JP2003238406A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition having an excellent cell proliferation suppressing activity. <P>SOLUTION: The pharmaceutical composition for preventing or treating cancers comprises a thiazolidinedione compound or the like represented by general formula (I) [wherein Ar is an aryl group (which may be substituted with an NR<SP>1</SP>R<SP>2</SP>group); R<SP>1</SP>and R<SP>2</SP>are same or different and they are each a hydrogen atom, a 1-6C alkyl group or the like; X is an oxygen atom or a sulfur atom; Y is a CH group or a nitrogen atom] and an RXR activating agent or the like as active ingredients. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to one or more kinds of thiazolidinedione compounds or pharmacologically acceptable salts thereof and one or more kinds of RXR (retinoid X receptor) activators or The present invention relates to a pharmaceutical composition for preventing or treating cancer containing a pharmacologically acceptable salt as an active ingredient.

[0002]

As a thiazolidinedione compound, a compound represented by the following general formula (A)

[0003]

[Chemical 2]

[In the above formula, R ^a is

[0005]

[Chemical 3]

[In the formula, R ^d is a phenyl group {amino group (C
1-10 alkyl group, C6-10 aryl group or C7-
16 aralkyl groups may be substituted) and the like, etc., etc., etc., etc., R ^e represents a hydrogen atom, etc., R ^f represents a C 1-6 alkyl group, etc., and D represents , An oxygen atom and the like, and E represents a ═CH— group and the like. A group represented by}, R ^b represents a hydrogen atom or the like, R ³ has the formula

[0007]

[Chemical 4]

And the like, A represents a C1-6 alkylene group, and B represents an oxygen atom or the like. ] The compound represented by these is disclosed, and it is described that this compound can be used as an anticancer agent (for example, Patent Document 1).
reference). However, this document neither describes nor suggests the combined use of this compound and an RXR activating agent.

It is already known that an RXR activating agent can be used as an anti-cancer agent (see, for example, Patent Documents 2 and 3 and Non-Patent Document 1). However, these documents neither describe nor suggest the combined use of an RXR activating agent and a thiazolidinedione compound.

A therapeutic agent for liposarcoma comprising a thiazolidinedione compound and an RXR activating agent is known (see, for example, Patent Document 4). Specifically, as a thiazolidinedione compound, 5-[[4- [2- (methyl-2-
Pyridinylamino) ethoxy] phenyl] methyl]-
2,4-thiazolidinedione (rosiglitazone or BR
L49653), 5-[[4-[(3,4-dihydro-
6-hydroxy-2,5,7,8-tetramethyl-2H
-1-Benzopyran-2-yl) methoxy] phenyl]
Methyl-2,4-thiazolidinedione (troglitazone) and 5-[[4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl] methyl-2,4-thiazolidinedione (pioglitazone) are described. , RXR
As the activation agent, 6- [1- (3,5,5,8,8
-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) cyclopropyl] nicotinic acid (LG1
[00268) and 6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) ethenyl] nicotinic acid (LG268) are known, The combined effect of these compounds was not sufficient as an anticancer agent.

[0011]

[Patent Document 1] Japanese Patent Laid-Open No. 11-193276

[Patent Document 2] Japanese Patent Laid-Open No. 6-107542

[Patent Document 3] International Publication No. 94/15901 pamphlet

[Patent Document 4] International Publication No. 98/29120 pamphlet

[Non-Patent Document 1] J. Thibonnet et al, Synlett, 1, pp1
41-143 (1999)

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to find a combination of compounds exhibiting a further excellent cancer cell proliferation inhibitory effect and to provide a useful cell proliferation inhibitor or anticancer agent.

[0013]

The present invention comprises one or more of the following general formula (I)

[0014]

[Chemical 5]

[Wherein Ar is an aryl group (which is substituted with at least one —NR ¹ R ² group and is 1 to 4).
Optionally substituted with a group selected from the substituent group α) or a heteroaryl group (at least one —NR ¹
R ² is substituted and may be substituted with a group selected from 1 to 3 substituent groups α),
R ¹ and R ² are the same or different and each is a hydrogen atom,
C1-6 alkyl group, C6-10 aryl group or C7-
16 aralkyl group is shown, X shows an oxygen atom or a sulfur atom, and Y shows a = CH- group or a nitrogen atom.

In the above, the substituent group α is a substituent group consisting of a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom and a hydroxyl group. ] The thiazolidinedione compound represented by or a pharmacologically acceptable salt thereof and one or more kinds of RXR activating agents or a pharmacologically acceptable salt thereof are contained as an active ingredient at the same time or for a certain period of time. It relates to a pharmaceutical composition for preventing or treating cancer, which is placed and administered separately.

The thiazolidinedione compound of the present invention is described in JP-A No. 11-193276.

Preferred examples of the thiazolidinedione compound represented by the general formula (I) of the present invention include the following compounds. (1) Ar is a phenyl group (at least one —NR ¹
R ² group and may be substituted with a group selected from 1 to 4 substituent groups α) or a pyridyl group (substituted with at least one —NR ¹ R ² group) And optionally substituted with a group selected from 1 to 3 substituent groups α). (2) Ar is a phenyl group (which may be substituted with one —NR ¹ R ² group and may be substituted with 1 to 4 C1-6 alkyl groups) or a pyridyl group (one -NR
¹ R ² group and may be substituted with 1 to 3 alkyl groups). (3) Ar is a phenyl group (at least one —NR ¹
A compound which is substituted with a R ² group and may be substituted with a group selected from 1 to 4 substituent groups α). (4) A compound in which Ar is a phenyl group (which is substituted with one —NR ¹ R ² group and may be substituted with 1 to 4 C 1-6 alkyl groups). (5) A compound in which Ar is a phenyl group (which is substituted with one —NR ¹ R ² group). (6) Ar is a phenyl group (3- or 4-position is -NR ¹ R ²
A compound which is substituted with a group). (7) A compound in which Ar is a phenyl group (the 3-position is substituted with a —NR ¹ R ² group). (8) A compound in which Ar is a pyridyl group (which is substituted with one —NR ¹ R ² group and may be substituted with 1 to 3 C 1-6 alkyl groups). (9) A compound in which Ar is a pyridyl group (which is substituted with one —NR ¹ R ² group). (10) A compound in which Ar is a 2-pyridyl group (which is substituted with one —NR ¹ R ² group). (11) A compound in which Ar is a 2-pyridyl group (5-position is substituted with -NR ¹ R ² group). (12) R ¹ and R ² are the same or different,
A compound which is a hydrogen atom, a C1-6 alkyl group or a C6-10 aryl group. (13) R ¹ and R ² are the same or different,
A compound which is a hydrogen atom or a C1-6 alkyl group. (14) A compound in which R ¹ is a C1-6 alkyl group and R ² is a hydrogen atom. (15) A compound in which R ¹ is a C1-4 alkyl group and R ² is a hydrogen atom. (16) A compound in which R ¹ is an isopropyl group and R ² is a hydrogen atom. (17) A compound in which X is an oxygen atom. (18) A compound in which Y is a = CH- group.

Further, as the thiazolidinedione compound of the present invention, the following general formula (I ')

[0020]

[Chemical 6]

A compound represented by the formula [wherein R ¹ 'represents a C 3-6 branched alkyl group and R ² ' represents a hydrogen atom or a C 1-6 alkyl group] is also suitable.

More preferred examples of the thiazolidinedione compound of the present invention include the following compounds.

5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione, 5- (4- (6- (3- (isopropyl-methyl-amino) -phenoxy) -1-methyl-1
H-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- (3 -Isobutylamino-phenoxy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy) -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- (3- (ethyl-isobutyl-amino)- Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy)-
Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (3-sec-butylamino-phenoxy) -1
-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5-
(4- (6- (3- (sec-butyl-methyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- ( 4- (6- (3- (sec
-Butyl-ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy)-
Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (3-t-Butylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy)
-Benzyl) -thiazolidine-2,4-dione, 5- (4
-(6- (3-diisopropylamino-phenoxy) -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- (4- (isopropyl-methyl-amino))
-Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione, 5- (4- (6- (4- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1
H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6-
(4-isobutylamino-phenoxy) -1-methyl-1
H-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- (4 -(Ethyl-isobutyl-
Amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-sec)
-Butylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (4-
(Sec-Butyl-methyl-amino) -phenoxy)-
1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
5- (4- (6- (4- (sec-butyl-ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5 -(4- (6- (4-t-butylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6 -(4-Diisopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (2-isopropylamino-phenoxy) ) -1-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (2-
(Isopropyl-methyl-amino) -phenoxy) -1
-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5
-(4- (6- (2- (ethyl-isopropyl-amino) -phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4 -(6- (2-isobutylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (2- ( Isobutyl-methyl-amino) -phenoxy) -1-methyl-
1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4-
(6- (2- (ethyl-isobutyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (6- (2-sec-butylamino-
Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (6- (2- (sec-butyl-methyl-amino) -phenoxy) -1-methyl-1H
-Benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6
-(2- (sec-Butyl-ethyl-amino) -phenoxy) -1-methyl-1H-benzimidazole-2-
Ilmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (6- (2-t-butylamino-phenoxy) -1-methyl-1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4-
Dione, 5- (4- (6- (2-diisopropylamino-
Phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,
4-dione, 5- (4- (6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 1-amino-7- [2- [4- (2,
4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6
-Yloxy] naphthalene, 1-amino-6- [2- [4
-(2,4-dioxothiazolidin-5-ylmethyl)
Phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene, 1-amino-5-
[2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene or 3-
[2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] aniline.

Of these, particularly preferred is 1-amino-7- [2- [4- (2,4-dioxothiazolidine-5
-Ylmethyl) phenoxymethyl] -1-methyl-1H-
Benzimidazol-6-yloxy] naphthalene, 1-
Amino-6- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene, 1-amino-5- [2 -[4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1
-Methyl-1H-benzimidazol-6-yloxy]
Naphthalene, 3- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] aniline, 5- (4- (6- (3-Isopropylamino-phenoxy) -1-methyl-1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4-
Dione or 5- (4- (6- (4-amino-3,5-
Dimethylphenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione.

The RXR activating agent which is one of the active ingredients of the present invention is a compound which enhances the action of retinoic acid or a compound having a physiological activity like retinoic acid (retinoid) by binding to RXR. .

Representative examples of the RXR activating agent of the present invention include, for example, J. Thibonnet et al, Synle.
The compounds described in tt, 1, pp141-143 (1999), JP-A-6-107542 and WO94 / 15901 can be mentioned.

The structural formulas of typical compounds as the RXR activating agent which is the active ingredient of the present invention are shown below.

[0028]

[Chemical 7]

Among the above compounds, ATRA is listed in Table 1
No. 5,119,948, the compound name is (E, E, E, E) -3,7-dimethyl-9- [2,
6,6-Trimethyl-1-cyclohexen-1-yl]
It is -2,4,6,8-nonatetraenoic acid (all-trans-retinoic acid). ATRA acts on RXR as it is or a part of it is converted into 9-cis-retinoic acid.

9-cis-retinoic acid is described in JP-A 6-1.
No. 07542, the compound name is
(E, Z, E, E) -3,7-dimethyl-9- [2,
6,6-Trimethyl-1-cyclohexen-1-yl]
It is -2,4,6,8-nonatetraenoic acid.

LG100268 is WO94 / 1590
No. 1, the compound name is 6- [1
-(3,5,5,8,8-pentamethyl-5,6,7,
8-tetrahydronaphthalen-2-yl) cyclopropyl] nicotinic acid.

Targretin is described in WO94 / 15901, and its compound name is 6- [1-
(3,5,5,8,8-pentamethyl-5,6,7,8
-Tetrahydronaphthalen-2-yl) ethenyl] benzoic acid.

The thiazolidinedione compound and the RXR activating agent, which are the active ingredients of the present invention, can be made into a salt according to a conventional method. Examples of such salts include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts, iron salts, zinc salts, copper salts, nickel. Salts, metal salts such as cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, Guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt, Tris (hydroxymethyl) aminometa Amine salts such as organic salts such as salts; hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; nitrates, perchlorates, sulfates, phosphates, etc. Inorganic acid salts; lower alkanesulfonic acid salts such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid; arylsulfonic acid salts such as benzenesulfonic acid, p-toluenesulfonic acid; glutamic acid, aspartic acid, etc. Salts of amino acids such as; organic acids such as salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid; and amino acids such as ornithine salts, glutamate salts, aspartate salts Examples of the salt of the thiazolidinedione compound include a hydrohalide salt and an organic acid salt, more preferably a hydrochloride salt.

The thiazolidinedione compound and the RXR activating agent, which are the active ingredients of the present invention, absorb water by adsorbing water by adsorbing water by leaving it in the air or by recrystallization. It may be Japanese. When forming such hydrates, all of them are included in the present invention.

Further, the thiazolidinedione compound and the RXR activating agent which are the active ingredients of the present invention may absorb some other solvent to form a solvate, and such a solvate may also be used. Included in the present invention.

The thiazolidinedione compound and the RXR activating agent which are the active ingredients of the present invention may have various isomers. For example, the thiazolidine ring of the thiazolidinedione compound having the structure of the general formula (I) contains an asymmetric carbon atom, and since an asymmetric carbon atom may be present on the substituent, it has an optical isomer. The present invention includes each of these isomers or a compound containing them in any proportion.

Such isomers are prepared by synthesizing the compound of the present invention by using the starting compound of each isomer, or by synthesizing the synthesized compound of the present invention by a conventional resolution method or separation method as desired. Can be obtained.

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

There is no particular limitation on the administration "separately at a certain time" as long as it can be administered separately at different times. For example, first, a thiazolidinedione compound or a pharmacologically acceptable compound thereof can be used. Of the RXR activating agent or a pharmacologically acceptable salt thereof is administered after a predetermined time.

When the thiazolidinedione compound or the pharmacologically acceptable salt thereof to be administered and the RXR activating agent or the pharmacologically acceptable salt thereof are 3 or more in total, , "Simultaneously or separately at a time" means to administer all of them at the same time, to administer each separately at a time, and to administer two or more kinds at the same time and a residual drug at a time. It includes a method of administration, a method of administering two or more kinds at a time, and a method of simultaneously administering the remaining drug, and the like.

In the present invention, "cancer" refers to sarcoma, cancer type, leukemia and the like, and these include fibrosarcoma, liposarcoma,
Osteosarcoma, angiosarcoma, lung cancer, gastric cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, esophageal cancer, tongue cancer, brain tumor,
Includes pharyngeal cancer, ovarian cancer, acute leukemia, chronic leukemia, lymphoma, etc.

[0042]

BEST MODE FOR CARRYING OUT THE INVENTION One of the active ingredients of the present invention,
The thiazolidinedione compound represented by the general formula (I) is
It can be easily manufactured by the method described in JP-A No. 11-193276.

Among the thiazolidinedione compounds represented by the general formula (I), which is one of the active ingredients of the present invention, the general formula (I ′)

[0044]

[Chemical 8]

A compound represented by the formula [wherein R ¹ 'represents a C3-6 branched alkyl group and R ² ' represents a hydrogen atom or a C1-6 alkyl group] can also be produced by the following method. can do.

In the following, R ¹ 'and R ² ' are the same as described above. (Method A) Method A is a method for producing the compound (Ia) in which R ² 'is a C1-6 alkyl group.

[0047]

[Chemical 9]

(Step A1) This step is a step of alkylating amine (1) to obtain amine (2). That is, the step of reacting the amine (1) with an aldehyde in the presence of a reducing agent in an inert solvent to obtain the amine (2).

Amine compound (1) used in this step
Can be produced according to Example 46 of JP-A No. 11-193276, or in accordance therewith.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but it is preferably an ether such as tetrahydrofuran or diethyl ether, benzene or toluene. Aromatic hydrocarbons and the like, and particularly preferably ethers such as tetrahydrofuran and diethyl ether.

Examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride and the like, and acetic acid and the like can be added if desired.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 100 ° C. The temperature is preferably 10 to 30 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 1 week, preferably 1 hour to 1 day.

After completion of the reaction, for example, the solvent is distilled off under reduced pressure, the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane and the like, and the extract is washed with water and saturated saline, It is obtained by drying over anhydrous sodium sulfate and then distilling off the solvent. If desired, various chromatographies or recrystallization methods can be used for isolation and purification. (Step A2) In this step, the compound (I
This is a step of obtaining a). That is, it is a step of reacting the amine (2) with an aldehyde or a ketone in an inert solvent in the presence of a reducing agent to obtain a compound (Ia), and can be performed in the same manner as the step A1. (Method B) Method B is a compound (Ib) in which R ² 'is a hydrogen atom.
And the method (A) using the compound (Ib) as a starting material and the method (A) separately.

[0055]

[Chemical 10]

(Step B1) In this step, the amine (1) is alkylated to obtain the compound (Ia). That is, it is a step of reacting an amine (1) with an aldehyde or a ketone in an inert solvent in the presence of a reducing agent to obtain a compound (Ia), and can be performed in the same manner as the step A1. (Step B2) In this step, compound (Ib) is alkylated to obtain compound (Ia). That is, the step of reacting the compound (Ib) with an aldehyde in the presence of a reducing agent in an inert solvent to obtain the compound (Ia).
It can be performed in the same manner as the process. (Method C) This method is a method for producing the compound (I ′) separately from the above method A or method B.

[0057]

[Chemical 11]

(Step C1) In this step, the chloro compound (3) is used.
(4) which is a phenyl ether by etherification of
Is a step of obtaining. That is, in the step of reacting the chloro compound (3) with a phenol having a desired position substituted with a bromine atom in an inert solvent, a compound (4) is obtained.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but N, N-dimethylformamide is preferably used.
Examples thereof include amides such as N, N-dimethylacetamide, ethers such as tetrahydrofuran and diethyl ether, aromatic hydrocarbons such as benzene and toluene, and particularly preferable are N, N-dimethylformamide and N. , N-dimethylacetamide.

The base used is not particularly limited as long as it does not affect other parts of the compound, but alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydride and potassium hydride. Examples thereof include alkali metal hydrides.

The reaction temperature varies depending on the compound, the solvent, etc., but is usually 20 to 160 ° C., preferably 80 to 100 ° C. The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 1 week, and preferably 1 hour to 1 day.

After completion of the reaction, the solvent is distilled off under reduced pressure, and the residue is immiscible with water, for example, ethyl acetate,
It can be obtained by extraction with dichloromethane or the like, washing the extract with water and saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods. (Step C2) In this step, compound (4) which is a bromo compound is used.
Is a step of obtaining a compound (5) which is an amine. That is, the compound (4) is used as a catalyst in an inert solvent,
In this step, compound (5) is obtained by reacting with a primary or secondary amine in the presence of a ligand and a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aromatic hydrocarbons such as benzene and toluene, 1,4 Ethers such as -dioxane and 1,2-dimethoxyethane are mentioned, and aromatic hydrocarbons such as benzene and toluene are particularly preferable.

Examples of the catalyst used include palladium-containing compounds such as palladium (II) acetate and tris (dibenzylideneacetone) dipalladium (0).

The ligand used is 2- (di-
Examples thereof include phosphorus compounds such as t-butylphosphino) biphenyl and 2- (dicyclohexylphosphino) biphenyl.

The base used is sodium t
-Butoxide, tripotassium phosphate, etc. may be mentioned.

The reaction temperature varies depending on the compound, solvent, etc., but is usually 20 to 160 ° C., preferably 80 to 100 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 1 week, and preferably 1
Hours to a day.

After completion of the reaction, for example, the solvent is distilled off under reduced pressure, water is added, and the mixture is neutralized with dilute hydrochloric acid and the like, and then ethyl acetate,
A water-immiscible solvent such as dichloromethane is added and the organic layer containing the target compound is separated. This extract is washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent is distilled off. If desired, it can be isolated and purified by various chromatography or recrystallization methods. (Step C3) In this step, the compound (5) which is a nitro compound is reduced to obtain the amine (6). This reaction is performed using a catalytic reduction reaction or a general method for reducing a nitro group, which uses a metal and an acid, and sodium dithionite as a reducing agent.

In the case of catalytic reduction reaction, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but alcohols such as methanol and ethanol, tetrahydrofuran are preferred. , Ethers such as diethyl ether, and particularly preferably alcohols such as methanol and ethanol.

Examples of the catalyst used include palladium-carbon, palladium-alumina, palladium chloride, platinum oxide and the like. The reaction temperature varies depending on the compound, the solvent and the like, but is usually 0 to 80 ° C. Suitably 1
It is 0 to 30 ° C.

The reaction time varies depending on the compound, reaction temperature and the like, but is usually 30 minutes to 1 week, preferably 1 hour to 1 day.

After completion of the reaction, for example, the catalyst is removed from the reaction mixture by filtration, and then the solvent is distilled off.

In the case of the method using a metal and an acid, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but alcohols such as methanol and ethanol are preferred. Examples thereof include organic carboxylic acids such as acetic acid, water, and mixed solvents thereof.

Examples of the metal used include zinc, iron and tin.

Examples of the acid used include organic carboxylic acids such as acetic acid, mineral acids such as hydrochloric acid, ammonium chloride and the like.

The reaction temperature varies depending on the compound, solvent and the like, but is usually 0 to 100 ° C. It is preferably 10 to 80 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 30 minutes to 1 week, preferably 1 hour to 1 day.

After completion of the reaction, for example, the reaction mixture is appropriately neutralized, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added to give the desired compound. The obtained organic layer is separated, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent is distilled off.

If desired, various chromatographic methods or recrystallization methods can be used for isolation and purification. (Step C4) In this step, the amine (6) is condensed with the carboxylic acid (7) to obtain the amide (8). That is, after reacting the carboxylic acid (7) with a mixed acid anhydride agent in the presence of a base in an inert solvent to produce mixed acid anhydrides, the mixed acid anhydride is reacted with an amine (6) and then an amide (8 ) Is a process of obtaining.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is an aliphatic hydrocarbon such as hexane or heptane, benzene or toluene. Such as aromatic hydrocarbons, dichloromethane, halogenated hydrocarbons such as 1,2-dichloroethane, tetrahydrofuran, ethers such as diethyl ether, ketones such as acetone, N, N-dimethylformamide, N , Amides such as N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfolane and the like, and ethers such as tetrahydrofuran and diethyl ether are particularly preferable.

Examples of the mixed acid anhydride agent to be used include ethyl chloride carbonate, alkyl halide carbonate such as isobutyl chloride, alkanoyl halide such as pivaloyl chloride, diethyl cyanophosphonate, diphenyl cyanophosphonate, and the like. Examples thereof include cyanophosphonic acid diesters.

Examples of the base used include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine and pyridine. , 4-
(N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2. 2.2] Octane (DABCO),
Organic amines such as 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) may be mentioned.

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the compound, the reagent, the solvent, etc., but is usually 0 to 100 ° C., and preferably 10 to 30 ° C.

The reaction time in the reaction for producing mixed acid anhydrides varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 15 minutes to 2 days, preferably 30 minutes to 1 day.

The reaction between the mixed acid anhydride and the amine (6) is carried out in the presence of a base in an inert solvent, and the base and the inert solvent used are the same as those mentioned above for producing the mixed acid anhydride. Is the same as that used in the reaction. The reaction temperature in the reaction between the mixed acid anhydride and the amine (6) is
Although it varies depending on the compound, reagent, solvent, etc., it is generally 0 to 100 ° C., and preferably 10 to 30 ° C.

The reaction time in the reaction between the mixed acid anhydride and the amine (6) varies depending on the compound, the reagent, the reaction temperature and the like, but is usually 30 minutes to 1 week, and preferably,
One hour to one day.

When cyanophosphoric acid diesters are used in this reaction, the amine (6) and the carboxylic acid (7) can be directly reacted in the presence of a base. After completion of the reaction, for example, the solvent is distilled off under reduced pressure, the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane and the like, the extract is washed with water and saturated saline, and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off. If desired, it can be isolated and purified by various chromatography or recrystallization methods. (Step C5) This is a step of obtaining the benzimidazole compound (I) of the present invention from phenylenediamine (8). That is, it is a step of reacting the phenylenediamine (8) with an acid in the presence or absence of an inert solvent to obtain the compound (I ′).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane, Tetrahydrofuran, ethers such as 1,4-dioxane, alcohols such as methanol, ethanol, t-butanol and diethylene glycol, water, or water or a mixed solvent of the above solvents, particularly preferably dichloromethane,
It is 1,4-dioxane.

The acid to be used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and acetic acid are preferred. Bronsted acids such as organic acids such as formic acid, p-toluenesulfonic acid and trifluoroacetic acid, Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, fluorine trichloride and bromine trichloride, acidic ion exchange resins And the like, and particularly preferable are hydrochloric acid, acetic acid, and trifluoroacetic acid.

The reaction temperature varies depending on the compound, the acid used, the solvent, etc., but is usually 0 ° C. to the boiling point temperature,
It is preferably 20 to 70 ° C.

The reaction time varies depending on the compound, the acid used, the reaction temperature and the like, but is usually 30 minutes to 2 days, preferably 1 hour to 1 day.

After completion of the reaction, the solvent is distilled off under reduced pressure, and the residue is immiscible with water, for example ethyl acetate,
It can be obtained by extraction with dichloromethane or the like, washing the extract with water and saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods. (Method D) This method is a method for separately producing the compound (5) which is an intermediate in the method C. The compound (5a) in which R ² 'is a C1-6 alkyl group can be produced by the following steps D1 to D3 or steps D1, D4 and D5.
The compound (5b) in which R ² 'is a hydrogen atom can be produced by the following steps D1 and D4.

[0094]

[Chemical 12]

(Step D1) Etherification This step is a step for obtaining a phenyl ether compound (9) from the chloro compound (3). That is, the chloro compound (3) is reacted with a phenol having a desired position substituted with an amino group in the presence of a base in an inert solvent to give a compound (9)
Which is the same as the step C1. (Step D2) In this step, the compound (9) which is an amine is alkylated to obtain the amine (10). That is, the step of reacting the amine (9) with a desired aldehyde in the presence of a reducing agent in an inert solvent to obtain the amine (10),
It can be performed in the same manner as the step A1. (Step D3) In this step, the amine (10) is alkylated to obtain the amine compound (5a). That is, it is a step of reacting the amine (10) with a desired aldehyde or ketone in an inert solvent in the presence of a reducing agent to obtain an amine compound (5a), which can be performed in the same manner as the step A1. (Step D4) This step is a step of alkylating amine (9) to obtain amine compound (5b). That is,
The amine (9) is reacted with the desired aldehyde or ketone in the presence of a reducing agent in an inert solvent to give an amine compound (5
This is a step of obtaining b) and can be performed in the same manner as the step A1. (Step D5) In this step, the amine compound (5b) is further alkylated to obtain the amine compound (5a). That is, it is a step of reacting an amine compound (5a) with an aldehyde in an inert solvent in the presence of a reducing agent to obtain an amine compound (5b), which can be performed in the same manner as the step A1. (Method E) This method is a method for producing the compound (5) which is an intermediate in the method C, separately from the methods C and D.

[0096]

[Chemical 13]

(Step E1) In this step, the bromo compound (1
It is a step of aminating 1) to obtain a compound (12) which is an amine. That is, the bromo compound (1
1) in the presence of a catalyst, a ligand and a base, primary or secondary
This is a step of reacting with a primary amine to obtain the compound (12), and can be performed in the same manner as the step C2. (Step E2) This step is a step of desilylating compound (12) which is a silyl ether to obtain phenol (13). That is, compound (12) in an inert solvent
Is a step of reacting with a fluoride to obtain phenol (13).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably a halogenated hydrocarbon such as dichloromethane or 1,2-dichloroethane, Tetrahydrofuran, ethers such as 1,4-dioxane, N, N-
Examples thereof include amides such as dimethylformamide and N, N-dimethylacetamide, water and the like, and particularly preferable are ethers such as tetrahydrofuran and 1,4-dioxane.

Examples of the fluoride used include potassium fluoride and tetra-n-butylammonium fluoride.

The reaction temperature varies depending on the compound, the solvent, etc., but is usually 0 to 100 ° C., and preferably 10 to 30 ° C.

The reaction time varies depending on the compound, the reaction temperature, etc., but it is usually 15 minutes to 2 days, and preferably 30 minutes.
Minutes to a day.

After completion of the reaction, the solvent is distilled off under reduced pressure, and the residue is immiscible with water, for example ethyl acetate,
It can be obtained by extraction with dichloromethane or the like, washing the extract with water and saturated saline, drying over anhydrous sodium sulfate, and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods. (Step E3) This step is a step of etherifying phenol (13) to obtain compound (5) which is a phenyl ether. That is, in an inert solvent, phenol (1
This is a step of reacting 3) with the chloro compound (3) in the presence of a base to obtain a phenyl ether (5), which can be performed in the same manner as in the C1 step.

Of the active ingredients of the present invention, the RXR activating agent is, for example, J. Thibonnet et al, Synlett,
1, pp141-143 (1999), JP-A-6-107542, and WO
It can be easily produced according to the method described in Japanese Patent Publication No. 94/15901. For example, ATRA is described by J. Thibonnet et al,
By the method described in Synlett, 1, pp 141-143 (1999), 9-
Cis-retinoic acid is commercially available from MF Boehm et al, J. Med. Chem.,
LG100268 by the method described in 37, pp408-414 (1994).
Can be produced by the method described in WO94 / 15901, and targretin can be produced by the method described in WO94 / 15901.

A thiazolidinedione compound or a pharmacologically acceptable salt thereof which is an active ingredient of the pharmaceutical composition of the present invention,
The RXR activating agent or a pharmacologically acceptable salt thereof is
Each can be individually adjusted into a separate unit dosage form, or can be mixed and physically adjusted into a single unit dosage form.

When the pharmaceutical composition of the present invention is used as a prophylactic or therapeutic agent for the above-mentioned diseases, a thiazolidinedione compound or a pharmacologically acceptable salt thereof which is an active ingredient of the pharmaceutical composition of the present invention is used. , RXR activating agent or a pharmacologically acceptable salt thereof is mixed with each itself or an appropriate pharmacologically acceptable vaginal agent, diluent or the like to give tablets, capsules, granules, It can be administered orally by means of powder or syrup, or parenterally by means of injection or suppository.

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. Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; sodium sulfate, etc.) Sulfate; glycol; fumaric acid; sodium benzoate; DL
Examples thereof include leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives. ), A binder (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), a disintegrant (for example, low-substituted hydroxypropylcellulose). , Cellulose derivatives such as carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; chemically modified starch / celluloses such as carboxymethylstarch, sodium carboxymethylstarch, crosslinked polyvinylpyrrolidone can be mentioned). Emulsifiers (eg,
Colloidal clays such as bentonite and bee gum; metal hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cationic interfaces such as benzalkonium chloride. Activators; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben, propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol;
Benzalkonium chloride; phenols, phenols such as cresol; thimerosal; dehydroacetic acid; and
Mention may be made of sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.) and diluents and the like can be used to produce the compound by a known method.

A thiazolidinedione compound or a pharmaceutically acceptable salt thereof which is an active ingredient of the pharmaceutical composition of the present invention,
The dose and administration ratio of the RXR activating agent or a pharmacologically acceptable salt thereof may change depending on various conditions such as the activity of each drug, the symptom of the patient, the age and the body weight.

The dose varies depending on the 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.

A thiazolidinedione compound or a pharmaceutically acceptable salt thereof which is an active ingredient of the pharmaceutical composition of the present invention,
The administration ratio of the RXR activating agent or the pharmacologically acceptable salt thereof may vary widely, but in general, the weight ratio is 1:
It can be in the range of 200 to 200: 1.

[0110]

EXAMPLES The present invention will be described in more detail below with reference to production examples, test examples, and formulation examples, but 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 0.74 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-d6) δ: 1.21 (6H, d, J =
6.4Hz), 3.11 (1H, dd, J = 14 and 9.0Hz), 3.34 (1H,
dd, J = 14 and 4.4Hz), 3.57-3.65 (1H, m), 3.95 (3H,
s), 4.91 (1H, dd, J = 9.0 and 4.4Hz), 5.63 (2H, s
), 6.70-7.20 (3H, m), 7.14 (2H, d, J = 8.7Hz), 7.
25 (2H, d, J = 8.7Hz), 7.25 (1H, d, J = 3.3Hz), 7.35
-7.45 (1H, m), 7.68 (1H, d, J = 1.9Hz), 7.83 (1H,
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-benzimidazol-2-ylmethoxy) -benzyl)-
Thiazolidine-2,4-dione dihydrochloride In Reference Example 5 instead of N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester of Production Example 1. 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-d6) δ: 0.86 (6H, d, J =
6.7Hz), 1.90-1.99 (1H, m), 2,91 (3H, s), 3.08-
3.14 (3H, m), 3.34 (1H, dd, J = 14 and 4.4Hz), 3.94
(3H, s), 4.91 (1H, dd, J = 9.0 and 4.4Hz), 5.65 (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)) -1-Methyl-1H-benzimidazol-2-ylmethoxy) -benzyl)-
Thiazolidine-2,4-dione dihydrochloride N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester of Production Example 1 was replaced by Reference Example 8 N- (2-methyl-5- (4- (isobutyl-methyl-
The title compound was obtained in the same manner as in Production Example 1 using amino) phenoxy) -phenyl) methylamine.

¹ H-NMR (DMSO-d6) δ: 0.90 (6H, d, J =
4.4Hz), 1.75-2.05 (1H, m), 1.99 (3H, s), 2.90-
3.10 (2H, m), 3.11 (1H, dd, J = 14 and 8.9Hz), 3.34
(1H, dd, J = 14 and 4.4Hz), 3.92 (3H, s), 4.91 (1H,
dd, J = 8.9 and 4.4Hz), 5.62 (2H, s), 6.65-7.20 (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-
Benzimidazol-2-ylmethoxy) -benzyl)
-Thiazolidine-2,4-dione 620 mg of 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-obtained in Preparation Example 1
Benzimidazol-2-ylmethoxy) -benzyl)
-Thiazolidine-2,4-dione dihydrochloride, 66 mg
Of acetaldehyde, 90 mg of acetic acid, 318 mg of sodium triacetoxyborohydride and 15 ml of anhydrous tetrahydrofuran were 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 subjected to silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/1).
The title compound (260 mg, yield 48%) was obtained by purification.

¹ H-NMR (DMSO-d6) 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-benzimidazol-2-ylmethoxy) -benzyl) -Thiazolidine-2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-of 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-
193276), and using acetone instead of acetaldehyde to obtain the title compound in the same manner as in Production Example 4.

¹ H-NMR (DMSO-d6) δ: 1.13 (6H, d, J =
6.3Hz), 3.05 (1H, dd, J = 14 and 9.1Hz), 3.31 (1H,
dd, J = 14 and 4.3Hz), 3.45-3.52 (1H, m), 3.75 (3H,
s), 4.87 (1H, dd, J = 9.1 and 4.3Hz), 5.24 (1H, br
; Disappeared by 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-benzimidazol-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-
Preparation Example 4 using (4-amino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione dihydrochloride, methyl ethyl ketone instead of acetaldehyde.
The title compound was obtained in the same manner as.

¹ H-NMR (DMSO-d6) δ: 0.90 (3H, t, J =
7.4Hz), 2.17 (3H, d, J = 6.4Hz), 1.34-1.46 (1H, m
), 1.48-1.59 (1H, m), 3.06 (1H, dd, J = 14 and 9.2H
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-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-
2,4-dione 5- (4- (6- (3-isopropylamino-phenoxy) -1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-of Preparation Example 4
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-d6) δ: 0.94 (6H, d, J =
6.7Hz), 1.77-1.88 (1H, m), 2.78-2.81 (2H, m),
3.05 (1H, dd, J = 14 and 9.3Hz), 3.31 (1H, dd, J = 14
And 4.3Hz), 3.74 (3H, s), 4.86 (1H, dd, J = 9.3 and 4.3Hz), 5.34 (2H, s), 5.50 (1H, s; 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 2.18 g containing 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-d6) 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) t-butyl N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamate 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-d6) 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 = 8.1Hz). (Reference Example 3) N- (5- (3-bromophenoxy) -2
-Nitrophenyl) -N-methylcarbamic acid t-butyl ester containing 2.5 g of sodium hydride (55% by weight) 50
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 (CDCl3)
δ: 1.24 (9H, s), 3.19 (3H, s), 6.97 (1H, dd, J =
9.0 and 2.4Hz), 7.22 (1H, d, J = 7.9Hz), 7.29 (1H,
d, J = 1.7Hz), 7.42-7.51 (3H, m), 8.03 (1H, d, J =
9.0 Hz). (Reference Example 4) N- (5- (3- (isobutyl-methyl-
Amino) phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester 700.0 mg of N- (5- (3-bromophenoxy) -2-nitrophenyl) -N-methylcarbamine obtained in Reference Example 3 Acid t-butyl ester, 0.24 ml isobutylmethylamine, 151.0 mg tris (dibenzylideneacetone) dipalladium, 115.7 mg 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 (CDCl3) 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) -N-methylcarbamic acid t-butyl ester obtained in Reference Example 4 was added to 10 ml. Dissolved in ethanol, 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 (CDCl3) 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 of (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 (CDCl3) 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) of (4- (isobutyl-methyl-amino) phenoxy) -t-butyldimethylsilane obtained in Reference Example 6 was dissolved in 20 ml of anhydrous tetrahydrofuran, 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 (CDCl3) 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 Referential Example 7 instead of N- (5- (3- (isobutyl-methyl-amino) phenoxy) -2-nitrophenyl) -N-methylcarbamic acid t-butyl ester of Referential Example 5. The title compound was obtained in the same manner as in Reference Example 5 by using N- (5- (4- (isobutyl-methyl-ami) phenoxy) -2-nitrophenyl) methylamine obtained in. ¹ H-NMR (CDCl3) 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) Enhancement of antitumor effect on human acute promyelocytic leukemia cell line HL-60 cells 1 group 9 animals BALB / c nude mice (female, 6 weeks old) subcutaneously,
Tumor piece of human acute promyelocytic leukemia cell line HL-60 (5 mm × 5 mm
Horn) transplanted. The test compound was suspended in 5% emulophore saline containing 2.5% dimethylacetamide, and the day after transplantation
Oral administration was carried out once a day on days 7 to 11 and 14 to 18 for a total of 14 times.

[0120] The effect is determined by the minor axis (mm) and major axis (mm) of the tumor.
Is measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on the 21st day after transplantation is evaluated by the following formula.

[0121]

## EQU1 ## GI (%) = (1-A / B) × 100 A: Average tumor volume on day 21 of compound administration group (*) B: Average tumor volume on day 21 of untreated control group (*) ) *: Tumor volume means 1/2 × [tumor major diameter] × [tumor minor diameter] ² . (Test Example 2) Enhancement of antitumor effect on human gastric cancer St-40 cells Group 1 subcutaneously into 10 BALB / c nude mice (female, 6 weeks old),
A tumor piece (5 mm × 5 mm square) of human gastric cancer strain St-40 was transplanted. The test compound was suspended in 5% emalphor saline containing 2.5% dimethylacetamide, and the day after transplantation: 4 days, 7 days to 11 days, 14 days
Oral administration was carried out once a day on days 18 to 21 and days 21 to 25, a total of 19 times.

[0122] The effect is determined by the minor axis (mm) and major axis (mm) of the tumor.
Is measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on the 28th day after transplantation is calculated as in Example 1. (Test Example 3) Enhancement of cancer cell growth inhibitory activity against human acute promyelocytic leukemia cells HL-60 HL-60 cells were seeded at 1 × 10 ³ cells / well in a 96-well plate, and various concentrations were simultaneously dissolved in DMSO. DMSO concentration of the drug
Add to be 0.1%. The concentration of the drug is 10 μM for the thiazolidinedione compound and 1 μM for the RXR activator. After adding the drug, the cells are cultured for 5 days. Then MTS
(Promega Co., Ltd.) Add 40 μl / well of each reagent,
After culturing in 5% CO2 for 2 hours, add OD490 from each well to MICROPLATE R
Measure using EADER (BIO RAD). The cell growth inhibitory activity is calculated from the average absorbance of each group by the following formula.

[0123]

[Equation 2] Cancer cell growth inhibition rate (%) = [1- (average absorbance (cell + drug) -average absorbance (medium)) / (average absorbance (cell + DMS
O) -average absorbance (medium))] × 100 (Test Example 4) Combined effect on human colon cancer cells COL-2-JCK Regarding combined effect of thiazolidinedione compound and RXR activator on cancer cell growth inhibitory activity, human colon Cancer cell CO
It examined using L-2-JCK. COL-2-JCK cells were seeded in a 96-well plate at 4 × 10 ³ cells / well, and at the same time, various concentrations of drugs dissolved in DMSO were added so that the DMSO concentration was 0.1%. The drug concentration was 10 μl for thiazolidinedione compounds
M and RXR activators were examined at 10 μM each (n = 4). After adding the drug, the cells were cultured for 4 days. Then, add 50% trichloroacetic acid (Wako Pure Chemical Industries, Ltd.) at 50 μl / well for 1 hour 4
Fix at ℃, wash with tap water, 0.4% sulforhodamine B
(Molecular Probe) -1% acetic acid solution 150 μl / well
The mixture was added, stained at room temperature for 30 minutes, and washed with 1% acetic acid. After air-drying the plate, 150 μl / well of 10 mM Tris was added, and the OD490 of each well was measured using a MICROPLATE READER (BIO RAD). The cell growth inhibitory activity was calculated from the average absorbance of each group by the following formula.

[0124]

[Equation 3] Cancer cell growth inhibition rate (%) = [1-{(average absorbance
(Cell + drug) -average absorbance (medium)) / (average absorbance (cell + D
MSO) -average absorbance (medium))}] × 100 In this test, the following compounds were used as thiazolidinedione compounds.

1-amino-7- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene (hereinafter referred to as " Compound A "),

[0126]

[Chemical 14]

1-amino-6- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene (hereinafter referred to as " Compound B ”),

[0128]

[Chemical 15]

1-amino-5- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene (hereinafter referred to as " Compound C ")),

[0130]

[Chemical 16]

3- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] aniline (hereinafter referred to as "Compound D") To tell.),

[0132]

[Chemical 17]

Compound of Preparation Example 1

[0134]

[Chemical 18]

(Hereinafter, referred to as "Compound E"). And 5- (4- (6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazole-2
-Ylmethoxy) -benzyl) -thiazolidine-2,4
-Dione dihydrochloride (hereinafter referred to as "Compound F")

[0136]

[Chemical 19]

The above-mentioned targretin and LG100268 were used as the RXR activating agents.

The results are shown in Table 1.

[0139]

[Table 1] ―――――――――――――――――――――――――――――――― Test Compound Growth Inhibition Rate (%) ――――― ――――――――――――――――――――――――――― Compound A 14% LG100268 6% Compound A + LG100268 48% ―――――――――――― ―――――――――――――――――――― Compound C 22% Targretin 10% LG100268 3% Compound C + Targretin 42% Compound C + LG100268 37% ――――――――――― ――――――――――――――――――――― Compound D 27% Targretin 10% LG100268 3% Compound D + Targretin 40% Compound D + LG100268 39% ―――――――――― ―――――――――――――――――――――― Compound B 21% LG100268 1% Compound B + LG100268 39% ―――――――――――――――――――――――――――――――― Compound E 26% LG100268 1% Compound E + LG100268 37% ―――――――――――――――――――――――――――――――― Compound F 28% Targretin 11% Compound F + Targretin 42% ―― ―――――――――――――――――――――――――――――― As is clear from Table 1, compounds A, B, C, which are thiazolidinedione compounds, It was revealed that D, E or F, and RXR activator LG100268 or targretin were administered alone, respectively, and when used in combination, marked growth inhibitory activity was exhibited. (Formulation Example) A drug containing the compound of the present invention as an active ingredient can be produced, for example, by the following method.

Tablets 4.0 mg of the compound of Production Example 1, 100.0 mg of talgretin, 244.0 mg of lactose, 50.0 g of corn starch and 2.0 mg of magnesium stearate were mixed and then tableted with a tableting machine to give tablets of 400 mg per tablet. can get.

[0141]

INDUSTRIAL APPLICABILITY The thiazolidinedione compound of the present invention or a pharmacologically acceptable salt thereof and the RXR activating agent or a pharmacologically acceptable salt thereof are used as a single agent by combining them. Compared to when administered in
Shows excellent effect.

Pharmaceutical composition for administering the thiazolidinedione compound of the present invention or a pharmacologically acceptable salt thereof and the RXR activating agent or a pharmacologically acceptable salt thereof simultaneously or separately at a time interval Has an excellent cell growth inhibitory effect, and is therefore useful as a therapeutic agent or preventive agent (especially therapeutic agent) for cancer (in particular, lung cancer, gastric cancer or colon cancer).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 35/00 A61P 35/00 43/00 105 43/00 105 121 121 121 // C07D 417/12 C07D 417 / 12 (72) Inventor Naomi Shimazaki 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term in company (reference) 4C063 AA01 BB08 CC62 DD26 EE01 4C084 AA19 NA05 ZB21 ZB26 ZC75 4C086 AA01 AA02 BC19 BC82 GA07 GA10 MA02 MA04 NA05 NA14 ZB21 ZB26 ZC75 4C206 AA01 AA02 DA12 DA17 KA01 MA02 MA04 NA05 ZB21 ZB26 ZC75

Claims (14)

[Claims] [Claim 1] One or more kinds of the following general formula (I): [In the formula, Ar represents an aryl group (at least one —NR
¹ R ² group and may be substituted with a group selected from 1 to 4 substituent groups α) or a heteroaryl group (at least one —NR ¹ R ² group). Substituted, and may be substituted with a group selected from 1 to 3 substituent groups α), R ¹ and R ² are the same or different, and each represent a hydrogen atom,
C1-6 alkyl group, C6-10 aryl group or C7-
16 represents an aralkyl group, X represents an oxygen atom or a sulfur atom, and Y represents a ═CH— group or a nitrogen atom. In the above,
Substituent group α is a substituent group consisting of a C1-6 alkyl group, a C1-6 alkoxy group, a halogen atom and a hydroxyl group. ] The thiazolidinedione compound represented by these or its pharmacologically acceptable salt, and 1 type, or 2 or more types of RXR
A pharmaceutical composition for preventing or treating cancer, which comprises an activating agent or a pharmacologically acceptable salt thereof as an active ingredient, and is administered simultaneously or separately at a time. 2. Ar is a phenyl group (at least one --N
R ¹ R ² group, and may be substituted with a group selected from 1 to 4 substituent groups α) or a pyridyl group (at least one —NR ¹ R ² group). The pharmaceutical composition according to claim 1, which is substituted and may be substituted with a group selected from 1 to 3 substituent groups α). 3. Ar is a phenyl group (one --NR¹R²On the basis
Substituted and 1 to 4 C1-6 alkyl
Optionally substituted by a group) or a pyridyl group (one-
NR ¹R²Substituted with a group and having 1 to 3
It may be substituted with a kill group).
Pharmaceutical composition. 4. Ar is a phenyl group (at least one --N
The pharmaceutical composition according to claim 1, which is substituted with a R ¹ R ² group and may be substituted with a group selected from 1 to 4 substituent groups α. 5. Ar is a phenyl group (which is substituted with one —NR ¹ R ² group and may be substituted with 1 to 4 C 1-6 alkyl groups). The pharmaceutical composition according to 1. 6. The pharmaceutical composition according to claim 1, wherein Ar is a phenyl group (substituted with one —NR ¹ R ² group). 7. The method according to claim ^1, wherein R ¹ and R ² are the same or different and each is a hydrogen atom, a C 1-6 alkyl group or a C 6-10 aryl group. Pharmaceutical composition. 8. The pharmaceutical composition according to any one of claims 1 to 6, wherein R ¹ and R ² are the same or different and each is a hydrogen atom or a C1-6 alkyl group. 9. The pharmaceutical composition according to any one of claims 1 to 6, wherein R ¹ is a C1-6 alkyl group and R ² is a hydrogen atom. 10. The pharmaceutical composition according to any one of claims 1 to 9, wherein X is an oxygen atom. 11. A compound according to claim 1, wherein Y is a ═CH— group.
The pharmaceutical composition according to any one of items 1. 12. A thiazolidinedione compound is 1-amino-7- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-. Iloxy] naphthalene, 1-amino-6- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene, 1- Amino-5- [2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] naphthalene, 3- [2- [4- (2,4-dioxothiazolidine-5-
Ilmethyl) phenoxymethyl] -1-methyl-1H-benzimidazol-6-yloxy] aniline, 5- (4- (6- (3-isopropylamino-phenoxy))
-1-methyl-1H-benzimidazol-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione,
Alternatively, 5- (4- (6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1H-benzimidazole-2-
The pharmaceutical composition according to claim 1, which is ilmethoxy) -benzyl) -thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof. 13. The RXR activating agent is ATRA, 9-
The pharmaceutical composition according to any one of claims 1 to 12, which is cis retinoic acid, LG100268 or targretin. 14. Any one selected from 1 to 13 for preventing or treating gastric cancer, lung cancer or colon cancer.
The pharmaceutical composition according to the item.