JP2011016722A - Thiazolidinedione compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound useful as a medicine, in particular as an insulin secretion promoter and a prophylactic and/or therapeutic agent for diseases associated with GPR40 such as diabetes.SOLUTION: The invention is accomplished based on a finding resulting from study on a compound having a GPR40 receptor agonist action, that a thiazolidinedione compound including thiazolidinedione binding to a 6-membered monocyclic aromatic ring via a carbon atom with the aromatic ring further binding to benzene substituted with a 6-membered monocyclic aromatic ring via a linker, and a salt thereof exhibit excellent GPR40 agonist activity. The thiazolidinedione compound can be used as an insulin secretion promoter, and a prophylactic and/or therapeutic agent for diabetes.

Description

  The present invention relates to a thiazolidinedione compound useful as a pharmaceutical, particularly an insulin secretagogue and a preventive and / or therapeutic agent for diabetes.

  Diabetes is a disease mainly characterized by chronic hyperglycemia and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly classified into insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM). In non-insulin dependent diabetes mellitus (NIDDM), a decrease in insulin secretion from pancreatic β cells is one of the major causes of the onset, and postprandial hyperglycemia due to early insulin secretion disorder is observed.

  Recently, large-scale clinical trials confirmed that correction of postprandial hyperglycemia is important for the onset and progression of diabetic complications. In addition, it has been reported that arteriosclerosis develops at the time of only postprandial hyperglycemia, and that the persistence of postprandial mild hyperglycemia increases the mortality due to causes such as cardiovascular disease. Postprandial hyperglycemia has been shown to be an independent risk factor for cardiovascular death, even if mild. Based on the above findings, the necessity of drug treatment for postprandial hyperglycemia has been recognized.

  Currently, sulfonylurea (SU) agents are the mainstream as insulin secretagogues, but they are prone to hypoglycemia and are known to cause secondary ineffectiveness due to pancreatic exhaustion in long-term administration. Moreover, although the SU agent is effective for blood glucose control between meals, it is difficult to suppress hyperglycemia after meals.

GPR40 is a G protein-coupled receptor that is highly expressed in pancreatic β-cells identified as a fatty acid receptor, and has been reported to be involved in the insulin secretory action of fatty acids (Non-patent literature). 1).
Therefore, since GPR40 receptor agonists are expected to correct postprandial hyperglycemia based on insulin secretion promoting action, insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and their boundary types (glucose tolerance, Abnormal fasting blood glucose level) It is useful as a preventive and / or therapeutic agent for mild diabetes.

（式中、環Pは置換基を有していてもよい芳香環を、環Qは

以外にさらに置換基を有していてもよい芳香環を、X及びYはスペーサーを、

はカチオンを放出しうる基を示す。） In Patent Document 1, it is reported that the compound represented by the formula (A) including a wide range of compounds has a GPR40 receptor modulating action and is useful as an insulin secretagogue and a preventive and / or therapeutic agent for diabetes. Yes. However, there is no specific disclosure of a compound having a thiazolidinedione structure.

(In the formula, ring P represents an aromatic ring which may have a substituent, and ring Q represents

In addition to the aromatic ring optionally having a substituent, X and Y are spacers,

Represents a group capable of releasing a cation. )

（式中の記号は当該公報参照。） In Patent Document 2, it is reported that the compound represented by the formula (B) has a blood glucose lowering action and is useful for the treatment of diabetes. Although a compound having a thiazolidinedione structure is disclosed as a specific compound, there is no specific disclosure of the compound of the present invention. Moreover, there is no description about the effect | action to a GPR40 receptor.

(See the official gazette for symbols in the formula.)

（式中のＡは酸素原子又は硫黄原子を意味する。他の記号は当該公報参照。） Patent Document 3 reports that the compound represented by the formula (C) is useful for hyperlipidemia, hyperglycemia, obesity and the like. Although a compound having a thiazolidinedione structure is disclosed as a specific compound, there is no specific disclosure of the compound of the present invention. Moreover, there is no description about the effect | action to a GPR40 receptor.

(A in the formula means an oxygen atom or a sulfur atom. Refer to this publication for other symbols.)

（式中の記号は当該文献参照。） In Patent Document 4, it is reported that the compound represented by the formula (D) has a GPR40 receptor modulating action and is useful for the treatment of diabetes. Although a compound having a thiazolidinedione structure is disclosed as a specific compound, there is no specific disclosure of the compound of the present invention.

(See the literature for symbols in the formula.)

（式中の記号は当該文献参照。） Patent Document 5 reports that the compound represented by the formula (E) has a GPR40 receptor modulating action and is useful for the treatment of diabetes. Although a compound having a thiazolidinedione structure is disclosed as a specific compound, it is limited to a compound in which thiazolidinedione is directly bonded to a bicyclic ring.

(See the literature for symbols in the formula.)

（式中の記号は当該文献参照。） In Patent Document 6, it is reported that the compound represented by the formula (F) has a GPR40 receptor modulating action and is useful for the treatment of diabetes. Although a compound having a thiazolidinedione structure is disclosed as a specific compound, it is limited to a compound in which thiazolidinedione is directly bonded to a bicyclic ring.

(See the literature for symbols in the formula.)

"Nature" (UK), 2003, 422, p.173-176 International Publication No. 2004/041266 Pamphlet WO 97/41097 pamphlet Japanese Patent Application Publication No. 7-2848 International Publication No. 2007/049050 Pamphlet International Publication No. 2006/083781 Pamphlet International Publication No. 2006/083612 Pamphlet

  Disclosed is a compound having a GPR40 receptor agonist activity, particularly an insulin secretion promoter, and a compound useful as a diabetes preventive and / or therapeutic agent.

（式中の記号は以下の意味を示す。
R¹は、

を示し、
R²は、-H又は-低級アルキルを示し、
R³は、同一又は互いに異なって、-OHで置換されていてもよい低級アルキル又は-ハロゲンを示し、
nは、1又は2を示し、
R⁴は、（保護されていてもよいOH）で置換されている低級アルキルを示し、
L¹は、CH又はNを示し、
L²は、-O-又は-NH-を示し、
L³はCH又はNを示す。
以下同様） As a result of studying a compound having a GPR40 receptor agonistic activity, the present inventors have found that thiazolidinedione is bonded to a 6-membered monocyclic aromatic ring via one carbon, and further the aromatic ring is bonded to a 6-membered single-ring aromatic ring via a linker. The present invention was completed by discovering that a thiazolidinedione compound or a salt thereof characterized by binding to benzene substituted with a ring aromatic ring has an excellent GPR40 receptor agonistic action.
That is, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable. The present invention relates to a pharmaceutical composition containing an excipient.

(The symbols in the formula have the following meanings.
R ¹ is

Indicate
R ² represents -H or -lower alkyl,
R ³ is the same or different from each other, and represents a lower alkyl or -halogen optionally substituted with -OH;
n represents 1 or 2,
R ⁴ represents lower alkyl substituted with (optionally protected OH);
L ¹ represents CH or N;
L ² represents -O- or -NH-
L ³ represents CH or N.
The same applies below)

The present invention also relates to a pharmaceutical composition for promoting insulin secretion, diabetes prevention and / or treatment comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, that is, a compound of formula (I) The present invention also relates to an insulin secretagogue and a prophylactic and / or therapeutic agent for diabetes containing a pharmaceutically acceptable salt thereof.
Further, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of an insulin secretagogue, a preventive and / or therapeutic agent for diabetes, and a compound of formula (I) The present invention relates to a method for promoting insulin secretion and preventing and / or treating diabetes, which comprises administering an effective amount of a compound or a pharmaceutically acceptable salt thereof to a patient.

  The compound of formula (I) or a pharmaceutically acceptable salt thereof has a GPR40 receptor agonistic action, and is an insulin secretagogue, diabetes (insulin-dependent diabetes (IDDM), non-insulin-dependent diabetes (NIDDM) And its borderline type (glucose tolerance / fasting blood glucose level abnormality) mild diabetes) and the like can be used as a prophylactic and / or therapeutic agent for diseases involving GPR40.

Hereinafter, the present invention will be described in detail.
In the present specification, “lower alkyl” means linear or branched alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C _1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like, and in another embodiment, C _1-5 alkyl, and in another embodiment, methyl, ethyl And n-propyl.

  “Halogen” means F, Cl, Br and I.

  In this specification, “optionally substituted” means unsubstituted or substituted with 1 to 5 substituents, and in another embodiment, unsubstituted or substituted with 1 It means having two or more. “Substituted” means having 1 to 5 substituents, and in another aspect, having 1 to 2 substituents. In addition, when it has a some substituent, those substituents may be the same or may mutually differ.

  The term “may be protected” in “optionally protected OH” means that the OH group is unsubstituted or protected by a protecting group generally used for protecting a hydroxyl group. In another embodiment, it means that it is unsubstituted or protected by an acyl group, an ether group, a silyl ether group or an acetal group. In still another embodiment, it means that it is unsubstituted or protected with a dimethylmethylenedioxy group when it has an acetyl group, a tetrahydropyranyl group, or two OH groups bonded to adjacent carbons.

である化合物。
（４）上記（１）乃至（３）のうち二以上の組み合わせである化合物。 Certain embodiments of the present invention are shown below.
(1) A compound in which R ² is —H or —lower alkyl, and in another embodiment, is —H or —methyl.
(2) R ³ is the same or different from each other, and is lower alkyl or -halogen optionally substituted with —OH. In another embodiment, the same or different from each other, —methyl, —CH ₂ OH or —F A compound that is
(3) R ⁴ is lower alkyl substituted with (optionally protected OH), and in another embodiment, an acetyl group, a tetrahydropyranyl group, or two OH groups bonded to adjacent carbons. May be protected with a dimethylmethylenedioxy group

A compound that is
(4) A compound which is a combination of two or more of the above (1) to (3).

The compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “compound of formula (I)”) may have a tautomer or geometric isomer depending on the type of substituent. There can be a body. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, separated isomers, or those isomers. And mixtures thereof.
In addition, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and optical isomers based on this may exist. The present invention also includes separated optical isomers of the compound of formula (I) or a mixture thereof.

  Furthermore, this invention also includes the pharmaceutically acceptable prodrug of the compound shown by a formula (I). Pharmaceutically acceptable prodrugs are compounds that are converted to the compounds of the present invention by solvolysis or under physiological conditions. Examples of the group that forms a prodrug include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Is mentioned.

  In addition, the compound of formula (I) may form an acid addition salt or a salt with a base depending on the type of substituent, and is included in the present invention as long as such a salt is a pharmaceutically acceptable salt. Is done. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition with organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, salts with various amino acids and amino acid derivatives such as acetylleucine and ammonium salts Etc.

  Furthermore, the present invention also includes various hydrates and solvates of the compound of the formula (I) and pharmaceutically acceptable salts thereof, and crystalline polymorphic substances. The present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.

(Production method)
The compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. Examples of such protecting groups include protecting groups described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by Greene and Wuts. What is necessary is just to select suitably according to reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group as necessary.
In addition, the prodrug of the compound of formula (I) may be further reacted by introducing a specific group at the raw material or intermediate stage, or by using the obtained compound of formula (I), in the same manner as the above protecting group. Can be manufactured. The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.

本製法は、化合物（１）と化合物（２）の縮合反応により、本発明化合物（Ｉ−a）を製造する方法である。
反応は、化合物（１）と化合物（２）を等量若しくは一方を過剰量用いてピペリジン等の塩基の存在中にジエチルエーテル、テトラヒドロフラン、ジオキサン、ジメトキシエタン等のエーテル類、メタノール、エタノール、2-プロパノール等のアルコール類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ベンゼン、トルエン、キシレン等の芳香族炭化水素類または水等の溶媒中、あるいはこれらの混合溶媒中、冷却下、室温下乃至加熱下に行うことができる。 Production method 1: Condensation reaction

This production method is a method for producing the present compound (Ia) by a condensation reaction of the compound (1) and the compound (2).
The reaction is carried out by using an equivalent amount of compound (1) and compound (2) or an excess of one in the presence of a base such as piperidine, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2- Cooling in alcohols such as propanol, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, or water, or a mixed solvent thereof The reaction can be carried out at room temperature or under heating.

本製法は、化合物（I-a）を水素添加反応または還元反応に付し、本発明化合物（Ｉ-b）を得る方法である。
反応は、水素雰囲気下、エーテル類、アルコール類、ハロゲン化炭化水素類、芳香族炭化水素類または水等の反応に不活性な溶媒中、あるいはこれらの混合溶媒中、化合物（I-a）を金属触媒存在下で、通常、冷却下、室温下乃至加熱下で行われる。金属触媒としては、パラジウム炭素、パラジウム黒、水酸化パラジウム等のパラジウム触媒、白金板、酸化白金等の白金触媒、還元ニッケル、ラネーニッケル等のニッケル触媒、テトラキストリフェニルホスフィンクロロロジウム等のロジウム触媒、還元鉄等の鉄触媒等が好適に用いられる。水素ガスの代わりに、化合物（１）に対し等量〜過剰量のギ酸またはギ酸アンモニウムを水素源として用いることもできる。
もしくは、エーテル類、アルコール類、ハロゲン化炭化水素類、芳香族炭化水素類または水等の溶媒あるいはこれらの混合溶媒中、アルコール類等の水素源存在下、マグネシウム、2,6-ジメチル-1,4-ジヒドロピリジン-3,5-ジカルボン酸ジエチル、ハイドロサルファイト、水素化ホウ素リチウム等の還元剤を用いて、冷却下、室温下乃至加熱下に反応させることにより行うことができる。 Production method 2: Hydrogenation or reduction reaction

This production method is a method for obtaining the compound (Ib) of the present invention by subjecting the compound (Ia) to a hydrogenation reaction or a reduction reaction.
The reaction is carried out by using compound (Ia) as a metal catalyst in a solvent inert to the reaction such as ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons or water in a hydrogen atmosphere or in a mixed solvent thereof. In the presence, it is usually carried out under cooling, at room temperature or under heating. As metal catalysts, palladium catalysts such as palladium carbon, palladium black and palladium hydroxide, platinum catalysts such as platinum plate and platinum oxide, nickel catalysts such as reduced nickel and Raney nickel, rhodium catalysts such as tetrakistriphenylphosphine chlororhodium, reduction An iron catalyst such as iron is preferably used. Instead of hydrogen gas, an equivalent to excess amount of formic acid or ammonium formate relative to compound (1) can be used as a hydrogen source.
Alternatively, in a solvent such as ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons or water or a mixed solvent thereof, in the presence of a hydrogen source such as alcohols, magnesium, 2,6-dimethyl-1, The reaction can be carried out by using a reducing agent such as diethyl 4-dihydropyridine-3,5-dicarboxylate, hydrosulfite, lithium borohydride and the like, and reacting under cooling at room temperature to under heating.

本製法は、化合物（３）と化合物（４）の縮合反応により、本発明化合物（Ｉ−c）を製造する方法である。
反応は、化合物（３）と化合物（４）を等量若しくは一方を過剰量用いて酢酸等のプロトン源またはチタニウム(IV)テトライソプロポキシド等のルイス酸の存在中にエーテル類、アルコール類、ハロゲン化炭化水素類又は芳香族炭化水素類等の溶媒中、あるいはこれらの混合溶媒中、冷却下、室温下乃至加熱下に行い、さらにトリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム等の還元剤を用いて、冷却下、室温下乃至加熱下に反応させることにより行うことができる。反応によっては、化合物（３）と化合物（４）との縮合によりイミンが生成し、安定な中間体として単離できる場合がある。そのような場合には、このイミン中間体の還元反応により化合物（Ｉ−c）を得ることができる。
〔文献〕
A. R. Katritzky及びR. J. K. Taylor著、「Comprehensive Organic Functional Group Transformations II」、第2巻、Elsevier Pergamon、2005年
日本化学会編「実験化学講座(第5版)」14巻(2005年)(丸善) Production method 3: Reductive amination

This production method is a method for producing the compound (Ic) of the present invention by a condensation reaction of the compound (3) and the compound (4).
The reaction is carried out using an equivalent amount of compound (3) and compound (4) or an excess of one of them in the presence of a proton source such as acetic acid or a Lewis acid such as titanium (IV) tetraisopropoxide. Reducing agent such as sodium triacetoxyborohydride, sodium borohydride, etc., in a solvent such as halogenated hydrocarbons or aromatic hydrocarbons, or in a mixed solvent thereof, under cooling, at room temperature to under heating Can be carried out by reacting under cooling at room temperature or under heating. Depending on the reaction, imine may be generated by condensation between compound (3) and compound (4), and may be isolated as a stable intermediate. In such a case, compound (Ic) can be obtained by the reduction reaction of this imine intermediate.
[Reference]
AR Katritzky and RJK Taylor, `` Comprehensive Organic Functional Group Transformations II '', Volume 2, Elsevier Pergamon, 2005 Chemical Society of Japan, `` Experimental Chemistry Course (5th Edition) '', Volume 14 (2005) (Maruzen)

(Production method of raw material compounds)
The raw material used for the production of the compound of the present invention is produced, for example, by applying the following method, the method described in the following production examples, a known method, a method obvious to those skilled in the art, or a modification thereof. Can do.

（式中、Lv¹、Lv²、Lv³は脱離基を示す。以下同様。） Raw material synthesis

(In the formula, Lv ¹ , Lv ² and Lv ³ represent a leaving group. The same applies hereinafter.)

First step: O-alkylation-1
In this step, compound (6) is O-alkylated with compound (5) to give compound (7). Examples of Lv ¹ include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy group and the like.
In the presence of a base such as potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride and the like, an equivalent amount of compound (5) and compound (6) or an excess of one of them is used to form a halogenated hydrocarbon, ether, aromatic The reaction can be carried out in a solvent such as a group hydrocarbon, N, N-dimethylformamide, or a mixed solvent thereof, under cooling, at room temperature to under heating.

Second Step: Coupling This step is a step of obtaining compound (3) by coupling compound (7) and compound (8). It can be carried out using a conventional method of Suzuki coupling reaction commonly used by those skilled in the art. Lv ² includes halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy groups, etc., and Lv ³ includes —B (OH) ₂ or —B (OZ) OW, where Z and W are The same or different from each other, lower alkyl, or Z and W together represent lower alkylene.
In this production method, compounds (7) and (8) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, at room temperature to heating under reflux, usually 0.1 hour to 5 This is done by stirring for days. This reaction is preferably performed in an inert gas atmosphere. The solvent is not particularly limited, and examples thereof include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, N, N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof. As the base, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and the like are preferable. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, bistriphenylphosphine chloride, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable. The compound (3) thus obtained can also be used as a raw material for the above-mentioned “Production method 3: Reductive amination”.

Third step: Reduction This step is a step of obtaining compound (9) by reducing compound (3).
The reaction is carried out in a solvent inert to the reaction such as ethers, alcohols, aromatic hydrocarbons, N, N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, etc. under cooling at room temperature to under heating. ) With an equal or excess amount of reducing agent. As the reducing agent, hydride reducing agents such as sodium borohydride or diisobutylaluminum hydride, and other reducing agents generally used by those skilled in the art are preferably used.

Fourth step: O-alkylation-2
In this step, compound (9) is O-alkylated with compound (10) to give compound (1). It can carry out using the usual method of the Mitsunobu reaction normally used by those skilled in the art.
Equal amounts of compounds (9) and (10), or one in excess, phosphorus compounds such as tributylphosphine and triphenylphosphine and azodicarboxylates such as diethyl azodicarboxylate and 1,1 '-(azodicarbonyl) dipiperidine Using an activator prepared from a carbonyl compound or a reagent such as cyanomethylenetributylphosphorane, in a solvent such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, under cooling, at room temperature to under heating Can be done. The compound (1) thus obtained can be used as a raw material for the aforementioned “Production method 1: Condensation reaction”.

The compounds of formula (I) are isolated and purified as free compounds, pharmaceutically acceptable salts, hydrates, solvates or crystalline polymorphic substances thereof. The pharmaceutically acceptable salt of the compound of formula (I) can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
Various isomers can be produced by selecting an appropriate raw material compound, or can be separated by utilizing a difference in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution of racemates (for example, fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). Further, it can also be produced from a suitable optically active raw material compound.

  The pharmacological activity of the compound of formula (I) was confirmed by the following test.

Test method 1: GPR40 agonist activity measurement
i) Cloning of human GPR40 The full-length sequence of GPR40 was obtained by PCR using human genomic DNA (Clontech) as a template according to the following procedure.
The oligonucleotide consisting of the base sequence represented by SEQ ID NO: 1 was used as a forward primer, and the oligonucleotide consisting of the base sequence represented by SEQ ID NO: 2 was used as a reverse primer. A base sequence containing an XbaI recognition site is added to the 5 ′ end of each of the forward primer and the reverse primer. PCR was performed using Taq DNA polymerase (Ex Taq DNA polymerase; Takara Bio Inc.) in the presence of 5% dimethyl sulfoxide (DMSO) at 94 ° C (15 seconds) / 55 ° C (30 seconds) / 72 ° C (1 minute) ) Was repeated 30 times. As a result, a DNA fragment of about 0.9 kbp was amplified. This DNA fragment was digested with XbaI and then inserted into the XbaI site of plasmid pEF-BOS-dhfr (Nucleic Acids Research, 18, 5322, 1990) to obtain plasmid pEF-BOS-dhfr-GPR40.
The base sequence of the GPR40 gene in the plasmid pEF-BOS-dhfr-GPR40 was determined by the dideoxy terminator method using a DNA sequencer (ABI377 DNA Sequencer; Applied Biosystems). The base sequence of the GPR40 gene was as shown in the base sequence represented by SEQ ID NO: 3. The base sequence represented by SEQ ID NO: 3 has an open reading frame (ORF) of 903 bases, and the amino acid sequence (300 amino acids) predicted from this ORF is the amino acid sequence represented by SEQ ID NO: 4. It was as follows.
ii) Acquisition of GPR40 stably expressing cells
CHO dhfr ⁻ cells (CHO cells lacking the dihydrofolate reductase (dhfr) gene) were used as cells that express GPR40 protein. Further, the plasmid pEF-BOS-dhfr-GPR40 obtained in i) was used as an expression plasmid for expressing the GPR40 protein. Inoculate 6-well plates (Asahi Techno Glass) in αMEM medium containing 10% fetal calf serum (FCS) so that CHO dhfr ⁻ cells become 80-90% confluent and culture overnight. 2 μg of plasmid pEF-BOS-dhfr-GPR40 per well was transfected using a transfection reagent (Lipofectamine 2000; Invitrogen). After culturing for 24 hours after gene transfer, the cells were diluted and seeded again. At that time, the αMEM medium containing 10% FCS was changed to the αMEM medium containing 10% FCS but not nucleic acid. After culturing for 20 days, the formed cell colonies were individually collected and cultured to obtain CHO cells stably expressing GPR40. From these cells, cells having high reactivity to the endogenous ligands oleic acid and linoleic acid were selected.
iii) Measurement of GPR40 agonist activity This test was carried out with FLIPR (registered trademark, Molecular Devices) using the fluctuation of intracellular calcium concentration as an index. The test method will be described below.
A CHO cell line expressing human GPR40 was seeded in a 384-well black plate (Becton Dickinson) at 6 × 10 ³ per well and cultured overnight in a CO ₂ incubator.
The luminescent dye was dissolved in 10 ml of HBSS-HEPES buffer (PH7.4, 1 × HBSS, 20 mM HEPES, Invitrogen) per bottle using a Calcium-3 assay kit (Molecular Device). Probenecid (Sigma) 35.68 mg was dissolved in 250 μl of 1M NaOH, and then adjusted by adding 250 μl of HBSS-HEPES buffer. The fluorescent dye solution was prepared by mixing 16 ml of HBSS-HEPES buffer, 640 μl of fluorescent dye, and 32 μl of probenecid per plate. The plate medium was removed, and 40 μl of the fluorescent dye solution was dispensed per well, followed by incubation at room temperature for 2 hours. The test compound was dissolved in DMSO, diluted with HBSS-HEPES buffer, and 10 μl was dispensed on a plate to start the reaction, and the change in intracellular calcium concentration was measured by FLIPR. The EC ₅₀ value of the test compound was calculated from the dose response curve of the fluorescence intensity change 1 minute after the measurement.
The test results are shown in Table 1. Ex represents an Example compound number described later.

Test Method 2: Insulin Secretion Promoting Action Using MIN6 Cells In this test, the insulin secretion promoting action of the test compound was examined using MIN6 cells, a mouse pancreatic β cell line. The test method is shown below.
MIN6 cells were seeded in a 96-well plate at 5 × 10 ⁴ cells / hole (200 μl). The medium used was DMEM (25 mM glucose) containing 10% FBS, 55 μM 2-mercaptoethanol, 100 U / ml penicillin, 100 μg / ml streptomycin. After 2 days, the medium was removed with an aspirator and KRB-HEPES containing 2.8 mM glucose (116 mM NaCl, 4.7 mM KCl, 1.2 mM KH ₂ PO ₄ , 1.2 mM MgSO ₄ , 0.25 mM CaCl ₂ , 25 mM) warmed to 37 ° C. The plate was washed once with 200 μl of NaHCO ₃ , 0.005% FFA Free BSA, 24 mM HEPES (pH 7.4), and again with 200 μl of the same buffer, and incubated at 37 ° C. for 1 hour. Remove the above buffer with an aspirator, wash again with buffer (200 μl), add KRB-HEPES containing 2.8 mM or 22.4 mM glucose to the test compound at a specific concentration, and add 100 μl to each well. In addition, it was incubated at 37 ° C. for 2 hours. The sample was collected, diluted 100 times, and the insulin concentration was quantified using an insulin RIA kit (Amersham RI).

Test Method 3: Normal Mouse Single Oral Glucose Tolerance Test In this test, a normal mouse was used to examine the inhibitory effect of the test compound on glucose elevation after glucose loading. The test method is shown below.
Male ICR mice (6 weeks old) preliminarily raised for 1 week were fasted overnight and used as test animals. The test compound was a 0.5% methylcellulose suspension, which was orally administered at 10 mg / kg 30 minutes before glucose (2 g / kg) loading. In the control group, 0.5% methylcellulose was administered. The blood glucose lowering rate (%) relative to the control group at the time of glucose load 30 minutes was calculated.

  As a result of the above test, the compound of formula (I) is an insulin secretagogue, diabetic (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and its borderline type (glucose tolerance / fasting blood glucose level abnormal) mild It was confirmed that it can be used as a preventive and / or therapeutic agent for diseases involving GPR40 such as diabetes.

A pharmaceutical composition containing one or more compounds of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient is a pharmaceutical excipient, a drug solution ordinarily used in the art. It can be prepared by a commonly used method using a carrier or the like.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.

As a solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.

  Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Non-aqueous solvents include, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.

  External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

  Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.

  For normal oral administration, the daily dose is about 0.0001 to 50 mg / kg body weight, in another embodiment about 0.001 to 10 mg / kg, and in yet another embodiment about 0.01 to 1 This is mg / kg, which is administered once or in 2 to 4 divided doses. When administered intravenously, the daily dose is about 0.0001 to 1 mg / kg per body weight, and in another embodiment, about 0.0001 to 0.1 mg / kg, and is administered once a day or in multiple doses. To do. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

  The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.

  Hereinafter, based on an Example, the manufacturing method of the compound of a formula (I) is demonstrated in detail. In addition, this invention is not limited to the compound as described in the following Example. Moreover, the manufacturing method of a raw material compound is shown to a manufacture example. Further, the production method of the compound of the formula (I) is not limited to the production methods of the specific examples shown below, and the compound of the formula (I) may be a combination of these production methods or a person skilled in the art. It can also be produced by methods that are self-evident.

Moreover, the following abbreviations may be used in Examples, Production Examples, and Tables below.
PEx: Production example number, Ex: Example number, Str: Structural formula (when HCl is present in the structural formula, it means that the compound is hydrochloride), Syn: Production method (only numbers) Is the example number produced in the same manner, and in the case where P precedes the number, the production example number produced in the same manner is shown.), Dat: physicochemical data (NMR1: in 1H NMR in DMSO-d ₆₎ δ (ppm), FAB +: FAB-MS (positive ion), FAB-: FAB-MS (negative ion), ESI +: ESI-MS (positive ion), ESI-: ESI-MS (negative ion), EI: EI -MS (cation), CI: CI-MS (cation)), Me: methyl, THP: tetrahydropyranyl, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, Boc: tert-butoxycarbonyl, TBS: tert-Butyl (dimethyl) silyl, Ac: acetyl.

Production Example 1
To a mixture of tert-butyl [5- (hydroxymethyl) pyridin-2-yl] carbamate (2.13 g), triethylamine (5.3 ml), DMSO (15 ml) under ice cooling, sulfur trioxide-pyridine complex (3.02 g) was added. DMSO (15 ml) solution was added dropwise and stirred at room temperature for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.00 g of tert-butyl (5-formylpyridin-2-yl) carbamate.

Production Example 2
To a suspension of tert-butyl (5-formylpyridin-2-yl) carbamate (5.00 g) in ethanol (50 ml) and THF (50 ml) was added 1,3-thiazolidine-2,4-dione (3.43 g), piperidine ( 1.0 ml) was added and the reaction mixture was stirred at 70 ° C. for 3 days and allowed to cool to room temperature. Water (250 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The precipitate was collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to give tert-butyl {5-[(Z)-(2 , 4-Dioxo-1,3-thiazolidine-5-ylidene) methyl] pyridin-2-yl} carbamate was obtained in an amount of 6.23 g.

Production Example 3
To a suspension of tert-butyl {5-[(Z)-(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] pyridin-2-yl} carbamate (5.00 g) in DMF (100 ml) 10% Palladium-activated carbon (4.5 g) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere of 4.0 to 4.5 kg / cm ² . The reaction mixture was filtered through celite, washed with DMF (200 ml), and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in DMF (100 ml), 10% palladium-activated carbon (4.5 g) was added, and the mixture was stirred at room temperature for 1 hour under 4.0 to 4.5 kg / cm ² hydrogen atmosphere. The reaction mixture was filtered through celite, washed with DMF (200 ml), and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in DMF (100 ml), 10% palladium-activated carbon (4.5 g) was added, and the mixture was stirred at room temperature for 1 hour under 4.0 to 4.5 kg / cm ² hydrogen atmosphere. The reaction mixture was filtered through celite, washed with DMF (200 ml), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate, then chloroform / THF), and tert-butyl {5-[(2,4-dioxo-1,3-thiazolidin-5-yl) methyl] 1.71 g of pyridin-2-yl} carbamate was obtained.

Production Example 4
tert-Butyl {5-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methyl] pyridin-2-yl} carbamate (1.71 g) in THF (15 ml) solution under ice-cooling with 4M chloride Hydrogen dioxane solution (15 ml) was added and stirred at room temperature for 5 days. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting solid was collected by filtration and dried by heating under reduced pressure to give 5-[(6-aminopyridin-3-yl) methyl] -1,3- 1.18 g of thiazolidine-2,4-dione hydrochloride was obtained.

Production Example 5
Under nitrogen atmosphere, methyl 3-bromo-2-methylbenzoate (53.00 g), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1, A mixture of 3,2-dioxaborolane (88.10 g), bistriphenylphosphine palladium chloride (8.12 g), triphenylphosphine (6.07 g), potassium acetate (68.10 g), dioxane (530 ml) was heated and stirred at 100 ° C. for 29 hours. And allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-methyl-3- (4,4,5,5-tetramethyl-1,3,2 54.00 g of methyl dioxaborolan-2-yl) benzoate were obtained.

Production Example 6
To a solution of 2- (4-bromo-3,5-dimethylphenoxy) tetrahydro-2H-pyran (58.7 g) in THF (1000 ml), a 1.65 M n-butyllithium-hexane solution (137 ml) with cooling in a dry ice-methanol bath. ) Was added dropwise and stirred for 40 minutes. To the reaction mixture, a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.5 g) in THF (100 ml) was added dropwise and stirred for 30 minutes. Water was added, the solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was distilled off under reduced pressure. Methanol was added to the residue, and the resulting solid was collected by filtration and then heated and dried under reduced pressure to give 2- [3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2 53.2 g of -dioxaborolan-2-yl) phenoxy] tetrahydro-2H-pyran were obtained.

Production Example 7
To a solution of 3- (hydroxymethyl) -6-methylpyridin-2 (1H) -one (5.77 g) in acetic acid (50 ml), 10% palladium-activated carbon (50% water-containing product, 4.42 g) was added, and 4 kg / cm ^The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere of ² . The catalyst was removed by celite filtration and washed with ethanol. The filtrate was concentrated under reduced pressure to obtain 6.26 g of 3,6-dimethylpyridin-2 (1H) -one.

Production Example 8
To a solution of 3,6-dimethylpyridin-2 (1H) -one (7.23 g) in acetic acid (60 ml), a solution of bromine (2.6 ml) in acetic acid (25 ml) was added dropwise at around 10 ° C. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (100 ml) was slowly added to the resulting residue, water (100 ml) was then added, and the pH was adjusted to 6 with acetic acid. The precipitate was collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to obtain 6.91 g of 5-bromo-3,6-dimethylpyridin-2 (1H) -one.

Production Example 9
To a DMF (100 ml) solution of 5-bromo-4,6-dimethylpyridin-2 (1H) -one (5.00 g), sodium hydride (addition of about 40% mineral oil, 1.48 g) was added under ice cooling, The mixture was warmed to room temperature and stirred for 2 hours. 2- (2-Bromomethoxy) tetrahydro-2H-pyran (7.76 g) was added to the reaction mixture and stirred for 4 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-bromo-2,4-dimethyl-6- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] pyridine 3.27. g got.

Production Example 10
A mixture of 4-bromo-2-fluoro-5-methylphenol (4.00 g), 2-bromoethyl acetate (3.3 ml), cesium carbonate (15 g), and DMF (40 ml) was stirred at 60 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5.00 g of 2- (4-bromo-2-fluoro-5-methylphenoxy) ethyl acetate.

Production Example 11
Under nitrogen atmosphere, sodium carbonate (5.67 g), water (28 ml), 4-bromo-3-methylphenol (5.00 g), (3-formylphenyl) boronic acid (4.40 g), ethanol (20 ml) and toluene (40 ml) ) Was added tetrakistriphenylphosphine palladium (1.54 g), stirred at 80 ° C. for 13 hours, and then allowed to cool to room temperature. Activated carbon (0.5 g) was added to the reaction mixture, stirred for 5 minutes, filtered through Celite, and washed with ethyl acetate and water. The obtained filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated aqueous sodium chloride solution, and anhydrous magnesium sulfate and activated carbon (0.5 g) were added. The desiccant and activated carbon were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4.42 g of 4′-hydroxy-2′-methylbiphenyl-3-carbaldehyde.

Production Example 12
Under a nitrogen atmosphere, tert-butyl [3,5-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] dimethylsilane (9.49 g), 3 -Methyl bromo-2-methylbenzoate (5 g), palladium (II) acetate (245 mg), dicyclohexyl (2 ′, 6′-dimethoxybiphenyl-2-yl) phosphine (896 mg), potassium phosphate (9.27 g), A mixture of toluene (100 ml) and water (10 ml) was stirred at 60 ° C. for 17 hours. The solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4 ′-{[tert-butyl (dimethyl) silyl] oxy} -2, 8.40 g of methyl 2 ′, 6′-trimethylbiphenyl-3-carboxylate was obtained.

Production Example 13
Under a nitrogen stream, lithium aluminum hydride (10.36 g) was added little by little to THF (500 ml) under ice cooling. Next, a solution of methyl 4 '-{[tert-butyl (dimethyl) silyl] oxy} -2,2', 6'-trimethylbiphenyl-3-carboxylate (69.98 g) in THF (200 ml) was added dropwise over 1 hour. Slowly added. After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours, and then ethyl acetate (40 ml) was slowly added dropwise over 1 hour, followed by stirring at the same temperature for 0.5 hour. Under cooling with ice, water (20 ml) was slowly added dropwise to the reaction mixture, and then THF (300 ml) was added. The mixture was stirred at the same temperature for 0.5 hour, and insoluble matters were removed by Celite filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give (4 ′-{[tert-butyl (dimethyl) silyl] oxy} -2,2 ′ 5,6'-Trimethylbiphenyl-3-yl) methanol (51.71 g) was obtained.

Production Example 14
Manganese dioxide (180 g) was added to a solution of [2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxy) biphenyl-3-yl] methanol (90.3 g) in chloroform (800 ml). And stirred at 55 ° C. for 26 hours. The insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain 95.9 g of 2,2 ′, 6′-trimethyl-4 ′-(tetrahydro-2H-pyran-2-yloxybiphenyl-3-carbaldehyde. Obtained.

Production Example 15
To a solution of 2,2 ', 6'-trimethyl-4'-(tetrahydro-2H-pyran-2-yloxybiphenyl-3-carbaldehyde (75.2 g) in THF (1000 ml) was added 1M hydrochloric acid (700 ML), and The solvent was distilled off under reduced pressure and extracted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was distilled under reduced pressure. Ether and hexane were added to the residue, and the resulting solid was collected by filtration and dried by heating under reduced pressure to obtain 42.1 g of 4′-hydroxy-2,2 ′, 6′-trimethylbiphenyl-3-carbaldehyde. Obtained.

Production Example 16
4 ′-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-carbaldehyde (2.12 g) in THF (2.12 g) To the solution, 1M hydrochloric acid (20 ml) was added at room temperature, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain 1.87 g of 4 ′-{[(2S) -2,3-dihydroxypropyl] oxy} -2,2 ′, 6′-trimethylbiphenyl-3-carbaldehyde.

Production Example 17
4 '-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (2.07 g) in THF ( To the solution, 1M hydrochloric acid (20 ml) was added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure, and the resulting colorless amorphous solid (1.80 g), acetic anhydride (1.2 ml), triethylamine (2.0 ml), N, N-dimethylpyridin-4-amine (70 mg) and dichloromethane (20 ml) The mixture was stirred at room temperature for 2 hours. Ethyl acetate (60 ml) was added to the reaction mixture and the layers were separated. The organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain 2.21 g of (2S) -3-[(3′-formyl-2,2 ′, 6-trimethylbiphenyl-4-yl) oxy] propane-1,2-diyl diacetate .

Production Example 18
4 '-{[(2S) -2,3-dihydroxypropyl] oxy} -2,2', 6'-trimethylbiphenyl-3-carbaldehyde (1.87 g), acetic anhydride (1.25 ml), triethylamine (2.10 ml ), N, N-dimethylpyridin-4-amine (73 mg) and dichloromethane (20 ml) were stirred at room temperature for 2 hours. Ethyl acetate (60 ml) was added to the reaction mixture and the layers were separated. The organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain 2.29 g of (2R) -3-[(3′formyl-2,2 ′, 6-trimethylbiphenyl-4-yl) oxy] propane-1,2-diyl diacetate.

Production Example 19
To a solution of ethyl 2-[(3'-formyl-2-methylbiphenyl-4-yl) oxy] acetate (12.20 g) in ethanol (150 ml) was added sodium borohydride (2.30 g) under ice-methanol bath cooling. In addition, the mixture was stirred at the same temperature for 30 minutes and further at room temperature for 1 hour. The reaction mixture was ice-cooled, saturated aqueous ammonium chloride solution (100 ml) was slowly added, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 8.70 g of ethyl 2-{[3 '-(hydroxymethyl) -2-methylbiphenyl-4-yl] oxy} acetate. .

Production Example 20
Under a nitrogen atmosphere and ice-cooled, lithium aluminum hydride (1.00 g) was added to THF (50 ml), and then 3- [6- (2-acetoxyethoxy) -2,5-dimethylpyridin-3-yl]- A solution of methyl 2-methylbenzoate (4.64 g) in THF (40 ml) was slowly added dropwise. After stirring the reaction mixture at the same temperature for 2 hours, water (3.0 ml) was slowly added dropwise, and then THF (100 ml) was added and stirred for 15 minutes. The reaction mixture was dried over anhydrous sodium sulfate, filtered through Celite, and washed with THF. By concentrating the obtained filtrate under reduced pressure, a crude product of 2-({5- [3- (hydroxymethyl) -2-methylphenyl] -3,6-dimethylpyridin-2-yl} oxy) ethanol was obtained. Was obtained as a brown syrupy substance. Obtained 2-({5- [3- (hydroxymethyl) -2-methylphenyl] -3,6-dimethylpyridin-2-yl} oxy) ethanol crude product (3.84 g) in chloroform (75 ml) Manganese dioxide (5.65 g) was added to the solution, and the reaction mixture was heated to 60 ° C., stirred at the same temperature for 17 hours, and then allowed to cool to room temperature. The insoluble material was removed by Celite filtration and washed with chloroform. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- [6- (2-hydroxyethoxy) -2,5-dimethylpyridine-3- 3.38 g of [Il] -2-methylbenzaldehyde was obtained.

Production Example 21
Acetic anhydride (2.0 ml) was added to a mixture of 5'-fluoro-4 '-(2-hydroxyethoxy) -2,2'-dimethylbiphenyl-3-carbaldehyde (3.00 g) and pyridine (15 ml) at room temperature. And stirred at room temperature for 4 days. Toluene (30 ml) and 1M hydrochloric acid (30 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid, water, and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.59 g of 2-[(5-fluoro-3′-formyl-2,2′dimethylbiphenyl-4-yl) oxy] ethyl acetate.

Production Example 22
3- [6- (3-hydroxy-3-methylbutoxy) -2,5-dimethylpyridin-3-yl] -2-methylbenzaldehyde (2.98 g), pyridine (1.8 ml), N, N-dimethylpyridine- Acetic anhydride (1.8 ml) was added dropwise to a mixed solution of 4-amine (1.12 g) and chloroform (25 ml). The reaction mixture was stirred at room temperature for 11 hours. Pyridine (1.8 ml) and acetic anhydride (1.8 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous ammonium chloride solution (50 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give acetic acid 3-{[5- (3-formyl-2-methylphenyl) -3,6-dimethylpyridin-2-yl There were obtained 1.01 g of oxy} -1,1-dimethylpropyl.

Production Example 23
Under a nitrogen atmosphere, (4 '-{[tert-butyl (dimethyl) silyl] oxy} -2,2', 6'-trimethylbiphenyl-3-yl) methanol (51.50 g), 4-hydroxybenzaldehyde (21.17 g) 1,1 ′-(azodicarbonyl) dipiperidine (47.40 g) was added to a THF (500 ml) solution under ice cooling, and then tributylphosphine (47 ml) was added dropwise. The reaction mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure after washing with THF. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-[(4 '-{[tert-butyl (dimethyl) silyl] oxy} -2,2', 6'- 59.68 g of trimethylbiphenyl-3-yl) methoxy] benzaldehyde were obtained.

Production Example 24
4-[(4 ′-{[tert-butyl (dimethyl) silyl] oxy} -2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] benzaldehyde (59.63 g) in THF (600 ml) under nitrogen atmosphere ) 1.0 M tetrabutylammonium fluoride THF solution (143 ml) was added dropwise to the solution under ice cooling, and the reaction mixture was stirred for 1 hour under ice cooling. The reaction mixture was diluted with ethyl acetate (500 ml) and saturated aqueous ammonium chloride (500 ml) was added. The mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. Diethyl ether (300 ml) was added to the obtained residue, and the precipitated solid was collected by filtration and washed with diethyl ether. Diethyl ether (300 ml) was added again to the obtained solid, and the precipitated solid was collected by filtration and washed with diethyl ether. The obtained solid was dissolved in THF (120 ml) by heating, then diethyl ether (300 ml) was added while allowing to cool, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried by heating under reduced pressure. Was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 25.25 g of 4-[(4′-hydroxy-2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] benzaldehyde. .

Production Example 25
2-{[5-Fluoro-3 '-(hydroxymethyl) -2,2'-dimethylbiphenyl-4-yl] oxy} ethyl acetate (1.00 g), 4-hydroxybenzaldehyde (0.45 g), tributylphosphine (0.98 ml) and THF (10 ml) were added 1,1 ′-(azodicarbonyl) dipiperidine (1.00 g) under ice cooling and stirred at room temperature for 2 days. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and 1M aqueous sodium hydroxide solution (10 ml) was added to a mixture of the obtained solid (1.20 g), THF (10 ml), and methanol (10 ml) at room temperature. The mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the resulting residue was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the resulting residue was dried under reduced pressure to obtain a solid (0.99 g). Acetic anhydride (0.48 ml) was added to a mixture of the obtained solid (0.99 g) and pyridine (3 ml) at room temperature, and the mixture was stirred at room temperature for 2 hours. Ethanol (5 ml) was added to the reaction mixture, and after stirring for 10 minutes, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and acetic acid 2-({5-fluoro-3 '-[(4-formylphenoxy) methyl] -2,2'-dimethylbiphenyl-4 1.00 g of -yl} oxy) ethyl was obtained.

In the same manner as in Production Examples 1 to 25, Production Example compounds 26 to 81 were produced using the corresponding raw materials. Tables 2 to 13 show production methods, structures and physicochemical data of the production example compounds.

Example 1
2-({3 '-[(4-formylmethoxy) methyl] -2-methylbiphenyl-4-yl} oxy) ethyl acetate (1.00 g), 1,3-thiazolidine-2,4-dione (360 mg), A mixture of piperidine (0.08 ml) and ethanol (20 ml) was stirred at 70 ° C. for 24 hours. The reaction mixture was allowed to cool, water (40 ml) and 1M hydrochloric acid were added until no insoluble material was left, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after removing the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and acetic acid 2-{[3 '-({4-[(Z)-(2,4-dioxo-1,3-thiazolidine-5 1.24 g of -ylidene) methyl] phenoxy} methyl) -2-methylbiphenyl-4-yl] oxy} ethyl were obtained.

Examples 2 and 15
2-{[3 '-({4-[(Z)-(2,4-Dioxo-1,3-thiazolidine-5-ylidene) methyl] phenoxy} methyl) -2-methylbiphenyl-4-yl] A mixture of oxy} ethyl (1.23 g), 20% palladium hydroxide-activated carbon (860 mg) and methanol (20 ml) was stirred at room temperature for 12 hours under a hydrogen atmosphere of 3 kg / cm ² . To the reaction mixture was added 1M aqueous sodium hydroxide solution (20 ml), and the mixture was filtered through celite. The residue was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 609 mg of an oily substance. Ethanol and 1M aqueous potassium hydroxide solution (1.3 ml) were added to this, and the solvent was distilled off under reduced pressure.The resulting residue was purified by ODS column chromatography (acetonitrile-water), and each of the resulting two components was purified. Washing with ethyl acetate, filtering the solid, and as Example 2, potassium 5- (4-{[4 '-(2-hydroxyethoxy) -2'-methylbiphenyl-3-yl] methoxy} benzyl) -2 97 mg of 1,4-dioxo-1,3-thiazolidine-3-ide and potassium (5Z) -5- (4-{[4 '-(2-hydroxyethoxy) -2'-methylbiphenyl as Example 15 79 mg of -3-yl] methoxy} benzylidene) -2,4-dioxo-1,3-thiazolidine-3-id were obtained.

Example 3
Acetic acid (1R) -3-{[3 '-({4-[(Z)-(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] phenoxy} methyl) -2,2', To a solution of 6-trimethylbiphenyl-4-yl] oxy} -1-methylpropyl (1.17 g) in THF (15 ml) and ethanol (15 ml), 10% palladium-activated carbon (50% water-containing product, 1.11 g) was added, The reaction mixture was stirred for 14 hours at room temperature under 4 kg / cm ² hydrogen atmosphere. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in THF (15 ml) and ethanol (15 ml), 10% palladium-activated carbon (50% water-containing product, 1.11 g) was added, and the reaction mixture was stirred at room temperature under 4 kg / cm ² hydrogen atmosphere at room temperature. Stir for hours. The catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give acetic acid (1R) -3-{[3 '-({4-[(2,4-dioxo-1,3-thiazolidine 939 mg of -5-yl) methyl] phenoxy} methyl) -2,2 ', 6-trimethylbiphenyl-4-yl] oxy} -1-methylpropyl were obtained.

Example 4
Acetic acid (1R) -3-{[3 '-({4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} methyl) -2,2', 6-trimethylbiphenyl To a solution of -4-yl] oxy} -1-methylpropyl (927 mg) in THF (9 ml) and ethanol (9 ml) was added 1M aqueous sodium hydroxide solution (5 ml), and the reaction mixture was stirred at 60 ° C. for 1 hour, It was left to cool. To the reaction mixture were added 1M hydrochloric acid (5 ml) and water (30 ml), and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 761 mg of a solid. The obtained solid (761 mg) was dissolved in THF (5 ml) and ethanol (5 ml), 1M aqueous sodium hydroxide solution (1.46 ml) was added, and the mixture was concentrated under reduced pressure. Diethyl ether (20 ml) was added to the resulting residue to solidify the powder, and after stirring at room temperature for 1 hour, the solid was collected by filtration and washed with diethyl ether. The obtained solid was dried at 60 ° C. under reduced pressure to obtain sodium 5- {4-[(4 '-{[(3R) -3-hydroxybutyl] oxy} -2,2', 6'-trimethyl. 690 mg of biphenyl-3-yl) methoxy] benzyl} -2,4-dioxo-1,3-thiazolidine-3-id was obtained.

Example 5
2-{[5- (3-Formyl-2-methylphenyl) -3,6-dimethylpyridin-2-yl] oxy} ethyl acetate (600 mg), 5- (4-aminobenzyl) -1,3-thiazolidine A mixture of -2,4-dione (489 mg) and acetic acid (8 ml) was stirred at room temperature for 17 hours. To the reaction mixture was added sodium triacetoxyborohydride (777 mg), and the mixture was stirred at room temperature for 3 hours. Water (30 ml) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 966 mg of a candy-like product. The obtained candy (966 mg) was dissolved in methanol (12 ml), sodium methoxide (400 mg) was added, and the reaction mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was ice-cooled, 10% aqueous citric acid solution (15 ml) and water (10 ml) were added, and the mixture was extracted with chloroform-2-propanol (5: 1, v / v). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 793 mg of a foam. The obtained foam (793 mg) was dissolved in acetonitrile (2 ml), and 1M aqueous sodium hydroxide solution (1.61 ml) was added. The mixed solution was purified by ODS column chromatography (acetonitrile-water) to obtain 672 mg of a solid. The obtained solid (672 mg) was powdered solid with diethyl ether, and the solid was collected by filtration and washed with diethyl ether. The obtained solid was dried at 60 ° C. under reduced pressure to give sodium 5- [4-({3- [6- (2-hydroxyethoxy) -2,5-dimethylpyridin-3-yl] -2-methyl 600 mg of [benzyl} amino) benzyl] -2,4-dioxo-1,3-thiazolidine-3-id was obtained.

Example 6
Acetic acid 2-{[3 '-({4-[(Z)-(2,4, -Dioxo-1,3-thiazolidine-5-ylidene) methyl] phenoxy} methyl) -5-fluoro-2,2' -Dimethylbiphenyl-4-yl] oxy} ethyl (0.35 g), 10% palladium-activated carbon (50% water-containing product, 0.73 g), THF (4.5 ml) and ethanol (4.5 ml) were mixed at 4 kg / cm ² . The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. A mixture of the obtained residue, 10% palladium-activated carbon (50% water-containing product, 0.70 g), THF (4.5 ml) and ethanol (4.5 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere of 4 kg / cm ² . . After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 0.23 g of an oil. A mixture of the obtained oil (0.23 g), sodium methoxide (70 mg) and methanol (5 ml) was stirred at 60 ° C. for 2 hours. To the reaction solution was added 10% aqueous citric acid solution (4 ml) under ice cooling, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 184 mg of an oil. A 1M aqueous sodium hydroxide solution (0.353 ml) was added to a THF (5 ml) solution of the obtained oil, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the resulting residue, and the resulting solid was collected by filtration and then heated and dried under reduced pressure to give sodium 5- (4-{[5'-fluoro-4 '-(2-hydroxyethoxy) -2, 0.16 g of 2′-dimethylbiphenyl-3-yl] methoxy} benzyl) -2,4-dioxo-1,3-thiazolidine-3-id was obtained.

Example 7
(5Z) -5- {4-[(4 '-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2', 6'-trimethylbiphenyl- 3-yl) methoxy] benzylidene} -1,3-thiazolidine-2,4-dione, 10% palladium-activated carbon (50% water content, 2.0 g) and THF (30 ml) in a 4 kg / cm ² hydrogen atmosphere The mixture was stirred at room temperature for 16 hours. After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. A mixture of the obtained residue, 10% palladium-activated carbon (50% water-containing product, 2.0 g) and THF (30 ml) was stirred at room temperature for 5 hours under a hydrogen atmosphere of 4 kg / cm ² . After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 768 mg of a solid. 1 M hydrochloric acid (10 ml) was added to a solid THF (10 ml) solution, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1M aqueous sodium hydroxide solution (12 ml), and the mixture was concentrated under reduced pressure. The obtained aqueous solution was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added to the residue and filtered, and sodium 5- {4-[(4 '-{[(2S) -2,3-dihydroxy 327 mg of propyl] oxy} -2,2 ′, 6′-trimethylbiphenyl-3-yl) methoxy] benzyl} -2,4-dioxo-1,3-thiazolidine-3-ide was obtained.

Example 8
4 ′-{[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] methoxy} -2,2 ′, 6′-trimethylbiphenyl-3-carbaldehyde (732 mg), 5- ( Acetic acid (1.1 ml) was added to a mixture of 4-aminobenzyl) -1,3-thiazolidine-2,4-dione (505 mg) and THF (7 ml), and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (660 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 days. Acetic acid (1.1 ml) and sodium triacetoxyborohydride (660 mg) were added and stirred for 1 day. Water was added to the reaction mixture, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an oil (580 mg). 1M hydrochloric acid (10 ml) was added to a THF (10 ml) solution of the obtained oil and stirred at room temperature for 1 hour. 1M aqueous sodium hydroxide solution (12 ml) was added, and the solvent was distilled off under reduced pressure. The residue was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added to the residue, and the resulting solid was collected by filtration and dried by heating under reduced pressure to give sodium 5- (4-{[(4'- {[(2S) -2,3-dihydroxy] oxo} -2,2 ', 6'-trimethylbiphenyl-3-yl) methyl] amino} benzyl) -2,4-dioxo-1,3-thiazolidine-3 -Obtained 347 mg of id.

Example 9
3- [6- (2-hydroxyethoxy) -2,4-dimethylpyridin-3-yl] -2-methylbenzaldehyde (768 mg) and 5- (4-aminobenzyl) -1,3-thiazolidine-2,4 -A solution of dione (900 mg) in acetic acid (5 ml) was stirred at room temperature for 11 hours. To the reaction mixture, sodium triacetoxyborohydride (860 mg) was added and stirred at room temperature for 1 hour. Water was added and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol followed by chloroform-ethyl acetate) to obtain an oil (239 mg). To a solution of this oily substance in methanol (5 ml) was added dropwise 1M aqueous sodium hydroxide solution (0.48 ml) under ice cooling, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting solid was collected by filtration and dried by heating under reduced pressure to give sodium 5- [4-({3- [6- (2-hydroxyethoxy) -2,4-dimethylpyridine- 242 mg of 3-yl] -2-methylbenzyl} amino) benzyl] -2,4-dioxo-1,3-thiazolidine-3-id were obtained.

Example 10
(5Z) -5- {4-[(3- {2,4-Dimethyl-6- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] pyridin-3-yl} -2-methylbenzyl) Oxy] benzylidene} -1,3-thiazolidine-2,4-dione (1.73 g), 10% palladium-activated carbon (50% water content, 3.0 g), THF (30 ml), 4 kg / cm ² hydrogen Stir for 5 hours at room temperature under atmosphere. After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. A mixture of the obtained residue 10% palladium-activated carbon (50% water-containing product, 3.0 g) and THF (30 ml) was stirred at room temperature for 3 hours under a hydrogen atmosphere of 3 kg / cm ² . After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. A mixture of the obtained residue 10% palladium-activated carbon (50% water-containing product, 3.0 g) and THF (30 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere of 3 kg / cm ² . After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an oil (420 mg). To a solution of this oily substance in THF (6 ml) was added 1M hydrochloric acid (6 ml), and the mixture was stirred at room temperature for 1 hour. 1M Aqueous sodium hydroxide solution (7 ml) was added, and the solvent was evaporated under reduced pressure. The residue was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added to the residue, and the resulting solid was collected by filtration and dried by heating under reduced pressure to give sodium 5- [4-({3- [6 150 mg of-(2-hydroxyethoxy) -2,4-dimethylpyridin-3-yl] -2-methylbenzyl} oxy) benzyl] -2,4-dioxo-1,3-thiazolidine-3-id was obtained.

Example 11
(2R) -3-[(3'-Formyl-2,2 ', 6-trimethylbiphenyl-4-yl) oxy] propane-1,2-diyl diacetate (757 mg), 5-[(6-aminopyridine- A mixture of 3-yl) methyl] -1,3-thiazolidine-2,4-dione (358 mg), acetic acid (4.5 ml) and THF (3 ml) was stirred at room temperature for 12 hours. After adding THF (3 ml) to the reaction mixture, sodium triacetoxyborohydride (725 mg) was added over 5 hours. The reaction mixture was stirred at room temperature for 1 hour, water (40 ml) was added, and the mixture was extracted with chloroform-2-propanol (3: 1, v / v). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and (2R) -3-({3 '-[({5-[(2,4-dioxo-1,3, -thiazolidine- 410 mg of 5-yl) methyl] pyridin-2-yl} amino) methyl] -2,2 ′, 6-trimethylbiphenyl-4-yl} oxy) propane-1,2-diyl diacetate were obtained.

Example 12
(2R) -3-({3 '-[({5-[(2,4-Dioxo-1,3, -thiazolidin-5-yl) methyl] pyridin-2-yl} amino) methyl] -2, A mixture of 2 ′, 6-trimethylbiphenyl-4-yl} oxy) propane-1,2-diyl diacetate (410 mg), sodium methoxide (183 mg) and methanol (6 ml) was stirred at 50 ° C. for 2 hours. After allowing to cool to room temperature, 10% aqueous citric acid solution (5 ml) was added to the reaction mixture, and the mixture was extracted with chloroform-2-propanol (3: 1, v / v). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was distilled off under reduced pressure. A 1M aqueous sodium hydroxide solution (2.0 ml) was added to a THF (5 ml) solution of the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added, and the resulting solid was collected by filtration and then heated and dried under reduced pressure to give sodium 5-[(6-{[(4 ' -{[(2S) -2,3-dihydroxypropyl] oxy} -2,2 ', 6'-trimethylbiphenyl-3-yl) methyl] amino} pyridin-3-yl) methyl] -2,4-dioxo 151 mg of -1,3-thiazolidine-3-id was obtained.

Example 13
(5Z) -5- (4-{[4 '-(2-hydroxyethoxy) -2'-(hydroxymethyl) biphenyl-3-yl] methoxy} benzylidene) -1,3-thiazolidine-2,4-dione A mixture of magnesium and methanol (3 drops) separately activated with iodine was added to a mixture of (663 mg), magnesium (shaved, 340 mg), and methanol (15 ml), and the mixture was stirred at room temperature for 4 hours. Magnesium (170 mg) was added to the reaction mixture and stirred for 3.5 hours. Water (30 ml) and 1M hydrochloric acid (45 ml) were added to the reaction mixture, and the mixture was extracted with chloroform-2-propanol (3: 1, v / v). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an oil (530 mg). To a solution of the obtained oily substance in THF (5 ml) was added 1M aqueous sodium hydroxide solution (1.10 ml), and the solvent was evaporated under reduced pressure. The obtained residue was purified by ODS column chromatography (acetonitrile-water), diethyl ether was added, and the resulting solid was collected by filtration and then heated and dried under reduced pressure to give sodium 5- (4-{[4 '-( 259 mg of 2-hydroxyethoxy) -2 '-(hydroxymethyl) biphenyl-3-yl] methoxy} benzyl) -2,4-dioxo-1,3-thiazolidine-3-id was obtained.

Example 14
Acetic acid (1R) -3-({5- [3-({4-[(Z)-(2,4-dioxo-1,3-thiazolidine-5-ylidene) methyl] phenoxy} methyl) -2-methyl Phenyl] -4,6-dimethylpyridin-2-yl} oxy) -1-methylpropyl, 10% palladium-activated carbon (50% water content, 400 mg) and methanol (15 ml) in a mixture of 3.1 kg / cm ² hydrogen Stir for 80 minutes under atmosphere. Insolubles were filtered off through Celite filtration, and the solvent was distilled off under reduced pressure.To the residue obtained, methanol (15 ml) and 10% palladium-activated carbon (50% water-containing product, 500 mg) were added, and 4.2 kg / cm ² The mixture was stirred for 55 minutes under a hydrogen atmosphere. Insoluble matter was removed by filtration through Celite, and the solvent was distilled off under reduced pressure.Methanol (15 ml), 10% palladium-activated carbon (50% water-containing product, 400 mg) was added, and 3.6 kg / cm ² Stir for 45 minutes under hydrogen atmosphere. The insoluble material was filtered off through Celite filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 132 mg of an oily product as methanol (1 ml), THF (1 ml) and 1M aqueous sodium hydroxide solution (1 ml) were added, and the mixture was stirred at room temperature for 1 hour. 1M Hydrochloric acid (1.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 124 mg of an oily substance to methanol (1 ml), THF (1 ml) and 1M Aqueous sodium hydroxide solution (0.238 ml) was added, and the mixture was stirred at room temperature for 10 min. The solvent was distilled off under reduced pressure, and the residue was purified by ODS column chromatography (acetonitrile-water) to form a foam by adding hexane, and the powder was collected by filtration, dried by heating under reduced pressure, sodium 5- (4-{[3- (6-{[(3R) -3-hydroxybutyl] oxy} -2,4-dimethylpyridin-3-yl) -2-methylbenzyl] oxy} benzyl) -2, 74 mg of 4-dioxo-1,3-thiazolidine-3-id was obtained.

In the same manner as in the above Examples 1 to 14, Example Compounds 15 to 40 were produced using the corresponding raw materials. The structures of the example compounds are shown in Tables 14 to 20, and the production methods and physicochemical data are shown in Tables 21 to 24.

The compound of formula (I) has an excellent GPR40 agonist activity, and is an insulin secretagogue, diabetes (insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM) and its boundary type (glucose tolerance / fasting) It can be used as a prophylactic and / or therapeutic agent for diseases involving GPR40, such as abnormal blood glucose levels) mild diabetes).

  The numerical heading <223> in the sequence listing below describes the “Artificial Sequence”. Specifically, the base sequence represented by the sequence of SEQ ID NO: 1 in the sequence listing is a base sequence of an artificially synthesized primer. Moreover, the base sequence represented by the sequence number 2 in the sequence listing is the base sequence of an artificially synthesized primer.

Claims (1)

A compound of formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.
R ¹ is

Indicate
R ² represents -H or -lower alkyl,
R ³ is the same or different from each other, and represents a lower alkyl or -halogen optionally substituted with -OH;
n represents 1 or 2,
R ⁴ represents lower alkyl substituted with (optionally protected OH);
L ¹ represents CH or N;
L ² represents -O- or -NH-
L ³ represents CH or N. )