WO2003053440A1

WO2003053440A1 - Medicinal composition

Info

Publication number: WO2003053440A1
Application number: PCT/JP2002/012939
Authority: WO
Inventors: Tomoyuki Shibata; Shinichi Kurakata; Naomi Shimazaki
Original assignee: Sankyo Company, Limited
Priority date: 2001-12-11
Filing date: 2002-12-10
Publication date: 2003-07-03
Also published as: TW200300677A; AU2002354460A1

Abstract

A medicinal composition for the prevention of or treatments for cancers, which comprises as active ingredients: a thiazolidinedione compound represented by the following general formula (I) [wherein Ar represents aryl (substituted by -NR1R2), etc.; R1 and R2 are the same or different and each represents hydrogen, C1-6 alkyl, etc.; X represents oxygen or sulfur; and Y represents =CH- or nitrogen] or the like; and an RXR activator or the like. It has excellent cytostatic activity.

Description

Description Pharmaceutical composition

(Technical field) '

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

(Background technology)

As the thiazolidinedione compound, the following general formula (A)

[In the above formula, ^Ra is

{Wherein R ^d is 1 to 5 substituted with a phenyl group {an amino group (which may be substituted by a C110 alkyl group, a C6-10 aryl group or a C716 arylalkyl group), etc. R ^e represents a hydrogen atom, etc., R ^f represents a C 1-6 alkyl group, etc., D represents an oxygen atom, etc., and E represents a = CH— group, etc. Show. }, R ^b represents a hydrogen atom or the like, and R ³ represents a group represented by the formula

A represents a C 1-6 alkylene group, and B represents an oxygen atom or the like. You. ] Is disclosed, and it is described that this compound can be used as an anticancer agent (for example, see Patent Document 1). However, this document does not describe or suggest the use of this compound in combination with an RXR activating agent.It is also known that RXR activating agents can be used as anticancer agents. (For example, see Patent Documents 2 and 3, and Non-Patent Document 1). However, neither of these documents describes or suggests the use of an RXR activator in combination with a thiazolidinedione compound.

A therapeutic agent for liposarcoma comprising a thiazolidinedione compound and an RXR activating agent is known (for example, see Patent Document 4). Specifically, thiazolidinedione compounds include 5-[[4- [2- (methyl-1-pyridinylamino) ethoxy] phenyl] methyl] —2,4-thiazolidinedione (mouth diglitazone or BRL 49653), 5- [[4-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl 2H-1-benzopyran-12-yl) methoxy] phenyl] methyl-2,4-thiazolidinedione (troglitazone ) And 5-[[4- [2- (5-ethyl-2-pyridyl) ethoxy] phenyl] methyl-1,2,4-thiazolidinedione (piodari zon) are described as RXR activating agents. — [1— (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-1-yl) cyclopropyl] nicotinic acid (LG100268) and 6— [1— ( 3, 5, 5, 8, 8—pentamethyl-5, 6, 7, 8 Although tetrahydronaphthalene one 2 f le) Eteni Le] nicotinic acid (LG 268) are known, the effect as an anticancer agent with a combination of these compounds has failed enough.

[Patent Document 1]

JP-A-11-1 93276

[Patent Document 2]

JP-A-6-107542

[Patent Document 3]

International Publication No. 94Z1 590 No. 1 pamphlet

[Patent Document 4] International Publication No. 98 No. 2 9 1 2 0 Pamphlet

[Non-Patent Document 1]

J. Thibonnet et al, Synlett, 1, pp 141-143 (1999)

(Disclosure of the Invention)

An object of the present invention is to find a combination of compounds exhibiting a more excellent cancer cell growth inhibitory effect, and to provide a useful cell growth inhibitor or anticancer agent.

The present invention relates to one or more of the following general formulas (I)

(i)

[In the formula, Ar is an aryl group (substituted with at least one —NR ¹ ! ^ ² group, and may be substituted with one to four substituent groups α. Or a heteroaryl group (substituted with at least one —NRiR ² group, and may be substituted with a group selected from 1 to 3 substituent groups <<).

Scale ¹ and 1 ² are the same or different and each is hydrogen atom, C 1-6 alkyl group, C 6 - 1 0 Ariru group or C 7 - 1 shows the 6 Ararukiru group,

X represents an oxygen atom or a sulfur atom,

Y represents a = CH- group or a nitrogen atom.

In the above, the substituent group a refers to a substituent group consisting of a C 16 alkyl group, a C 1-6 alkoxy group, a halogen atom, and a hydroxyl group. A thiazolidinedione compound or a pharmacologically acceptable salt thereof and one or more RXR activating agents or a pharmacologically acceptable salt thereof represented by the formula Or a pharmaceutical composition for preventing or treating cancer, which is separately administered at intervals. The thiazolidinedione compound of the present invention is described in JP-A-11-193,276.

The thiazolidinedione compound represented by the general formula (I) of the present invention is preferably The following compounds can be mentioned.

(1) Ar is a phenyl group (substituted with at least one —NRiR ² group and may be substituted with a group selected from 1 to 4 substituent groups) or pyridyl A compound which is substituted with at least one NR ¹ ! ^ ² group and may be substituted with 1 to 3 groups selected from the substituent group α.

(2) Ar is a phenyl group (substituted with one —NRiR ² group and may be substituted with 1 to 4 C 1-6 alkyl groups) or a pyridyl group (one A compound which is substituted with one N RiR ² group and may be substituted with an alkyl group of 1 to 3 ^).

(3) Ar is a phenyl group (substituted with at least one —NRiR ² group, and may be substituted with 1 to 4 substituent groups 0;) A compound. . ''

(4) The compound wherein Ar is a phenyl group (substituted with ^one —NR ¹ ! ^ ² group and may be substituted with one to four C 16 alkyl groups).

(5) The compound wherein Ar is a phenyl group (substituted with one NRiR ² group).

(6) The compound wherein Ar is a phenyl group (the 3- or 4-position is substituted with one NRiR ² group).

(7) The compound wherein Ar is a phenyl group (the 3-position is substituted with —NR ¹ R ² group).

(8) The compound wherein Ar is a pyridyl group (substituted with ^one —NR ¹ R ² group and may be substituted with one to three C 1-6 alkyl groups).

(9) The compound wherein Ar is a pyridyl group (substituted by one NRiR ² group).

(10) A compound in which Ar is a 2-pyridyl group (substituted by one NRiR ² group).

(11) A compound in which Ar is a 2-pyridyl group (the 5-position is substituted with a —NR ¹ ! ^ ² group).

(12) The compound 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.

(1 3) 1 ¹ and 11 ² are the same or different, a hydrogen atom or a C 1-6 Al A compound that is a kill group.

(14) The compound wherein R ¹ is a C 1 _'6 alkyl group and R ² is a hydrogen atom.

(15) The compound wherein R ¹ is a C 1-4 alkyl group and R ² is a hydrogen atom.

(16) The compound wherein R ¹ is an isopropyl group and R ² is a hydrogen atom.

(17) The compound wherein X is an oxygen atom.

(18) The compound wherein 丫 is one group of 〇11.

Further, the thiazolidinedione compound of the present invention has the following general formula (1 ′)

[Wherein, R ¹ ′ represents a C 3-6 branched alkyl group, and R ² ′ represents a hydrogen atom or a C 16 alkyl group].

More preferably, the thiazolidinedione compound of the present invention includes the following compounds.

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

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

5- (4-(6- (3- (ethyl-isopropyl-amino) -l-hydroxy) -l-methyl-l-H-benzoimidazo-l-l-l-methoxy) -benzyl) thiazolidine-l, 4-dione,

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

5— (4— (6— (3— (isobutyl-methyl-amino) -phenoxy) 1 1 1 Methyl-1H_benzimidazoyl 2-ylmethoxy) 1-benzyl) 1-thiazolidin-1 2,4-dione,

• 5— (4— (6— (3— (ethyl-isobutyl-1-amino) -phenoxy) -1-methyl-1-H—benzoimidazo-1-lu-2-ylmethoxy) -benzyl) —thiazolidin-1 2,4-dione ,

5— (4— (6— (3−sec—butylaminophenol) —1-methyl—1H—benzimidazo-l- 2-ylmethoxy) —benzyl) -thiazolidine—2,4-dione,

5-(4-(6-(3-(sec-butyl-methyl-mono-amino) 1-phenoxy)-1 -methyl-1 H-benzoimidazole-2-ylmethoxy)-benzyl) 1 thiazolidine-1, 2, 4-dione ,

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

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

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

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

5- (4-(6- (4- (isopropyl-methyl-amino) -phenoxy) -1-1-methyl-1-H-benzimidazo-l- 2-ylmethoxy) -benzyl) -thiazolidine- 1,2-dione,

5-(4-(6-(4-(ethyl-isopropyl-amino) 1-phenoxy) 1-1-methyl-1 H-benzoimidazoyl-2-ylmethoxy)-benzyl) 1-thiazolidine-1, 4-dione, 5- (4- (6- (4-isobutylamino-phenoxy) -1-1-methyl-1H-ben-zoimidazoyl-2-ylmethoxy) -benzyl) -thiazolidine-1,2,4-dione,

5- (4- (6- (4-(isobutyl-methyl-amino) -phenoxy) -1-1-methyl-1 H-benzimidazo-l- 2-ylmethoxy) -benzyl) -thiazolidin--1,2-dione,

5- (4- (6- (4-(Ethyl-isobutyl-l-amino) -phenoxy) 1-l-methyl- 1H-benzimidazo-l- 2-l-methoxy) 1-benzyl) -thiazolidin- 2,4-dione,

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

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

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

5- (4- (6- (4-t-butylamino-phenoxy) -1-1-methyl-1H-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1,2-dione,

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

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

5- (4-(6-(2- (isopropyl-methyl-amino) -phenoxy) -1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-dione, 5- (4- (6- (2- (ethyl-isopropyl-amino) -phenoxy) _-1 mono-methyl-1H-benzimidazo-l- 2-ylmethoxy) 1-benzyl) -thiazolidine-l, 4-dione,

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

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

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

5- (4- (6- (2-sec-butylamino-phenoxy) -1-methyl-1H-benzimidazo-l-2-T-methoxy) -benzyl) -thiazolidine-2,4-dione,

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

5- (4- (6- (2- (sec-butyl-ethyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazole- 2-T-methoxy) -benzyl) -thiazolidine-1, 4 Geon,

5- (4- (6- (2-t-butylamino-phenoxy) -1-methyl-1 H-benzoimidazo-1-ru-2-ylmethoxy) -1-benzyl) thiazolidine-1 2,4-dione, δ- (4- ( 6- (2-diisopropylamino-phenoxy) -1-methyl-1 1-benzimidazole-2-ylmethoxy) -benzyl) -thiazolidine-1 2,4-dione,,

5- (4- (6- (4-amino-1,3,5-dimethylphenoxy) -1-methyl-1-dibenzoimidazole-2-dimethoxy) -benzyl) -thiazolidine-2,4-dione, 1-Amino-7- [2- [4-I- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] naphthalene,

1-Amino-6- [2-[4- (2,4-dioxothiazolidine-1-5-ylmethyl) phenoxymethyl]]-1-Methyl-1H-Benzimidazo-1-ru 6-yloxy] na

1-Amino-5- [2- [4-I- (2,4-dioxothiazolidine-l-ylmethyl) phenoxymethyl] -l-methyl-lH-Benzoimidazo-l-6-yloxy] naphthalene, or

3— [2— [4— (2,4-Dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] aniline.

Of these, particularly preferably,

1-amino _ 7 _ [2— [4- (2,4-dioxothiazolidine_5-ylmethyl) phenoxymethyl] — 1-methyl-1H-benzimidazoyl 6-yloxy] na

1-amino-6- [2- [4- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-benzoimidazo-1-lu-6-yloxy] na

1-amino-5- [2- [4- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-1-methyl-1H-benzoimidazo-1-6-yloxy] na

3— [2 -— [4- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] —1-methyl-1H-benzoimidazole-6-yloxy] aniline,

5- (4- (6- (3-isopropylamino-phenoxy) -11-methyl-1H-benzoimidazole-2-ylmethoxy) -1-benzyl) -thiazolidine-12,4-dione or

5- (4- (6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1-H-benzoimidazole-2-ylmethoxy) -benzyl) -thiazolidine-2,4-di Is on.

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

Representative agents for activating the RXR of the present invention include, for example,

Compounds described in J. Tibonnet et al, Synlett, 1, ppl41-143 (1999), JP-A-6-107542, and WO94Zl5901 can be exemplified. The structural formulas of typical compounds as R X R activating agents, which are the active ingredients of the present invention, are shown below.

LG100268 Targretin

Among the above compounds, ATRA is described in JP-T-10-511948, and its compound name is (E, E, E, E) -3,7-dimethyl-9- [2,6 , 6-trimethyl-1-cyclohexene-11-yl] —2,4,6,8-nonatetraenoic acid (all-trans-retinoic acid). ATRA acts on RXR as it is or part of it is converted to 9-cis-retinoic acid.

9-cis-retinoic acid is described in JP-A-6-107542, and its compound name is (E, Z, E, E) -13,7-dimethyl-91 [2,6,6 _Trimethyl-1-cyclohexene-1f1] 1,2,4,6,8 _nonatetraenoic acid

LG 100268 is described in WO 94Z15901, and its compound The name of the product is 6- [11- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-12-yl) cycloporyl] nicotinic acid.

Targretin is described in WO9415901, and its compound name is 6— [1— (3,5,5,8,8-pentamethyl_5,6,7,8 —Tetrahydronaphthyl-2-yl) ethenyl] benzoic acid.

The thiazolidinedione compound and the R XR activating agent which are the active ingredients of the present invention can be converted into a salt according to a conventional method. Examples of such salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, iron salt, zinc salt, copper salt, nickel Metal salts such as salts and cobalt salts; inorganic salts such as ammonium salts; octylamine salts, dibenzylamine salts, morpholine salts, dalcosamine salts, phenyldaricin alkylester salts, ethylenediamine salts, N-methyldalcamine salts, guanidine Salts, getyl amine salts, triethylamine salts, dicyclohexylamine salts, Ν, Ν'-dibenzylethylenediamine salts, black pro-proin salts, pro-in salts, diethanolamine salts, エタノール -benzyl-Ν-phenethylamine salts, pi ぺRazine salt, tetramethylammonium salt, tris Amines such as organic salts such as roxymethyl) aminomethane salt; hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; nitrates, perchlorates, sulfates, 'Inorganic acid salts such as phosphates; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; arylsulfonic acids such as benzenesulfonic acid and Ρ-toluenesulfonic acid Salts; salts of amino acids such as glutamic acid,, aspartic acid; organic acids such as carboxylic acid salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid; and orditin acid salts Amino acid salts such as glutamate, aspartate and the like are preferable. An organic acid salt, more preferably a hydrochloride.

In addition, the thiazolidinedione compound and the RXR activating agent, which are the active ingredients of the present invention, absorb water by adhering to the air or recrystallize to absorb water and form hydrates. May be. If such hydrates are formed, All of them are included in the present invention.

Furthermore, 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. Included in the invention. Various isomers may exist. For example, the thiazolidine ring of the thiazolidinedione compound having the structure of the general formula (I) contains an asymmetric carbon, and also has an optical isomer because an asymmetric carbon may be present on a substituent. Each of these isomers, or any compound containing them in any proportion, is encompassed by the present invention.

Such isomers can be obtained by synthesizing the compound of the present invention using the starting compound of each isomer or, if desired, resolving the synthesized compound of the present invention using a usual resolution method or separation method. be able to.

In the present invention, “simultaneous” administration is not particularly limited as long as the administration form can be administered at about the same time, but administration as a single composition is preferred.

The term “separately administered at different times” is not particularly limited as long as it can be administered separately at different times.For example, a thiazolidinedione compound or a pharmacologically acceptable salt thereof may be first administered. And then, after a predetermined period of time, administering an RXR activating agent or a pharmaceutically acceptable salt thereof.

If the number of thiazolidinedione compounds or pharmacologically acceptable salts to be administered and the number of RXR activating agents or pharmacologically acceptable salts thereof are three or more in total, '', `` Simultaneously or separately at different times '' means that all of them are administered at the same time, each is separately administered at a later time, or two or more are administered at the same time and the remaining This includes a method of administering drugs or a method of administering two or more drugs at a time and then administering the remaining drugs simultaneously.

In the present invention, the term "cancer" refers to sarcoma, carcinoma, leukemia, etc., and includes fibrosarcoma, lipoma, osteosarcoma, angiosarcoma, lung cancer, stomach cancer, colon cancer, breast cancer, prostate cancer. · Renal cancer · Liver cancer · Tengue cancer · Esophageal cancer · Tongue cancer · Brain tumor · Pharyngeal cancer · Ovarian cancer · Acute leukemia · Chronic leukemia · Lymphoma etc. The thiazolidinedione compound represented by the general formula (I), which is one of the active ingredients of the present invention, can be easily produced by the method described in JP-A-11-193276.

In addition, among the thiazolidinedione compounds represented by the general formula (Γ), which is one of the active ingredients of the present invention, the compound represented by the general formula (I ′)

[Wherein, R ¹ ′ represents a C 3-6 branched alkyl group, and R ² ′ represents a hydrogen atom or C 1—

Which represents a 6-alkyl group] can also be produced by the following method.

In the following, scale ¹ ', R ^2' are the same as those described above.

Law)

Method A is a method for producing compound (Ia) wherein R ² ′ is a C 16 alkyl group.

(Step A 1)

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

The amine compound (1) used in this step can be produced according to or according to Example 46 of JP-A-11-193276.

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 is preferably an ether such as tetrahydrofuran or getyl ether, or an aromatic such as benzene or toluene. Group hydrocarbons, and particularly preferred are ethers such as tetrahydrofuran and geethylether. Examples of the reducing agent used include sodium triacetoxyborohydride and sodium cyanoborohydride, and acetic acid and the like can be added as required. The reaction temperature varies depending on the compound, the solvent and the like, but is usually from 0 to 100 ° C. Preferably, it is 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, and the residue is extracted with a water-immiscible solvent, for example, ethyl acetate, dichloromethane, etc., and the extract is washed with water and saturated saline, and then sulfuric anhydride is added. It is obtained by drying with sodium and distilling off the solvent. If desired, it can be isolated and purified by various chromatographic or recrystallization methods.

(Step A 2)

This step is a step of obtaining a compound (Ia) from the amine (2). That is, this is a step of reacting an amine (2) with an aldehyde or ketone in the presence of a reducing agent in an inert solvent to obtain a compound (la), and can be carried out in the same manner as in Step A1. (Method B)

Method B is a method for producing compound (Ib) in which R ² ′ is a hydrogen atom, and a method for producing compound (Ia) separately from method A using compound (Ib) as a raw material.

(B 1 process)

This step is a step of alkylating the amine (1) to obtain the compound (Ia). That is, a step of reacting an amine (1) with an aldehyde or ketone in an inert solvent in the presence of a reducing agent to obtain a compound (Ia), which can be carried out in the same manner as in Step A1. .

(B 2 process)

This step is a step of obtaining a compound (Ia) by alkylating the compound (Ib). That is, this is a step of reacting the compound (lb) with an aldehyde in an inert solvent in the presence of a reducing agent to obtain a compound (la), and can be carried out in the same manner as in the step A1. (Method C)

This method is a method for producing compound (1 ′) separately from method A or method B described above.

C3 process

(Step C 1)

In this step, the compound (4) which is a phenyl ether is obtained by etherifying the compound (3). That is, a step of reacting the compound (3) with a phenol in which the desired position is substituted with a bromine atom in the presence of a base in an inert solvent to obtain a compound (4). 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. Preferably, amides such as N, N-dimethylformamide and N, N-dimethylacetamide are used. And ethers such as tetrahydrofuran and getyl ether; and aromatic hydrocarbons such as benzene and toluene. Particularly preferred are N, N-dimethylformamide and N, N-dimethylacetamide. These are amides.

The base used is not particularly limited as long as it does not affect the other parts of the compound. Examples of the base include alkali metal carbonates such as sodium carbonate and potassium carbonate, sodium hydride, and lithium hydride. Such metal hydrides may be mentioned. '

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

After completion of the reaction, for example, the solvent is distilled off under reduced pressure, and the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane, etc., and the extract is washed with water and saturated saline, and then 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 C 2)

In this step, the bromo compound (4) is aminated to give the amine compound (5). That is, this is a step of reacting compound (4) with a primary or secondary amine in an inert solvent in the presence of a catalyst, a ligand or a base to obtain compound (5). The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably aromatic hydrocarbons such as benzene and toluene, 1,4-dioxane, Examples include ethers such as 1,2-dimethoxyethane, and particularly preferred are aromatic hydrocarbons such as benzene and toluene.

Examples of the catalyst used include palladium-containing compounds such as palladium acetate (I 1) and tris (dibenzylideneaceton) dipalladium (0). Examples of the ligand used include phosphorus compounds such as 2- (di-tert-butylphosphino) biphenyl and 2- (dicyclohexylphosphino) biphenyl. Examples of the base used include sodium t-butoxide, tripotassium phosphate and the like.

After completion of the reaction, for example, the solvent is distilled off under reduced pressure, water is added, the mixture is neutralized with dilute hydrochloric acid, etc., and a water-immiscible solvent such as ethyl acetate or dichloromethane is added, and the organic layer containing the target compound is separated. I do. 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 chromatographic methods or recrystallization.

(Step C3)

This is a step in which the nitro compound (5) is reduced to obtain an amine (6). This reaction is carried out by using a metal and an acid, which is a general method for reducing a nitro group, using a catalytic reduction reaction, or using sodium dithionite as a reducing agent.

In the case of the catalytic reduction reaction, 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.Preferably, alcohols such as methanol and ethanol, tetrahydrofuran, Examples thereof include ethers such as getyl ether, and particularly preferred are 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, solvent and the like, but is usually 0 to 80 ° C. Preferably, it is 10 to 30.

After completion of the reaction, for example, after removing the catalyst from the reaction mixture by filtration, the solvent is distilled off. Thus obtained.

In the case of a 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 is preferably alcohols such as methanol and ethanol, and acetic acid. Organic carboxylic acids, water or a mixed solvent thereof.

Examples of metals 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, and ammonium chloride.

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

After completion of the reaction, for example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is added. Is separated, 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 C4)

In this step, the amine (6) is condensed with the carboxylic acid (7) to obtain the amide (8). That is, a carboxylic acid (7) is reacted with a mixed acid anhydride in the presence of a base in an inert solvent to produce a mixed acid anhydride, and then reacted with an amine (6) to give an amide (8). ) Is obtained.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane or heptane, or benzene or toluene. Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, ethers such as tetrahydrofuran and getyl ether, ketones such as acetone, N, N-dimethylformamide, And amides such as N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfolane. Particularly preferred are ethers such as tetrahydrofuran and getylether.

Examples of the mixed acid anhydride agent used include ethyl halides, alkyl halides such as ethyl chloride, isobutyl chloride, alkanoyl halides such as bivaloyl chloride, cyanophosphonic acid diesters such as cyanophosphonic acid getyl, and diphenyl cyanophosphonate. can give.

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, Pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-Jetylaniline, 1,5-diazapicyclo [4.3.0] non-5-ene, 1,4 Organic amines such as diazabicyclo [2.2.2] octane (DAB CO) and 1,8-diazabicyclo [5.4.0] -7-ndecene (DBU).

The reaction temperature in the reaction for producing mixed acid anhydrides varies depending on the compound, the reagent, the solvent and the like, but is usually 0 to 100, preferably 10 to 30. 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 anhydrides and the amine (6) is carried out in an inert solvent in the presence of a base. The base and the inert solvent used are the same as those used in the reaction for producing the mixed acid anhydrides described above. It is the same as that used in the above.

The reaction temperature in the reaction between the mixed acid anhydrides and the amine (6) varies depending on the compound, reagent, solvent and the like, but is usually 0 to 100 ° C, preferably 10 to 30 ° C. .

The reaction time in the reaction of the mixed acid anhydrides with the amine (6) varies depending on the compound, reagent, reaction temperature and the like, but is usually 30 minutes to 1 week, preferably 1 hour to 1 hour. Day. In addition, in the present reaction, when a cyanophosphate diester is used, 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, and the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane, etc., and the extract is washed with water and saturated saline, and anhydrous sodium sulfate. After drying with, the solvent is distilled off. If desired, it can be isolated and purified by various mouth 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, a step of reacting phenylenediamine (8) with an acid in the presence or absence of an inert solvent to obtain a compound (1 ').

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a halogenated hydrocarbon such as dichloromethane, 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. 4 is one 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 is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, acetic acid, or formic acid. , P-toluenesulfonic acid, Bronsted acids such as organic acids such as trifluoroacetic acid, Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, fluorine trichloride, and bromine trichloride, and acidic ion exchange resins. Particularly preferred fc are hydrochloric acid, acetic acid, and trifluoroacetic acid.

The reaction temperature varies depending on the compound, the acid used, the solvent and the like, but is usually from 0 to a boiling point, preferably from 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, for example, the solvent is distilled off under reduced pressure, and the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane, etc., and the extract is washed with water and saturated saline, It is obtained by 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 compound (5) which is an intermediate in method C. The compound (5a) in which R ² ′ is a C 1-6 alkyl group is obtained through the following steps D 1 to D 3 or steps D 1, D 4 and D 5, whereby R ² ′ is a hydrogen atom Compound (5b) can be produced through the following steps D1 and D4.

(Step D 1) Etherification

This step is a step of obtaining a compound (9) which is a phenyl ether from the macrophage (3). That is, a step of reacting the compound (3) with a phenol having a desired position substituted with an amino group in the presence of a base in an inert solvent to obtain a compound (9). You can do it. (Step D 2)

In this step, an amine (10) is obtained by alkylating the compound (9) which is an amine. That is, this is a step in which an amine (9) is reacted with a desired aldehyde in an inert solvent in the presence of a reducing agent to obtain an amine (10), which can be carried out in the same manner as the step A1.

(Step D 3)

In this step, the amine (10) is alkylated to obtain the amine compound (5a). That is, the 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 the amine compound (5a), which is performed in the same manner as in Step A1 Can be.

(Step D4)

In this step, the amine (9) is alkylated to obtain the amine compound (5b). In other words, this is a step of reacting the amine (9) with a desired aldehyde or ketone in an inert solvent in the presence of a reducing agent to obtain the amine compound (5b). it can.

(Step D5)

In this step, the amine compound (5b) is further alkylated to obtain the amine compound (5a). That is, this is a step of reacting the amine compound (5a) with the aldehyde in an inert solvent in the presence of a reducing agent to obtain the amine compound (5b), and can be carried out in the same manner as in Step A1.

(Method E)

This method is a method for producing compound (5), which is an intermediate in Method C, separately from Method C and Method D.

(Step El)

This step is a step of aminating the bromo compound (11) to obtain an amine compound (12). That is, the step of reacting the bromo compound (11) with a primary or secondary amine in an inert solvent in the presence of a catalyst, a ligand and a base to obtain a compound (12). Can be done.

(Step E 2)

In this step, the silyl ether compound (12) is desilylated to obtain a phenol (13). That is, this is a step of reacting compound (12) with fluoride in an inert solvent to obtain phenol (13).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 1 And amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and water. Particularly preferred are tetrahydrofuran and 1,4-dioxane. Ethers such as sun.

Examples of the fluoride used include potassium fluoride, tetra-n-butylammonium fluoride and the like. . The reaction temperature varies depending on the compound, the solvent and the like, but is usually 0 to 100 ° C, preferably 10 to 30 ° C.

The reaction time varies depending on the compound, the reaction temperature and the like, but is usually 15 minutes to 2 days, preferably 30 minutes to 1 day.

After completion of the reaction, for example, the solvent is distilled off under reduced pressure, and the residue is extracted with a solvent immiscible with water, for example, ethyl acetate, dichloromethane, etc., and the extract is washed with water, saturated saline, and then dried. It is obtained by drying over sodium sulfate and distilling off the solvent. If desired, it can be isolated and purified by various chromatography or recrystallization methods.

(Step 3)

In this step, phenol (13) is etherified to obtain compound (5) which is phenyl ether. That is, in the inert solvent, the phenol (13) is reacted with the clopentine (3) in the presence of a base to obtain the phenol (5). It can be carried out.

Further, among the active ingredients of the present invention, RXR activating agents include, for example, J. Thibonnet et al, Synlett, 1, ppl41-143 (1999), JP-A-6-107542, and WO94 / 15901. It can be easily manufactured according to the method described in the gazette. For example, ATRA is prepared by the method described in J. Thibonnet et al, Synlett. 1, ρρ141143 (1999), and 9-cis-retinoic acid is obtained by M. RBoehm et al, J. Med. Chem., 37. pp. 408-414 (1994), LG100268 can be produced by the method described in WO94 / 15901, and targretin can be produced by the method described in WO94 / 15901.

The thiazolidinedione compound or the pharmacologically acceptable salt thereof, which is the active ingredient of the pharmaceutical composition of the present invention, and the RXR activating agent or the pharmacologically acceptable salt thereof are each independently in a separate unit dosage form, Alternatively, they can be mixed and physically adjusted to one 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, and an RXR activity The compound or its pharmacologically acceptable salt is mixed with itself or an appropriate pharmacologically acceptable excipient, diluent, etc. It can be administered orally, for example, in the form of capsules, granules, powders or syrups, or parenterally, for example, by injection or suppository.

These preparations may contain excipients (e.g., lactose, sucrose, dextrose, mannitol, sugar derivatives such as sorbitol); corn starch, potato starch, starch derivatives such as alpha starch, dextrin; Cellulose derivatives; Arabic gum; Dextran; Organic excipients such as pullulan; Salts; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, magnesium stearate). Metal salts of stearates such as; talc; colloidal silica; Waxes such as beeswax and gay; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium lauryl sulfate; lauryl such as magnesium lauryl sulfate. Sulfates; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.) Binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and And the same compounds as the above-mentioned excipients.), Disintegrants (for example, low-substituted hydroxypropylcellulose, lipoxymethylcellulose calcium, carboxymethylcellulose calcium, internal crosslinkability lipoxymethylcellulose-sunadmium) Cells like Loose derivatives; mention may be made of chemically modified starch and celluloses such as carboxymethyl starch, carboxymethyl starch sodium, cross-linked polyvinyl pyrrolidone), emulsifiers (eg colloids such as bentonite and pea gum) Metallic hydroxides such as magnesium hydroxide and aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cation surfactants such as benzalkonium chloride; and polyoxy Examples include nonionic surfactants such as ethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester. ), Stabilizers (paraoxy repose like methyl paraben, propyl paraben) Alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid be able to. ), Flavoring agents (for example, commonly used sweetening agents, souring agents, flavoring agents, etc.) and diluents can be used in a well-known method.

The dosage and administration ratio of the thiazolidinedione compound or the pharmaceutically acceptable salt thereof, which is the active ingredient of the pharmaceutical composition of the present invention, and the RXR activating agent or the pharmaceutically acceptable salt thereof are determined for each drug. The activity may vary depending on various conditions such as activity of the patient, the condition of the patient, age and weight.

The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 100 Omg (preferably 50 Omg) each time. In the case of parenteral administration, the lower limit is 0.0 lmg (preferably 0.05 mg) and the upper limit is 10 Omg (preferably 5 Omg) per dose, for adults 1 to 6 times a day. It can be administered simultaneously or separately at intervals depending on the condition.

Although the administration ratio of the thiazolidinedione compound or the pharmaceutically acceptable salt thereof, which is the active ingredient of the pharmaceutical composition of the present invention, and the RXR activating agent or the pharmaceutically acceptable salt thereof can vary significantly, In addition, the weight ratio may be in the range of 1: 200 to 200: 1.

(Best mode for carrying out the invention)

(Production Example 1)

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

0.74 g of N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl ester obtained in Reference Example 2, 0.70 g of 4- (2, 4-dioxothiazolidine-1-ylmethyl) monophenoxyacetic acid (JP-A-11-93276), 0.41 g of getyl cyanophosphonate, 0.2 A mixture of 5 g of triethylamine and 30 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate: Zn-hexane = 2/3) to obtain an intermediate. N- (5- (3-Isopropylamino-phenoxy) -1-2- (4- (2,4-dioxothiazolidine-1-ylmethyl) -phenoxyacetylamino) -phenyl) -N-methylcarbamic acid The butyl ester was obtained. This intermediate was dissolved in 50 ml of 4N 1,4-dioxane hydrochloride, allowed to stand at room temperature for 16 hours, and the precipitated product was collected by filtration, washed with ethyl acetate, and washed with the title compound (0.76). g, yield 64%).

_{Ή-NMR (DMSO-d 6} ) (5: 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 = 8.9Hz), 12.05 (1H, s; disappeared by adding heavy water).

(Production Example 2)

5- (4- (6- (3- (isobutyl-methyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) -thiazolidin-1 2,4-dione .2 Hydrochloride N- (2-Amino-5- (3-isopropylamino-1-phenoxy) -phenyl) of Preparation Example 1 N- (2-Amino) obtained in Reference Example 5 instead of N-methylcarbamic acid t-butyl ester The title compound was obtained in the same manner as in Production Example 1 using 1- (3- (isobutyl-methyl-l-amino) phenoxy) -l-phenyl) -N-methylcarbamic acid t-butyl ester. ! H-NMR (DMSO-de) <5: 0.86 (6H, d, J = 6.7Hz), 1.90.1.99 (IH, m), 2,91 (3H, s), 3.08-3.14 (3H, m) , 3.34 (IH, dd, J = 14 and 4.4Hz), 3.94 (3H, s), 4.9l (IH, dd, J = 9.0 and 4.4Hz), 5.65 (2H, s), 6.2l (IH, br ), 6.39 (IH, br), 6.53 (1H, br), 7.15-7.27 (6H, m), 7.62 (IH, d, J = 2.lHz), 7.80 (IH, d, J = 8.9 Hz), 12.04 (IH, br; disappeared by adding heavy water).

(Production Example 3)

5- (4- (6- (4- (isobutyl-methyl-amino) -phenoxy) -1-1-methyl-1H-benzoimidazole-2- ^ permethoxy ')-benzyl) -thiazolidinine_2, 4-dione'dihydrochloride N- (2-amino-5- (3-isopropylamino-phenoxy) -phenyl) -N-methylcarbamic acid t-butyl obtained in Reference Example 8 in place of Production Example 1 2-Methyl-1- (4- (isobutylmethyl-1-amino) phenoxy) -phenyl) The title compound was obtained in the same manner as in Production Example 1 using methylamine.

Ή-NMR (DMSO-de) δ: 0.90 (6Η, d, J = 4.4Hz), 1.75-2.05 (IH, m), 1.99 (3H, s), 2.90-3, 10 (2H, m), 3.11 (IH, dd, J = 14 and 8.9 Hz), 3.34 (IH, dd, J = 14 and 4.4 Hz), 3.92 (3H, s) '4.9 l (IH, dd, J = 8.9 and 4.4 Hz), 5.62 (2H, s),

6.65-7.20 (5H, m), 7.13 (2H, d, J = 8.7Hz), 7.25 (2H'd, J = 8.7Hz), 7.45 · 7.6θ (IH, m), 7.78 (IH, d, J = 8.9Hz), 12.05 (IH, s; disappeared by heavy hydrogenation).

(Production Example 4)

5-(4-1 (6-(3-(Ethyl-1-isopropyl-1-amino) 1-phenoxy)-1-Methyl-1 H-Benzimidazole-2-ylmethoxy) 1-Benzyl)-Thiazolidine-1, 4-dione 5— (4- (6- (3-Isopropylamino-phenoxy) -1-1-methyl-1H-benzoimidazo-l-2-ylmethoxy) -benzyl) obtained in Preparation Example 1 of 62 Omg 1-thiazolidine-1 2 A mixture of 2,4-dione 'dihydrochloride, .66 mg of acetoaldehyde, 90 mg of acetic acid, 318 mg of sodium triacetoxyborohydride and 15 ml of anhydrous tetrahydrofuran was stirred at room temperature for 1 hour. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl ethyl acetate Zn-hexane = 1/1) to give the title compound ( 260 mg, 48% yield).

Ή-NMR (DMSO-de) δ: 1.06 (3H, t, J = 7.0Hz), 1.11 (6H, d, J = 6.6Hz), 3.05 (1H, dd, J = 14 and 9.2Hz), 3.18 ( 2H, q, J = 7.0Hz) _f 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 (lH, d, J = 8.7Hz), 7.28 (1H, d, J = 2.3Hz), 7.63 ( 1H, d, J = 8.7Hz), 12.02 (1H, s; disappeared by adding heavy water).

(Production Example 5)

5- (4- (6- (4-Isopropylamino-phenoxy) -1-1-methyl- 1 H-benzimidazo-l- 2-ylmethoxy) -i-benzyl) -thiazolidine-2,4-dione Preparation Example 4-5 — (4- (6- (3-isopropylamino-1-phenoxy) -11-methyl-1H-benzimidazole-2-ylmethoxy) -1-benzyl) —thiazolidin-1,2,4-dione 5 instead of dihydrochloride — (4-(6-(4-Amino-phenoxy) -1 1-methyl-1 H-Benzoimidazole-2-ylmethoxy) -benzyl) 1-thiazolidine-2,4-dione dihydrochloride 1-193276), and the title compound was obtained in the same manner as in Production Example 4 using acetone instead of acetate aldehyde. ()

'(^ ¾Q ^ 2 ¥ 绺氺 weight: jq' ΗΤ) 10'ZI '(zH8'8 = f' Ρ 'HT) L ^ L' (8 = f 'P' HS) QVL '(∞ ¾8) 60 'L-WL' ( ^Z HZ'Z ll

'P "RZ) T8'9' (ZH 8 = P 'Ρ' ΉΖ) A9'9 '(s ¾S) f' 9 '(¥ Weight:' ΗΤ) SS'S '(^' f, S'6 = f 'PP' HT) 8 '' (s' HS) SS '(' HS) s's-ws

'(NQ¾ ^ I = f' PP ¾T) 90'8 '(^' HT) 69Ί-8 Ί '(∞' HI) 9Π ΐ '(f9 =' Ρ 'HS) LVZ' (zH ^ '' i = f 'HS) 06: ρ ( ⁹ P-OS customer) 丽 Ν-Ηι 呦 ^ ¾2

((-(Ku, hiichi z- ー ^ tv-HI-ί-^^-ι-(ku, ye:-/ one) one 9) ー) one S CiQ ^ G) 鏹 ¾ ニ・く ^^ 1 'Z-<τ— (^ Φ ^ Ζ:-5Zirao ^ A-ε) -9) —)-g ω ^ wm d

Τ -Λ

-ο 3 s-one 9)-) ― 9

α ¾ Q? 绺氺胡: ^j 'HI) SO'ST

'(zH8'8 = f' P 'HT) L9'L'(zH9'8 = f 'P' HS) 6ΓΔ '(∞ ¾8) Δ0 · 0-0'(ZHS'S fll δ-8 = Γ Γ ΡΡ 'HI) S8'9' (ZH9 "8 = f 'P' HS) T8'9 '(ZH8'8 ST = f' ΡΡ 'ΈΖ) 9S'9' (s 'HS) ^ 8-9' ( Q f 3t ¾ 氺; ^J q 'HI) S' (NQ¾ X 6 = f 'ΡΡ ¾T) Δ8

'(s' HS) 9L '' («i 'HT) SS-8-Sf'S' (^ HS'f † T = f 'PP' HT) T8'8 ((r6 NQ¾ fT = f 'PP' HI) S0S ', (zHS'9 = f' P 'H9) 8ΤΊ g ( ⁹ P-OS a) so-called Ν-Ηΐ

T8

6 £ 6Zl / Z dT / IDd OM ^ CSO / CO OAV 5- (4- (6- (4-isobutylamino-1-phenoxy) -1-methyl-1-H-benzimidazole-2-ylmethoxy) -1-benzyl) thiazolidine-1,2,4-dione Preparation Example 4 5- (4- ( 6- (3-Isopropylamino-1-phenoxy) 1-1-methyl-1H-benzoimidazole-2-ylmethoxy) -benzyl) monothiazolidin-2,4-dione. Instead of dihydrochloride, 5- (4 — (6 -— (4-amino-phenoxy) -1-methyl-1-H-benzoimidazole-2-ylmethoxy) —benzyl) monothiazolidine—2,4-dione dihydrochloride, isobutane instead of acetaldehyde The title compound was obtained in the same manner as in Production Example 4 using tylaldehyde.

Ή-NMR (DMSO-de) δ: 0 · 94 (6Η, d, J = 6.7Hz), 1.77-1.88 (1H, m),

2.78-2.8l (2H, m), 3.05 (1H, dd, J = 14 and 9.3Hz), 3.3l (1H, dd, J = 14 and 4.3Hz), 3.74 (3H, s), 4.86 (1H, dd, J = 9.3 and 4.3 Hz), 5.34 (2H, s), 5.50 (1H, s; disappeared by adding heavy water), 6.57 (2H, dd, J = 6.8 and 2.0 Hz), 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) ), 12.0l (1H, s; disappeared by adding heavy water).

(Reference example 1)

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

2. Add 5.45 g of 3-aminophenol to 80 ml of a suspension of anhydrous N, N-dimethylformamide containing 18 g of sodium hydride (55% by weight), and add at room temperature. Stirred for 20 minutes. Next, 14.3 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester (Japanese Patent Laid-Open No. 11-193 276) was added little by little, and 100 ° C was added. The mixture was stirred at C for 6 hours. The reaction mixture was concentrated, water was added, and neutralized using 3N hydrochloric acid and sodium bicarbonate powder. The precipitated insoluble precipitate was collected by filtration, washed with water, Drying under reduced pressure gave the title compound (16.6 g, yield 92%).

Ή-NMR (DMSO-de) (5: 1.23 and 1.42 (1 † 9H, each s), 3.18 (3H, s), 5.38 (2H, s; disappeared by adding heavy water), 6.25 (1H, dd, J = 7.6 and 2.4Hz), 6.3l (1H, s), 6.46 (IH, dd, J = 8.1 and 1.0Hz), 6.88 (IH, dd, J = 9.0 and 2.1Hz), 7.09 (IH, t, J = 8.0Hz), 7.16 (1H, s), 8.00 (IH, 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) 1 N—methylcarbamic acid t-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10. A mixture of 6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2Z3) to be an intermediate. N- (5- (3-isopropylamino-phenoxy) -1-2-trophenyl) -N-methylcarbamic acid t-butyl ester was obtained. This intermediate was dissolved in 200 ml of methanol, 2.02 g of 10% palladium-carbon was added, and the mixture was vigorously stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration and the solvent was distilled off to obtain the title compound (12.0 g, yield: 81%).

Ή-NMR (DMSO-de) <5: 1.08 (6H, d, J = 6.4Hz), 129 (9H, s), 2.98 (3Η, s), 3.40-3.47 (IH, m), 4.78 ( 2H, s; disappeared by adding heavy water), 5.45 (IH, d, J = 7.8Hz; disappeared by adding heavy water), 5.96 (IH, d, J = 7.2Hz), 6.07 (IH, t, J = 2.2Hz) ), 6.20 (IH, dd, J = 8.1 and 1.9 Hz), 6.60 (IH, s), 6.7 l (2H, s), 6.93 (IH, t, J = 8.lHz). (Reference example 3)

N— (5- (3-bromophenoxy) 1-2-nitrophenyl) N-methylcarbamic acid t-butyl ester

2. Add 10.0 g of 3-bromophenol to a suspension of 50 ml of anhydrous N, N-dimethylformamide containing 5 g of sodium hydride (55% by weight), and stir for 15 minutes under ice-cooling did. Then, a solution prepared by dissolving 16.6 g of N- (5-chloro-2-nitrophenyl) -N-methylcarbamic acid t-butyl ester in 70 ml of anhydrous N, N-dimethylformamide was added dropwise. Stirred at ° C for 3 hours. The reaction mixture was concentrated, added with water, neutralized with 3N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the precipitated insoluble product was washed with hexane, collected by filtration, and dried under reduced pressure to obtain the title compound (20.2 g, yield 83%).

Ή-NMR (CDCls) δ: 1.24 (9Η, s), 3.19 (3H, s), 6.97 (1H, dd, J = 9.0 and 2.4Ηζ), 7.22 (1H, d, J = 7.9Hz), 7.29 (1H, d, J = 1.7Hz), 7.42-7.5l (3H, m), 8.03 (1H, d, J = 9.0Hz).

(Reference example 4)

N— (5- (3- (isobutyl-methyl-amino) phenoxy) —2-ditrophenyl) N-methylcarbamic acid t-butyl ester

700 mg of N- (5- (3-bromophenoxy) -1-2-trophenyl) _N-methylcarbamic acid t-butyl ester obtained in Reference Example 3, 0.24 ml of isobutylmethylamine, 15.1.Omg Of tris (dibenzylideneacetone) dipalladium, 15.7 mg of 2- (dicyclohexylphosphino) biphenyl and 277.7 mg of potassium t-butoxide are suspended in 4 ml of anhydrous toluene, and 1. Stirred for 5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n_hexane = 17) to give the title compound (204.2 mg, yield 29%).

_{Ή-NMR (CDC1 3) δ} : 0.80 (6H, d, J = 6.6Hz), 1.25 (9H, s), 1.88-2.0K IH, m), 2.85 (3H, s), 2.95 (2H, d, J = 7.3Hz), 3.14 (3H, s), 6.20-6.27 (2H, m), 6.43 (IH, dd, J = 8.8 and 2.2Hz), 6.72-6.83 (2H, m), 7.1l (IH, t, J = 8.lHz), 7.81 (IH, d,

J = 9.5Hz).

(Reference example 5)

N- (2-Amino-5- (3- (isobutyl-methyl-amino) pheno, xy) -phenyl) -N-methylcarbamic acid t-butyl ester

204.2 mg of N- (5- (3- (isobutyl-methyl-amino) phenoxy) -12-nitrophenyl) -N-methylcarbamic acid t-butyl ester obtained in Reference Example 4 in 10 ml of ethanol After dissolution, 100.Omg of 10% palladium-carbon was added, and the mixture was vigorously stirred at room temperature for 2.5 hours under a hydrogen atmosphere. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1Z4-1 / 1/3) to obtain the title compound (145.4 mg, yield: 77%). . '

_{Ή-NMR (CDC1 3) 6} : 0.90 (6H, d, J = 6.6Hz), 1.57 (9H, s) '1.98-2.09 (1H,

m), 2.92 (3H, s), 3.06 (2H, d, J = 7.3Hz), 3.13 (3H, s), 3.64 (2H, s; disappeared by adding heavy water), 6.30 (IH, t, J = 2.2Hz), 6.35 (1H, dd, J = 8.1 and 2.2Hz), 6.706.88 (3H, m), 7.08 (1H, t, J = 8.2Hz), 7.25-7.3l (lH, m).

(Reference example 6)

(4-1- (isobutyl-methyl-amino) phenoxy) 1-t-butyldimethylsilane 5 ml of (4-bromophenoxy) -t-butyldimethylsilane, 2.9 ml of isobutylmethylamine, 458. Omg of palladium acetate, 1.2 g of 2— (di-t-butylphosphine) No.) Biphenyl and 2.9 g of sodium t-butoxide were suspended in 4 Om 1 of anhydrous toluene, and stirred at 100 for 1.5 hours. After filtering off the catalyst, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate n-hexane = 1Z40 → 1-20) ) To give the title compound (3.83 g, yield 64%).

Ή-band R (CDCls) δ: 0.16 (6H, s), 0 · 91 (6Η, d, J = 6.6Hz), 0 · 97 (9Η, s),

1.94-2.05 (1H, m), 2.87 (3H, s), 2.98 (2H, d, J = 7.3Hz), 6.57 (2H, d, J = 8.8Hz), 6.72 (2H, d, J = 8.8Hz) ).

(Reference example 7)

N— (5- (4-Methyl-ami) phenoxy) 1-2-Nitrophenyl) Methylamine

3. 83 g of (4- (isobutyl-methyl-amino) phenoxy) 1 t-butyldimethylsilane obtained in Reference Example 6 was dissolved in 2 Om 1 of anhydrous tetrahydrofuran, and 2 Om 1 of 1 M tetra-n-butyl fluoride Ammonia tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate n-hexane = 1/5). Was purified. The obtained product was dissolved in 4N hydrochloric acid-1-1,4-dioxane and stirred at room temperature for 30 minutes. After concentrating the reaction solution and washing with diethyl ether, an intermediate, 4-isobutylmethylaminoaminophenol monohydrochloride, was obtained. 2 Om 1 containing 500. Omg of this intermediate and 2.6 g of potassium carbonate Of anhydrous N, N-dimethylformamide was stirred at room temperature for 15 minutes. Next, 66.47 mg of N- (5-chloro-1--2-phenyl) -N-methylcarbamic acid t-butyl ester was added, and the mixture was stirred at 150 ° C for 3 hours. The reaction mixture was concentrated, water was added, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate, toluene = 1Z30). Then, the title compound (256.1 mg, yield 34%) was obtained.

_{Ή-NMR (CDC1 3) δ} : 0.96 (6H, d, J = 6.8Hz), 2.00-2.13 (1H, m), 2.92 (3H, d, J = 5.9Hz), 2.98 (3H, s), 3.12 (2H, d, J = 7.8Hz), 6.19-6.23 (2H, m), 6.68 (2H, d, J = 8.8Hz), 6.96 (2H, d, J = 8.8Hz), 8.13 (1H, d, J = 9.8Hz).

(Reference Example 8) ''

N- (2-amino-1-5- (4- (isobutyl-methyl-amino) phenoxy) -phenyl) methylamine N- (5- (3- (isobutyl-methyl-1-amino) phenoxy) of Reference Example 5 —2— Reference Example using N- (5- (4-1 (isobutyl-methyl-ami) phenoxy) -2-2-trophenyl) methylamine obtained in Reference Example 7 in place of t-butyl nitrophenyl) -N-methylcarbamate The title compound was obtained in the same manner as in 5.

_{Ή-NMR (CDC1 3) 5} : 0.88 (6H, d, J = 6.6Hz), 1.94-2.04 (lH, m), 2.77 (3H, s), 2.87 (3H, s), 2.99 (2H, d, J = 7.3Hz), 3.22 (2H, s), 6.16 (lH, dd, J = 8.1 and 2.5Hz), 6.33 (1H, d, J = 2.5Hz), 6.57 (lH, d, J = 8.lHz ), 6.59 (2H, d, J = 8.8Hz), 6.87 (2H, d, J = 8.8Hz).

(Test Example 1) Enhancement of anti-tumor effect on human acute promyelocytic leukemia cell line HL-60 cells 9 human BALB / c nude mice (female, 6 weeks old) subcutaneously in human acute promyelocytic leukemia A tumor piece (5 mm × 5 mm square) of the disease cell line HL-60 was transplanted. The test compound was orally administered 14 times, once a day, on the following day, 4 days, 7 days to 11 days, and 14 days to 18 days after transplantation, with a 2.5% dimethylacetamide-containing 5% emalphore saline solution.

To determine the effect, the short diameter (mm) and long diameter (mm) of the tumor are measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on day 21 after transplantation is evaluated by the following formula.

G I (%) = (1 -A / B) X 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 refers to 1/2 X [tumor major axis] X [tumor minor axis] ² .

(Test Example 2) Enhancement of antitumor effect on human gastric cancer cell line St-40 cells

Ten BALB / c nude mice (female, 6 weeks old) in one group were subcutaneously implanted with a tumor piece (5 mm × 5 mm square) of human gastric cancer cell line St-40. The test compound was suspended in 2.5% dimethylacetamide-containing 5% Emalphor saline, and the following day from transplantation to 4 days, 7 to 11 days, 14 to 18 days,

Oral administration was performed once a day for a total of 19 times on the 21st to 25th days.

To determine the effect, the short diameter (mm) and long diameter (mm) of the tumor are measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on day 28 after transplantation is calculated as in Example 1.

(Test Example 3) Enhancement of cancer cell growth inhibitory activity against human acute promyelocytic leukemia cell HL-60

Seed HL-60 cells in a 96-well plate at IX 10 ³ cells / well, and simultaneously add various concentrations of the drug dissolved in DMSO so that the DMS 0 concentration becomes 0.1%. The concentration of the drug should be examined at 10 ^ M for the thiazolidinedione compound and at lM for the RXR activator. After drug addition, cells are cultured for 5 days. Thereafter, MTS (Promega Corporation) reagent each 40; was added til / _we ll, after 2 hours incubation, the MICROPLATE READER the OD ₄₉₀ of each well (BIO RAD) using under ₂ 37 ° C, 5% C0 And measure. The cell growth inhibitory activity is calculated from the average absorbance of each group by the following formula.

Cancer cell growth inhibition rate (%) = [1- (average absorbance (cell + drug)-average absorbance (medium)) (Average absorbance (cell + DMSO)-Average absorbance (medium))] X 100

(Test Example 4) Combination effect on human colorectal cancer cells COL-2-JCK

The combined effect of a thiazolidinedione compound and an RXR activator on cancer cell growth inhibitory activity was examined using human colon cancer cells COL-2-JCK. The COL-2-JCK cells were 4xl0 ³ cells / well seeded in 96 well plates, drugs were added at various concentrations dissolved in DMSO at the same time so that DMSO concentration of 0.1%. The concentration of the drug was examined at 10 M for each thiazolidinedione compound and 10 M for each RXR activator (n = 4). After drug addition, cells were cultured for 4 days. Then, add 50 l / well of 50% trichloromouth acetic acid (Wako Pure Chemical Industries), fix at 4 ° C for 1 hour, wash with tap water, and then add 0.4% sulforhodamine B (Molecular Probe) An acetic acid solution was added at 150 1 / well, stained at room temperature for 30 minutes, and washed with 1% acetic acid. After air-drying the plate, 10 mM Tris was added at 150 [I 1 / well], 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. Cancer cell growth inhibition rate (%) = [1- {(average absorbance (cell + drug) average absorbance (medium))

Z (average absorbance (cell + DMSO) -average absorbance (medium))}] X100 In this test, the following compounds were used as thiazolidinedione compounds.

1—Amino-7— [2— [41- (2,4-dioxothiazolidine-15-ylmethyl) phenoxymethyl] —1-methyl-1H-benzoimidazole-6-yloxy] naphthalene (hereinafter “Compound A ")

1-amino-1 6— [2— [4-1 (2,4-dioxothiazolidine-1-5-ylmethyl) phenoxymethyl] —1-methyl-1H—benzoimidazo-1-ru 6-yloxy] naphthalene (hereinafter “Compound B”) .),

1-Amino-5- [2- [4-I- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-Benzimidazo-1-ru 6-yloxy] naphthalene (hereinafter referred to as "Compound C") .),

3_ [2— [4— (2,4-dioxothiazolidine-5-ylmethyl) phenoxymethyl] -1-methyl-1-H—benzimidazoyl-6-yloxy] aniline (hereinafter “Compound D”) .),

Compound of Production Example 1

(Hereinafter, referred to as “compound E”).

as well as

5- (4-(6- (4-Amino-3,5-dimethylphenoxy) -1 1-methyl- 1H-Benzimidazole-2-ylmethoxy) -benzyl) -thiazolidine- 1,2,4-dione, dihydrochloride (hereinafter referred to as "Compound F")

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

The results are shown in Table 1.

[Table 1] Test compound growth inhibition rate (%) Compound A 14%

L G 1 0 0 2 6 8 6%

Compound A + L G 100 2 68 48% Compound C 2 2%

Targretin 10%

L G 1 0 0 2 6 8 3%

Compound C + taldaretine 4 2%

Compound C + LG 1 0 0 2 6 8 3 7% Compound D 2 7%

Taldaletin 10%

L G 1 0 0 2 6 8 3%

Compound D + taldaletin 40% Compound D + LG 100 268 39% Compound B 2 1

LG 1 00268 1%

Compound B + L G 100 268 39% Compound E 26%

LG 1 00268 1%

Compound E + L G 100 268 37% Compound F 28%

Targretin 1 1%

Compound F + taldaretin 42% As is clear from Table 1, thiazolidinedione compounds A, B, C, D, E or F and RXR activator LG 100268 or talgretin were compared with single administration, respectively. Thus, it was clarified that the combined use of both exhibited remarkable growth inhibitory activity.

(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

A mixture of 4.0 mg of the compound of Production Example 1, 100.0 mg of targretin, 244.0 mg of lactose, 50.0 g of corn starch and 2.0 mg of magnesium stearate is mixed with a tableting machine to give a tablet of 400 mg per tablet.

(Industrial applicability)

The thiazolidinedione compound of the present invention or a pharmaceutically acceptable salt thereof and an RXR activating agent or a pharmaceutically acceptable salt thereof may be used in combination. Respectively, show superior effects as compared to the case where each is administered alone.

A pharmaceutical composition for administering the thiazolidinedione compound of the present invention or a pharmaceutically acceptable salt thereof and an RXR activating agent or a pharmaceutically acceptable salt thereof simultaneously or separately at an interval comprises: Since it has an excellent cell growth inhibitory effect, it is useful as a therapeutic or preventive agent (particularly a therapeutic agent) for cancer (particularly, lung cancer, stomach cancer or colon cancer).

Claims

'The scope of the claims

One or more of the following general formulas (I)

[Wherein, Ar is an aryl group (substituted with at least one NRiR ² group, and may be substituted with 1 to 4 substituent groups α) or A heteroaryl group (substituted with at least one —NRiR ² group, and may be substituted with a group selected from 1 to 3 substituent groups);

1 and! ² are the same or different and each represent a hydrogen atom, a C 1-6 alkyl group, a C 6-10 aryl group or a C 7-16 aralkyl group,

X represents an oxygen atom or a sulfur atom,

Y represents a = CH- group or a nitrogen atom.

In the above, the substituent group α is a substituent group consisting of a C 16 alkyl group, a C 1-6 alkoxy group, a halogen atom, and a hydroxyl group. A thiazolidinedione compound or a pharmacologically acceptable salt thereof and one or more RXR activating agents or a pharmacologically acceptable salt thereof represented by the formula Or a pharmaceutical composition for preventing or treating cancer, which is separately administered at a later time.

2. Ar is substituted with a phenyl group (at least one NRiR ² group, and

A group selected from 1 to 4 substituent groups, or a pyridyl group (substituted with at least one —NR ¹ ! ^ ² group, and 1 to 3 May be substituted with a group selected from group a)).

3. Ar is a phenyl group (substituted with one —NRiR ² group, and may be substituted with 1 to 4 C 16 alkyl groups) or a pyridyl group (1 偭 —NR

Substituted with ² groups, and may be substituted with 1 to 3 alkyl groups) The pharmaceutical composition according to 1, wherein

4. Ar is a phenyl group (substituted with at least one —NRiR ² group and may be substituted with 1 to 4 groups selected from the substituent group α). A pharmaceutical composition according to claim 1.

5. The pharmaceutical composition according to 1, wherein Ar is a phenyl group (substituted with one —NRiR ² group and may be substituted with one to four C 1-6 alkyl groups). object.

6. The pharmaceutical composition according to 1, wherein Ar is a phenyl group (substituted with one —NRiR ² group).

7. The pharmaceutical composition according to any one of 1 to 6, wherein R ¹ and R ² are the same or different and are each a hydrogen atom, a C 1-6 alkyl group or a C 6-10 aryl group. object.

8.1 ¹ and 1 ² are the same or different, is a hydrogen atom or a C 1 one 6 alkyl group, a pharmaceutical composition according to any one selected from 1 to 6.

9. The pharmaceutical composition according to any one of 1 to 6, wherein R ¹ is a C 16 alkyl group and R ² is a hydrogen atom.

10. The pharmaceutical composition according to any one of 1 to 9, wherein X is an oxygen atom.

1 1. The pharmaceutical composition according to any one of 1 to 10, wherein 丫 is one group of 〇11.

12. When the thiazolidinedione compound is

1-Amino-7- [2-1- (4- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-benzimidazole-6-yloxy] na

1-Amino-6- [2_ [4- (2,4-dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-Venzoimidazo-1-lu-6-yloxy] na

1-Amino-5- [2— [4— (2,4-Dioxothiazolidine-1-ylmethyl) phenoxymethyl] -1-methyl-1H-Benzoimidazole-6-yloxy] na 3— [2— [4— (2,4-Dioxothiazolidine-1-ylmethyl) phenoxymethyl] —1-methyl-1H-benzimidazole-6-yloxy] aniline,

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

5- (4- (6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1-H-benzoimidazo-1-yl-2-ylmethoxy) -benzyl) -thiazolidine-12,4-dione or a mixture thereof 2. The pharmaceutical composition according to claim 1, which is a pharmacologically acceptable salt.

13. The pharmaceutical composition according to any one of 1 to 12, wherein the RXR activating agent is ATRA, 9-cis retinoic acid, LG 100268 or targretin.

14. The pharmaceutical composition according to any one of 1 to 13, for preventing or treating gastric cancer, lung cancer, or colorectal cancer.