HK1135377B

HK1135377B - ACTIVATING AGENT FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR δ

Info

Publication number: HK1135377B
Application number: HK09111822.2A
Authority: HK
Inventors: 佐久间诏悟; 望月信孝; 潮田胜俊; 高桥理惠; 山川富雄; 增井诚一郎
Original assignee: 日本化学医药株式会社
Priority date: 2006-04-18
Filing date: 2007-04-18
Publication date: 2012-12-21

Description

Activator of peroxisome proliferator activated receptor delta

Technical Field

The present invention relates to an activator of peroxisome proliferator-activated receptor (PPAR).

Background

Peroxisome proliferator-activated receptors (PPARs) are known to exist in 3 subtypes, referred to as PPARalpha, PPARgamma and PPARdelta. (Proc. Natl. Acad. Sci. USA, 91, p7335-7359, 1994: non-patent document 1 for short.)

Further, transcriptional activation of PPAR subtypes and blood glucose lowering and lipid metabolism improving effects have been reported for various compounds. For example, as selective α agonists (agonst) having a lipid metabolism-improving effect, GW-590735(GSK), KRP-101(キョ - リン), NS-220 (New Roche-Japan drug), and the like have been reported. (J Pharmacol Exp Ther 309 (3): 970, Jun 2001: hereinafter referred to as non-patent document 2)

In addition, various drugs showing dual PPAR γ and PPAR α agonistic (dualaconist) activities are also known, and there have been reported KRP-297(Kyorin) of TZD (thiazolidinedione) derivative represented by the following formula and mogroside (Muraglitazar) (BMS) of non-TZD derivative, ticagrelor (teoglitazar) (AstraZeneca), and the like. It has also been reported that these compounds are developed as a therapeutic agent for diabetes by mainly using the action of PPAR γ, and that PPAR α activity is not necessarily strong.

Muraglitazer: moglosazole

Tesaglitazer: tige lattice column

In addition, as a PPAR δ selective agonist, GW-501516(GSK) of the phenoxyacetic acid type represented by the following formula is known, and it is reported that its development as a lipid metabolism improving agent is currently underway. (WO 01/603: hereinafter referred to simply as patent document 1, Bioorg Medchem Lett 13(2003)1517-

Patent document 1 also describes compounds of the phenylpropanoid type and the phenylglycine type represented by the following formulae.

On the other hand, the present inventors have also found that a phenylacetic acid-type compound represented by the following formula has a PPAR δ transcription activation effect, and have filed for a patent. (WO 02/76957: hereinafter referred to simply as patent document 2.) it was also found that a compound of the substituted phenoxyacetic acid type also has an excellent PPAR δ transcription activation effect, and a patent was filed. (WO 03/16291: hereinafter referred to simply as patent document 3.)

Recently, among the phenylpropanoid compounds, there is also a patent application for PPAR regulatory factors (modulators) having thiophene in the structure. (WO 04/63184: hereinafter abbreviated as patent document 4)

However, non-patent document 3 describes that the PPAR δ activity of the phenylalanine type is about 30 times weaker than that of the phenoxyacetic acid type.

Further, patent document 1 and non-patent document 3 describe no specific drug effect in the phenylglycine type.

The compounds of the present invention represented by the following general formulae (I), (II) and (III) are clearly different in structure from the above-mentioned GW-501516 and the like, and these compounds are not described in the above-mentioned publicly known documents.

Disclosure of Invention

The present invention aims to provide compounds represented by the following general formulae (I), (II) and (III) having an activating effect on peroxisome proliferator-activated receptors.

The present inventors have conducted extensive studies and, as a result, have unexpectedly found that a phenylpropanoid type compound has an excellent activating action of peroxisome proliferator-activated receptor δ, which is different from that described in the above non-patent document 3, and have completed the present invention.

That is, the present invention relates to a compound represented by the following general formula (I):

(in the formula, W¹And W²May be the same or different and represents CH or a nitrogen atom; x represents NR⁵Or CR⁶R⁷Wherein R is⁵Represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms and substituted with a halogen atom, an alkyl group having 1 to 8 carbon atoms and substituted with an alkoxy group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 membered rings, an alkyl group having 1 to 8 carbon atoms and substituted with a phenyl group, an acyl group having 2 to 8 carbon atoms or an alkenyl group having 2 to 8 carbon atoms; r⁶And R⁷May be the same or different and represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;

y represents- (CR)⁸R⁹)_n-, in which R⁸And R⁹May be the same or different and represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, n represents 1 to 4, or X and Y may be combined to represent- (CR)¹⁰＝CR¹¹) -or ethynylene, wherein R¹⁰And R¹¹May be the same or different and represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;

z represents a carboxyl group or a tetrazolyl group;

g represents O, S or CR¹²R¹³Wherein R is¹²And R¹³May be the same or different and represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;

a represents a 5-membered heterocyclic ring selected from thiazole, oxazole, imidazole, pyrazole, thiophene, furan or pyrrole, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms and substituted with a halogen atom, a hydroxyl group, a nitro group, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heterocyclic group having 5 or 6-membered ring;

b represents an alkylene chain having 1 to 8 carbon atoms, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 membered rings, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom, wherein when B is an alkylene chain having 2 or more carbon atoms, it may have a double bond or a triple bond;

R¹and R²The same or different, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atomHydroxyl, nitro, acyl with 2-8 carbon atoms, aryl with 6-10 carbon atoms or heterocyclic radical with 5 or 6 membered ring;

R³and R⁴May be the same or different and represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms;

m represents an integer of 0 to 3. )

Further, the present invention relates to a compound represented by the following general formula (II):

(in the formula, G^aDenotes O, S or CH₂；

A^aRepresents a 5-membered heterocyclic ring selected from thiazole, oxazole or thiophene, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms;

B^arepresents an alkylene chain having 1 to 8 carbon atoms, wherein when B is^bWhen it represents an alkylene chain having 2 or more carbon atoms, it may have a double bond;

R^1aand R^2aThe alkyl group may be the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms. )

Further, the present invention relates to a compound represented by the following general formula (III):

(in the formula, G^bDenotes O, S or CH₂；

A^bRepresents a 5-membered heterocyclic ring selected from thiazole, oxazole or thiophene, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms;

B^brepresents an alkylene chain having 1 to 8 carbon atoms, wherein when B is^bWhen it represents an alkylene chain having 2 or more carbon atoms, it may have a double bond;

R^1band R^2bThe same or different, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms;

R^3brepresents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. )

The present invention also relates to an activator of peroxisome proliferator-activated receptor δ comprising a compound represented by the above general formula (I), (II) or (III) or a salt thereof as an active ingredient.

The present invention also relates to a method for activating PPAR δ, which comprises administering a compound represented by the general formula (I), (II) or (III) or a salt thereof as an active ingredient.

In addition, the present invention relates to a method for the treatment and/or prevention of PPAR δ -mediated (Mediat) diseases, which are: a method for treating various lipid disorders, metabolic syndrome, obesity, atherosclerosis and related diseases thereof, and diabetes, characterized by administering a compound represented by the general formula (I), (II) or (III) or a salt thereof as an active ingredient.

The present invention further relates to the use of a compound represented by the above general formula (I), (II) or (III) for the treatment and/or prevention of a PPAR δ -mediated (Mediat) disease, wherein the disease is: various lipid disorders, metabolic syndrome, obesity, atherosclerosis and related diseases, and diabetes.

Detailed Description

The present invention will be described in detail below.

In the above general formula (I), as R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹、R¹²、R¹³The alkyl group having 1 to 8 carbon atoms which is a substituent which may be contained in the 5-membered heterocyclic ring of A and a substituent which may be contained in the alkylene chain having 1 to 8 carbon atoms of B, includes: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or the like.

As R¹、R²、R⁵And the C2-8 alkenyl group as the substituent which the 5-membered heterocyclic ring of A may have, for example, a vinyl group or an allyl group.

As R¹、R²And the alkynyl group having 2 to 8 carbon atoms as a substituent which the 5-membered heterocyclic ring of A may have, for example, propargyl group.

As R¹、R²The alkoxy group having 1 to 8 carbon atoms which is a substituent that the 5-membered heterocyclic ring of A may have and the substituent that the alkylene chain having 1 to 8 carbon atoms of B may have include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, or the like.

As R¹、R²A substituent which the 5-membered heterocyclic ring of A may have, and an alkylene chain having 1 to 8 carbon atoms of B may haveExamples of the halogen atom of the substituent include: fluorine atom, chlorine atom, bromine atom, or the like.

As R¹、R²、R⁵And a C1-8 alkyl group substituted with a halogen atom as a substituent which the 5-membered heterocyclic ring of A may have, and examples thereof include: methyl, ethyl, propyl, isopropyl, butyl or tert-butyl substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom or bromine atom, etc., preferably trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl or 2-fluoroethyl, etc.

As R¹、R²And a C1-8 alkoxy group substituted with a halogen atom as a substituent which the 5-membered heterocyclic ring of A may have, and examples thereof include: methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom or bromine atom, etc., preferably trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-fluoroethoxy, etc.

As R¹、R²、R⁵And the acyl group having 2 to 8 carbon atoms which may be a substituent of the 5-membered heterocyclic ring of A, and examples thereof include acetyl group and propionyl group.

As R¹、R²And the aryl group having 6 to 10 carbon atoms as a substituent which the 5-membered heterocyclic ring of A may have, and examples thereof include phenyl groups.

As R¹、R²And a 5-or 6-membered heterocyclic group which may be substituted by the 5-membered heterocyclic ring of A, and examples thereof include a pyridyl group and the like.

As R⁵The C1-8 alkyl group substituted with the C1-8 alkoxy group includes: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl and the like substituted with methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy and the like.

As R⁵Cycloalkyl of 3 to 7 membered ring of (A), mayThe following are listed: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the like.

As R⁵The C1-8 alkyl group substituted with a cycloalkyl group having 3-7 membered rings includes: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl, etc., substituted with cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

As R⁵The alkyl group having 1 to 8 carbon atoms substituted with a phenyl group in (b) includes: benzyl, phenethyl, and the like.

Examples of the cycloalkyl group having a 3 to 7-membered ring as a substituent which may be contained in the C1-8 alkylene chain of B include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

As R in the above general formula (II)^1a、R^2aAnd A^aExamples of the C1-8 alkyl group, C1-8 alkoxy group, halogen atom, C1-8 alkyl group substituted with halogen atom, C1-8 alkoxy group substituted with halogen atom and C2-8 acyl group as the substituent which the 5-membered heterocyclic ring may have include¹、R²And the substituents which the 5-membered heterocyclic ring of A may have are the same as those listed above.

R in the above general formula (III) is^1b、R^2bAnd A^bThe 5-membered heterocyclic ring of (A) may have a substituent of C1-8 alkyl group, C1-8 alkoxy group, halogen atom, C1-8 alkyl group substituted with halogen atom, C1-8 alkoxy group substituted with halogen atom, and C2-8 acyl group, and those mentioned above and R in the general formula (I)¹、R²And the substituents which the 5-membered heterocyclic ring of A may have are the same as those listed above.

Further, R in the above general formula (III)^3bExamples of the C1-8 alkyl group include the groups represented by the formula (I) and R⁵The groups listed are the same.

In the above general formula (I), R is¹、R²R in the general formula (II)^1a、R^2aAnd R in the general formula (III)^1b、R^2b，R¹And 1 to 3 substituted benzene rings may be present, and they may be the same or different.

Further, as the compound of the present invention, the following compounds are preferable.

(1) A compound represented by the general formula (I) or a salt thereof, wherein W¹And W²Are both CH.

(2) The compound of the general formula (I) or (1) or a salt thereof, wherein X is CR⁶R⁷。

(3) The compound of the general formula (I) or (1) or a salt thereof, wherein X is CH₂。

(4) The compound of the general formula (I) or (1) or a salt thereof, wherein X is NR⁵。

(5) The compound of the general formula (I) or (1) or a salt thereof, wherein X is NH.

(6) The compound of the general formula (I) or (1) or a salt thereof, wherein X is N (an alkyl group having 1 to 8 carbon atoms).

(7) The compound of the above general formula (I) or the above (1) to (6) or a salt thereof, wherein Y is CH₂。

(8) The compound according to the above general formula (I) or the above (1) to (7) or a salt thereof, wherein Z is a carboxyl group.

(9) The compound according to the above general formula (I) or the above (1) to (8) or a salt thereof, wherein G is O.

(10) The compound according to the above general formula (I) or (1) to (9) or a salt thereof, wherein A is thiazole which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, an acyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms or a 5-or 6-membered heterocyclic group.

(11) The compound according to the above general formula (I) or the above (1) to (10) or a salt thereof, wherein B is an ethylene chain.

(12) The compound of the general formula (I) or (1) to (11) above or a salt thereof, wherein R is¹And R²The same or different, represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom.

(13) The compound of the general formula (I) or (1) to (11) above or a salt thereof, wherein R is¹And R²The alkyl groups may be the same or different and each represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a halogen atom, or an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom.

(14) The compound of the general formula (I) or (1) to (13) above or a salt thereof, wherein R is³And R⁴Are all hydrogen atoms.

(15) The compound of the above general formula (I) or (1) to (13) or a salt thereof, wherein m is 0.

(16) A compound represented by the general formula (II) or a salt thereof, wherein G^aIs O.

(17) The compound or salt thereof according to claim 17 or 18, which is the compound or salt thereof according to the general formula (II) or (16), wherein A is^aIs a thiazole, which may have a substituent selected from the group consisting of: alkyl group having 1 to 8 carbon atoms, alkoxy group having 1 to 8 carbon atoms, halogen atom, alkyl group having 1 to 8 carbon atoms substituted with halogen atom, substituted with alkyl group having 1 to 8 carbon atomsA halogen atom-substituted alkoxy group having 1 to 8 carbon atoms, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms.

(18) The compound of the general formula (II) or the compound of the formula (16) or (17) or a salt thereof, wherein B is^aIs an ethylene chain.

(19) The compound of the above general formula (II) or the above (16) to (18) or a salt thereof, wherein R is^1aAnd R^2aThe alkyl group may be the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom.

(20) A compound represented by the general formula (III) or a salt thereof, wherein G^bIs O.

(21) The compound of the general formula (III) or (20) or a salt thereof, wherein A^bIs a thiazole, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, and an acyl group having 2 to 8 carbon atoms.

(22) The compound of the general formula (III) or the compound of the formula (20) or (21) or a salt thereof, wherein B is^bIs an ethylene chain.

(23) The compound of the above general formula (III) or the above (20) to (22) or a salt thereof, wherein R is^1bAnd R^2bThe alkyl group may be the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom.

The compounds of the present invention represented by the above general formulae (I), (II) and (III) may be pharmacologically acceptable salts, and examples thereof include: alkali metal salts such as sodium, potassium and lithium.

In addition, optical isomers such as optical isomers and racemates, cis-and trans-geometric isomers, and the like may exist in the compounds of the present invention, and these are included in the present invention.

Next, the synthesis method of the compound of the present invention represented by the above general formula (I) is as follows.

Preparation process 1 (when G is O, B, Z is carboxyl)

(wherein R represents a lower alkyl group, W¹、W²、X、Y、A、R¹、R²、R³、R⁴And m is the same as described above. )

The compound represented by the general formula (c) can be obtained by the following method: the aldehyde compound of the general formula (a) and the acetophenone derivative of the general formula (b) are reacted in an inert solvent such as THF, methanol, ethanol or the like in the presence of a base such as sodium methoxide, sodium ethoxide or the like.

The ester compound represented by the general formula (d) can be obtained by subjecting the obtained compound represented by the general formula (c) to catalytic hydrogenation reduction reaction in an inert solvent such as THF or methanol in the presence of palladium-activated carbon. Then, the ester compound represented by the general formula (d) is subjected to hydrolysis reaction in the presence of lithium hydroxide or the like to obtain the compound of the present invention represented by the general formula (e).

And when X-Y-CO₂When H is propionic acid, an acrylic ester may be used as the compound represented by the above general formula (b), and in this case, in the step of obtaining the general formula (d) by reducing the obtained general formula (c), the acrylic ester is reduced to a propionic ester.

Preparation of (G ═ CH)₂Z as carboxyl group

(wherein R represents a lower alkyl group, W¹、W²、X、Y、A、B、R¹、R²、R³、R⁴And m is the same as described above. )

The ester compound represented by the general formula (g) can be obtained by allowing the ketone compound represented by the general formula (f) to act on methyltriphenylphosphonium bromide or sodium amide in an inert solvent such as THF. Then, the ester compound represented by the general formula (g) is subjected to hydrolysis reaction in the presence of lithium hydroxide or the like to obtain the compound of the present invention represented by the general formula (h).

Preparation of 3(X ═ NR)⁵Z as carboxyl group

(wherein R represents a lower alkyl group, hal represents a halogen atom, W¹、W²、Y、A、B、R¹、R²、R³、R⁴、R⁵And m is the same as described above. )

The amino compound represented by the general formula (i) is reacted with the fatty acid ester derivative represented by the general formula (j) to obtain the ester compound represented by the general formula (k). Then, the ester compound represented by the general formula (k) is subjected to hydrolysis reaction in the presence of lithium hydroxide or the like to obtain the compound of the present invention represented by the general formula (l).

In this case, R in the amino compound represented by the general formula (i) as a starting material⁵The compound having an alkyl group can be obtained, for example, by the following synthesis method.

(in the formula, R⁵Represents an alkyl group, Q represents a protecting group such as o-nitrobenzenesulfonyl group, W¹、W²、A、B、R¹、R²、R³、R⁴And m is the same as described above. )

Further, in the amino compound represented by the general formula (i) as a starting material, R is⁵The compound of ═ H can be obtained, for example, by the following synthesis method.

(in the formula, W¹、W²、A、R¹、R²、R³、R⁴And m is the same as described above. )

The compounds of the present invention represented by the above general formulae (I), (II) and (III) can be prepared by referring to the above patent documents, publicly known documents, and the like, in addition to the above synthetic methods and examples described below.

Examples of the compounds of the present invention are shown in tables 1 to 37.

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 1 to 3)

[ Table 1]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	4-Me	Hexyl	2-Me	1
						CH₂	C(Me)₂	4-CF₃	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	t Bu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	2-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，5-Me	3
						CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	2-Allyl	1
CH₂	CH₂	4-CF₃	4-CF₃Ph	2-Pr	2
						CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	2-OMe	2
CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1

[ Table 2]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-Me	Heptyl	2，6-Me	1
NH	CH₂	4-CF₃	iPr	H	1
						N(Me)	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	4-CF₃	iPr	2-Me	1
						N(Et)	CH₂	4-CF₃	iPr	2-Me	1
N(Allyl)	CH₂	4-CF₃	iPr	2-Me	1
						N(Ac)	CH₂	2-OH，4-Cl	iPr	3-Me	3
NH	CH₂	4-CF₃	iPr	2-Me	1
						N(Me)	(CH₂)₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	4-CN	iPr	2-OH	2
						CH₂	CH₂	4-tBu	iPr	2-Ac	1
CH₂	CH₂	4-iPr	iPr	2-CF₃	1

[ Table 3]

X	Y	R^a	R^b	R^c	n
						CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	2-Me	2
CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	3
NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
						N(Me)	CH₂	4-tBu	cyclohexyl	2-F	2
N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	2，5-Me	1
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	2，5-Me	1
						N(Ac)	CH₂	2，4-Me	iPr	2-Me	1
N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 4)

[ Table 4]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
						NH	CH₂	4-CF₃	iPr	H/H	S
N(Me)	(CH2)₂	4-CF₃	iPr	H/H	CH₂
						CH₂	CH₂	4-CN	iPr	H/H	C(Me)₂
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/H	CH₂
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	Me/H	0
N(Me)	CH₂	4-tBu	cyclohexyl	Pr/H	0
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	Me/H	0
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
						N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 5 and 6)

[ Table 5]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	2
CH₂	CH₂	4-Me	Hexyl	2-Me	2
						CH₂	C(Me)₂	4-CF₃	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₃	4-CF₃	iPr	4-Me	1
CH₂	(CH₂)₃	4-CF₃	cyclopropyl	3，6-Me	1
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1

[ Table 6]

X	Y	R^a	R^b	R^c	n
						N(Me)	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	4-CF₃	iPr	Me	1
						N(Et)	CH₂	4-CF₃	iPr	H	1
N(Allyl)	CH₂	4-CF₃	iPr	H	1
						N(Ac)	CH₂	2-OH，4-Cl	iPr	3-Me	3
CH₂	CH₂	4-iPr	iPr	2-CF₃	1
						CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
						N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 7)

[ Table 7]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
						NH	CH₂	4-CF₃	iPr	H/H	S
N(Me)	(CH₂)₂	4-CF₃	iPr	H/H	CH₂
						CH₂	CH₂	4-CN	iPr	H/H	C(Me)₂
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/Me	CH₂
						N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 8 and 9)

[ Table 8]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	4-Me	Hexyl	2-Me	1
						CH₂	C(Me)₂	4-CF₃	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，5-Me	3
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1

[ Table 9]

X	Y	R^a	R^b	R^c	n
						N(Me)	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	4-CF₃	iPr	2-Me	1
						N(Et)	CH₂	4-CF₃	iPr	H	1
N(Allyl)	CH₂	4-CF₃	iPr	H	1
						N(Ac)	CH₂	2-OH，4-Cl	iPr	H	3
CH₂	CH₂	4-iPr	iPr	2-CF₃	1
						CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
						N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 10)

[ Table 10]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	Me/H	0
						CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
NH	CH₂	4-CF₃	ipr	H/H	S
						N(Me)	(CH₂)₂	4-CF₃	ipr	H/H	CH₂
CH₂	CH₂	4-CN	ipr	H/H	C(Me)₂
						CH₂	CH₂	4-tBu	ipr	Et/H	0
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/Me	CH₂
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	Me/Me	0
N(Me)	CH₂	4-tBu	cyclohexyl	Me/Me	0
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	Me/Me	0
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
						N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 11 to 13)

[ Table 11]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	4-Me	Hexyl	2-Me	1
						CH₂	CH₂	4-CF₃	iPr	2-Me	2
CH₂	C(Me)₂	4-CF₃	Pr	2-Me	1
						CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
						CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
CH₂	(CH₂)₂	4-CF₃	iPr	2-Me	1
						CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，4-Me	3
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	2-Allyl	1
						CH₂	CH₂	4-CF₃	4-CF₃Ph	2-Pr	2
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	2-OMe	2

[ Table 12]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
CH₂	CH₂	4-Me	Heptyl	2，6-Me	1
						NH	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	4-CF₃	iPr	H	1
						N(Me)	CH₂	4-CF₃	iPr	2-Me	1
N(Et)	CH₂	4-CF₃	iPr	H	1
						N(Allyl)	CH₂	4-CF₃	iPr	H	1
N(Ac)	CH₂	2-OH，4-Cl	iPr	H	3
						NH	CH₂	4-CF₃	iPr	2-Me	1
N(Me)	(CH₂)₂	4-CF₃	iPr	2-Me	1
						CH₂	CH₂	4-CN	iPr	2-OH	2
CH₂	CH₂	4-tBu	iPr	2-Ac	1

[ Table 13]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-iPr	iPr	2-CF₃	1
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	2-Me	2
						CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	3
						NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
N(Me)	CH₂	4-tBu	cyclohexyl	2-F	2
						N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
N(Et)	CH₂	4-CF₃	(CH2)₅CH(Me)₂	2，6-Me	1
						N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	2，6-Me	1
N(Ac)	CH₂	2，4-Me	iPr	2-Me	1
						N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 14)

[ Table 14]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	Me/H	0
						CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
NH	CH₂	4-CF3	iPr	H/H	S
						N(Me)	(CH₂)₂	4-CF₃	iPr	H/H	CH₂
CH₂	CH₂	4-CN	iPr	H/H	C(Me)₂
						CH₂	CH₂	4-tBu	iPr	Et/H	0
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/H	CH₂
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	Me/H	0
N(Me)	CH₂	4-tBu	Cyclohexyl	Me/H	0
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	Me/Me	0
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
						N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 15 to 17)

[ Table 15]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	H	iPr	2-Me	1
CH₂	CH₂	2-OH，4-Cl	Hexyl	2-Me	1
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Me	1
CH₂	C(Me)₂	2，4-Cl	Pr	2-Me	1
						CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
						CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
						CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，5-Me	3
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	2-Allyl	1
						CH₂	CH₂	4-CF₃	4-CF₃Ph	2-Pr	2
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	2-OMe	2

[ Table 16]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
CH₂	CH₂	4-Me	Heptyl	2，6-Me	1
						NH	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	4-CF₃	iPr	H	1
						N(Me)	CH₂	4-CF₃	iPr	2-Me	1
N(Et)	CH₂	4-CF₃	iPr	H	1
						N(Allyl)	CH₂	4-CF₃	iPr	H	1
N(Me)	CH₂	2-OH，4-Cl	iPr	H	1
						NH	CH₂	4-CF₃	iPr	2-Me	1
N(Me)	(CH₂)₂	4-CF₃	iPr	2-Me	1
						CH₂	CH₂	4-CN	iPr	2-OH	2
CH₂	CH₂	4-tBu	iPr	2-Ac	1

[ Table 17]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-iPr	iPr	2-CF₃	1
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	2-Me	2
						CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	3
						NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
N(Me)	CH₂	4-tBu	cyclohexyl	2-F	2
						N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	2，5-Me	1
						N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	2，5-Me	1
N(Ac)	CH₂	2，4-Me	iPr	2-Me	1
						N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 18)

[ Table 18]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	2-OH，4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	Me/H	0
						CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
NH	CH₂	4-CF₃	iPr	H/H	S
						N(Me)	(CH₂)₂	4-CF₃	iPr	H/H	CH₂
CH₂	CH₂	4-CN	iPr	H/H	C(Me)₂
						CH₂	CH₂	4-tBu	iPr	Et/H	0
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/Me	CH₂
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	Me/Me	0
N(Me)	CH₂	4-tBu	cyclohexyl	Me/Me	0
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	Me/Me	0
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
						N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 19 and 20)

[ Table 19]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	H	iPr	2-Me	1
CH₂	CH₂	2-OH，4-Cl	Hexyl	2-Me	1
						CH₂	C(Me)₂	2，4-Cl	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，6-Me	3
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1

[ Table 20]

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 21)

[ Table 21]

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 22 and 23)

[ Table 22]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	2-OH，4-Cl	Hexyl	2-Me	1
						CH₂	C(Me)₂	2，4-Cl	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，5-Me	3
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1
						N(Me)	CH₂	4-CF₃	iPr	H	1

[ Table 23]

X	Y	R^a	R^b	R^c	n
						N(Me)	CH₂	4-CF₃	iPr	2-Me	1
N(Et)	CH₂	4-CF₃	iPr	H	1
						N(Allyl)	CH₂	4-CF₃	iPr	H	1
N(Ac)	CH₂	2-OH，4-Cl	iPr	H	3
						N(Me)	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	4-iPr	iPr	2-CF₃	1
						CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
						N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 24)

[ Table 24]

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 25 and 26)

[ Table 25]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	2-OH，4-Cl	Hexyl	2-Me	1
						CH₂	C(Me)₂	2，4-Cl	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，6-Me	3
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1
						N(Me)	CH₂	4-CF₃	iPr	H	1

[ Table 26]

X	Y	R^a	R^b	R^c	n
						N(Me)	CH₂	4-CF₃	iPr	2-Me	1
N(Et)	CH₂	4-CF₃	iPr	2-Me	1
						N(Allyl)	CH₂	4-CF₃	iPr	2-Me	1
N(Ac)	CH₂	2-OH，4-Cl	iPr	3-Me	3
						CH₂	CH₂	4-iPr	iPr	2-CF₃	1
CH₂	CH₂	4-CF₃	CH₂OBu	2-Me	3
						NH	CH₂	4-OCF₃	(CH₂)₅OMe	2-OMe	1
N(Me)	CH₂	4-CF₃	Hexyl	2-F	1
						N(Me)	(CH₂)₂	4-Ac	iPr	2-Me	2

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 27)

[ Table 27]

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 28 and 29)

[ Table 28]

[ Table 29]

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 30)

[ Table 30]

X	Y	R^a	R^b	R^d/R^e	G
						CH₂	CH₂	2-OH，4-CF₃	iPr	H/H	CH₂
CH(Me)	CH₂	4-CF₃	cyclopropylmethyl	H/H	S
						CH₂	CH₂	4-CF₃	4-CF₃Ph	H/H	C(Me)₂
CH₂	CH₂	2，4-Cl	CH₂CH₂OMe	Me/H	0
						CH₂	CH₂	4-Me	Heptyl	H/H	CH₂
NH	CH₂	4-CF₃	iPr	H/H	S
						N(Me)	(CH₂)₂	4-CF₃	iPr	H/H	CH₂
CH₂	CH₂	4-CN	iPr	H/H	C(Me)₂
						CH₂	CH₂	4-tBu	iPr	Et/H	0
CH₂	(CH₂)₃	4-OCF₃	CH₂OBu	Me/H	CH₂
						CH₂	CH₂	4-OCF₃	(CH₂)₅OMe	Me/H	0
N(Me)	CH₂	4-tBu	cyclohexyl	Me/H	0
						N(Et)	CH₂	4-CF₃	(CH₂)₅CH(Me)₂	Me/Me	0
N(Allyl)	CH₂	4-CF₃	4-CF₃Bn	H/H	S
						N(Ac)	CH₂	2，4-Me	iPr	Me/Me	CH₂

(in the formula, X, Y, R^a、R^b、R^cAnd n is as shown in tables 31 and 32)

[ Table 31]

X	Y	R^a	R^b	R^c	n
						CH₂	CH₂	4-CF₃	iPr	2-Me	1
CH₂	CH₂	2-OH，4-Cl	Hexyl	2-Me	1
						CH₂	C(Me)₂	2，4-Cl	Pr	2-Me	1
CH₂	CH(Me)	4-CF₃	secBu	3-Me	1
						CH₂	CH(Et)	4-CF₃	tBu	3-Me	2
CH₂	CH(Pr)	4-CF₃	Hexyl	2，6-Me	3
						CH₂	(CH₂)₂	4-CF₃	iPr	3-Me	3
CH₂	(CH₂)₂	4-CF₃	cyclopropyl	3，6-Me	3
						CH₂	CH₂	2-OH，4-CF₃	iPr	2-Cl	1
NH	CH₂	4-CF₃	iPr	H	1

[ Table 32]

(in the formula, X, Y, R^a、R^b、R^d、R^eAnd G is as shown in Table 33)

[ Table 33]

(in the formula, A, R¹、R²M, n and G are as shown in tables 34 and 35)

[ Table 34]

[ Table 35]

(in the formula, A, R¹、R²N and G are as shown in tables 36 and 37)

[ Table 36]

[ Table 37]

(in tables 1 to 37, Me represents a Methyl group, Methyl represents a Methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents an isopropyl group, Bu represents a butyl group, secBu represents a sec-butyl group, tBu represents a tert-butyl group, Hexyl represents a Hexyl group, Heptyl represents a Heptyl group, Allyl represents an Allyl group, OMe represents a methoxy group, Ph represents a phenyl group, Ac represents an acetyl group, cyclopropyl represents a cyclopropyl group, cyclopropyl Methyl represents a cyclopropylmethyl group, cyclohexyl represents a cyclohexyl group, and Bn represents a benzyl group.)

The pharmacological actions of the present invention will be explained below.

The PPAR activating effects of the compounds of the present invention were determined by the following methods.

A receptor expression plasmid (pSG5-GAL4-hPPAR α or γ or δ (LBD)), a luciferase expression plasmid (MH 100X 4-TK-Luc), and a β -galactosidase expression plasmid (pCMX- β -GAL) (Kliewer, S.A.et. al., (1992) Nature, 358: 771-. After gene transfer using Lipofectamine (2000(Invitrogen)), the cells were cultured in the presence of the test compound for about 40 hours. The luciferase activity and β -GAL activity of the lysed cells were determined. Luciferase activity was corrected by β -GAL activity, and the relative ligand activities of PPAR α, γ, and δ were calculated as follows: p was calculated as the value of luciferase activity of the cells treated with GW-590735 (PPAR. alpha. selective agonist) being 100%Relative ligand activity of PAR α; calculating the relative ligand activity of PPAR γ with the luciferase activity value of the cells treated with Rosiglitazone as 100%; the relative ligand activity of PPAR. delta. was calculated with the luciferase activity value of GW-501516 treated as 100%, and EC was determined₅₀(examples 14 and 15 described later).

Contrary to the conclusion that the PPAR δ activating effect of the phenylpropanoid compounds described in non-patent document 3 is weak, it is clear from tables 38 and 39 that the compounds of the present invention exhibit excellent PPAR δ transcriptional activating effect. The compounds of the general formulae (I), (II) and (III) according to the invention are therefore potent PPAR δ agonists.

The pharmaceutical composition of PPAR δ agonist of the present invention can be used for treating or preventing all diseases mediated by PPAR δ. These diseases include: hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL blood level, high LDL and/or non-HDL blood level, high VLDL blood level, lipoprotein abnormality, low apolipoprotein A-I blood level, atherosclerosis, arteriosclerotic diseases, coronary artery diseases, cerebrovascular diseases, peripheral vascular diseases, metabolic syndrome, syndrome X, obesity such as visceral fat obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, fatty liver, nonalcoholic steatohepatitis, thrombosis, Alzheimer's disease, neurodegenerative diseases, demyelinating diseases, multiple sclerosis, adrenoleukodystrophy (adrenal leukodystrophy), dermatitis, psoriasis, acne, skin aging, abnormal hair, Inflammation, arthritis, asthma, irritable bowel syndrome, ulcerative colitis, Crohn's disease, pancreatitis, colon cancer, carcinoma of large intestine, skin cancer, breast cancer, prostate cancer, ovarian cancer, lung cancer, etc.

The compound of the present invention can be administered to a human by a suitable administration method such as general oral administration or non-oral administration.

For preparing the preparation, the preparation can be prepared into tablets, granules, powder, capsules, suspending agents, injections, suppositories and other dosage forms by adopting a method which is commonly used in the technical field of preparation.

In the preparation of these dosage forms, conventional excipients, disintegrants, binders, lubricants, pigments, diluents, and the like can be used. Among these, examples of the excipient include: lactose, D-mannitol, crystalline cellulose, glucose, and the like; examples of the disintegrant include: starch, carboxymethylcellulose calcium (CMC-Ca), and the like; examples of the lubricant include: magnesium stearate, talc, and the like; examples of the binder include: carboxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.

The dose is usually about 0.1mg to 100mg per 1 day when the compound of the present invention as an active ingredient is administered by injection for an adult; the dose for oral administration is 1mg to 2000mg per day, and the dose can be increased or decreased depending on age, symptoms, and the like.

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

Examples

Example 1

3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl]Propionyl group]-2-methylphenyl radical]Propionic acid

(1) 4-hexyl-2- (4-methylphenyl) thiazole-5-carbaldehyde

Reacting [ 4-hexyl-2- (4-methylphenyl) thiazole-5-yl]Methanol (500mg, 1.727mmol) was dissolved in anhydrous dichloromethane (6ml) and molecular sieves (3A powder, 890mg) and Curie reagent (クロロクロム) were addedピリジゥム) (745mg, 3.455 mmol). After stirring at room temperature for 30 minutes, diethyl ether (20mL) and silica gel (Wako-gel, C-300HG, 2g) were added and further stirred at room temperature for 10 minutes. The reaction mixture was filtered through a glass filter, and the residue was washed with diethyl ether to obtain a filtrate, from which the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (346mg, yield 70%) was obtained as white crystals from a hexane/ethyl acetate (8:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

0.89(3H，t，J＝7Hz)，

1.3—1.4(6H，m)，

1.8—1.9(2H，m)，

2.41(3H，s)，

3.09(2H，t，J＝7Hz)，

7.27(2H，d，J＝8Hz)，

7.90(2H，d，J＝8Hz)，

10.08.(1H，s).

(2)3- (4-acetyl-2-methylphenyl) -2-bromopropionic acid methyl ester

1- (4-amino-3-methylphenyl) ethanone (1.70g, 11.39mmol) was dissolved in methanol (15mL) -acetone (38mL) and cooled to 0 ℃. 48% hydrobromic acid (5.15mL, 45.56mmol) was added dropwise over 1 min, followed by sodium nitrite (943mg, 13.67mmol) dissolved in water (1.8mL) and stirred at the same temperature for 30 min. After allowing to stand at room temperature, methyl acrylate (7.23mL, 80.30mmol) and cuprous oxide (117mg) were added. After stirring at 40 ℃ for 30 minutes, the solvent was distilled off under reduced pressure. Ice water (150mL) was added to the residue, which was neutralized with aqueous ammonia, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound as a brown oil (2.79g, yield 82%).

¹H NMR(CDCl₃，400MHz)：δ＝

2.41(3H，s)，

2.58(3H，s)，

3.33(1H，dd，J＝7，15Hz)，

3.52(1H，dd，J＝7，15Hz)，

3.74(3H，s)，

4.43(1H，t，J＝7Hz)，

7.2—7.9(3H，m).

(3)3- (4-acetyl-2-methylphenyl) acrylic acid

Methyl 3- (4-acetyl-2-methylphenyl) -2-bromopropionate (2.79g, 9.33mmol) obtained above was dissolved in methanol (80mL), cooled to 5 ℃, and sodium methoxide (1.51g, 27.98mmol) was added. After stirring at room temperature for 20 minutes, the mixture was refluxed for 1 hour. After cooling to room temperature, 1N hydrochloric acid was added for acidification. After water (50mL) was added, methanol was distilled off under reduced pressure, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give the title compound (657mg, yield 34%) as yellow crystals.

¹H NMR(CD₃OD，400MHz)：δ＝

2.49(3H，s)，

2.59(3H，s)，

6.49(1H，d，J＝16Hz)，

7.73(1H，d，J＝8Hz)，

7.8—7.9(3H，m)，

7.97(1H，d，J＝16Hz).

(4)3- (4-acetyl-2-methylphenyl) acrylic acid methyl ester

The 3- (4-acetyl-2-methylphenyl) acrylic acid (657mg, 3.22mmol) obtained above was dissolved in methanol (20mL), concentrated sulfuric acid (250. mu.L) was added thereto, and the mixture was refluxed for 2 hours. After cooling to room temperature, water (50mL) was added, and then methanol was distilled off under reduced pressure. After extraction with ethyl acetate, the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound (665mg, yield 95%) as yellow crystals from a hexane/ethyl acetate (9:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

2.49(3H，s)，

2.60(3H，s)，

3.83(3H，s)，

6.43(1H，d，J＝16Hz)，

7.62(1H，d，J＝9Hz)，

7.7—7.8(2H，m)，

7.96(1H，d，J＝16Hz).

(5)3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl ] acryloyl ] -2-methylphenyl ] acrylic acid methyl ester

The methyl 3- (4-acetyl-2-methylphenyl) acrylate (200mg, 0.916mmol) obtained above was dissolved in anhydrous tetrahydrofuran (1mL) under a nitrogen atmosphere, and molecular sieves (3A powder, 200mg) were added. 0.5M sodium methoxide methanol solution (1.83mL, 0.916mmol) was added under stirring with ice cooling, and after stirring at the same temperature for 10 minutes, a solution of 4-hexyl-2- (4-methylphenyl) thiazole-5-carbaldehyde (132mg, 0.458mmol) obtained in example 1(1) in anhydrous tetrahydrofuran (1mL) was slowly added. After stirring for 3 hours under ice-cooling, the reaction mixture was neutralized with a 1N aqueous hydrochloric acid solution and filtered with celite (セライト). The filtrate was washed with water, and the organic layer was separated, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The obtained residue was recrystallized from hexane and ethyl acetate to give the title compound (185mg, yield 83%) as yellow crystals.

¹H NMR(CDCl₃，400MHz)：δ＝

0.89(3H，t，J＝7Hz)，

1.3—1.5(6H，m)，

1.7—1.8(2H，m)，

2.41(3H，s)，

2.53(3H，s)，

2.93(2H，t，J＝7Hz)，

3.84(3H，s)，

6.46(1H，d，J＝16Hz)，

7.20(1H，d，J＝16Hz)，

7.8—7.9(2H，m)，

7.66(1H，d，J＝8Hz)，

7.8—7.9(4H，m)，

7.99(1H，d，J＝16Hz)，

8.02(1H，d，J＝16Hz).

(6)3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl ] propionyl ] -2-methylphenyl ] propionic acid methyl ester

Methyl 3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl ] acryloyl ] -2-methylphenyl ] acrylate (112mg, 0.230mmol) obtained above was dissolved in methanol (1mL) and tetrahydrofuran (1mL), and 10% palladium on charcoal (22mg) was added to replace hydrogen in the system. After stirring at room temperature for 3 hours, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure to give a residue, and the obtained residue was subjected to silica gel column chromatography to give the title compound (46mg, yield 41%) as a colorless oil from hexane: ethyl acetate (5:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

0.88(3H，t，J＝7Hz)，

1.2-1.4(6H，m)，

1.6-1.8(2H，m)，

2.37(3H，s)，

2.38(3H，s)，

2.61(2H，t，J＝8Hz)，

2.72(2H，t，J＝8Hz)，

2.99(2H，t，J＝8Hz)，

3.2-3.3(4H，m)，

3.68(3H，s)，

7.19(2H，d，J＝8Hz)，

7.23(1H，d，J＝8Hz)，

7.7-7.8(4H，m).

(7)3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl ] propanoyl ] -2-methylphenyl ] propanoic acid

Methyl 3- [4- [3- [ 4-hexyl-2- (4-methylphenyl) thiazol-5-yl ] propionyl ] -2-methylphenyl ] propanoate (45mg, 0.0915mmol) obtained above was suspended in ethanol (2mL) and water (1mL), and lithium hydroxide hydrate (12mg, 0.275mmol) was added. After refluxing under heating for 1 hour, 1N hydrochloric acid (5mL) and ice water (2mL) were added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from hexane and ethyl acetate to give the title compound (38mg, yield 87%) as white crystals.

FAB-MS(m/e)：478(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

0.88(3H，t，J＝7Hz)，

1.3-1.4(6H，m)，

1.6-1.8(2H，m)，

2.37(3H，s)，

2.38(3H，s)，

2.6-2.8(4H，m)，

3.00(2H，t，J＝8Hz)，

3.1-3.3(4H，m)，

7.19(2H，d，J＝8Hz)，

7.24(1H，s)，

7.7-7.8(4H，m).

Example 2

3- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl]Thien-2-yl]Propionyl group]-2-methylphenyl radical] Propionic acid

(1) 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophene-2-carbaldehyde

The title compound was obtained in the same manner as in example 1(1) using [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] methanol.

Pale yellow crystals

The yield thereof was found to be 57%

¹H NMR(CDCl₃，400MHz)：δ＝

1.39(6H，d，J＝7Hz)，

3.6—3.8(1H，m)，

7.37(1H，s)，

7.6.8(2H，d，J＝8Hz)，

7.77(2H，d，J＝8Hz)，

10.11(1H，s).

(2)3- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] acryloyl ] -2-methylphenyl ] acrylic acid methyl ester

The title compound was obtained in the same manner as in example 1 (5).

Yellow crystals

The yield thereof is 67%

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

2.54(3H，s)，

3.3—3.5(1H，m)，

3.84(3H，s)，

6.46(1H，d，J＝16Hz)，

7.3—7.4(1H，m)，

7.6—7.9(8H，m)，

8.00(1H，d，J＝15Hz)，

8.11(1H，d，J＝15Hz).

(3)3- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] propanoyl ] -2-methylphenyl ] propanoic acid methyl ester

The title compound was obtained in the same manner as in example 1 (6).

Pale yellow crystals

The yield is 58 percent

¹H NMR(CDCl₃，400MHz)：δ＝

1.26(6H，d，J＝7Hz)，

2.38(3H，s)，

2.61(2H，t，J＝8Hz)，

2.99(2H，t，J＝8Hz)，

3.0—3.1(1H，m)，

3.2—3.4(4H，m)，

3.68(3H，s)，

7.20(1H，s)，

7.23(1H，d，J＝8Hz)，

7.58(2H，d，J＝8Hz)，

7.64(2H，d，J＝8Hz)，

7.7—7.8(2H，m).

(4)3- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] propanoyl ] -2-methylphenyl ] propanoic acid

The title compound was obtained in the same manner as in example 1 (7).

White crystal

The yield thereof was found to be 79%

FAB—MS(m/e)：488(M)

¹H NMR(CDCl₃，400MHz)：δ＝

1.25(6H，d，J＝7Hz)，

2.38(3H，s)，

2.67(2H，t，J＝8Hz)，

3.01(2H，t，J＝8Hz)，

3.0—3.1(1H，m)，

3.2—3.4(4H，m)，

7.20(1H，s)，

7.24(1H，s)，

7.58(2H，d，J＝8Hz)，

7.64(2H，d，J＝8Hz)，

7.7—7.8(1H，m)，

7.77(1H，s).

Example 3

3- [4- [3- (5-isopropyl-2-phenyl-4-oxazolyl) propanoyl group]-2-methylphenyl radical]Propionic acid

(1) 5-isopropyl-2- (2, 4-dichlorophenyl) oxazole-4-carbaldehyde

The title compound was obtained in the same manner as in example 1(1) using 5-isopropyl-2- (2, 4-dichlorophenyl) oxazole-4-methanol.

Pale yellow crystals

¹H NMR(CDCl₃，400MHz)：δ＝

1.39(6H，d，J＝7Hz)，

3.72(1H，dq，J＝7，7Hz)，

7.37(1H，dd，J＝2，8Hz)，

7.5.5(1H，d，J＝2Hz)，

7.99(1H，d，J＝8Hz)，

10.06(1H，s).

(2)3- [4- [3- [ 5-isopropyl-2- (2, 4-dichlorophenyl) -4-oxazolyl ] acryloyl ] -2-methylphenyl ] acrylic acid methyl ester

The title compound was obtained in the same manner as in example 1(5) using 5-isopropyl-2- (2, 4-dichlorophenyl) oxazole-4-carbaldehyde obtained above and methyl 3- (4-acetyl-2-methylphenyl) acrylate.

Pale yellow crystals

¹H NMR(CDCl₃，400MHz)：δ＝

1.39(6H，d，J＝7Hz)，

2.52(3H，s)，

3.39(1H，dq，J＝7，7Hz)，

3.83(3H，s)，

6.46(1H，d，J＝16Hz)，

7.38(1H，dd，J＝2，8Hz)，

7.55(1H，d，J＝2Hz)，

7.66(1H，d，J＝8Hz)，

7.75(1H，d，J＝15Hz)，

7.80(1H，d，J＝15Hz)，

7.9—8.0(2H，m)，

7.99(1H，d，J＝16Hz)，

8.01(1H，d，J＝8Hz).

(3)3- [4- [3- [ 5-isopropyl-2-phenyl-4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid methyl ester

The title compound was obtained in the same manner as in example 1(6) using methyl 3- [4- [3- [ 5-isopropyl-2- (2, 4-dichlorophenyl) -4-oxazolyl ] acryloyl ] -2-methylphenyl ] acrylate obtained above.

Colorless oil

¹H NMR(CDCl₃，400MHz)：δ＝

1.30(6H，d，J＝7Hz)，

2.35(3H，s)，

2.59(2H，t，J＝7Hz)，

2.9—3.1(4H，m)，

3.17(1H，dq，J＝7，7Hz)，

3.36(2H，t，J＝7Hz)，

3.67(3H，s)，

7.20(1H，d，J＝8Hz)，

7.3—7.5(3H，m)，

7.7—7.9(2H，m)，

7.9—8.1(2H，m).

(4)3- [4- [3- [ 5-isopropyl-2-phenyl-4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid

The title compound was obtained in the same manner as in example 1(7) using methyl 3- [4- [3- [ 5-isopropyl-2-phenyl-4-oxazolyl ] propionyl ] -2-methylphenyl ] propionate obtained above.

Colorless oil

FAB—MS(m/e)：406(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.30(6H，d，J＝7Hz)，

2.35(3H，s)，

2.63(2H，t，J＝7Hz)，

2.9—3.1(4H，m)，

3.17(1H，dq，J＝7，7Hz)，

3.34(2H，t，J＝7Hz)，

7.21(1H，d，J＝8Hz)，

7.3—7.5(3H，m)，

7.7—7.9(2H，m)，

7.9—8.1(2H，m).

Example 4

3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl]Thiazol-5-yl]Acryloyl group]-2-methylbenzene Base of]Acrylic acid

The title compound was obtained in the same manner as in example 1(5) using methyl 3- (4-acetyl-2-methylphenyl) acrylate and [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] carbaldehyde.

Yellow crystals

FAB—MS(m/e)：486(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.40(6H，d，J＝7Hz)，

2.56(3H，s)，

3.4—3.5(1H，m)，

6.49(1H，d，J＝16Hz)，

7.28(1H，d，J＝16Hz)，

7.7—7.8(3H，m)，

7.8—7.9(2H，m)，

8.0—8.2(4H，m).

Example 5

3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl]Thiazol-5-yl]Propionyl group]-2-methylphenyl radical] Propionic acid

The title compound was obtained in the same manner as in example 1(6) using 3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] acryloyl ] -2-methylphenyl ] acrylic acid obtained in example 4.

White crystal

FAB—MS(m/e)：490(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.33(6H，d，J＝7Hz)，

2.38(3H，s)，

2.66(2H，t，J＝8Hz)，

3.00(2H，t，J＝8Hz)，

3.1—3.2(1H，m)，

3.2—3.3(4H，m)，

7.25(1H，d，J＝7Hz)，

7.64(2H，d，J＝8Hz)，

7.7—7.8(2H，m)，

8.00(2H，d，J＝8Hz).

Example 6

3- [4- [1- [2- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl]Thiazol-5-yl]Ethyl radical]Vinyl radical]-2- Methyl phenyl]Propionic acid

(1)3- [4- [1- [2- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] ethyl ] vinyl ] -2-methylphenyl ] propanoic acid methyl ester

Methyltriphenylphosphonium bromide (89mg, 0.250mmol) was suspended in anhydrous tetrahydrofuran (3.5mL) under a nitrogen atmosphere, and sodium amide (13mg, 0.332mmol) was added. After stirring at room temperature for 30 minutes, a solution of methyl 3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propanoyl ] -2-methylphenyl ] propanoate (84mg, 0.167mmol) in anhydrous tetrahydrofuran (1.5mL) was added dropwise. After stirring at the same temperature for 19 hours, a saturated aqueous ammonium chloride solution was added, and extraction was performed with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (70mg, yield 84%) was obtained as a pale yellow oil from the hexane/ethyl acetate (8:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.28(6H，d，J＝7Hz)，

2.34(3H，s)，

2.5—2.7(2H，m)，

2.8—2.9(2H，m)，

2.9-3.1(5H，m)，

3.69(3H，s)，

5.06(1H，s)，

5.31(1H，s)，

7.13(1H，d，J＝9Hz)，

7.1—7.3(2H，m)，

7.64(2H，d，J＝8Hz)，

8.01(2H，d，J＝8Hz).

(2)3- [4- [1- [2- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] ethyl ] vinyl ] -2-methylphenyl ] propionic acid

The title compound was obtained in the same manner as in example 1 (7).

White crystal

FAB—MS(m/e)：488(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.28(6H，d，J＝7Hz)，

2.35(3H，s)，

2.66(2H，dd，J＝7，8Hz)

2.82(2H，dd，J＝7，8Hz)

2.9—3.0(5H，m)，

5.07(1H，s)，

5.32(1H，s)，

7.1—7.3(3H，m)，

7.64(2H，d，J＝8Hz)，

8.00(2H，d，J＝8Hz).

Example 7

N- [4- [3- [ 4-isopropyl-2- [4-, (Trifluoromethyl) phenyl]Thiazol-5-yl]Propionyl group]Phenyl radical]-N-methyl Glycine radical

(1)3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -1- (4-nitrophenyl) propenone

4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazole-5-carbaldehyde (4.53g, 15.14mmol) and 4-nitroacetophenone (2.50g, 15.14mmol) were dissolved in a mixed solution of anhydrous methanol (30mL) -anhydrous tetrahydrofuran (30mL), and sodium methoxide (258mg, 3.79mmol) was added thereto, followed by stirring under nitrogen at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the mixture was suspended in chloroform. After insoluble matter was filtered off, the filtrate was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated brine, and the solvent was again distilled off under reduced pressure. The residue was recrystallized from n-hexane-ethyl acetate (1:1) to give the title compound (4.08g, yield 60%) as yellow crystals.

¹H NMR(CDCl₃，400MHz)：δ＝

1.40(6H，d，J＝7Hz)，

3.4—3.5(1H，m)，

7.24(1H，d，J＝12Hz)，

7.73(2H，d，J＝8Hz)，

8.14(5H，m)，

8.37(2H，d，J＝8Hz).

(2)1- (4-aminophenyl) -3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -propan-1-one

After 3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -1- (4-nitrophenyl) propenone (4.08g, 9.14mmol) was dissolved in tetrahydrofuran (120mL) and methanol (100mL), a methanol suspension (20mL) of 10% palladium on carbon (400mg) was added and stirred under hydrogen at 60 ℃ for 2 hours. After cooling to room temperature, insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound (2.31g, yield 60%) was obtained as yellow crystals from a hexane/ethyl acetate (7:3, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.33(6H，d，J＝7Hz)，

3.1—3.3(5H，m)，

4.12(2H，brs)，

6.65(2H，td，J＝2，8Hz)，

7.63(2H，d，J＝8Hz)，

7.82(2H，td，J＝2，8Hz)，

8.00(2H，d，J＝8Hz).

(3) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] -2-nitrobenzenesulfonamide

1- (4-aminophenyl) -3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -propan-1-one (250mg, 0.597mmol) obtained above was dissolved in anhydrous pyridine (5mL), and o-nitrobenzenesulfonyl chloride (146mg, 0.659mmol) was added. After stirring at room temperature for 1 hour, the temperature was raised to 80 ℃ and then stirred for 16 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (265mg, yield 74%) as yellow crystals from a hexane/ethyl acetate (8:2, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

3.0—3.2(1H，m)，

3.2—3.3(4H，m)，

7.32(2H，d，J＝8Hz)，

7.45(1H，s)，

7.6—7.7(4H，m)，

7.87(1H，d，J＝8Hz)，

7.90(2H，d，J＝8Hz)，

7.94(1H，dd，J＝1，8Hz)，

7.99(2H，d，J＝8Hz).

(4) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] -N-methyl-2-nitrobenzenesulfonamide

The N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propanoyl ] phenyl ] -2-nitrobenzenesulfonamide (265mg, 0.439mmol) obtained above was dissolved in anhydrous dimethylformamide (10mL), and iodomethane (30. mu.L, 0.483mmol) and potassium carbonate (121mg, 0.875mmol) were added and stirred at room temperature for 16 hours. After neutralization with 0.2N aqueous hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and the title compound (230mg, yield 85%) was obtained as a yellow oil from the hexane/ethyl acetate (7:3, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.34(6H，d，J＝7Hz)，

3.1—3.2(1H，m)，

3.2—3.4(4H，m)，

3.41(3H，s)，

7.38(2H，d，J＝8Hz)，

7.5—7.8(6H，m)，

7.94(2H，d，J＝8Hz)，

8.00(2H，d，J＝8Hz).

(5)3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -1- (4-methylaminophenyl) propan-1-one

N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] -N-methyl-2-nitrobenzenesulfonamide (230mg, 0.372mmol) obtained above was dissolved in anhydrous dimethylformamide (5mL), and potassium carbonate (154mg, 1.116mmol) and thiophenol (46. mu.L, 0.446mmol) were added to stir at room temperature for 1 hour. After dilution with water, extraction with ethyl acetate. The organic layer was separated, washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (154mg, yield 95%) as yellow crystals from a hexane/ethyl acetate (8:2, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.33(6H，d，J＝7Hz)，

2.90(3H，d，J＝5Hz)，

3.1—3.3(5H，m)，

4.26(1H，brs)，

6.56(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.85(2H，d，J＝8Hz)，

8.00(2H，d，J＝8Hz).

(6) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] -N-methylglycine ethyl ester

3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -1- (4-methylaminophenyl) propan-1-one (40mg, 0.0931mmol) obtained above and diisopropylethylamine (80. mu.L, 0.462mmol) were dissolved in anhydrous dimethylformamide (2mL), ethyl bromoacetate (66mg, 0.393mmol) was added, and the mixture was stirred at 110 ℃ for 16 hours. Cooled to room temperature, added water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was subjected to silica gel column chromatography to give the title compound (56mg, yield 47%) as yellow crystals from a hexane/ethyl acetate (7:3, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.25(3H，t，J＝7Hz)，

1.33(6H，d，J＝7Hz)，

3.14(3H，s)，

3.1—3.2(1H，m)，

3.2—3.3(4H，m)，

4.12(2H，s)，

4.19(2H，q，J＝7Hz)，

6.65(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.88(2H，d，J＝8Hz)，

8.00(2H，d，J＝8Hz).

(7) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propanoyl ] phenyl ] -N-methylglycine

Ethyl N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propanoyl ] phenyl ] -N-methylglycine (54mg, 0.104mmol) obtained above was dissolved in ethanol (1mL) -THF (1mL), 1N sodium hydroxide (208. mu.L, 0.208mmol) was added, and the mixture was stirred at room temperature for 20 minutes. After dilution with water (2mL), the mixture was neutralized with a 1N aqueous hydrochloric acid solution. After further stirring at 5 ℃ for 30 minutes, the precipitate was filtered off and then washed with water. Drying under reduced pressure at 60 ℃ for 2 hours gave the title compound as yellow crystals (40mg, yield 78%).

FAB—MS(m/e)：491(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

3.1—3.2(4H，m)，

3.2—3.3(4H，m)，

4.17(2H，s)，

6.66(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.89(2H，d，J＝8Hz)，

7.99(2H，d，J＝8Hz).

Example 8

N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl group]Thiazol-5-yl]Propionyl group]Phenyl radical]Glycine Acid(s)

(1) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] glycine ethyl ester

The title compound was obtained in the same manner as in example 7(6) using 1- (4-aminophenyl) -3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] -propan-1-one.

Pale yellow amorphous

The yield thereof is 83%

¹H NMR(CDCl₃，400MHz)：δ＝

1.31(3H，t，J＝7Hz)，

1.33(6H，d，J＝7Hz)，

3.1—3.3(5H，m)，

3.95(2H，d，J＝5Hz)，

4.27(2H，q，J＝7Hz)，

4.82(1H，m)，

6.58(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.86(2H，d，J＝8Hz)，

8.00(2H，d，J＝8Hz).

(2) N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] glycine

The title compound was obtained in the same manner as in example 7(7) using ethyl N- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazol-5-yl ] propionyl ] phenyl ] glycinate.

Yellow crystals

The yield is 75 percent

¹H NMR(CDCl₃，400MHz)：δ＝

1.33(6H，d，J＝7Hz)，

2.17(1H，s)，

3.1—3.3(5H，m)，

4.06(2H，s)，

6.60(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.87(2H，d，J＝8Hz)，

7.99(2H，d，J＝8Hz).

Example 9

N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl]Thien-2-yl]Propionyl group]Phenyl radical]-N-methyl Glycine radical

(1) N- (4-Acetylphenyl) -N-methylglycine ethyl ester

4-methylaminophenone (277mg, 1.86mmol) and diisopropylethylamine (485. mu.L, 2.79mmol) were dissolved in anhydrous DMF (10ml), ethyl bromoacetate (372mg, 2.23mmol) was added, and the mixture was stirred under nitrogen at 110 ℃ for 16 hours. Cooled to room temperature, diisopropylethylamine (162. mu.L, 0.93mmol) and ethyl bromoacetate (155mg, 0.93mmol) were added, and the mixture was stirred at 110 ℃ for 16 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound (274mg, yield 63%) as a brown oil from a hexane: chloroform (1:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.26(3H，t，J＝7Hz)，

2.51(3H，s)，

3.14(3H，s)，

4.12(2H，s)，

4.20(2H，q，J＝7Hz)，

6.65(2H，d，J＝8Hz)，

7.87(2H，d，J＝8Hz).

(2) N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] acryloyl ] phenyl ] -N-methylglycine ethyl ester

The ethyl N- (4-acetylphenyl) -N-methylglycine (92mg, 0.389mmol) obtained above was dissolved in anhydrous THF (2ml), and molecular sieves (3A, powder) (200mg) were added to the solution, followed by cooling to 5 ℃. A21 wt% ethanol solution of sodium ethoxide (145. mu.L, 0.389mmol) was added dropwise under a nitrogen atmosphere, and stirred at the same temperature for 10 minutes. A solution of 3-isopropyl-5- (4-trifluoromethylphenyl) thiophene-2-carbaldehyde (116mg, 0.389mmol) in anhydrous THF (10mL) was added, and the mixture was stirred at the same temperature for 30 minutes. After neutralization with 1N aqueous hydrochloric acid, the mixture was diluted with chloroform. After insoluble matter was filtered off, it was washed with 0.2N aqueous hydrochloric acid solution and saturated brine, then dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give the crude product of the title compound (100mg) from hexane/ethyl acetate (9:1, v/v) fraction.

(3) N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] propanoyl ] phenyl ] -N-methylglycine ethyl ester

The crude N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] acryloyl ] phenyl ] -N-methylglycine ethyl ester (100mg) obtained above was dissolved in tetrahydrofuran (5mL) and methanol (4mL), and then 10% palladium-activated carbon (10mg) methanol suspension (1mL) was added and stirred under a hydrogen atmosphere at room temperature for 2 hours. Insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound was obtained as a colorless oil (37mg, 2steps, yield 18%) from the hexane/ethyl acetate (9:1, v/v) fraction.

¹H NMR(CDCl₃，400MHz)：δ＝

1.2—1.3(9H，m)，

3.0—3.1(1H，m)，

3.14(3H，s)，

3.2—3.3(4H，m)，

4.12(2H，s)，

4.19(2H，q，J＝7Hz)，

6.65(2H，d，J＝9Hz)，

7.20(1H，s)，

7.57(2H，d，J＝8Hz)，

7.64(2H，d，J＝8Hz)，

7.90(2H，d，J＝9Hz).

(4)N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl]Thien-2-yl]Propionyl group]Benzene and its derivatives Base of]-N-methylglycine

The ethyl N- [4- [3- [ 3-isopropyl-5- [4- (trifluoromethyl) phenyl ] thiophen-2-yl ] propanoyl ] phenyl ] -N-methylglycinate (37mg, 0.071mmol) obtained above was dissolved in ethanol (0.5mL) -THF (0.5mL), 1N sodium hydroxide (143. mu.L, 0.143mmol) was added and stirred at room temperature for 30 minutes. After neutralization with 1N aqueous hydrochloric acid, the mixture was stirred at 5 ℃ for 20 minutes. The precipitated crystal was filtered, washed with water and cold ethanol, and dried under reduced pressure at 50 ℃ for 1 hour to obtain the title compound (26mg, yield 75%) as white crystals.

FAB—MS(m/e)：490(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.25(6H，d，J＝7Hz)，

3.0—3.1(1H，m)，

3.14(3H，s)，

3.1—3.3(4H，m)，

4.18(2H，s)，

6.67(2H，d，J＝8Hz)，

7.19(1H，s)，

7.57(2H，d，J＝8Hz)，

7.63(2H，d，J＝8Hz)，

7.91(2H，d，J＝8Hz).

Example 10

N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl]Propionyl group]Phenyl radical]-N-methyl Glycine

(1) N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] acryloyl ] phenyl ] -N-methylglycine ethyl ester

The title compound was obtained in the same manner as in example 9(2) using 2- (4-chloro-2-hydroxyphenyl) -5-isopropyloxazolyl-4-carbaldehyde and ethyl N- (4-acetylphenyl) -N-methylglycine.

Yellow brown crystal

The yield thereof was found to be 49%

¹H NMR(CDCl₃，400MHz)：δ＝

1.27(3H，t，J＝7Hz)，

1.39(6H，d，J＝7Hz)，

3.18(3H，s)，

3.3—3.5(1H，m)，

4.16(2H，s)，

4.22(2H，q，J＝7Hz)，

6.71(2H，d，J＝9Hz)，

6.97(1H，dd，J＝2Hz，8Hz)，

7.13(1H，d，J＝2Hz)，

7.66(1H，d，J＝15Hz)，

7.71(1H，d，J＝15Hz)，

7.76(1H，d，J＝8Hz)，

8.03(2H，d，J＝9Hz)，

11.38(1H，s).

(2) N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] phenyl ] -N-methylglycine ethyl ester

The title compound was obtained in the same manner as in example 9(3) using the above-obtained ethyl N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] acryloyl ] phenyl ] -N-methylglycine.

Yellowish crystal

The yield thereof was found to be 53%

¹H NMR(CDCl₃，400MHz)：δ＝

1.25(3H，t，J＝7Hz)，

1.31(6H，d，J＝7Hz)，

2.93(2H，t，J＝7Hz)，

8.13(3H，s)，

3.1—3.3(1H，m)，

3.25(2H，t，J＝7Hz)，

4.11(2H，s)，

4.19(2H，q，J＝7Hz)，

6.64(2H，d，J＝9Hz)，

6.90(1H，dd，J＝1Hz，8Hz)，

7.05(1H，d，J＝1Hz)，

7.68(1H，d，J＝8Hz)，

7.88(2H，d，J＝9Hz)，

11.53(1H，s).

(3) N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] phenyl ] -N-methylglycine

The title compound was obtained in the same manner as in example 9(4) using ethyl N- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] phenyl ] -N-methylglycine obtained above.

Pale yellow crystals

The yield is 85 percent

Melting point 166-

FAB—MS(m/e)：457(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.31(6H，d，J＝7Hz)，

2.93(2H，t，J＝7Hz)，

3.14(3H，s)，

3.1—3.3(1H，m)，

3.26(2H，t，J＝7Hz)，

4.18(2H，s)，

6.66(2H，d，J＝9Hz)，

6.90(1H，dd，J＝2Hz，9Hz)，

7.04(1H，d，J＝2Hz)，

7.68(1H，d，J＝9Hz)，

7.89(2H，d，J＝9Hz).

Example 11

3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl]-5-thiazolyl]Propionyl group]-2-ethylphenyl radical] Propionic acid

(1)3- [ 2-Ethyl-4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] acryloyl ] phenyl ] acrylic acid methyl ester

The title compound was obtained in the same manner as in example 1(5) using 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] thiazole-5-carbaldehyde and methyl 3- (4-acetyl-2-ethylphenyl) acrylate.

Yellow crystals

Yield 55% (2steps)

¹H NMR(CDCl₃，400MHz)：δ＝

1.29(3H，t，J＝8Hz)，

1.39(6H，d，J＝7Hz)，

2.88(2H，q，J＝8Hz)，

3.4—3.5(1H，m)，

3.84(3H，s)，

6.47(1H，d，J＝15Hz)，

7.28(1H，d，J＝15Hz)，

7.7—7.8(3H，m)，

7.8—7.9(2H，m)，

8.0—8.2(4H，m).

(2)3- [ 2-Ethyl-4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] propanoyl ] phenyl ] propanoic acid methyl ester

The title compound was obtained in the same manner as in example 1(6) using methyl 3- [ 2-ethyl-4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] acryloyl ] phenyl ] acrylate obtained above.

Yellow oil

The yield is 60 percent

¹H NMR(CDCl₃，400MHz)：δ＝

1.26(3H，t，J＝8Hz)，

1.34(6H，d，J＝7Hz)，

2.61(2H，t，J＝8Hz)，

2.72(2H，q，J＝8Hz)，

3.02(2H，t，J＝8Hz)，

3.1—3.2(1H，m)，

3.2—3.4(4H，m)，

3.68(3H，s)，

7.24(1H，d，J＝8Hz)，

7.64(2H，d，J＝8Hz)，

7.73(1H，dd，J＝2Hz，8Hz)，

7.80(1H，d，J＝2Hz)，

8.00(2H，d，J＝8Hz).

(3)3- [4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] propionyl ] -2-ethylphenyl ] propionic acid

The title compound was obtained in the same manner as in example 1(7) using methyl 3- [ 2-ethyl-4- [3- [ 4-isopropyl-2- [4- (trifluoromethyl) phenyl ] -5-thiazolyl ] propionyl ] phenyl ] propionate obtained above.

Pale yellow crystals

The yield thereof is 74%

FAB—MS(m/e)：504(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.26(3H，t，J＝7Hz)，

1.33(6H，d，J＝7Hz)，

2.6—2.8(4H，m)，

3.03(2H，t，J＝8Hz)，

3.1—3.2(1H，m)，

3.2—3.4(4H，m)，

7.26(1H，d，8Hz)，

7.64(2H，d，J＝8Hz)，

7.74(1H，dd，J＝8Hz，2Hz)，

7.80(1H，d，J＝2Hz)，

8.00(2H，d.J＝8Hz).

Example 12

3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl]Propionyl group]-2-methylphenyl radical]C3 Acid(s)

(1)3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] acryloyl ] -2-methylphenyl ] acrylic acid methyl ester

The title compound was obtained in the same manner as in example 1(5) using 2- (4-chloro-2-hydroxyphenyl) -5-isopropyloxazole-4-carbaldehyde and methyl 3- (4-acetyl-2-ethylphenyl) acrylate.

Light brown crystal

The yield thereof was found to be 61%

¹H NMR(CDCl₃，400MHz)：δ＝

1.41(6H，d，J＝7Hz)，

2.54(3H，s)，

3.3—3.5(1H，m)，

3.84(3H，s)，

6.47(1H，d，J＝16Hz)，

6.98(1H，dd，J＝2Hz，9Hz)，

7.13(1H，d，J＝2Hz)，

7.64(1H，d，J＝15Hz)，

7.67(1H，d，J＝9Hz)，

7.73(1H，d，J＝15Hz)，

7.77(1H，d，J＝8Hz)，

7.8—7.9(2H，m)，

7.99(1H，d，J＝16Hz)，

11.27(1H，s).

(2)3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid methyl ester

The title compound was obtained in the same manner as in example 1(6) using methyl 3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] acryloyl ] -2-methylphenyl ] acrylate obtained above.

Colorless oil

The yield thereof was found to be 47%

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

2.36(3H，s)，

2.59(2H，t，J＝8Hz)，

2.94(2H，t，J＝7Hz)，

2.98(2H，t，J＝8Hz)，

3.1—3.3(1H，m)，

3.33(2H，t，J＝7Hz)，

3.68(3H，s)，

6.90(1H，dd，J＝2Hz，8Hz)，

7.04(1H，d，J＝2Hz)，

7.21(1H，d，J＝8Hz)，

7.68(1H，d，J＝8Hz)，

7.7—7.8(2H，m)，

11.47(1H，s).

(3)3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid

The title compound was obtained in the same manner as in example 1(7) using methyl 3- [4- [3- [2- (4-chloro-2-hydroxyphenyl) -5-isopropyl-4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoate obtained above.

White crystal

The yield thereof was found to be 93%

Melting point 141-144 DEG C

FAB—MS(m/e)：456(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

2.37(3H，s)，

2.65(2H，t，J＝8Hz)，

2.95(2H，t，J＝7Hz)，

2.99(2H，t，J＝8Hz)，

3.1—3.3(1H，m)，

3.33(2H，t，J＝7Hz)，

6.90(1H，dd，J＝2Hz，8Hz)，

7.04(1H，d，J＝2Hz)，

7.24(1H，d，J＝8Hz)，

7.68(1H，d，J＝8Hz)，

7.7—7.8(2H，m).

Example 13

3- [4- [3- [ 5-isopropyl-2- (2-hydroxyphenyl) -4-oxazolyl]Propionyl group]-2-methylphenyl radical]Propionic acid

(1)3- [4- [3- [ 5-isopropyl-2- (2-hydroxyphenyl) -4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid methyl ester

Methyl 3- [4- [3- [ 5-isopropyl-2- (2-methoxyphenyl) -4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoate (24mg, 0.0534mmol) was dissolved in dichloromethane (1.2mL), and 1M trichloroborane-dichloromethane solution (127 μ L, 0.127mmol) was added at 0 ℃. After stirring at room temperature for 24 hours, ice water (5mL) was added and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium carbonate solution and water, and then dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give the title compound (4mg, yield 17%) as white crystals from a hexane/ethyl acetate (3:1, v/v) fraction.

White crystal

The yield thereof was found to be 17%

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

2.36(3H，s)，

2.59(2H，t，J＝7Hz)，

2.9—3.0(4H，m)，

3.1—3.3(1H，m)，

3.34(2H，t，J＝7Hz)，

3.68(3H，s)，

6.92(1H，t，J＝8Hz)，

7.03(1H，d，J＝8Hz)，

7.21(1H，d，J＝8Hz)，

7.2—7.3(1H，m)，

7.7—7.8(3H，m).

(2)3- [4- [3- [ 5-isopropyl-2- (2-hydroxyphenyl) -4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoic acid

The title compound was obtained in the same manner as in example 1(7) using methyl 3- [4- [3- [ 5-isopropyl-2- (2-hydroxyphenyl) -4-oxazolyl ] propanoyl ] -2-methylphenyl ] propanoate obtained above.

White powder

The yield is 75 percent

FAB—MS(m/e)：422(M+1)

¹H NMR(CDCl₃，400MHz)：δ＝

1.32(6H，d，J＝7Hz)，

2.37(3H，s)，

2.65(2H，t，J＝7Hz)，

2.9—3.0(4H，m)，

3.1—3.3(1H，m)，

3.34(2H，t，J＝7Hz)，

6.92(1H，t，J＝8Hz)，

7.02(1H，d，J＝8Hz)，

7.2—7.3(2H，m)，

7.7—7.8(3H，m).

EXAMPLE 14 pharmacological test (1)

I. Test method

The PPAR activation of the test compound (example compound) was determined using the following method.

Introduction of receptor expression plasmid (pSG5-GAL4-hPPAR α, γ or δ (LBD), luciferase expression plasmid (pUC8-MH 100X 4-TK-Luc) and β -galactosidase expression plasmid (pCMX- β -GAL) (Kilewer, S.A.et.al., (1992) Nature, 358: 771-774) into CV-1 cells (ATCC), after gene introduction using Lipofectamine 2000(Invitrogen), incubation was carried out for about 40 hours in the presence of test compounds, soluble cells were used in luciferase activity and β -GAL activity assays.luciferase activity was corrected with β -GAL activity, relative ligand activity of PPAR α was calculated with the value of luciferase activity after treatment with GW-590735(PPAR α selective agonist) being 100%, relative ligand activity of PPAR α was calculated with the value of PPAR activity of cells after treatment with Rosigazone being 100%, The relative ligand activity of PPAR. delta. was calculated using the luciferase activity value of the cells treated with GW-501516 as 100%, and EC was determined₅₀。

Test IIResults

The test results are shown in Table 38.

[ Table 38]

PPAR activity: test Compound 10 at 100% control^-7Relative value of M meter

α：GW-590735 10^-6M

γ：Rosiglitazone 10^-5M

δ：GW-501516 10^-7M

(however, the test compound of examples 3 and 8 was 10^-6Measured value of M meter)

As can be seen from table 38, the test compounds showed excellent PPAR δ activator effects, and particularly, the compound of example 5 showed potent and selective PPAR δ activator effects.

EXAMPLE 15 pharmacological test (2)

The test was carried out by the same test method as in (1) of example 14, and the results are shown in table 39.

Test results

[ Table 39]

PPAR activity: test Compound 10 at 100% control^-7Relative value of M meter

α：GW-590735 10^-6M

γ：Rosiglitazone 10^-5M

δ：GW-501516 10^-7M

(however, the test compound of example 13 was 10^-6Measured value of M meter)

As can be seen from table 39, the test compounds showed excellent PPAR δ activator effects.

Claims

1. A compound represented by the following general formula (III):

in the formula, G^bDenotes O, S or CH₂；

A^bRepresents a 5-membered heterocyclic ring selected from thiazole, oxazole or thiophene, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms,An alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms and substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms and substituted with a halogen atom, a hydroxyl group, a nitro group, or an acyl group having 2 to 8 carbon atoms;

R^3brepresents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.

2. The compound or salt according to claim 1, wherein G is^bIs O.

3. The compound or salt according to claim 1 or 2, wherein A is^bIs a thiazole, which may have a substituent selected from the group consisting of: an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with a halogen atom, a hydroxyl group, a nitro group, and an acyl group having 2 to 8 carbon atoms.

4. The compound or salt thereof according to claim 1 or 2, wherein B is^bIs an ethylene chain.

5. The compound or salt thereof according to claim 1 or 2, wherein R is^1bAnd R^2bMay be the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, a halogen atom, an alkyl group having 1 to 8 carbon atoms substituted with a halogen atom, or an alkyl group having 1 to 1 carbon atoms substituted with a halogen atom8 alkoxy group.

6. An activator of peroxisome proliferator-activated receptor δ, comprising the compound according to any one of claims 1 to 5 or a salt thereof as an active ingredient.

7. A pharmaceutical composition comprising a compound or salt thereof according to any one of claims 1-5 and at least one pharmaceutically acceptable excipient.

8. Use of a compound according to any one of claims 1 to 5 or a salt thereof for the manufacture of a medicament for the treatment and/or prevention of a PPAR δ -mediated disease.

9. The use according to claim 8, wherein the PPAR δ -mediated disease is: hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL blood level, high LDL and/or non-HDL blood level, high VLDL blood level, lipoprotein abnormality, low apolipoprotein A-I blood level, arteriosclerotic disease, coronary artery disease, cerebrovascular disease, peripheral vascular disease, metabolic syndrome, syndrome X, obesity, diabetes, hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinemia, diabetic complications, heart failure, myocardial infarction, cardiomyopathy, hypertension, fatty liver, nonalcoholic steatohepatitis, thrombosis, Alzheimer's disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenoleukodystrophy, dermatitis, psoriasis, acne, skin aging, abnormal hair, inflammation, asthma, irritable bowel syndrome, ulcerative colitis, inflammatory bowel disease, Crohn's disease, pancreatitis, and cancers including colon cancer, large bowel cancer, skin cancer, breast cancer, prostate cancer, ovarian cancer, lung cancer.

10. The use according to claim 8, wherein the PPAR δ -mediated disease is: various dyslipidemias, metabolic syndrome, obesity, atherosclerosis or diabetes.

11. The use according to claim 9 or 10, wherein the obesity is visceral fat obesity.