JP2003192592A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having excellent cell proliferation suppressing activity. <P>SOLUTION: The pharmaceutical composition contains a compound expressed by general formula (I), etc., and a compound expressed by general formula (II) [X is a benzimidazole ring group; Y<SP>1</SP>is O or S; Z is a thiazolidinedione group or the like; R is H, a 1-6C alkyl or the like; (m) is an integer of 1-5; R<SP>a</SP>is Br or I; R<SP>b</SP>is H, a halogen atom or the like; R<SP>c</SP>is NR<SP>k</SP>OR<SP>l</SP>(R<SP>k</SP>is H or the like; and R<SP>l</SP>is a 3-10C cycloalkyl or the like) or the like; R<SP>d</SP>, R<SP>e</SP>and R<SP>f</SP>are each independently H, a halogen atom or the like]. These compounds are administered at the same time or separately interposing an interval. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a fused heterocyclic compound having a PPARγ activating ability or a pharmacologically acceptable salt thereof and a diphenylamine derivative having a MEK inhibiting ability or a pharmacologically acceptable salt thereof at the same time or The present invention relates to a pharmaceutical composition, a cytostatic agent, or an antitumor agent, which are administered separately at intervals.

[0002]

2. Description of the Related Art A cell growth inhibitor comprising a PPARγ activator and a MAP kinase inhibitor has been disclosed (see, for example, Patent Document 1). However, the publication only predicts that the combination of these compounds will suppress the cell growth on the basis of the increase in fat accumulation, and the combined use of these compounds actually suppresses the cell growth. It does not show that. Further, in the publication, for example,
Using troglitazone as a PPARγ activator, M
Although a cell growth inhibitor using PD098059 as an AP kinase inhibitor is specifically disclosed, the cell growth inhibitory effect obtained by using these in combination is not sufficient.

[0003]

[Patent Document 1] US Pat. No. 6,242,196

[0004]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted extensive studies to find a combination of agents having a more excellent cell growth inhibitory activity, and as a result, have a compound (I) and a compound (III) having a PPARγ activating ability. ) Or compound (I
It has been found that the combined use of V) or a pharmaceutically acceptable salt thereof and a diphenylamine derivative having MEK inhibitory ability or a pharmaceutically acceptable salt thereof is more useful as a cell growth inhibitor.

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

[0006]

The present invention relates to a pharmaceutical composition containing a compound capable of activating PPARγ and a compound capable of inhibiting MEK.

A compound having the ability to activate PPARγ, which is one of the active ingredients of the pharmaceutical composition of the present invention, has the following general formula (I):

[0008]

[Chemical 15]

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

[0010]

[Chemical 16]

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

In the above, "substituent group α1" means 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 (which may be substituted with 1 or 2 groups selected from the substituent group α2), C6 -10 aryl group (substituent group α
1 to 5 may be substituted by a group selected from 3) and a C7-11 aralkyl group (which may be substituted by 1 to 5 by a group selected from the substituent group α3) And the “substituent group α2” is 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 group. The “substituent group α3” is a substituent group consisting of an acyl group, and 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 is a substituent group consisting of an alkyl group and an amino group (which may be substituted with 1 or 2 groups selected from the substituent group α2). ] A fused heterocyclic compound having the general formula (III)

[0013]

[Chemical 17]

[In the above formula, R ¹ is

[0015]

[Chemical 18]

[Wherein R ⁴ is a phenyl group (substituent group β 1
1 to 5 are substituted with a group selected from) or a pyridyl group (which may be substituted with 1 to 4 with a group selected from the substituent group β1), R ⁵ is a hydrogen atom, Halogen atom, hydroxy group, C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group, C
A 1-6 alkylthio group, an amino group (which may be substituted with a group selected from the substituent group β3), a C3-10 cycloalkyl group (which is substituted with 1 to 3 by a group selected from the substituent group β2) C6-10 aryl group (may be substituted with 1 to 3 groups selected from the substituent group β2), C7-C16 aralkyl group (groups selected from the substituent group β2 from 1 to 3) May be substituted), C6-C
10 aryloxy groups (which may be substituted with 1 to 3 groups selected from the substituent group β2), C7-16 aralkyloxy groups (1 to 3 groups selected from the substituent group β2)
C6-10 arylthio groups (which may be substituted by 1 to 3 with a group selected from the substituent group β2), C1-7 aliphatic acyloxy groups, 4 to 4 containing a nitrogen atom. 7-membered saturated heterocyclic group, containing a nitrogen atom 5
Or a 6-membered aromatic heterocyclic group, a nitro group or a cyano group, R ⁶ is a hydrogen atom, a C 1-6 alkyl group, or C 6-1.
0 aryl group (which may be substituted by 1 to 3 with a group selected from substituent group β2) or C7-16 aralkyl group (which may be substituted by 1 to 3 with a group selected from substituent group β2) ), Y ⁴ represents an oxygen atom or a sulfur atom, and E ¹ represents a ═CH— group or a nitrogen atom. } R < ² > is 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. (It may be substituted with a group selected from the substituent group β3), C3-10 cycloalkyl group (1 to 3 may be substituted with a group selected from the substituent group β2), C6-10 aryl A group (1 to 3 may be substituted with a group selected from the substituent group 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 groups may be substituted with a group selected from the substituent group β2) ), A C7-16 aralkyloxy group (which may be substituted with 1 to 3 groups selected from the substituent group β2), a C6-10 arylthio group (1 to 3 groups selected from the substituent group β2) Optionally substituted), C1-7
Represents an 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 or a cyano group, and R ³ is a group represented by the formula:

[0017]

[Chemical 19]

A ² is a C1-6 alkylene group, and Y ³ is an oxygen atom or a sulfur atom.

In the above, "substituent group β1" means halogen atom, hydroxy group, C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group, C1.
-6 alkylthio group, amino group (may be substituted with a group selected from the substituent group β3), C3-10 cycloalkyl group (may be substituted with 1 to 3 groups with a group selected from the substituent group β2) Good), C6-10 aryl group (substituent group β
1 to 3 may be substituted with a group selected from 2),
C7-C16 aralkyl group (which may be substituted with 1 to 3 groups selected from the substituent group β2), C6-C10 aryloxy group (which is substituted with 1 to 3 groups selected from the substituent group β2) C7-16 aralkyloxy group (may be substituted with 1 to 3 groups selected from the substituent group β2), C6-10 arylthio group (1 group selected from the substituent group β2) To 3 may be substituted), a C1-7 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 “substituent group β2” is a substituent group consisting of a cyano group,
Hydroxy group, C1-6 alkyl group, halogenated C1-
A substituent group consisting of a C6 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. Group β3 ”is a C1-10 alkyl group, a C6-10 aryl group, a C7-16 aralkyl group, a C1-7 aliphatic acyl group, a C7-11 aromatic acyl group, a C8-12 aromatic aliphatic acyl group, C4-. 5 to 6 containing 11 cycloalkylcarbonyl groups and nitrogen atoms
A group of substituents composed of a membered aromatic heterocyclic carbonyl group. ]
A substituted fused heterocyclic compound having the general formula (IV)

[0020]

[Chemical 20]

[In the formula, R ⁷ is a carbamoyl group (which may be substituted with one or two groups selected from the substituent group γ1) and a thiocarbamoyl group (a group selected from the substituent group γ1). 1 or 2 may be substituted), a sulfonyl group (having one group selected from the substituent group γ1) or a carbonyl group (having one group selected from the substituent group γ1) R ⁸ and R ⁹ are each independently a hydrogen atom, a C 1-10 alkyl group, a C 6-10 aryl group (1 to 3 substituted with a group selected from the substituent group γ2). Or a C7-16 aralkyl group (wherein the aryl moiety is a group selected from the substituent group γ2 and is 1 to 3)
^May be substituted), and A ³ , A ⁴ and A ⁵ are
Each independently represents a single bond or a C1-8 alkylene group, Y ^5, Y ⁶ and Y ⁷ are each independently an oxygen atom or a sulfur atom, E ² is = 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, and each is a hydrogen atom, a C1-6 alkyl group, or a C6-10.
Aryl group (a group selected from the substituent group γ2, which is 1 to 3
Or a C7-16 aralkyl group (the aryl part may be substituted with 1 to 3 groups selected from the substituent group γ2).

In the above, "substituent group γ1" means C1
-10 alkyl group, halogenated C1-6 alkyl group, C
3-10 cycloalkyl group, C6-10 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group γ3), C7-16 aralkyl group (the aryl moiety is selected from the substituent group γ3) Optionally substituted with 1 to 3 groups), a C4-11 cycloalkylcarbonyl group,
C7-11 aromatic acyl group (aryl group is a substituent group γ
1 to 3 may be substituted with a group selected from 3), and a C8-17 aralkylcarbonyl group (the aryl part may be substituted with 1 to 3 by a group selected from the substituent group γ3) 5- or 6-membered aromatic heterocyclic group (which may be substituted with 1 to 3 groups selected from the substituent group γ3) 5- or 6-membered aromatic heterocyclic carbonyl group (selected from the substituent group γ3 Optionally substituted by 1 to 3 groups), C1-6 alkylsulfonyl group, halogenated C1
-6 alkylsulfonyl group, C6-10 arylsulfonyl group (the aryl part may be substituted with 1 to 3 groups selected from the substituent group γ3) and C7-16 aralkylsulfonyl group (the aryl part is a substituent) 1 to 3 may be substituted with a group selected from the group γ3), and the “substituent group γ2” is C1-6.
Alkyl group, halogenated C1-6 alkyl group, C1-6
Alkoxy group, halogen atom, hydroxy group, C6-1
0 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group γ4), C7-16 aralkyl group
(The aryl part may be substituted with 1 to 3 groups selected from the substituent group γ4), cyano group, nitro group and amino group (1 or 2 substituted with a group selected from the substituent group γ4) Which may be present), and the "substituent group γ3" is a C1-6 alkyl group, a halogenated C1
-6 alkyl group, C1-6 alkoxy group, halogen atom, hydroxy group, cyano group, nitro group, C3-10 cycloalkyl group, C6-10 aryl group (C1-6 alkyl group, halogenated C1-6 alkyl group, A group selected from a C1-6 alkoxy group and a halogen atom, which may be substituted by 1 to 3), a C7-16 aralkyl group (wherein the aryl moiety is a C1-6 alkyl group, a halogenated C).
1 to 6 alkyl groups, C1-6 alkoxy groups and halogen atoms, which may be substituted by 1 to 3), C1-7 aliphatic acyl groups, C1-7 aliphatic acyloxy groups, amino Group, a diC1-6 alkylamino group and a C1-4 alkylenedioxy group, and “substituent group γ4” is a C1-10 alkyl group, C6.
-10 aryl group (C1-6 alkyl group, halogenated C
A 1-6 alkyl group, a C1-6 alkoxy group and a group selected from a halogen atom, which may be substituted by 1 to 3), a C7-16 aralkyl group (wherein the aryl moiety is C
1-6 alkyl group, halogenated C1-6 alkyl group, C
1-6 alkoxy groups and groups selected from halogen atoms, which may be substituted by 1 to 3), C1-7 aliphatic acyl groups, C4-11 cycloalkylcarbonyl groups,
C7-11 aromatic acyl group (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), C8- 17 aralkylcarbonyl group (wherein the aryl moiety is a C1-6 alkyl group, halogenated C1-
6 alkyl groups, C1-6 alkoxy groups and 1 to 3 groups which may be substituted with groups selected from halogen atoms), 5 or 6 membered aromatic heterocyclic carbonyl groups (C1-6
Alkyl group, halogenated C1-6 alkyl group, C1-6
1 to 3 may be substituted with a group selected from an alkoxy group and a halogen atom). ] And an amine derivative having 5- (4- (6-hydroxy-2,5,7,8-tetramethyl-chroman-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (2- (5-ethyl-pyridine-2
-Yl) -ethoxy) benzyl) -thiazolidine-2,
4-dione or 5- (4- (2- (methyl-pyridin-2-yl-amino) -ethoxy) -benzyl)
-Thiazolidine-2,4-dione, or a pharmacologically acceptable salt thereof.

The compound having MEK inhibitory activity, which is one of the active ingredients of the pharmaceutical composition of the present invention, has the following general formula (II):

[0024]

[Chemical 21]

[Wherein R^aIs a bromine atom or an iodine atom
Indicates R^bIs a hydrogen atom, a hydroxy group, C1-8
Rucyl group (substituted by a group selected from Substituent group δ
, C1-8 alkoxy group, halogen atom,
Represents a fluoromethyl group or a cyano group, R^cIs -C
OOR^gGroup, tetrazolyl group, -CONR^gR^hGroup, -C
ONHNR ⁱR^jGroup, -CH₂OR^gGroup or -C (= O)-
NR^kOR^lGroup {in the formula, R^gAnd R^hEach independently,
Hydrogen atom, C1-8 alkyl group (selected from the substituent group δ
Optionally substituted with a group), C2-8 alkenyl
Group (may be substituted with a group selected from Substituent group δ
C2-8 alkynyl group (selected from the substituent group δ
May be substituted with a group), C1-8 alkylcalcyl
Bonyl group, C6-10 aryl group, 5- or 6-membered aromatic compound
Monocyclic group, 3- to 10-membered aliphatic heterocyclic group or C3-10 silane
Represents a chloroalkyl group or R^gAnd R^hIs the nitrogen atom to which
Together with represents a 3- to 10-membered aliphatic heterocycle, Rⁱ
And R^jAre each independently a hydrogen atom, C1-8
Represents a rualkyl group or RⁱAnd R^jIs a bond with a nitrogen atom
And a 3- to 10-membered aliphatic heterocyclic group, R
^kIs a hydrogen atom, a C1-8 alkyl group (from the substituent group δ
Optionally substituted with selected groups), C1-8ar
Killcarbonyl group, C6-10 aryl group, C7-14
An aralkyl group or a C3-10 cycloalkyl group,
R^lIs a hydrogen atom, a C1-8 alkyl group (substituent group δ or
Optionally substituted by a group selected from the group), C2-8
Lucenyl group (substituted by a group selected from Substituent group δ
C2-8 alkynyl group (from the substituent group δ
Optionally substituted by selected groups), C3-10
A chloroalkyl group or a 3- to 10-membered aliphatic heterocyclic group}
Indicates R^d, R^eAnd R^fAre each independently hydrogen
Atom, hydroxy group, halogen atom, trifluoromethyl
Group, C1-8 alkyl group (selected from the substituent group δ
Group may be substituted), a C1-8 alkoxy group,
Nitro group, cyano group or -Y²A¹R^mIndicates a group (wherein
Y²Represents a single bond, an oxygen atom or a —NH— group, and A
¹Represents a single bond or a C1-4 alkylene group, R^mIs
Hydrogen atom, hydroxy group, carboxyl group or -NRⁱ
R^jGroup (RⁱAnd R^jHas the same meaning as above).

In the above, the substituent group δ means a halogen atom, a hydroxy group, a C1-6 alkoxy group, an amino group (which may be substituted with 1 to 2 C1-6 alkyl groups), C3-10 cycloalkyl. Group, a C6-10 aryl group, a C6-10 aryloxy group, a 5- or 6-membered aromatic heterocyclic group, and a 5- or 6-membered aromatic heterocyclic oxy group. ] The diphenylamino derivative represented by these, or its pharmacologically acceptable salt.

In the above, "C1-6 alkyl group",
"C1-8 alkyl group" or "C1-10 alkyl group"
Means 1 to 6 carbon atoms, 1 to 8 carbon atoms, or 1
To 10 linear or branched alkyl groups.

Examples of the "C1-6 alkyl group" include methyl, ethyl, n-propyl, isopropyl and 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 A 2-ethylbutyl group can be mentioned, and a linear or branched alkyl group having 1 to 4 carbon atoms is preferable.

As the "C1-8 alkyl group", for example, the groups mentioned above 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-methyl Examples thereof include heptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl and 5,5-dimethylhexyl groups, preferably linear or branched alkyl groups having 1 to 4 carbon atoms.

Examples of the "C1-10 alkyl group" include the groups mentioned above as examples of the "C1-8 alkyl group" or nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyl. Octyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl or
A 7,7-dimethyloctyl group can be mentioned, and a linear or branched alkyl group having 1 to 4 carbon atoms is preferable.

"Halogenated C1-6 alkyl group" means
The aforementioned "C1-6 alkyl group" substituted with a halogen atom
And, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2 Mention may be made of -chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl groups.

The "C3-10 cycloalkyl group" is a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms,
Examples thereof include a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl or cyclodecanyl group, and a 5- to 10-membered saturated cyclic hydrocarbon group is preferable.

The "C1-4 alkylene group", "C1-6 alkylene group" or "C1-8 alkylene group" means 1 to 4 carbon atoms, 1 to 6 carbon atoms or 1 carbon atom, respectively.
To 8 linear or branched alkylene groups.

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

The "C1-6 alkylene group" is the group mentioned above as an example of the "C1-4 alkylene group" or pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, 4 -Methyltetramethylene, 5-methyltetramethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltriethylene, 1,1-dimethyltrimethylene, 1,2
There may be mentioned the dimethyltrimethylene, 1,3-dimethyltrimethylene or hexamethylene groups.

The "C1-8 alkylene group" is the group mentioned above as an example of the "C1-6 alkylene group", or
Mention may be made of heptamethylene or octamethylene groups.

"C1-4 alkylenedioxy group" means
The above-mentioned "C1-4 alkylene group" is a group bonded at both ends via oxygen atoms, and includes, for example, methylenedioxy, methylmethylenedioxy, ethylenedioxy,
Mention may be made of trimethylenedioxy, 1-methyltrimethylenedioxy, 2-methyltrimethylenedioxy, 3-methyltrimethylenedioxy or tetramethylenedioxy groups.

The "C2-8 alkenyl group" has 2 carbon atoms.
To 8 linear or branched alkenyl groups, 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 may be mentioned.

The "C2-8 alkynyl group" has 2 carbon atoms.
To 8 linear or branched alkenyl groups, such as 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,
Mention may be made of 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl groups.

The "C6-10 aryl group" has 6 carbon atoms.
To 10 aromatic hydrocarbon groups, for example,
Examples thereof include a phenyl group and a naphthyl group, and a phenyl group is preferable.

"C7-11 aralkyl group", "C7-1
“4 aralkyl group” or “C7-16 aralkyl group” means that the above “aryl group” has 7 to 11 carbon atoms, 7 to 14 carbon atoms or 7 to 16 carbon atoms, respectively, and is the above “alkyl group”. It is a group bonded.

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

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

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

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

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

Examples of the "C1-6 alkoxy group" include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy and te.
rt-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,
Examples thereof include a 3-dimethylbutoxy group and a 2,3-dimethylbutoxy group, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms.

As the "C1-8 alkoxy group", for example, the groups mentioned above 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-methyl Examples thereof include heptyloxy, 5-methylheptyloxy, 6-methylheptyloxy, 1-propylpentyloxy, 2-ethylhexyloxy and 5,5-dimethylhexyloxy groups, preferably having 1 to 4 carbon atoms. It is a linear or branched alkoxy group.

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

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

Examples of the "C7-11 aralkyloxy group" include benzyloxy, α-naphthylmethoxy,
β-naphthylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, 1-phenylbutoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy , 1-phenylpentyloxy, 2-phenylpentyloxy, 3-phenylpentyloxy, 4-phenylpentyloxy or 5-phenylpentyloxy groups.

Examples of the "C7-16 aralkyloxy group" include the groups mentioned above as examples of the "C7-11 aralkyloxy group" or diphenylmethoxy, 1-naphthylethoxy, 2-naphthylethoxy, 1-naphthylpropoxy, 2-naphthylpropoxy, 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-
A naphthylhexyloxy group can be mentioned, preferably an aralkyloxy group in which a phenyl group is bonded to a C1-4 alkyl group, and more preferably a benzyloxy group.

The "C1-6 alkylthio group" is a group to which the above "C1-6 alkyl group" is bonded via a sulfur atom, and examples thereof include methylthio, ethylthio and n-.
Propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio, tert-butylthio, n
-Pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2 −
Dimethylbutylthio, 1,1-dimethylbutylthio,
Mention may be made of 1,2-dimethylbutylthio, 1,3-dimethylbutylthio or 2,3-dimethylbutylthio groups.

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

The "C1-8 alkylcarbonyl group" means
The "C1-8 alkyl group" is a group bonded via a carbonyl group, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl,
Mention may be made of isovaleryl, hexanoyl, heptanoyl or octanoyl groups.

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

Examples of the "C1-7 aliphatic acyl group" include formyl, acetyl, propionyl, butyryl,
An alkylcarbonyl group such as an isobutyryl, pivaloyl, valeryl, isovaleryl or hexanoyl group;
(E) an alkenylcarbonyl group such as a 2-methyl-2-butenoyl group; or an alkynylcarbonyl group such as a 3-butynoyl group.

As the "C1-11 aliphatic acyl group",
For example, the groups mentioned above as examples of the "C1-7 aliphatic acyl group" or octanoyl, nonylcarbonyl, decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl, 3-ethyloctylcarbonyl or 3,7-dimethyl. Examples thereof include an alkylcarbonyl group such as an octylcarbonyl group.

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 machine" is an oxygen atom, respectively. It is a group that is bonded via.

Examples of the "C1-7 aliphatic acyloxy group" include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy,
Alkylcarbonyloxy group such as pivaloyloxy, valeryloxy, isovaleryloxy or hexanoyloxy group; (E) alkenylcarbonyloxy group such as 2-methyl-2-butenoyloxy group; or 3-
Mention may be made of alkynylcarbonyloxy groups such as butynoyloxy groups.

The "C1-11 aliphatic acyloxy group" is, for example, the above-mentioned "C1-7 aliphatic acyloxy group".
Or an octanoyloxy, nonylcarbonyloxy, decylcarbonyloxy, 3-methylnonylcarbonyloxy, 8-methylnonylcarbonyloxy, 3-ethyloctylcarbonyloxy or 3,7-dimethyloctylcarbonyloxy group. Such alkyl carbonyloxy group etc. can be mentioned.

The "C4-11 cycloalkylcarbonyl group" is a group to which the above "C3-10 cycloalkyl group" is bonded via a carbonyl group, and for example,
Cyclopropylcarbonyl, cyclobutylcarbonyl,
Mention may be made of cyclopentylcarbonyl, cyclohexylcarbonyl or cycloheptylcarbonyl groups,
Preferred is a C6-8 cycloalkylcarbonyl group.

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

The "C7-11 aralkylcarbonyl group" is a group obtained by substituting the above "C7-11 aralkyl group" with a carbonyl group, and examples thereof include a benzylcarbonyl group.

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

"C8-12 araliphatic acyl group" means
Consisting of a linear or branched saturated or unsaturated hydrocarbon group,
It is a group in which an araliphatic group is bonded via a carbonyl group, and examples thereof include a benzylcarbonyl group.

"C1-6 alkylsulfonyl group" means
The "C1-6 alkyl group" is a group bonded via a sulfonyl group, and examples thereof include 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- A dimethylbutylsulfonyl or 2,3-dimethylbutylsulfonyl group can be mentioned.

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

The "C7-16 aralkylsulfonyl group" is a group to which the above "C7-16 aralkylsulfonyl group" is bonded via a sulfonyl group, and examples thereof include benzylsulfonyl, α-naphthylmethylsulfonyl and β-naphthyl. Methylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-phenylbutylsulfonyl, 2
-Phenylbutylsulfonyl, 3-phenylbutylsulfonyl, 4-phenylbutylsulfonyl, 1-phenylpentylsulfonyl, 2-phenylpentylsulfonyl, 3-phenylpentylsulfonyl, 4-phenylpentylsulfonyl, 5-phenylpentylsulfonyl,
Diphenylmethylsulfonyl, 1-naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthylpropylsulfonyl, 3-naphthylpropylsulfonyl, 1-naphthylbutylsulfonyl, 2-naphthylbutylsulfonyl, 3-
Naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 1-phenylhexylsulfonyl, 2-phenylhexylsulfonyl, 3-phenylhexylsulfonyl, 4-phenylhexylsulfonyl, 5-phenylhexylsulfonyl, 6-phenylhexylsulfonyl,
Mention may be made of 5-naphthylpentylsulfonyl or 6-naphthylhexylsulfonyl groups.

The "diC1-6 alkylamino group" is an amino group substituted with two "C1-6 alkyl groups", and the substituents may be the same or different. Examples of such a group include a dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, methylisopropylamino, butylmethylamino, t-butylmethylamino, methylpentylamino or hexylmethylamino group.

The "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 / or nitrogen atoms.
Or a 6-membered aromatic heterocyclic group, for example, furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,
Mention may be made of triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups.

The “3- to 10-membered aliphatic heterocyclic group” is a 3- to 10-membered aliphatic heterocyclic group containing 1 to 3 sulfur, oxygen or / and nitrogen atoms, such as morpholinyl and thiomorpholinyl. , Pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperazinyl groups.

The "4- to 7-membered saturated heterocyclic group containing a nitrogen atom" means a 4- to 7-membered saturated heterocyclic group containing at least one nitrogen atom and optionally an oxygen atom or a sulfur atom. And, for example, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
Mention may be made of imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl or piperazinyl groups.

The "5- or 6-membered aromatic heterocyclic group containing a nitrogen atom" is a 5- or 6-membered aromatic heterocyclic group containing at least one nitrogen atom and optionally an oxygen atom or a sulfur atom. Is, for example, pyrrolyl, azepinyl,
Mention may be made of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups.

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, and examples thereof include furyloxy and thienyloxy. , Pyrrolyloxy, azepinyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thia Mention may be made of diazolyloxy, pyranyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy or pyrazinyloxy groups.

"5- or 6-membered aromatic heterocyclic carbonyl group"
The term "a 5- or 6-membered aromatic heterocyclic group" refers to a group bonded via a carbonyl group, and includes, for example, furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl,
Azepinylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl, tetrazoli Lucarbonyl, thiadiazolylcarbonyl, pyranylcarbonyl,
Mention may be made of pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl or pyrazinylcarbonyl groups.

"Substituent group α1" is a 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 (substituent group α
1 or 2 may be substituted with a group selected from 2), a C6-10 aryl group (which may be substituted with 1 to 5 groups selected from a substituent group α3) and C7-
11 aralkyl groups (groups selected from the substituent group α3 are 1
To 5 optionally substituted).

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

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 or a halogenated C1.
-6 is a substituent group consisting of an alkyl group and an amino group (which may be substituted with 1 or 2 groups selected from the substituent group α2).

In the above, "substituent group β1" means halogen atom, hydroxy group, C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group, C1.
-6 alkylthio group, amino group (may be substituted with a group selected from the substituent group β3), C3-10 cycloalkyl group (may be substituted with 1 to 3 groups with a group selected from the substituent group β2) Good), C6-10 aryl group (substituent group β
1 to 3 may be substituted with a group selected from 2),
C7-C16 aralkyl group (which may be substituted with 1 to 3 groups selected from the substituent group β2), C6-C10 aryloxy group (which is substituted with 1 to 3 groups selected from the substituent group β2) C7-16 aralkyloxy group (may be substituted with 1 to 3 groups selected from the substituent group β2), C6-10 arylthio group (group selected from the substituent group β2 1 To 3 may be substituted), a C1-7 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 group of substituents consisting of a cyano group, preferably a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, an amino group (one or two substituted with a group selected from the substituent group β3 The nitrogen atom It is a substituent group β1 consisting of a 4- to 7-membered saturated heterocyclic group contained and a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom.

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

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

In the above, "substituent group γ1" means C1
-10 alkyl group, halogenated C1-6 alkyl group, C
3-10 cycloalkyl group, C6-10 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group γ3), C7-16 aralkyl group (the aryl moiety is selected from the substituent group γ3) Optionally substituted with 1 to 3 groups), a C4-11 cycloalkylcarbonyl group,
C7-11 aromatic acyl group (aryl group is a substituent group γ
1 to 3 may be substituted with a group selected from 3), and a C8-17 aralkylcarbonyl group (the aryl part may be substituted with 1 to 3 by a group selected from the substituent group γ3) 5- or 6-membered aromatic heterocyclic group (which may be substituted with 1 to 3 groups selected from the substituent group γ3) 5- or 6-membered aromatic heterocyclic carbonyl group (selected from the substituent group γ3 Optionally substituted by 1 to 3 groups), C1-6 alkylsulfonyl group, halogenated C1
-6 alkylsulfonyl group, C6-10 arylsulfonyl group (the aryl part may be substituted with 1 to 3 by a group selected from the substituent group γ3) and C7-16 aralkylsulfonyl group (the aryl part is a substituent) 1 to 3 groups may be substituted with a group selected from the group γ3).

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, a C6-10 aryl group (selected from the substituent group γ4. 1 to 3 groups may be substituted with a group), a C7-16 aralkyl group (the aryl part may be substituted with 1 to 3 groups selected from the substituent group γ4), a cyano group, a nitro group. A group of substituents consisting of a group and an amino group (which may be substituted with 1 or 2 groups selected from the group of substituents γ4).

"Substituent group γ3" means 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 aryl group (which may be substituted with 1 to 3 groups selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom), C7-
16 aralkyl groups (the aryl part may be substituted with 1 to 3 by a group selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom), C1 -7 aliphatic acyl group, C
It is a substituent group consisting of a 1-7 aliphatic acyloxy group, an amino group, a diC1-6 alkylamino group and a C1-4 alkylenedioxy group.

The "substituent group γ4" is a group selected from a C1-10 alkyl group, a C6-10 aryl group (C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and halogen atom). And optionally substituted by 1 to 3), a C7-16 aralkyl group (wherein the aryl moiety is selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom). 1 to 3 groups may be substituted with a group), C1
-7 aliphatic acyl group, C4-11 cycloalkylcarbonyl group, C7-11 aromatic acyl group (C1-6 alkyl group, halogenated C1-6 alkyl group, C1-6 alkoxy group and a group selected from halogen atoms) 1 to 3 may be substituted with), a C8-17 aralkylcarbonyl group (the aryl moiety is selected from a C1-6 alkyl group, a halogenated C1-6 alkyl group, a C1-6 alkoxy group and a halogen atom). 1 to 3 groups may be substituted with a group) 5- or 6-membered aromatic heterocyclic carbonyl group (C1
-6 alkyl group, halogenated C1-6 alkyl group, C1
-6 alkoxy group and a group selected from a halogen atom may be substituted by 1 to 3).

"Substituent group δ" means a halogen atom, a hydroxy group, a C1-6 alkoxy group, an amino group (C1-6
1 or 2 may be substituted with an alkyl group), C3-
10 cycloalkyl group, C6-10 aryl group, C6-
10 is a substituent group consisting of an 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

[0089]

[Chemical formula 22]

(Wherein W ¹ and W ² each independently represent a hydrogen atom or a group selected from the substituent group α1). (2) In (1), W ¹ is a hydrogen atom or C1-
A compound which is a 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 C1-6 alkoxy group or a C7-11 aralkyloxy group. (5) A compound in which W ² is a benzyloxy group. (6) A compound in which Y ¹ 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 formula 23]

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

The compound (III) which is one of the active ingredients of the pharmaceutical composition of the present invention is preferably (11) R ¹ is represented by the following formula:

[0094]

[Chemical formula 24]

A compound which is a group represented by: (12) A compound in which R ⁵ is a hydrogen atom. (13) A compound in which R ⁶ is a methyl group. (14) A compound in which Y ⁴ is an oxygen atom. (15) R ⁴ is 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 a substituent group β1) May also be). (16) Y ³ is an oxygen atom compound. (17) A compound in which R ² is a hydrogen atom. (18) A compound in which A ² is a methylene group. (19) R ³ is the following formula

[0096]

[Chemical 25]

A compound which is a group represented by: (20) (11), (12), (13), (1
The compound which combined 4), (15), (16), (17), (18), and (19) suitably.

The compound (IV), which is one of the active ingredients of the pharmaceutical composition of the present invention, is preferably (21) R ⁷ has one sulfonyl group (a group selected from the substituent group γ1). Are) compounds. (22) R ⁷ is a sulfonyl group (C 1-6 alkyl group,
Substituted with a group selected from a halogenated C1-6 alkyl group and a C6-10 aryl group (which may be substituted with 1 to 3 groups selected from the substituent group γ3).
Is a compound. (23) A compound in which R ⁷ is a sulfonyl group (which is substituted with a C1-6 alkyl group). (24) A compound in which R ⁸ is a hydrogen atom or a C1-6 alkyl group. (25) A compound in which A ³ is a single bond. (26) A compound in which A ⁴ is a single bond. (27) A compound in which A ⁵ is a methylene group. (28) A compound in which Y ⁵ is an oxygen atom. (29) A compound in which Y ⁶ is an oxygen atom. (30) A compound in which Y ⁷ is a sulfur atom. (31) A compound in which E ² is a = 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) Above (21) to (23), (24), (2
5), (26), (27), (28), (29), (3
Compounds in which 0), (31), (32) and (33) are appropriately combined.

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

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 referred to as "troglitazone") is disclosed in JP-A-6-51189. The following structural formula described in

[0101]

[Chemical formula 26]

Is a compound having

5- (4- (2- (5-ethyl-pyridin-2-yl) -ethoxy) benzyl) -thiazolidine-
2,4-dione (hereinafter referred to as "pioglitazone")
Is the following structural formula described in European Patent Publication No. 00030228.

[0104]

[Chemical 27]

Is a compound having:

5- (4- (2- (methyl-pyridine-2
-Yl-amino) -ethoxy) -benzyl) -thiazolidine-2,4-dione (hereinafter, referred to as "rosiglitazone") has the following structural formula described in WO 91/2003.

[0107]

[Chemical 28]

Is a compound having:

The compound (I), compound (III), compound (IV) and diphenylamine derivative or troglitazone, rosiglitazone and pioglitazone, which are the active ingredients of the pharmaceutical composition of the present invention, can be prepared according to a conventional method, if desired. , A salt, and such a salt is also included in the present invention. Among such salts, examples of salts with acids include hydrochloride, hydrobromide, sulfate, nitrate,
Salts of inorganic acids such as phosphates; salts of carboxylic acids such as acetate, fumarate, maleate, oxalate, malonate, succinate, citrate, malate; methanesulfonic acid Examples thereof include salts, salts of sulfonic acids such as ethanesulfonate, benzenesulfonate and toluenesulfonate; salts of amino acids such as glutamate and aspartate. Examples of salts with bases include: Salts with alkali metals such as lithium salts, sodium salts, potassium salts; salts with alkaline earth metals such as calcium salts, magnesium salts; or ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts Mention may be made of salts with organic bases.

Compound (I), compound (III) or compound (IV) and the diphenylamine derivative, which are the active ingredients of the pharmaceutical composition of the present invention, are stereoisomers and / or
Or, geometric isomers may exist, and each of them or a mixture thereof is included in the present invention.

Compound (I), compound (III) or compound (IV) and diphenylamine derivative or troglitazone, rosiglitazone and pioglitazone, which are the active ingredients of the pharmaceutical composition of the present invention, are each as a hydrate or solvate. Although present, each of them or any of their mixtures are included in the present invention.

In the present invention, "administered at the same time" is not particularly limited as long as it is an administration form which can be administered at substantially the same time, but it is preferable to administer it as a single composition.

The term "administered separately at a certain time" is not particularly limited as long as it is a dosage form that can be administered separately at different times. For example, the diphenylamine derivative or its pharmacologically acceptable first Administration of the salt, and then administration of the compound (I), the compound (III) or the compound (IV) or a pharmacologically acceptable salt thereof after a predetermined time is included.

In the pharmaceutical composition of the present invention, preferably
5- (4- (6-Methoxy-1-methyl-1H-benzimidazol-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-1)
H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6
-Benzyloxy-1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6-pentafluorophenoxy-1H-be Nzoimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4
-Dione, 5- (4- (6- (4-amino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4 -(6- (3-amino-phenoxy)-
1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
5- (4- (6- (4-amino-3,5-dimethyl-phenoxy) -1-methyl-1H-benzimidazole-
2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (1-methyl-6- (pyridin-2-yloxy) -1H-benzimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (6- (5-amino-pyridine-2
-Yloxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione, 5- (4- (6- (4-isopropylamino-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, 5- (4- ( 6- (4-
(Ethyl-isopropyl-amino) -phenoxy) -1
-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5
-(4- (6- (3- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (isobutyl-methyl-amino) -phenoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(6- (3- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (6- (4-dimethylamino-phenoxy) -1-methyl-1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4
-Dione, 5- (4- (6- (3-dimethylamino-phenoxy) -1-methyl-1H-benzimidazole-
2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (6- (4- (ethyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4 -Dione, 5- (4- (6- (3-
(Ethyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy)-
Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (4- (Butyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3- (Butyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- ( 6- (4-diethylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3-diethylamino- Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (butyl-ethyl-amino)) -Phenoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(6- (3- (Butyl-ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- ( 1-Methyl-6- (4-phenylamino-phenoxy) -1H-benzimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (1-methyl-6- (3-phenylamino-phenoxy) -1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4
-Dione, 5- (4- (1-methyl-6- (4-pyrrolidin-1-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (3
-Pyrrolidin-1-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidin-2,4-dione, 5- (4- (1-methyl-
6- (4-piperidin-1-yl-phenoxy) -1H
-Benzoimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1
-Methyl-6- (3-piperidin-1-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy)
-Benzyl) -thiazolidine-2,4-dione, 5-
(4- (1-Methyl-6- (4-morpholin-4-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (3-morpholine-
4-yl-phenoxy) -1H-benzimidazole-
2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (1-methyl-6- (4-methanesulfonylamino-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, or , 5- (4- (1-methyl-6- (3-methanesulfonylamino-phenoxy) -1H-benzimidazol-2-ylmethoxy)
-Benzyl) -thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof and 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-
A pharmaceutical composition for administration of 3,4-difluoro-benzamide or a pharmacologically acceptable salt thereof at the same time or separately at a time, more preferably 5- (4
-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6-benzyloxy-
1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
5- (4- (1-Methyl-6-pentafluorophenoxy-1H-benzimidazol-2-ylmethoxy)-
Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (4-Amino-3,5-dimethyl-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-
2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4- (ethyl-
Isopropyl-amino) -phenoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(6- (3- (Ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4
-Dione, 5- (4- (6- (4- (isobutyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4- Dione, 5- (4- (6- (3-
(Isobutyl-methyl-amino) -phenoxy) -1-
Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5
-(4- (6- (4-dimethylamino-phenoxy)-
1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
5- (4- (6- (3-dimethylamino-phenoxy))
-1-Methyl-1H-benzimidazol-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-benzazoimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (1-methyl-6- (4-pyrrolidin-1-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione, 5- (4- (1-methyl-6- (3-
Pyrrolidin-1-yl-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6)
-(4-morpholin-4-yl-phenoxy) -1H-
Benzoimidazol-2-ylmethoxy) -benzyl)
-Thiazolidine-2,4-dione, 5- (4- (1-methyl-6- (3-morpholin-4-yl-phenoxy)
-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(1-Methyl-6- (4-methanesulfonylamino-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
Alternatively, 5- (4- (1-methyl-6- (3-methanesulfonylamino-phenoxy) -1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione or pharmacology thereof The above-accepted salts and 2- (2-chloro-4-iodophenylamino) -N-
A pharmaceutical composition for administering cyclopropylmethoxy-3,4-difluoro-benzamide or a pharmacologically acceptable salt thereof at the same time or separately at a time,
Most preferably 5- (4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(6-benzyloxy-1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (1-methyl-6-
Pentafluorophenoxy-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione, 5- (4- (6- (4-amino-3,
5-Dimethyl-phenoxy) -1-methyl-1H-benzimidazol-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-benzimidazol-2-ylmethoxy)-
Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (4- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-
2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-
Benzoimidazol-2-ylmethoxy) -benzyl)
-Thiazolidine-2,4-dione, 5- (4- (6-
(4- (isobutyl-methyl-amino) -phenoxy)
-1-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (3- (isobutyl-methyl-amino) -phenoxy)- 1-methyl-1H-benzimidazol-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-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof and 2- (2-chloro-
A pharmaceutical composition for administering 4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or a pharmacologically acceptable salt thereof at the same time or separately at a time.

[0115]

BEST MODE FOR CARRYING OUT THE INVENTION Compound (I), which is one of the active ingredients of the pharmaceutical composition of the present invention, is described in JP-A-2000-001487 (WO00 / 18081) and compound (III).
JP-A-11-193276 (WO99 / 180
81), the compound (IV) is disclosed in JP-A-2000-35.
It can be easily produced according to the method described in Japanese Patent No. 1779 (WO00 / 61581).

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

Compound (I), compound (III) or compound (IV) or a pharmacologically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, and a diphenylamine derivative or a pharmacologically acceptable salt thereof are Each can be formulated alone in separate unit dosage forms, or mixed to form a physically single dosage form.

When such a pharmaceutical composition of the present invention in a single unit dosage form or a mixed single dosage form is used as a prophylactic or therapeutic agent for the above-mentioned diseases, the pharmaceutical composition of the present invention (I), compound (III) or compound (IV) or a pharmaceutically acceptable salt thereof and / or a diphenylamine derivative or a pharmaceutically acceptable salt thereof, which are the active ingredients of Orally by using tablets, capsules, granules, powders or syrups, etc., or by parenteral injection, suppositories, etc. Can be administered to.

These formulations include excipients such as lactose,
Sugar derivatives such as white sugar, glucose, mannitol, sorbitol; corn starch, potato starch,
Starch derivatives such as α-starch and dextrin; Cellulose derivatives such as crystalline cellulose; Gum arabic; Dextran; Organic excipients such as pullulan; and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and aluminometasilicate. Silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate) and lubricants For example, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycols; Fumaric acid; Sodium benzoate; DL
Leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic acid anhydride and silicic acid hydrate; and the above starch derivatives), binders (for example, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (eg,
Cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally crosslinked sodium carboxymethyl cellulose; carboxymethyl starch,
Sodium carboxymethyl starch, chemically modified starch / celluloses such as cross-linked polyvinylpyrrolidone may be mentioned), emulsifiers (eg colloidal clays such as bentonite, bee gum; magnesium hydroxide, aluminum hydroxide, etc. Metal hydroxide;
Anionic surfactants such as sodium lauryl sulfate, calcium stearate; cationic surfactants such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters Nonionic surfactants can be mentioned), stabilizers (paraoxybenzoic acid esters such as methylparaben, propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride; phenol, Phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, commonly used sweeteners, acidulants, flavors, etc.), diluted Agent It is prepared in a known manner using a pressurized agent.

Administration of compound (I), compound (III) or compound (IV) or a pharmaceutically acceptable salt thereof, which is an active ingredient of the pharmaceutical composition of the present invention, and a diphenylamine derivative or a pharmaceutically acceptable salt thereof. The amount and administration ratio can be changed depending on various conditions such as the activity of each drug, symptoms of the patient, age and weight.

The dose varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 each time.
mg (preferably 0.5 mg), upper limit 1000 mg (preferably 5)
00 mg), in the case of parenteral administration, the lower limit is 0.01 mg (preferably 0.05 mg) and the upper limit is 100 mg (preferably 50 mg) per administration for 1 to 6 per day for adults.
It may be administered simultaneously or separately depending on the time and symptoms.

The compound (I), the compound (III) or the compound (IV) or a pharmacologically acceptable salt thereof is used in the present invention rather than the dose as an antihyperlipidemic agent which is its original use. In the case of use for prevention or treatment of arteriosclerosis in
These doses can be lower, and the dose can be further reduced by the excellent effect of the combined use with the diphenylamine derivative or a pharmacologically acceptable salt thereof.

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

[0124]

EXAMPLES 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. (Production Example 1) 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride 0 0.74 g of N- (2-amino-5-obtained in Reference Example 2)
(3-Isopropylamino-phenoxy) -phenyl)
-N-methylcarbamic acid t-butyl ester, 0.
70 g of 4- (2,4-dioxothiazolidin-5-ylmethyl) -phenoxyacetic acid (JP-A-11-19327)
6), 0.41 g of diethyl cyanophosphonate, 0.2
A mixture of 5 g triethylamine and 30 ml anhydrous 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 was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 2/3) to give N as an intermediate. -(5- (3-Isopropylamino-phenoxy) -2- (4- (2,4-dioxothiazolidin-5-ylmethyl) -phenoxyacetylamino) -phenyl) -N-methylcarbamic acid t-butyl ester was obtained. It was This intermediate was dissolved in 50 ml of 4N hydrochloric acid / 1,4-dioxane and allowed to stand at room temperature for 16 hours. The precipitated product was collected by filtration and washed with ethyl acetate to give the title compound (0.76 g, yield). 64%).

¹ H-NMR (DMSO-d ₆ ) 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,
d, J = 8.9 Hz), 12.05 (1H, s; disappeared by addition of heavy water). (Production Example 2) 5- (4- (6- (3- (isobutyl-methyl-amino) -phenoxy) -1-methyl -1H-Benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N of Preparation Example 1 -Methylcarbamic acid N- (2-amino-5- (3- (isobutyl-methyl-
The title compound was obtained in the same manner as in Production Example 1 using amino) phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester.

¹ H-NMR (DMSO-d ₆ ) 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 (2
H, 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 addition of heavy water). (Production Example 3) 5- (4- (6- (4- (isobutyl-methyl-amino) -phenoxy)) N- (2-amino-5- (3-isopropylamino-phenoxy) -of -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride Preparation Example 1 Phenyl) -N-methylcarbamic acid N- (2-methyl-5- (4- (isobutyl-methyl-methyl) -obtained in Reference Example 8 instead of t-butyl ester.
The title compound was obtained in the same manner as in Production Example 1 using amino) phenoxy) -phenyl) methylamine.

¹ H-NMR (DMSO-d ₆ ) 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 (5
H, 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 addition of heavy water). (Production Example 4) 5- (4- (6- (3- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy ) -Benzyl) -thiazolidine-2,4-dione 620 mg of 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-) obtained in Preparation Example 1.
Benzimidazole 2-ylmethoxy) -benzyl)-
A mixture of thiazolidine-2,4-dione dihydrochloride, 66 mg acetaldehyde, 90 mg acetic acid, 318 mg sodium triacetoxyborohydride 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 was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/1) to give the title compound (260 mg, Yield 48%) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ: 1.06 (3H, t, J = 7.0
Hz), 1.11 (6H, d, J = 6.6Hz), 3.05 (1H, dd, J = 14 and
9.2Hz), 3.18 (2H, q, J = 7.0Hz), 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 = 8.7Hz), 12.0
2 (1H, s; disappeared by addition of heavy water). (Production Example 5) 5- (4- (6- (4-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl)- Thiazolidine-2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-from Preparation Example 4
Instead of 2,4-dione dihydrochloride, 5- (4- (6-
(4-Amino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride (JP-A-11-1
93276), but using acetone instead of acetaldehyde in the same manner as in Production Example 4 to obtain the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 addition of heavy water), 5.34 (2H, s), 6.56 (2H, d
d, J = 12 and 3.3Hz), 6.81 (2H, d, J = 8.6Hz), 6.83 (1
H, 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 addition of heavy water). (Production Example 6) 5- (4- (6- (4-sec-butylamino-phenoxy) -1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -Thiazolidine-2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-from Preparation Example 4
Instead of 2,4-dione dihydrochloride, 5- (4- (6-
(4-Amino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride, similar to Production Example 4 using methyl ethyl ketone instead of acetaldehyde To give the title compound.

¹ H-NMR (DMSO-d ₆ ) 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 9.2H
z), 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 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 (1H, d, J = 8.8Hz), 12.01 (1H, br; disappeared by addition of heavy water). (Production Example 7) 5- (4- (6- (4-isobutylamino-phenoxy) -1-methyl- 1H-Benzimidazole 2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazole 2- of Preparation Example 4 Ilmethoxy) -benzyl) -thiazolidine-
Instead of 2,4-dione dihydrochloride, 5- (4- (6-
Production Example 4 using (4-amino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride, isobutyraldehyde instead of acetaldehyde.
The title compound was obtained in the same manner as.

¹ H-NMR (DMSO-d ₆ ) 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; lost by addition of heavy water), 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 addition of heavy water). (Reference Example 1) N- (5- (3-aminophenoxy) -2-nitrophenyl) -N-methylcarbamic acid t -Butyl ester containing 2.18 g of sodium hydride (55% by weight) 8
5.45 g of 3-aminophenol was added to 0 ml of an anhydrous N, N-dimethylformamide suspension, and the mixture was allowed to stand at room temperature for 20 minutes.
Stir for minutes. Then 14.3 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t
-Butyl ester (JP-A-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 the mixture was neutralized with 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%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.23 and 1.42 (total 9
H, each s), 3.18 (3H, s), 5.38 (2H, s; disappeared by addition of heavy water), 6.25 (1H, dd, J = 7.6 and 2.4Hz), 6.31 (1
H, s), 6.46 (1H, dd, J = 8.1 and 1.0Hz), 6.88 (1H, d
d, 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 of N- (5- (3-aminophenoxy) -2
-Nitrophenyl) -N-methylcarbamic acid t-butyl ester, a mixture of 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. did. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: ethyl acetate / n
-Hexane = 2/3) and purified to give 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 under a hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off to obtain the title compound (12.0 g, yield 81%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (6H, d, J =
6.4Hz), 1.29 (9H, s), 2.98 (3H, s), 3.40-3.47 (1
H, m), 4.78 (2H, s; disappears by adding heavy water), 5.45 (1
H, d, J = 7.8Hz; disappears 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), 6.9
3 (1H, t, J = 8.1 Hz). (Reference Example 3) N- (5- (3-bromophenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester 2.5 g of sodium hydride 50 including (55% by weight)
1 in 1 ml of anhydrous N, N-dimethylformamide suspension
0.0 g of 3-bromophenol was added, 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-
A solution of butyl ester dissolved in 70 ml of anhydrous N, N-dimethylformamide was added dropwise, and the mixture was stirred at 100 ° C for 3 hours. The reaction mixture was concentrated, water was added, the mixture was neutralized with 3N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline 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 give the title compound (20.2 g, yield 83%). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (9H, s), 3.19 (3H, s),
6.97 (1H, dd, J = 9.0 and 2.4Hz), 7.22 (1H, d, J = 7.9
Hz), 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 0.0 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 ( Dibenzylideneacetone) dipalladium, 115.7 mg of 2
-(Dicyclohexylphosphino) biphenyl and 2
77.7 mg of potassium t-butoxide was suspended in 4 ml of 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 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 / n-hexane = 1/7). Then, the title compound (204.2 m
g, yield 29%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.80 (6H, d, J = 6.6Hz), 1.25 (9
H, 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 (1
H, 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 204.2 mg of N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) -obtained in Reference Example 4 N-methylcarbamic acid t-butyl ester was dissolved in 10 ml of ethanol to give 100.0 mg.
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 give the title compound (14
5.4 mg, yield 77%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (6H, d, J = 6.6Hz), 1.57 (9
H, 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; lost by addition of 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 = 8.2
Hz), 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, 45
8.0 mg palladium acetate, 1.2 g 2- (di-t-
Butylphosphino) biphenyl and 2.9 g of sodium t-butoxide were suspended in 40 ml of anhydrous toluene and stirred at 100 ° C. for 1.5 hours. After the catalyst was filtered off, 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 subjected to silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/40 →
Purification by 1/20) gave the title compound (3.83 g, yield 64%). ¹ H-NMR (CDCl ₃ ) δ: 0.16 (6H, s), 0.91 (6H, d, J = 6.6
Hz), 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 (2
H, d, J = 8.8 Hz). Reference Example 7 N- (5- (4- (isobutyl-methyl-ami) phenoxy) -2-nitrophenyl) methylamine 3.83 g was obtained in Reference Example 6 (4 -(Isobutyl-methyl-amino) phenoxy) -t-butyldimethylsilane was dissolved in 20 ml of anhydrous tetrahydrofuran to give 20
ml 1M tetra-n-butylammonium fluoride
Tetrahydrofuran solution was added and 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 was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography (eluting solvent: ethyl acetate /
It was purified with n-hexane = 1/5. The obtained product was dissolved in 4N hydrochloric acid-1,4-dioxane, and the solution was mixed at room temperature for 3 hours.
Stir for 0 minutes. The reaction solution was concentrated and washed with diethyl ether to obtain an intermediate 4-isobutylmethylaminophenol monohydrochloride. This intermediate 500.0m
g and 2.6 g of potassium carbonate in 20 ml of anhydrous N,
The N-dimethylformamide suspension 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. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.8Hz), 2.00-2.1
3 (1H, m), 2.92 (3H, d, J = 5.9Hz), 2.98 (3H, s), 3.12 (2
H, d, J = 7.8Hz), 6.19-6.23 (2H, m), 6.68 (2H, d, J = 8.8
Hz), 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 Reference Example 5 Instead of N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester of Reference Example 5. The title compound was obtained in the same manner as in Reference Example 5 by using N- (5- (4- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) methylamine obtained in 7. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (6H, d, J = 6.6Hz), 1.94-2.0
4 (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) Antitumor effect on mouse colon cancer cell line Colon 26 cells
Enhancement 1 group 9 CDF1 mice (female, 7 weeks old) were subcutaneously transplanted with 1 × 10 ⁶ cells of the mouse colon cancer cell line Colon 26. The test compound was suspended in 5% emulophore saline containing 2.5% dimethylacetamide, 50 mg / kg of the compound of Production Example 1 was used as a PPARγ activator once a day, and PD-184352 was used as a MEK inhibitor.
50 mg / kg was orally administered twice a day for 5 days a week until death.

The effect was evaluated by the tumor growth inhibitory effect and life prolonging effect. The tumor growth inhibitory effect was evaluated by measuring the tumor minor axis (mm) and major axis (mm) with an electronic digital caliper and evaluating the tumor growth inhibitory rate (GI%) 14 days after transplantation by the following formula.

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

The life extension effect was evaluated by the life extension rate (ILS%) according to the following formula.

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

[0138]

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

A; p <0.05 vs cancer-bearing control group b; p <0.05 vs compound single agent administration group of Production Example 1 c; p <0.05 vs PD-184352 single agent administration group As apparent from Table 1, PPARγ The compound of Activator Production Example 1 and the MEK inhibitor PD-184352 each had a single inhibitory effect on the growth-suppressing effect and life-prolonging effect on mouse colon cancer cells, which were significantly enhanced by the combined administration of both compounds.

(Test Example 2) Antitumor effect on human colon cancer lines WiDr and COL-2-JCK
Enhancement 1 group 10 BALB / c nude mice (female, 5 weeks old) subcutaneously, human colon cancer line WiDr or tumor pieces COL-2-JCK (5 mm
x 5 mm square) was transplanted. The test compound was suspended in 5% emulophore saline containing 2.5% dimethylacetamide,
50 mg / kg of the compound of Production Example 1 was administered as the γ activator, and 200 mg / kg of PD-184352 was administered as the MEK inhibitor. For WiDr, 22 times from the next day to 4th, 7th to 11th, 14th to 18th, 21st to 25th and 28th to 30th day, COL-2-JCK
In contrast, a total of 14 oral administrations were performed from the day after transplantation to 4 days, 7 days to 11 days, and 14 days to 18 days.

The effect was determined by measuring the short diameter (mm) and long diameter (m) of the tumor.
m) was measured with an electronic digital caliper, and WiDr calculated the tumor growth inhibition rate (GI%) on the 31st day after transplantation and COL-2-JCK on the 21st day after transplantation in the same manner as in Test Example 1. The results are summarized in Table 2.

[0142]

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

A; p <0.05 vs cancer-bearing control group b; p <0.05 vs compound single agent administration group of Production Example 1 c; p <0.05 vs PD-184352 single agent administration group As apparent from Table 2, PPARγ Activator The compound of Production Example 1 and the MEK inhibitor PD-184352 were administered individually, but the growth inhibitory activity of human colon cancer cells was significantly enhanced by the combined administration of both compounds.

From 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. By doing so, it showed an excellent effect as compared with the case where each was used alone.

(Formulation Example) Tablets 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) are mixed and compressed by a tableting machine to give tablets of 500 mg each. This tablet can be coated (preferably sugar-coated) if necessary.

Injectable 1.5% by weight of the compound of Preparation 1 and 1.5% by weight of PD-184
352 was stirred in 10% by volume propylene glycol,
Then, the mixture was made up to a certain volume with water for injection and then sterilized to manufacture.

[0147]

The compound (I) and the compound (II of the present invention
I) or compound (IV) or a pharmacologically acceptable salt thereof and a diphenylamine derivative or a pharmacologically acceptable salt thereof are administered simultaneously or separately at different times, and the resulting pharmaceutical composition has excellent cell growth. Since it has suppressive activity and weak toxicity, it is a drug (in particular, a preventive agent or treatment for cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer, and liposarcoma). It is useful as an agent or a cell growth inhibitor).

Also, troglitazone, pioglitazone or pioglitazone of the present invention or a pharmacologically acceptable salt thereof, and 2- (2-chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide. Or, a pharmacologically acceptable salt thereof, a pharmaceutical composition for administering separately at the same time or at a time, has excellent cytostatic activity and weak toxicity,
It is useful as a medicine (particularly, a preventive or therapeutic agent for cancers such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer, and liposarcoma, or a cell growth inhibitor). .

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Naomi Shimazaki             1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.             Inside the company F term (reference) 4C063 AA01 BB08 CC62 DD26 EE01                 4C086 AA01 AA02 AA03 BC39 BC82                       GA02 GA08 GA10 MA03 MA17                       MA35 MA52 MA66 NA14 ZB26                 4C206 AA01 AA02 AA03 FA01 MA37                       MA55 MA72 MA86 NA14 ZB26

Claims (39)

[Claims] 1. A general formula (I) [Chemical 1] [In the formula, X is a benzimidazole ring group (substituent group α1
1 to 5 may be substituted with a group selected from
Indicates Y¹Represents an oxygen atom or a sulfur atom, and Z represents [Chemical 2] Indicates R is a hydrogen atom, C1-6 alkyl group, C1-6 alcohol
Xy group, halogen atom, hydroxy group, nitro group, amine
Group (1 or 2 substituted with a group selected from the substituent group α2)
Optionally) or a C7-11 aralkyl group (substituted)
Which may be substituted with a group selected from the group α3)
Shows, m represents an integer of 1 to 5. In the above, "substituent
Group α1 ”is a C1-6 alkyl group, C1-6 alkoxy.
Group, C7-11 aralkyloxy group, halogen atom,
Droxy group, C1-11 aliphatic acyloxy group, C1-
6 alkylthio group, halogenated C1-6 alkyl group, dialkyl
Toro group, amino group (group selected from the substituent group α2 is 1
Or two may be substituted), C6-10 aryl
A group (1 to 5 substituted with a group selected from the substituent group α3)
May be present) and C7-11 aralkyl group (substituent
1 to 5 groups substituted with a group selected from the group α3
Is a substituent group consisting of The "substituent group α2" is a C1-6 alkyl group, C7-11.
Aralkyl group, C6-10 aryl group, C1-11 fatty acid
Group acyl group, C7-11 aralkylcarbonyl group and C
7-11 is a substituent group consisting of an aromatic acyl group, The "substituent group α3" is a C1-6 alkyl group or a C1-6 alkyl group.
Lucoxy group, halogen atom, hydroxy group, nitro group,
C6-10 aryl group, halogenated C1-6 alkyl group
And an amino group (a group selected from the substituent group α2 is 1 or
2 groups may be substituted)
It ] A fused heterocyclic compound or a salt thereof having
General formula (II) [Chemical 3] [In the formula, R^aRepresents a bromine atom or an iodine atom, R^bIs a hydrogen atom, a hydroxy group, a C1-8 alkyl group
(It may be substituted with a group selected from the substituent group δ.
I), C1-8 alkoxy group, halogen atom, triflu
Indicates an oromethyl group or a cyano group, R^cIs -COOR^gGroup, tetrazolyl group, -CONR^g
R^hGroup, -CONHNR ⁱR^jGroup, -CH₂OR^gGroup or-
C (= O) -NR^kOR^lGroup {in the formula, R^gAnd R^hIs that
Independently, a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C2-
8 alkenyl group (substituted by a group selected from the substituent group δ
C2-8 alkynyl group (substituent group δ
Optionally substituted with a group selected from), C1-8
Alkylcarbonyl group, C6-10 aryl group, 5 or
6-membered aromatic heterocyclic group, 3- to 10-membered aliphatic heterocyclic group or
A C3-10 cycloalkyl group or R^gAnd R^hIs a bond
3- to 10-membered aliphatic heterocycle with nitrogen atom
Indicates RⁱAnd R^jAre each independently a hydrogen atom,
C1-8 alkyl group or RⁱAnd R^jJoins
Represents a 3- to 10-membered aliphatic heterocyclic group together with an elementary atom
And R^kIs a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C1-
8 alkylcarbonyl group, C6-10 aryl group, C7
-14 aralkyl group or C3-10 cycloalkyl group
Show, R^lIs a hydrogen atom, a C1-8 alkyl group (substituent
Optionally substituted with a group selected from group δ), C2
-8 alkenyl group (substituted with a group selected from the substituent group δ
C2-8 alkynyl group (substituent group)
optionally substituted with a group selected from δ), C3-
10 cycloalkyl group, 3 to 10 membered aliphatic heterocyclic group
Shows}, R^d, R^eAnd R^fAre each independently a hydrogen atom,
Droxy group, halogen atom, trifluoromethyl group, C
1-8 alkyl group (substituted with a group selected from the substituent group δ
Optionally), C1-8 alkoxy group, nitro
Group, cyano group or -Y²A¹R^mRepresents a group (in the formula, Y²Is
A single bond, an oxygen atom or a -NH- group is shown, and A¹Is simple
Or a C1-4 alkylene group, R^mIs the hydrogen source
Child, hydroxy group, carboxyl group or -NRⁱR^jBasis
(RⁱAnd R^jHas the same meaning as above). In the above, the substituent group δ is a halogen atom or a hydroxy group.
Si group, C1-6 alkoxy group, amino group (C1-6 alk
1 or 2 may be substituted by a kill group), C3-10
Cycloalkyl group, C6-10 aryl group, C6-10
Aryloxy group, 5- or 6-membered aromatic heterocyclic group and 5- or 5-
Is a substituent group consisting of a 6-membered aromatic heterocyclic oxy group.
It ] A diphenylamine derivative represented by
Administer the above acceptable salt simultaneously or separately at a time
A pharmaceutical composition for the treatment. 2. A compound represented by the general formula (I):
X is (In the formula, W ¹ and W ² each independently represent a hydrogen atom or a group selected from the substituent group α1), The pharmaceutical composition according to claim 1. In the above, "substituent group α1" means a 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 (from the substituent group α2 1 or 2 may be substituted by a selected group), C6-
10 aryl groups (which may be substituted with 1 to 5 groups selected from the substituent group α3) and C7-11 aralkyl groups (which are substituted with 1 to 5 groups selected from the substituent group α3) May also)). 3. The pharmaceutical composition according to claim 2, wherein W ¹ is a hydrogen atom or a C1-6 alkyl group. 4. The pharmaceutical composition according to claim 2, wherein W ¹ is a methyl group. 5. W ² is a C 1-6 alkoxy group or C 7-
The pharmaceutical composition according to any one of claims 2 to 4, which is an 11 aralkyloxy group. 6. The pharmaceutical composition according to any one of claims 2 to 4, wherein W ² is a benzyloxy group. 7. A compound represented by the general formula (I):
The pharmaceutical composition according to any one of claims 1 to 6, wherein Y ¹ is an oxygen atom. 8. A compound represented by the general formula (I):
The pharmaceutical composition according to any one of claims 1 to 7, wherein m is 1. 9. A compound represented by the general formula (I):
The pharmaceutical composition according to claim 1, wherein R is a hydrogen atom. 10. In the compound represented by formula (I), Z is represented by the following formula: The pharmaceutical composition according to any one of claims 1 to 9, which is a group represented by: 11. General formula (III) [Chemical 6] [In the above formula, R¹Is [Chemical 7] [Where R^FourIs a phenyl group (selected from the substituent group β1
Substituted by 1 to 5 groups) or pyridyl groups (positions
1 to 4 substituted with a group selected from the substituent group β1
May be) R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C1
-6 alkyl group, halogenated C1-6 alkyl group, C1
-6 alkoxy group, C1-6 alkylthio group, amino group
(It may be substituted with a group selected from the substituent group β3.
C3-10 cycloalkyl group (from the substituent group β2
1 to 3 may be substituted with a selected group), C6-
10 aryl groups (one selected from the substituent group β2
Up to 3 may be substituted), C7-C16 aralkyl group
(1 to 3 substituted with a group selected from the substituent group β2
May be used), C6-C10 aryloxy group (substituent group)
1 to 3 groups may be substituted with a group selected from β2
C), C7-16 aralkyloxy group (substituent group β2?
1 to 3 may be substituted with a group selected from the group), C6
-10 arylthio group (group selected from the substituent group β2
1 to 3 may be substituted with), C1-7 aliphatic acyl
4- to 7-membered saturated heterocycle containing a ruoxy group and a nitrogen atom
Group, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom,
Represents a toro group or a cyano group, R⁶Is a hydrogen atom, C1-6 alkyl group, C6-10 alkyl group.
Reel group (1 to 3 groups selected from the substituent group β2
Optionally substituted) or C7-16 aralkyl group (substituted)
It may be substituted with 1 to 3 groups selected from the group β2.
Indicating that Y^FourRepresents an oxygen atom or a sulfur atom, E¹Represents a = CH- group or a nitrogen atom. } Represents
Shows the group R²Is a hydrogen atom, a halogen atom, a hydroxy group, C1
-6 alkyl group, halogenated C1-6 alkyl group, C1
-6 alkoxy group, C1-6 alkylthio group, amino group
(It may be substituted with a group selected from the substituent group β3.
C3-10 cycloalkyl group (from the substituent group β2
1 to 3 may be substituted with a selected group), C6-
10 aryl groups (one selected from the substituent group β2
Up to 3 may be substituted), C7-C16 aralkyl group
(1 to 3 substituted with a group selected from the substituent group β2
May be used), C6-C10 aryloxy group (substituent group)
1 to 3 groups may be substituted with a group selected from β2
C), C7-16 aralkyloxy group (substituent group β2?
1 to 3 may be substituted with a group selected from the group), C6
-10 arylthio group (group selected from the substituent group β2
1 to 3 may be substituted with), C1-7 aliphatic acyl
4- to 7-membered saturated heterocycle containing a ruoxy group and a nitrogen atom
Group, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom,
Represents a toro group or a cyano group, R³Is the expression [Chemical 8] Represents a group having A²Represents a C1-6 alkylene group, Y³Represents an oxygen atom or a sulfur atom. In the above,
The "substituent group β1" is a halogen atom, a hydroxy group, C
1-6 alkyl group, halogenated C1-6 alkyl group, C
1-6 alkoxy group, C1-6 alkylthio group, amino
Group (may be substituted with a group selected from Substituent group β3)
C3-10 cycloalkyl group (from the substituent group β2
1 to 3 may be substituted with a selected group), C6-
10 aryl groups (one selected from the substituent group β2
Up to 3 may be substituted), C7-C16 aralkyl group
(1 to 3 substituted with a group selected from the substituent group β2
May be used), C6-C10 aryloxy group (substituent group)
1 to 3 groups may be substituted with a group selected from β2
C), C7-16 aralkyloxy group (substituent group β2?
1 to 3 may be substituted with a group selected from the group), C6
-10 arylthio group (group selected from the substituent group β2
1 to 3 may be substituted with), C1-7 aliphatic acyl
4- to 7-membered saturated heterocycle containing a ruoxy group and a nitrogen atom
Group, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom,
Is a group of substituents consisting of a toro group and a cyano group.
Group β2 ”is a halogen atom, a hydroxy group, a C1-6 alkenyl group.
Alkyl group, halogenated C1-6 alkyl group, C1-C6
Alkoxy group, amino group (selected from the substituent group β3
Optionally substituted with a group), a C6-C10 aryl group
And a substituent group consisting of a nitro group,
3 "is a C1-10 alkyl group, C6-10 aryl
Group, C7-16 aralkyl group, C1-7 aliphatic acyl
Group, C7-11 aromatic acyl group, C8-12 araliphatic
An acyl group, a C4-11 cycloalkylcarbonyl group and
5- or 6-membered aromatic heterocyclic carbonyl group containing nitrogen atom
It is a substituent group consisting of. ] Substituted fused heterocyclization with
Compound or a pharmaceutically acceptable salt thereof, and a compound represented by the following general formula (I
I) [Chemical 9] [In the formula, R^aRepresents a bromine atom or an iodine atom, R^bIs a hydrogen atom, a hydroxy group, a C1-8 alkyl group
(It may be substituted with a group selected from the substituent group δ.
I), C1-8 alkoxy group, halogen atom, triflu
Indicates an oromethyl group or a cyano group, R^cIs -COOR^gGroup, tetrazolyl group, -CONR^g
R^hGroup, -CONHNR ⁱR^jGroup, -CH₂OR^gGroup or-
C (= O) -NR^kOR^lGroup {in the formula, R^gAnd R^hIs that
Independently, a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C2-
8 alkenyl group (substituted by a group selected from the substituent group δ
C2-8 alkynyl group (substituent group δ
Optionally substituted with a group selected from), C1-8
Alkylcarbonyl group, C6-10 aryl group, 5 or
6-membered aromatic heterocyclic group, 3- to 10-membered aliphatic heterocyclic group or
A C3-10 cycloalkyl group or R^gAnd R^hIs a bond
3- to 10-membered aliphatic heterocycle with nitrogen atom
Indicates RⁱAnd R^jAre each independently a hydrogen atom,
C1-8 alkyl group or RⁱAnd R^jJoins
Represents a 3- to 10-membered aliphatic heterocyclic group together with an elementary atom
And R^kIs a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C1-
8 alkylcarbonyl group, C6-10 aryl group, C7
-14 aralkyl group or C3-10 cycloalkyl group
Show, R^lIs a hydrogen atom, a C1-8 alkyl group (substituent
Optionally substituted with a group selected from group δ), C2
-8 alkenyl group (substituted with a group selected from the substituent group δ
C2-8 alkynyl group (substituent group)
optionally substituted with a group selected from δ), C3-
10 cycloalkyl group, 3 to 10 membered aliphatic heterocyclic group
Shows}, R^d, R^eAnd R^fAre each independently a hydrogen atom,
Droxy group, halogen atom, trifluoromethyl group, C
1-8 alkyl group (substituted with a group selected from the substituent group δ
Optionally), C1-8 alkoxy group, nitro
Group, cyano group or -Y²A¹R^mRepresents a group (in the formula, Y²Is
A single bond, an oxygen atom or a -NH- group is shown, and A¹Is simple
Or a C1-4 alkylene group, R^mIs the hydrogen source
Child, hydroxy group, carboxyl group or -NRⁱR^jBasis
(RⁱAnd R^jHas the same meaning as above). Above
The substituent group δ is a halogen atom, a hydroxy group,
C1-6 alkoxy group, amino group (C1-6 alkyl group
1 or 2 may be substituted with), C3-10 cyclo
Alkyl group, C6-10 aryl group, C6-10 aryl
Roxy group, 5- or 6-membered aromatic heterocyclic group and 5- or 6-membered
It is a substituent group consisting of an aromatic heterocyclic oxy group. ]]
Diphenylamine derivative or its pharmacologically acceptable
A doctor to administer salt at the same time or separately at a time.
Medicinal composition. 12. A compound represented by the general formula (III), wherein R ¹ is a compound represented by the following formula: The pharmaceutical composition according to claim 11, which is a group represented by: 13. The pharmaceutical composition according to claim 11, wherein R ⁵ in the compound represented by the general formula (III) is a hydrogen atom. 14. The pharmaceutical composition according to claim 11, 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 claims 11 to 14, wherein in the compound represented by the general formula (III), Y ⁴ is an oxygen atom. 16. A compound represented by the general formula (III), wherein R ⁴ is a phenyl group (1 to 5 substituted with a group selected from the substituent group β1) or a pyridyl group (substituent group β1). 1 to 4 may be substituted with a group selected from the group).
The pharmaceutical composition according to the item. In the above, "substituent group β1
Contains a halogen atom, a C1-6 alkyl group, a halogenated C1-6 alkyl group, an amino group (which may be substituted with 1 or 2 groups selected from the substituent group β3), and a nitrogen atom. A substituent group consisting of a 4- to 7-membered saturated heterocyclic group and a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom. Further, the "substituent group β3" is a C1-10 alkyl group, a C6-10 aryl group, a C7-16 aralkyl group,
5 to 6 containing a C1-C7 aliphatic acyl group, a C7-11 aromatic acyl group, a C8-12 aromatic-aliphatic acyl group, a C4-11 cycloalkylcarbonyl group and a nitrogen atom.
A group of substituents composed of a membered aromatic heterocyclic carbonyl group. 17. The pharmaceutical composition according to any one of claims 11 to 15, wherein in the compound represented by formula (III), Y ³ is an oxygen atom. 18. The pharmaceutical composition according to any one of claims 11 to 17, wherein in the compound represented by the general formula (III), R ² is a hydrogen atom. 19. The pharmaceutical composition according to any one of claims 11 to 18, wherein in the compound represented by formula (III), A ² is a methylene group. 20. In the compound represented by formula (III), R ³ is represented by the following formula: The group represented by any one of claims 11 to 19, which is
The pharmaceutical composition according to the item. 21. A compound represented by the general formula (III):
The following general formula: The pharmaceutical composition according to any one of claims 11 to 20, which is a compound represented by: 22. The general formula (IV) [Chemical 13] [In the formula, R⁷Is a carbamoyl group (selected from the substituent group γ1
1 or 2 may be substituted with a selected group), thio
A carbamoyl group (a group selected from the substituent group γ1
Is optionally substituted by 2), sulfonyl group (substituent
Having one group selected from group γ1) or carbo
Nyl group (having one group selected from the substituent group γ1
), R⁸And R⁹Are each independently a hydrogen atom, C1-1
0 alkyl group, C6-10 aryl group (substituent group γ2?
1 to 3 may be substituted with a group selected from
Is a C7-16 aralkyl group (wherein the aryl moiety is a substituent group γ2
1 to 3 may be substituted with a group selected from
Indicates A³, A^FourAnd A^FiveAre each independently a single bond or C
1-8 alkylene group is shown, Y^Five, Y⁶And Y⁷Are each independently an oxygen atom or
Indicates a sulfur atom, E²Represents 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,
Hydrogen atom, C1-6 alkyl group, C6-10 aryl, respectively
Group (1 to 3 substituted with a group selected from the substituent group γ2)
Optionally) or a C7-16 aralkyl group (arly
1 to 3 groups are selected from the substituent group γ2
May be replaced). In the above, "substituent
Group γ1 ”is a C1-10 alkyl group, halogenated C1-
6 alkyl group, C3-10 cycloalkyl group, C6-1
0 aryl group (a group selected from the substituent group γ3, 1 to
3 may be substituted), C7-16 aralkyl group
(The aryl moiety is a group selected from the substituent group γ3
Up to 3 may be substituted), C4-11 cycloal
Killcarbonyl group, C7-11 aromatic acyl group (arly
1 to 3 groups are selected from the substituent group γ3
C8-17 aralkylcarbonyl
Group (the aryl moiety is a group selected from the substituent group γ3
1 to 3 may be substituted) 5- or 6-membered aromatic
Heterocyclic group (1 to 3 groups selected from the substituent group γ3
(Optionally substituted) 5- or 6-membered aromatic heterocyclic
Bonyl group (1 to 3 groups selected from the substituent group γ3
(May be substituted), C1-6 alkylsulfonyl
Group, halogenated C1-6 alkylsulfonyl group, C6-
10 Arylsulfonyl group (the aryl part is a substituent group γ
1 to 3 groups may be substituted with a group selected from 3
I) and C7-16 aralkylsulfonyl group (aryl
Substitution of 1 to 3 moieties with a group selected from the substituent group γ3
A substituent group consisting of “Substituent group γ2” is a C1-6 alkyl group, halogenated
C1-6 alkyl group, C1-6 alkoxy group, halogen
Atom, hydroxy group, C6-10 aryl group (substituent group
1 to 3 groups may be substituted with a group selected from γ4
C), a C7-16 aralkyl group (the aryl moiety is a substituent group)
1 to 3 groups may be substituted with a group selected from γ4
), Cyano group, nitro group and amino group (substituent group γ4
1 or 2 may be substituted with a group selected from
Is a group of substituents consisting of “Substituent group γ3” is a 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 aryl group (C1-6
Alkyl group, halogenated C1-6 alkyl group, C1-6 alkyl group
A group selected from a lucoxy group and a halogen atom.
Up to 3 may be substituted), C7-16 aralkyl
Group (aryl moiety is C1-6 alkyl group, halogenated
C1-6 alkyl group, C1-6 alkoxy group and halogen
1 to 3 substituted by a group selected from
, C1-7 aliphatic acyl group, C1-7 aliphatic acyl group
Syloxy group, amino group, diC1-6 alkylamino group
And a substituent group consisting of a C1-4 alkylenedioxy group
Yes, “Substituent group γ4” is a C1-10 alkyl group, C6-1
0 aryl group (C1-6 alkyl group, halogenated C1-
6 alkyl group, C1-6 alkoxy group and halogen atom
1 to 3 groups may be substituted with a group selected from
C), a C7-16 aralkyl group (wherein the aryl moiety is C1
-6 alkyl group, halogenated C1-6 alkyl group, C1
-6 Group selected from alkoxy group and halogen atom
, 1 to 3 may be substituted), C1-7 fat
Group acyl group, C4-11 cycloalkylcarbonyl group,
C7-11 aromatic acyl group (C1-6 alkyl group, halo
Genated C1-6 alkyl group, C1-6 alkoxy group and
Substituted with 1 to 3 groups selected from halogen atoms
), A C8-17 aralkylcarbonyl group (ar
Reel part is C1-6 alkyl group, halogenated C1-
6 alkyl group, C1-6 alkoxy group and halogen atom
1 to 3 groups may be substituted with a group selected from
5) or 6-membered aromatic heterocyclic carbonyl group (C1-6
Alkyl group, halogenated C1-6 alkyl group, C1-6
1 group selected from alkoxy groups and halogen atoms
A substituent group consisting of up to 3 substituents)
It ] Or an amine derivative compound having
And a salt of the following general formula (II) [Chemical 14] [In the formula, R^aRepresents a bromine atom or an iodine atom, R^bIs a hydrogen atom, a hydroxy group, a C1-8 alkyl group
(It may be substituted with a group selected from the substituent group δ.
I), C1-8 alkoxy group, halogen atom, triflu
Indicates an oromethyl group or a cyano group, R^cIs -COOR^gGroup, tetrazolyl group, -CONR^g
R^hGroup, -CONHNR ⁱR^jGroup, -CH₂OR^gGroup or-
C (= O) -NR^kOR^lGroup {in the formula, R^gAnd R^hIs that
Independently, a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C2-
8 alkenyl group (substituted by a group selected from the substituent group δ
C2-8 alkynyl group (substituent group δ
Optionally substituted with a group selected from), C1-8
Alkylcarbonyl group, C6-10 aryl group, 5 or
6-membered aromatic heterocyclic group, 3- to 10-membered aliphatic heterocyclic group or
A C3-10 cycloalkyl group or R^gAnd R^hIs a bond
3- to 10-membered aliphatic heterocycle with nitrogen atom
Indicates RⁱAnd R^jAre each independently a hydrogen atom,
C1-8 alkyl group or RⁱAnd R^jJoins
Represents a 3- to 10-membered aliphatic heterocyclic group together with an elementary atom
And R^kIs a hydrogen atom, a C1-8 alkyl group (substituent group
optionally substituted with a group selected from δ), C1-
8 alkylcarbonyl group, C6-10 aryl group, C7
-14 aralkyl group or C3-10 cycloalkyl group
Show, R^lIs a hydrogen atom, a C1-8 alkyl group (substituent
Optionally substituted with a group selected from group δ), C2
-8 alkenyl group (substituted with a group selected from the substituent group δ
C2-8 alkynyl group (substituent group)
optionally substituted with a group selected from δ), C3-
10 cycloalkyl group, 3 to 10 membered aliphatic heterocyclic group
Indicates}, and R^d, R^eAnd R^fAre each independent
Hydrogen atom, hydroxy group, halogen Atom, trifluoromethyl group, C1-8 alkyl group (position
It may be substituted with a group selected from the substituent group δ),
C1-8 alkoxy group, nitro group, cyano group or -Y²
A¹R^mRepresents a group (in the formula, Y²Is a single bond, an oxygen atom or
A -NH- group is shown, and A¹Is a single bond or C1-4 alk
Len group, R^mIs a hydrogen atom, hydroxy group, cal
Boxyl group or -NRⁱR^jGroup (RⁱAnd R^jIs the same as above
Meaning). In the above, the substituent group δ is
Rogen atom, hydroxy group, C1-6 alkoxy group,
A mino group (one or two substituted with a C1-6 alkyl group,
, C3-10 cycloalkyl group, C6-10
Reel group, C6-10 aryloxy group, 5 or 6-membered aromatic group
From aromatic heterocyclic group and 5- or 6-membered aromatic heterocyclic oxy group
Is a group of substituents. ] Induced by diphenylamino
Conductor or its pharmacologically acceptable salt at the same time or for
Composition for separate administration in 23. The drug according to claim 22, wherein in the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (having one group selected from the substituent group γ1). Composition. 24. In the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (C1-6 alkyl group, halogenated C1-6 alkyl group and C6-10 aryl group (selected from the substituent group γ3. 23. The pharmaceutical composition according to claim 22, which is substituted with a group selected from 1 to 3 which may be substituted with a group). 25. The pharmaceutical composition according to claim 22, wherein in the compound represented by the general formula (IV), R ⁷ is a sulfonyl group (which is substituted with a C1-6 alkyl group). 26. In the compound represented by the general formula (IV), R ⁸ is a hydrogen atom or a C 1-6 alkyl group,
The pharmaceutical composition according to any one of claims 22 to 25. 27. The pharmaceutical composition according to any one of claims 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 claims 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 claims 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 claims 22 to 29, wherein in the compound represented by general formula (IV), Y ⁵ is an oxygen atom. 31. The pharmaceutical composition according to any one of claims 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 claims 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 claims 22 to 32, wherein in the compound represented by formula (IV), E ² is a ═CH— group. 34. The pharmaceutical composition according to any one of claims 22 to 33, wherein in the compound represented by the general formula (IV), Ar is a benzene ring. 35. The pharmaceutical composition according to any one of claims 22 to 34, wherein in the compound represented by the general formula (IV), L is a hydrogen atom or a C1-6 alkyl group. 36. The diphenylamine derivative is 2- (2-
Chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide, The pharmaceutical composition according to claims 1-35. 37. 5- (4- (6-hydroxy-2,5)
7,8-Tetramethyl-chroman-2-ylmethoxy)
-Benzyl) -thiazolidine-2,4-dione, 5-
(4- (2- (5-Ethyl-pyridin-2-yl) -ethoxy) benzyl) -thiazolidine-2,4-dione or 5- (4- (2- (methyl-pyridin-2-yl-amino) -Ethoxy) -benzyl) -thiazolidine-
2,4-dione or a pharmacologically acceptable salt thereof, and 2
-(2-Chloro-4-iodophenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or a pharmacologically acceptable salt thereof for simultaneous or separate administration of a pharmaceutical composition object. 38. A cell growth inhibitor comprising the pharmaceutical composition according to any one of claims 1 to 37. 39. An antitumor agent comprising the pharmaceutical composition according to any one of claims 1 to 37.