JP2007001912A - Substituted phenylpropionic acid derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound which can activate the target gene transcription activity of a peroxisome proliferator-activated receptor (PPAR), namely can reinforce the transcription-activating ability of the PPAR, and to provide a peroxisome proliferator-activated receptor transcription-activating agent containing the compound as an active ingredient. <P>SOLUTION: This peroxisome proliferator-activated receptor transcription-activating agent contains a substituted phenylpropionic acid derivative represented by the general formula (1) or its pharmaceutically acceptable salt or their hydrates as an active ingredient. Therein, R1 is trifluoromethyl, trifluoromethoxy, or phenoxy which is not substituted or may be substituted; R2 is a halogen atom; R3 is a 1 to 3C lower alkoxy; R4 is a 1 to 6C lower alkyl; X is -CH<SB>2</SB>NHCO- or -CONHCH<SB>2</SB>-. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a substituted phenylpropionic acid derivative or an addition salt thereof or a hydrate thereof that is effective as a human peroxisome proliferator activated receptor (PPAR) agonist in the treatment of lipid metabolism, sugar metabolism abnormality, cancer treatment, etc. The present invention relates to a pharmaceutical composition containing these compounds.

  Peroxisome proliferator-activated receptor (PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily and induces transcription of a target gene in a ligand-dependent manner. That is, when a ligand binds to PPAR, PPAR binds to a PPAR responsive element (PPRE) present in the promoter region of the target gene, and transcription of the target gene is induced.

  So far, three types of isoforms (α type, β (or δ) type, and γ type) having different tissue distributions have been identified in various animal species including humans. Among these, PPARα is distributed in the liver, kidney, etc. where fatty acid catabolism is high, and high expression is observed particularly in the liver. When transcription of the target gene is induced by PPARα, Reduction, increase in HDL cholesterol, weight loss, promotion of angiogenesis, etc. are induced. In addition, PPARβ is ubiquitously expressed in tissues in the body centering on nerve cells, and when transcription of a target gene is induced by PPARβ, fat burning in skeletal muscle, increase in energy metabolism, etc. are induced. . PPARγ is highly expressed in adipocytes, and when transcription of a target gene is induced by PPARγ, adipogenesis, improvement of insulin resistance, enhancement of angiogenesis, etc. are induced. Thus, each isoform of PPAR performs a specific function in a specific organ or tissue.

［式中、Ｒ^１は炭素数１から４の低級アルキル基、炭素数１から３の低級アルコキシ基、トリフルオロメチル基、トリフルオロメトキシ基、無置換または置換基を有していても良いフェニル基、無置換または置換基を有していても良いフェノキシ基、無置換または置換基を有していても良いベンジルオキシ基を表し、Ｒ^２は水素原子、炭素数１から４の低級アルキル基、炭素数１から３の低級アルコキシ基を表し、Ｒ^３は炭素数１から３の低級アルコキシ基を表し、Ａ部分の結合様式は−ＣＨ_２ＣＯＮＨ−、−ＮＨＣＯＣＨ_２−、−ＣＨ_２ＣＨ_２ＣＯ−、−ＣＨ_２ＣＨ_２ＣＨ_２−、−ＣＨ_２ＣＨ_２Ｏ−、−ＣＯＮＨＣＨ_２−、−ＣＨ_２ＮＨＣＨ_２−、−ＣＯＣＨ_２Ｏ−、−ＯＣＨ_２ＣＯ−、−ＣＯＣＨ_２ＮＨ−及び−ＮＨＣＨ_２ＣＯ−を表す］で表される置換フェニルプロピオン酸誘導体（特許文献１）、及び下記式：

［式中、Ｒ^１は炭素数１から４の低級アルキル基、炭素数１から３の低級アルコキシ基、トリフルオロメチル基、トリフルオロメトキシ基、無置換または置換基を有していても良いフェニル基、無置換または置換基を有していても良いフェノキシ基、無置換または置換基を有していても良いベンジルオキシ基を表し、Ｒ^２は炭素数１から４の低級アルキル基、２，２，２−トリフルオロエチル基、炭素数１から３の低級アルコキシ基、フェノキシ基、炭素数１から３の低級アルキルチオ基、フェニルチオ基、ベンジルチオ基を表し、Ｒ^３はＲ^２が炭素数１から４の低級アルキル基、２，２，２−トリフルオロエチル基の場合には水素原子または炭素数１から４の低級アルキル基を表し、Ｒ^２が炭素数１から３の低級アルコキシ基、フェノキシ基、炭素数１から３の低級アルキルチオ基、フェニルチオ基、ベンジルチオ基の場合には水素原子を表し、Ｒ^４は炭素数１から３の低級アルコキシ基を表す］で表される置換フェニルプロピオン酸誘導体（特許文献２）が知られている。
国際公開ＷＯ０１／０９２２０１号パンフレット 国際公開ＷＯ００／７５１０３号パンフレット Conventionally, as a PPARα agonist, the following formula:

[Wherein R ¹ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, an unsubstituted or optionally substituted phenyl group. A phenoxy group which may be unsubstituted or substituted, a benzyloxy group which may be unsubstituted or substituted, R ² is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms Represents a lower alkoxy group having 1 to 3 carbon atoms, R ³ represents a lower alkoxy group having 1 to 3 carbon atoms, and the bonding mode of the A moiety is —CH ₂ CONH—, —NHCOCH ₂ —, —CH ₂ CH _{2. CO -, - CH 2 CH 2} CH 2 -, - CH 2 CH 2 O -, - CONHCH 2 -, - CH 2 NHCH 2 -, - COCH 2 O -, - OCH 2 CO -, - COCH 2 NH- and − HCH-substituted phenylpropionic acid derivative represented by ₂ represents a CO-] (Patent Document 1), and the following formula:

[Wherein R ¹ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, a trifluoromethyl group, a trifluoromethoxy group, an unsubstituted or optionally substituted phenyl group. A phenoxy group which may be unsubstituted or substituted, a benzyloxy group which may be unsubstituted or substituted, R ² is a lower alkyl group having 1 to 4 carbon atoms, 2, 2,2-trifluoroethyl group, a lower alkoxy group having 1 to 3 carbon atoms, a phenoxy group, a lower alkylthio group having 1 to 3 carbon atoms, a phenylthio group, a benzylthio group, R ³ is R ² is from 1 to 4 carbon atoms 4 lower alkyl group, 2,2,2-trifluoro in the case of ethyl group represents a lower alkyl group having 1 to 4 hydrogen atoms or carbon atoms, R ² is a lower alkoxy group having 1 to 3 carbon atoms, phenol Shi group, a lower alkylthio group having 1 to 3 carbon atoms, a phenylthio group, a hydrogen atom in the case of benzylthio group, a substituted phenylpropionic acid R ⁴ is represented by 'represents a lower alkoxy group with carbon atoms of 1 to 3 Derivatives (Patent Document 2) are known.
International Publication WO01 / 092201 Pamphlet International Publication WO00 / 75103 Pamphlet

  The present invention relates to a novel compound capable of activating the transcription activity of a target gene possessed by a peroxisome proliferator-activated receptor (PPAR) (that is, capable of enhancing the transcription activation ability of PPAR), and peroxy containing the compound as an active ingredient It is an object of the present invention to provide a transcriptional activator of a some proliferator-responsive receptor.

[式中、Ｒ１はトリフルオロメチル基、トリフルオロメトキシ基、又は無置換若しくは置換基を有していても良いフェノキシ基を表し、Ｒ２はハロゲン原子を表し、Ｒ３は炭素数１〜３の低級アルコキシ基を表し、Ｒ４は炭素数１〜６の低級アルキル基を表し、Ｘは−ＣＨ_２ＮＨＣＯ−又は−ＣＯＮＨＣＨ_２−を表す。]で表される置換フェニルプロピオン酸誘導体若しくはその薬剤上許容される塩又はそれらの水和物。
（２）一般式（１）：

[式中、Ｒ１はトリフルオロメチル基、トリフルオロメトキシ基、無置換又は置換基を有していても良いフェノキシ基を表し、Ｒ２はハロゲン原子を表し、Ｒ３は炭素数１〜３の低級アルコキシ基を表し、Ｒ４は炭素数１〜６の低級アルキル基を表し、Ｘは−ＣＨ_２ＮＨＣＯ−又は−ＣＯＮＨＣＨ_２−を表す。]で表される置換フェニルプロピオン酸誘導体若しくはその薬剤上許容される塩又はそれらの水和物を有効成分として含有するペルオキシゾーム増殖剤応答性受容体の転写活性化剤。 In order to achieve the above object, the present invention provides the following compounds and drugs.
(1) General formula (1):

[Wherein R 1 represents a trifluoromethyl group, a trifluoromethoxy group, or an unsubstituted or optionally substituted phenoxy group, R 2 represents a halogen atom, and R 3 represents a lower group having 1 to 3 carbon atoms. Represents an alkoxy group, R 4 represents a lower alkyl group having 1 to 6 carbon atoms, and X represents —CH ₂ NHCO— or —CONHCH ₂ —. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(2) General formula (1):

[Wherein R1 represents a trifluoromethyl group, a trifluoromethoxy group, an unsubstituted or optionally substituted phenoxy group, R2 represents a halogen atom, and R3 represents a lower alkoxy having 1 to 3 carbon atoms. R4 represents a lower alkyl group having 1 to 6 carbon atoms, and X represents —CH ₂ NHCO— or —CONHCH ₂ —. A peroxysome proliferator-activated receptor comprising a substituted phenylpropionic acid derivative represented by the formula:

  According to the present invention, a novel compound capable of activating the transcriptional activity of a target gene possessed by a peroxisome proliferator-activated receptor (PPAR) (that is, capable of enhancing the transcriptional activation ability of PPAR), and the compound as an active ingredient Peroxisome proliferator-activated receptor transcriptional activators are provided.

  In the general formula (1), R1 may be any of a trifluoromethyl group, a trifluoromethoxy group, and an unsubstituted or optionally substituted phenoxy group. A phenoxy group which may have a group or a substituent is preferable.

  In the general formula (1), the “unsubstituted or optionally substituted phenoxy group” represented by R1 is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group. A linear or branched lower alkyl group having 1 to 6 carbon atoms such as isobutyl group, s-butyl group, t-butyl group, n-pentyl group, isopentyl group, t-pentyl group and neopentyl group; A linear or branched lower alkoxy group having 1 to 3 carbon atoms such as a group, an ethoxy group, an n-propoxy group or an isopropoxy group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; Although it can have 1 type, or 2 or more types of substituents among fluoromethyl groups etc., the kind of substituent is not limited to these. The number of substituents is usually 1 to 5, preferably 1 to 3, and the substitution position may be arbitrary, but is preferably 4-position, 3, 4-position, or 3, 4, 5-position.

  In the general formula (1), examples of the halogen atom represented by R2 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a fluorine atom or a chlorine atom is preferable.

  In the general formula (1), the lower alkoxy group having 1 to 3 carbon atoms represented by R3 is, for example, a straight chain having 1 to 3 carbon atoms such as a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group. Among them, a methoxy group or an ethoxy group is preferable.

  In the general formula (1), examples of the lower alkyl group having 1 to 6 carbon atoms represented by R4 include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s- Examples thereof include linear or branched lower alkyl groups having 1 to 6 carbon atoms such as butyl group, t-butyl group, n-pentyl group, isopentyl group, t-pentyl group, and neopentyl group. An ethyl group or an n-propyl group is preferred.

In general formula (1), X may be either —CH ₂ NHCO— or —CONHCH ₂ —.

  The pharmaceutically acceptable salt of the substituted phenylpropionic acid derivative represented by the general formula (1) is not particularly limited, and a conventional salt, for example, an alkali metal salt such as sodium salt, potassium salt, lithium salt; Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts.

  The substituted phenylpropionic acid derivative represented by the general formula (1) includes optical isomers based on the propionic acid moiety, and all such optical isomers and mixtures thereof are included in the scope of the present invention. Is.

Among the compounds represented by the general formula (1) of the present invention, the compound represented by the general formula (1a) in which X is —CH ₂ NHCO— can be produced, for example, by the following method (Scheme 1). ).

[式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記と同義である。]
で表される化合物は、一般式（２）：

［式中、Ｒ３及びＲ４は前記と同義であり、Ｒ５は、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｓ−ブチル基、ｔ−ブチル基等の炭素数１〜４の直鎖状又は分岐鎖状の低級アルキル基を表す。］で表される公知の化合物（例えばＷＯ００／７５１０３号参照）と、一般式（４）：

［式中、Ｒ１及びＲ２は前記と同義である。］で表される化合物とを反応させ（第一工程）、得られた一般式（３）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される化合物のＣＯＯＲ５部位を加水分解する（第二工程）ことにより製造することができる。 That is, the general formula (1a):

[Wherein, R1, R2, R3 and R4 have the same meanings as described above. ]
The compound represented by general formula (2):

[Wherein, R3 and R4 are as defined above, and R5 represents a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, etc. A linear or branched lower alkyl group having 1 to 4 carbon atoms is represented. A known compound represented by the general formula (4), for example (see WO 00/75103):

[Wherein, R 1 and R 2 have the same meanings as described above. And a compound represented by the general formula (3):

[Wherein, R1, R2, R3, R4 and R5 have the same meanings as described above. It can manufacture by hydrolyzing the COOR5 site | part of the compound represented by (2nd process).

  For the reaction in the first step, the reactivity of the carboxyl group of the compound represented by the general formula (1a) is used as it is, or the carboxyl group is converted into a reactive inducing group and the reactivity is used. Can be implemented.

  Examples of the “reactive induction group for carboxyl group” include acid chloride, acid bromide, acid anhydride, carbonylimidazole and the like. The reaction utilizing the reactivity of the carboxyl group-reducing derivative is carried out by using a base (for example, an alkali metal hydride such as sodium hydride; an alkali metal such as sodium hydroxide) in a solvent such as dioxane or N, N-dimethylformamide. It can be carried out in the presence or absence of hydroxide; alkali metal carbonate such as potassium carbonate; organic base such as pyridine and triethylamine). The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 60 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (1a), Preferably it is 1-2 molar equivalent.

  The reaction using the reactivity of the carboxyl group as it is is carried out in a solvent such as methylene chloride, chloroform, dioxane, N, N-dimethylformamide, in the presence of a condensing agent, in the presence or absence of a base, in the presence of an additive. Or it can carry out in absence. Examples of the condensing agent include N, N-dimethylimidazolinium chloride, dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphate azide, and carbonyldioxide. Examples include imidazole. Examples of the base include alkali metal hydroxides such as sodium hydroxide; alkali metal carbonates such as potassium carbonate; organic bases such as pyridine and triethylamine. Examples of the additive include N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, and the like. The reaction temperature at this time is usually -20 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (1a), Preferably it is 1-2 molar equivalent.

  The hydrolysis reaction in the second step can be carried out under alkaline conditions. The alkaline conditions are usually pH 8 to 14, preferably pH 9 to 13. For adjusting the alkaline conditions, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. The reaction temperature at this time is usually 0 to 80 ° C., preferably room temperature to 60 ° C., and the reaction time is usually 1 to 48 hours, preferably 3 to 24 hours.

Among the compounds represented by the general formula (1), the compound represented by the general formula (1b) in which X is —CONHCH ₂ — can be produced, for example, by the following method (Scheme 2).

[式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記と同義である。]で表される化合物は、一般式（５）：

［式中、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される公知の化合物（ＷＯ０１／９２２０１号参照）と、一般式（７）：

［式中、Ｒ１及びＲ２は前記と同義である。］で表される化合物とを反応させ（第三工程）、得られた一般式（６）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される化合物のＣＯＯＲ５部位を加水分解する（第四工程）ことにより製造することができる。 That is, general formula (1b):

[Wherein, R1, R2, R3 and R4 have the same meanings as described above. The compound represented by the general formula (5):

[Wherein, R3, R4 and R5 have the same meanings as described above. And a known compound represented by general formula (7):

[Wherein, R 1 and R 2 have the same meanings as described above. And a compound represented by the general formula (6):

[Wherein, R1, R2, R3, R4 and R5 have the same meanings as described above. ] It can manufacture by hydrolyzing the COOR5 site | part of the compound represented by (4th process).

  For the reaction in the third step, the reactivity of the carboxyl group of the compound represented by the general formula (7) is used as it is, or the carboxyl group is converted into a reactive inducing group and the reactivity is used. Can be implemented.

  Examples of the “reactive induction group for carboxyl group” include acid chloride, acid bromide, acid anhydride, carbonylimidazole and the like. The reaction utilizing the reactivity of the carboxyl group-reducing derivative is carried out by using a base (for example, an alkali metal hydride such as sodium hydride; an alkali metal such as sodium hydroxide) in a solvent such as dioxane or N, N-dimethylformamide. It can be carried out in the presence or absence of hydroxide; alkali metal carbonate such as potassium carbonate; organic base such as pyridine and triethylamine). The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 60 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (7) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (1b), Preferably it is 1-2 molar equivalent.

  The reaction using the reactivity of the carboxyl group as it is is carried out in a solvent such as methylene chloride, chloroform, dioxane, N, N-dimethylformamide, in the presence of a condensing agent, in the presence or absence of a base, in the presence of an additive. Or it can carry out in absence. Examples of the condensing agent include N, N-dimethylimidazolinium chloride, dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphate azide, and carbonyldioxide. Examples include imidazole. Examples of the base include alkali metal hydroxides such as sodium hydroxide; alkali metal carbonates such as potassium carbonate; organic bases such as pyridine and triethylamine. Examples of the additive include N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, and the like. The reaction temperature at this time is usually -20 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (7) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (1b), Preferably it is 1-2 molar equivalent.

  The hydrolysis reaction in the fourth step can be carried out under alkaline conditions. The alkaline conditions are usually pH 8 to 14, preferably pH 9 to 13. For adjusting the alkaline conditions, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. The reaction temperature at this time is usually 0 to 80 ° C., preferably room temperature to 60 ° C., and the reaction time is usually 1 to 48 hours, preferably 3 to 24 hours.

Among the compounds represented by the general formula (1), the optically active compound represented by the general formula (1c) in which X is —CH ₂ NHCO— and R4 represents the configuration of S is, for example, It can be produced by the method (Scheme 3).

[式中、Ｒ１は、Ｒ２、Ｒ３及びＲ４は前記と同義である。]で表される化合物は、一般式（８）：

［式中、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される公知の化合物（ＷＯ００／７５１０３号参照）と、一般式（４）：

［式中、Ｒ３及びＲ４は前記と同義である。］で表される化合物とを反応させ（第五工程）、得られた一般式（９）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される化合物のＣＯＯＲ５部位を加水分解する（第六工程）ことにより製造することができる。 That is, general formula (1c):

[Wherein R1, R2, R3 and R4 have the same meanings as described above. The compound represented by the general formula (8):

[Wherein, R3, R4 and R5 have the same meanings as described above. A known compound represented by the general formula (4):

[Wherein, R3 and R4 have the same meanings as described above. And the compound represented by the general formula (9):

[Wherein, R1, R2, R3, R4 and R5 have the same meanings as described above. ] Can be produced by hydrolyzing the COOR5 site of the compound represented by formula (sixth step).

  The reaction in the fifth step uses the reactivity of the carboxyl group of the compound represented by the general formula (8) as it is, or converts the carboxyl group into a reactivity-inducing group and uses the reactivity. Can be implemented.

  Examples of the “reactive induction group for carboxyl group” include acid chloride, acid bromide, acid anhydride, carbonylimidazole and the like. The reaction utilizing the reactivity of the carboxyl group-reducing derivative is carried out by using a base (for example, an alkali metal hydride such as sodium hydride; an alkali metal such as sodium hydroxide) in a solvent such as dioxane or N, N-dimethylformamide. It can be carried out in the presence or absence of hydroxide; alkali metal carbonate such as potassium carbonate; organic base such as pyridine and triethylamine). The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 60 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (8), Preferably it is 1-2 molar equivalent.

  The reaction using the reactivity of the carboxyl group as it is is carried out in a solvent such as methylene chloride, chloroform, dioxane, N, N-dimethylformamide, in the presence of a condensing agent, in the presence or absence of a base, in the presence of an additive. Or it can carry out in absence. Examples of the condensing agent include N, N-dimethylimidazolinium chloride, dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphate azide, and carbonyldioxide. Examples include imidazole. Examples of the base include alkali metal hydroxides such as sodium hydroxide; alkali metal carbonates such as potassium carbonate; organic bases such as pyridine and triethylamine. Examples of the additive include N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, and the like. The reaction temperature at this time is usually -20 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (8), Preferably it is 1-2 molar equivalent.

  The hydrolysis reaction in the sixth step can be carried out under alkaline conditions. The alkaline conditions are usually pH 8 to 14, preferably pH 9 to 13. For adjusting the alkaline conditions, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. The reaction temperature at this time is usually 0 to 80 ° C., preferably room temperature to 60 ° C., and the reaction time is usually 1 to 48 hours, preferably 3 to 24 hours.

Among the compounds represented by the general formula (1), the optically active compound represented by the general formula (1d) in which X is —CH ₂ NHCO— and R4 represents the configuration of R is, for example, It can be produced by a method (Scheme 4).

[式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記と同義である。]で表される化合物は、一般式（１０）：

［式中、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される公知の化合物（ＷＯ２００５／００９９４２号参照）と、一般式（４）：

［式中、Ｒ１及びＲ２は前記と同義である。］で表される化合物とを反応させ（第七工程）、得られた一般式（１１）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は前記と同義である。］で表される化合物のＣＯＯＲ５部位を加水分解する（第八工程）ことにより製造することができる。 That is, the general formula (1d):

[Wherein, R1, R2, R3 and R4 have the same meanings as described above. The compound represented by general formula (10):

[Wherein, R3, R4 and R5 have the same meanings as described above. A known compound represented by the general formula (4):

[Wherein, R 1 and R 2 have the same meanings as described above. And the compound represented by the general formula (11):

[Wherein, R1, R2, R3, R4 and R5 have the same meanings as described above. ] It can manufacture by hydrolyzing the COOR5 site | part of the compound represented by (8th process).

  In the reaction of the seventh step, the reactivity of the carboxyl group of the compound represented by the general formula (10) is used as it is, or the carboxyl group is converted into a reactive inducing group and the reactivity is used. Can be implemented.

  Examples of the “reactive induction group for carboxyl group” include acid chloride, acid bromide, acid anhydride, carbonylimidazole and the like. The reaction utilizing the reactivity of the carboxyl group-reducing derivative is carried out by using a base (for example, an alkali metal hydride such as sodium hydride; an alkali metal such as sodium hydroxide) in a solvent such as dioxane or N, N-dimethylformamide. It can be carried out in the presence or absence of hydroxide; alkali metal carbonate such as potassium carbonate; organic base such as pyridine and triethylamine). The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 60 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (10), Preferably it is 1-2 molar equivalent.

  The reaction using the reactivity of the carboxyl group as it is is carried out in a solvent such as methylene chloride, chloroform, dioxane, N, N-dimethylformamide, in the presence of a condensing agent, in the presence or absence of a base, in the presence of an additive. Or it can carry out in absence. Examples of the condensing agent include N, N-dimethylimidazolinium chloride, dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphate azide, and carbonyldioxide. Examples include imidazole. Examples of the base include alkali metal hydroxides such as sodium hydroxide; alkali metal carbonates such as potassium carbonate; organic bases such as pyridine and triethylamine. Examples of the additive include N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine, and the like. The reaction temperature at this time is usually -20 to 100 ° C, preferably 0 to 50 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours. Moreover, the addition amount of the compound represented by General formula (4) is 0.5-3 molar equivalent normally with respect to the compound represented by General formula (10), Preferably it is 1-2 molar equivalent.

  The hydrolysis reaction in the eighth step can be carried out under alkaline conditions. The alkaline conditions are usually pH 8 to 14, preferably pH 9 to 13. For adjusting the alkaline conditions, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. The reaction temperature at this time is usually 0 to 80 ° C., preferably room temperature to 60 ° C., and the reaction time is usually 1 to 48 hours, preferably 3 to 24 hours.

  The transcriptional activator of peroxisome proliferator-responsive receptor (PPAR) is a substituted phenylpropionic acid derivative represented by the general formula (1), a pharmaceutically acceptable salt thereof, or one of these hydrates. It is good also as an active ingredient, and it is good also considering 2 or more types as an active ingredient.

  The transcriptional activator of PPAR may be composed of only the substituted phenylpropionic acid derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, It is formulated according to a conventional method together with one or more types of carriers and / or additives that are acceptable for the above. When formulating, the amount of the active ingredient in the formulation is usually 0.1 to 50% by mass, preferably 0.5 to 20% by mass.

  Examples of pharmaceutically acceptable carriers include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, xanthan gum. Arabic gum, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose and the like.

  Additives used in the formulation include, for example, fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, excipients, stabilizers, bactericides, and buffering agents. , Tonicity agents, chelating agents, pH adjusters, surfactants and the like, and these additives are appropriately selected depending on the dosage unit form of the preparation. Of these, components used in normal protein preparations, such as stabilizers, bactericides, buffers, isotonic agents, chelating agents, pH adjusters, surfactants and the like are preferably selected.

  It is desirable to use the administration route and the dosage form which are most effective in the treatment. Examples of administration routes include oral administration; parenteral administration such as buccal, intratracheal, rectal, subcutaneous, intramuscular, intravenous, etc. Examples of dosage forms include tablets, capsules, and granules. Powders, inhalants, syrups, emulsions, suppositories, injections and the like.

  The dose and frequency of administration vary depending on the intended therapeutic effect, administration method, treatment period, age, body weight, etc., but the dose is usually 0.001 to 100 mg / kg body weight per day for an adult in terms of the amount of active ingredient The number of administrations can be appropriately selected from a range of once to several times a day. The administration target animal is not particularly limited, and examples thereof include mammals including humans.

  The transcriptional activator of PPAR can activate transcription of a target gene by PPAR such as PPARα, δ, and γ, that is, can enhance the transcription activation ability of PPAR. The transcription activation ability of PPAR means the ability of PPAR to activate transcription of a target gene by binding to a PPAR response element (PPAR) existing upstream of the target gene. Examples of target genes that can activate transcription of PPAR include acyl Co-A oxidase (ACO), lipoprotein lipase (LPL), fatty acid binding protein (FABP), and adiponectin (AD). When transcription of the target gene is activated by PPARα, a decrease in blood neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced, and transcription of the target gene is activated by PPARδ When fat transcription in skeletal muscle, increase in energy metabolism, etc. are induced and transcription of the target gene is activated by PPARγ, adipogenesis, improvement of insulin resistance, enhancement of angiogenesis, etc. are induced . Therefore, the transcriptional activator of PPAR is useful for the prevention and treatment of diseases such as hyperlipidemia, diabetes, obesity, arteriosclerosis, and cancer.

EXAMPLES Hereinafter, although this invention is demonstrated based on an Example, the scope of the present invention is not limited by these Examples.
Example 1 2-Ethyl-3- [4-methoxy-3- [N-[[2-fluoro-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl] propionic acid

  Ethyl 3- (3-carboxy-4-methoxyphenyl) -2-ethylpropionate (compound described in Example 1 of WO 00/75103; 400 mg, 1.43 mmol) was dissolved in 10 mL of dehydrated dichloromethane and dissolved at -10 ° C. To -15 ° C. Triethylamine (0.5 mL, 3.58 mmol) was added with stirring. Next, ethyl chlorocarbonate (185 mg, 1.71 mmol) was dissolved in 10 mL of dehydrated dichloromethane and added dropwise. After stirring at −10 ° C. for 10 minutes, 2-fluoro-4- (trifluoromethyl) benzylamine hydrochloride (392 mg, 1.71 mmol) was added, followed by washing with 10 mL of dehydrated dichloromethane. After stirring at −10 ° C. for 10 minutes, the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent n-hexane: ethyl acetate = 1: 1 v / v), and 270 mg of 2-ethyl-3- [4-methoxy-3- [N-[[2-fluoro Ethyl-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl] propionate was obtained as an oil.

  The obtained compound was mixed with 30 mL of ethanol and 30 mL of 1 mol / L sodium hydroxide aqueous solution, stirred at 50 ° C. for 6 hours, and then concentrated under reduced pressure. The residue was poured into dilute hydrochloric acid. The resulting precipitate was filtered and dried, and then recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 165 mg (27%) of the title compound.

Melting point 102-103 ° C .;
Elemental analysis _{C 21 H 21 F 4 NO 4} (427.40):
Calculated C, 59.02; H, 4.95; N, 3.28.
Found C, 58.80; H, 5.00; N, 3.01 .;
High resolution mass spectrometry value C ₂₁ H ₂₂ F ₄ NO ₄ (M + H) :
Calculated value 428.1485
Actual value 428.1453

Example 2 2-Ethyl-3- [4-methoxy-3- [N-[[3-fluoro-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl] propionic acid

The title compound was obtained in the same manner as in Example 1.
Melting point 120-121 ° C;
Elemental analysis _{C 21 H 21 F 4 NO 4} (427.40):
Calculated C, 59.02; H, 4.95; N, 3.28.
Found C, 58.85; H, 5.03; N, 3.21 .;
High resolution mass spec C ₂₆ H ₂₆ F ₂ NO ₅ (M + H):
Calculated value 470.1779
Actual value 470.1762

Example 3 N- [3-Fluoro-4- (4-fluorophenoxy)] benzylphthalimide

  4-fluorophenol (1.12 g, 10.0 mmol), 3,4-difluorobenzaldehyde (1.42 g, 10.0 mmol) and 30 mL of N, N-dimethylformamide were mixed, and the mixture was heated and stirred at 150 ° C. for 5 hours. . The reaction solution was poured into ice water with stirring, and after further stirring, the precipitate was filtered. The filtrate was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 2.34 g of crude 3-fluoro-4 (4-fluorophenoxy) benzaldehyde.

  The obtained compound was dissolved in 50 mL of ethanol, and sodium borohydride (378 mg, 10.0 mmol) was added little by little under stirring with ice cooling. After completion of the addition, the mixture was stirred for 30 minutes under ice cooling and then stirred overnight at room temperature. Next, the reaction solution was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 2.26 g of crude 3-fluoro-4 (4-fluorophenoxy) benzyl alcohol.

  The obtained compound and 10.0 mL of thionyl chloride were mixed and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was mixed with N, N-dimethylformamide (30 mL) and potassium phthalimide (2.00 g, 10.8 mmol), and heated and stirred at 100 ° C. for 3 hours. The reaction solution was poured into ice water with stirring and stirred for a while. The precipitate was filtered and dried, and recrystallized with a mixed solvent of ethyl acetate and ethanol to obtain 3.00 g (82%) of the title compound.

Melting point 103-105 ° C;
High resolution mass spectrometry value C ₂₁ H ₁₃ F ₂ NO ₃ : (M + H):
Calculated value 365.0863
Actual value 365.0815

Ｎ−[３−フルオロ−４−(４−フルオロフェノキシ)]ベンジルフタルイミド(３．００ｇ, ８．２１ｍｍｏｌ)、ヒドラジン・水和物(０．５１ｇ, １６．０ｍｍｏｌ)及びエタノール１００ｍＬを混合し、６時間加熱還流した。反応液に１ｍｏｌ／Ｌ塩酸５０ｍＬを加え、氷冷下３０分撹拌後、析出した不溶物を濾別した。濾液を減圧下濃縮し、析出物を濾過し、酢酸エチルで洗浄した。濾過物をエタノールから再結晶し、表題化合物を１．９５ｍｇ（８７％）得た。 Example 4 N- [3-Fluoro-4- (4-fluorophenoxy)] benzylamine hydrochloride

N- [3-fluoro-4- (4-fluorophenoxy)] benzylphthalimide (3.00 g, 8.21 mmol), hydrazine hydrate (0.51 g, 16.0 mmol) and ethanol 100 mL were mixed, and 6 Heated to reflux for hours. 50 mL of 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was stirred for 30 minutes under ice cooling. The filtrate was concentrated under reduced pressure, and the precipitate was filtered and washed with ethyl acetate. The filtrate was recrystallized from ethanol to give 1.95 mg (87%) of the title compound.

Mp 148-150 ° C;
High resolution mass spec C ₂₁ H ₁₃ F ₂ NO ₃ (M + H):
Calculated value 365.0863
Actual value 365.0815

Example 5 2-Ethyl-3- [4-methoxy-3- [N-[[3-fluoro-4- (4-fluorophenoxy)] phenyl] methyl] carbamoyl] phenyl] propionic acid

The title compound was obtained in the same manner as in Example 1.
Mp 148-149 ° C;
Elemental analysis _{C 21 H 22 F 3 NO 4} · 1 / 3H 2 O (475.50):
Calculated C, 65.67; H, 5.44; N, 2.95.
Found C, 65.79; H, 5.33; N, 2.93 .;
High resolution mass spec C ₂₆ H ₂₆ F ₂ NO ₅ (M + H):
Calculated value 470.1779
Actual value 470.1762

Example 6 [3-Fluoro-4- (4-fluorophenoxy)] benzoic acid

  4-fluorophenol (1.12 g, 10.0 mmol), methyl 3,4-difluorobenzoate (1.72 g, 10.0 mmol) and 30 mL of N, N-dimethylformamide were mixed and heated at 150 ° C. for 5 hours. Stir. The reaction solution was poured into ice water with stirring, and the precipitate was filtered after further stirring. The filtrate was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. After filtration, it was concentrated to obtain crude methyl 3-fluoro-4 (4-fluorophenoxy) benzoate.

  The resulting compound was mixed with 30 mL of ethanol and 30 mL of 1 mol / L aqueous sodium hydroxide solution and stirred at 50 ° C. for 6 hours, and then the reaction solution was concentrated under reduced pressure. The residue was poured into ice-cooled dilute hydrochloric acid with stirring. The resulting precipitate was filtered and dried, and then recrystallized with a mixed solvent of n-hexane and ethyl acetate to obtain 2.00 g (80%) of the title compound.

Mp 148-149 ° C;
High resolution mass spec C ₁₃ H ₈ F ₂ O ₃ (M + H):
Calculated value 250.0442
Actual value 250.0397

Example 7 2-Ethyl-3- [4-methoxy-3- [N-[[3-fluoro-4- (4-fluorophenoxy)] benzoyl] amino] carbamoylmethyl] phenyl] propionic acid

  Ethyl 3- (3-carboxyaminomethyl-4-methoxyphenyl) -2-ethylpropionate hydrochloride (compound described in Example 108 of WO 01/92201; 350 mg, 1.16 mmol), triethylamine (0.56 mL) , 4.00 mmol), 3-fluoro-4- (4-fluorophenoxy) benzoic acid (Example 6; 351 mg, 1.40 mmol) and 15 mL of dehydrated dichloromethane were mixed and stirred with ice-cooling, 2-chloro-1,3 -Imidazolinium chloride (254 mg, 1.50 mmol) was added in small portions and washed with 5 mL of dehydrated dichloromethane. After stirring for 10 minutes under ice cooling, the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent n-hexane: ethyl acetate = 1: 1 v / v to ethyl acetate only), and 2-ethyl-3- [4-methoxy-3- [N-[[3 -Fluoro-4- (4-fluorophenoxy)] benzoyl] amino] carbamoylmethyl] phenyl] ethyl propionate was obtained as an oil.

  The obtained compound was mixed with 30 mL of ethanol and 30 mL of 1 mol / L sodium hydroxide aqueous solution, stirred at 50 ° C. for 8 hours, and then concentrated under reduced pressure. The residue was poured into ice-cooled dilute hydrochloric acid. The resulting precipitate was filtered and dried, and then recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 105 mg (19%) of the title compound.

Mp 148-150 ° C;
Elemental analysis _{C 21 H 21 F 4 NO 4} · 1 / 3H 2 O (469.49):
Calculated C, 65.67; H, 5.44; N, 2.95.
Found C, 65.57; H, 5.33; N, 2.65 .;
High resolution mass spec C ₂₆ H ₂₆ F ₂ NO ₃ (M + H):
Calculated value 470.1779
Actual value 470.1727

Example 8 (S)-(+)-2-Ethyl-3- [4-methoxy-3- [N-[[2-fluoro-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl ] Propionic acid

  [5 (2S, 4′R)]-2-methoxy-5-[[2- (2-oxo-4-benzyloxazolidin-3-yl) carbonyl] butyl] benzoic acid (Example 167 of WO 00/75103) 600 mg, 1.46 mmol), triethylamine (0.61 mL, 4.37 mmol) and dichloromethane 25 mL were mixed, and ethyl chlorocarbonate (0.17 mL, 1.75 mmol) was added dropwise with stirring under ice cooling. After stirring at 0 ° C. for 20 minutes, 2-fluoro-4- (trifluoromethyl) benzylamine hydrochloride (335 mg, 1.75 mmol) was added little by little and washed with 5 mL of dichloromethane. After stirring at 0 ° C. for 30 minutes, the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed successively with 10% citric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent n-hexane: ethyl acetate = 1: 1 v / v), and [3 (2S), 4R] -3- [2-ethyl-3- [4-methoxy- 3- [N-[[2-Fluoro-4- (trifluoromethyl)] carbamoyl] phenyl] propionyl] -4-benzyloxazolidine-2-one was obtained as a colorless oil. This compound was dissolved in 20 mL of a mixed solvent of tetrahydrofuran and water (4: 1 v / v), purged with argon and then ice-cooled. Under stirring, 30% hydrogen peroxide solution (0.70 mL, 6.9 mmol) was added dropwise. Next, lithium hydroxide (110 mg, 2.63 mmol) was dissolved in 3 mL of water and added dropwise. The mixture was further stirred for 1 hour under ice cooling. Sodium sulfite (1.00 g, 9.63 mmol) was dissolved in 4 mL of water and added dropwise to the reaction solution. The reaction solution was poured into water, acidified with hydrochloric acid, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent n-hexane: ethyl acetate = 2: 3 v / v) to obtain 263 mg (yield 42%) of the target compound as colorless crystals.

Melting point 102-103 ° C .;
Elemental analysis _{C 21 H 21 F 4 NO 4} · 1 / 6H 2 O (430.401):
Calculated C, 58.60; H, 5.00; N, 3.25.
Found C, 58.34; H, 5.05; N, 3.39 .;
High resolution mass spec C ₂₁ H ₂₂ F ₄ NO ₄ (M + H) ::
Calculated value 428.1485
Actual value 428.1453

Example 9 (S)-(+)-2-Ethyl-3- [4-methoxy-3- [N-[[3-fluoro-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl ] Propionic acid

The title compound was obtained in the same manner as in Example 8.
Melting point 120-121 ° C;
Elemental analysis _{C 21 H 21 F 4 NO 4} (427.40):
Calculated C, 59.02; H, 4.95; N, 3.28.
Found C, 58.97; H, 5.12; N, 3.16 .;
High resolution mass spec C ₂₁ H ₂₂ F ₄ NO ₄ (M + H):
Calculated value 428.1485
Actual value 428.1490

Example 10 (R)-(−)-2-Ethyl-3- [4-methoxy-3- [N-[[2-fluoro-4- (trifluoromethyl)] phenyl] methyl] carbamoyl] phenyl ] Propionic acid

  [5 (2R, 4 ′S)]-2-methoxy-5-[[2- (2-oxo-4-benzyloxazolidin-3-yl) carbonyl] butyl] benzoic acid (WO2005) in the same manner as in Example 8. The compound described in Example 2 of No./009942 was used as a starting material to give the title compound.

Melting point 108-110 ° C .;
Elemental analysis _{C 21 H 21 F 4 NO 4} · 1 / 3H 2 O (433.41):
Calculated C, 58.20; H, 5.04; N, 3.23.
Found C, 58.27; H, 4.99; N, 3.14 .;
High resolution mass spec C ₂₁ H ₂₂ F ₄ NO ₄ (M + H):
Calculated value 428.1485
Actual value 428.1519

[Example 10] Transcriptional activation of human peroxisome proliferator-responsive receptor (PPAR) Human embryonic kidney cells (HEK293) cultured in Dulbecco's modified Eagle medium (FCS / DMEM) containing 10% defatted bovine serum A receptor plasmid that expresses a fusion protein of a yeast transcription factor (GAL4) DNA binding region and a ligand binding region of each subtype (α, δ, γ) of human PPAR, and its reporter plasmid; A standard β-galactosidase plasmid was co-transfected in the serum-free state by the calcium phosphate method. Thereafter, test compounds (Examples 1, 2, 5, 7 to 10) were added, and after 16 hours, luciferase activity and β-galactosidase activity were measured and corrected with an internal standard.

As a result of evaluation by this test method, the compounds of the present invention (Examples 1, 2, 5, 7 to 10) showed EC ₅₀ values of several hundred nM or less for human PPARα. EC ₅₀ values of several μM were shown for human PPARδ. EC ₅₀ values of several μM were shown for human PPARγ. This indicates that the compounds of the present invention (Examples 1, 2, 5, 7 to 10) have a strong transcriptional activation effect on human peroxisome proliferator-responsive receptors. From the above results, it was shown that the substituted phenylpropionic acid derivatives of the present invention are a novel group of compounds having an excellent human PPAR transcription activation action. Since these compounds of the present invention have an agonistic activity against human PPAR, the lipid-lowering drugs described above, particularly lipid-lowering drugs in the liver, inhibitors against the progression of arteriosclerosis, anti-obesity drugs, insulin resistance-improving drugs, anti-cancers It can be said that the compound is effective as a medicine.

Claims (2)

General formula (1):

[Wherein R 1 represents a trifluoromethyl group, a trifluoromethoxy group, or an unsubstituted or optionally substituted phenoxy group, R 2 represents a halogen atom, and R 3 represents a lower group having 1 to 3 carbon atoms. Represents an alkoxy group, R 4 represents a lower alkyl group having 1 to 6 carbon atoms, and X represents —CH ₂ NHCO— or —CONHCH ₂ —. ]
Or a pharmaceutically acceptable salt thereof, or a hydrate thereof. General formula (1):

[Wherein R1 represents a trifluoromethyl group, a trifluoromethoxy group, an unsubstituted or optionally substituted phenoxy group, R2 represents a halogen atom, and R3 represents a lower alkoxy having 1 to 3 carbon atoms. R4 represents a lower alkyl group having 1 to 6 carbon atoms, and X represents —CH ₂ NHCO— or —CONHCH ₂ —. ]
A peroxisome proliferator-responsive receptor transcriptional activator comprising a substituted phenylpropionic acid derivative represented by the formula: or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.