WO2002013864A1

WO2002013864A1 - Medicinal compositions for preventing and treating cancer

Info

Publication number: WO2002013864A1
Application number: PCT/JP2001/007037
Authority: WO
Inventors: Shinichi Kurakata; Kosaku Fujiwara; Naomi Shimazaki; Takashi Fujita
Original assignee: Sankyo Company, Limited
Priority date: 2000-08-16
Filing date: 2001-08-15
Publication date: 2002-02-21
Also published as: AU2001278738A1

Abstract

Medicinal compositions for preventing or treating cancer wherein one or more PPARη activation agonists and one or more RXR activation agonists are used simultaneously or successively.

Description

Description Pharmaceutical composition for preventing and treating cancer

(Technical field)

The present invention relates to a method for activating one or more PPs (peroxisomes 'proliferatives', 'activitides', 'receptors') for preventing and treating cancers (particularly human cancers). The present invention relates to a pharmaceutical composition, comprising using an agent and one or more agents for activating RXR (retinoid X receptor) simultaneously or sequentially.

(Background technology)

W098 / 29120 discloses that piogliyuzone alone is administered as a PPARa activating agent! An experiment on the effect of administration of LG100268 alone as an Offi activating agent and administration of both in combination on adipocyte filtration is described. However, in this experiment, the effect of promoting cell division was measured, and the single dose of pioglisun was 1 zM and the single dose of LG100268 was 50 nM. In the combined administration, the dose of pioglisunzone was 5 zM and the dose of LG100268 was 50 nM, and it is not an experimental system that can measure the combined effect. The publication also describes an experiment on the promotion of differentiation of liposarcoma cells by co-administration of pioglisuzone and LG100268, but this experiment only measures the promotion of differentiation. According to the publication, the present invention clarifies the effect of the compound of the present invention on cancer as a cancer cell growth inhibitory effect by direct experiment, This shows that the effect of suppressing the growth of human cancer cells when used in combination with an agonist is remarkably superior to each of the individual administrations.

In addition, the gazette discloses that as a PPMa activating agent, specifically, oral diglyuzone ( BRL49653), troglisuzone and pioglisuzone are described, but the PPMa activating agent used in the present invention has a significantly stronger PPARa activating effect than these compounds.

(Disclosure of the Invention)

The present inventors have found that the combined use of a PPARa activating agent and an MR activating agent enhances the cancer cell growth inhibitory effect. That is, the invention of a compound having an excellent PPARa activating effect was carried out, and by combining this PPARa activating agent and the MR activating agent, the tumor growth inhibitory effect of each single agent administration was obtained. The present invention was completed as a pharmaceutical composition for preventing or treating cancer by the combined use thereof.

The present invention relates to a method for preventing and treating cancer (particularly human cancer), comprising simultaneously or simultaneously using one or more PPARa activating agents and one or more m-activating agents. Pharmaceutical composition by sequential use.

A PPARa activating agent, one of the active ingredients of the present invention, activates PPMa as a ligand of PPMa belonging to the nuclear receptor family, and is characterized by a thiazolidinedione structure. Conventionally, it has been used as a therapeutic agent for diabetes.

Representative examples of such a PPMa activating agent include, for example, JP-A-7-330728, JP-A-9-295970, JP-A-11-193276, W095 / 18125, Compounds described in JP-A-6-247945, W097 / 31907, and JP-A-9-48771 can be exemplified.

The following compounds can be mentioned as the PPMa activating agent which is the active ingredient of the present invention.

(A) described in JP-A-7-33028, General formula ( ^Ia )

z ^a (i ^a )

[Where,

X ^a is India Ichiru Hajime Tamaki (which may have 1 to 3 of substituents a ^a to be described later.) Indoline璟基(optionally having 1 to 3 substituents secretions ^a described later good.), Azai Ndoru Hajime Tamaki (which may have 1 to 3 substituents secretions ^a to be described later.) may have 1 to 3 of substituents ^a, which Azain polyhedrin Hajime Tamaki (described later .), Imidazopi lysine Hajime Tamaki (which may have 1 to 3 of substituents ^a described later.), or Imida Zopirimijin Hajime Tamaki (which may have 1 to 3 substituents secretions ^a described later ).

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

Z ^a is a chemical structural formula

O

(iv) O H or (v) N NHo

T I O OH

Represents a group represented by

R ^a is a hydrogen atom, C - C ₄ alkyl group, - ₍₄ alkoxy group, a halogen atom, water group may nitro group, which may have an amino group (to be described later substituent T), or C ₇ -C represents an ^ aralkyl group.

m ^a represents an integer of 1 to 5.

The substituent ^a is a CC ₄ alkyl group,-(^ alkoxy group, benzyloxy group, A halogen atom, a hydroxyl group, an acetyl group, a phenylthio group, an alkylthio group, a trifluoromethyl group, a nitro group, an amino group (which may have ^a substituent / ^a as described below), C ₆ -C _{1 (} 37 reel group (may have ^a substituent y ^a to be described later), and C?

-c ^ y represents a group selected from the group consisting of an aralkyl group (which may have a substituent α & described later).

Substituent 5 ^a is, C ₈ alkyl group, (Cu Ararukiru group, C ₆ -C ₁₀ 7 aryl group, C i - aliphatic Ashiru group, C ₈ -C ₁₂ aromatic aliphatic Ashiru group, and C ₇ - Cu aromatic And represents a group selected from the group consisting of aromatic group.

Substituents § ^&, the (^ - ₍₄ alkyl group, - c ₄ alkoxy group, Tei has a halogen atom, a hydroxyl group, a nitro group, phenyl group, triflate Ruo Russia methyl group, and an amino group (substituent / ^a? And a group selected from the group consisting of:

And a salt thereof.

(B) described in JP-A-9-295970,

General formula (I ^b )

[Where,

X ^b represents a benzimidazole group (which may have 1 to 5 substituents ^b described below).

Y ^b represents an oxygen atom or a sulfur atom. Z ^b is a chemical structural formula

(')

O

(iv) O ^ / NH or (v) human NH ₂

Π

And represents a group represented by O.

R ^b is a hydrogen atom, C厂C ₄ alkyl groups, C "C ₄ alkoxy group, a halogen atom, water group, a nitro group, an amino group (to be described later substituent 5 ^b may be in o Nl Yes H ) Or C ₇ -C aralkyl.

m ^b represents an integer of 1 to 5.

Substituent ^b is:-alkyl group, CC ₄ alkoxy group, benzyloxy group, phenol, hydrogen atom, hydroxyl group, acetoxy group, phenylthio group, C factory C ₄ alkylthio group, trifluoromethyl group, nitro group, amino group (which may have a substituent 5 ^b to be described later), -. Ariru group (which may have a substituent § ¹⁵ to be described later.), And is selected from the group consisting of (which may. Optionally having substituents 7 ^b to be described later) C ₇ -Cu aralkyl group Represents a group.

Substituents ^b are -C ₈ alkyl group, (^ -Cu aralkyl group, C ₆ -C ₁₀ aryl group, C aliphatic acyl group, C ₈ -C ₁₂ araliphatic acyl group, and (Cu aromatic acyl group) A group selected from the group consisting of groups is shown.

Substituents 7 ^b is, C厂C ₄ alkyl group, - an alkoxy group, a halogen atom, a hydroxyl group, a nitro group, phenyl group, triflate Ruo Russia methyl group, and amino group (which may have a substituent ^b?. ) Represents a group selected from the group consisting of: ] And a salt thereof.

(C) It is described in Japanese Patent Publication No. 11-193276,

General formula (P)

[In the above formula,

R ^ei is a general formula

Or general formula

[Where,

Shows phenyl group (which may have one to five of the substituents described below.) Or a pyridyl group (which may have 1 to four substituents a ^e to be described later.).

R ^e5 represents a hydrogen atom or a substituent described below.

R ^C6 are hydrogen atom, - alkyl, C ₆ -C ₁₀ 7 aryl group (. Which may have 1 to 3 substituents min / ?. described later) or C ₇ - ₆ Ararukiru group (described later May have 1 to 3 substitutions /? ⁰ ).

^De represents an oxygen atom or a sulfur atom.

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

R ^G2 represents a hydrogen atom or a substituent ^e described later. R ^e3 is a chemical structural formula

O

N U

(iv) O ^ NH or (v) N NH ₂

T I O OH

Represents a group represented by .

A ^c is - represents an alkylene group.

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

Substitution. Are a halogen atom, a hydroxyl group, a C ₆ alkyl group, a halogeno-alkyl group, a C ₆ alkoxy group, a CrCe alkylthio group, an amino group (which may have a substituent described later), C ₃ -C ₁₀ cycloalkyl (may have 1 to 3 substitutions ^ described below), C ₆ -C ₁₀ 7 reel (1 to 3 substitutions /? Described below) and may be), C ₇ -. the C ₁₀ 7 Riruokishi (described later substituent / ?. -?. C ₁₆ Ararukiru (substituents to be described later may have 1 to 3), C _6. May have 1 to 3), C ₇ -C ₁₆ arylalkyloxy (may have 1 to 3 substituents described below), C ₆ -C ₁₀ arylthio group (which may have 1 to 3 substituents min / ?. described later.), C ₆ aliphatic Ashiruokishi group, the nitrogen atom a 4- to 7-membered saturated heterocyclic group containing, ChissoHara 5 or 6-membered aromatic heterocyclic group containing, represents a group selected from the group consisting of nitro group, and shea § cyano group.

Replacement / 5. Represents a halogen atom, a hydroxyl group, C厂C ₆ alkyl group, halogeno -.. Which (] ₆ Al kill groups, C厂C ₆ alkoxy group, an amino group (which may have a later-described substituent §), C And a group selected from the group consisting of a _6- Ci0 aryl group and a nitro group.

Replacement part. The CfC. Alkyl group, optionally substituted C _6- . Reel, replaced Optionally substituted c ₇ -c ₁₆ aralkyl group, -c ₇ aliphatic acyl group, optionally substituted c ₇ -aromatic acyl, optionally substituted c ₈ -c ₁₂ araliphatic acyl, substituted Or-containing cycloalkylcarbonyl and optionally substituted nitrogen atoms

It represents a group selected from the group consisting of a 5- or 6-membered aromatic heterocyclic carbonyl group.

However, 5- [4- [5- (3,5-di-t-butyl-4-hydroxyphenylthio) -3-methyl-3H-imidazo [4,5-b] pyridine-2-ylmethoxy] benzyl ] Excluding thiazolidine-2,4-dione. ]

Or a pharmacologically acceptable salt thereof.

Here, the substituent in “may be substituted” is a halogen atom, a hydroxyl group, Ci

-c ₆ alkyl group, halogeno - alkyl, - alkoxy group, and - c ₆ is 1 to 3 substituents selected from the group consisting § alkylthio group.

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

General formula (I)

[Where,

W represents a hydrogen atom, a -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group (which may have 1 to 5 substituents described below), a monocyclic heteroaromatic group (substituted Or a C ₇ -C ₁₂ aralkyl group (which may have 1 to 5 substituents described later on the aryl).

Represents an oxygen atom or a sulfur atom.

Y represents a = CH- group or a nitrogen atom. Substitution refers to a group selected from the group consisting of -alkyl, alkoxy, halogen, and hydroxyl. ]

Or a pharmacologically acceptable salt thereof.

Here, the “monocyclic heteroaromatic group” refers to a 5- or 6-membered monocyclic aromatic heterocyclic group having one or two nitrogen atoms, for example, pyridyl, virazyl, pyrimidinyl , Pyridazinyl, pivalyl, imidazolyl, and pyrazolyl.

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

From the definition of the group shown above,

If W indicates "C ₆ -C _{1 0} 7 aryl group (which may have one to five of the substituents.)" As the group, for example phenyl, methylphenyl, 2,3,4-trimethyl Phenyl, t-butylphenyl, di-1-butylphenyl, methoxyphenyl, dimethoxyphenyl, fluorophenyl, difluorophenyl, penfluorofluorophenyl, chlorophenyl, dichlorophenyl, 2-, 3- and 4-hydroxyphenyl Enyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-methylphenyl, 2-1-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-hydroxy Phenyl, 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, black naphthyl, and hydroxynaphthyl.

Represents a “C ₇ -C ₂ aralkyl group (which may have 1 to 5 substituents on the aryl).” Examples of the group include pendyl, methylbenzyl, t- Butylpentyl, methoxypentyl, hydroxypentyl, fluorobenzyl, chlorobenzyl, hydroxybenzyl, 4-hydroxy-3,5-dimethylbenzyl, 3,5-di-t-butyl-4-hydroxybenzyl, phenethyl, methylphenethyl, t -Butyl phenyl, methoxyphenyl, hydroxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, 4-phenylbutyl, 4- (methylphenyl) butyl, 4- (hydroxyphenyl) butyl, 6 -(Methylphenyl) hexyl, 6-phenylhexyl, and 6- (hydroxyphenyl) hexyl. C The method for producing the compound having the structure of the above general formula (I) is disclosed in It is described in JP-A-330728, JP-A-9-295970, or JP-A-11-193276.

In the compound having the structure of the general formula (I),

(1)

W is a C factory C ₄ alkyl group, a C ₆ -C ₁₀ aryl group (which may have 1 to 5 substituents), a monocyclic heteroaromatic group (substituents Or a thiazolidinedione conjugate or a C?-^ ₂ aralkyl group (which may have 1 to 5 substituents on the aryl). Its pharmacologically acceptable salts.

(2)

W is a -C ₄ alkyl group, a phenyl group (which may have 1 to 5 substituent (s)), a pyridyl group (which may have 1 to 3 substituent (s)), or A thiazolidinedione compound showing a benzyl group (which may have 1 to 3 substituent (s) on the aryl) or a pharmacologically acceptable salt thereof.

(3)

A thiazolidinedione compound or a pharmacologically acceptable salt thereof, in which W represents a C factory C ₄ alkyl group or a phenyl group (which may have 1 to 5 substituent (s) :).

( Four )

Represents a phenyl group (which may have 1 to 5 substituents). Zindione compound or a pharmacologically acceptable salt thereof.

(Five)

Is a thiazolidinedione compound showing an oxygen atom or its pharmacologically acceptable (6)

A thiazolidinedione compound in which X represents a sulfur atom or a pharmacologically acceptable salt thereof.

(7)

A thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein Y represents one group = CH.

(8)

A thiazolidinedione compound in which Y represents a nitrogen atom or a pharmaceutically acceptable plate thereof.

(9)

A thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein the substituted group represents a group selected from the group consisting of-( ₆ alkyl group, halogen atom, and hydroxyl group. (10)

A thiazolidinedione compound in which the substituent represents a group selected from the group consisting of a -c ₆ alkyl group and a hydroxyl group, or a pharmacologically acceptable salt thereof.

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 (which may have 1 to 5 substituents).

X represents an oxygen atom.

Y represents a = CH- group.

The substituent represents a group selected from the group consisting of a CfC _fi alkyl group and a hydroxyl group. A thiazolidinedione compound or a pharmacologically acceptable salt thereof. More preferably, the PPMa-activating agent of the present invention includes the following compounds, but the PPARa-activating agent of the present invention is not limited to these compounds.

Two In the table above,

Preferably, the exemplified compound number,

1 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) pentyl] thiazolidine-2,4-dione,

3 5- [4- [6- (4-hydroxyphenoxy) -methylpenzimidazole-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

5 5- [4- [6- (3-Hydroxyphenoxy) -methylbenzimidazole-2-ylmethoxy] pentyl] thiazolidine-2,4-dione,

6 5- [4- [6- (4-Hydroxy-3-methylphenoxy) -methylbenzimidazol-2-ylmethoxy] pentyl] thiazolidine-2,4-dione,

9 5- [4- [6- (4-Hydroxy-3,5-dimethylphenoxy)-;!-Methylpenzimidazo-l-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

10 5- [4- [6- (4-Hydroxy-2,3-dimethylphenoxy) -methylbenzimidazol-2-ylmethoxy] pentyl] thiazolidine-2,4-dione,

1 3 5- [4- [6- (4-hydroxy-2,3,5-trimethylphenoxy) -methylbenzimidazole-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

1 4-5- [4- [5- (4-Hydroxy-2,3,5-trimethylphenoxy) -3-methylimidazo [5,4-b] pyridine-2-ylmethoxydipendyl] thiazolidine-2, 4-dione,

1 5 5- [4- [6- (2-chloro-4-Hydroxy-3,5-dimethylphenoxy) -methyl} nzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

16- [4- (6-Penthylfluorophenoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione, and

1 8 5- [4- (6-benzyloxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,

And pharmacologically acceptable salts thereof. More preferably, the exemplified compound number,

1 5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,

6 5- [4- [6- (4-hydroxy-3-methylphenoxy)-;!-Methylbenzimidazole

-2 -ylmethoxy] benzyl] thiazolidine-2,4-dione,

10 5- [4- [6- (4-Hydroxy-2,3-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] pentyl] thiazolidine-2,4-dione,

1 3 5- [4- [6- (4-hydroxy-2,3,5-trimethylphenoxy) -methylpentzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

1 5-5- [4- [6- (2-chloro-4-hydroxy-3,5-dimethylphenoxy) -1-methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione , as well as

1 8 5- [4- (6-Penzyloxy-1-methylbenzimidazol-2-ylmethoxy) pendyl] thiazolidine-2,4-dione,

And pharmacologically acceptable salts thereof.

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

It is described in W095 / 18125 publication,

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 W095 / 18125, and it is described in J. Terasaki et al, Diabetologia, 41 (4), pp400-409 (1998) that the compound activates PPMa. Has been described.

Four It is described in JP-A-6-247945,

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 PPARa by Mauricio J. Reginato et al, J. Bio.Chem, 273 (49), pp32679. -32684 (1998).

It is described in W097 / 31907,

2 (S)-(2-Benzoylphenylamino) -3- [4- [2- (5-methyl-2-phenyloxazo-l-4-yl) ethoxy] phenyl] propionic acid or a drug thereof Physically acceptable salt. The production method of the compound and the fact that the compound has a PPMa activating action are described in W097 / 31907.

It is described in JP-A-9-48771,

N- (4-trifluoromethylpentyl) -5- (2,4-dioxothiazolidine-5-yl) methyl-2-methoxybenzamide or a pharmaceutically acceptable salt thereof. The production method of the compound is described in JP-A-9-48771, and the fact that the compound activates PPMy is described in K. Muratami et al, Diabetes, 47, ppl841-1847 (1998). ing. An RXR activating agent, which is one of the active ingredients of the present invention, is a compound having an action of enhancing the action of a compound having retinoic acid-retinoic acid-like physiological activity (retinoide) by binding to RXR. It is.

As the RXR activating agent as an active ingredient of the present invention, typical examples include, for example, J. Thiboimet et al, Synlett, 1, ppl41-143 (1999), JP-A-6-107542, and The compounds described in W094 / 15901 can be exemplified. The structural formula of a typical compound as an active ingredient of the present invention as an RXR activation agent is shown below.

ATRA 9-cis-retinoic acid

LG100268 Evening Lugretin

The compound name of ATRA is (E, E, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1-cyclohexene-1-yl] -2,4,6 , 8-Nonatetraenoic acid (all-trans-retinoic acid). The method of producing ATRA is described in J. Thibonnet et al, Synlett, 1, ppl4 143 (1999), and ATRA acts on RXR by itself or part of it is converted to 9-cis-retinoic acid. This is described in Japanese Patent Publication No. 10-511948.

9-cis-retinoic acid is described in JP-A-6-107542, and its compound name is (E, E, E) -3,7-dimethyl-9- [2,6,6-trimethyl-1 -Cyclohexene-1-yl]-2,4,6,8-nonatetraenoic acid (9-cis-retinoic acid). The preparation of 9-cis-retinoic acid and the fact that 9-cis-retinoic acid is et al, J. Med. Chem., 37, pp. 408-414 (1994).

LG100268 is described in W094 / 15901, and its compound name is 6- [1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthylene-2) -Yl) cyclopropyl] nicotinic acid. The method for producing the compound and the fact that the compound is an RXR activating agent are described in W094 / 15901.

Lugretin is described in W094 / 15901, and its compound name is 6- [1- (3,5,5,8,8-dimethyl-5,6,7,8-tetrahydronaphthylene). -2-yl) ethenyl] is benzoic acid. The method for producing the compound and the fact that the compound is an RXR activating agent are described in W094 / 15901.

The PPARa activating agent and the RXR activating agent, which are the active ingredients of the present invention, can be converted into a salt 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 and magnesium salts; aluminum salts, iron salts, zinc salts, copper salts, Metal salts such as nickel salts and cobalt salts; inorganic salts such as ammonium salts; t-octylamine salts, dipendylamine salts, morpholine salts, glucosamine salts, phenylglycine alkylester salts, ethylenediamine salts, N-methylglucamine salts, Guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, Ν, Ν'-dibenzylethylenediamine salt, black mouth pro-force salt, pro-force salt, diethanolamine salt, エタノール -benzyl-Ν -Phenethylamine, piperazine, tetramethylammonium, tris Amine salts such as organic salts such as hydroxymethyl) aminomethane salts; hydrohalides such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; nitrates, perchlorates, and sulfates And inorganic salts such as phosphates; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and ethanesulfonic acid; and arylsulfuric acids such as benzenesulfonic acid and トルエン -toluenesulfonic acid. Fonates; salts of amino acids such as glutamic acid, aspartic acid, etc .; fumaric acid, Organic acids such as salts of carboxylic acids such as succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid; and amino acids such as ortinate, glutamate, and aspartate. The salt of the PPM active agent is preferably a hydrohalide or an organic acid salt, and more preferably a hydrochloride.

In addition, the compound of the present invention may be left in the air or recrystallized to absorb water, adsorb water, or form a hydrate. When formed, these are all included in the present invention.

Furthermore, the compounds of the present invention may absorb certain other solvents and form solvates, which are also included in the present invention.

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

Such isomers can be obtained by synthesizing the compound of the present invention using the starting conjugate of each isomer or, if desired, resolving the compound of the present invention by a conventional resolution method or separation method. Can be obtained.

Furthermore, the present invention 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, when the compound having the general formula (I) of the present invention has a phenolic hydroxyl group, a protecting group which can be cleaved in vivo by a biological method such as hydrolysis in a living body. Refers to a protected compound.

"A protecting group that can be cleaved in vivo by a biological method such as hydrolysis" means a free phenolic hydroxyl group or a salt thereof that is cleaved in a human body by a biological method such as hydrolysis. Means a protective group that produces such a derivative or not, Can be determined by administering the compound to an experimental animal by intravenous injection, examining the body fluid of the animal thereafter, and detecting the original compound or a pharmacologically acceptable salt thereof. Such protecting groups include, for example, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, ptyryloxymethyl, bivaloyloxymethyl, 1-formyloxetyl, 1-acetoxethyl, 1- 1- (lower aliphatic acyloxy) lower alkyl groups such as propionyloxyl, 1-butyryloxyl, 1-piparyloxyl, methoxycarbonyloxyloxymethyl, ethoxycarbonyloxyloxymethyl, propoxycarbonyloxyloxymethyl, iso Propoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) 1- (such as 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, l- (t-butoxycarbonyloxy) ethyl Lower alkoxycarbonyloxy) alkyl groups; and fluoridyl groups such as fluoridyl, dimethylfuridyl and dimethoxyfuridyl.

The prevention and treatment of cancer in the present invention is performed by using a PPy activating agent and an RXR activating agent in combination. That is, by using one or more PPMa activating agents and one or more RXR activating agents simultaneously or sequentially, the superior effect compared to each single agent It shows.

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

"Sequentially" means that individual agents are administered one after the other at appropriate intervals Say.

In addition, when there are three or more kinds of one or more PPMase-activating agents and one or more kinds of RXR-activating agents to be administered, `` simultaneously or sequentially '' May be administered simultaneously or sequentially, with two or more being administered simultaneously and the remaining drug being administered sequentially, or two or more being being administered sequentially and the remaining being being administered simultaneously. It may be administered.

The term “cancer” as used herein refers to sarcomas, carcinomas, leukemias, etc. These include fibrosarcoma, liposarcoma, osteosarcoma, angiosarcoma, lung cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, kidney cancer. -Includes liver cancer, lenticular cancer, esophageal cancer, tongue cancer, brain tumor, laryngeal cancer, bladder cancer, ovarian cancer, acute leukemia, chronic leukemia and lymphoma.

The agent of the present invention, which is a PPARa-activating agent and an RXR-activating agent, can be used as such or mixed with an appropriate pharmacologically acceptable excipient, lubricant, etc. -It can be administered orally by tablets or capsules or parenterally by injection or suppository.

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; Cellulose derivatives such as arabia; dextran; organic excipients such as pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium magnesium silicate; calcium hydrogen phosphate Inorganic excipients such as phosphates, carbonates such as calcium carbonate, and 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 bi-gum and gay dandelion; boric acid; adipic acid; Like sodium Sodium sulfate, glycol; fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acid; radium sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; Derivatives may be mentioned.

The dosage form of the PPARa activating agent and the agent that is the MR activating agent used in the present invention is preferably oral administration. Therefore, the two types of drugs can be adjusted individually into separate unit dosage forms, or mixed and physically adjusted into one unit dosage form.

The dosage and the administration ratio of the PPMa activating agent and the RXR activating agent used in the present invention may vary depending on the activity of each drug, the symptoms of patients (warm-blooded animals, especially humans), age, body weight, etc. However, in general, the oral dose of each of the PPMa activating agent and the RXR activating agent per dose is 0.005 mg / kg as a lower limit. Body weight (preferably 0.05 mg / kg body weight), upper limit of 50 Omg / k body weight (preferably 5 mg / kg body weight) 0.001 mg / kg body weight (preferably 0.01 mg / kg body weight) and up to 5 O mg / k body weight (preferably 5 mg / kg body weight) from 1 to It is desirable to administer several times depending on the symptoms.

Also, the administration ratio of the PPMa activating agent to the MR activating agent can vary greatly, but can generally be in the range of 1: 200 to 200: 1 by weight.

(Best mode for carrying out the invention)

Example 1 PPARa activation

A reporter called Luciferase using aP2-12 cells in which a PPMy-responsive gene (enhancer region of aP2, a fat cell differentiation marker gene) has been introduced into CH0 cells (Chain hamhamus varian cells). By Atsushi Yuichi, PPARPAR activation was measured.

aP2-12 Cells were seeded 2 x l0 ⁴ cell / Ueru to 96 © El plate was added test compound at various concentrations dissolved in DMS0 at the same time so that DMS0 concentration of 0.1%. The concentration of the test compound was lnM, IOIIMS lOnOnMs 1〃M, 10 zM. After adding the test conjugate, the cells are cultured for 24 hours, washed with PBS (phosphate buffered saline), and then lysed with a 30〃1 pitkadin cell lysate (Toyo Inki). It was adjusted. Then, 10〃1 of the cell lysate was dispensed into a white plate of Mcrolite 1 (DYNEXTECHN0L0GIES), and luciferase was added to each well by adding 50 ツ 1 of Pitka Gene luminescent substrate solution (Toyo Ink). Activity was measured. Measurements using a luminometer Isseki one ML3000 (Dynatech Laboratorie Co.), test I showing a half amount of a saturated emission amount from the light emission amount obtained _c light emission was measured for 10 seconds from the luminescent substrate solution added 2 seconds The concentration of the arsenic compound is excel (Microsoft)

Calculated as a linear function approximation using EC _{5 for the} PPARa activating effect of the test compound. The value (〃M) was determined.

(Table 2) Test compound PPMa activation

Of the EC _{5 0} value (j) door opening Gris evening Zon 0.90

Mouth jiggle evening zone 0.14

Piogli Evenson 0.73

Exemplary Compound No. 1 hydrochloride 0.042

2 0.0088

3 0.0034 4-hydrochloride 0.008

5-hydrochloride 0.004

6 hydrochloride 0.0026

7 hydrochloride 0.0072

8-hydrochloride 0.0067

9 hydrochloride 0.003

1.0 hydrochloride 0.0025

1 1 hydrochloride 0.0073

1 2 0.0097

1 3 Hydrochloride 0.0022

14 Hydrochloride 0.0036

1 5 hydrochloride 0.0027

1 6 hydrochloride 0.0034

1 7 0.0065

1 8 hydrochloride 0.0064

As is evident from Table 2, the PPARa activating agent of the present invention also shows excellent PPARa activating action in the oral gizzinozone, the oral diglyuzone and the pioglizanzone.

Therefore, the agent of the present invention comprising the combination of the PPMa-activating agent and the RXR-activating agent is a combination of troglisuzone, oral diglyuzone or pioglisuzone and the RXR-activating agent. It is suggested that it has a better cancer cell growth inhibitory effect than any other drug. Example 2 Enhancement of antitumor effect on human acute promyelocytic leukemia cell line HL-60 cells 9 human BALB / c nude mice (female, 6 weeks old) A tumor piece (5 awake x 5 angle) of the HL-60 hematopoietic cell line was transplanted. The test compound was suspended in a 5% saline solution containing 2.5% dimethylacetamide and orally administered once a day on the following day, 4 to 7, 7 to 11, and 14 to 18 days after transplantation, a total of 14 times.

To determine the effect, the short diameter (thigh) and long diameter (fiber) of the tumor were measured with an electronic digital caliper, and the tumor growth inhibition rate (GI%) 21 days after transplantation was evaluated by the following formula.

G I (%) = (1 -A / B) X 1 0 0

A: Average tumor volume on day 21 of compound administration group (*)

B: Average tumor volume of the 21th control group (*)

*: Tumor volume means 1/2 X [tumor major axis] X [tumor minor axis] ² .

Table 3 summarizes the results.

(Table 3)

From Table 3, it can be seen that the proliferation of human acute promyelocytic leukemia cells was more pronounced in the combined use of the hydrochloride of Exemplified Compound 1 as the PPMa activating agent and talgretin as the RXR activating agent than with both compounds. It was clarified that the administration significantly suppressed it. That is, according to Table 3, administration of evening lugretin alone has no effect on the suppression of proliferation of human acute promyelocytic leukemia cells. However, evening lugretin, when used in combination with the hydrochloride salt of Exemplified Compound 1, clearly enhances the inhibitory effect of single administration of the hydrochloride salt of Exemplified Compound 1 on the proliferation of human acute promyelocytic leukemia cells. Therefore, the embodiment The experimental results in 2 show a synergistic inhibitory effect on cancer cell growth by the combined use of a PPARa activating agent and an RXR activating agent. Example 3 Enhancement of Antitumor Effect on Human Gastric Cancer St-40 Cell

Ten BALB / c nude mice (female, 6 weeks of age) per group were subcutaneously implanted with tumor pieces (5 × 5 thigh angle) 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 after transplantation: 1 to 4 days, 7 to 11 days, 14 to 18 days, 21 to 25 days 1 day Oral administration was performed 19 times in total.

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

The results are summarized in Table 4.

(Table 4)

From Table 4, it can be seen that the proliferation of human gastric cancer cells is more remarkable in the combined administration of both compounds than the hydrochloride of Exemplified Compound 1 as the PPMa activating agent and LG100268 as the RXR activating agent, respectively. It became clear that it was suppressed.

That is, according to Table 4, administration of LG100268 alone has little 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 administering the hydrochloride of Exemplified Compound 1 alone was clarified. Crab has been strengthened. Therefore, the experimental results of Example 3 show a synergistic inhibitory effect on cancer cell proliferation by the combined use of the PPMa activating agent and the RXR activating agent. Example 4 _ Increase in cancer cell growth inhibitory activity against human acute promyelocytic leukemia cells HL-60

HL-60 cells were seeded at 1 × 10 ³ cells / well in a 96-well plate, and at the same time, various concentrations of drugs dissolved in DMS0 were added to the solution so that the DMS0 concentration was 0.1%. The concentration of the drug was examined at 10〃M of Exemplified Compound 18 as a PPARa activator and at 1〃M of LG100268 as an RXR activator (n = 4). After the drug was added, the cells were cultured for 5 days. Then, was added MTS (flop port Mega Ltd.) reagent each 40 l / well, 37 ° ( , after 2 hours incubation, the 0D _49Q the MICROPLATE READER of each well (BIO RAD) used in 5% C0 ₂ under 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 (cells + DMS0) —Average absorbance (medium)) 100 Results are shown in Table 5.

(Table 5) Cancer cell growth inhibition rate

Test compound

(%)

PPAR activating agent Exemplified compound 1 8 40

RXR-specific ligand LG100268 18 Exemplified compound 18 Combination administration + 58

LG100268 Table 5 shows that the proliferation of human acute promyelocytic leukemia cells is a PPMa activator. It was revealed that the combined administration of Compound 18 and the RXR activator, LG100268, was significantly suppressed by the combined administration of both compounds, as compared to the single administration. Example 5 Enhancement of cancer cell growth inhibitory activity against human colon cancer cells C0L-2-JCK

COL-2-JCK cells were seeded at 4 × 10 ³ cells / well in a 96-well plate, and at the same time, various concentrations of drugs dissolved in the image were added so that the DMS0 concentration was 0.1%. The concentration of the drug was examined using Exemplified Compound 18 as a PPARa activator at 10〃M and Talgretin or LG100268 as an EXR activator (n = 4). After drug addition, cells were cultured for 4 days. Then, 50% trichloro mouth acetic acid (Wako Pure Chemical Industries) is added at 50〃l / well, fixed at 4 ° C for 1 hour, washed with tap water, and washed with 0.4% sulfolo-damine B (Molecular Probe). A 1% acetic acid solution was added at 150 zl / well, stained at room temperature for 30 minutes, and washed with 1% acetic acid. After the plate was air-dried, 150 μl / well of 10 mM Tris was added, and 0D49 ₍₎ 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 (cells + drug)-Average absorbance (medium))] (Average absorbance (cells + MS0)-Average absorbance (medium))] X 100

The results are shown in Table 6.

(Table 6) Test compound Cancer cell growth inhibition rate (%)

PPAR activating agent Exemplified compound 1 8 14

RXR specific ligand LG 100268 2

Illustrative compound 18

Combination + 37

LG100268

RXR-specific ligand taldaletin 7

Illustrative compound 18

Combination. + 40

Taldaletin From Table 6, it can be seen that human colon carcinoma cells proliferate in combination with a bifunctional activator rather than single-agent administration of the exemplified compound 18 as a PPMa activator and LG100268 or MR lugretin as activators. It was clarified that these were significantly suppressed. Formulation example

A drug containing the compound of the present invention as an active ingredient can be produced, for example, by the following method.

5- [4- (6-methoxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride (Hydrochloride of Exemplified Compound 1) 4.0 mg, Lugretin lOO Omg, lactose 44.0 Big Corn starch 50. Og and magnesium stearate 2.0 mg were mixed together, and the mixture was compressed with a tableting machine to give a tablet of 400 m / tablet. (Possibility of industrial use)

The pharmaceutical composition of the present invention obtained by simultaneously or sequentially using one or more PPMa activating agents and one or two or more RXR activating agents can be used for cancer (particularly, It is useful in preventing and treating human cancer.

That is, the present invention provides a method for simultaneously or sequentially using one or more PPMa activating agents and one or more RXR activating agents as a novel antitumor substance. Which provides a pharmaceutical composition.

Claims

Claims Use of one or more PPMa-activating agents and one or more RXR-activating agents simultaneously or sequentially for the prevention or treatment of cancer According to a pharmaceutical composition. In claim 1,

The PPM active agent has the general formula (I)

[Where,

W represents a hydrogen atom, a C ₆ C ₆ alkyl group, a C _6- aryl group (which may have 1 to 5 substituents described below), a monocyclic heteroaromatic group (substituted Or a C ₇ -C ₁₂ aralkyl group (which may have 1 to 5 substituted moieties described later on the aryl). Show.

X represents an oxygen atom or a sulfur atom.

Y represents a 2 C H— group or a nitrogen atom.

Represents a group selected from the group consisting of a -C ₆ alkyl group, a-(] ₆ alkoxy group, a halogen atom, and a hydroxyl group.] Or a pharmacologically acceptable thiazolidinedione compound represented by the formula: A pharmaceutical composition for preventing or treating cancer which is a salt. In claim 2,

A thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein W represents a-() ₄ alkyl group or a phenyl group (which may have 1 to 5 substituents), or prevent or prevent cancer. A pharmaceutical composition for treating.

A pharmaceutical composition for preventing or treating cancer, which is a thiazolidinedione compound or a pharmacologically acceptable salt thereof, wherein W represents a phenyl group (which may have 1 to 5 substituted moieties). . In any one of claims 2 to 4,

A pharmaceutical composition for preventing or treating cancer, which is a thiazolidinedione compound showing an oxygen atom or a pharmacologically acceptable salt thereof. In any one of claims 2 to 5,

A pharmaceutical composition for preventing or treating cancer, wherein Y is a thiazolidinedione compound representing a = CH- group or a pharmacologically acceptable salt thereof. In any one selected from claims 2 to 6, the substituents Higa, - C ₆ alkyl group, a halogen atom, and thiazolidinedione compound or a pharmacologically represents a group selected from the group consisting of hydroxyl group A pharmaceutical composition for preventing or treating cancer, which is an acceptable salt. In claim 1,

PPARa activating agent, 5- [4- (6-methoxy-1-methylbenzimidazole-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,

5- [4- [6- (4-hydroxy-3-methylphenoxy) -1-methylbenzimidazole-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

5- [4- [6- (4-hydroxy-2,3-dimethylphenoxy) -methylbenzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione,

5-[4- [6- (4-hydroxy-2,3,5-trimethylphenoxy) -1-methylbenzimidazole-2-ylmethoxy] pentyl] thiazolidine-2,4-dione;

5- [4- [6- (2-chloro-4--4-hydroxy-3,5-dimethylphenoxy) -1-methyl-benzimidazol-2-ylmethoxy] benzyl] thiazolidine-2,4-dione or ,

5-[4- (6-benzyloxy-1-methylbenzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione,

Or a pharmaceutical composition for preventing or treating cancer, which is a pharmacologically acceptable salt thereof. In claim 1,

PPMa activating agent,

4- [4- [2- (2-phenyl-5-methyl-4-oxazolyl) ethoxy] benzyl-3,5-isoxazolidinedione,

5- [6- (2-fluorobenzyloxy) -2-naphthyl] methyl-2,4-thiazolidy

2 (S)-(2-benzylphenylamino) -3- [4- [2- (5-methyl-2-phenyloxazolyl-4-yl) ethoxy] phenyl] propionic acid or

N- (4-trifluoromethylbenzyl) -5- (2,4-dioxothiazolidine-5- Yl) methyl-2-methoxybenzamide,

Or a pharmaceutical composition for preventing or treating cancer, which is a salt that is physiologically acceptable. In any one of claims 1 to 9,

A pharmaceutical composition for preventing or treating cancer, wherein the agent for acting as an RXR activator is ATRA, 9-cis-retinoic acid, LG100268 or evening lugretin. In any one of claims 1 to 9,

A pharmaceutical composition for preventing or treating cancer in which the agent for activating RXR is LG100268 or lugretin. 2. A method for producing a medicament for preventing or treating cancer, according to claim 1.

Use of the pharmaceutical composition according to any one of the preceding claims. A method for preventing or treating cancer, which comprises administering a pharmacologically effective amount of the pharmaceutical composition according to any one of claims 1 to 11 to a warm-blooded animal.