JP2012041334A - Novel alpha-substituted propionic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel α-substituted propionic acid derivative, and the α-substituted propionic acid derivative which functions as an agonist selective to PPARγ.SOLUTION: The α-substituted propionic acid derivative is expressed by general formula (I) [wherein Ris adamantyl, phenyl which may have not a substituent or may have a substituent, pyridyl, pyrimidinyl, pyrazinyl, piperidine, azepyl or piperazinyl (substituent is a halogen atom) or the like; Rand Rare the same or different and are each hydrogen or halogen; Ris straight chain or branched 1-10C alkyl; Ris phenyl which may have a substituent, or cyclohexyl; and n is an integer of 0-10].

Description

  The present invention relates to a novel α-substituted propionic acid derivative and an agonist which is the α-substituted propionic acid derivative and is selective for peroxisome proliferator-activated receptor (PPAR) γ, and further, abnormal PPARγ activity The present invention relates to a medicament or pharmaceutical composition for the treatment and / or prevention of a disease or the like caused by a disease, and a method for the treatment and / or prevention of a disease or the like caused by an abnormality in PPARγ activity.

Peroxisome proliferator-activated receptor (PPAR, hereinafter referred to as PPAR) is a ligand-dependent transcription factor belonging to the nuclear receptor superfamily, and induces transcription of target genes in a ligand-dependent manner. To do. 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.
In the cell, PPAR forms a heterodimer with the retinoid X receptor (RXR). This heterodimer binds to a DNA sequence known as the PPAR response element (PPRE) and activates transcription of various genes. In addition, the PPAR / RXR heterodimer incorporates an activation cofactor such as DRIP-205 and SRC-1 to regulate the expression level of mRNA encoded by the target gene.

  So far, three types of subtypes (α type, β / δ type, γ type) with different tissue distributions have been identified in various animal species including humans. Among these, PPARα is distributed in the liver, kidney, heart, muscle and the like with high fatty acid catabolism, and is particularly highly expressed in the liver. When transcription of the target gene is induced by PPARα, A decrease in neutral fat, an increase in HDL cholesterol, a decrease in body weight, promotion of angiogenesis, etc. are induced. PPARβ / δ is ubiquitously expressed in various tissues in the body centering on skeletal muscle, and activation of PPARβ / δ causes fatty acid catabolism in skeletal muscle, increase in HDL cholesterol, improvement in insulin resistance, obesity It has been clarified that the suppression or the like is induced (Non-Patent Document 1, Non-Patent Document 2).

  PPARγ is highly expressed in adipocytes and macrophages and induces proteins involved in adipocyte differentiation and acquisition of insulin sensitivity. As isoforms, at least three types of PPARγ1, γ2 and γ3 have been confirmed, and these are considered to be expressed as a result of alternative splicing. Moreover, the expression of PPARγ has been confirmed in many cancer cells such as colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymphoid leukemia cells (Non-Patent Documents 3 to 5). ). Furthermore, thiazolidinediones (TZDs), which are ligands for PPARγ, have been reported to inhibit the growth of various different types of tumor cells (gastrointestinal, bile duct and pancreatic adenocarcinoma) (Non-patent Document 4). As a target for anticancer drugs, it is attracting attention. The anti-tumor mechanism by PPARγ is also expected to be different for tumors derived from various tissues, and the whole has not yet been clarified. However, PPARγ promotes the degradation of cyclin D1 and stops cell growth in the G1 phase (Non-patent Document 6), and inhibits the DNA binding of E2F-DP and suppresses its transcription activity (Non-patent Document 7). From these reports, it is suggested that PPARγ is directly involved in the suppression of cell proliferation. Furthermore, it has been reported that when the activity of PPARγ increases, the production of VEGF, which is an angiogenic factor, decreases, and the angiogenesis inhibitory action of PPARγ is also considered (Non-patent Document 8).

  Each subtype of PPAR contributes to alleviation of various symptoms known as metabolic syndrome, such as improvement of fat metabolism and insulin resistance, or suppression of cancer cell proliferation by inducing transcription of each target gene. It is expected that Already known so-called fibrates such as fenofibrate, bezafibrate and clofibrate as exogenous ligands for PPARα, and so-called thiazolidine-based agents such as troglitazone, pioglitazone and rosiglitazone are known as exogenous ligands for PPARγ. ing. In addition to the fibrates and thiazolidines, several compounds targeting each PPAR isoform have been reported (see Patent Documents 1 to 6).

WO01 / 092201 WO00 / 75103 WO2004 / 0567748 WO2004 / 046091 WO03 / 051821 WO02 / 098840

Oliver et al., Proc. Natl. Acad. Sci. USA. 98: 5306-531 2001 Tanaka et al., Proc. Natl. Acad. Sci. USA. 100: 15924-15929 2003 Smith et al., Invest New Drugs. 20: 195-200 2002 Tsujie et al., Exp. Cell Res. 289: 143-151 2003 Campbell et al., PPAR Research Volume 2008, Article ID 314974. Qin et al., Cancer Res. 63 958-964 2003 Altiok et al., Genes Dev. 11 1987-1988 1997 Panography et al. Clin. Invest. 110 923-932 2002

An object of the present invention is to provide a novel α-substituted propionic acid derivative and an agonist which is the α-substituted propionic acid derivative and is selective for PPARγ.
Another object of the present invention is to provide a PPARγ transcription activator comprising the α-substituted propionic acid derivative as an active ingredient.
Furthermore, an object of the present invention is to provide a therapeutic and / or prophylactic agent for diseases (for example, cancer) caused by abnormal PPARγ transcriptional activity, comprising the α-substituted propionic acid derivative as an active ingredient.

As described above, although it is a PPAR agonist that is attracting attention as a therapeutic agent for metabolic syndrome and cancer such as abnormal fat metabolism, there are problems to be solved. Among existing PPAR agonists (eg, PPARγ agonists), compounds that induce side effects (eg, liver dysfunction, edema, weight gain, etc.) based on their potent agonist activity have been reported (JP 2007- 314464 and the like). Therefore, development of a PPAR agonist having higher pharmacological effect and less side effects (absolute or relative) and a therapeutic agent containing the same is desired even at this stage.
In light of the above circumstances, the present inventors have conducted extensive research and synthesized a novel α-substituted propionic acid derivative, which is an α-substituted propionic acid derivative that exhibits high agonist activity selective for PPARγ. The present invention was completed.

［式中、Ｒ_１はアダマンチル基、無置換又は置換基を有していても良いフェニル基、ピリジル基、ピリミジニル基、ピラジニル基、ピペリジン基、アゼピル基若しくはピペラジニル基（置換基は、ハロゲン原子）、あるいは、２−チエニル基、モルホリノ基、Ｒ_２及びＲ_４は同一又は相異なって水素原子又はハロゲン原子、Ｒ_３は炭素数１から１０の直鎖状又は分岐状アルキル基、Ｒ_５は置換基を有していても良いフェニル基又はシクロヘキシル基（置換基は、ハロゲン原子、炭素数１から１０の直鎖状又は分岐状アルキル基、炭素数１から１０の直鎖状又は分岐状アルコキシ基）、ｎは０から１０の整数を表す］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学上許容される塩又は水和物である。
さらに、本発明は上記一般式（Ｉ）で表されるα−置換フェニルプロピオン酸誘導体であるＰＰＡＲγに選択的なアゴニストである。 That is, the present invention relates to the general formula (I):

[Wherein R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ and R ₄ are the same or different and are a hydrogen atom or a halogen atom, R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, and R ₅ is a substituted group Phenyl group or cyclohexyl group which may have a group (the substituent is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms) ), N represents an integer of 0 to 10] or a pharmaceutically acceptable salt or hydrate thereof.
Furthermore, the present invention is an agonist selective for PPARγ, which is an α-substituted phenylpropionic acid derivative represented by the above general formula (I).

  The present invention also provides a PPARγ transcription activator comprising an α-substituted phenylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

  Furthermore, the present invention is a medicament containing an α-substituted phenylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

［式中、Ｒ_１はアダマンチル基、無置換又は置換基を有していても良いフェニル基、ピリジル基、ピリミジニル基、ピラジニル基、ピペリジン基、アゼピル基若しくはピペラジニル基（置換基は、ハロゲン原子）、あるいは、２−チエニル基、モルホリノ基、Ｒ_２及びＲ_４は同一又は相異なって水素原子又はハロゲン原子、Ｒ_３は炭素数１から１０の直鎖状又は分岐状アルキル基を表す］

［式中、Ｒ_３は炭素数１から１０の直鎖状又は分岐状アルキル基、Ｒ_４は水素原子又はハロゲン原子、Ｒ_５は置換基を有していても良いフェニル基又はシクロヘキシル基（置換基は、ハロゲン原子、炭素数１から１０の直鎖状又は分岐状アルキル基、炭素数１から１０の直鎖状又は分岐状アルコキシ基）、Ｐは、不斉補助基又は炭素数１から１０の直鎖状又は分岐状アルキル基、ｎは０から１０の整数を表す］ Moreover, this invention is a compound of the following general formula (II) and general formula (III) suitable for manufacture of the compound represented by the said general formula (I).

[Wherein R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ and R ₄ are the same or different and represent a hydrogen atom or a halogen atom, and R ₃ represents a linear or branched alkyl group having 1 to 10 carbon atoms.

[Wherein R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, R ₄ is a hydrogen atom or a halogen atom, R ₅ is a phenyl group or a cyclohexyl group (substituted) which may have a substituent. Group is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms), and P is an asymmetric auxiliary group or 1 to 10 carbon atoms. A linear or branched alkyl group, and n represents an integer of 0 to 10.]

  According to the present invention, a novel α-substituted phenylpropionic acid derivative and an α-substituted phenylpropionic acid derivative which are selective to PPARγ are provided. The present invention also provides a PPARγ transcription activator.

  Furthermore, according to the present invention, diseases caused by abnormal PPARγ transcription activity such as cancer, metabolic syndrome (eg, diabetes, hyperlipidemia, hypercholesterolemia, hypertension, obesity, arteriosclerosis, etc.) Prophylactic or therapeutic agents are provided.

  In addition, the compound represented by the general formula (I) of the present invention can be rapidly and efficiently produced by using the intermediate compound of the general formula (II) or the general formula (III).

Effect of the compound of the present invention on proliferation of cancer cells. The apoptosis induction effect (apoptosis) with respect to the cancer cell (OCUM-2MD3) of the compound of this invention (compound of Example 1) and the proliferation inhibitory effect (growth inhibition) are shown. The compound of Example 1 was used at 0.1, 1, 10, 100 μM. As a control, experiments were carried out by adding DMSO alone (cont) or troglitazone (Tro; 10 μM, 100 μM). Effect of the compounds of the present invention on normal cells. The apoptosis induction rate with respect to the cancer cell (OCUM-2MD3) and the normal cell (OUMS-24) of the compound of the present invention (compounds of Example 1, Example 13 and Example 15) is shown.

One embodiment of the present invention is an α-substituted propionic acid derivative represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof, or the α-substituted propionic acid derivative. It is an agonist selective for PPARγ. Here, the “agonist” is a compound that binds to PPARγ and induces transcriptional activation of a target gene by PPARγ.
In the general formula (I), R ₁ represents an adamantyl group, an unsubstituted or substituted phenyl group, an unsubstituted or optionally substituted pyridyl group, an unsubstituted or substituted group. A pyrimidinyl group which may have, a pyrazinyl group which may be unsubstituted or substituted, a piperidine group which may be unsubstituted or substituted, an unsubstituted or substituted group It is a good azepyr group, an unsubstituted or optionally substituted piperazinyl group, or a 2-thienyl group or a morpholino group. Here, as a substituent of the phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group, and piperazinyl group having a substituent, for example, a halogen atom is preferable, and a fluorine atom is particularly preferable.
R ₂ and R ₄ are the same or different and are a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom.
R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms, and more preferably a propyl group.
R ₅ is a phenyl group or a cyclohexyl group which may have a substituent, and the substituent of the phenyl group or cyclohexyl group having a substituent is a halogen atom, a linear or branched alkyl having 1 to 10 carbon atoms. A straight-chain or branched alkoxy group having 1 to 10 carbon atoms, preferably a phenyl group, a fluorophenyl group or a cyclohexyl group, more preferably a phenyl group or a fluorophenyl group. Although the position of the substituent of R ₅ is arbitrary, for example, the 2-position, 4-position, etc. are preferable. n represents an integer of 0 to 10, preferably an integer of 1 to 3.

The compound of the present invention represented by the general formula (I) is not only an α-substituted propionic acid derivative represented by the general formula (I) but also a salt thereof, a solvate or a hydrate thereof. good. The salt of the α-substituted propionic acid derivative is not particularly limited, and a conventional salt, for example, an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; Examples include metal salts such as aluminum salts, preferably pharmaceutically acceptable.
Further, unless otherwise specified, the α-substituted propionic acid derivative represented by the general formula (I) includes tautomers, geometric isomers (for example, E isomer, Z isomer, etc.), enantiomers and the like. Stereoisomers are also included. That is, when one or more asymmetric carbons are contained in the α-substituted propionic acid derivative represented by the general formula (I), the stereochemistry of the asymmetric carbon is independently (R ) Form or (S) form, and may exist as stereoisomers such as enantiomers or diastereoisomers of the derivatives.
As the active ingredient of the medicament of the present invention, any stereoisomer in a pure form, any mixture of stereoisomers, racemate and the like can be used.

  Moreover, other embodiment of this invention is a compound shown by general formula (II) or general formula (III). The compound represented by general formula (II) or general formula (III) is a compound suitable for producing an α-substituted propionic acid derivative of general formula (I).

In the general formula (II), R ₁ has an adamantyl group, an unsubstituted or substituted phenyl group, an unsubstituted or optionally substituted pyridyl group, an unsubstituted or substituted group. An optionally substituted pyrimidinyl group, an unsubstituted or optionally substituted pyrazinyl group, an unsubstituted or optionally substituted piperidine group, an unsubstituted or optionally substituted group. An azepyr group, an unsubstituted or optionally substituted piperazinyl group, or a 2-thienyl group, a morpholino group, and a substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group As a substituent of azepyr group and piperazinyl group, for example, a halogen atom is preferable, and a fluorine atom is particularly preferable. Preferable R _{1 includes} an adamantyl group, a pyrimidin-2-yl group, and a piperidinyl group.
R ₂ is a hydrogen atom or a halogen atom, preferably a halogen atom, particularly preferably a fluorine atom. R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms, and more preferably a propyl group. R ₄ represents a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom.

In the general formula (III), R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, preferably a linear alkyl group having 1 to 5 carbon atoms, and more preferably a propyl group. R ₄ represents a hydrogen atom or a halogen atom, preferably a hydrogen atom or a fluorine atom. R ₅ is a phenyl group or a cyclohexyl group which may have a substituent, and the substituent of the phenyl group or cyclohexyl group having a substituent is a halogen atom, a linear or branched alkyl having 1 to 10 carbon atoms. A straight-chain or branched alkoxy group having 1 to 10 carbon atoms, preferably a phenyl group, a fluorophenyl group or a cyclohexyl group, more preferably a phenyl group or a fluorophenyl group. Although the position of the substituent of R ₅ is arbitrary, for example, the 2-position, 4-position, etc. are preferable. n represents an integer of 0 to 10, preferably an integer of 1 to 3. P is an asymmetric auxiliary group. Any known chiral auxiliary can be used as long as the reaction is not hindered. For example, 4-benzyl oxazolidinone, 4-isopropyl oxazolidinone, etc. can be mentioned.

Examples of agonists and salts thereof selective for PPARγ represented by the general formula (I) include, but are not limited to, the following.
(R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid,
(S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid,
(S) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid,
(R) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid,
(R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid,
(S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid,
(2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
(3-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
(4-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
2-benzyl-3- (2-fluoro-5-((2-fluoro-4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
2- (2-fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid,
2- (2-Fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid.
(R) -2-benzyl-3- (4-propoxy-3-((4- (pyrimidin-2-yl) benzamido) methyl) phenyl) propanoic acid (R) -2-benzyl-3- (4-propoxy -3-((4- (thiophen-2-yl) benzamido) methyl) phenyl) propanoic acid (R) -2-benzyl-3- (3-((4- (piperidin-1-yl) benzamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3-((2'-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2- Benzyl-3- (3-((3′-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3-((2′6′di Fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3- (2′-methylbiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl ) Propanoic acid (R) -2-benzyl-3- (3- (biphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

Among the compounds represented by the general formula (I) of the present invention, an optically active compound (Ia) in which R ₄ is a hydrogen atom and R ₅ is an unsubstituted phenyl group can be produced by the following method ( Scheme 1).

［式中、Ｒ_１はアダマンチル基、無置換又は置換基を有していても良いフェニル基、ピリジル基、ピリミジニル基、ピラジニル基、ピペリジン基、アゼピル基若しくはピペラジニル基（置換基は、ハロゲン原子）、あるいは、２−チエニル基、モルホリノ基、Ｒ_２は同一又は相異なって水素原子又はハロゲン原子、Ｒ_３は炭素数１から１０の直鎖状又は分岐状アルキル基、ｎは０から１０の整数を表す］
で表される化合物は、以下の：

［式中、Ｒ_３は前記と同義である］で表される化合物（Ａ）と、以下の：

［式中、ｎは前記と同義である］で表される化合物（Ｇ）とを反応させ（第一工程）、得られた以下の：

［式中、Ｒ_３及びｎは前記と同義である］で表される化合物（Ｂ）を還元する（第二工程）ことにより製造することができる以下の：

［式中、Ｒ_３及びｎは前記と同義である］で表される化合物（Ｃ）を還元する（第三工程）ことにより製造することができる以下の：

［式中、Ｒ_３及びｎは前記と同義である］で表される化合物（Ｄ）を酸化する（第四工程）ことにより製造することができる以下の：

［式中、Ｒ_３及びｎは前記と同義である］で表される化合物（Ｅ）と以下の：

［式中、Ｒ_１及びＲ_２は前記と同義である］で表わされる化合物（Ｈ）を還元的アミドアルキル化（第五工程）ことにより製造することができる以下の：、

［式中、Ｒ_１、Ｒ_２、Ｒ_３およびｎは前記と同義である］で表わされる化合物（Ｆ）の不斉補助基を脱保護する（第六工程）ことにより合成することができる。 That is, the general formula (Ia):

[Wherein, R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ is the same or different and is a hydrogen atom or a halogen atom, R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, and n is an integer of 0 to 10 Represents]
The compound represented by:

[Wherein R ₃ is as defined above] and the following:

[Wherein n has the same meaning as described above] (G) is reacted (first step), and the following:

[Wherein R ₃ and n are as defined above], which can be produced by reducing (second step) the following compound (B):

[Wherein R ₃ and n are as defined above], which can be produced by reducing (third step) the following compound (C):

[Wherein R ₃ and n are as defined above] can be produced by oxidizing (fourth step) the following compound (D):

[Wherein R ₃ and n are as defined above] and the following:

[Wherein R ₁ and R ₂ are as defined above], which can be produced by reductive amide alkylation (fifth step),

[Wherein R ₁ , R ₂ , R ₃ and n are as defined above] can be synthesized by deprotecting the asymmetric auxiliary group of the compound (F) (sixth step).

  The reaction in the first step is carried out by using, for example, an alkali metal hydride such as sodium hydride, an organometallic compound such as butyl lithium, lithium diisopropylamide, sodium bis (trimethylsilyl) amide as a base in a solvent such as tetrahydrofuran, diethyl ether or hexane. A metal amide such as can be used. The reaction can be carried out at a temperature from -100 ° C to room temperature, preferably -80 ° C to 0 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

  The reaction in the second step is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, rhodium-supported alumina, etc. in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and the like. It can be carried out at 1 kPa to 491 kPa. The reaction temperature can be 0 to 150 ° C., preferably room temperature to 100 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.

  The reaction in the third step can be carried out using a base such as borane THF complex or diisobutylaluminum hydride as a base in a solvent such as tetrahydrofuran, diethyl ether or hexane. The reaction can be performed at -50 ° C to 100 ° C, preferably -20 ° C to 50 ° C. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

  The reaction in the fourth step can be carried out using a base oxidizing agent such as activated manganese dioxide, pyridinium chlorochromate or pyridinium dichromate as an oxidizing agent in a solvent such as methylene chloride or chloroform. The reaction temperature may be -50 ° C to 100 ° C, preferably -0 ° C to the reflux temperature of the solvent. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

  The reaction of the fifth step is the presence of triethylsilane as a reducing agent in the presence of an acid (for example, trifluoroacetic acid, trifluoromethanesulfonic acid) in a solvent such as toluene, benzene, acetonitrile, dioxane, 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 reaction in the sixth step can be carried out under alkaline conditions. As alkaline conditions, a mixture of lithium hydroxide and hydrogen peroxide is used. The reaction can be carried out at a temperature of -20 ° C to 100 ° C, preferably 0 ° C to 50 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

Of the compounds represented by the general formula (I) of the present invention, R ₁ is an adamantyl group, R ₂ and R ₄ are fluorine atoms, R ₃ is a propyl group, R ₅ is a hydrogen atom, a halogen atom, and a carbon number. A linear or branched alkyl group having 1 to 10 carbon atoms, a phenyl group or cyclohexyl group having a linear or branched alkoxy group having 1 to 10 carbon atoms, and compound (Ib) in which n is 1 are obtained by the following method. Can be prepared (Scheme 2).

［式中、Ｒ_５は置換基を有していても良いフェニル基又はシクロヘキシル基（置換基は、ハロゲン原子、炭素数１から１０の直鎖状又は分岐状アルキル基、炭素数１から１０の直鎖状又は分岐状アルコキシ基）を表す］で表される化合物は、以下の：

で表される化合物（Ｉ）をホルミル化（第七工程）して得られる以下の：

化合物（Ｊ）と以下の：

化合物（O）とを還元的アミドアルキル化（第八工程）して得られる以下の：

化合物（Ｋ）をホルミル化する（第九工程）ことにより製造することができる以下の：

化合物（Ｌ）と以下の：

［式中、Ｒ_５は前記と同義である］で表される化合物（Ｐ）とを反応させる（第十工程）ことにより製造することができる以下の：

［式中、Ｒ_５は前記と同義である］で表される化合物（Ｍ）を還元する（第十一工程）ことにより製造することができる以下の：

［式中、Ｒ_５は前記と同義である］で表わされる化合物（Ｎ）を加水分解（第十二工程）することにより製造することができる。 That is, the general formula (Ib):

[Wherein, R ₅ is a phenyl group or a cyclohexyl group which may have a substituent (the substituent is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, or a group having 1 to 10 carbon atoms. The compound represented by] represents a linear or branched alkoxy group):

The following is obtained by formylation (seventh step) of the compound (I) represented by:

Compound (J) and the following:

The following obtained by reductive amide alkylation with compound (O) (8th step):

The following can be produced by formylating compound (K) (9th step):

Compound (L) and the following:

[Wherein R ₅ is as defined above] (10th step) and can be produced by reacting the compound (P):

[Wherein R ₅ has the same meaning as described above] and can be produced by reducing (eleventh step) the following compound (M):

[Wherein, R ₅ has the same meaning as described above] can be produced by hydrolyzing (step 12).

  The reaction in the seventh step is produced using dichloromethyl methyl ether as a formylating agent in a solvent such as dichloromethane, chloroform, carbon tetrachloride, and further using titanium tetrachloride, titanium tetraisopropoxide, or aluminum chloride as a Lewis acid. I can do things. The reaction can be carried out at a temperature from -100 ° C to room temperature, preferably -80 ° C to 0 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

  The reaction in the eighth step is the presence of triethylsilane as a reducing agent in the presence of an acid (for example, trifluoroacetic acid, trifluoromethanesulfonic acid) in a solvent such as toluene, benzene, acetonitrile, dioxane, 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 reaction in the ninth step is produced using dichloromethyl methyl ether as a formylating agent in a solvent such as dichloromethane, chloroform, carbon tetrachloride, and further using titanium tetrachloride, titanium tetraisopropoxide, or aluminum chloride as a Lewis acid. I can do things. The reaction can be carried out at a temperature from -100 ° C to room temperature, preferably -80 ° C to 0 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

  The reaction in the tenth step is carried out in a solvent such as tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, as a base, for example, an alkali metal hydride such as sodium hydride, an organometallic compound such as butyl lithium, lithium diisopropylamide And metal alkoxides such as sodium methoxide and potassium t-butoxide can be used. The reaction can be performed at -20 ° C to 150 ° C, preferably 0 ° C to 50 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

  The reaction in the eleventh step is carried out in the presence of a metal catalyst such as palladium-supported activated carbon, platinum-supported activated carbon, platinum oxide, rhodium-supported alumina, etc. in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and the like. It can be carried out at 1 kgf / cm 2 to 5 kgf / cm 2. The reaction temperature can be 0 to 100 ° C., preferably room temperature to 80 ° C. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

  The reaction in the twelfth step can be performed under alkaline conditions. As alkaline conditions, lithium hydroxide, sodium hydroxide, potassium hydroxide or the like is used. The reaction temperature can be 0 to 80 ° C., preferably room temperature to 60 ° C. The reaction time is usually 1 to 48 hours, preferably 2 to 24 hours.

  The present invention includes a PPARγ transcription activator (an agent that activates (or induces) transcription of a PPARγ target gene) containing an α-substituted propionic acid derivative represented by the general formula (I).

Furthermore, a pharmaceutical that is an α-substituted propionic acid derivative of the present invention and contains an agonist selective for PPARγ is also included in the scope of the present invention.
The medicament of the present invention can be used as a therapeutic or prophylactic agent for diseases that develop due to abnormal regulation of PPARγ, in particular, suppression of its activity. In addition to the fact that thiazolidine derivatives, which are existing agonists of PPARγ, improve insulin resistance (for example, Yamauchi et al., J. Biol. Chem., 276: 41245-41254, 2001) and are effective in adjusting blood glucose levels , Blood free fatty acid, TG lowering action, HDL-C increasing action and the like have been confirmed (for example, Lee et al., Endocrinology, 144: 2201-2207, 2003, etc.), and PPARγ agonists are diabetes and hyperlipidemia. It is known that it can be used for the treatment of diseases related to metabolic syndrome. Furthermore, the expression of PPARγ has been confirmed in many cancer cells such as colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymphoid leukemia cells (Non-Patent Documents 3 to 5). ). In addition, since thiazolidinediones (TZDs), which are PPARγ agonists, inhibit the growth of various different types of tumor cells (gastrointestinal, bile duct and pancreatic adenocarcinoma) (Non-patent Document 4), It can also be used as an anticancer agent.

  A pharmaceutical comprising an agonist selective for PPARγ represented by the general formula (I) is based on metabolic syndrome such as abnormal lipid metabolism, hyperlipidemia, diabetes, hypertension, hypercholesterolemia, obesity, and the like, and metabolic syndrome For example, it can be used as a therapeutic or prophylactic agent for arteriosclerotic diseases. Furthermore, a medicament containing an agonist selective for PPARγ represented by the general formula (I) is a therapeutic or preventive agent for cancer, such as colon cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer, myeloid leukemia cells and lymph. It can be used as a therapeutic or preventive agent for adenocarcinoma that develops in the gastrointestinal tract, bile duct, pancreas, etc. in addition to leukemia cells. In addition, the medicament of the present invention containing the compound represented by the general formula (I) includes signet ring cell carcinoma (including advanced poorly differentiated adenocarcinoma, non-solid type (including Sirrrhous), etc.) among gastric adenocarcinoma It can also be used for treatment.

In addition to the compound represented by the above general formula (I), physiologically acceptable salts thereof may be used as the active ingredient of the medicament of the present invention. Examples of the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris ( A salt of an amine such as hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine; Salts with basic amino acids such as δ-hydroxylysine and arginine can be formed. If basic groups are present, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
Furthermore, a solvate or hydrate of the compound represented by the general formula (I) or a salt thereof can be used as the active ingredient of the medicament of the present invention.

  The medicament of the present invention may be administered with an active ingredient compound represented by general formula (I) and a pharmacologically acceptable salt thereof, or a solvate thereof or a hydrate thereof. However, it is generally desirable to administer in the form of a pharmaceutical composition comprising the compound of general formula (I) as the active ingredient and one or more pharmaceutical additives. As an active ingredient of the medicament of the present invention, two or more compounds of the general formula (I) can be used in combination, and the pharmaceutical composition includes cancer, diabetes, hyperlipidemia, hypercholesterolemia, hypertension. It is also possible to formulate other known active ingredients for the prevention or treatment of various symptoms such as symptom, obesity and arteriosclerosis.

  The type of pharmaceutical composition is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, An injection agent etc. are mentioned. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. good. It is provided in any dosage form for oral or parenteral administration. For example, a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, for intravenous administration, for intramuscular administration, Alternatively, it can be prepared as a pharmaceutical composition for parenteral administration in the form of injections, drops, transdermal absorbents, transmucosal absorbents, nasal drops, inhalants, suppositories, etc. for subcutaneous administration. Injections, infusions, and the like can be prepared as powdered dosage forms such as freeze-dried forms, and can be used by dissolving in an appropriate aqueous medium such as physiological saline at the time of use. It is also possible to administer a sustained release preparation coated with a polymer directly into the brain.

  A person skilled in the art can appropriately select the type of pharmaceutical additive used for the production of the pharmaceutical composition, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical composition depending on the form of the composition. It is. As the additive for preparation, an inorganic or organic substance, or a solid or liquid substance can be used, and generally it can be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient. Specifically, examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium. , Ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polyso Bate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.

  In order to produce a solid preparation for oral administration, an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules. In order to produce tablets, these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate and talc. These granules or tablets may be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained preparation. it can. In order to produce capsules, powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.

  In order to produce injections, active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc. It can be dissolved in distilled water for injection together with an isotonic agent, filtered aseptically and filled into ampoules, or further lyophilized by adding mannitol, dextrin, cyclodextrin, gelatin, etc. . In addition, reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to give an emulsion for injection.

  To produce a rectal dosage form, the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient is made of polyethylene. After dissolving in glycol, soybean oil, etc., it may be covered with a gelatin film.

  The dose and frequency of administration of the medicament of the present invention are not particularly limited, and conditions such as prevention and / or progression of the disease to be treated and / or purpose of treatment, type of disease, patient weight and age, severity of the disease, etc. Depending on the situation, it is possible to make an appropriate selection based on the judgment of the doctor. In general, the dose per day for an adult is about 0.01 to 1000 mg (weight of active ingredient), and can be administered once or several times a day or every few days. it can. When used as an injection, daily doses of 0.001 to 100 mg (active ingredient weight) are preferably administered continuously or intermittently to adults.

  The medicament of the present invention can be prepared as a sustained-release preparation such as a delivery system encapsulated in implantable tablets and microcapsules using a carrier that can prevent immediate removal from the body. As the carrier, for example, biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, and polylactic acid can be used. 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.

The medicament of the present invention can be included as a pharmaceutical composition in the form of a kit together with instructions for administration in a container or pack. When the pharmaceutical composition of the present invention is supplied as a kit, different components of the 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.
The reagent contained in the kit is supplied into a container made of a material that maintains the activity of the component effectively for a long period of time, does not adsorb inside the container, and does not alter the component. For example, the sealed glass ampoule may include a buffer sealed in the presence of a neutral and non-reactive gas such as nitrogen gas. The ampoule is composed of glass, polycarbonate, organic polymers such as polystyrene, ceramic, metal, or any other suitable material commonly used to hold reagents.

  In addition, instructions for use may be attached to the kit. Instructions for using the kit are printed on paper and / or electrically and / or electromagnetically readable such as floppy disk, CD-ROM, DVD-ROM, Zip disk, video tape, audio tape, etc. It may be stored in a medium and supplied to the user. The 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 includes diseases that develop due to abnormal PPARγ transcription activity (for example, cancer, diabetes, hyperlipidemia, hypercholesterolemia, hypertension, obesity, arteriosclerosis, etc.). Prophylactic or therapeutic methods are included.
Here, “treatment” means to prevent or alleviate the progression and worsening of the disease state in a mammal suffering from a disease that develops due to abnormal PPARγ transcriptional activity. And treatment aimed at preventing or mitigating exacerbations.
In addition, “prevention” means to prevent in advance the onset or illness of a mammal that is likely to suffer from a disease or the like that develops due to an abnormality in PPARγ transcriptional activity. It is a treatment aimed at preventing the onset of various symptoms.

  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, cats, rabbits, cows, pigs, sheep , Livestock animals such as horses. Particularly preferred “mammals” are humans.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

式（Ｉ）の化合物の１つである（Ｒ）−２−（（３−（（（４−（１−アダマンチル）ベンゾイル）アミノ）メチル）−４−プロポキシフェニル）メチル）−３−フェニルプロパン酸を以下の通り合成した。 [Example 1] (R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid Synthesis example

(R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropane which is one of the compounds of formula (I) The acid was synthesized as follows.

（４Ｓ）−４−ベンジル−３−（３−フェニルプロパノイル）オキサゾリジン−２−オン（０．７４ｇ，２．３７ｍｍｏｌ）と脱水ＴＨＦ（２０ｍｌ）をアルゴン雰囲気下混合した。反応液を−５０℃に冷却し、ＬｉＨＭＤＳのＴＨＦ溶液（８．０ｍｌ，８．０ｍｍｏｌ）をシリンジで注加した。同温度で２０分撹拌後、−１５℃に昇温後さらに２５分撹拌した。再度−５０℃に冷却し、ベンジル ５−（ブロモメチル）−２−プロポキシ−ベンゾアート（０．８６ｇ，２．３７ｍｍｏｌ）を脱水ＴＨＦ（１０ｍｌ）に溶かした溶液をゆっくり滴下した。反応液は７５分かけて段階的に−５０℃から０℃に昇温させた。０℃ にてさらに１時間撹拌後１０％塩化アンモニウム水溶液中に反応液を注加し、酢酸エチル抽出（５×３０ｍｌ）した。 抽出液は飽和食塩水で洗浄後無水硫酸マグネシウム乾燥し、濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ９：２ ｖ／ｖ）、黄色油状の目的化合物を０．８９ｇ、収率６４％で得た。
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９２ Ｃ_３７Ｈ_３７ＮＯ_６ Synthesis of benzyl 5-((R) -2-benzyl-3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -3-oxopropyl) -2-propoxybenzoate

(4S) -4-benzyl-3- (3-phenylpropanoyl) oxazolidine-2-one (0.74 g, 2.37 mmol) and dehydrated THF (20 ml) were mixed in an argon atmosphere. The reaction solution was cooled to −50 ° C., and a solution of LiHMDS in THF (8.0 ml, 8.0 mmol) was added by syringe. After stirring at the same temperature for 20 minutes, the temperature was raised to −15 ° C., followed by further stirring for 25 minutes. The solution was cooled again to −50 ° C., and a solution of benzyl 5- (bromomethyl) -2-propoxy-benzoate (0.86 g, 2.37 mmol) in dehydrated THF (10 ml) was slowly added dropwise. The reaction solution was heated from −50 ° C. to 0 ° C. stepwise over 75 minutes. After further stirring at 0 ° C. for 1 hour, the reaction solution was poured into 10% aqueous ammonium chloride solution and extracted with ethyl acetate (5 × 30 ml). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 9: 2 v / v) to obtain 0.89 g of the target compound as a yellow oil in a yield of 64%.
MS (FAB, (M + H) ⁺ ) m / z 592 C ₃₇ H ₃₇ NO ₆

１０％ Ｐｄ／Ｃ （０．２０ｇ）、上記ベンジル ５−［（Ｒ）−２−ベンジル−３−［（Ｓ）−４−ベンジル−２−オキソ−オキサゾリジン−３−イル］−３−オキソプロピル］−２−プロポキシベンゾアート（０．８９ｇ，１．５０ｍｍｏｌ）及びＡｃＯＥｔ（８０ｍｌ）を混合した。反応液を室温にて２．２５時間接触還元を行った。反応液をセライトろ過し、ろ液を濃縮し、酢酸エチルで洗浄後ろ液と洗浄液を合わせ濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ５：２ ｖ／ｖ）、無色油状の目的化合物を０．４１ｇ、収率５５％で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１０．９８（ｓ，１Ｈ），８．０６（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），７．２４−７．２２（ｍ，５Ｈ），７．２０−７．１６（ｍ，３Ｈ），７．０３（ｄｄ，Ｊ＝７．２，２．０Ｈｚ，２Ｈ），６．９７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．５６−４．４８（ｍ，１Ｈ），４．４６−４．４０（ｍ，１Ｈ），４．２２−４．１３（ｍ，２Ｈ），３．９７（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，２Ｈ），３．８１（ｔ，Ｊ＝８．２Ｈｚ，１Ｈ），３．１６（ｄｄ，Ｊ＝１３．８，８．２Ｈｚ，１Ｈ），３．０８−２．９８（ｍ，２Ｈ），２．８４−２．７６（ｍ，２Ｈ），２．５４（ｄｄ，Ｊ＝１３．４，９．４Ｈｚ，１Ｈ），１．９６−１．８８（ｍ，２Ｈ），１．０８（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５０２ Ｃ_３０Ｈ_３１ＮＯ_６． Synthesis of 5-((R) -2-benzyl-3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -3-oxopropyl) -2-propoxybenzoic acid

10% Pd / C (0.20 g), benzyl 5-[(R) -2-benzyl-3-[(S) -4-benzyl-2-oxo-oxazolidine-3-yl] -3-oxopropyl ] -2-propoxybenzoate (0.89 g, 1.50 mmol) and AcOEt (80 ml) were mixed. The reaction solution was subjected to catalytic reduction at room temperature for 2.25 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 5: 2 v / v) to obtain 0.41 g of the target compound as a colorless oil in a yield of 55%.
¹ H NMR (400 MHz, CDCl ₃ ) δ 10.98 (s, 1 H), 8.06 (d, J = 2.4 Hz, 1 H), 7.52 (dd, J = 8.4, 2.4 Hz, 1 H ), 7.24-7.22 (m, 5H), 7.20-7.16 (m, 3H), 7.03 (dd, J = 7.2, 2.0 Hz, 2H), 6.97. (D, J = 8.4 Hz, 1H), 4.56-4.48 (m, 1H), 4.46-4.40 (m, 1H), 4.22-4.13 (m, 2H) 3.97 (dd, J = 8.8, 2.4 Hz, 2H), 3.81 (t, J = 8.2 Hz, 1H), 3.16 (dd, J = 13.8, 8.2 Hz) , 1H), 3.08-2.98 (m, 2H), 2.84-2.76 (m, 2H), 2.54 (dd, J = 13.4, 9.4 Hz, 1H), 1 96-1.88 m, 2H), 1.08 (t, J = 7.2Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 502 C 30 H 31 NO 6.

上記５−［（Ｒ）−２−ベンジルｌ−３−［（Ｓ）−４−ベンジル−２−オキソ−オキサゾリジン−３−イル］−３−オキソ−プロピル］−２−プロポキシ安息香酸（０．４１ｇ，０．８２ｍｍｏｌ）と脱水ＴＨＦ（３０ｍｌ）を混合した。アルゴン雰囲気下反応液を０℃に冷却し、１ｍｏｌ／ＬのＢＨ３−ＴＨＦコンプレックス１．６０ｍＬ（１．６０ｍｍｏｌ）をシリンジで滴下した。反応液は０℃で２時間撹拌後室温にて一晩撹拌した。反応液を飽和塩化アンモニウム水溶液中に注加し、酢酸エチルにて抽出した。抽出液は飽和食塩水洗浄後無水硫酸マグネシウム乾燥し濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ３：１ ｖ／ｖ）、無色油状の目的化合物を０．４０ｇ、収率１００％で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．２８−７．１５（ｍ，１０Ｈ），６．９９（ｄｄ，Ｊ＝７．２，２．０Ｈｚ，２Ｈ），６．７８（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．６６（ｄ，Ｊ＝６．４Ｈｚ，２Ｈ），４．６０−４．５３（ｍ，１Ｈ），４．４３−４．３８（ｍ，１Ｈ），３．９８−３．８９（ｍ，２Ｈ），３．７７（ｔ，Ｊ＝８．２Ｈｚ，１Ｈ），３．０８（ｄｄ，Ｊ＝１３．４，８．６Ｈｚ，１Ｈ），３．０１−２．９４（ｍ，２Ｈ），２．８５−２．７５（ｍ．２Ｈ），２．４９（ｄｄ，Ｊ＝１３．４，９．４Ｈｚ，１Ｈ），２．３７（ｔ，Ｊ＝６．６Ｈｚ，１Ｈ），１．８５−１．７６（ｍ，２Ｈ），１．０３（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ４８８ Ｃ_３０Ｈ_３３ＮＯ_５． Synthesis of (S) -4-benzyl-3-((R) -2-benzyl-3- (3- (hydroxymethyl) -4-propoxyphenyl) propanoyl) oxazolidine-2-one

5-[(R) -2-Benzyll-3-[(S) -4-benzyl-2-oxo-oxazolidine-3-yl] -3-oxo-propyl] -2-propoxybenzoic acid (0. 41 g, 0.82 mmol) and dehydrated THF (30 ml) were mixed. The reaction solution was cooled to 0 ° C. under an argon atmosphere, and 1.60 mL (1.60 mmol) of 1 mol / L BH3-THF complex was added dropwise with a syringe. The reaction was stirred at 0 ° C. for 2 hours and then at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 3: 1 v / v) to obtain 0.40 g of the target compound as a colorless oil in a yield of 100%.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28-7.15 (m, 10H), 6.99 (dd, J = 7.2, 2.0 Hz, 2H), 6.78 (d, J = 8 .4 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.60-4.53 (m, 1H), 4.43-4.38 (m, 1H), 3.98. -3.89 (m, 2H), 3.77 (t, J = 8.2 Hz, 1H), 3.08 (dd, J = 13.4, 8.6 Hz, 1H), 3.01-2. 94 (m, 2H), 2.85-2.75 (m.2H), 2.49 (dd, J = 13.4, 9.4 Hz, 1H), 2.37 (t, J = 6.6 Hz) , 1H), 1.85-1.76 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 488 C 30 H 33 NO 5.

活性化二酸化マンガン（５．７ｇ，６５．６ｍｍｏｌ）、上記（Ｓ）−４−ベンジル−３−［（Ｒ）−２−ベンジル−３−［３−（ヒドロキシメチル）−４−プロポキシ−フェニル］プロパノイル］オキサゾリジン−２−オン（０．４０ｇ，３．０ｍｍｏｌ）とＣＨ２Ｃｌ２（４０ｍｌ）を混合し２３時間還流した。反応液をアセトンで希釈しセライトを通して反応液を濾過し、ろ液を濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ３：１ ｖ／ｖ）、無色油状の目的化合物を０．２０ｇ、収率５０％で得た。
^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１０．４７（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），７．７０（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．４９（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），７．２７−７．１６（ｍ，８Ｈ），７．０１（ｄｄ，Ｊ＝７．４，１．８Ｈｚ，２Ｈ），６．９０（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），４．５６−４．４８（ｍ，１Ｈ），４．４５−４．３９（ｍ，１Ｈ），４．０３−３．９７（ｍ，２Ｈ），３．９５（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），３．８０（ｔ，Ｊ＝８．４Ｈｚ，１Ｈ），３．１２（ｄｄ，Ｊ＝１３．６，８．８Ｈｚ，１Ｈ），３．０５−２．９７（ｍ，２Ｈ），２．７９（ｄｄ，Ｊ＝１４．０，６．４Ｈｚ，２Ｈ），２．５１（ｄｄ，Ｊ＝１３．２，９．２Ｈｚ，１Ｈ），１．８９−１．８０（ｍ，２Ｈ），１．０５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ４８６ Ｃ_３０Ｈ_３１ＮＯ_５． Synthesis of 5-[(R) -2-benzyl-3-[(S) -4-benzyl-2-oxo-oxazolidine-3-yl] -3-oxo-propyl] -2-propoxybenzaldehyde

Activated manganese dioxide (5.7 g, 65.6 mmol), (S) -4-benzyl-3-[(R) -2-benzyl-3- [3- (hydroxymethyl) -4-propoxy-phenyl] above Propanoyl] oxazolidine-2-one (0.40 g, 3.0 mmol) and CH 2 Cl 2 (40 ml) were mixed and refluxed for 23 hours. The reaction solution was diluted with acetone, filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 3: 1 v / v) to obtain 0.20 g of the target compound as a colorless oil in a yield of 50%.
¹ H NMR (400 MHz, CDCl ₃ ) δ 10.47 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.4) , 2.4 Hz, 1H), 7.27-7.16 (m, 8H), 7.01 (dd, J = 7.4, 1.8 Hz, 2H), 6.90 (d, J = 8. 8 Hz, 1H), 4.56-4.48 (m, 1H), 4.45-4.39 (m, 1H), 4.03-3.97 (m, 2H), 3.95 (dd, J = 8.8, 2.4 Hz, 1H), 3.80 (t, J = 8.4 Hz, 1H), 3.12 (dd, J = 13.6, 8.8 Hz, 1H), 3.05 -2.97 (m, 2H), 2.79 (dd, J = 14.0, 6.4 Hz, 2H), 2.51 (dd, J = 13.2, 9.2 Hz, 1H), 1. 89-1.8 (M, 2H), 1.05 (t, J = 7.4Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 486 C 30 H 31 NO 5.

４−（１−アダマンチル）ベンズアミド（０．２７ｇ，１．０３ｍｍｏｌ）、上記５−［（Ｒ）−２−ベンジル−３−［（Ｓ）−４−ベンジル−２−オキサゾリジン−３−イル］−３−オキソ−プロピル］−２−プロポキシ−ベンズアルデヒド（０．２０ｇ，０．４１ｍｍｏｌ）、トリエチルシラン（０．１６ｍｌ，１．０３ｍｍｏｌ）、ＴＦＡ（０．０８ｍｌ，１．０３ｍｍｏｌ）および脱水トルエン（３０ｍｌ）を混合し、アルゴン雰囲気下４９時間加熱還流した。水（１００ｍｌ）に反応液を注加し、酢酸エチルで抽出した。抽出液は飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、ろ過後濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ２：１ ｖ／ｖ）、褐色油状の目的化合物を０．２９ｇ、収率９７％で得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．６１（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．３５（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．２８−７．１６（ｍ，１０Ｈ），６．８８−６．８５（ｍ，２Ｈ），６．８０（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．７１（ｔ，Ｊ＝５．７Ｈｚ，１Ｈ），４．７０−４．５２（ｍ，３Ｈ），４．４２−４．３４（ｍ，１Ｈ），３．９８−３．８８（ｍ，２Ｈ），３．７４（ｔ，Ｊ＝８．４Ｈｚ，１Ｈ），３．０７（ｄｄ，Ｊ＝１３．８，８．７Ｈｚ，１Ｈ），３．０１−２．８４（ｍ，２Ｈ），２．７９（ｄｄ，Ｊ＝１３．８，６．３Ｈｚ，２Ｈ），２．４８（ｄｄ，Ｊ＝１３．２，９．０Ｈｚ，１Ｈ），２．１０（ｓ，３Ｈ），１．８９−１．７２（ｍ，１４Ｈ），１．０３（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ７２５ Ｃ_４７Ｈ_５２Ｎ_２Ｏ_５． 4- (1-adamantyl) -N-[[5-[(R) -2-benzyl-3-[(S) -4-benzyl-2-oxo-oxazolidine-3-yl] -3-oxo-propyl ] -2-Propoxyphenyl] methyl] benzamide

4- (1-adamantyl) benzamide (0.27 g, 1.03 mmol), 5-[(R) -2-benzyl-3-[(S) -4-benzyl-2-oxazolidine-3-yl]- 3-Oxo-propyl] -2-propoxy-benzaldehyde (0.20 g, 0.41 mmol), triethylsilane (0.16 ml, 1.03 mmol), TFA (0.08 ml, 1.03 mmol) and dehydrated toluene (30 ml) Were mixed and heated to reflux under an argon atmosphere for 49 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 2: 1 v / v) to obtain 0.29 g of the target compound as a brown oil in a yield of 97%.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.28-7.16 (m, 10H) ), 6.88-6.85 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 5.7 Hz, 1H), 4.70-4. .52 (m, 3H), 4.42-4.34 (m, 1H), 3.98-3.88 (m, 2H), 3.74 (t, J = 8.4 Hz, 1H), 3 .07 (dd, J = 13.8, 8.7 Hz, 1H), 3.01-2.84 (m, 2H), 2.79 (dd, J = 13.8, 6.3 Hz, 2H), 2.48 (dd, J = 13.2, 9.0 Hz, 1H), 2.10 (s, 3H), 1.89-1.72 (m, 14H), 1.03 (t, J = 7 .5Hz, 3H ;
^{MS (FAB, (M + H} ) +) m / z 725 C 47 H 52 N 2 O 5.

Final of (R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid (target compound of Example 1) Synthesis process 30% H ₂ O ₂ (0.4 mL, 4.0 mmol), 4- (1-adamantyl) -N-[[5-[(R) -2-benzyl-3-[(S ) -4-Benzyl-2-oxo-oxazolidin-3-yl] -3-oxo-propyl] -2-propoxyphenyl] methyl] benzamide (290 mg, 0.4 mmol), THF (24 ml), water (6 ml). Then, lithium hydroxide monohydrate (100 mg, 2.38 mmol) was dissolved in water (2 ml) and added. Under an argon atmosphere, the reaction solution was stirred at 0 ° C. for 2.5 hours and at room temperature for 3 hours, and then NaHSO ₃ (1.0 g) was dissolved in H ₂ O (6 ml) and added to the reaction solution. The reaction mixture was diluted with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 2: 1 v / v) to obtain 0.19 g of a colorless powdery target compound (target compound of Example 1) in a yield of 86%. It was.
mp 177-178 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.26-7.14 (m, 6H) ), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.77-6.70 (m, 2H), 4.64-4.51 (m, 2H), 3.94. (T, J = 6.5 Hz, 2H), 3.01-2.71 (m, 5H), 2.10 (s, 3H), 1.90-1.72 (m, 14H), 1.06 (T, J = 7.4 Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 566 C 37 H 43 NO 4.
[Α] D −3 ° (c0.10, CH ₃ CN, 26 ° C.).

実施例１と同様の操作により、実施例２の化合物を合成した。
ｍｐ １７７−１７８℃．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．６８（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．２６−７．１４（ｍ，６Ｈ），７．０３（ｄｄ，Ｊ＝８．１，１．８Ｈｚ，１Ｈ），６．７７−６．７０（ｍ，２Ｈ），４．６４−４．５１（ｍ，２Ｈ），３．９４（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），３．０１−２．７１（ｍ，５Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．７２（ｍ，１４Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋）ｍ／ｚ ５６６ Ｃ_３７Ｈ_４３ＮＯ_４．
［α］Ｄ ＋３°（ｃ０．１０，ＣＨ_３ＣＮ，２６℃）． [Example 2] (S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid [Chemical Formula 30] Synthesis example

The compound of Example 2 was synthesized in the same manner as in Example 1.
mp 177-178 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.26-7.14 (m, 6H) ), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.77-6.70 (m, 2H), 4.64-4.51 (m, 2H), 3.94. (T, J = 6.5 Hz, 2H), 3.01-2.71 (m, 5H), 2.10 (s, 3H), 1.90-1.72 (m, 14H), 1.06 (T, J = 7.4 Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 566 C 37 H 43 NO 4.
[Α] D + 3 ° (c0.10, CH ₃ CN, 26 ° C).

実施例１と同様の操作により、実施例３の化合物を合成した。
ｍｐ １４０−１４１℃．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．６９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．２６−７．１３（ｍ，６Ｈ），７．０２（ｄｄ，Ｊ＝８．４，２．１Ｈｚ，１Ｈ），６．７６−６．７０（ｍ，２Ｈ），４．５９（ｄ，Ｊ＝４．５Ｈｚ，２Ｈ），３．９３（ｔ，Ｊ＝６．４５Ｈｚ，２Ｈ），２．９１（ｄｄ，Ｊ＝１３．１，７．７Ｈｚ，１Ｈ），２．７７−２．５３（ｍ，４Ｈ），２．１０（ｓ，３Ｈ），２．０４−１．７２（ｍ，１７Ｈ），１．０５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５８０ Ｃ_３８Ｈ_４５ＮＯ_４．
［α］Ｄ −４°（ｃ０．２５，ＣＨ_３ＣＮ，２２℃）． Example 3 Synthesis Example of (S) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid [Chemical Formula 31]

The compound of Example 3 was synthesized by the same operation as in Example 1.
mp 140-141 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.26-7.13 (m, 6H) ), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 6.76-6.70 (m, 2H), 4.59 (d, J = 4.5 Hz, 2H), 3 .93 (t, J = 6.45 Hz, 2H), 2.91 (dd, J = 13.1, 7.7 Hz, 1H), 2.77-2.53 (m, 4H), 2.10 ( s, 3H), 2.04-1.72 (m, 17H), 1.05 (t, J = 7.4 Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 580 C 38 H 45 NO 4.
[Α] D -4 ° (c0.25 , CH 3 CN, 22 ℃).

実施例１と同様の操作により、実施例４の化合物を合成した。
ｍｐ １４０−１４１℃．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．６９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．１Ｈｚ，２Ｈ），７．２６−７．１３（ｍ，６Ｈ），７．０２（ｄｄ，Ｊ＝８．４，２．１Ｈｚ，１Ｈ），６．７６−６．６９（ｍ，２Ｈ），４．５９（ｄ，Ｊ＝４．５Ｈｚ，２Ｈ），３．９３（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），２．９１（ｄｄ，Ｊ＝１３．１，７．７Ｈｚ，１Ｈ），２．７７−２．５３（ｍ，４Ｈ），２．１０（ｓ，３Ｈ），２．０４−１．７２（ｍ，１７Ｈ），１．０５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５８０ Ｃ_３８Ｈ_４５ＮＯ_４．
［α］Ｄ＋４°（ｃ０．２５，ＣＨＣｌ_３，２２℃）． Example 4 Synthesis of (R) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid

The compound of Example 4 was synthesized in the same manner as in Example 1.
mp 140-141 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.26-7.13 (m, 6H) ), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 6.76-6.69 (m, 2H), 4.59 (d, J = 4.5 Hz, 2H), 3 .93 (t, J = 6.5 Hz, 2H), 2.91 (dd, J = 13.1, 7.7 Hz, 1H), 2.77-2.53 (m, 4H), 2.10 ( s, 3H), 2.04-1.72 (m, 17H), 1.05 (t, J = 7.4 Hz, 3H);
^{MS (FAB, (M + H} ) +) m / z 580 C 38 H 45 NO 4.
[Α] D + 4 ° (c 0.25, CHCl ₃ , 22 ° C.).

実施例１と同様の操作により、実施例５の化合物を合成した。
ｍｐ １７７−１７８℃．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．７０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．１４（ｓ，１Ｈ），７．０４（ｄｄ，Ｊ＝８．４，２．１Ｈｚ，１Ｈ），６．７８−６．７０（ｍ，２Ｈ），４．６５−４．５３（ｍ，２Ｈ），３．９５（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），２．８７−２．６４（ｍ，３Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．５４（ｍ，２０Ｈ），１．３４−１．１２（ｍ，５Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），０．９２−０．７３（ｍ，２Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５７２ Ｃ_３７Ｈ_４９ＮＯ_４．
［α］Ｄ −５．５°（ｃ０．５０，ＣＨＣｌ_３，２３℃）． [Example 5] (R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid [Chemical Formula 33] Synthesis example

The compound of Example 5 was synthesized in the same manner as in Example 1.
mp 177-178 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7. 04 (dd, J = 8.4, 2.1 Hz, 1H), 6.78-6.70 (m, 2H), 4.65-4.53 (m, 2H), 3.95 (t, J = 6.5 Hz, 2H), 2.87-2.64 (m, 3H), 2.10 (s, 3H), 1.90-1.54 (m, 20H), 1.34-1.12. (M, 5H), 1.06 (t, J = 7.4 Hz, 3H), 0.92-0.73 (m, 2H);
^{MS (FAB, (M + H} ) +) m / z 572 C 37 H 49 NO 4.
[Α] D −5.5 ° (c 0.50, CHCl ₃ , 23 ° C.).

実施例１と同様の操作により、実施例６の化合物を合成した。
ｍｐ １７７−１７８℃．
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．７０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．１４（ｓ，１Ｈ），７．０３（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．７８−６．７０（ｍ，２Ｈ），４．６５−４．５３（ｍ，２Ｈ），３．９５（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），２．８７−２．６４（ｍ，３Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．５４（ｍ，２０Ｈ），１．３４−１．１２（ｍ，５Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），０．９２−０．７３（ｍ，２Ｈ）；
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５７２ Ｃ_３７Ｈ_４９ＮＯ_４．
［α］Ｄ ＋５．５°（ｃ０．５０，ＣＨＣｌ_３，２１℃）． [Example 6] (S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid [Chemical Formula 34] Synthesis example

The compound of Example 6 was synthesized in the same manner as in Example 1.
mp 177-178 ° C.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7. 03 (dd, J = 8.4, 2.4 Hz, 1H), 6.78-6.70 (m, 2H), 4.65-4.53 (m, 2H), 3.95 (t, J = 6.5 Hz, 2H), 2.87-2.64 (m, 3H), 2.10 (s, 3H), 1.90-1.54 (m, 20H), 1.34-1.12. (M, 5H), 1.06 (t, J = 7.4 Hz, 3H), 0.92-0.73 (m, 2H);
^{MS (FAB, (M + H} ) +) m / z 572 C 37 H 49 NO 4.
[Α] D + 5.5 ° (c 0.50, CHCl ₃ , 21 ° C.).

式（Ｉ）の化合物の１つである（２−フルオロベンジル）−３−（３−（（４−アダマンチルベンズアミド）メチル）−４−プロポキシフェニル）プロパン酸〔化３５〕の合成例を以下に示す。
式（Ｉ）を合成するための中間化合物である式（ＩＩ）の化合物の１つである４−アダマンチル−２−フルオロ−Ｎ−（４−フルオロ−５−ホルミル−２−プロポキシベンジル）ベンズアミド〔化３６〕を以下のように合成した。

Example 7 Synthesis Example of (2-Fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid [Chemical Formula 35]

A synthesis example of (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid [Chemical Formula 35], which is one of the compounds of formula (I), is shown below. Show.
4-adamantyl-2-fluoro-N- (4-fluoro-5-formyl-2-propoxybenzyl) benzamide, one of the compounds of formula (II), which is an intermediate compound for the synthesis of formula (I) [ Embedded image was synthesized as follows.

３−フルオロフェノール（２．００ｇ，１７．８ｍｍｏｌ）とＤＭＦ（６ｍｌ）を混合し、１−ヨードプロパン（４．２５ｇ，２５．０ｍｍｏｌ）および無水炭酸カリウム、Ｋ２ＣＯ_３（２．７６ｇ，２０．０ｍｍｏｌ）を加え、室温にて一晩撹拌した。反応液は飽和塩化アンモニウム水溶液中に注加し、塩化メチレンで抽出した。抽出液は飽和食塩水で洗浄し、無水硫酸マグネシウム乾燥後、ろ過、濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン）、無色油状の目的化合物を２．４９ｇ、収率９１％で得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ７．２０（ｑ，Ｊ＝７．７Ｈｚ，１Ｈ），６．６９−６．５９（ｍ，３Ｈ），３．９０（ｔ，Ｊ＝６．７Ｈｚ，２Ｈ），１．８１（ｍ， ２Ｈ），１．０４（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ） Synthesis of 3-fluoro-1-propoxybenzene

Mixed 3- fluorophenol (2.00 g, 17.8 mmol) and DMF to (6 ml), 1-iodopropane (4.25 g, 25.0 mmol) and anhydrous potassium _carbonate, K2CO 3 _(2.76g, 20.0mmol ) And stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane) to obtain 2.49 g of the target compound as a colorless oil in a yield of 91%.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 7.20 (q, J = 7.7 Hz, 1H), 6.69-6.59 (m, 3H), 3.90 (t, J = 6.7 Hz, 2H), 1.81 (m, 2H), 1.04 (t, J = 7.6 Hz, 3H)

上記３−フルオロ−１−プロポキシベンゼン（２．３９ｇ，１５．５ｍｍｏｌ）とＣＨ_２Ｃｌ_２（１００ｍＬ）を混合し−７８℃に冷却した。次にＴｉＣｌ４（５ｍＬ）、ＣＨＣｌ_２ＯＣＨ_３（２ｍＬ）を順次加え同温度で３０分撹拌した。室温に戻しさらに一晩撹拌した。反応液は２ｍｏｌ／Ｌ塩酸中に注加し、塩化メチレンにて抽出した。抽出液は飽和食塩水で洗浄し、無水硫酸マグネシウム乾燥後、ろ過、濃縮した。残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ ５：１ ｖ／ｖ）、無色油状の目的化合物を１．７４ｇ、収率６２％で得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ１０．３９（ｓ，１Ｈ），７．８３（ｔ，Ｊ＝７．９Ｈｚ，１Ｈ），６．７０−６．６４（ｍ，２Ｈ），４．００（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），１．８７（ｍ，２Ｈ），１．０６（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ） Synthesis of 4-fluoro-2-propoxybenzaldehyde

The above 3-fluoro-1-propoxybenzene (2.39 g, 15.5 mmol) and CH ₂ Cl ₂ (100 mL) were mixed and cooled to −78 ° C. Next, TiCl 4 (5 mL) and CHCl ₂ OCH ₃ (2 mL) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. The mixture was returned to room temperature and further stirred overnight. The reaction solution was poured into 2 mol / L hydrochloric acid and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 5: 1 v / v) to obtain 1.74 g of the target compound as a colorless oil in a yield of 62%.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 10.39 (s, 1 H), 7.83 (t, J = 7.9 Hz, 1 H), 6.70-6.64 (m, 2 H), 4.00 (T, J = 6.4 Hz, 2H), 1.87 (m, 2H), 1.06 (t, J = 7.6 Hz, 3H)

上記４−フルオロ−２−プロポキシベンズアルデヒド（６６１ｍｇ，３．６３ｍｍｏｌ）、２−フルオロ−４−アダマンチルベンズアミド（〔化１８〕）（１．０２ｇ，３．７３ｍｍｏｌ）、トルエン（０．５ｍＬ）を混合し、トリフルオロ酢酸（０．５ｍＬ）、トリエチルシラン（１．６ｍＬ）を順次加えた。アルゴン雰囲気下、８０℃にて３日撹拌した。反応液を濃縮し、残留物はシリカゲルカラムクロマトグラフィーにて精製し（ｎ−ヘキサン／ＡｃＯＥｔ １０／１から５／１ ｖ／ｖ）、無色油状の目的化合物を１．０５ｇ、収率６６％で得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ８．０４（ｔ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３０−７．２３（ｍ，３Ｈ），７．０５（ｄ，Ｊ＝１４．６Ｈｚ，１Ｈ），６．６１−６．５８（ｍ，２Ｈ），４．６１（ｄ，Ｊ＝５．５Ｈｚ，２Ｈ），３．９５（ｔ，Ｊ＝６．４ Ｈｚ，２Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．７２（ｍ，１４Ｈ），１．０８（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）；
ＭＳ （ＦＡＢ） ４４０ （Ｍ＋Ｈ）^＋ Synthesis of 4-adamantyl-2-fluoro-N- (4-fluoro-2-propoxybenzyl) benzamide

4-fluoro-2-propoxybenzaldehyde (661 mg, 3.63 mmol), 2-fluoro-4-adamantylbenzamide ([Chemical Formula 18]) (1.02 g, 3.73 mmol), and toluene (0.5 mL) were mixed. , Trifluoroacetic acid (0.5 mL) and triethylsilane (1.6 mL) were sequentially added. The mixture was stirred at 80 ° C. for 3 days under an argon atmosphere. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt 10/1 to 5/1 v / v). 1.05 g of the target compound as a colorless oil, yield 66% Obtained.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.04 (t, J = 8.5 Hz, 1H), 7.30-7.23 (m, 3H), 7.05 (d, J = 14.6 Hz, 1H), 6.61-6.58 (m, 2H), 4.61 (d, J = 5.5 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 2.10 (S, 3H), 1.90-1.72 (m, 14H), 1.08 (t, J = 7.3 Hz, 3H);
MS (FAB) 440 (M + H) ⁺

Next, the 4-adamantyl-2-fluoro-N- (4-fluoro-2-propoxybenzyl) benzamide (1.01 g, 2.30 mmol) and CH ₂ Cl ₂ (20 mL) were mixed and brought to −78 ° C. Cooled down. Next, TiCl ₄ (1.0 mL) and CHCl ₂ OCH ₃ (0.3 mL) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. The mixture was returned to room temperature and further stirred for 3 hours. The reaction solution was poured into 2 mol / L hydrochloric acid and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt 5: 1 v / v) to obtain 1.02 g of the target compound (compound of [Chemical Formula 36]) as a colorless powder in a yield of 62%. .
¹ H-NMR (500 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 8.04 (t, J = 8.5 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7 .26-7.21 (m, 2H), 7.07 (dd, J = 14.6, 1.8 Hz, 1H), 6.62 (d, J = 12.2 Hz, 1H), 4.64 ( d, J = 5.5 Hz, 2H), 4.04 (t, J = 6.7 Hz, 2H), 2.11 (s, 3H), 1.93-1.73 (m, 14H), 1. 09 (t, J = 7.3 Hz, 3H);
MS (FAB) 468 (M + H) ⁺

^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ９．８７（ｓ，１Ｈ），７．８６（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），７．８２（ｄｄ，Ｊ＝８．４，２．１Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４３（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．５９（ｔ，Ｊ＝５．７Ｈｚ，１Ｈ），４．７０（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），４．０９（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），２．１１（ｓ，３Ｈ），１．９０−１．７３（ｍ，１４Ｈ），１．１０（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ４３２ Ｃ_２８Ｈ_３３ＮＯ_３ Similarly to the synthesis of [Chemical Formula 36], synthesis of 4-adamantyl-N- (5-formyl-2-propoxybenzyl) benzamide (compound of [Chemical Formula 40]), which is one of the compounds of formula (II), is also possible. went.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.87 (s, 1H), 7.86 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.4, 2.1 Hz, 1H ), 7.73 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.59 (T, J = 5.7 Hz, 1H), 4.70 (d, J = 6.0 Hz, 2H), 4.09 (t, J = 6.5 Hz, 2H), 2.11 (s, 3H) 1.90-1.73 (m, 14H), 1.10 (t, J = 7.4 Hz, 3H)
MS (FAB, (M + H) ⁺ ) m / z 432 C ₂₈ H ₃₃ NO ₃

カリウムｔｅｒｔ−ブトキシド（０．３６ｇ，３．２ｍｍｏｌ）の脱水ＴＨＦ（２０ｍＬ）溶液に０℃、アルゴン雰囲気下、ホスホノ酢酸トリメチル（０．４３ｍＬ，２．７ ｍｍｏｌ）を加え３０分撹拌した。次に２−フルオロベンジルブロミド（０．３２ｍＬ，２．７ｍｍｏｌ）の脱水ＴＨＦ溶液（１０ｍＬ）を加えた後、室温で１９時間撹拌した。反応液を水（５０ｍＬ）中にあけ、酢酸エチル（３０ｍｌ×５）で抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥後濃縮した。残留物をシリカゲルカラムクロマトグラフィー（溶出液 ｎ−ヘキサン：酢酸エチル＝１：１ ｖ／ｖ）で精製し、０．６６ｇ（８６％）の表題化合物を無色油状物質として得た。
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ２９１ Ｃ_１２Ｈ_１６ＦＯ_５Ｐ Synthesis of methyl 2- (dimethoxyphosphoryl) -3- (2-fluorophenyl) propanoate

Trimethylphosphonoacetate (0.43 mL, 2.7 mmol) was added to a dehydrated THF (20 mL) solution of potassium tert-butoxide (0.36 g, 3.2 mmol) in an argon atmosphere at 0 ° C. and stirred for 30 minutes. Next, a dehydrated THF solution (10 mL) of 2-fluorobenzyl bromide (0.32 mL, 2.7 mmol) was added, followed by stirring at room temperature for 19 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 ml × 5). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 1: 1 v / v) to obtain 0.66 g (86%) of the title compound as a colorless oil.
MS (FAB, (M + H) ⁺ ) m / z 291 C ₁₂ H ₁₆ FO ₅ P

〔化４１〕の化合物と同様にして、表題化合物を得た。
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ２９１ Ｃ_１２Ｈ_１６ＦＯ_５Ｐ Synthesis of methyl 2- (dimethoxyphosphoryl) -3- (3-fluorophenyl) propanoate

In the same manner as in the compound of [Chemical Formula 41], the title compound was obtained.
MS (FAB, (M + H) ⁺ ) m / z 291 C ₁₂ H ₁₆ FO ₅ P

カリウムｔｅｒｔ−ブトキシド（０．１５ｇ，１．３４ｍｍｏｌ）の脱水ＴＨＦ（２０ｍＬ）溶液に０℃、アルゴン雰囲気下、化合物メチル ２−（ジメトキシホスホリル）−３−（２−フルオロフェニル）プロパノアート（〔化４１〕の化合物）（０．３０ｇ，１．０３ｍｍｏｌ）の脱水ＴＨＦ（４ｍＬ）溶液を加え、３０分撹拌した。次にアルデヒド誘導体（〔化４０〕の化合物）（０．４５ｇ，１．０３ｍｍｏｌ）の脱水ＴＨＦ溶液（４ｍＬ）を加えた後、室温で１６時間撹拌した。反応液を水（５０ｍＬ）中にあけ、酢酸エチル（３０ｍｌ×５）で抽出した。有機層を飽和食塩水で、洗浄後無水硫酸マグネシウムで乾燥後濃縮した。残留物をシリカゲルカラムクロマトグラフィー（溶出液 ｎ−ヘキサン：酢酸エチル＝４：１ ｖ／ｖ）で精製し、０．４２ｇ（６９％）の表題化合物を無色油状物質として得た。
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９７ Ｃ_３８Ｈ_４４ＦＮＯ_４ Synthesis of methyl 2- (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) acrylate

To a solution of potassium tert-butoxide (0.15 g, 1.34 mmol) in dehydrated THF (20 mL) at 0 ° C. under an argon atmosphere, the compound methyl 2- (dimethoxyphosphoryl) -3- (2-fluorophenyl) propanoate ( ] (0.30 g, 1.03 mmol) in dehydrated THF (4 mL) was added and stirred for 30 minutes. Next, a dehydrated THF solution (4 mL) of an aldehyde derivative (compound of [Chemical Formula 40]) (0.45 g, 1.03 mmol) was added, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 ml × 5). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 4: 1 v / v) to obtain 0.42 g (69%) of the title compound as a colorless oil.
MS (FAB, (M + H) ⁺ ) m / z 597 C ₃₈ H ₄₄ FNO ₄

メチル ２−（２−フルオロベンジル）−３−（３−（（４−アダマンチルベンズアミド）メチル）−４−プロポキシフェニル）アクリラート（０．４２ｇ，０．７０ｍｍｏｌ） の酢酸エチル（３０ｍＬ）溶液に、１０％パラジウム担持活性炭（５０ｍｇ）を加え、室温、２００−３００ｋＰａ水素加圧化２時間水素添加した。触媒をセライトで濾取し、酢酸エチルで洗浄した。濾液を濃縮し、残留物をシリカゲルカラムクロマトグラフィー（溶出液、ｎ−ヘキサン：酢酸エチル＝４：１ ｖ／ｖ）で精製し、０．３７ｇ（８９％）の表題化合物を無色油状物質として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）＝δ７．７０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．２４−７．１０（ｍ，３Ｈ），７．０５−６．９５（ｍ，３Ｈ），４．６１（ｄ，Ｊ＝５．７Ｈｚ，２Ｈ），３．９６（ｔ，Ｊ＝６．３Ｈｚ，２Ｈ），３．５０（ｓ，３Ｈ），３．００−２．８９（ｍ，４Ｈ），２，７４（ｄｄ，Ｊ＝１３．２，４．８Ｈｚ，１Ｈ），２．１０（ｓ，３Ｈ），１．９１−１．７０（ｍ，１４Ｈ），１．０６（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ）
ＭＳ （ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９８ Ｃ_３８Ｈ_４４ＦＮＯ_４ Synthesis of methyl (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoate

To a solution of methyl 2- (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) acrylate (0.42 g, 0.70 mmol) in ethyl acetate (30 mL) was added 10 % Palladium on activated carbon (50 mg) was added and hydrogenated at room temperature and 200-300 kPa hydrogen pressure for 2 hours. The catalyst was filtered off through celite and washed with ethyl acetate. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluent, n-hexane: ethyl acetate = 4: 1 v / v) to give 0.37 g (89%) of the title compound as a colorless oil. It was.
¹ H NMR (300 MHz, CDCl ₃ ) = δ 7.70 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.24-7.10 (m, 3H), 7.05-6.95 (m, 3H), 4.61 (d, J = 5.7 Hz, 2H), 3.96 (t, J = 6.3 Hz, 2H), 3.50 ( s, 3H), 3.00-2.89 (m, 4H), 2, 74 (dd, J = 13.2, 4.8 Hz, 1H), 2.10 (s, 3H), 1.91- 1.70 (m, 14H), 1.06 (t, J = 7.2 Hz, 3H)
MS (FAB, (M + H) ⁺ ) m / z 598 C ₃₈ H ₄₄ FNO ₄

Final synthetic process of (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid (compound of [Chemical Formula 35]) ) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoate (0.37 g, 0.62 mmol) in an ethanol solution of 2 mol / L sodium hydroxide (3.1 mL, 6 0.2 mmol) and stirred at 60 ° C. for 48 hours. The reaction mixture was concentrated, 10% hydrochloric acid was added until the solution reached pH 1, and the resulting solid was stirred and filtered. The obtained solid was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent n-hexane: ethyl acetate = 2: 1 v / v), and 0.32 g (89%) of the title compound (target compound of [Example 7]) was white. Obtained as a solid.
m. p. 158-159 ° C
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.21-7.15 (m, 3H ), 7.06-6.95 (m, 3H), 6.77-6.72 (m, 2H), 4.57 (d, J = 5.4 Hz, 2H), 3.94 (t, J = 6.5 Hz, 2H), 2.98-2.80 (m, 4H), 2.76 (dd, J = 13.8, 4.8 Hz, 1H), 2.10 (s, 3H), 1 .90-1.71 (m, 14H), 1.06 (t, J = 7.4 Hz, 3H)
MS (FAB, M + H) ⁺ ) m / z 584 C ₃₇ H ₄₂ NO ₄ F

[Example 8] Synthesis example of (2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid [Chemical Formula 45]

〔化４３〕の合成操作と同様にして、表題化合物を得た。
ＭＳ（ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９７ Ｃ_３８Ｈ_４４ＦＮＯ_４ Synthesis of methyl 2- (3-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) acrylate

The title compound was obtained in the same manner as in the synthetic operation of [Chemical Formula 43].
MS (FAB, (M + H) ⁺ ) m / z 597 C ₃₈ H ₄₄ FNO ₄

〔化４４〕の合成操作と同様にして、表題化合物を無色油状物質として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．７０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．２４−７．１７（ｍ，１Ｈ），７．１０（ｓ，１Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．９２−６．７６（ｍ，４Ｈ），６．６６（ｔ，Ｊ＝５．７Ｈｚ，１Ｈ），４．６１（ｄ，Ｊ＝５．７Ｈｚ，２Ｈ），３．９６（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），３．５１（ｓ，３Ｈ），２．９３−２．８６（ｍ，３Ｈ），２．８０−２．６９（ｍ，２Ｈ），２．１０（ｓ，３Ｈ），１．９０−１．７２（ｍ，１４Ｈ），１．０７（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ）．
ＭＳ （ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９８ Ｃ_３８Ｈ_４４ＦＮＯ_４ Synthesis of methyl (3-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoate

In the same manner as in the synthesis operation of [Chemical Formula 44], the title compound was obtained as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.24-7.17 (m, 1H ), 7.10 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.92-6.76 (m, 4H), 6.66 (t, J = 5.7 Hz) , 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.96 (t, J = 6.5 Hz, 2H), 3.51 (s, 3H), 2.92-2.86. (M, 3H), 2.80-2.69 (m, 2H), 2.10 (s, 3H), 1.90-1.72 (m, 14H), 1.07 (t, J = 7 .5Hz, 3H).
MS (FAB, (M + H) ⁺ ) m / z 598 C ₃₈ H ₄₄ FNO ₄

Next, in the same manner as the compound of Example 7, the compound of Example 8 ([Chemical Formula 45]) was obtained.
m. p. 201-202 ° C
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.23-7.15 (m, 2H) ), 7.02 (dd, J = 2.1, 8.1 Hz, 1H), 6.94-6.85 (m, 3H), 6.78-6.71 (m, 2H), 4.58 (D, J = 5.4 Hz, 2H), 3.95 (t, J = 6.6 Hz, 2H), 2.99-2.87 (m, 3H), 2.79-2.72 (m, 2H), 2.09 (s, 3H), 1.90-1.71 (m, 14H), 1.06 (t, J = 7.35 Hz, 3H).
MS (FAB, (M + H) ⁺ ) m / z 584 C ₃₇ H ₄₂ FNO ₄

Example 9 Synthesis Example of (4-Fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid (compound of [Chemical Formula 48])

〔化４７〕の合成操作と同様にして、表題化合物を無色油状物質として得た。
^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．７０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．１２−７．０６（ｍ，３Ｈ），７．００（ｄｄ，Ｊ＝８．３，２．３Ｈｚ，１Ｈ），６．９３（ｔ，Ｊ＝８．７Ｈｚ，２Ｈ），６．７７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．６６（ｔ，Ｊ＝５．６Ｈｚ，１Ｈ），４．６１（ｄ，Ｊ＝５．７Ｈｚ，２Ｈ），３．９６（ｔ，Ｊ＝６．５Ｈｚ，２Ｈ），３．４９（ｓ，３Ｈ），２．９３−２．８４（ｍ，３Ｈ），２．７８−２．６６（ｍ，２Ｈ），２．１０（ｓ，３Ｈ），１．９１−１．７２（ｍ，１４Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ）．
ＭＳ （ＦＡＢ，（Ｍ＋Ｈ）^＋） ｍ／ｚ ５９８ Ｃ_３８Ｈ_４４ＦＮＯ_４ Synthesis of methyl- (4-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoate

In the same manner as in the synthesis procedure of [Chemical Formula 47], the title compound was obtained as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.12-7.06 (m, 3H ), 7.00 (dd, J = 8.3, 2.3 Hz, 1H), 6.93 (t, J = 8.7 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H) , 6.66 (t, J = 5.6 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.96 (t, J = 6.5 Hz, 2H), 3.49 ( s, 3H), 2.93-2.84 (m, 3H), 2.78-2.66 (m, 2H), 2.10 (s, 3H), 1.91-1.72 (m, 14H), 1.06 (t, J = 7.4 Hz, 3H).
MS (FAB, (M + H) ⁺ ) m / z 598 C ₃₈ H ₄₄ FNO ₄

Next, in the same manner as the compound of Example 7, the compound of Example 9 ([Chemical Formula 48]) was obtained.
m. p. 167-168 ° C
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.16-7.09 (m, 3H ), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 6.92 (t, J = 8.4 Hz, 2H), 6.77-6.73 (m, 2H), 4 .58 (d, J = 6.0 Hz, 2H), 3.95 (t, J = 6.5 Hz 2H), 2.96-2.85 (m, 3H), 2.76-2.68 (m , 2H), 2.10 (s, 3H), 1.90-1.71 (m, 14H), 1.06 (t, J = 7.4 Hz, 3H).
MS (FAB, (M + H) ⁺ ) m / z 584 C ₃₇ H ₄₂ NO ₄ F

実施例７と同様の操作により、実施例１０の化合物（〔化５０〕）を得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ８．００（ｔ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３５（ｍ，１Ｈ），７．２５−７．１５（ｍ，７Ｈ），７．０５（ｄｄ，Ｊ＝１４．６，１．８Ｈｚ，１Ｈ），６．５４（ｄ，Ｊ＝１１．６Ｈｚ，１Ｈ），４．５５（ｍ，２Ｈ），３．９１（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），３．０２−２．９６（ｍ，２Ｈ），２．８６−２．７７（ｍ，３Ｈ），２．１０（ｓ，３Ｈ），１．８７−１．７２（ｍ，１４Ｈ）， １．０６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）；
ＭＳ （ＦＡＢ） ６０２ （Ｍ＋Ｈ）^＋ [Example 10] Synthesis example of 2-benzyl-3- (2-fluoro-5-((2-fluoro-4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 10 ([Chemical Formula 50]) was obtained in the same manner as in Example 7.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.00 (t, J = 8.5 Hz, 1H), 7.35 (m, 1H), 7.25-7.15 (m, 7H), 7.05 (Dd, J = 14.6, 1.8 Hz, 1H), 6.54 (d, J = 11.6 Hz, 1H), 4.55 (m, 2H), 3.91 (t, J = 6. 4 Hz, 2H), 3.02-2.96 (m, 2H), 2.86-2.77 (m, 3H), 2.10 (s, 3H), 1.87-1.72 (m, 14H), 1.06 (t, J = 7.3 Hz, 3H);
MS (FAB) 602 (M + H) ⁺

実施例７の同様の操作により、実施例１１の化合物（〔化５１〕）を得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ８．０２（ｔ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３４（ｍ，１Ｈ），７．２４−７．１４（ｍ，７Ｈ），７．０４（ｄｄ，Ｊ＝１４．６，１．８Ｈｚ，１Ｈ），６．５４（ｄ，Ｊ＝１２．２Ｈｚ，１Ｈ），４．５５（ｓ，２Ｈ），３．９１（ｔ，Ｊ＝６．７Ｈｚ，２Ｈ），２．８６（ｍ，２Ｈ），２．７１（ｍ，２Ｈ）， ２．６０（ｍ，１Ｈ），２．０９（ｓ，３Ｈ），２．００−１．７２（ｍ，１６Ｈ），１．０６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）；
ＭＳ （ＦＡＢ） ６１６ （Ｍ＋Ｈ）^＋ [Example 11] Synthesis example of 2- (2-fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid

The compound of Example 11 ([Chemical Formula 51]) was obtained in the same manner as in Example 7.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.02 (t, J = 8.5 Hz, 1H), 7.34 (m, 1H), 7.24-7.14 (m, 7H), 7.04 (Dd, J = 14.6, 1.8 Hz, 1H), 6.54 (d, J = 12.2 Hz, 1H), 4.55 (s, 2H), 3.91 (t, J = 6. 7 Hz, 2H), 2.86 (m, 2H), 2.71 (m, 2H), 2.60 (m, 1H), 2.09 (s, 3H), 2.00-1.72 (m , 16H), 1.06 (t, J = 7.3 Hz, 3H);
MS (FAB) 616 (M + H) ⁺

実施例７と同様の操作により、実施例１２の化合物（〔化５２〕）を得た。
^１Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ_３）δ８．０２（ｔ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３３（ｍ，１Ｈ），７．２８−７．１２（ｍ，７Ｈ），７．０４（ｄｄ，Ｊ＝１４．６，１．８Ｈｚ，１Ｈ），６．５４（ｄ，Ｊ＝１１．６Ｈｚ，１Ｈ），４．５５（ｄ，Ｊ＝５．５Ｈｚ，２Ｈ），３．９１（ｔ，Ｊ＝６．７Ｈｚ，２Ｈ），２．８５−２．７７（ｍ，２Ｈ），２．６７−２．５７（ｍ，３Ｈ），２．１０（ｓ，３Ｈ），１．９２−１．５４（ｍ，１８Ｈ），１．０７（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ）；
ＭＳ （ＦＡＢ） ６３０ （Ｍ＋Ｈ）^＋ [Example 12] Synthesis example of 2- (2-fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid

The compound of Example 12 ([Chemical Formula 52]) was obtained in the same manner as in Example 7.
¹ H-NMR (500 MHz, CDCl ₃ ) δ 8.02 (t, J = 8.5 Hz, 1H), 7.33 (m, 1H), 7.28-7.12 (m, 7H), 7.04 (Dd, J = 14.6, 1.8 Hz, 1H), 6.54 (d, J = 11.6 Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.91 ( t, J = 6.7 Hz, 2H), 2.85-2.77 (m, 2H), 2.67-2.57 (m, 3H), 2.10 (s, 3H), 1.92- 1.54 (m, 18H), 1.07 (t, J = 7.3 Hz, 3H);
MS (FAB) 630 (M + H) ⁺

実施例１と同様の操作により、実施例１３の化合物〔化５３〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ１２．０６（ｓ，１Ｈ），８．９４（ｄ，Ｊ＝４．８Ｈｚ，２Ｈ），８．９１（ｔ，Ｊ＝５．８Ｈｚ，１Ｈ），８．４７（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），８．０４（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４９（ｔ，Ｊ＝４．８Ｈｚ，１Ｈ），７．１９−７．１６（ｍ，２Ｈ），７．１２−７．０９（ｍ，３Ｈ），７．０２−７．０１（ｍ，２Ｈ），６．８７（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），４．５０−４．４０（ｍ，２Ｈ），３．９３（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８２−２．７１（ｍ，３Ｈ），２．７０−２．５８（ｍ，２Ｈ），１．７７−１．６９（ｍ，２Ｈ），０．９８（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） Example 13 Synthesis example of (R) -2-benzyl-3- (4-propoxy-3-((4- (pyrimidin-2-yl) benzamido) methyl) phenyl) propanoic acid

The compound of Example 13 [Chemical Formula 53] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.94 (d, J = 4.8 Hz, 2H), 8.91 (t, J = 5.8 Hz, 1H), 8.47 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 4.8 Hz, 1H), 7.19-7 .16 (m, 2H), 7.12-7.09 (m, 3H), 7.02-7.01 (m, 2H), 6.87 (d, J = 9.2 Hz, 1H), 4 .50-4.40 (m, 2H), 3.93 (t, J = 6.4 Hz, 2H), 2.82-2.71 (m, 3H), 2.70-2.58 (m, 2H), 1.77-1.69 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１４の化合物〔化５４〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ１２．０５（ｓ，１Ｈ），８．８１（ｔ，Ｊ＝５．６Ｈｚ，１Ｈ），７．９４（ｔ，Ｊ＝８．８Ｈｚ，２Ｈ），７．７６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．６４（ｄｄ，Ｊ＝３．６，１．２Ｈｚ，１Ｈ），７．６２（ｄｄ，Ｊ＝５．２，１．２Ｈｚ，１Ｈ），７．１９−７．１５（ｍ，３Ｈ），７．１２−７．０９（ｍ，３Ｈ），７．０２−６．９９（ｍ，２Ｈ），６．８６（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．４９−４．３８（ｍ，２Ｈ），３．９２（ｔ，Ｊ＝６．２Ｈｚ，２Ｈ），２．８１−２．７１（ｍ，３Ｈ），２．６８−２．５６（ｍ，２Ｈ），１．７７−１．６８（ｍ，２Ｈ），０．９８（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） Example 14 Synthesis Example of (R) -2-Benzyl-3- (4-propoxy-3-((4- (thiophen-2-yl) benzamido) methyl) phenyl) propanoic acid

The compound [Chemical Formula 54] of Example 14 was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 7.94 (t, J = 8.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 3.6, 1.2 Hz, 1H), 7.62 (dd, J = 5.2, 1.2 Hz, 1H), 7.19-7.15 (m, 3H), 7.12-7.09 (m, 3H), 7.02-6.99 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.49-4.38 (m, 2H), 3.92 (t, J = 6.2 Hz, 2H), 2.81-2.71 (m, 3H), 2. 68-2.56 (m, 2H), 1.77-1.68 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１５の化合物〔化５５〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ１２．０５（ｓ，１Ｈ），８．４６（ｔ，Ｊ＝５．８Ｈｚ，１Ｈ），７．７６（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．１８−７．０８（ｍ，５Ｈ），６．９９（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），６．９５−６．９２（ｍ，３Ｈ），６．８４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．４４−４．３３（ｍ，２Ｈ），３．９１（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），３．２７（ｔ，Ｊ＝５．２Ｈｚ，４Ｈ），２．７７−２．６９（ｍ，３Ｈ），２．６５−２．５２（ｍ，２Ｈ），１．７７−１．６８（ｍ，２Ｈ），１．５７（ｓ，６Ｈ），０．９８（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） [Example 15] Synthesis example of (R) -2-benzyl-3- (3-((4- (piperidin-1-yl) benzamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 15 [Chemical Formula 55] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.46 (t, J = 5.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.18-7.08 (m, 5H), 6.99 (dd, J = 8.4, 2.0 Hz, 1H), 6.95-6.92 (m, 3H), 6.84 (d , J = 8.4 Hz, 1H), 4.44-4.33 (m, 2H), 3.91 (t, J = 6.4 Hz, 2H), 3.27 (t, J = 5.2 Hz, 4H), 2.77-2.69 (m, 3H), 2.65-2.52 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (s, 6H) , 0.98 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１６の化合物〔化５６〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．８０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５９（ｄｄ，Ｊ＝８．４，１．６Ｈｚ，２Ｈ），７．４３（ｄｔ，Ｊ＝７．６，１．８Ｈｚ，１Ｈ），７．３７−７．３２（ｍ，１Ｈ），７．２８−７．１４（ｍ，８Ｈ），６．８０−６．７６（ｍ，２Ｈ），４．６５−４．５６（ｍ，２Ｈ），３．９５（ｔ，Ｊ＝６．６Ｈｚ，２Ｈ），３．０１−２．８７（ｍ，３Ｈ），２．８２−２．７３（ｍ，２Ｈ），１．８８−１．７９（ｍ，２Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） [Example 16] Synthesis example of (R) -2-benzyl-3- (3-((2'-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

The compound [Chemical Formula 56] of Example 16 was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 8.4, 1.6 Hz, 2H), 7.43 (dt, J = 7.6, 1.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.28-7.14 (m, 8H), 6.80-6.76 (m, 2H) ), 4.65-4.56 (m, 2H), 3.95 (t, J = 6.6 Hz, 2H), 3.01-2.87 (m, 3H), 2.82-2.73. (M, 2H), 1.88-1.79 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１７の化合物〔化５７〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ８．８７（ｔ，Ｊ＝５．６Ｈｚ，１Ｈ），８．００（ｄ，Ｊ＝８．４，２Ｈ），７．８２（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．６１−７．５８（ｍ，２Ｈ），７．５５−７．４９（ｍ，１Ｈ），７．２３（ｄｔ，Ｊ＝８．８，１．６Ｈｚ，１Ｈ），７．１９−７．１５（ｍ，２Ｈ），７．１２−７．０９（ｍ，３Ｈ），７．０３−７．００（ｍ，２Ｈ），６．８６（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．５０−４．４０（ｍ，２Ｈ），３．９２（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．７９−２．７１（ｍ，３Ｈ），２．６９−２．５６（ｍ，２Ｈ），１．７７−１．６９（ｍ，２Ｈ），０．９９（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） Example 17 Synthesis Example of (R) -2-Benzyl-3- (3-((3′-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 17 [Chemical Formula 57] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.6 Hz, 1H), 8.00 (d, J = 8.4, 2H), 7.82 (d, J = 8 .8 Hz, 2H), 7.61-7.58 (m, 2H), 7.55-7.49 (m, 1H), 7.23 (dt, J = 8.8, 1.6 Hz, 1H) 7.19-7.15 (m, 2H), 7.12-7.09 (m, 3H), 7.03-7.00 (m, 2H), 6.86 (d, J = 8. 4 Hz, 1H), 4.50-4.40 (m, 2H), 3.92 (t, J = 6.4 Hz, 2H), 2.79-2.71 (m, 3H), 2.69- 2.56 (m, 2H), 1.77-1.69 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１８の化合物〔化５８〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δ１２．０６（ｓ，１Ｈ），７．９５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．４，２Ｈ），７．５３−７．４６（ｍ，１Ｈ），７．２５（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），７．１７−７．１４（ｍ，２Ｈ），７．１１−７．０９（ｍ，３Ｈ），７．０３−７．００（ｍ，２Ｈ），６．８７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），４．５１−４．４０（ｍ，２Ｈ），３．９３（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），２．８１−２．６９（ｍ，３Ｈ），２．６８−２．５７（ｍ，２Ｈ），１．７８−１．６９
（ｍ，２Ｈ），０．９９（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） [Example 18] Synthesis example of (R) -2-benzyl-3- (3-((2'6'fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 18 [Chemical Formula 58] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4, 2H), 7.53-7.46 (m, 1H), 7.25 (t, J = 8.2 Hz, 2H), 7.17-7.14 (m, 2H), 7.11-7.09 (m , 3H), 7.03-7.00 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 4.51-4.40 (m, 2H), 3.93 (t , J = 6.4 Hz, 2H), 2.81-2.69 (m, 3H), 2.68-2.57 (m, 2H), 1.78-1.69
(M, 2H), 0.99 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例１９の化合物〔化５９〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．７８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．３５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．２８−７．２２（ｍ，５Ｈ），７．２０−７．１７（ｍ，５Ｈ），７．０４（ｄｄ，Ｊ＝８．４，２．２Ｈｚ，１Ｈ），６．８１−６．７６（ｍ，２Ｈ），４．６５−４．５６（ｍ，２Ｈ），３．９６（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），３．０２−２．８７（ｍ，３Ｈ），２．８２−２．７３（ｍ，２Ｈ），２．２４（ｓ，３Ｈ），１．８８−１．８０（ｍ，２Ｈ），１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） [Example 19] Synthesis example of (R) -2-benzyl-3- (3- (2'-methylbiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 19 [Chemical Formula 59] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.28-7.22 (m, 5H), 7.20-7.17 (m, 5H), 7.04 (dd, J = 8.4, 2.2 Hz, 1H), 6.81-6.76 (m, 2H), 4. 65-4.56 (m, 2H), 3.96 (t, J = 6.4 Hz, 2H), 3.02-2.87 (m, 3H), 2.82-2.73 (m, 2H) ), 2.24 (s, 3H), 1.88-1.80 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H)

実施例１と同様の操作により、実施例２０の化合物〔化６０〕を得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．８０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．６３−７．５７（ｍ，４Ｈ），７．４５（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），７．３７（ｔ，Ｊ ＝７．４Ｈｚ，１Ｈ），７．２７−７．２３（ｍ，２Ｈ），７．０４（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．８１（ｔ，Ｊ＝５．８Ｈｚ，１Ｈ），６．７７（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），４．６５−４．５５（ｍ，２Ｈ），３．９５（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），３．０２−２．８６（ｍ，３Ｈ），２．８０−２．７３（ｍ，２Ｈ），１．８８−１．７９（ｍ，２Ｈ），１．０５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ） Example 20 Synthesis Example of (R) -2-Benzyl-3- (3- (biphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid

The compound of Example 20 [Chemical Formula 60] was obtained in the same manner as in Example 1.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.4 Hz, 2H), 7.63-7.57 (m, 4H), 7.45 (t, J = 7.4 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.27-7.23 (m, 2H), 7.04 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (t, J = 5.8 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.65-4.55 (m, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.02-2.86 (m, 3H), 2.80-2.73 (m, 2H), 1.88-1.79 (m, 2H), 1.05 (T, J = 7.4Hz, 3H)

[Experimental example]
1. Measurement of PPARγ agonist activity of compounds of the present invention Human fetal kidney cells (HEK293) cultured in Dulbecco's modified Eagle's medium (FCS / DMEM) containing 10% defatted bovine serum were added to yeast transcription factor (GAL4). A receptor plasmid that expresses a fusion protein of a DNA binding region and a ligand binding region of each subtype (α, δ, γ) of human PPAR, a reporter plasmid thereof, and a β-galactosidase plasmid for an internal standard by the calcium phosphate method Co-transfected in a serum-free state. Thereafter, the luciferase activity and β-galactosidase activity were measured 16 hours after the addition of the test compound and corrected by the internal standard.
The EC50 values for PPAR (Examples 1 to 12) measured by the above method are shown in Table 1.

Moreover, the general formula R ₁ in (I) in the substituent group other than an adamantyl group, tried to improve the water solubility (Example 13-20). The results are shown in Table 2.

As shown in Table 1, the compounds of the present invention have agonist activity that selectively acts on PPARγ. These EC50s are rosiglitazone (EC50 = 43 nM) which is a known PPARγ selective agonist measured by the same method and TIPP703 ((S) -2- (3-((4-adamantyl) which is a PPAR pan agonist. Even when compared with benzamido) methyl) -4-propoxybenzyl) butanoic acid, EC50 = 37 nM; compound number 12) described in Bioorg Med Chem Lett. 2008, 18 (3), 1110-1115 It was shown and proved to be a good PPARγ selective agonist.
Further, when R ₁ in the general formula (I) is a substituent other than an adamantyl group, EC ₅₀ may be slightly deteriorated, but the water solubility is a compound in which R ₁ is an adamantyl group (for example, Example 1). The compound is improved compared to In particular, the compounds of Examples 13, 15 and 18 have improved water solubility compared to the compound of Example 1, and the EC50 value is equal to or greater than that of rosiglitazone which is a known PPARγ selective agonist. Is shown.

2. Effects of PPARγ agonists on cancer cells Next, the effects of the compounds of the present invention on cancer cells were examined. In this example, an experiment was performed using the Skills gastric cancer cell line OCUM-2MD3 (provided by Prof. Masakazu Yashiro of Osaka City University School of Medicine) that exhibits the clinical course of typical Skills gastric cancer. Moreover, in order to examine the influence of the compound with respect to a normal cell, it experimented using OUMS-24 (Bai L, et al., Int J Cancer. 1993; 53: 451-456) which is a normal cell line.
OCUM-2MD3 or OUMS-24 was seeded in a 6-well plate at 1.5 × 10 ⁴ cells / well (medium: DMEM + 10% FBS) and the next day (Day 1), the compound of the present invention (the compound of Example 1, The compound of Example 13 and the compound of Example 15), troglitazone and DMSO alone were treated, the medium was replaced with a medium containing the compound on the fourth day (Day 4), and the number of cells was counted on the fifth day (Day 5). (Measured in 5 fields of view). The ratio of apoptotic cells was calculated by (trypan blue stained cell number) / (total cell number).
FIG. 1 shows the measurement results regarding the apoptosis-inducing effect and cell growth-inhibiting effect of the compound of Example 1. The compound of Example 1 was added to be 0.1 μM, 1 μM, 10 μM, and 100 μM, and troglitazone was added to be 10 μM and 100 μM as a control. While troglitazone exhibits activity (apoptosis-inducing activity and cell growth-inhibiting activity) at 100 μM, the compound of Example 1 exhibited an apoptosis-inducing effect and a cell growth-inhibiting effect at 10 μM, which is 1/10 of the activity.

Next, the effect of the compound of the present invention on normal cells that are not cancer cells was examined. FIG. 2 shows the apoptosis-inducing effect of the compounds of the present invention (the compound of Example 1, the compound of Example 13 and the compound of Example 15) on Skills gastric cancer cells (OCUM-2MD) and normal cells (OUMS-24). It is the result of examination. The compound of Example 1 induced OCUM-2MD apoptosis in a concentration-dependent manner, whereas OUMS-24 did not induce apoptosis until at least 10 μM. On the other hand, the compounds of Example 13 and Example 15 selectively induced apoptosis in OCUM-2MD even at 100 μM.
From the above results, it can be seen that the compound of the present invention exhibits a growth inhibitory effect on cancer cells at a dose lower than that of troglitazone (FIG. 1) and hardly affects the growth of normal cells (FIG. 2). .

  The compounds of the present invention have PPARγ agonist activity. Therefore, a medicament containing these compounds as an active ingredient is expected to exert an effect on the treatment of diseases caused by abnormal PPARγ activity.

Claims (13)

An α-substituted phenylpropionic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof.

[Wherein R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ and R ₄ are the same or different and are a hydrogen atom or a halogen atom, R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, and R ₅ is a substituted group Phenyl group or cyclohexyl group which may have a group (the substituent is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms) N represents an integer of 0 to 10] An agonist selective for PPARγ represented by the following general formula (I).

[Wherein R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ and R ₄ are the same or different and are a hydrogen atom or a halogen atom, R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, and R ₅ is a substituted group Phenyl group or cyclohexyl group which may have a group (the substituent is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms) N represents an integer of 0 to 10] The PPARγ according to claim 2, wherein R ₁ is any _one of an adamantyl group, a pyrimidinyl group, a piperidinyl group, a 2-thienyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, and a 2,6-difluorophenyl group. Agonist. The agonist selective for PPARγ according to claim 2, wherein R ₂ is a hydrogen atom or a fluorine atom. The agonist selective for PPARγ according to claim 2, wherein R ₃ is a propyl group. The agonist selective for PPARγ according to claim 2, wherein R ₄ is a hydrogen atom or a fluorine atom. The agonist selective for PPARγ according to claim 2, wherein R ₅ is an unsubstituted phenyl group or a fluorophenyl group. The compound represented by the general formula (I) is:
(R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid,
(S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-phenylpropanoic acid,
(S) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid,
(R) -2- (4-propoxy-3-(((4-adamantanyl) benzamido) methyl) benzyl) -4-phenylbutanoic acid,
(R) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid,
(S) -2-((3-(((4- (1-adamantyl) benzoyl) amino) methyl) -4-propoxyphenyl) methyl) -3-cyclohexylpropanoic acid,
(2-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
(3-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
(4-fluorobenzyl) -3- (3-((4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
2-benzyl-3- (2-fluoro-5-((2-fluoro-4-adamantylbenzamido) methyl) -4-propoxyphenyl) propanoic acid,
2- (2-fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid,
2- (2-fluoro-5-((4-adamantyl-2-fluorobenzamido) methyl) -4-propoxybenzyl) -4-phenylbutanoic acid,
(R) -2-benzyl-3- (4-propoxy-3-((4- (pyrimidin-2-yl) benzamido) methyl) phenyl) propanoic acid (R) -2-benzyl-3- (4-propoxy -3-((4- (thiophen-2-yl) benzamido) methyl) phenyl) propanoic acid (R) -2-benzyl-3- (3-((4- (piperidin-1-yl) benzamido) methyl) -4-propoxyphenyl) propanoic acid,
(R) -2-Benzyl-3- (3-((2′-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3- ( (3′-fluorobiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3-((2′6′difluorobiphenyl-4-ylcarboxamido) methyl) ) -4-propoxyphenyl) propanoic acid (R) -2-benzyl-3- (3- (2′-methylbiphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid (R) -2- The PP according to claim 2, which is any of benzyl-3- (3- (biphenyl-4-ylcarboxamido) methyl) -4-propoxyphenyl) propanoic acid. Selective agonists to Rγ.   A PPARγ transcriptional activator comprising an agonist selective for PPARγ according to claim 2.   An anticancer agent comprising an agonist selective for PPARγ according to any one of claims 2 to 8. The intermediate compound for the synthesis | combination of the compound of general formula (I) represented by the following general formula (II).

[Wherein R ₁ is an adamantyl group, unsubstituted or optionally substituted phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, piperidine group, azepyr group or piperazinyl group (the substituent is a halogen atom) Or a 2-thienyl group, a morpholino group, R ₂ and R ₄ are the same or different and represent a hydrogen atom or a halogen atom, and R ₃ represents a linear or branched alkyl group having 1 to 10 carbon atoms. The intermediate compound for the synthesis | combination of the compound of general formula (I) represented by the following general formula (III).

[Wherein R ₃ is a linear or branched alkyl group having 1 to 10 carbon atoms, R ₄ is a hydrogen atom or a halogen atom, R ₅ is a phenyl group or a cyclohexyl group (substituted) which may have a substituent. Group is a halogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, a linear or branched alkoxy group having 1 to 10 carbon atoms), and P is an asymmetric auxiliary group or 1 to 10 carbon atoms. A linear or branched alkyl group, and n represents an integer of 0 to 10.]   The manufacturing method of the compound represented by general formula (I) using the compound represented by general formula (II) or general formula (III).

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