyl groups such as groups; or alkynylcarbonyl groups such as 3-butinoyl groups can be mentioned.

【0058】

Examples of the "C1-11 aliphatic acyl group" include the groups mentioned as examples of the "C1-7 aliphatic acyl group" or octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl. , 3-Ethyloctylcarbonyl, alkylcarbonyl groups such as 3,7-dimethyloctylcarbonyl group and the like.

【0059】

The "C1-7 aliphatic acyloxy group" or "C1-11 aliphatic acyloxy group" means that the "C1-7 aliphatic acyl group" or "C1-11 aliphatic acyl group" is bonded via an oxygen atom, respectively. It is a group that does.

【0060】

Examples of the "C1-7 aliphatic acyloxy group" include alkylcarbonyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy, isovaleryloxy or hexanoyloxy groups. An alkenylcarbonyloxy group such as (E) -2-methyl-2-butenoyloxy group; or an alkynylcarbonyloxy group such as 3-butinoyloxy group can be mentioned.

【0061】

Examples of the "C1-11 aliphatic acyloxy group" include the groups mentioned as examples of the "C1-7 aliphatic acyloxy group" or octanoyloxy, nonylcarbonyloxy, decylcarbonyloxy, 3-methylnonylcarbonyloxy, and the like. Examples thereof include alkylcarbonyloxy groups such as 8-methylnonylcarbonyloxy, 3-ethyloctylcarbonyloxy or 3,7-dimethyloctylcarbonyloxy group.

【0062】

The "C4-11 cycloalkylcarbonyl group" is a group to which the "C3-10 cycloalkyl group" is bonded via a carbonyl group, and is, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexyl. A carbonyl or cycloheptylcarbonyl group can be mentioned, preferably a C6-8 cycloalkylcarbonyl group.

【0063】

The "C7-11 aromatic acyl group" is a group to which the "C1-6 aryl group" is bonded via a carbonyl group, and examples thereof include benzoyl, α-naphthoyl and β-naphthoyl groups. it can.

【0064】

The "C7-11 aralkylcarbonyl group" is a group in which the carbonyl group is substituted with the "C7-11 aralkyl group", and examples thereof include a benzylcarbonyl group.

【0065】

The "C8-12 aralkylcarbonyl group" is a group to which the "C7-11 aralkyl group" is bonded via a carbonyl group, and examples thereof include a benzylcarbonyl group.

【0066】

The "C8-12 aromatic aliphatic acyl group" is a group consisting of a linear or branched saturated or unsaturated hydrocarbon group to which an aromatic aliphatic group is bonded via a carbonyl group, for example. A benzylcarbonyl group can be mentioned.

【0067】

The "C1-6 alkylsulfonyl group" is a group to which the "C1-6 alkyl group" is bonded via a sulfonyl group, and is, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n. -Butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, n-hexylsulfonyl, 4-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl , 2,2-Dimethylbutylsulfonyl, 3-dimethylbutylsulfonyl or 2,3-dimethylbutylsulfonyl group.

【0068】

The "C6-10 arylsulfonyl group" is a group to which the "C1-6 aryl group" is bonded via a sulfonyl group, and examples thereof include a phenylsulfonyl group, an indenylsulfonyl group, and a naphthylsulfonyl group. ..

【0069】

The "C7-16 aralkyl sulfonyl group" is a group to which the "C7-16 aralkyl sulfonyl group" is attached via a sulfonyl group, and is, for example, benzylsulfonyl, α-naphthylmethylsulfonyl, β-naphthylmethylsulfonyl, 1-Phenetyl Sulfonyl, 2-Phenetyl Sulfonyl, 1-Phenylpropyl Sulfonyl, 2-Phenylpropyl Sulfonyl, 3-Phenylpropyl Sulfonyl, 1-Phenylbutyl Sulfonyl, 2-Phenylbutyl Sulfonyl, 3-Phenylbutyl Sulfonyl, 4-Phenylbutyl Sulfonyl, 1-phenylpentylsulfonyl, 2-phenylpentylsulfonyl, 3-phenylpentylsulfonyl, 4-phenylpentylsulfonyl, 5-phenylpentylsulfonyl, diphenylmethylsulfonyl, 1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1- Naftylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 1-phenylhexylsulfonyl, 2-phenylhexyl Sulfonyl, 3-phenylhexylsulfonyl, 4-phenylhexylsulfonyl, 5-phenylhexylsulfonyl, 6-phenylhexylsulfonyl, 5-naphthylpentylsulfonyl or 6-naphthylhexylsulfonyl groups can be mentioned.

【0070】

The "di-C1-6 alkylamino group" is an amino group substituted with two of the "C1-6 alkyl group", and the substituents may be the same or different. Examples of such a group include dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, methylisopropylamino, butylmethylamino, t-butylmethylamino, methylpentylamino or hexylmethylamino group.

【0071】

A "5- or 6-membered aromatic heterocyclic group" is a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / and nitrogen atoms, for example, frills, thienyl, and the like. Examples thereof include pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridadinyl, pyrimidinyl or pyrazinyl groups.

【0072】

The "3- to 10-membered aliphatic heterocyclic group" is a 3- to 10-membered aliphatic heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms or / and nitrogen atoms, and is morpholinyl, thiomorpholinyl, pyrrolidinyl, and the like. Examples thereof include pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolydinyl, pyrazolinyl, piperidyl, and piperazinyl groups.

【0073】

A "4- to 7-membered saturated heterocyclic group containing a nitrogen atom" is a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom and may contain an oxygen atom or a sulfur atom. For example, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazoridinyl, pyrazolinyl, piperidyl or piperazinyl groups can be mentioned.

【0074】

A "5- to 6-membered aromatic heterocyclic group containing a nitrogen atom" is a 5- to 6-membered aromatic heterocyclic group containing at least one nitrogen atom and may contain an oxygen atom or a sulfur atom. There are, for example, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl or pyrazinyl groups.

【0075】

The "5- or 6-membered aromatic heterocyclic oxy group" is a group to which the "5- or 6-membered aromatic heterocyclic group" is bonded via an oxygen atom. Azepinyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thiadiazolyloxy , Pyraniloxy, pyridyloxy, pyridadinyloxy, pyrimidinyloxy or pyrazineloxy groups.

【0076】

The "5- or 6-membered aromatic heterocyclic carbonyl group" is a group to which the "5- or 6-membered aromatic heterocyclic group" is bonded via a carbonyl group, and is, for example, a frill carbonyl, a thienyl carbonyl, or a pyrrolyl. Lucarbonyl, Azepinylcarbonyl, Pyrazolylcarbonyl, Imidazolylcarbonyl, Oxazolylcarbonyl, Isoxazolylcarbonyl, Thiazolylcarbonyl, Isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, Triazolylcarbonyl , Tetrazolylcarbonyl, thiadiazolylcarbonyl, pyranylcarbonyl, pyridylcarbonyl, pyridadinylcarbonyl, pyrimidinylcarbonyl or pyrazineylcarbonyl groups.

【0077】

"Substituent group α1" includes C1-6 alkyl group, C1-6 alkoxy group, C7-11 aralkyloxy group, halogen atom, hydroxy group, C1-11 aliphatic acyloxy group, C1-6 alkylthio group, halogenated C1. -6 Alkyl group, nitro group, amino group (1 or 2 may be substituted with a group selected from the substituent group α2), C6-10 aryl group (1 with a group selected from the substituent group α3) It is a substituent group consisting of up to 5 substituents) and a C7-11 aralkyl group (1 to 5 may be substituted with a group selected from the substituent group α3).

【0078】

The "substituent group α2" consists of a C1-6 alkyl group, a C7-11 aralkyl group, a C6-10 aryl group, a C1-11 aliphatic acyl group, a C7-11 aralkylcarbonyl group and a C7-11 aromatic acyl group. It is a group of substituents.

【0079】

"Substituent group α3" includes C1-6 alkyl group, C1-6 alkoxy group, halogen atom, hydroxy group, nitro group, C6-10 aryl group, halogenated C1-6 alkyl group and amino group (substituent group α2). It is a group of substituents (which may be substituted with 1 or 2 groups selected from).

【0080】

In the above, the "substituent group β1" refers to a halogen atom, a hydroxy group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 alkylthio group, and an amino group (substituent group β3). C3-10 cycloalkyl group (may be substituted with 1 to 3 groups selected from substituent group β2), C6-10 aryl group (may be substituted with a group selected from), C6-10 aryl group (substituent group) 1 to 3 substituted with a group selected from β2), C7-C16 aralkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-C10 aryloxy Group (1 to 3 may be substituted with a group selected from the substituent group β2), C7-16 aralkyloxy group (1 to 3 may be substituted with a group selected from the substituent group β2) , C6-10 arylthio group (1 to 3 may be substituted with a group selected from the substituent group β2), C1-7 aliphatic acyloxy group, 4- to 7-membered saturated heterocyclic group containing a nitrogen atom, A group of substituents consisting of a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, a nitro group and a cyano group, preferably a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, an amino. A group (which may be substituted with one or two groups selected from the substituent group β3), a 4- to 7-membered saturated heterocyclic group containing a nitrogen atom and a 5- or 6-membered aromatic complex containing a nitrogen atom. It is a substituent group β1 consisting of a ring group.

【0081】

The "substituent group β2" is substituted with a halogen atom, a hydroxy group, a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-C6 alkoxy group, and an amino group (a group selected from the substituent group β3). A group of substituents consisting of a C6-C10 aryl group and a nitro group.

【0082】

"Substituent group β3" includes C1-10 alkyl group, C6-10 aryl group, C7-16 aralkyl group, C1-7 aliphatic acyl group, C7-11 aromatic acyl group, C8-12 aromatic aliphatic acyl group. , C4-11 A group of substituents consisting of a 5- to 6-membered aromatic heterocyclic carbonyl group containing a cycloalkylcarbonyl group and a nitrogen atom.

【0083】

In the above, the "substituent group γ1" is a C1-10 alkyl group, a halogenated C1-6 alkyl group, a C3-10 cycloalkyl group, a C6-10 aryl group (a group selected from the substituent group γ3, 1 to 1 to 3 substituted), C7-16 aralkyl group (aryl moiety may be substituted 1 to 3 with a group selected from the substituent group γ3), C4-11 cycloalkylcarbonyl group, C7 -11 Aromatic acyl group (aryl moiety may be substituted with 1 to 3 groups selected from substituent group γ3), C8-17 Aralkylcarbonyl group (aryl moiety is selected from substituent group γ3) 1 to 3 substituted with a group), 5 or 6-membered aromatic heterocyclic group (may be 1 to 3 substituted with a group selected from the substituent group γ3), 5 or 6-membered Aromatic heterocyclic carbonyl group (1 to 3 may be substituted with a group selected from the substituent group γ3), C1-6 alkylsulfonyl group, halogenated C1-6 alkylsulfonyl group, C6-10 arylsulfonyl Group (1 to 3 aryl moieties may be substituted with a group selected from the substituent group γ3) and C7-16 aralkylsulfonyl group (1 to 3 aryl moieties selected from the substituent group γ3) It is a group of substituents (which may be substituted).

【0084】

The "substituent group γ2" is a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom, a hydroxy group, and a C6-10 aryl group (a group selected from the substituent group γ4). 1 to 3 substituted), C7-16 aralkyl group (aryl moiety may be substituted 1 to 3 with a group selected from the substituent group γ4), cyano group, nitro group and amino It is a group of substituents consisting of groups (one or two may be substituted with a group selected from the group of substituents γ4).

【0085】

"Substituent group γ3" includes C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group, halogen atom, hydroxy group, cyano group, nitro group, C3-10 cycloalkyl group, C6-10. Aaryl group (a group selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom, which may be substituted 1 to 3), a C7-16 aralkyl group ( The aryl moiety is a group selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom, which may be substituted 1 to 3), C1-7 aliphatic. It is a group of substituents composed of an acyl group, a C1-7 aliphatic acyloxy group, an amino group, a diC1-6 alkylamino group and a C1-4 alkylenedioxy group.

【0086】

"Substituent group γ4" is a group selected from C1-10 alkyl group, C6-10 aryl group (C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom, 1 Up to 3 substituted), C7-16 aralkyl group (aryl moiety selected from C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom. 1 to 3 substituted), C1-7 aliphatic acyl group, C4-11 cycloalkylcarbonyl group, C7-11 aromatic acyl group (C1-6 alkyl group, halogenated C1-6 alkyl group, 1 to 3 substituted with a group selected from C1-6 alkoxy group and halogen atom), C8-17 aralkylcarbonyl group (aryl moiety is C1-6 alkyl group, halogenated C1-6 alkyl group , C1-6 alkoxy groups and groups selected from halogen atoms, which may be substituted 1 to 3), 5- or 6-membered aromatic heterocyclic carbonyl groups (C1-6 alkyl groups, halogenated C1-6 alkyls) It is a group of substituents (1 to 3 may be substituted with a group selected from a group, a C1-6 alkoxy group and a halogen atom).

【0087】

The "substituent group δ" is a halogen atom, a hydroxy group, a C1-6 alkoxy group, an amino group (one or two may be substituted with a C1-6 alkyl group), a C3-10 cycloalkyl group, and a C6. It is a group of substituents consisting of a -10aryl group, a C6-10aryloxy group, a 5- or 6-membered aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic oxy group.

【0088】

As compound (I), which is one of the active ingredients of the pharmaceutical composition of the present invention, (1) X is preferably used. [0089]

[Chemical 22]

<img file="JP2003192592A_D0008.tif" />【0090】

(During the formula, W¹And W²Independently indicate a hydrogen atom or a group selected from the substituent group α1. ) Is the base compound. (2) In (1), W¹Is a compound that is a hydrogen atom or a C1-6 alkyl group. (3) In (1), W¹Is a compound that is a methyl group. (4) In (1), W²Is a compound which is a C1-6 alkoxy group or a C7-11 aralkyloxy group. (5) W²Is a compound that is a benzyloxy group. (6) Y¹A compound in which is an oxygen atom. (7) A compound in which m is 1. (8) A compound in which R is a hydrogen atom. (9) Z is the following formula [0091]

[Chemical 23]

<img file="JP2003192592A_D0009.tif" />【0092】

The compound which is the group represented by. (10) A compound in which the above (1) to (4), (5), (6), (7), (8) and (9) are appropriately combined.

【0093】

Suitable as compound (III), which is one of the active ingredients of the pharmaceutical composition of the present invention, (11) R¹Is the following formula [0094]

[Chemical 24]

<img file="JP2003192592A_D0010.tif" />【0095】

The compound which is the group represented by. (12) R⁵Is a compound in which is a hydrogen atom. (13) R⁶A compound in which is a methyl group. (14) Y⁴A compound in which is an oxygen atom. (15) R⁴Is a phenyl group (1 to 5 substituted with a group selected from the substituent group β1) or a pyridyl group (1 to 4 may be substituted with a group selected from the substituent group β1). Compound. (16) Y³Is an oxygen atom compound. (17) R²Is a compound in which is a hydrogen atom. (18) A²Is a compound that is a methylene group. (19) R³Is the following formula [0096]

[Chemical 25]

<img file="JP2003192592A_D0011.tif" />【0097】

The compound which is the group represented by. (20) A compound in which the above (11), (12), (13), (14), (15), (16), (17), (18) and (19) are appropriately combined.

【0098】

Suitable as compound (IV), which is one of the active ingredients of the pharmaceutical composition of the present invention, (21) R⁷Is a sulfonyl group (having one group selected from the substituent group γ1). (22) R⁷Is a group selected from a sulfonyl group (C1-6 alkyl group, halogenated C1-6 alkyl group and C6-10 aryl group (1 to 3 may be substituted with a group selected from the substituent group γ3). A compound that is (replaced with). (23) R⁷Is a sulfonyl group (substituted with a C1-6 alkyl group). (24) R⁸Is a compound that is a hydrogen atom or a C1-6 alkyl group. (25) A³Is a single bond compound. (26) A⁴Is a single bond compound. (27) A⁵Is a compound that is a methylene group. (28) Y⁵A compound in which is an oxygen atom. (29) Y⁶A compound in which is an oxygen atom. (30) Y⁷A compound in which is a sulfur atom. (31) E²Is a compound whose = CH-group. (32) A compound in which Ar is a benzene ring. (33) A compound in which L is a hydrogen atom or a C1-6 alkyl group. (34) The above (21) to (23), (24), (25), (26), (27), (28), (29), (30), (31), (32) and (33) ) Appropriately combined.

【0099】

Further, 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide is preferably used as a diphenylamine derivative which is one of the active ingredients of the pharmaceutical composition of the present invention. (Hereinafter referred to as "PD-184352").

【0100】

In the pharmaceutical composition of the present invention, 5- (4- (6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione (hereinafter, " "Troglitazone") is described in JP-A-6-51189 with the following structural formula. [0101]

[Chemical 26]

<img file="JP2003192592A_D0012.tif" />【0102】

It is a compound having.

【0103】

5- (4- (2- (5-Ethyl-pyridin-2-yl) -ethoxy) benzyl) -thiazolidine-2,4-dione (hereinafter referred to as "pioglitazone") is published in European Patent Publication No. 00306228. The following structural formula described in [0104]

[Chemical 27]

<img file="JP2003192592A_D0013.tif" />【0105】

It is a compound having.

【0106】

5- (4- (2- (Methyl-pyridine-2-yl-amino) -ethoxy) -benzyl) -thiazolidine-2,4-dione (hereinafter referred to as "logiglitazone") is published in International Publication No. 91 / The following structural formula described in Gazette No. 2003 [0107]

[Chemical 28]

<img file="JP2003192592A_D0014.tif" />【0108】

It is a compound having.

【0109】

Compound (I), compound (III), compound (IV) and a diphenylamine derivative or troglitazone, rosiglitazone and pioglitazone, which are the active ingredients of the pharmaceutical composition of the present invention, are each added to a salt according to a conventional method, if desired. Such salts are also included in the present invention. Among such salts, the salt with the acid includes, for example, salts of inorganic acids such as hydrochlorides, hydrobromates, sulfates, nitrates, phosphates; acetates, fumarates, maleates. , Salts of carboxylic acids such as oxalate, malonate, succinate, citrate, malate; sulfonic acids such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate, etc. Salts; salts of amino acids such as glutamate and asparagate; salts with bases include, for example, salts with alkali metals such as lithium salt, sodium salt, potassium salt; calcium salt, Salts with alkaline earth metals such as magnesium salts; or salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts can be mentioned.

【0110】

The compound (I), compound (III) or compound (IV) and the diphenylamine derivative, which are the active ingredients of the pharmaceutical composition of the present invention, may have steric isomers and / or geometric isomers, respectively. Each or a mixture thereof is included in the present invention.

【0111】

Compound (I), compound (III) or compound (IV) and a diphenylamine derivative or troglitazone, rosiglitazone and pioglitazone, which are the active ingredients of the pharmaceutical composition of the present invention, are present as hydrates or solvates, respectively. However, each of them or any mixture thereof is included in the present invention.

【0112】

In the present invention, "simultaneous administration" is not particularly limited as long as it can be administered at substantially the same time, but it is preferably administered as a single composition.

【0113】

Further, "administer separately at intervals" is not particularly limited as long as it can be administered separately at different times, but for example, a diphenylamine derivative or a pharmacologically acceptable salt thereof is first administered. Then, after a predetermined time, compound (I), compound (III) or compound (IV) or a pharmacologically acceptable salt thereof may be administered.

【0114】

In the pharmaceutical composition of the present invention, preferably 5- (4- (6-methoxy-1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5 -(4- (6-ethoxy-1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6-isopropoxy-1-methyl) -1H-Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6-benzyloxy-1-methyl-1H-Benzoimidazole-2-ylmethoxy)) -Benzyl) -thiazolidine-2,4-dione, 5-(4- (1-methyl-6-pentafluorophenoxy-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione , 5- (4- (6- (4-Amino-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-( 6- (3-Amino-Phenoxy) -1-Methyl-1H-Benzoimidazole-2-ylmethoxy) -benzyl) -Thiazolidine-2,4-dione, 5- (4- (6- (4-Amino-) 3,5-dimethyl-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (pyridine) -2-yloxy) -1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (5-amino-pyridine-2-yloxy) -1) -Methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-be Nzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-( 4- (6- (3- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4 -(6- (4- (Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (4- (6- (3- (Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-( 6- (4-Dimethylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-dimethyl) Amino-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (ethyl-methyl-amino)) -Phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3- (ethyl-methyl-amino))- Phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (4- (butyl-methyl-amino))-phenoxy) ) -1-Methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (3- (butyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4 -Dione, 5- (4- (6- (4-diethylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4 -(6- (3-diethylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (4- (4-) 4-) (Butyl-Ethyl-Amino) -Phenoxy) -1-Methyl-1H-Benzoimidazol-2-ylmethoxy) -benzyl) -Thiazolidine-2,4-dione, 5- (4- (6- (3- (3-) Butyl-ethyl-amino) -phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- ( 4-Phenylamino-phenoxy) -1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (3-phenylamino-phenoxy)) ) -1H-Benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (4-pyrrolidin-1-yl-phenoxy))-1H -Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (3-pyrrolidin-1-yl-phenoxy))-1H-ben Zoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (1-methyl-6- (4-piperidin-1-yl-phenoxy) -1H-benzo) Imidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (1-methyl-6- (3-piperidin-1-yl-phenoxy) -1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4 -Dione, 5-(4- (1-methyl-6- (4-morpholin-4-yl-phenoxy) -1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-Methyl-6- (3-morpholin-4-yl-phenoxy) -1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-( 4- (1-Methyl-6- (4-methanesulfonylamino-phenoxy) -1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, or 5- (4- (4- ( 1-Methyl-6- (3-Methylsulfonylamino-phenoxy) -1H-Benzoimidazole-2-ylmethoxy) -benzyl) -Thiazolidine-2,4-dione or their pharmacologically acceptable salts and 2- Pharmaceutical composition for administering (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or pharmaceutically acceptable salts thereof simultaneously or separately at intervals. And more preferably 5- (4- (6-methoxy-1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4). -(6-Benzyloxy-1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (1-methyl-6-pentafluorophenoxy-) 1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (4-amino-3,5-dimethyl-phenoxy) -1-methyl-1H -Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-Isopropylamino-phenoxy) -1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (6-) (4- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (6-( 3- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4) -(Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3- (3- (3-) 3-) (Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-dimethyl) Amino-phenoxy) -1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-dimethylamino-phenoxy) -1) -Methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-diethylamino-phenoxy) -1-methyl-1H-ben Zoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-diethylamino-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -Benzyl) -thiazolidine-2,4-dione, 5-(4- (1-methyl-6- (4-pyrrolidin-1-yl-phenoxy) -1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione , 5- (4- (1-Methyl-6- (3-pyrrolidin-1-yl-phenoxy) -1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-Methyl-6- (4-morpholin-4-yl-phenoxy) -1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-) (1-Methyl-6- (3-morpholin-4-yl-phenoxy) -1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1- (1-) Methyl-6- (4-Methylsulfonylamino-phenoxy) -1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione or 5- (4- (1-methyl-6) -(3-Methylsulfonylamino-phenoxy) -1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione or their pharmacologically acceptable salts and 2- (2-chloro- A pharmaceutical composition for administering 4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or a pharmaceutically acceptable salt thereof simultaneously or separately at intervals, and the most. Preferably, 5- (4- (6-methoxy-1-methyl-1H-benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6-benzyl) Oxy-1-methyl-1H-benzoymidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6-pentafluorophenoxy-1H-benzo) Imidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-amino-3,,)5-Dimethyl-phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-isopropylamino-phenoxy)) -1-Methyl-1H-Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H -Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (4- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H- Benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-be Nzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (4- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-ben Zoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-(4- (6- (3- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzo Imidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (4-methanesulfonylamino-phenoxy) -1H-benzoimidazol-2-ylmethoxy) )-Benzyl) -Thiazolidine-2,4-dione, or 5- (4- (1-methyl-6- (3-methanesulfonylamino-phenoxy) -1H-benzoimidazol-2-ylmethoxy) -benzyl )-Thiazolidine-2,4-dione or pharmaceutically acceptable salts thereof and 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or their pharmacology A pharmaceutical composition for administering the above acceptable salts simultaneously or separately at intervals.A pharmaceutical composition for administering 4-difluoro-benzamide or a pharmacologically acceptable salt thereof separately at the same time or at intervals.

【0115】

BEST MODE FOR CARRYING OUT THE INVENTION

One of the active ingredients of the pharmaceutical composition of the present invention, compound (I) is JP-A-2000-001487 (WO00 / 18081), and compound (III) is JP-A-11-193276 (WO99 / 18081). The compound (IV) can be easily produced according to the method described in JP-A-2000-351779 (WO00 / 61581).

【0116】

The diphenylamine derivative, which is another active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof can be easily produced according to the method described in WO98 / 37881.

【0117】

Compound (I), compound (III) or compound (IV), which is the active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof, and a diphenylamine derivative or a pharmacologically acceptable salt thereof are used alone. It can be adjusted to a separate unit dosage form or a mixture to physically adjust to a single dosage form.

【0118】

When the pharmaceutical composition of the present invention in such a single unit administration form or a mixed single administration form is used as a prophylactic or therapeutic agent for the above-mentioned diseases, the active ingredient of the pharmaceutical composition of the present invention is used. Compound (I), compound (III) or compound (IV) or a pharmacologically acceptable salt thereof, and / or a diphenylamine derivative or a pharmacologically acceptable salt thereof, respectively, or as appropriate pharmacology. Mix with pharmacologically acceptable excipients, diluents, etc., and administer orally with tablets, capsules, granules, powders, syrups, etc., or parenterally with injections, suppositories, etc. be able to.

【0119】

These formulations are excipients (eg, sugar derivatives such as lactose, sucrose, grape sugar, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α starch, dextrin; cellulose derivatives such as crystalline cellulose; Arabian gum; dextran; organic excipients such as purulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate; phosphates such as calcium hydrogen phosphate; carbonic acid Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate can be mentioned), lubricants (eg, metal stearate such as stearic acid, calcium stearate, magnesium stearate). Tarku; Colloidal silica; Bead waxes, waxes such as gay wax; Boric acid; Excipients; Sulfates such as sodium sulfate; Glycols; Fumaric acid; Sodium benzoate; DL leucine; Sodium lauryl sulfate, Magnesium lauryl sulfate Such as lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; and the above-mentioned starch derivatives can be mentioned, binders (eg, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, etc.). And cellulose derivatives such as disintegrants (eg, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally crosslinked sodium carboxymethyl cellulose; carboxymethyl starch). , Carboxymethyl starch sodium, chemically modified starches and celluloses such as crosslinked polyvinylpyrrolidone, emulsifiers (eg, bentonite, colloidal clays such as bee gum; magnesium hydroxide, aluminum hydroxide, etc. Metal hydroxides; Anionic surfactants such as sodium lauryl sulfate, calcium stearate; Cationic surfactants such as benzalkonium chloride;And nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters), stabilizers (paraoxybenzoic acid esters such as methylparaben, propylparaben; Alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenols, phenols such as cresol; timerosal; dehydroacetic acid; and sorbic acid can be mentioned), flavoring agents (eg, sorbic acid). , Usually used, such as sweeteners, acidulants, fragrances, etc.), produced by a well-known method using additives such as diluents.

【0120】

Dosage and administration of compound (I), compound (III) or compound (IV), which is the active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof, and a diphenylamine derivative or a pharmacologically acceptable salt thereof. The ratio can vary depending on various conditions such as the activity of the individual drug, the patient's symptoms, age, weight and the like.

【0121】

The dose varies depending on the symptoms, age, etc., but in the case of oral administration, the lower limit of 0.1 mg (preferably 0.5 mg) and the upper limit of 1000 mg (preferably 500 mg) are administered parenterally, respectively. In some cases, the lower limit is 0.01 mg (preferably 0.05 mg) and the upper limit is 100 mg (preferably 50 mg), 1 to 6 times a day for adults, at the same time or at intervals depending on the symptoms. It can be administered separately.

【0122】

In addition, compound (I), compound (III) or compound (IV) or a pharmacologically acceptable salt thereof has an arteriosclerosis in the present invention rather than the dose as an antihyperlipidemic agent which is the original use. For prophylactic or therapeutic applications of arteriosclerosis, their doses can be lower and the doses can be further reduced due to the superior effect of the combination with the diphenylamine derivative or a pharmacologically acceptable salt thereof.

【0123】

In addition, the dose of compound (I), compound (III) or compound (IV), which is the active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof, and a diphenylamine derivative or a pharmacologically acceptable salt thereof. The ratio of compound (I), compound (III) or compound (IV) or a pharmacologically acceptable salt thereof and a dose of a diphenylamine derivative or a pharmacologically acceptable salt thereof, for example, may vary significantly. The ratio can be in the range of 1: 500 to 500: 1 by weight.

【0124】

[Example]

Hereinafter, the present invention will be described in more detail with reference to production examples, test examples, and formulation examples, but the scope of the present invention is not limited thereto. (Manufacturing example 1) 5- (4- (6- (3-Isopropylamino-phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid obtained in Reference Example 2 of 0.74 g t-Butyl ester, 0.70 g 4- (2,4-dioxothiazolidine-5-ylmethyl) -phenoxyacetic acid (Japanese Patent Laid-Open No. 11-193276), 0.41 g diethyl cyanophosphonate, 0.25 g triethylamine and 30 ml anhydrous The mixture of tetrahydrofuran was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated, water was added and the mixture was 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 (eluting solvent: ethyl acetate / n-hexane = 2/3) to be an intermediate N. -(5- (3-Isopropylamino-phenoxy) -2- (4- (2,4-dioxothiazolidine-5-ylmethyl) -phenoxyacetylamino) -phenyl) -N-methylcarbamic acid t-butyl ester is obtained. It was. This intermediate was dissolved in 50 ml of 4N hydrochloric acid / 1,4-dioxane, left at room temperature for 16 hours, and the precipitated results were collected by filtration, washed with ethyl acetate, and the title compound (0.76 g, yield 64) was obtained. %) Was obtained.

【0125】

¹H-NMR (DMSO-d₆) δ: 1.21 (6H, d, J = 6.4Hz), 3.11 (1H, dd, J = 14 and 9.0Hz), 3.34 (1H, dd, J = 14 and 4.4Hz), 3.57-3.65 (1H, m) ), 3.95 (3H, s), 4.91 (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, 1H, d, J = 8.9Hz), 12.05 (1H, s; disappeared by adding heavy water). (Manufacturing example 2) 5- (4- (6- (3- (Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride N- (2-amino-5) obtained in Reference Example 5 instead of N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester of Production Example 1 -(3- (Isobutyl-methyl-amino) phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester was used to obtain the title compound in the same manner as in Production Example 1.

【0126】

¹H-NMR (DMSO-d₆) δ: 0.86 (6H, d, J = 6.7Hz), 1.90-1.99 (1H, m), 2,91 (3H, s), 3.08-3.14 (3H, m), 3.34 (1H, dd, J = 14 and 4.4Hz), 3.94 (3H, s), 4.91 (1H, dd, J = 9.0 and 4.4Hz), 5.65 (2H, s), 6.21 (1H, br), 6.39 (1H, br), 6.53 ( 1H, br), 7.15-7.27 (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). (Manufacturing example 3) 5- (4- (6- (4- (Isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride N- (2-Methyl-5) obtained in Reference Example 8 instead of N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester of Production Example 1 -(4- (Isobutyl-methyl-amino) phenoxy) -phenyl) methylamine was used to obtain the title compound in the same manner as in Production Example 1.

【0127】

¹H-NMR (DMSO-d₆) δ: 0.90 (6H, d, J = 4.4Hz), 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). (Manufacturing example 4) 5- (4- (6- (3- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione 5- (4- (6- (3-Isopropylamino-phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione-2 obtained in Production Example 1 of 620 mg A mixture of hydrochloride, 66 mg acetaldehyde, 90 mg acetic acid, 318 mg sodium triacetoxyhydride and 15 ml anhydrous tetrahydrofuran was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added and the mixture was 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 (eluting solvent: ethyl acetate / n-hexane = 1/1) to obtain the title compound (260 mg, Yield 48%) was obtained.

【0128】

¹H-NMR (DMSO-d₆) δ: 1.06 (3H, t, J = 7.0Hz), 1.11 (6H, d, J = 6.6Hz), 3.05 (1H, dd, J = 14 and 9.2Hz), 3.18 (2H, q, J = 7.0) Hz), 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 2.0Hz), 6.34 (1H, t, J = 2.2Hz), 6.46 (1H, dd, J = 8.5 and 2.3Hz), 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 = 8.7) Hz), 12.02 (1H, s; disappeared by adding heavy water). (Manufacturing example 5) 5- (4- (6- (4-Isopropylamino-phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione Substitute for 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride in Production Example 4 5- (4- (6- (4-Amino-phenoxy) -1-methyl-1H-benzimidazol 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride (Japanese Patent Laid-Open No. 11-193276) ), Using acetone instead of acetaldehyde, the title compound was obtained in the same manner as in Production Example 4.

【0129】

¹H-NMR (DMSO-d₆) δ: 1.13 (6H, d, J = 6.3Hz), 3.05 (1H, dd, J = 14 and 9.1Hz), 3.31 (1H, dd, J = 14 and 4.3Hz), 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 heavy water addition), 5.34 (2H, s), 6.56 (2H, dd, J = 12 and 3.3Hz), 6.81 (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 = 8.6) Hz), 7.57 (1H, d, J = 8.8Hz), 12.02 (1H, br; disappeared by adding heavy water). (Manufacturing example 6) 5- (4- (6- (4-sec-Butylamino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione Substitute for 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride in Production Example 4 5- (4- (6- (4-Amino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride, methyl ethyl ketone instead of acetaldehyde Was used to obtain the title compound in the same manner as in Production Example 4.

【0130】

¹H-NMR (DMSO-d₆) δ: 0.90 (3H, t, J = 7.4Hz), 2.17 (3H, d, J = 6.4Hz), 1.34-1.46 (1H, m), 1.48-1.59 (1H, m), 3.06 (1H, dd) , J = 14 and 9.2Hz), 3.24-3.34 (2H, m), 3.75 (3H, s), 4.87 (1H, dd, J = 9.2 and 4.3Hz), 5.23 (1H, br; disappeared by heavy water addition) , 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 (1H, d, J = 8.8Hz), 12.01 (1H, br; disappeared by adding heavy water). (Manufacturing example 7) 5- (4- (6- (4-isobutylamino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione Substitute for 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride in Production Example 4 5- (4- (6- (4-Amino-phenoxy) -1-methyl-1H-benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride, isobutyl instead of acetaldehyde The title compound was obtained in the same manner as in Production Example 4 using aldehyde.

【0131】

¹H-NMR (DMSO-d₆) δ: 0.94 (6H, d, J = 6.7Hz), 1.77-1.88 (1H, m), 2.78-2.81 (2H, m), 3.05 (1H, dd, J = 14 and 9.3Hz), 3.31 (1H) , dd, J = 14 and 4.3Hz), 3.74 (3H, s), 4.86 (1H, dd, J = 9.3 and 4.3Hz), 5.34 (2H, s), 5.50 (1H, s; disappeared by heavy water addition) , 6.57 (2H, dd, J = 6.8 and 2.0Hz), 6.81 (2H, d, J = 8.8Hz), 6.83 (1H, dd, J = 8.6 and 2.4Hz), 7.04-7.07 (3H, m), 7.19 (2H, d, J = 8.6Hz), 7.56 (1H, d, J = 8.8Hz), 12.01 (1H, s; disappeared by adding heavy water). (Reference example 1) N-(5- (3-Aminophenoxy) -2-nitrophenyl) -N-Methylcarbamic acid t-butyl ester 5.45 g of 3-aminophenol was added to 80 ml of anhydrous N, N-dimethylformamide suspension containing 2.18 g of sodium hydride (55% by weight), and the mixture was stirred at room temperature for 20 minutes. Then, 14.3 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester (Japanese Patent Laid-Open No. 11-193276) was added little by little, and the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was concentrated, water was added and neutralized with 3N hydrochloric acid and baking soda powder. The precipitated insoluble results were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (16.6 g, yield 92%).

【0132】

¹H-NMR (DMSO-d₆) δ: 1.23 and 1.42 (total 9H, each s), 3.18 (3H, s), 5.38 (2H, s; disappeared by heavy water addition), 6.25 (1H, dd, J = 7.6 and 2.4Hz), 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 = 8.0Hz), 7.16 (1H, s) , 8.00 (1H, d, J = 9.0Hz). (Reference example 2) N- (2-Amino-5- (3-Isopropylamino-Phenoxy) -Phenyl) -N-Methylcarbamic Acid t-Butyl Ester 14.4 g N- (5- (3-aminophenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester, 2.90 g acetone, 3.00 g acetic acid, 10.6 g triacetoxyhydroborane sodium And 200 ml of a mixture of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, water was added and the mixture was 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 (eluting solvent: ethyl acetate / n-hexane = 2/3) to be an intermediate N. -(5- (3-Isopropylamino-phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester was obtained. This intermediate was dissolved in 200 ml of methanol, 2.02 g 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 to obtain the title compound (12.0 g, yield 81%).

【0133】

¹H-NMR (DMSO-d₆) δ: 1.08 (6H, d, J = 6.4Hz), 1.29 (9H, s), 2.98 (3H, s), 3.40-3.47 (1H, m), 4.78 (2H, s; disappeared by heavy water addition), 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 1.9Hz), 6.60 (1H, s), 6.71 (2H, s), 6.93 (1H, t, J = 8.1Hz). (Reference example 3) N-(5- (3-Bromophenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester 10.0 g of 3-bromophenol was added to 50 ml of anhydrous N, N-dimethylformamide suspension containing 2.5 g of sodium hydride (55% by weight), and the mixture was stirred under ice-cooling for 15 minutes. Then, 16.6 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester dissolved in 70 ml of anhydrous N, N-dimethylformamide was added dropwise, and the mixture was added dropwise at 100 ° C. for 3 hours. Stirred. The reaction mixture was concentrated, water was added, neutralized with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the precipitated insoluble results were washed with hexane and collected by filtration, and dried under reduced pressure to give the title compound (20.2 g, yield 83%).¹H-NMR (CDCl₃) δ: 1.24 (9H, 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) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester 700.0 mg of N- (5- (3-bromophenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester obtained in Reference Example 3, 0.24 ml of isobutylmethylamine, 151.0 mg of tris (dibenzylidene) Alpine) dipalladium, 115.7 mg 2- (dicyclohexylphosphino) biphenyl and 277.7 mg potassium t-butoxide were suspended in 4 ml anhydrous toluene and stirred at 100 ° C. for 1.5 hours . Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/7). Then, the title compound (204.2 mg, yield 29%) was obtained.¹H-NMR (CDCl₃) δ: 0.80 (6H, d, J = 6.6Hz), 1.25 (9H, s), 1.88-2.01 (1H, m), 2.85 (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 t-butyl ester The N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester obtained in Reference Example 4 of 204.2 mg was dissolved in 10 ml of ethanol and 100.0. 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 filtered off and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/4 1/3) to obtain the title compound (145.4 mg, yield 77%).¹H-NMR (CDCl₃) δ: 0.90 (6H, d, J = 6.6Hz), 1.57 (9H, s), 1.98-2.09 (1H, m), 2.92 (3H, s), 3.06 (2H, d, J = 7.3Hz), 3.13 (3H, s), 3.64 (2H, s; disappeared by heavy water addition), 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) -t-butyldimethylsilane 5 ml (4-bromophenoxy) -t-butyldimethylsilane, 2.9 ml isobutylmethylamine, 458.0 mg palladium acetate, 1.2 g 2- (dit-butylphosphino) biphenyl and 2.9 g sodium t-butoxide Was suspended in 40 ml anhydrous toluene and stirred at 100 ° C. for 1.5 hours. After removing the catalyst by filtration, water was added and the mixture was extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is subjected to silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/40 1 /). Purification with 20) gave the title compound (3.83 g, yield 64%).¹H-NMR (CDCl₃) δ: 0.16 (6H, s), 0.91 (6H, 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-ami) phenoxy) -2-nitrophenyl) methylamine The (4- (isobutyl-methyl-amino) phenoxy) -t-butyldimethylsilane obtained in 3.83 g of Reference Example 6 was dissolved in 20 ml of anhydrous tetrahydrofuran and 20 ml of 1M tetra-n-butylammonium fluoride tetrahydrofuran solution was dissolved. Was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, water was added and the mixture was extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/5). did. The obtained results were dissolved in 4N hydrochloric acid-1,4-dioxane and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and washed with diethyl ether to obtain an intermediate 4-isobutylmethylaminophenol monohydrochloride. A 20 ml anhydrous N, N-dimethylformamide suspension containing 500.0 mg of this intermediate and 2.6 g of potassium carbonate was stirred at room temperature for 15 minutes. Then 664.7 mg of N- (5-chloro-2-nitrophenyl) -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 the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / toluene = 1/30). The title compound (256.1 mg, yield 34%) was obtained.¹H-NMR (CDCl₃) δ: 0.96 (6H, d, J = 6.8Hz), 2.00-2.13 (1H, m), 2.92 (3H, d, J = 5.9Hz), 2.98 (3H, s), 3.12 (2H, d, J) = 7.8Hz), 6.19-6.23 (2H, 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-Amino-5-(4- (isobutyl-methyl-amino) phenoxy) -phenyl) methylamine N- (5- (5-) obtained in Reference Example 7 instead of N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester of Reference Example 5 Using (4- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) methylamine, the title compound was obtained in the same manner as in Reference Example 5.¹H-NMR (CDCl₃) δ: 0.88 (6H, d, J = 6.6Hz), 1.94-2.04 (1H, m), 2.77 (3H, s), 2.87 (3H, s), 2.99 (2H, d, J = 7.3Hz), 3.22 (2H, s), 6.16 (1H, dd, J = 8.1 and 2.5Hz), 6.33 (1H, d, J = 2.5Hz), 6.57 (1H, d, J = 8.1Hz), 6.59 (2H, d) , J = 8.8Hz), 6.87 (2H, d, J = 8.8Hz). (Test Example 1) Enhanced antitumor effect on mouse colon cancer cell line Colon 26 cells 1x10 mouse colon cancer cell line Colon 26 under the skin of 9 CDF1 mice (female, 7 weeks old) per group⁶cells were transplanted. The test compound was suspended in a 5% emalphore saline containing 2.5% dimethylacetamide, and the compound of Production Example 1 as a PPARγ activator was 50 mg / kg once a day, and PD-184352 was 50 mg as a MEK inhibitor. / kg was orally administered twice daily until death, both 5 days a week.

【0134】

The effect was evaluated by the tumor growth inhibitory effect and the life-prolonging effect. The tumor growth inhibitory effect was measured by measuring the minor axis (mm) and major axis (mm) of the tumor with an electronic digital caliper, and evaluated by the tumor growth inhibition rate (GI%) on the 14th day after transplantation by the following formula.

【0135】

GI (%) = (1-A / B) x 100 A: Mean tumor volume on day 14 of the compound-administered group (*) B: Mean tumor volume on day 14 of the untreated control group (*) *: Tumor volume is 1/2 x [tumor major axis] x [tumor minor axis]²To say.

【0136】

The life-prolonging effect was evaluated by the life-prolonging rate (ILS%) using the formula shown below.

【0137】

ILS (%) = (1-A / B) x 100 A: Median survival time in the compound-administered group B: Median survival time in untreated control group The results are summarized in Table 1.

【0138】

[table 1]

Test compound Dosage (mg / kg) GI (%) ILS (%) Compound 50 -6 14 of Production Example 1^a PD-184352 50 52^a -20 Compound 50 70 of Production Example 1^{a, b, c} 49^{a, b, c} + PD-184352 50 In the above table, a, b and c show the following significant differences.

【0139】

a; p &lt;0.05 vs cancer-bearing control group b; p &lt;0.05 vs Compound single agent administration group of Production Example 1 c; p &lt;0.05 vs PD-184352 monotherapy group As is clear from Table 1, the growth inhibitory effect and life-prolonging effect of mouse colon cancer cells by the compound of PPARγ activator production example 1 and the MEK inhibitor PD-184352 alone were significantly increased by the combined administration of both compounds. It was enhanced.

【0140】

(Test Example 2) Enhanced antitumor effect on human colorectal cancer strains WiDr and COL-2-JCK Tumor fragments (5 mm x 5 mm square) of human colorectal cancer strain WiDr or COL-2-JCK were transplanted subcutaneously into 10 BALB / c nude mice (female, 5 weeks old) in one group. The test compound was suspended in a 5% emalphore saline containing 2.5% dimethylacetamide, and 50 mg / kg of the compound of Production Example 1 was administered as a PPARγ activator and 200 mg / kg of PD-184352 was administered as a MEK inhibitor. .. For WiDr, 22 times in total from the day after transplantation to 4th, 7th to 11th, 14th to 18th, 21st to 25th, and 28th to 30th, for COL-2-JCK A total of 14 doses were orally administered from the day after transplantation to 4 days, 7 days to 11 days, and 14 days to 18 days.

【0141】

To determine the effect, the minor axis (mm) and major axis (mm) of the tumor were measured with an electronic digital caliper. WiDr was used on the 31st day after transplantation, and COL-2-JCK was used on the 21st day after transplantation. %) Was calculated in the same manner as in Test Example 1. The results are summarized in Table 2.

【0142】

[Table 2]

Test compound Dosage (mg / kg) GI (%) WiDr COL-2-JCK Compound 50 36 of Production Example 1^a 26^a PD-184352 200 20^a 25^a Compound 50 53 of Production Example 1^{a, b, c} 55^{a, b, c} + PD-184352 200 In the above table, a, b and c show the following significant differences.

【0143】

a; p &lt;0.05 vs cancer-bearing control group b; p &lt;0.05 vs Compound single agent administration group of Production Example 1 c; p &lt;0.05 vs PD-184352 monotherapy group As is clear from Table 2, the growth inhibitory activity of human colorectal cancer cells by the compound of PPARγ activator production example 1 and the MEK inhibitor PD-184352 alone was significantly enhanced by the combined administration of both compounds. ..

【0144】

Based on the above, the compound (I), compound (III) or compound (IV) of the present invention or a pharmacologically acceptable salt thereof and the diphenylamine derivative or a pharmacologically acceptable salt thereof are used in combination. As a result, an excellent effect was shown as compared with the case where each was used alone.

【0145】

(Formulation example) tablet The compound of Production Example 1 (30.0 mg), PD-184352 (30.0 mg), lactose (408.0 mg), corn starch (50.0 mg) and magnesium stearate (2.0 mg) were mixed and tableted with a tableting machine. , 1 tablet 500 mg tablet. The tablets can be coated (preferably sugar-coated) as needed.

【0146】

Injection 1.5% by weight of the compound of Production Example 1 and 1.5% by weight of PD-184352 were stirred in 10% by weight of propylene glycol, then made into a constant volume with water for injection, and then sterilized.

【0147】

[Effect of the invention]

To administer the compound (I), compound (III) or compound (IV) of the present invention or a pharmacologically acceptable salt thereof and a diphenylamine derivative or a pharmacologically acceptable salt thereof at the same time or separately at intervals. Because the pharmaceutical composition of is excellent in cell growth inhibitory activity and weakly toxic, it is a drug (particularly gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer, fat). It is useful as a preventive or therapeutic agent for cancer such as sarcoma or a cell growth inhibitor).

【0148】

Further, the troglycazone, pioglycazone or pioglycazone of the present invention or a pharmacologically acceptable salt thereof and 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or its pharmacology The pharmaceutical composition for administering the above-acceptable salts simultaneously or separately at intervals has excellent cell growth inhibitory activity and is weakly toxic, so that the pharmaceuticals (particularly gastric cancer, lung cancer, breast cancer, colon) It is useful as a preventive or therapeutic agent for cancers such as cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer, and liposarcoma, or a cell growth inhibitor).