JP5147071B2 - α-Substituted phenylpropionic acid derivatives - Google Patents

Description

  The present invention relates to α-substituted phenylpropionic acid derivatives and their addition salts or their hydrates that are effective for lipid metabolism, treatment of abnormal sugar metabolism, cancer treatment, etc. as human peroxisome proliferator-activated receptor ligands, and their The present invention relates to a pharmaceutical composition containing a compound.

Peroxisome proliferator-activated receptor (PPAR, hereinafter referred to as PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, and transcription of a target gene is dependent on a ligand. Induce. That is, when a ligand binds to PPAR, PPAR binds to a PPAR response element (PPAR) present in the promoter region of the target gene, and transcription of the target gene is induced.
So far, three types of isoforms with different tissue distributions (α type, β (or δ, hereinafter referred to as δ type), and γ type) 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, PPARδ is ubiquitously expressed in tissues in the body centering on nerve cells. When PPARδ induces transcription of a target gene, 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.

  That is, each isoform of PPAR is expected to contribute to alleviation of various symptoms known as metabolic syndrome such as improvement of fat metabolism and insulin resistance by inducing transcription of each target gene. ing. So-called fibrates such as fenofibrate, bezafibrate and clofibrate are already known as exogenous ligands for PPARα, and so-called thiazolidine-based agents such as troglitazone and pioglitazone are known as exogenous ligands for PPARγ. . In addition to the fibrates and thiazolidines, several substituted phenylpropionic acid derivatives have been reported as compounds targeting each PPAR isoform (see Patent Documents 1 to 5).

WO01 / 092201 WO00 / 75103 WO2004 / 0567748 WO2004 / 046091 WO03 / 051821

The present invention provides a novel compound capable of enhancing the transcription activation ability of all peroxisome proliferator-responsive receptors α, δ and γ (hereinafter referred to as PPARα, δ and γ) and a method for producing the same, An object of the present invention is to provide a transcription activator for a peroxisome proliferator-responsive receptor comprising the compound as an active ingredient.
Another object of the present invention is to provide a method for treating and / or preventing a disease using the compound.

[式中、Ｒ１はトリフルオロメチル基、無置換又は置換基を有していても良いフェニル基、炭素数４から８の環状アルキル基、無置換又は置換基を有していても良いアダマンチル基、カルボラニル基又はダイアマンチル基を表し、Ｒ２は水素原子又はハロゲン原子を表し、Ｒ３は炭素数１〜１０のアルコキシ基、ベンジルオキシ基を表し、Ｒ４は炭素数１〜６の低級アルキル基を表し、Ｒ５は水素原子又はハロゲン原子を表す。]
で表されるα―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、無置換又は置換基を有していても良いフェニル基、炭素数４から８の環状アルキル基、無置換又は置換基を有していても良いアダマンチル基、カルボラニル基又はダイアマンチル基を表し、Ｒ２は水素原子又はハロゲン原子を表し、Ｒ３は炭素数１〜１０のアルコキシ基、ベンジルオキシ基を表し、Ｒ４は炭素数１〜６の低級アルキル基を表し、Ｒ５は水素原子又はハロゲン原子を表す。]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。The present inventors have created a novel drug that is effective and highly safe as a therapeutic agent for various diseases characterized as lifestyle diseases such as hyperlipidemia, diabetes, hypertension, obesity, or metabolic syndrome. As a result of extensive research in the development of compounds that act as agonists of PPAR, the substituted phenylpropionic acid derivatives represented by the following general formulas have excellent ligand activity for all of PPARα, δ and γ. As a result, the present invention was completed.
That is, the present invention
(1) General formula (1):

[Wherein, R1 is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, a cyclic alkyl group having 4 to 8 carbon atoms, an unsubstituted or optionally substituted adamantyl group. , A carboranyl group or a diamantyl group, R2 represents a hydrogen atom or a halogen atom, R3 represents an alkoxy group having 1 to 10 carbon atoms, a benzyloxy group, R4 represents a lower alkyl group having 1 to 6 carbon atoms, R5 represents a hydrogen atom or a halogen atom. ]
An α-substituted phenylpropionic acid derivative represented by the formula: or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
(2) General formula (1):

[Wherein, R1 is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, a cyclic alkyl group having 4 to 8 carbon atoms, an unsubstituted or optionally substituted adamantyl group. , A carboranyl group or a diamantyl group, R2 represents a hydrogen atom or a halogen atom, R3 represents an alkoxy group having 1 to 10 carbon atoms, a benzyloxy group, R4 represents a lower alkyl group having 1 to 6 carbon atoms, R5 represents a hydrogen atom or a halogen atom. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient, a transcription activator for a peroxisome proliferator-responsive receptor.

The compound of the present invention has an activity of enhancing the ability to activate transcription of target genes of the α, δ and γ types among the peroxisome proliferator-responsive receptors.
Therefore, according to the present invention, a novel compound capable of activating the transcriptional activity of a target gene possessed by PPAR (that is, capable of enhancing the transcriptional activation ability of PPAR), and a peroxisome proliferator-responsive receptor comprising the compound as an active ingredient A transcription activator is provided.

In addition, a prophylactic or therapeutic agent for lifestyle-related diseases (for example, diabetes, hypertension, obesity, arteriosclerosis, etc.) comprising the compound of the present invention as an active ingredient is provided.
Furthermore, a drug having a medicinal effect for alleviating various symptoms characterized as metabolic syndrome, which comprises the compound of the present invention as an active ingredient, is provided.

In general formula (1), R1 may have a trifluoromethyl group, an unsubstituted or substituted phenyl group, a cyclic alkyl group having 4 to 8 carbon atoms, an unsubstituted or substituted group. Any of a good adamantyl group, carboranyl group and diamantyl group may be used, but among these, a cyclohexyl group or an unsubstituted adamantyl group is preferable. Examples of the substitution position include 2-position, 3-position, and 4-position, but 4-position is particularly preferable.
In the general formula (1), in the hydrogen atom and halogen atom represented by R2, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a fluorine atom or hydrogen Atoms are preferred.

In General formula (1), as a C1-C10 alkoxy group represented by R3, C1-C10, such as a methoxy group, an ethoxy group, n-propoxy group, an isopropoxy group, a hexyloxy group, etc. Of these, a methoxy group, an n-propoxy group or an n-butoxy 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 the general formula (1), in the hydrogen atom and halogen atom represented by R5, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a fluorine atom or a hydrogen atom Atoms are preferred.

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.

The compound represented by the general formula (1) of the present invention can be produced, for example, by the following method (Scheme 1).

[式中、Ｒ１はトリフルオロメチル基、無置換又は置換基を有していても良いフェニル基、炭素数４から８の環状アルキル基、無置換又は置換基を有していても良いアダマンチル基、カルボラニル基又はダイアマンチル基を表し、Ｒ２は水素原子又はハロゲン原子を表し、Ｒ３は炭素数１〜１０の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、Ｒ５は水素原子又はハロゲン原子を表す。]
で表される化合物は、一般式（２）：

［式中、Ｒ３、Ｒ４及びＲ５は前記と同義であり、Ｒ６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ＷＯ０１／９２２０１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、Ｒ５及びＲ６は前記と同義である。］で表される化合物のＣＯＯＲ６部位を加水分解する（第２工程）ことにより製造することができる。
第１工程の反応は、一般式（１）で表される化合物が有するカルボキシル基の反応性をそのまま利用するか、又は当該カルボキシル基を反応性誘導基に変換し、その反応性を利用して実施することができる。That is, the general formula (1):

[Wherein, R1 is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, a cyclic alkyl group having 4 to 8 carbon atoms, an unsubstituted or optionally substituted adamantyl group. Represents a carboranyl group or a diamantyl group, R2 represents a hydrogen atom or a halogen atom, R3 represents an alkoxy group having 1 to 10 carbon atoms, R4 represents a lower alkyl group having 1 to 6 carbon atoms, and R5 represents a hydrogen atom. Or represents a halogen atom. ]
The compound represented by general formula (2):

[Wherein, R3, R4 and R5 are as defined above, and R6 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. Represents a linear or branched lower alkyl group having 1 to 4 carbon atoms such as. And a known compound represented by general formula (4):

[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, R5 and R6 have the same meanings as described above. ] It can manufacture by hydrolyzing the COOR6 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 (1) 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 (2), 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.

  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.

Moreover, the compound represented by General formula (1) can be manufactured with the following method, for example (scheme 2).

[式中、Ｒ１はトリフルオロメチル基、無置換又は置換基を有していても良いフェニル基、炭素数４から８の環状アルキル基、無置換又は置換基を有していても良いアダマンチル基、カルボラニル基又はダイアマンチル基を表し、を表し、Ｒ２は水素原子又はハロゲン原子を表し、Ｒ３は炭素数１〜１０の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、Ｒ５は水素原子又はハロゲン原子を表す。]
で表される化合物は、一般式（５）：

［式中、Ｒ３、Ｒ４、Ｒ５及びＲ６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（６）：

［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３工程）、得られた一般式（３）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は前記と同義である。］で表される化合物のＣＯＯＲ６部位を加水分解する（第４工程）ことにより製造することができる。That is, the general formula (1):

[Wherein, R1 is a trifluoromethyl group, an unsubstituted or optionally substituted phenyl group, a cyclic alkyl group having 4 to 8 carbon atoms, an unsubstituted or optionally substituted adamantyl group. Represents a carboranyl group or a diamantyl group, R2 represents a hydrogen atom or a halogen atom, R3 represents an alkoxy group having 1 to 10 carbon atoms, R4 represents a lower alkyl group having 1 to 6 carbon atoms, R5 Represents a hydrogen atom or a halogen atom. ]
The compound represented by general formula (5):

[Wherein, R3, R4, R5 and R6 have the same meanings as described above. And a known compound represented by general formula (6):

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

[Wherein, R1, R2, R3, R4, R5 and R6 have the same meanings as described above. ] It can manufacture by hydrolyzing the COOR6 site | part of the compound represented by (4th process).

The reaction in the third step involves the presence of triethylsilane as a reducing agent in the presence of an acid (eg, trifluoroacetic acid or trifluoromethanesulfonic acid) in a solvent such as toluene, benzene, acetonitrile, dioxane, or N, N-dimethylformamide. Can be implemented below. The reaction temperature at this time is usually -20 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.
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 R4 represents the steric configuration of S can be produced, for example, by the following method (Scheme 3). ).

[式中、Ｒ１は、Ｒ２、Ｒ３、Ｒ４及びＲ５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、Ｒ５及びＲ６前記と同義である。］で表される化合物（ＷＯ００／７５１０３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５工程）、得られた一般式（９）：

［式中、 Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は前記と同義である。］で表される化合物のＣＯＯＲ６部位を加水分解する（第６工程）ことにより製造することができる。
第５工程の反応は、一般式（８）で表される化合物が有するカルボキシル基の反応性をそのまま利用するか、又は当該カルボキシル基を反応性誘導基に変換し、その反応性を利用して実施することができる。That is, general formula (1c):

[Wherein R1, R2, R3, R4 and R5 are as defined above. The compound represented by the general formula (8):

[Wherein, R3, R4, R5 and R6 have the same meanings as described above. And a compound represented by the general formula (7):

[Wherein, R 1 and R 2 have the same meanings as described above. And the compound represented by the general formula (9):

[Wherein, R1, R2, R3, R4, R5 and R6 have the same meanings as described above. ] It can manufacture by hydrolyzing the COOR6 site | part of the compound represented by (6th process).
For the reaction in the fifth step, the reactivity of the carboxyl group of the compound represented by the general formula (8) is used as it is, or the carboxyl group is converted into a reactivity-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 (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.

  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.

  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.

The compound of the present invention represented by the general formula (1) can enhance the transcription activation ability of the target gene by PPARα, δ, and γ. 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, by incorporating the compound of the present invention as an active ingredient, it can be used as a transcription activator of peroxisome proliferator-activated receptor (PPAR). Furthermore, by including the compound of the present invention as an active ingredient, it is characterized as a state in which lifestyle-related diseases such as obesity, hyperlipidemia, hyperglycemia (diabetes), hypertension, arteriosclerosis are easily caused. In addition, it can be used as a drug having medicinal effects for alleviating various symptoms of metabolic syndrome or cancer.
The drug may contain one or more kinds of substituted phenylpropionic acid derivatives represented by the general formula (1), pharmaceutically acceptable salts or hydrates thereof. Further, when the compound of the present invention represented by the general formula (1) is formulated, it is usually contained in the preparation so as to be 0.1 to 50% by mass, preferably 0.5 to 20% by mass. Is done.

The compounds of the present invention can be used as therapeutic agents for specific diseases in the form of pharmaceutical compositions that do not adversely affect the living body. Such compositions typically include a pharmaceutically acceptable carrier in addition to the compound of the present invention.
“Pharmaceutically acceptable carriers” are those suitable for pharmaceutical administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, agents that act isotonically to delay adsorption and the like. Examples of preferred for diluting the carrier and the carrier include, but are not limited to, water, saline, finger solution, dextrose solution, collagen, human serum albumin, organic solvent, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, Carboxyvinyl polymer, sodium alginate, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petroleum jelly, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol , Lactose and the like. Non-aqueous media such as liposomes and non-volatile oils are also used. In addition, certain compounds that protect or promote the activity of the compounds of the present invention may be included in the composition.

The pharmaceutical composition according to the present invention includes intravenous, intradermal, subcutaneous, oral (including inhalation, etc.), transdermal and transmucosal administration, and is formulated to be suitable for a therapeutically appropriate route of administration. It becomes. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application include, but are not limited to, sterile diluents such as water for injection, saline solutions, non-volatile oils, polyethylene glycols, Glycerin, propylene glycol, or other synthetic solvents, benzyl alcohol or other preservatives such as methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, soothing agents such as benzalkonium chloride, procaine hydrochloride, ethylenediaminetetraacetic acid Chelating agents such as (EDTA), buffering agents such as acetate, citrate, or phosphate, and agents for osmotic pressure adjustment such as sodium chloride or dextrose.
The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations are contained in ampoules, glass or plastic disposable syringes or multiple dose vials.

  Pharmaceutical compositions suitable for injection include sterile aqueous solutions (water soluble) or dispersion media and sterile powders for the preparation of sterile injectable solutions or dispersion media at the time of use. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, or phosphate buffered saline (PBS). When used as an injection, the composition must be sterile and must be fluid enough to be administered with a syringe. The composition must be stable to chemical changes, corrosion, and the like during formulation and storage, and must prevent contamination from microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures. For example, using a coating agent such as lectin, maintaining a required particle size in the dispersion medium, and maintaining a proper fluidity by using a surfactant. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal can be used to prevent microbial contamination. In addition, polyalcohols such as sugar, mannitol, sorbitol, and agents that maintain isotonicity such as sodium chloride may be included in the composition. Compositions that can delay adsorption include agents such as aluminum monostearate and gelatin.

  Sterile injectable solutions are prepared by adding the required ingredients alone or in combination with other ingredients to the required amount of the active compound in a suitable solvent and sterilizing. Generally, a dispersion medium is prepared by incorporating the active compound into a sterile medium that contains a basic dispersion medium and the other necessary ingredients described above. Methods for preparing a sterile powder for preparing a sterile injectable solution include vacuum drying and lyophilization to prepare a powder containing the active ingredient and any desired ingredients derived from the sterile solution. .

Oral compositions include inert diluents or carriers that are not harmful when incorporated into the body. Oral compositions are, for example, contained in gelatin capsules or compressed into tablets. For oral treatment, the active compound is incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a flowable carrier, and the composition in the flowable carrier is applied orally. In addition, pharmaceutically compatible binding agents, and / or adjuvant materials may be included.
Tablets, pills, capsules, troches and the like may contain any of the following components or compounds with similar properties: excipients such as microcrystalline cellulose, binding such as gum arabic, tragacanth or gelatin Agents; bulking agents such as alginic acid, PRIMOGEL or corn starch such as starch or lactose; lubricants such as magnesium stearate or STRROTES; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or peppermint, methyl A fragrance additive such as salicylic acid or orange flavor.

  The compounds of the present invention can be prepared as sustained release formulations such as delivery systems encapsulated in implantable tablets and microcapsules using a carrier that can prevent immediate removal from the body. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such materials can be readily prepared by those skilled in the art. Liposome suspensions can also be used as pharmaceutically acceptable carriers. Useful liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanol (PEG-PE) through a filter of appropriate pore size to obtain a size suitable for use, and reverse phase. Purified by evaporation.

In the prevention or treatment of a specific disease with the compound of the present invention, the appropriate dosage level depends on the condition of the patient to be administered, the administration method, etc., but can be easily optimized by those skilled in the art. It is.
In the case of injection administration, for example, it is preferable to administer about 0.1 μg / kg to about 500 mg / kg of the patient's body weight per day, and it will generally be possible to administer a single dose or divided into multiple doses. Preferably, the dosage level is about 0.1 μg / kg to about 250 mg / kg per day, more preferably about 0.5 μg to about 100 mg / kg per day.
For oral administration, the composition is preferably provided in the form of a tablet containing 1.0 to 1000 mg of active ingredient, preferably 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750. 0, 800.0, 900.0 and 1000.0 mg. The compounds are administered on a regimen of 1 to 4 times daily, preferably once or twice daily.

  A pharmaceutical composition or formulation must consist of uniform unit doses to ensure a constant dose. A unit dose is a unit formulated with a pharmaceutically acceptable carrier, including a single dose effective for treating a patient. The unit dosage of the present invention is determined by the physical and chemical characteristics of the compound to be formulated, the expected therapeutic effect, and the formulation considerations specific to the compound. .

  The pharmaceutical composition of the present invention can be included in the form of a kit in a container or pack together with instructions for administration. When the pharmaceutical composition according to the present invention is supplied as a kit, different constituents of the pharmaceutical composition are packaged in separate containers and mixed immediately before use. The reason why the components are packaged separately in this way is to enable long-term storage without losing the function of the active component.

  Reagents contained in the kit are supplied in any type of container in which the components remain active for an extended period of time, are not adsorbed by the container material, and are not subject to alteration. For example, a sealed glass ampoule includes a buffer packaged under a neutral and non-reactive gas such as nitrogen gas. Ampoules are composed of glass, polycarbonate, organic polymers such as polystyrene, ceramics, metals, or any other suitable material commonly used to hold reagents. Examples of other suitable containers include simple bottles made from similar materials such as ampoules, and packaging materials that are internally lined with foil such as aluminum or an alloy. Other containers include test tubes, vials, flasks, bottles, syringes, or the like. The container has a sterile access port such as a bottle having a stopper that can be penetrated by a hypodermic needle.

  The kit also includes instructions for use. Instructions for using the kit comprising the pharmaceutical composition are printed on paper or other material and / or floppy disk, CD-ROM, DVD-ROM, Zip disk, video tape, audio tape, etc. It may be supplied as an electrically or electromagnetically readable medium. Detailed instructions for use may be actually attached to the kit, or may be posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail or the like.

Furthermore, the present invention relates to a disease of a mammal suffering from or at risk of suffering from a disease such as obesity, hyperlipidemia, hyperglycemia (diabetes), hypertension, arteriosclerosis or cancer. Prophylactic or therapeutic methods are also included.
Here, “treatment” means to prevent or alleviate the progression of the pathology of the disease in a mammal that may or may be affected by the disease. Used as a broad meaning including. The term “disease” means any disease that develops due to an abnormal function of the peroxisome proliferator-activated receptor (PPAR), and is not particularly limited. For example, the concept includes obesity, hyperlipidemia, hyperglycemia (diabetes), hypertension, arteriosclerosis, various symptoms characterized as metabolic syndrome, or cancer.

  The “mammal” to be treated means any animal classified as a mammal, and is not particularly limited. For example, in addition to humans, pet animals such as dogs and cats, cows, pigs, sheep, horses It is a domestic animal. Particularly preferred “mammals” are humans.

  Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

４−フェニル安息香酸(１９８ｍｇ, １．００ｍｍｏｌ)、３−(３−アミノメチル−４−メトキシフェニル)−２−エチルプロピオン酸エチル・塩酸塩(ＷＯ０１／９２２０１号の実施例１０８に記載の化合物) (３０２ｍｇ, １．００ｍｍｏｌ)、トリエチルアミン０．４８５ｍＬをジクロロメタン１５ｍＬに溶かし０℃にて撹拌した。そこに２−クロロ−１，３−ジメチルイミダゾリウムクロライド (２５４ｍｇ, １．５０ｍｍｏｌ) を加え室温で５時間撹拌。溶媒をクエン酸水溶液、飽和炭酸水素ナトリウム水溶液で洗浄後無水硫酸マグネシウム乾燥し、溶媒を留去。カラムクロマトグラフィー（Ｈｅｘａｎｅ／ＡｃＯＥｔ＝２：１ｖ／ｖ）により精製して２９０ｍｇの２−エチル−３−［４−メトキシ−３−［Ｎ−（４−フェニル）ベンゾイルアミノ］メチル］フェニルプロピオン酸エチルエステルを得た。
得られた化合物とエタノ−ル３０ｍＬ及び１ｍｏｌ／Ｌ 水酸化ナトリウム水溶液３０ｍＬとを混合し、５０℃で８時間撹拌後、反応液を減圧下濃縮した。残留物を氷冷した希塩酸中に注加した。生じた沈殿を濾過、乾燥した後、ｎ−ヘキサンと酢酸エチルの混合溶媒にて再結晶し、表題化合物を２７３ｍｇ（２工程 ６５％）得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８２（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．６２（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．５９（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），７．４５（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），７．３７（ｔ，Ｊ＝７．２Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０９（ｄｄ，Ｊ＝８．６，２．１Ｈｚ，１Ｈ）， ６．８０（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．７７（ｍ，１Ｈ），４．６０（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．８５（ｓ，３Ｈ），２．８９（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．６，６．４Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），１．６５（ｍ，１Ｈ），１．５８（ｍ，１Ｈ），０．９５（ｔ，Ｊ ＝７．３Ｈｚ，３Ｈ）．
元素分析値
Ｃ_２６Ｈ_２７Ｆ_４ＮＯ_４: 計算値 Ｃ,７４．８０; Ｈ, ６．５２; Ｎ, ３．３５. 実測値 Ｃ, ７４．６２; Ｈ, ６．５７; Ｎ, ３．２１.
質量分析値
ＭＳ（ＦＡＢ）；４１８（Ｍ＋Ｈ）Example 1 2-Ethyl-3- [4-methoxy-3- [N- (4-phenyl) benzoylamino] methyl] phenylpropionic acid (10)

4-phenylbenzoic acid (198 mg, 1.00 mmol), ethyl 3- (3-aminomethyl-4-methoxyphenyl) -2-ethylpropionate hydrochloride (compound described in Example 108 of WO01 / 92201) (302 mg, 1.00 mmol) and 0.485 mL of triethylamine were dissolved in 15 mL of dichloromethane and stirred at 0 ° C. 2-Chloro-1,3-dimethylimidazolium chloride (254 mg, 1.50 mmol) was added thereto and stirred at room temperature for 5 hours. The solvent was washed with aqueous citric acid solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. 290 mg of ethyl 2-ethyl-3- [4-methoxy-3- [N- (4-phenyl) benzoylamino] methyl] phenylpropionate purified by column chromatography (Hexane / AcOEt = 2: 1 v / v) An ester was obtained.
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 273 mg (65% of 2 steps) of the title compound.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.82 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 7 .7 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H) 7.09 (dd, J = 8.6, 2.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.77 (m, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 2.89 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.6, 6) .4 Hz, 1H), 2.56 (m, 1H), 1.65 (m, 1H), 1.58 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H).
Elemental analysis value C ₂₆ H ₂₇ F ₄ NO ₄ : Calculated value C, 74.80; H, 6.52; N, 3.35. Actual value C, 74.62; H, 6.57; N, 3. 21.
Mass spectrometry value
MS (FAB); 418 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．９９（ｓ，１Ｈ），７．６９（ｍ，２Ｈ），７．５９（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），７．４４（ｍ，３Ｈ），７．３６（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０８（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），６．７９（ｂｒ，１Ｈ），６．７８（ｄ，Ｊ＝８．６ Ｈｚ，１Ｈ），４．６０（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．８３（ｓ，３Ｈ），２．８９（ｄｄ，Ｊ＝１３．７，７．９Ｈｚ，１Ｈ），２．６９（ｄｄ，Ｊ＝１３．７，６．９ Ｈｚ，１Ｈ），２．５５（ｍ，１Ｈ），１．６３（ｍ，１Ｈ），１．５６（ｍ，１Ｈ）， ０．９３（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
元素分析値
Ｃ_２６Ｈ_２７ＮＯ_４: 計算値 Ｃ,７４．８０; Ｈ, ６．５２; Ｎ, ３．３５. 実測値 Ｃ, ７４．５２; Ｈ, ６．３８; Ｎ, ３．１５.
質量分析値
ＭＳ（ＦＡＢ）；４１８（Ｍ＋Ｈ）Example 2 2-Ethyl-3- [4-methoxy-3- [N- (3-phenyl) benzoylamino] methyl] phenylpropionic acid (11)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.9 (s, 1H), 7.69 (m, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.44 (m, 3H), 7.36 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.5, 2.1 Hz, 1H) ), 6.79 (br, 1H), 6.78 (d, J = 8.6 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.83 (s, 3H) , 2.89 (dd, J = 13.7, 7.9 Hz, 1H), 2.69 (dd, J = 13.7, 6.9 Hz, 1H), 2.55 (m, 1H), 1 .63 (m, 1H), 1.56 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).
Elemental analysis value C ₂₆ H ₂₇ NO ₄ : Calculated value C, 74.80; H, 6.52; N, 3.35. Found C, 74.52; H, 6.38; N, 3.15.
Mass spectrometry value MS (FAB); 418 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．７１（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．４５（ｔ，Ｊ＝７．３Ｈｚ，１Ｈ），７．３８（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），７．３３（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．３−７．２（ｍ，５Ｈ），７．０１（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），６．９３（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），６．５７（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），５．８２（ｂｒ，１Ｈ），４．３０（ｍ，２Ｈ），３．５６（ｓ，３Ｈ），２．８６（ｄｄ，Ｊ＝１３．７，８．１Ｈｚ，１Ｈ），２．６５（ｄｄ，Ｊ＝１３．７，６．８Ｈｚ，１Ｈ），２．５４（ｍ，１Ｈ），１．６４（ｍ，１Ｈ）， １．５７（ｍ，１Ｈ），０．９５（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ）．
高分解能質量分析値
（Ｍ＋Ｈ） 計算値Ｃ_２６Ｈ_２８ＮＯ_４，４１８．２０１８， 実測値 ４１８．２０４３Example 3 2-Ethyl-3- [4-methoxy-3- [N- (2-phenyl) benzoylamino] methyl] phenylpropionic acid (12)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.71 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7) .7 Hz, 1 H), 7.33 (d, J = 7.3 Hz, 1 H), 7.3-7.2 (m, 5 H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 5.82 (br, 1H), 4.30 (m, 2H) 3.56 (s, 3H), 2.86 (dd, J = 13.7, 8.1 Hz, 1H), 2.65 (dd, J = 13.7, 6.8 Hz, 1H), 2. 54 (m, 1H), 1.64 (m, 1H), 1.57 (m, 1H), 0.95 (t, J = 7.7 Hz, 3H).
High-resolution mass analysis value (M + H) Calculated value C ₂₆ H ₂₈ NO ₄ , 418.2018, measured value 418.2043

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．０６（ｍ，２Ｈ），６．７７（ｄ， Ｊ＝９．０Ｈｚ，１Ｈ），６．１９（ｂｒ，１Ｈ），４．６（ｂｒ，１Ｈ），４．３７（ｍ，２Ｈ），３．８３（ｓ，３Ｈ），２．８８（ｄｄ，Ｊ＝１３．７，８．６Ｈｚ，１Ｈ），２．６９（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５４（ｍ，１Ｈ），２．０３（ｓ，３Ｈ），１．８３（ｄ，Ｊ＝２．６Ｈｚ，６Ｈ），１．７０（ｍ，７Ｈ），１．５８（ｍ，１Ｈ），０．９５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
元素分析値
Ｃ_２１Ｈ_２１ＮＯ_４.０．３Ｈ_２Ｏ: 計算値 Ｃ,７１．１５; Ｈ, ８．３３; Ｎ, ３．５１. 実測値 Ｃ,７１．２２; Ｈ, ８．２４; Ｎ, ３．３３.
質量分析値
ＭＳ（ＦＡＢ）；４００（Ｍ＋Ｈ）Example 4 2-Ethyl-3- [4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid (13)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.06 (m, 2H), 6.77 (d, J = 9.0 Hz, 1H), 6.19 (br, 1H), 4.6 (br, 1H), 4.37 (m, 2H), 3.83 (s, 3H), 2.88 (dd, J = 13.7, 8.6 Hz, 1H), 2.69 (dd, J = 13. 7, 6.4 Hz, 1 H), 2.54 (m, 1 H), 2.03 (s, 3 H), 1.83 (d, J = 2.6 Hz, 6 H), 1.70 (m, 7 H) , 1.58 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H).
Elemental analysis _{C 21 H 21 NO 4 .0.3H 2} O:. Calcd C, 71.15; H, 8.33; N, 3.51 Found C, 71.22; H, 8.24; N, 3.33.
Mass spectrometry MS (FAB); 400 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．６−７．４（ｍ，８Ｈ），７．１８（ｓ，１Ｈ），７．１０（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．８１（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．７５（ｂｒ，１Ｈ），４．５９（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．８６（ｓ，３Ｈ），３．０−２．５（ｂｒ，１Ｈ），２．８９（ｄｄ，Ｊ＝１３．７，９．０ Ｈｚ，１Ｈ），２．７３（ｄｄ，Ｊ＝１４．１，６．０Ｈｚ，１Ｈ），２．５７（ｍ，１Ｈ），１６７（ｍ，１Ｈ），１．５９（ｍ，１Ｈ），０．９６（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４３６（Ｍ＋Ｈ） Example 5 2-Ethyl-3- [4-methoxy-3- [N- (4-phenyl-2-fluoro) benzoylamino] methyl] phenylpropionic acid (14)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.6-7.4 (m, 8H), 7.18 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6. 81 (d, J = 8.1 Hz, 1H), 6.75 (br, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.0− 2.5 (br, 1H), 2.89 (dd, J = 13.7, 9.0 Hz, 1H), 2.73 (dd, J = 14.1, 6.0 Hz, 1H), 2. 57 (m, 1H), 167 (m, 1H), 1.59 (m, 1H), 0.96 (t, J = 7.7 Hz, 3H).
Mass spectrometry value MS (FAB); 436 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．６７（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．２４（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．１７（ｄ，Ｊ＝２．１Ｈｚ，２Ｈ），７．０７（ｄｄ，Ｊ＝８．１，２．１Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．６８（ｓ，１Ｈ），４．５７（ｍ，２Ｈ），３．８５（ｓ，３Ｈ），２．８７（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．７，６．０Ｈｚ，１Ｈ），２．５４（ｍ，１Ｈ），１．８４（ｍ，４Ｈ），１．７５（ｍ，１Ｈ），１．６６（ｍ，１Ｈ），１．５７（ｍ，１Ｈ），１．３９（ｍ，４Ｈ），１．２６（ｍ，１Ｈ），０．９５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４２４（Ｍ＋Ｈ）Example 6 2-Ethyl-3- [4-methoxy-3- [N- (4-cyclohexyl) benzoylamino] methyl] phenylpropionic acid (15)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.67 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 2) .1 Hz, 2H), 7.07 (dd, J = 8.1, 2.1 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 4 .57 (m, 2H), 3.85 (s, 3H), 2.87 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.7, 6. 0 Hz, 1H), 2.54 (m, 1H), 1.84 (m, 4H), 1.75 (m, 1H), 1.66 (m, 1H), 1.57 (m, 1H), 1.39 (m, 4H), 1.26 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 424 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ８．０２（ｔ，Ｊ＝８．１Ｈｚ，１Ｈ），７．４０（ｍ，１Ｈ），７．２３（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），７．１７（ｓ，１Ｈ），７．０６（ｍ，２Ｈ），６．７９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），４．６１（ｓ，２Ｈ），３．８６（ｓ，３Ｈ），３．０−２．４（ｂｒ，１Ｈ），２．８８（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），２．１（ｍ，３Ｈ），１．９（ｍ，６Ｈ），１．８（ｍ，６Ｈ）， １．６５（ｍ，１Ｈ），１．５７（ｍ，１Ｈ），０．９５（ｔ，Ｊ ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４９４（Ｍ＋Ｈ）Example 7 2-Ethyl-3- [4-methoxy-3- [N- [4- (1-adamantyl) -2-fluoro] benzoylamino] methyl] phenylpropionic acid (16)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 8.02 (t, J = 8.1 Hz, 1H), 7.40 (m, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.06 (m, 2H), 6.79 (d, J = 8.5 Hz, 1H), 4.61 (s, 2H), 3.86 (s, 3H) 3.0-2.4 (br, 1H), 2.88 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.7, 6.4 Hz, 1H) ), 2.56 (m, 1H), 2.1 (m, 3H), 1.9 (m, 6H), 1.8 (m, 6H), 1.65 (m, 1H), 1.57 (M, 1H), 0.95 (t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 494 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．６９（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．１８（ｓ，１Ｈ），７．０８（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．６６（ｓ，１Ｈ）， ４．５８（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．８５（ｓ，３Ｈ），２．８７（ｄｄ，Ｊ＝１３．９，８．５Ｈｚ，１Ｈ），２．７３（ｄｄ，Ｊ＝１３．９，６．４Ｈｚ，１Ｈ），２．５７（ｍ，２Ｈ），１．６７−１．５８（ｍ，２Ｈ），１．４４（ｓ，６Ｈ），１．１４（ｓ，６Ｈ），０．９６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．８９（ｓ，９Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；５１８（Ｍ＋Ｈ）[Example 8] 2-ethyl-3- [4-methoxy-3- [N- (4-trimethyladaman-1-yl) benzoylamino] methyl] phenylpropionic acid (17)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.69 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.18 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.66 (s, 1H), 4.58 (d, J = 5.6 Hz) , 2H), 3.85 (s, 3H), 2.87 (dd, J = 13.9, 8.5 Hz, 1H), 2.73 (dd, J = 13.9, 6.4 Hz, 1H) , 2.57 (m, 2H), 1.67-1.58 (m, 2H), 1.44 (s, 6H), 1.14 (s, 6H), 0.96 (t, J = 7) .3 Hz, 3 H), 0.89 (s, 9 H).
Mass spectrometry value MS (FAB); 518 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８６（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ， ７．６７（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），６．９５（ｓ，１Ｈ），６．８８（ｄｄ，Ｊ＝１２．４，２．１Ｈｚ，１Ｈ），６．７５（ｓ，１Ｈ），４．５９（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．９７（ｄ，Ｊ＝２．１Ｈｚ，３Ｈ），２．８７（ｄｄ，Ｊ＝１３．７，９．０Ｈｚ，１Ｈ），２．７０（ｄｄ，Ｊ＝１３．７，６．０Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），１．６６（ｍ，１Ｈ），１．５９（ｍ，１Ｈ），０．９６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４２８（Ｍ＋Ｈ）Example 9 2-Ethyl-3- [5-fluoro-4-methoxy-3- [N- (4-trifluoromethyl) benzoylamino] methyl] phenylpropionic acid (18)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.86 (d, J = 8.3 Hz, 2H, 7.67 (d, J = 8.3 Hz, 2H), 6.95 (s, 1H), 6 .88 (dd, J = 12.4, 2.1 Hz, 1H), 6.75 (s, 1H), 4.59 (d, J = 5.6 Hz, 2H), 3.97 (d, J = 2.1 Hz, 3H), 2.87 (dd, J = 13.7, 9.0 Hz, 1H), 2.70 (dd, J = 13.7, 6.0 Hz, 1H), 2.56 (m , 1H), 1.66 (m, 1H), 1.59 (m, 1H), 0.96 (t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 428 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ ＭＨｚ，ＣＤＣｌ_３）；δ７．８４（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．６３（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．５９（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），７．４６（ｔ，Ｊ＝７．７Ｈｚ，２Ｈ），７．３８（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），６．９８（ｓ，１Ｈ），６．８８（ｄ，Ｊ＝１２．４Ｈｚ，１Ｈ），６．７２（ｓ，１Ｈ），４．６１（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．９８（ｄ，Ｊ＝１．７Ｈｚ，３Ｈ），２．８８（ｄｄ，Ｊ＝１３．７，９．０Ｈｚ，１Ｈ），２．７０（ｄｄ，Ｊ＝１３．７，６．０Ｈｚ，１Ｈ），２．５７（ｍ，１Ｈ），１．６７（ｍ，１Ｈ），１．５９（ｍ，１Ｈ），０．９６（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４３６（Ｍ＋Ｈ）Example 10 2-Ethyl-3- [5-fluoro-4-methoxy-3- [N- (4-phenyl) benzoylamino] methyl] phenylpropionic acid (19)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.84 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.88 ( d, J = 12.4 Hz, 1H), 6.72 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.98 (d, J = 1.7 Hz, 3H), 2.88 (dd, J = 13.7, 9.0 Hz, 1H), 2.70 (dd, J = 13.7, 6.0 Hz, 1H), 2.57 (m, 1H), 1.67 (M, 1H), 1.59 (m, 1H), 0.96 (t, J = 7.7 Hz, 3H).
Mass spectrometry value MS (FAB); 436 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．７１（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．４１（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），６．９６（ｓ，１Ｈ），６．８６（ｄ，Ｊ＝１２．４Ｈｚ，１Ｈ），６．６３（ｓ，１Ｈ），４．５９（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．９６（ｄ，Ｊ＝２．１Ｈｚ，３Ｈ），２．８６（ｄｄ，Ｊ＝１３．９，８．５Ｈｚ，１Ｈ），２．６９（ｄｄ，Ｊ＝１３．９，６．０Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），２．１０（ｓ，３Ｈ），１．９０（ｓ，６Ｈ），１．７７（ｍ，６Ｈ），１．６６（ｍ，１Ｈ），１．５８（ｍ，１Ｈ），０．９６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４９４（Ｍ＋Ｈ）Example 11 2-Ethyl-3- [5-fluoro-4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid (20)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.71 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 6.96 (s, 1H), 6.86 (d, J = 12.4 Hz, 1H), 6.63 (s, 1H), 4.59 (d, J = 6.0 Hz, 2H), 3.96 (d, J = 2.1 Hz) 3H), 2.86 (dd, J = 13.9, 8.5 Hz, 1H), 2.69 (dd, J = 13.9, 6.0 Hz, 1H), 2.56 (m, 1H) , 2.10 (s, 3H), 1.90 (s, 6H), 1.77 (m, 6H), 1.66 (m, 1H), 1.58 (m, 1H), 0.96 ( t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 494 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）；δ７．８４（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．６６（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．１８（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．７０（ｓ，１Ｈ），６．５９（ｄ，Ｊ＝１１．５Ｈｚ，１Ｈ），４．５３（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．８３（ｓ，３Ｈ），２．８２（ｍ，２Ｈ），２．６０（ｍ，１Ｈ），１．６９（ｍ，１Ｈ），１．５９（ｍ，１Ｈ），０．９６（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４２８（Ｍ＋Ｈ）Example 12 2-Ethyl-3- [5-fluoro-4-methoxy-3- [N- (4-trifluoromethyl) benzoylamino] methyl] phenylpropionic acid (21)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl 3); δ 7.84 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8. 5 Hz, 1 H), 6.70 (s, 1 H), 6.59 (d, J = 11.5 Hz, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 3.83 (s, 3H), 2.82 (m, 2H), 2.60 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H), 0.96 (t, J = 7.7 Hz) , 3H).
Mass spectrometry value MS (FAB); 428 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．７０（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．１７（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０７（ｄｄ，Ｊ＝８．１，２．１Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．６７（ｓ，１Ｈ），４．５８（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．８５（ｓ，３Ｈ），２．８７（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．７，６．０Ｈｚ，１Ｈ），２．６３（ｍ，１Ｈ），２．１０（ｓ，３Ｈ），１．９０（ｄ，Ｊ＝２．１Ｈｚ，２Ｈ），１．７６（ｍ，６Ｈ），１．６４（ｍ，１Ｈ），１．４７（ｍ，１Ｈ），１．３７（ｍ，２Ｈ），０．９０（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４９０（Ｍ＋Ｈ）Example 13 2-n-Propyl-3- [4-methoxy-3- [N- [4- (1-adamantyl] benzoylamino] methyl] phenylpropionic acid (22)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.70 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 2) .1 Hz, 1H), 7.07 (dd, J = 8.1, 2.1 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 4 .58 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 2.87 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.7, 6.0 Hz, 1H), 2.63 (m, 1H), 2.10 (s, 3H), 1.90 (d, J = 2.1 Hz, 2H), 1.76 (m, 6H), 1.64 (m, 1H), 1.47 (m, 1H), 1.37 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 490 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．７０（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．１８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．０８（ｄｄ，Ｊ＝８．３，１．９Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），６．６７（ｓ，１Ｈ），４．５９（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．８５（ｓ，３Ｈ），２．９６（ｄｄ，Ｊ＝１３．５，６．８Ｈｚ，１Ｈ），２．７２（ｍ，１Ｈ），２．６４（ｄｄ，Ｊ＝１３．５，７．７Ｈｚ，１Ｈ），２．１０（ｓ，３Ｈ），１．９０（ｄ，Ｊ＝２．６Ｈｚ，６Ｈ），１．７７（ｍ，６Ｈ），１．１６（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４６２（Ｍ＋Ｈ）Example 14 2-Methyl-3- [4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid (23)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.70 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 1) .9 Hz, 1H), 7.08 (dd, J = 8.3, 1.9 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.67 (s, 1H), 4 .59 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 2.96 (dd, J = 13.5, 6.8 Hz, 1H), 2.72 (m, 1H) , 2.64 (dd, J = 13.5, 7.7 Hz, 1H), 2.10 (s, 3H), 1.90 (d, J = 2.6 Hz, 6H), 1.77 (m, 6H), 1.16 (d, J = 6.8 Hz, 3H).
Mass spectrometry value MS (FAB); 462 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８５（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．１２（ｓ，１Ｈ），７．０６（ｄ，Ｊ ＝ ８．５Ｈｚ，１Ｈ），６．８３（ｓ，１Ｈ），６．７９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），４．６２（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），４．０７（ｍ，２Ｈ），４．００（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８６（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．６８（ｄｄ，Ｊ＝１３．７，６．４ Ｈｚ，１Ｈ），２．５３（ｍ，１Ｈ），１．７８（ｍ，２Ｈ），１．６２（ｍ，１Ｈ），１．５５（ｍ，１Ｈ），１．４４（ｍ，２Ｈ），１．２８（ｍ，４Ｈ），１．１７（ｔ，Ｊ＝６． Ｈｚ，３Ｈ），０．９１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．８６（ｔ，Ｊ＝６．８Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４８０（Ｍ＋Ｈ）Example 15 2-Ethyl-3- [4-n-hexyloxy-3- [N- (4-trifluoromethyl) benzoylamino] methyl] phenylpropionic acid (24)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.85 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.62 (d, J = 5.6 Hz) , 2H), 4.07 (m, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.86 (dd, J = 13.7, 8.5 Hz, 1H), 2.68. (Dd, J = 13.7, 6.4 Hz, 1H), 2.53 (m, 1H), 1.78 (m, 2H), 1.62 (m, 1H), 1.55 (m, 1H), 1.44 (m, 2H), 1.28 (m, 4H), 1.17 (t, J = 6 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H) , 0.86 (t, J = .8Hz, 3H).
Mass spectrometry value MS (FAB); 480 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５９（ｄ，Ｊ＝７．５Ｈｚ，２Ｈ），７．４５（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），７．３８（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０７（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），６．７９（ｍ，２Ｈ），４．６２（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），４．００（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８９（ｄｄ，Ｊ＝１３．７，８．５ Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５７（ｍ，１Ｈ），１．８１（ｍ，２Ｈ），１．６６（ｍ，１Ｈ），１．５９（ｍ，１Ｈ），１．４７（ｍ，２Ｈ），１．３１（ｍ，４Ｈ），０．９５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．８８（ｔ，Ｊ＝６．８Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４８８（Ｍ＋Ｈ）Example 16 2-Ethyl-3- [4-n-hexyloxy-3- [N- (4-phenyl) benzoylamino] methyl] phenylpropionic acid (25)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.82 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 7 .5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H) 7.07 (dd, J = 8.5, 2.1 Hz, 1H), 6.79 (m, 2H), 4.62 (d, J = 5.6 Hz, 2H), 4.00 (t, J = 6.4 Hz, 2H), 2.89 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.7, 6.4 Hz, 1H), 2. 57 (m, 1H), 1.81 (m, 2H), 1.66 (m, 1H), 1.59 (m, 1H), 1.47 (m, 2H), 1.31 (m, 4H) ), 0.95 (t, = 7.3Hz, 3H), 0.88 (t, J = 6.8Hz, 3H).
Mass spectrometry value MS (FAB); 488 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．６９（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．１６（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０５（ｄｄ，Ｊ＝８．１，２．１Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．７３（ｓ，１Ｈ），４．５９（ｄ，Ｊ＝５．１Ｈｚ，２Ｈ），３．９８（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８７（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７０（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），２．１０（ｓ，３Ｈ），１．９０（ｄ，Ｊ＝２．１Ｈｚ，６Ｈ），１．８３−１．７３（ｍ，８Ｈ），１．６６（ｍ，１Ｈ），１．５７（ｍ，１Ｈ），１．４５（ｍ，２Ｈ），１．３１（ｍ，４Ｈ），０．９５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．８８（ｔ，Ｊ＝６．８Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；５４６（Ｍ＋Ｈ）Example 17 2-Ethyl-3- [4-n-hexyloxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid (26)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.69 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 2) .1 Hz, 1H), 7.05 (dd, J = 8.1, 2.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 4 .59 (d, J = 5.1 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 2.87 (dd, J = 13.7, 8.5 Hz, 1H), 2. 70 (dd, J = 13.7, 6.4 Hz, 1H), 2.56 (m, 1H), 2.10 (s, 3H), 1.90 (d, J = 2.1 Hz, 6H), 1.83-1.73 (m, 8H), 1.66 (m, 1H), 1.57 (m, 1H), 1.45 (m, 2H), 1.31 (m, 4H), 0 .95 (t, J = 7 3Hz, 3H), 0.88 (t, J = 6.8Hz, 3H).
Mass spectrometry value MS (FAB); 546 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８４（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．６６（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．１５（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．０７（ｄｄ，Ｊ＝８．５，１．９Ｈｚ，１Ｈ），６．７９（ｍ，２Ｈ），４．６１（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．９６（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８８（ｄｄ， Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７１（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５６（ｍ，１Ｈ），１．８２（ｍ，２Ｈ），１．６６（ｍ，１Ｈ），１．５８（ｍ，１Ｈ），１．０４（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．９５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４３８（Ｍ＋Ｈ）[Example 18] 2-ethyl-3- [4-n-propoxy-3- [N- (4-trifluoromethyl) benzoylamino] methyl] phenylpropionic acid (27)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.84 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 1) .9 Hz, 1H), 7.07 (dd, J = 8.5, 1.9 Hz, 1H), 6.79 (m, 2H), 4.61 (d, J = 5.6 Hz, 2H), 3 .96 (t, J = 6.4 Hz, 2H), 2.88 (dd, J = 13.7, 8.5 Hz, 1H), 2.71 (dd, J = 13.7, 6.4 Hz, 1H) ), 2.56 (m, 1H), 1.82 (m, 2H), 1.66 (m, 1H), 1.58 (m, 1H), 1.04 (t, J = 7.3 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H).
Mass spectrometry value MS (FAB); 438 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．８２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６３（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６０（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），７．４５（ｔ，Ｊ＝７．７Ｈｚ，２Ｈ），７．３８（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．０７（ｄｄ，Ｊ＝８．３，２．１Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝８．３Ｈｚ，１Ｈ），６．７７（ｓ，１Ｈ），４．６３（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．９７（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８９（ｄｄ，Ｊ＝１３．７，８．５Ｈｚ，１Ｈ），２．７２（ｄｄ，Ｊ＝１３．７，６．４Ｈｚ，１Ｈ），２．５８（ｍ，１Ｈ），１．８５（ｍ，２Ｈ），１．６５（ｍ，１Ｈ），１．５８（ｍ，１Ｈ），１．０６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），０．９６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；４４６（Ｍ＋Ｈ）Example 19 2-Ethyl-3- [4-n-propoxy-3- [N- (4-phenyl) benzoylamino] methyl] phenylpropionic acid (28)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.82 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7 .7 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H) 7.07 (dd, J = 8.3, 2.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.63 (d, J = 6.0 Hz, 2H), 3.97 (t, J = 6.4 Hz, 2H), 2.89 (dd, J = 13.7, 8.5 Hz, 1H), 2.72 (dd, J = 13.7, 6.4 Hz, 1H), 2.58 (m, 1H), 1.85 (m, 2H), 1.65 (m, 1H), 1.58 (m, 1H), 1. 06 (t, J = 7 3Hz, 3H), 0.96 (t, J = 7.3Hz, 3H).
Mass spectrometry value MS (FAB); 446 (M + H)

実施例１と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．７０（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．１５（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．０５（ｄｄ，Ｊ＝８．５，１．９Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），６．７２（ｓ，２Ｈ），４．６０（ｄ，Ｊ＝５．６Ｈｚ，２Ｈ），３．９５（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８８（ｄｄ，Ｊ＝１３．７，８．１Ｈｚ，１Ｈ），２．６９（ｄｄ，Ｊ＝１３．７，６．８Ｈｚ，１Ｈ），２．５５（ｍ，１Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．７３（ｍ，１４Ｈ），１．６３（ｍ，１Ｈ），１．５６（ｍ，１Ｈ），１．０６（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ），０．９４（ｔ，Ｊ＝７．７Ｈｚ，３Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；５０４（Ｍ＋Ｈ）Example 20 2-Ethyl-3- [4-n-propoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid (29)

The title compound was obtained in the same manner as in Example 1.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.70 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 1) .9 Hz, 1H), 7.05 (dd, J = 8.5, 1.9 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.72 (s, 2H), 4 .60 (d, J = 5.6 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 2.88 (dd, J = 13.7, 8.1 Hz, 1H), 2. 69 (dd, J = 13.7, 6.8 Hz, 1H), 2.55 (m, 1H), 2.10 (s, 3H), 1.90-1.73 (m, 14H), 1. 63 (m, 1H), 1.56 (m, 1H), 1.06 (t, J = 7.7 Hz, 3H), 0.94 (t, J = 7.7 Hz, 3H).
Mass spectrometry value MS (FAB); 504 (M + H)

耐圧反応管に１−ブロモアダマンタン（１．０９ｇ，５．０ｍｍｏｌ）、マグネシウム粉末３６０ｍｇとジエチルエーテル５ｍＬを入れて０℃撹拌。そこへ４−ブロモ−２−フルオロトルエン（１．９ｍＬ，１５ｍｍｏｌ）を滴下により加えた。封をして１００℃まで加熱、１００℃で二時間撹拌後、加熱をやめて冷めるまで３時間撹拌した。水にあけてエーテルで抽出、ＭｇＳＯ_４処理後溶媒を留去。カラムクロマトグラフィー（Ｈｅｘａｎｅのみ）により精製して表題化合物を２０４ｍｇ（１７％）得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．１２（ｍ，１Ｈ），７．０２（ｍ，２Ｈ），２．２４（ｓ，３Ｈ），２．１（ｍ，３Ｈ），１．９（ｍ，６Ｈ），１．８（ｍ，６Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；２４４（Ｍ）^＋ [Reference Example 1] 4- (1-adamantyl) -2-fluorotoluene (30)

1-bromoadamantane (1.09 g, 5.0 mmol), magnesium powder 360 mg and diethyl ether 5 mL were placed in a pressure-resistant reaction tube and stirred at 0 ° C. 4-Bromo-2-fluorotoluene (1.9 mL, 15 mmol) was added dropwise thereto. Sealed, heated to 100 ° C., stirred at 100 ° C. for 2 hours, and then stirred for 3 hours until the heating was stopped and the system cooled. Extracted with ether poured into water, distilled off MgSO ₄ processed the solvent. Purification by column chromatography (Hexane only) gave 204 mg (17%) of the title compound.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.12 (m, 1H), 7.02 (m, 2H), 2.24 (s, 3H), 2.1 (m, 3H), 1.9 (M, 6H), 1.8 (m, 6H).
Mass spectrometry MS (FAB); 244 (M) ⁺

４−（１−アダマンチル）トルエン（５６６ｍｇ，２．５ｍｍｏｌ）と酢酸コバルト（２０ｍｇ，０．１１ｍｍｏｌ）、酢酸マグネシウム（２．５ｍｇ，０．０１３ｍｍｏｌ）、臭化ナトリウム（１２ｍｇ，０．１２ｍｍｏｌ）を９５％酢酸１０ｍＬとジオキサン１ｍＬに溶かし、酸素ガス雰囲気下で９０℃一晩撹拌した。半分ほど溶媒を留去した後冷水を加え、析出している結晶をろ取して表題化合物６００ｍｇ（９４％）を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７７．８７（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．４７（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），２．０５（ｓ，３Ｈ），１．８７（ｄ，Ｊ＝２．６Ｈｚ，６Ｈ），１．７３（ｓ，６Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；５７６（Ｍ）^＋ [Reference Example 2] 4- (1-adamantyl) benzoic acid (31)

95 of 4- (1-adamantyl) toluene (566 mg, 2.5 mmol), cobalt acetate (20 mg, 0.11 mmol), magnesium acetate (2.5 mg, 0.013 mmol), sodium bromide (12 mg, 0.12 mmol) It was dissolved in 10 mL of% acetic acid and 1 mL of dioxane, and stirred overnight at 90 ° C. in an oxygen gas atmosphere. Half of the solvent was distilled off, cold water was added, and the precipitated crystals were collected by filtration to obtain 600 mg (94%) of the title compound.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 77.87 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 2.05 (s, 3H), 1.87 (d, J = 2.6 Hz, 6H), 1.73 (s, 6H).
Mass spectrometry MS (FAB); 576 (M) ⁺

参考例２と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ７．９５（ｔ，Ｊ＝８．１Ｈｚ，１Ｈ），７．２（ｍ，２Ｈ），２．１（ｓ，３Ｈ），１．９（ｓ，６Ｈ），１．８（ｍ，６Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；２７５（Ｍ＋Ｈ）^＋ [Reference Example 3] 4- (1-adamantyl) -2-fluorobenzoic acid (32)

The title compound was obtained in the same manner as in Reference Example 2.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 7.95 (t, J = 8.1 Hz, 1H), 7.2 (m, 2H), 2.1 (s, 3H), 1.9 (s, 6H), 1.8 (m, 6H).
Mass spectrometry MS (FAB); 275 (M + H) ⁺

参考例２と同様にして表題化合物を得た。
核磁気共鳴スペクトル
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）；δ８．０４（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．４６（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），１．４９（ｍ，６Ｈ），１．１６（ｓ，６Ｈ），０．９１（ｓ，９Ｈ）．
質量分析値
ＭＳ（ＦＡＢ）；２９９（Ｍ＋Ｈ）^＋ [Reference Example 4] 4- (Trimethyladamantan-1-yl) -benzoic acid (33)

The title compound was obtained in the same manner as in Reference Example 2.
Nuclear magnetic resonance spectrum
¹ H-NMR (500 MHz, CDCl ₃ ); δ 8.04 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 1.49 (m, 6H), 1.16 (s, 6H), 0.91 (s, 9H).
Mass spectrometry MS (FAB); 299 (M + H) ⁺

[Experimental Example 1] Transcriptional activation of human peroxisome proliferator-responsive receptor (PPAR) Human embryonic kidney cells (HEK293) cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum A receptor plasmid that expresses a fusion protein of the DNA binding region of the transcription factor (GAL4) of yeast and the 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, 16 hours after the addition of the test compound, the luciferase activity and β-galactosidase activity were measured and corrected by the internal standard.
The test results are shown in Table 1.

本発明化合物はヒトＰＰＡＲα、ヒトＰＰＡＲδ、ヒトＰＰＡＲγのそれぞれに対し１μＭ以下のＥＣ_５０値を示した。このことより本発明化合物はヒトペルオキシゾ−ム増殖剤応答性受容体に対して強力な転写活性化作用を有することが示された。上述の結果から、本発明の置換フェニルプロピオン酸誘導体は優れたヒトＰＰＡＲ転写活性化作用を有する新規な化合物群であることが示された。これら本発明の化合物では、ヒトＰＰＡＲに対する作動活性を有する事から前述した脂質低下薬、特に肝臓における脂質の低下薬、動脈硬化の進展に対する抑制薬、抗肥満薬、インスリン抵抗性改善薬、抗癌薬として有効な化合物と言える。

The compound of the present invention showed an EC ₅₀ value of 1 μM or less for each of human PPARα, human PPARδ, and human PPARγ. From these results, it was shown that the compound of the present invention has a strong transcriptional activation effect on the human peroxisome proliferator-responsive receptor. 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 aforementioned lipid-lowering drugs, 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 (6)

General formula (1):

[ Wherein , R1 represents an adamantyl group or adamantyl group having a methyl group , R2 represents a hydrogen atom or a halogen atom, R3 represents an alkoxy group having 1 to 10 carbon atoms , and R4 represents a lower group having 1 to 6 carbon atoms. Represents an alkyl group, and R5 represents a hydrogen atom or a halogen atom. ]
Or a pharmaceutically acceptable salt thereof or a hydrate thereof. The α according to claim 1, wherein R1 is an adamantyl group or trimethyladamantyl group, R2 is a hydrogen atom or a fluorine atom, R3 is a methoxy group or an n-propoxy group, R4 is an ethyl group, and R5 is a hydrogen atom. A substituted phenylpropionic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof; The compound represented by the general formula (1)
2-ethyl-3- [4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid,
2-ethyl-3- [4-methoxy-3- [N- [4- (1-adamantyl) -2-fluoro] benzoylamino] methyl] phenylpropionic acid,
2-ethyl-3- [4-methoxy-3- [N- (4-trimethyladaman-1-yl) benzoylamino] methyl] phenylpropionic acid,
2-ethyl-3- [5-fluoro-4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid,
2-n-propyl-3- [4-methoxy-3- [N- [4- (1-adamantyl] benzoylamino] methyl] phenylpropionic acid,
2-methyl-3- [4-methoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid,
2-ethyl-3- [4-n-hexyloxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid,
2-ethyl-3- [4-n-propoxy-3- [N- [4- (1-adamantyl)] benzoylamino] methyl] phenylpropionic acid,
The α-substituted phenylpropionic acid derivative or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 1, which is selected from the group consisting of: All of peroxisome proliferator-responsive receptors α, β and γ containing the α-substituted phenylpropionic acid derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a hydrate thereof. Transcriptional activator against. A therapeutic or preventive agent for metabolic syndrome, comprising a transcriptional activator for all of the peroxisome proliferator-responsive receptors α, β and γ according to claim 4. A therapeutic or prophylactic agent for obesity, hyperlipidemia, diabetes, hypertension or arteriosclerosis comprising the transcriptional activator for all of the peroxisome proliferator-responsive receptors α, β and γ according to claim 4 .