JP2002128700A - Pharmaceutical composition for preventing and treating cancer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent useful for a pharmaceutical composition for preventing or treating cancers. SOLUTION: A pharmaceutical composition for preventing or treating cancers in which one or more kinds of PPARγ activators and one or more kinds of RXR activators are simultaneously or successively used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to one or more PPAs for preventing and treating cancer (particularly human cancer).
A medicine by simultaneously or sequentially using R (peroxisome proliferator-activated receptor) γ-activating agent and one or more RXR (retinoid X receptor) activating agents Composition.

[0002]

2. Description of the Related Art WO 98/29120 describes experiments on the effect of adipocyte differentiation on the administration of pioglitazone alone as a PPARγ activating agent, LG100268 alone as an RXR activating agent or a combination of the two. Have been. However, this experiment only measures the cell differentiation promoting effect, and the single dose of pioglitazone is 1
μM, whereas the single dose of LG100268 is 50 nM,
Pioglitazone dose of 5 μM in combination administration of both
In addition, the dose of LG100268 is 50 nM, which is not an experimental system capable of measuring the combined effect. The publication also describes an experiment for promoting the differentiation of liposarcoma cells by the combined administration of pioglitazone and LG100268, but this experiment also only measures the differentiation promoting effect. In response to the publication, the present invention has clarified the effect on cancer of the compound of the present invention as a cancer cell growth inhibitory effect by direct experiment,
Further, it shows that the combined use of a PPARγ activator and an RXR activator has a remarkably superior effect of suppressing the growth of human cancer cells as compared to the respective administrations alone.

[0003] Further, in this publication, rosiglitazone (BRL49653), troglitazone and pioglitazone are specifically described as PPARγ activating agents, but the PPARγ activating agent used in the present invention includes Have a significantly stronger PPARγ activating effect than the compound of No.

[0004]

In the field of cancer chemotherapy, many compounds have already been put into practical use as pharmaceuticals. However, its effect is not always sufficient for various types of tumors, and may have side effects. In addition, as the phenomenon of resistance of tumor cells to these drugs is clinically revealed, the clinical Application is becoming more complex. Under such circumstances, in the field of cancer treatment, the development of new antitumor substances is always required.

An object of the present invention is to provide an antitumor substance which has no side effects due to no cytotoxicity and is effective against tumor cells which have a relatively new mechanism of action and thus are resistant. Is to provide.

[0006]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have found that the combined use of a PPARγ activating agent and an RXR activating agent enhances the effect of suppressing the growth of cancer cells. Was found. In other words, a compound having an excellent PPARγ activating effect is proposed and synthesized, and by using this PPARγ activating agent and an RXR activating agent in combination, the tumor growth inhibitory effect of each single agent administration is further enhanced. Thus, the present invention has been completed as a pharmaceutical composition for preventing or treating cancer by these combinations.

[0007] The present invention relates to one or more PPARγ activating agents and one or more RXR activating agents for preventing and treating cancer (particularly human cancer). Pharmaceutical composition by simultaneous or sequential use.

The PPARγ activating agent, which is one of the active ingredients of the present invention, activates PPARγ as a ligand of PPARγ belonging to the nuclear receptor superfamily, is characterized by a thiazolidinedione structure, and has been conventionally used in the treatment of diabetes. It has been used as a therapeutic agent.

[0009] Such PPARγ activating agents include:
Representative examples, for example, JP-A-7-330728, JP-A-9-295970, JP-A-11-193276, WO95 / 18
No. 125, JP-A-6-247945, WO97 / 31907, and JP-A-9-48771.

The PPARγ activating agent which is an active ingredient of the present invention includes the following compounds. (A) General formula described in JP-A-7-33028
(I ^a )

[0011]

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[In the formula, X ^a represents an indole ring group (which may have 1 to 3 substituents α ^a to be described later), an indoline ring group (1 to 3 substituents α ^a to be described later) may have.), azaindole Hajime Tamaki (which may have 1 to 3 of substituents alpha ^a, which will be described later.), 1 to 3 of substituents alpha ^a of Azaindorin Hajime Tamaki (described later may have.), an imidazopyridine Hajime Tamaki (which may have 1 to 3 of substituents alpha ^a, which will be described later.), or imidazopyrimidine Hajime Tamaki (to be described later to substituent alpha ^a 1 to 3 May be included.)

[0013] Y ^a represents an oxygen atom or a sulfur atom.

[0014] Z ^a is a chemical structural formula

[0015]

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The group represented by

^Ra is a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C
_{(4) an} alkoxy group, a halogen atom, a hydroxyl group, a nitro group, an amino group (which may have ^a substituent βa described later), or C
Shows a ₇ -C _{1 1} aralkyl group.

[0018] m ^a represents an integer of 1 to 5.

Substitution α^aIs C₁-C_FourAlkyl group, C₁-C_FourA
Lucoxy group, benzyloxy group, halogen atom, hydroxyl
Group, acetoxy group, phenylthio group, C₁-C_FourAlkyl
O group, trifluoromethyl group, nitro group, amino group (later
Substitution β to be described^a), C₆-C_TenAryl
Group (substituent γ described later)^aMay be provided. ), And C₇-
C ₁₁Aralkyl group (substituent γ described below)^aMay have
No. ) Represents a group selected from the group consisting of:

The substituent β ^a is a C ₁ -C ₈ alkyl group, a C ₇ -C ₁₁ aralkyl group, a C ₆ -C ₁₀ aryl group, a C ₁ -C ₁₁ aliphatic acyl group, a C ₈ -C ₁₂ araliphatic A group selected from the group consisting of an aromatic acyl group and a C ₇ -C ₁₁ aromatic acyl group.

The substituted γ ^a is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a trifluoromethyl group, and an amino group (substituted β ^a
May be provided. ) Represents a group selected from the group consisting of: And a salt thereof. (B) General formula described in JP-A-9-295970
(I ^b )

[0022]

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Wherein X ^b is a benzimidazole ring group
(Which may have one to five of the substituents alpha ^b to be described later.)
Is shown.

Y ^b represents an oxygen atom or a sulfur atom.

Z ^b is a chemical structural formula

[0026]

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The group represented by

R ^b is a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C
_{(4) an} alkoxy group, a halogen atom, a hydroxyl group, a nitro group, an amino group (which may have a substituent β ^b described later), or C
Shows a ₇ -C _{1 1} aralkyl group.

[0029] m ^b is an integer of 1 to 5.

Substitution α^bIs C₁-C_FourAlkyl group, C₁-C_FourA
Lucoxy group, benzyloxy group, halogen atom, hydroxyl
Group, acetoxy group, phenylthio group, C₁-C_FourAlkyl
O group, trifluoromethyl group, nitro group, amino group (later
Substitution β to be described^b), C₆-C_TenAryl
Group (substituent γ described later)^bMay be provided. ), And C₇-
C ₁₁Aralkyl group (substituent γ described below)^bMay have
No. ) Represents a group selected from the group consisting of:

The substituent β ^b is a C ₁ -C ₈ alkyl group, a C ₇ -C ₁₁ aralkyl group, a C ₆ -C ₁₀ aryl group, a C ₁ -C ₁₁ aliphatic acyl group, or a C ₈ -C ₁₂ araliphatic A group selected from the group consisting of an aromatic acyl group and a C ₇ -C ₁₁ aromatic acyl group.

The substituted γ ^b is a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a halogen atom, a hydroxyl group, a nitro group, a phenyl group, a trifluoromethyl group, and an amino group (substituted β ^b
May be provided. ) Represents a group selected from the group consisting of: And a salt thereof. (C) General formula (I ^c ) described in JP-A-11-193276

[0033]

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[In the above formula, R ^C1 is a general formula

[0035]

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Or a general formula

[0037]

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[0038] [wherein, R ^C4 has 1 to four substituents alpha ^c (a substituent alpha ^c may have from 1 to 5 carbon atoms. Which will be described later) or the pyridyl group (to be described later phenyl May be shown).

R ^C5 represents a hydrogen atom or a substitution α ^c
Is shown.

R ^C6 represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C _6-
A C ₁₀ aryl group (which may have 1 to 3 substituents β ^c described below) or a C ₇ -C ₁₆ aralkyl group (which may have 1 to 3 substituents β ^c which will be described later) ).

D ^c represents an oxygen atom or a sulfur atom.

E ^c represents a ＝ CH— group or a nitrogen atom. ] Is shown.

R ^C2 is a hydrogen atom or a substituent α ^c described later.
Is shown.

R ^C3 is a chemical structural formula

[0045]

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The group represented by

[0047] A ^c represents a C ₁ -C ₆ alkylene group.

B ^c represents an oxygen atom or a sulfur atom.

The substituted α ^c is a halogen atom, a hydroxyl group, C _1-
A C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkylthio group, an amino group (which may have a substituent γ ^c described later), C ₃ -C ₁₀ cycloalkyl
(It may have 1 to 3 substituents β ^c described below.), C ₆ -C ₁₀ aryl (the substituents β ^c described later are 1 to 3)
You may have one. ), C ₇ -C ₁₆ aralkyl (may have 1 to 3 substituents β ^c described below), C ₆ -C ₁₀ aryloxy (having 1 to 3 substituents β ^c described later) ), C ₇ -C ₁₆ aralkyloxy (substituted β
^It may have one to three ^c . ), A C ₆ -C ₁₀ arylthio group (which may have 1 to 3 substituents β ^c described later), a C ₁ -C ₆ aliphatic acyloxy group, and a 4- to 7-membered saturated nitrogen atom-containing group And a group selected from the group consisting of a heterocyclic group, a 5- or 6-membered aromatic heterocyclic group containing a nitrogen atom, a nitro group, and a cyano group.

The substituent β ^c is a halogen atom, a hydroxyl group, C _1-
A C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, an amino group (which may have a substituent γ ^c described later), a C ₆ -C ₁₀ aryl group, and Shows a group selected from the group consisting of nitro groups.

Substitution γ^cIs C₁-C_TenAlkyl group, substituted
May be C₆-C_TenAryl, optionally substituted C₇-C₁₆A
Aralkyl group, C₁-C₇Aliphatic acyl group, optionally substituted C
₇-C_{1 1}Aromatic acyl, optionally substituted C₈-C₁₂Aromatic fat
Group acyl, optionally substituted C _Four-C₁₁Cycloalkylcal
Carbonyl, and optionally substituted nitrogen atom
Selected from the group consisting of a 6-membered aromatic heterocyclic carbonyl group
Group.

Provided that 5- [4- [5- (3,5-di-t-butyl-4-hydroxyphenylthio) -3-methyl-3H-imidazo [4,5-b] pyridin-2-ylmethoxy Excludes [benzyl] thiazolidine-2,4-dione. Or a pharmacologically acceptable salt thereof.

Here, the substituent in "may be substituted" includes a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, a halogeno C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, and a C ₁ -C ₆ alkoxy group. ₁ -C
1 to 3 substituents selected from the group consisting of ₆ alkylthio groups.

The following compounds are also suitable as the PPARγ activating agent which is the active ingredient of the present invention.

General formula (I)

[0056]

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[Wherein, W is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (which may have 1 to 5 substituents α described below), a monocyclic ring A heteroaromatic group of the formula (which may have 1 to 4 substituents α described below), or C ₇ -C ₁₂
And an aralkyl group (which may have 1 to 5 substituents α described later on the aryl).

X represents an oxygen atom or a sulfur atom.

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

The substitution α is a group selected from the group consisting of a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, and a hydroxyl group. Or a pharmacologically acceptable salt thereof.

Here, the term "monocyclic heteroaromatic group" refers to a 5- or 6-membered monocyclic aromatic heterocyclic group having one or two nitrogen atoms, such as pyridyl and pyrazyl. , Pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, and pyrazolyl.

When the compound having the structure of the general formula (I) has 2 to 5 substituents α, the substituents α may be the same or different.

According to the definition of the group shown above, W is represented by “C ₆ -C ₁₀
When an aryl group (which may have 1 to 5 substituents α) ”is shown, the group includes, for example, phenyl, methylphenyl, 2,3,4-trimethylphenyl, t-
Butylphenyl, di-t-butylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, difluorophenyl, pentafluorophenyl, chlorophenyl, dichlorophenyl, 2-, 3- and 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-
Methylphenyl, 2-t-butyl-4-hydroxyphenyl,
3-t-butyl-4-hydroxyphenyl, 4-hydroxy-2,3
-Dimethylphenyl, 4-hydroxy-3,5-dimethylphenyl, 4-hydroxy-3,6-dimethylphenyl, 3,5-di-t-butyl-4-hydroxyphenyl, 3,6-di-t-butyl -4-hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 4-hydroxy-3,5,6-trimethylphenyl, 2-chloro-4-hydroxy-3,5-dimethylphenyl, naphthyl,
Mention may be made of methylnaphthyl, t-butylnaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl and hydroxynaphthyl.

When W represents a “C ₇ -C ₁₂ aralkyl group (which may have 1 to 5 substituents α on the aryl)”, the group includes, for example, benzyl, methylbenzyl, t -Butylbenzyl, methoxybenzyl, hydroxybenzyl, fluorobenzyl, chlorobenzyl, hydroxybenzyl, 4-hydroxy-3,5-dimethylbenzyl,
3,5-di-t-butyl-4-hydroxybenzyl, phenethyl,
Methylphenethyl, t-butylphenethyl, methoxyphenethyl, hydroxyphenethyl, fluorophenethyl,
Chlorophenethyl, hydroxyphenethyl, 4-phenylbutyl, 4- (methylphenyl) butyl, 4- (hydroxyphenyl) butyl, 6- (methylphenyl) hexyl, 6-phenylhexyl, and 6- (hydroxyphenyl) hexyl be able to.

The method for producing the compound having the structure of the general formula (I) is described in JP-A-7-330728, JP-A-9-295970,
Alternatively, it is described in JP-A-11-193276.

In the compound having the structure of the general formula (I), (1) W is preferably a C ₁ -C ₄ alkyl group or a C ₆ -C ₁₀ aryl group (1 to 5 substituents α). A monocyclic heteroaromatic ring group (which may have 1 to 3 substituents α), or a C ₇ -C ₁₂ aralkyl group (substituent α on aryl). Thiazolidinedione compound or a pharmacologically acceptable salt thereof. (2) W is a C ₁ -C ₄ alkyl group, a phenyl group (which may have 1 to 5 substituents α), a pyridyl group (a substituent α)
May be provided. ) Or a benzyl group (may have 1 to 3 substituents α on the aryl)
Or a pharmacologically acceptable salt thereof. (3) A thiazolidinedione compound or a pharmaceutically acceptable salt thereof, wherein W represents a C ₁ -C ₄ alkyl group or a phenyl group (which may have 1 to 5 substituents α). (4) A thiazolidinedione compound or a pharmacologically acceptable salt thereof, in which W represents a phenyl group (which may have 1 to 5 substituents α). (5) A thiazolidinedione compound in which X represents an oxygen atom or a pharmacologically acceptable salt thereof. (6) A thiazolidinedione compound in which X represents a sulfur atom or a pharmacologically acceptable salt thereof. (7) A thiazolidinedione compound in which Y represents a = CH- group or a pharmacologically acceptable salt thereof. (8) A thiazolidinedione compound in which Y represents a nitrogen atom or a pharmacologically acceptable salt thereof. (9) When the substituted α is a C ₁ -C ₆ alkyl group, a halogen atom,
And a thiazolidinedione compound or a pharmacologically acceptable salt thereof, which represents a group selected from the group consisting of: (10) A thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein the substituted α represents a group selected from the group consisting of a C ₁ -C ₆ alkyl group and a hydroxyl group.

Further, among the compounds having the structure of the above general formula (I), the following compounds are also suitable. (11) W represents a phenyl group (may have 1 to 5 substituents α).

X represents an oxygen atom.

Y represents a = CH- group.

A thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein the substituted α represents a group selected from the group consisting of a C ₁ -C ₆ alkyl group and a hydroxyl group. PP of the present invention
The ARγ activating agent may more preferably include the following compounds, but the PPARγ activating agent of the present invention is not limited to these compounds.

[0071]

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[0072]

[Table 1]

In the above table, preferably, the exemplified compound number, 15- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 35- [ 4- [6- (4-hydroxyphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 5-5- [4- [6- (3-hydroxyphenoxy) -1- Methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 65- [4- [6- (4-hydroxy-3-methylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] Thiazolidine-2,4-dione, 9 5- [4- [6- (4-hydroxy-3,5-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 10 5- [4- [6- (4-
Hydroxy-2,3-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-
2,4-dione, 13 5- [4- [6- (4-hydroxy-2,3,5-trimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 14
5- [4- [5- (4-hydroxy-2,3,5-trimethylphenoxy) -3-methylimidazo [5,4-b] pyridin-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 15 5- [4- [6
-(2-chloro-4-hydroxy-3,5-dimethylphenoxy) -1-
Methylbenzimidazol-2-ylmethoxy] benzyl]
Thiazolidine-2,4-dione, 16 5- [4- (6-pentafluorophenoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and 18
5- [4- (6-benzyloxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and pharmacologically acceptable salts thereof.

More preferably, the exemplified compound number, 15- [4
-(6-Methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 65- [4- [6
-(4-Hydroxy-3-methylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-
2,4-dione, 105- [4- [6- (4-hydroxy-2,3-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 135 -
[4- [6- (4-hydroxy-2,3,5-trimethylphenoxy) -1-
Methylbenzimidazol-2-ylmethoxy] benzyl]
Thiazolidine-2,4-dione, 15 5- [4- [6- (2-chloro-4
-Hydroxy-3,5-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-
2,4-dione, and 18 5- [4- (6-benzyloxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and pharmacologically acceptable salts thereof are listed. be able to.

The following compounds are also suitable as the PPARγ activating agent of the present invention.

As described in WO95 / 18125,

[0077]

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4- [4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl-3,5-isoxazolidinedione or a pharmacologically acceptable salt thereof. The production method of the compound is described in WO95 / 18125,
Activating PPARγ is described in J. Terasaki et al, Diabet
ologia, 41 (4), pp400-409 (1998).

As described in JP-A-6-247945,

[0080]

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5- [6- (2-fluorobenzyloxy) -2-naphthyl] methyl-2,4-thiazolidinedione or a pharmacologically acceptable salt thereof. The production method of the compound is described in JP-A-6-247945, and it is confirmed that the compound activates PPARγ according to Mauricio J. Reginato et al, J. Bio.
73 (49), pp 32679-32684 (1998).

As described in WO 97/31907,

[0083]

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2 (S)-(2-benzoylphenylamino) -3- [4
-[2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl] propionic acid or a pharmacologically acceptable salt thereof. The production method of the compound and the fact that the compound has a PPARγ activating action are described in WO97 / 31907.

As described in JP-A-9-48771,

[0086]

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N- (4-trifluoromethylbenzyl) -5- (2,
4-dioxothiazolidine-5-yl) methyl-2-methoxybenzamide or a pharmacologically acceptable salt thereof. The production method of the compound is described in JP-A-9-48771, and the activation of PPARγ by the compound is determined by K. Murakami et al.
al, Diabetes, 47, pp1841-1847 (1998).

The RXR activating agent, one of the active ingredients of the present invention, is a compound (retinoid) having a retinoic acid or retinoic acid-like physiological activity by binding to RXR.
Is a compound that has the effect of enhancing the action of

As the RXR activating agent which is the active ingredient of the present invention, representative examples include, for example, J. Thibonnet et al.
al, Synlett, 1, pp 141-143 (1999), JP-A-6-107542, and WO94 / 15901.

The structural formulas of representative compounds as an active ingredient of the present invention as an RXR activating agent are shown below.

[0091]

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The compound name of ATRA is (E, E, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1-cyclohexen-1-yl] -2,
4,6,8-Nonatetraenoic acid (all-trans-retinoic acid). ATRA is manufactured by J. Thibonnet et al, Synle
TT, 1, pp 141-143 (1999), that ATRA acts on RXR as it is or a part of it is converted to 9-cis-retinoic acid, JP-T-10-511948. It is described in the gazette.

9-cis-retinoic acid is disclosed in JP-A-6-107542.
And its compound name is (E, Z, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1-cyclohexen-1-yl] -2,4 , 6,8-Nonatetraenoic acid (9-cis-retinoic acid). The preparation of 9-cis-retinoic acid and that 9-cis-retinoic acid is an RXR activating agent is described in MFBoehm
et al., J. Med. Chem., 37, pp. 408-414 (1994).

LG100268 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) cyclopropyl] nicotinic acid. The production method of the compound and the fact that the compound is an RXR activating agent are described in WO94 / 15901.

Targretin is described in WO 94/15901, and its compound name is 6- [1- (3,5,5,8,8-pentamethyl-
5,6,7,8-tetrahydronaphthalen-2-yl) ethenyl] benzoic acid. The method for preparing the compound and the compound is RXR
Activation agents are described in WO 94/15901.

The PPARγ activating agent and the RXR activating agent, which are the active ingredients of the present invention, can be converted into salts according to a conventional method. Such salts include, for example, alkali metal salts such as sodium, potassium and lithium salts;
Alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts; Dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, Amine salts such as organic salts such as chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt; hydrofluoric acid, Halo such as hydrochloric acid, hydrobromic acid, hydroiodic acid Inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; benzenesulfonic acid Aryl sulfonates such as p-toluenesulfonic acid; salts of amino acids such as glutamic acid and aspartic acid; salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid And organic acids such as ornithate, glutamate, and aspartate. Examples of the salt of the PPARγ activating agent include hydrohalides and organic acid salts. More preferably, it is a hydrochloride.

The compound of the present invention may be left in the air or recrystallized to absorb water and become adsorbed or hydrated. When forming a hydrate, all of these are included in the present invention.

Furthermore, the compound of the present invention may absorb some other solvent and form a solvate, and such a compound is also included in the present invention.

Various active isomers of the PPARγ activating agent and the RXR activating agent of the present invention may exist. For example, the thiazolidine ring of the thiazolidinedione compound having the structure of the general formula (I) contains an asymmetric carbon, and may have an asymmetric carbon on the substituent, and thus has an optical isomer. Each of these isomers or compounds in any proportion thereof are encompassed by the present invention.

For such isomers, the compound of the present invention is synthesized using the starting compound of each isomer, or the synthesized compound of the present invention is optionally separated using a conventional separation method or separation method. Can be obtained.

Furthermore, the present invention also includes all compounds that are metabolized in vivo and converted into the compound of the present invention or a pharmacologically acceptable salt, so-called prodrugs.
As the prodrug, for example, the general formula of the present invention
When the compound having (I) has a phenolic hydroxyl group, it refers to a compound in which the hydroxyl group is protected by a protecting group that can be cleaved in vivo by a biological method such as hydrolysis.

The term "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" refers to a free phenolic hydroxyl group or a salt thereof which is cleaved in a human body by a biological method such as hydrolysis. Means whether or not such a derivative is administered by intravenous injection to an experimental animal such as a rat or a mouse, and then examines the body fluid of the animal to determine whether the original compound or its pharmacologically It can be determined by detecting an acceptable salt.

Examples of such a protecting group include formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1- (lower aliphatic acyloxy) lower alkyl groups such as 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, Isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1-
(Ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-
1- (lower alkoxycarbonyloxy) alkyl groups such as butoxycarbonyloxy) ethyl; and phthalidyl groups such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl.

[0104]

BEST MODE FOR CARRYING OUT THE INVENTION The prevention and treatment of cancer in the present invention is carried out by using a PPARγ activating agent and an RXR activating agent in combination. That is, by using one or more PPARγ activating agents and one or two or more RXR activating agents simultaneously or sequentially, a superior effect as compared with each single agent is obtained. It is shown.

Here, the term “simultaneously” means that one or more PPARγ activating agents and one or more RXR activating agents are combined with each other in the form of a combination drug or these agents. When it is not preferable to mix them, it means that these drugs are individually and simultaneously administered.

"Sequentially" refers to the administration of individual agents, one after the other, at appropriate intervals.

Also, one or more PPARs to be administered
When there are three or more γ-activating agents and one or more RXR-activating agents in total, “simultaneously or sequentially” means that they may be administered simultaneously or sequentially. Often, two or more species may be administered simultaneously and the remaining drugs may be administered sequentially, or two or more species may be administered sequentially and the remaining medications administered simultaneously.

The term “cancer” used herein refers to sarcomas, carcinomas, leukemias, etc., including fibrosarcoma, liposarcoma, osteosarcoma, angiosarcoma, lung cancer, gastric cancer, colon cancer, breast cancer, prostate cancer, Kidney, liver, pancreas, esophagus, tongue, brain, larynx, bladder,
Includes ovarian cancer, acute leukemia, chronic leukemia, lymphoma, etc.

The agent which is the PPARγ activating agent and the RXR activating agent of the present invention is mixed with the agent itself or an appropriate pharmacologically acceptable excipient, lubricant and the like. It can be administered orally in the form of preparations, tablets, capsules or the like or parenterally in the form of injections or suppositories.

Here, “excipients” include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch and dextrin; Organic excipients such as gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate Inorganic excipients such as carbonates such as calcium carbonate; sulfates such as calcium sulfate.

Examples of the "lubricants" include metal salts of stearic acid such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay wax; boric acid; adipic acid; Sulfates such as sodium; glycols;
Fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate;

The dosage form of the PPARγ activating agent and RXR activating agent used in the present invention is preferably oral administration. Thus, the two systems of the agents can each be adjusted individually into separate unit dosage forms, or mixed together to form a physically single unit dosage form.

The dose and the administration ratio of the PPARγ activating agent and the RXR activating agent used in the present invention are determined by the activity of each drug, the symptom / age of a patient (warm-blooded animal, especially human), age,
Although it may vary greatly depending on various conditions such as body weight, the oral dose of each of the PPARγ activating agent and the RXR activating agent is generally 0.005 mg as a lower limit.
/ kg body weight (preferably 0.05 mg / kg body weight), with an upper limit of 500 mg / kg body weight (preferably 50 mg / kg body weight), and in the case of intravenous administration, a lower limit of 0.001 mg / time. / kg body weight (preferably 0.01 mg / kg body weight), with an upper limit of 50 mg / kg body weight (preferably 5 mg / kg body weight).
/ kg body weight) once or several times a day depending on the symptoms.

Further, the administration ratio of the PPARγ activating agent to the RXR activating agent can also vary greatly, but can generally be in the range of 1: 200 to 200: 1 by weight.

[0115]

EXAMPLES Example 1 PPARγ activating action CHO cells (Chinese hamster ovarian cells)
The PPARγ activating effect was measured by a reporter assay called luciferase assay using aP2-12 cells into which a PARγ-responsive gene (enhancer region of aP2, an adipocyte differentiation marker gene) was introduced.

AP2-12 cells were placed in a 96-well plate at 2 × 10 ⁴ ce
II / well were seeded, and at the same time, various concentrations of test compounds dissolved in DMSO were added so that the DMSO concentration was 0.1%. The concentrations of the test compounds were 1 nM, 10 nM, 100 nM, 1 μM, and 10 μM. After the test compound is added, the cells are cultured for 24 hours, and PBS is added.
After washing with (phosphate buffered saline), a cell lysate was prepared using 30 μl of Picker Gene cell lysate (Toyo Ink). Thereafter, 10 μl of the cell lysate was dispensed into a Microlite 1 white plate (DYNEXTECHNOLOGIES), and 50 μl was added to each well.
Luciferase activity was measured by adding μl of Picker Gene Luminescent Substrate Solution (Toyo Ink). The luminescence was measured using a luminometer ML3000 (Dynatech Laboratorie) for 10 seconds from 2 seconds after the addition of the luminescent substrate solution. The resulting concentrations of the test compound from the light emission amount indicating a half amount of a saturated amount of light emission using Excel (Microsoft Corporation) was calculated as a linear function approximation, EC ₅₀ values in the PPARγ activation effect of a test compound ( μM).

[0117]

[Table 2]

As is clear from Table 2, the PPARγ of the present invention
The activating agent exhibits a PPARγ activating effect superior to troglitazone, rosiglitazone and pioglitazone.

Therefore, the PPARγ activating agent of the present invention and RX
Drugs that are used in combination with R-activating agents are those that are suggested to have superior cancer cell growth inhibitory effects than drugs that are used in combination with troglitazone, rhodiglitazone or pioglitazone and RXR-activating agents. is there.

Example 2 Human acute promyelocytic leukemia cell line
Enhancement of antitumor effect on HL-60 cells 1 group 9 BALB / c nude mice (female, 6 weeks old) subcutaneously,
Tumor pieces of human acute promyelocytic leukemia cell line HL-60 (5 mm x 5 mm
Horn) was transplanted. The test compound was suspended in a 5% emulphor saline containing 2.5% dimethylacetamide, and was suspended for 4 to 4 days after transplantation.
Oral administration was performed once daily on days 7, 7 to 11, and 14 to 18 a total of 14 times.

The effect was determined by determining the minor axis (mm) and major axis (mm) of the tumor.
Was measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on day 21 after transplantation was evaluated by the following formula.

GI (%) = (1-A / B) × 100 A: Average tumor volume on day 21 of the compound-administered group (*) B: Average tumor volume on day 21 of the untreated control group (*) *: Tumor volume refers to ×× [tumor major axis] × [tumor minor axis] ² .

Table 3 summarizes the results.

[0124]

[Table 3]

From Table 3, it can be seen that the proliferation of human acute promyelocytic leukemia cells was more pronounced with the administration of the hydrochloride of Exemplified Compound 1 which is a PPARγ activating agent and with talgretin which is an RXR activating agent, as compared with the case of single administration of both compounds. It was clarified that the combined administration of the compound significantly suppressed the administration.

That is, according to Table 3, it is found that administration of targretin alone has no effect on suppressing the growth of human acute promyelocytic leukemia cells. However, targretin, when used in combination with the hydrochloride salt of Exemplified Compound 1, clearly enhances the inhibitory effect of the administration of Exemplified Compound 1 hydrochloride alone on the proliferation of human acute promyelocytic leukemia cells. Therefore, Example 2
The experimental results show that the combined use of a PPARγ activator and an RXR activator has a synergistic inhibitory effect on cancer cell proliferation.

Example 3 Against Human Gastric Cancer St-40 Cell
Enhancement of antitumor effect 1 group of 10 BALB / c nude mice (female, 6 weeks old) subcutaneously,
A tumor piece (5 mm × 5 mm square) of human gastric cancer line St-40 was transplanted. The test compound was suspended in 5% emulphor saline containing 2.5% dimethylacetamide, and the following day from transplantation to 4 days, 7 days to 11 days, and 14 days after transplantation.
Oral administration was carried out once a day, a total of 19 times, on days 18 to 18, and on days 21 to 25.

The effect was determined by determining the minor axis (mm) and major axis (mm) of the tumor.
Was measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) on day 28 after transplantation was calculated as in Example 1.

Table 4 summarizes the results.

[0130]

[Table 4]

From Table 4, it can be seen that the proliferation of human gastric cancer cells was PPARγ
It was revealed that the combined administration of both compounds was more remarkable than the single administration of the hydrochloride of Exemplified Compound 1 as the activating agent and LG100268 as the RXR activating agent.

That is, according to Table 4, administration of LG100268 alone has almost no effect on suppressing the growth of human gastric cancer cells. However, when used in combination with the hydrochloride of Exemplified Compound 1, the effect of suppressing the growth of human gastric cancer cells by administration of the hydrochloride of Exemplified Compound 1 alone is clearly enhanced. Therefore, the experimental results of Example 3 indicate that the PPARγ activator and RXR
It shows a synergistic inhibitory effect on cancer cell growth when used in combination with an activating agent.

Example 4 Human acute promyelocytic leukemia cell HL
Enhanced HL-60 cells of cancer cell growth inhibitory activity against -60 96 well pre - 1 × 10 ³ cells / well were seeded in bets, the drug DMSO concentration of various concentrations dissolved in DMSO at the same time
0.1% was added. The concentration of the drug was 10 μM of Exemplified Compound 18 as a PPARγ activator, and
LG100268 was tested at 1 μM (n = 4). After the drug was added, the cells were cultured for 5 days. Thereafter, MTS (the Promega Corporation) reagent were added each 40μl / well, 37 ℃, after 2 hours incubation under 5% CO _2, was measured using MICROPLATE READER the OD ₄₉₀ of each well (BIO RAD). The cell growth inhibitory activity was calculated from the average absorbance of each group by the following formula.

[0134]

(Equation 1) The results are shown in Table 5.

[0135]

[Table 5]

From Table 5, it can be seen that the proliferation of human acute promyelocytic leukemia cells is more remarkable by the combined administration of Exemplified Compound 18, which is a PPARγ activator, and LG100268, which is an RXR activator, than by single administration of both compounds. It became clear that it was suppressed.

Example 5 Human Colorectal Cancer Cell COL-2-JCK
96well enhanced COL-2-JCK cells of cancer cell growth inhibitory activity to pre - DOO to 4 × to 10 ³ cells / well seeded, addition of agents of various concentrations dissolved in DMSO at the same time as DMSO concentration of 0.1% did. The concentration of the drug was examined at 10 μM of Exemplified Compound 18 as a PPARγ activator and at 10 μM of talgretin or LG100268 as an RXR activator (n
= 4). After drug addition, cells were cultured for 4 days. Then 5
0% trichloroacetic acid (Wako Pure Chemical Industries, Ltd.) was added at 50 μl / well for 1 hour at 4 ° C., washed with tap water, and 0.4% sulforhodamine B (Molecular Probe) -1% acetic acid solution was added.
After adding 50 μl / well, the mixture was stained at room temperature for 30 minutes, and washed with 1% acetic acid. After air drying the plate, add 10 mM Tris to 150 μl / wel
l Add OD ₄₉₀ of each well to MICROPLATE READER (BIO RA
It measured using D). The cell growth inhibitory activity was calculated from the average absorbance of each group by the following formula.

[0138]

(Equation 2) The results are shown in Table 6.

[0139]

[Table 6]

From Table 6, it can be seen that the proliferation of human colon cancer cells was PPARγ
Exemplary compound 18 which is an activator and L which is an RXR activator
Rather than single administration of G100268 or Targretin respectively,
It was clarified that the combined administration of both activators significantly suppressed the activity. Formulation Examples 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 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride (hydrochloride of Exemplified Compound 1), 100.0 mg of talgretin,
After mixing powder of lactose 244.0mg, corn starch 50.0g and magnesium stearate 2.0mg, one tablet of 400mg is obtained by tableting with a tableting machine.

[0142]

The pharmaceutical composition of the present invention obtained by using one or more PPARγ activating agents and one or more RXR activating agents simultaneously or sequentially is as follows: It is useful in preventing and treating cancer (particularly human cancer).

That is, the present invention uses one or more PPARγ activating agents and one or two or more RXR activating agents simultaneously or sequentially as a novel antitumor substance. Thereby providing a pharmaceutical composition.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/455 A61K 31/455 A61P 35/00 A61P 35/00 // C07D 417/12 C07D 417/12 ( 72) Inventor Naomi Shimazaki 1-58, Hiromachi, Shinagawa-ku, Tokyo, Japan Inside Sankyo Co., Ltd. (72) Inventor Gaku Fujita 1-2-58, Hiromachi, Shinagawa-ku, Tokyo F-term in Sankyo Corporation ( Reference) 4C063 AA01 BB08 CC52 CC62 DD25 DD51 EE01 4C084 AA18 MA02 NA05 ZB261 ZB262 4C086 AA02 BC19 BC69 BC82 GA07 GA09 MA02 MA04 NA05 ZB26 4C206 AA02 DA05 DA17 KA01 MA02 MA04 NA05 ZB26

Claims (11)

[Claims] Claims: 1. One or two types for preventing or treating cancer
One or more PPARγ activating agents and one or more RX
A pharmaceutical composition by using the R-activating agent simultaneously or sequentially. 2. The method according to claim 1, wherein the PPARγ activating agent has the general formula (I): [Wherein W is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group
(It may have 1 to 5 substituents α described later.),
A monocyclic heteroaromatic group (which may have 1 to 4 substituents α described below), or a C ₇ -C ₁₂ aralkyl group (which has 1 to 5 substituents α described later on the aryl) May be performed). X represents an oxygen atom or a sulfur atom. Y
Represents a = CH- group or a nitrogen atom. The substitution α is C ₁ -C
_And a group selected from the group consisting of a ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom, and a hydroxyl group. Or a pharmacologically acceptable salt thereof, for the prevention or treatment of cancer. 3. The method according to claim 2, wherein W is a C ₁ -C ₄ alkyl group or a phenyl group (substituted α is 1
You may have five to five. A thiazolidinedione compound or a pharmacologically acceptable salt thereof for the prevention or treatment of cancer. 4. The method according to claim 2, wherein W is a thiazolidinedione compound showing a phenyl group (which may have 1 to 5 substituents α) or a pharmacologically acceptable salt thereof. A pharmaceutical composition for preventing or treating. 5. The method according to claim 2, wherein X is a thiazolidinedione compound showing an oxygen atom or a pharmacologically acceptable salt thereof, for preventing or treating cancer. Pharmaceutical composition. 6. The method according to claim 2, wherein Y is a thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein Y is a ＣＨCH— group. A pharmaceutical composition for: 7. The method according to claim 2, wherein the substituent α is a group selected from the group consisting of a C ₁ -C ₆ alkyl group, a halogen atom, and a hydroxyl group. A pharmaceutical composition for preventing or treating cancer, which is a thiazolidinedione compound or a pharmacologically acceptable salt thereof. 8. The method according to claim 1, wherein the PPARγ activating agent is 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, 5- [ 4- [6- (4-hydroxy-3-methylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 5- [4- [6- (4-hydroxy-2 , 3-Dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 5- [4- [6- (4-hydroxy-2,3,5-trimethylphenoxy)-
1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 5- [4- [6- (2-chloro-4-hydroxy-3,5-dimethylphenoxy) -1-methylbenzimidazole -2-ylmethoxy] benzyl] thiazolidine-2,4-dione or 5- [4- (6-benzyloxy-1-methylbenzimidazole-
2-ylmethoxy) benzyl] thiazolidine-2,4-dione,
Or a pharmaceutical composition for preventing or treating cancer, which is a pharmacologically acceptable salt thereof. 9. The method according to claim 1, wherein the PPARγ activating agent is 4- [4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl-3,5-isoxazolidinedione. 5- [6- (2-fluorobenzyloxy) -2-naphthyl] methyl-
2,4-thiazolidinedione, 2 (S)-(2-benzoylphenylamino) -3- [4- [2- (5-methyl-2-phenyloxazol-4-yl) ethoxy] phenyl] propionic acid, or Preventing or treating cancer which is N- (4-trifluoromethylbenzyl) -5- (2,4-dioxothiazolidine-5-yl) methyl-2-methoxybenzamide or a pharmaceutically acceptable salt thereof A pharmaceutical composition for: 10. The method according to any one of claims 1 to 9, wherein the RXR activating agent is ATRA, 9-cis-retinoic acid, LG10
[0268] A pharmaceutical composition for preventing or treating cancer that is targretin. 11. A pharmaceutical composition for preventing or treating a cancer according to any one of claims 1 to 9, wherein the RXR activating agent is LG100268 or targretin.