JP2002201171A - Ureacarboxylic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal agent effective as preventing and curing agent for diabetics, hyperlipemia, impaired glucose tolerance and the like, a hypoglycemic agent, a blood lipid depressing agent and an agent for reducing blood glucose and blood lipid. SOLUTION: This ureacarboxylic acid derivative is a novel one expressed by general formula 1 [R1 expresses a cycloalkyl ring or a phenyl ring which may be substituted with halogens; R2 expresses H, a 1-15C straight chain or branched alkyl or an aralkyl which may be substituted with halogens on the phenyl ring; R3 expresses H or a lower alkyl; R4 expresses H, a lower alkyl, benzoyl, benzyl, a halogen, an amino which may be substituted or a single heterocycle; X expresses a single bond or O; Y expresses O or S; Z expresses CH2 or CH2-O-CH2; m expresses an integer of 0 or 1; n expresses 1-4 integer] or its pharmacologically allowable salt. Its application is also claimed.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel ureacarboxylic acid derivative and a medicament containing the same as an active ingredient. This compound is useful as an agent for preventing and treating diabetes and hyperlipidemia.

[0002]

2. Description of the Related Art In recent years, with the westernization of eating habits and the tendency of lack of exercise, the number of patients with lifestyle-related diseases, especially diabetes and hyperlipidemia, has increased. Diabetes and hyperlipidemia are important underlying diseases that lead to arteriosclerosis and the resulting ischemic heart disease. Diabetes is insulin dependent (type I, ID
DM) and non-insulin dependent (type II, NIDDM), and about 90% or more of the diabetic patients are the latter. In addition, NIDDM frequently causes hyperlipidemia, and patients who coexist with hyperlipidemia are more likely to develop arteriosclerosis and consequent ischemic heart disease. Was desired. JP-A-9-48771 is disclosed as a compound exhibiting these effects, and the compound described therein is structurally different from the compound of the present invention in that it has a thiazolidine-2,4-dione ring. Are different. Amidecarboxylic acid derivatives as compounds exhibiting these effects include W
O99 / 18066. However, the compounds described therein are structurally different from the compounds of the present invention having a urea structure in the side chain of the carboxylic acid derivative. On the other hand, carboxylic acid derivatives having a urea structure are described, for example, in WO 00/23407. However, these compounds do not disclose a hypoglycemic effect and are different from the compounds of the present invention in that they have a thioisobutyric acid structure.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel ureacarboxylic acid derivative or a pharmacologically acceptable salt thereof, which is used as a prophylactic / therapeutic agent for diabetes, hyperlipidemia, impaired glucose tolerance and the like. An object of the present invention is to provide an effective medicine, a blood sugar lowering agent, a blood lipid lowering agent, and a blood sugar and blood lipid lowering agent.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that ureacarboxylic acid derivatives have excellent blood sugar lowering action and blood lipid lowering action, and have completed the present invention. That is, the present invention relates to the general formula (1)

[0005]

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[0006] [wherein, R ¹ represents a phenyl group optionally substituted cycloalkyl group or a halogen atom, R ²
Represents a hydrogen atom, a linear or branched alkyl group having 1 to 15 carbon atoms, or an aralkyl group which may have a halogen atom on the phenyl ring, and R ³ represents a hydrogen atom or a lower alkyl group. R ⁴ represents a hydrogen atom, a lower alkyl group, a benzoyl group, a benzyl group, a halogen atom, an optionally substituted amino group or a monocyclic heterocyclic group,
Represents a single bond or an oxygen atom, Y represents an oxygen atom or a sulfur atom, Z is -CH ₂ - or -CH ₂ -O-CH ₂ - indicates, m represents an integer of 0 or 1, n Which represents an integer of 1 to 4], or a pharmaceutically acceptable salt thereof.

In the general formula (1), the cycloalkyl group of R ¹ is a carbon ring having 5 to 7 carbon atoms, for example,
Examples thereof include a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and among them, a cyclohexyl group is preferable. The phenyl group optionally substituted with a halogen atom for R ¹ is a phenyl group or a phenyl group substituted with a halogen atom. Examples of the halogen atom as a substituent of the phenyl group include, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. When the phenyl group has a substituent, the number of halogen atoms is 1 to 5, Of these, one to three are preferred. Examples of the phenyl group substituted with a halogen atom include a 2-chlorophenyl group, a 2-bromophenyl group, a 2-fluorophenyl group,
2-iodophenyl, 3-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, 3-iodophenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-iodophenyl Group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6
-Difluorophenyl group, 3,4-difluorophenyl group, 2,4,6-trifluorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,
Examples thereof include a 4-dichlorophenyl group, a 2,4-dibromophenyl group, a 3,4-dibromophenyl group, a 4-chloro-2-fluorophenyl group, and a 2-chloro-4-fluorophenyl group. Among them, a 2,4-difluorophenyl group and a 4-chlorophenyl group are preferred.

Examples of the linear or branched alkyl group having 1 to 15 carbon atoms for R ² include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, Examples include a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Of these, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and a heptyl group are preferred. The aralkyl group in which a halogen atom may be substituted on the phenyl ring of R ² is an aralkyl group or an aralkyl group having a halogen atom on the phenyl ring. Here, the aralkyl group is an arylalkyl group in which the aryl portion is a phenyl group and the alkyl portion has 1 to 6 carbon atoms, and examples thereof include a benzyl group, a phenethyl group, and a phenylpropyl group. Further, as the halogen atom of the aralkyl group having a halogen atom on the phenyl ring, for example,
Examples thereof include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. When the phenyl group has a substituent, the number of halogen atoms is 1 to 5. Examples of the halogen atom on the phenyl ring include a 2-chloro group, a 2-bromo group,
-Fluoro group, 2-iodo group, 3-chloro group, 3-bromo group, 3-fluoro group, 3-iodo group, 4-chloro group,
4-bromo group, 4-fluoro group, 4-iodo group, 2,3
-Difluoro group, 2,4-difluoro group, 2,5-difluoro group, 2,6-difluoro group, 3,4-difluoro group, 2,4,6-trifluoro group, 2,3-dichloro group, 2 , 4-dichloro group, 3,4-dichloro group, 2,4
-Dibromo group, 3,4-dibromo group, 4-chloro-2-
A fluoro group, a 2-chloro-4-fluoro group, a 2-chloro-6-fluoro group, and the like. That is, examples of the aralkyl group having a halogen atom on the phenyl ring include a 2-chloro-6-fluorophenethyl group, a 4-fluorophenethyl group, and a 3,5-difluorophenethyl group.

The lower alkyl group represented by R ³ has 1 carbon atom.
To four linear or branched alkyl groups, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl, sec-butyl and the like. Among them, a linear alkyl group having 1 to 4 carbon atoms, that is, a methyl group, an ethyl group, an n-propyl group, and an n-butyl group is preferable.

The lower alkyl group for R ⁴ has 1 carbon atom.
To four linear or branched alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and the like. Of these, an ethyl group, an isopropyl group and a tert-butyl group are preferred. Examples of the halogen atom for R ⁴ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, with a fluorine atom being preferred. R ⁴
Examples of the amino group which may be substituted include an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group and the like, and among them, a dimethylamino group is preferable. Examples of the monocyclic heterocyclic group represented by R ⁴ include a pyrrolyl group, an imidazolyl group, a furyl group, a thienyl group, a pyridinyl group, and a pyrimidinyl group. Among them, a 1-pyrrolyl group is preferable. n represents an integer of 1 to 4, and preferably 2 or 3.

[0011]

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The substitution position may be any of the ortho, meta and para positions, but the meta or para position is particularly preferred.

The pharmacologically acceptable salts of the compounds represented by the general formula (1) in the present invention include metal salts such as sodium salts and potassium salts which are alkali metal salts, and calcium salts which are alkaline earth metal salts. , Magnesium salts and the like.

The following compounds can be mentioned as specific examples. 3- [4- [2- [3- (2,4-difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [3- (4-chlorophenyl) -1-
n-heptylureido] ethoxy] phenyl] -2-
(4-Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [3- (3,4-dichlorophenyl)]
-1-n-heptylureido] ethoxy] phenyl]-
2- (4-isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [3- (2,3-dichlorophenyl)]
-1-n-heptylureido] ethoxy] phenyl]-
2- (4-isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- (3-cyclohexyl-1-n-heptylureido) ethoxy] phenyl] -2- (4-isopropylphenoxy ) -2-Methylpropionic acid and its sodium salt 3- [4- [2- (3-phenyl-1-n-heptylureido) ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid And its sodium salt

3- [4- [2- [3- (2,4-difluorophenyl) -1-n-decylureido] ethoxy]
Phenyl] -2- (4-isopropylphenoxy) -2
-Methylpropionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) -1-n-pentylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2 -Methylpropionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid and its salt Sodium salt 3- [4- [2- [1- [2- (2-chloro-6-fluorophenyl) ethyl] -3- (2,3-dichlorophenyl) ureido] ethoxy] phenyl] -2- (4- Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [1- [2- (2-chloro-6-fluorophenyl) e] Tyl] -3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-
Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2-methyl-2 Phenoxypropionic acid and its sodium salt

3- [4- [2- [3- (2,4-difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (isopropylphenyl) propionic acid and its sodium salt 3- [ 3- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] pheninoxy] -2- (4-
Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [3- [2- [3- (2,4-difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (4- Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) -1-n-heptylureido] ethyl] phenyl]
2- (4-Isopropylphenoxy) -2-methylpropionic acid and its sodium salt 3- [4- [3- [3- (2,4-difluorophenyl) -1-n-heptylureido] propyl] phenyl] 2- (4-Isopropylphenoxy) -2-methylpropionic acid and its sodium salt

3- [4- [2- [3- (2,4-difluorophenyl) ureido) ethoxy] phenyl] -2-
Methyl-2-phenoxy] propionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- [4- (pyrrol-1-yl) Phenoxy] propionic acid and its sodium salt 3- [4- [2- (3-phenylureido) ethoxy]
Phenyl] -2- [4- (pyrrol-1-yl) phenoxy] propionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2 -(4-Dimethylaminophenoxy) propionic acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-benzoylphenoxy) propionic acid And its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-benzylphenoxy) propionic acid and its sodium salt 3- [4- [ 2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-isopropylphenylthio) propion Acid and its sodium salt 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-fluorobenzyloxy) propionic acid and its sodium salt 3- [4 -[3- (2,4-difluorophenyl) ureidomethyl] benzyloxy] -2- (4-isopropylphenoxy) propionic acid and its sodium salt

[0018]

Next, a method for producing a ureacarboxylic acid derivative or a pharmacologically acceptable salt thereof will be described. The compound of the general formula (1) of the present invention can be produced by the production method described by the following reaction formula.

[0019]

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In the above reaction formula, R ¹ , R ² , R ³ , R ⁴ ,
X, Y, Z, m and n are as defined above,
M represents a substituent which can be easily converted to a carboxylic acid, for example, an ester group or a hydroxymethyl group which may be protected by a suitable protecting group. As the ester group, a methyl ester group, an ethyl ester group, a propyl ester group,
Examples thereof include an alkyl ester group such as an isopropyl ester group or a butyl ester group, and an aralkyl ester group such as a diphenylmethyl ester group or a p-methoxybenzyl ester group. Examples of the hydroxymethyl group that may be protected with a suitable protecting group include a hydroxymethyl group, an acetoxymethyl group, a methoxymethoxymethyl group, a p-nitrobenzyloxymethoxymethyl group,
An ethoxymethoxymethyl group, a 2-tetrahydropyranyloxymethyl group, or a suitable alkyl or aryl-substituted silyloxymethyl group, for example, tert-butyldimethylsilyloxymethyl group, tert-butyldiphenylsilyloxymethyl group, triphenylsilyl Oxymethyl group, triisopropylsilyloxymethyl group,
Or a triethylsilyloxymethyl group.

Step 1 This is a step of preparing a compound of the general formula (3). can do. That is, 1 to 10 equivalents of the compound of the general formula (2) and the isocyanate which can be produced by a generally known method,
The compound of the general formula (3) can be obtained by reacting preferably 1 to 2 equivalents in an organic solvent. Examples of the organic solvent that can be used in this reaction include halogenated hydrocarbons such as dichloromethane and chloroform, and ethers such as tetrahydrofuran and dioxane. Of these, dichloromethane and chloroform are preferable. The reaction temperature includes a temperature from 0 ° C. to the boiling point of the solvent used, and particularly preferably a temperature from 0 ° C. to room temperature. The reaction time is 1 to 48 hours, and preferably 1 to 12 hours.

Step 2 This is a step of producing a compound of the general formula (1), which is carried out by converting M of the compound of the general formula (3) into a carboxylic acid. That is, when M of the compound of the general formula (3) is an ester group, alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; water;
The compound of the general formula (1) can be obtained by reacting in the presence of a base such as an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide. The reaction temperature is from 0 ° C. to 100 ° C., and especially from 0 ° C. to 6 ° C.
0 ° C. is preferred. The reaction time is from 1 to 48 hours, and preferably from 1 to 24 hours. Also,
When M of the compound of the general formula (3) is an ester group shown below, that is, when an aralkyl ester group such as a tert-butyl ester group, a diphenylmethyl ester group or a p-methoxybenzyl ester group, methanol,
The compound of the general formula (1) can be obtained by reacting with an acid in an alcohol such as ethanol, an ether such as diethyl ether, tetrahydrofuran, dioxane or a mixed solvent thereof or in the absence of a solvent. Examples of the acid in this case include organic acids such as formic acid, acetic acid, and trifluoroacetic acid, and mineral acids such as hydrochloric acid and sulfuric acid. Among them, trifluoroacetic acid or hydrochloric acid is preferable, and the reaction temperature is 0 ° C to 100 ° C. The reaction time is 10 minutes to 12 minutes.
Time is up.

When M in the compound of the formula (3) is a hydroxymethyl group which may be protected with a suitable protecting group, the compound may be subjected to a commonly used deprotection reaction if necessary. A hydroxyl group is directly oxidized to a carboxylic acid under an oxidation reaction condition known in general, or a hydroxyl group is oxidized to an aldehyde and then oxidized to a carboxylic acid to obtain a compound represented by the general formula (1):
Can be obtained. Further, the pharmacologically acceptable salt of the compound represented by the general formula (1) of the present invention may be treated with an inorganic base such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an organic base in a conventional manner. Can be obtained by The compound of formula (2) (intermediate) can be produced by the following methods A to E.

[Method A] In the compound of the general formula (2),
General formula (2) wherein R ² is a hydrogen atom and X is an oxygen atom
The compound of a) can be easily produced according to the following Method A.

[0025]

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In the above reaction formula, R ³ , R ⁴ , M, Y,
Z, m and n are as defined above. R ⁵ represents a hydrogen atom or an amino-protecting group, and R ⁶ represents an amino-protecting group. R ⁵ and R ⁶ may together represent a protecting group for an amino group. The protecting group for the amino group of R ⁵ or R ⁶ is a commonly known protecting group, for example, an aralkyl group such as a benzyl group, a diphenylmethyl group, and a trityl group, a tert-butoxycarbonyl group, and a benzyloxycarbonyl group. When R ⁵ and R ⁶ together represent a protecting group for an amino group, examples thereof include a phthaloyl group. Of these, a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a phthaloyl group is preferred.

Step A-1 This is a step of producing a compound of the general formula (6). The compound of the general formula (4) and the compound of the general formula (5) are subjected to a usual Mitsunobu reaction [O. Mitsunobu, Synthesis,
1 (1981), Tetsuto Kakuda et al., Journal of Synthetic Organic Chemistry, 5
5 (7), 631 (1997), etc.]. That is, the compound of the general formula (4) and the compound of the general formula (5) are converted into hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane and chloroform, and ethers such as diethyl ether, tetrahydrofuran and dioxane. Or a mixed solvent thereof in the presence of a Mitsunobu reagent such as N, N, N ', N'-tetramethylazodicarboxamide and a phosphine such as tributylphosphine at a reaction temperature of 10 ° C to 80 ° C. For 48 hours to give a compound of the general formula (6).

Step A-2 This is a step of producing the compound of the general formula (2a), which is carried out by removing the amino-protecting group of the compound of the general formula (6). When the protecting group R ⁵ or R ⁶ is an aralkyl group or a benzyloxycarbonyl group, the reaction is carried out by subjecting the compound of the general formula (6) to a catalytic reduction reaction with hydrogen. That is, the compound of the general formula (6) is prepared by reacting a compound such as methanol, ethanol or the like, an ether such as diethyl ether, tetrahydrofuran or dioxane or a mixed solvent thereof in the presence of a catalyst such as palladium-carbon, palladium black or platinum oxide. 1 to 48 at a reaction temperature of 10 ° C to 80 ° C.
The compound of the general formula (2a) can be obtained by reacting for a time.

On the other hand, when the protecting group R ⁵ or R ⁶ is a tert-butoxycarbonyl group, diphenylmethyl group or trityl group, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or ethers thereof. The compound of the general formula (2a) can be obtained by reacting with an acid in a mixed solvent or in the absence of a solvent at a reaction temperature of 0 ° C to 100 ° C for 10 minutes to 12 hours. Examples of the acid include organic acids such as formic acid, acetic acid and trifluoroacetic acid, and mineral acids such as hydrochloric acid and sulfuric acid. When the protecting group R ⁵ or R ⁶ together forms a phthaloyl group as the protecting group for the amino group, methanol,
Alcohols such as ethanol, tetrahydrofuran, ethers such as dioxane, dichloromethane, halogenated hydrocarbons such as chloroform or a mixed solvent thereof, hydrazine, methylhydrazine, hydrazines such as phenylhydrazine or methylamine, ethylamine,
The compound of the general formula (2a) can be obtained by reacting at a reaction temperature of 0 ° C. to 100 ° C. for 30 minutes to 24 hours in the presence of a primary amine such as propylamine and butylamine.

[Method B] In the compound of the general formula (2),
General formula (2) wherein R ² is a hydrogen atom and X is a single bond
The compound of b) can be easily produced according to the following method.

[0031]

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In the above reaction formula, R ³ , R ⁴ , R ⁵ , R ⁶ ,
M, Y, Z, and m are as defined above.
m ′ represents an integer of 0 to 2, and n ′ represents an integer of 2 to 4. Y ′ represents a halogen atom. Here, examples of the halogen atom of Y ′ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Step B-1 This is a step of producing a compound of the general formula (9).
ck reaction [R. F. Heck, Organic Rea
ctions, 27 , 345 (1972), etc.]. That is, the compound of the general formula (7) and the compound of the general formula (8) are
In a hydrocarbon such as benzene, toluene and xylene, an ether such as diethyl ether, tetrahydrofuran and dioxane, acetonitrile or a mixed solvent thereof, a palladium catalyst such as palladium acetate and a phosphine ligand such as tri-tolylphosphine are present. Below, using a base such as N, N-diisopropylethylamine or the like, from 0 ° C. to 80 ° C.
By reacting at the reaction temperature of 1 to 48 hours, the compound of the general formula (9) can be obtained.

Step B-2 Step B-2 is a step of producing the compound of the general formula (10), and is carried out by subjecting the compound of the general formula (9) to a catalytic reduction reaction with hydrogen. That is, a compound of the general formula (9) is converted into palladium-carbon, in alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, or a mixed solvent thereof.
In the presence of a catalyst such as palladium black, tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst), platinum oxide, etc., at a reaction temperature of 10 ° C to 80 ° C, 1 to 24
Formula (10) by hydrogen-catalyzed reduction reaction for a time
Can be obtained.

Step B-3 Step B-3 is a step for producing a compound of the general formula (2b), which is carried out by removing the protecting group for the amino group of the compound of the general formula (10). This reaction is performed in the same manner as in the deprotection method already described in Step A-2 of Method A.

[Method C] In the compound of the general formula (2),
Formula (2) wherein R ² is an alkyl group or an aralkyl group.
The compound of c) can be easily produced according to the following method.

[0037]

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In the above reaction formula, R^Three, R^Four, M, X, Y,
Z, m and n are as defined above. R^Two’
Is a linear or branched alkyl having 1 to 15 carbons
A halogen atom is substituted on the kill group or phenyl ring
Represents a good aralkyl group. R ⁷Is the alkyl chain moiety
R with one less carbon^Two’And R⁸Is a hydrogen atom or
R having one less carbon atom in the alkyl chain portion^Two’.

Step C-1 This is a step for producing a compound of the general formula (2c), which is carried out by reacting a compound of the general formula (2a) with a compound of the general formula (11). That is, a compound represented by the general formula (2a) is converted into a hydrocarbon such as benzene, toluene, or xylene, an alcohol such as methanol or ethanol, an ether such as diethyl ether, tetrahydrofuran, or dioxane; N, N-dimethylformamide; In amides such as N-dimethylacetamide or a mixed solvent thereof, sodium borohydride, reduction reaction with a metal hydride such as sodium cyanoborohydride or palladium-carbon, hydrogen catalytic reduction reaction using Raney nickel or the like as a catalyst At a reaction temperature of 0 ° C to 100 ° C, 1 to 24
The compound of the general formula (2c) can be obtained by reacting for a time.

[Method D] In the compound of the general formula (2), the compound of the general formula (2c) wherein R ² is an alkyl group or an aralkyl group can be easily produced according to the following method.

[0041]

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In the above reaction formula, R ² ′, R ³ , R ⁴ , R ⁷ ,
M, X, Y, Z, m and n are as defined above.

Step D-1 A step of producing a compound of the general formula (12), which is carried out by acylating a compound of the general formula (2a).
This reaction is a well-known acid amide bond forming reaction. That is, the carboxylic acid or a salt thereof and the compound of the general formula (2a) used in this reaction are converted into halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, or Among amides such as N, N-dimethylformamide, in the presence of a condensing agent for carbodiimides such as N-hydroxysuccinimide, N-hydroxybenzotriazole and the like, and N, N-diisopropylcarbodiimide and N, N-dicyclohexylcarbodiimide, 0 ° C
The reaction is carried out at a reaction temperature of 1 to 100 ° C for 1 to 48 hours to obtain a compound of the general formula (12).

Further, the carboxylic acid or its salt used in the present reaction and the compound of the general formula (2a) are converted into halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, and carbonized compounds such as benzene and toluene. Among amides such as hydrogens and N, N-dimethylformamide, N, N-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N-cyclohexylcarbodiimide-N′- Propoxy polystyrene (hereinafter, PS-
At a reaction temperature of 0 ° C to 100 ° C in the presence of a condensing agent for carbodiimides such as carbodiimide).
The compound of the general formula (12) can be obtained by reacting for a time. Further, the carboxylic acid or a salt thereof used in this reaction is reacted with a halogenating agent such as oxalyl chloride and thionyl chloride to obtain a corresponding acid chloride, and then a compound of the general formula (2a) is added to dichloromethane, Halogenated hydrocarbons such as chloroform, tetrahydrofuran, ethers such as dioxane or benzene,
Among hydrocarbons such as toluene, -20 ° C to 100 ° C
The compound of the general formula (12) can also be obtained by reacting at a reaction temperature of 1 hour to 24 hours.

Step D-2 This is a step for producing a compound of the general formula (2c), which is carried out by reducing an amide bond of the compound of the general formula (12). That is, a compound represented by the general formula (12) is prepared from ethers such as diethyl ether, tetrahydrofuran and dioxane or hydrocarbons such as benzene, toluene and xylene in the presence of boron such as borane-tetrahydrofuran complex at 0 ° C. At a reaction temperature of 100 ° C., 1 to 48
The compound of the general formula (2c) can be obtained by performing a time reduction reaction.

[Method E] In the compound of the general formula (2a), the compound of the general formula (2d) wherein Z is -CH ₂ -O-CH ₂ -can be easily produced according to the following method.

[0047]

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In the above reaction formula, R ³ , R ⁴ , X, Y, M, m
And n have the same meaning as described above. R ⁹ represents a functional group that can be converted into H ₂ N— (CH ₂ ) _n —X of the general formula (2), for example, a cyano group, a carboxylic ester group, or a carboxylic amide group. W represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a sulfonyl group such as a methanesulfonyl group, a benzenesulfonyl group or a p-toluenesulfonyl group.

Step E-1 This is a step of producing the compound of the general formula (15), which is carried out by etherifying the compound of the general formula (13). That is, the compound of the formula (13) and a halide or a sulfonylate used in the present reaction are combined with halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and dioxane, benzene,
In a hydrocarbon such as toluene, an amide such as N, N-dimethylformamide, or a mixed solvent thereof, 1 to 10 equivalents of sodium hydride, potassium hydride, calcium hydride, potassium carbonate, cesium carbonate, Sodium methoxide, sodium t-butoxide, potassium t-
It can be obtained by reacting in the presence of a base such as butoxide at a reaction temperature of -20 ° C to 100 ° C for a reaction time of 1 to 48 hours.

[0050]Step E-2 A step of producing a compound of the general formula (2d),
R of the compound of (15) ⁹A side chain having an amino group at the terminal
Manufactured by converting to That is, general
The compound of the formula (15) is converted into methanol, ethanol,
Alcohols such as propanol, diethyl ether,
Ethers such as trahydrofuran and dioxane;
Hydrocarbons such as toluene, xylene,
Sodium borohydride, lithium hydride in a mixed solvent
Aluminum or diisopropyl aluminum hydride
Such as borane tetrahydrofuran complex
In the presence of borons, from -20 ° C to 100 ° C, preferably-
1 to 48 hours at 10 ° C to 30 ° C, preferably 1 hour
Amine for 24 hours
Alternatively, an alcohol serving as a precursor thereof can be obtained.
Alcohols used as precursors are generally known alcohols.
Conversion from coal to amine allows easy
Can be converted to amines.

The compound of the general formula (1) in the present invention has an asymmetric carbon atom, and has optical isomers or stereoisomers based on the asymmetric carbon atom. Both bodies and mixtures thereof are included in the present invention. Furthermore, the compound of the general formula (1) includes hydrates and various solvates. Further, the compound of the general formula (1) includes all the crystal forms.

The compound of general formula (1) or a pharmaceutically acceptable salt thereof can be administered orally or parenterally (for example, intravenously or intramuscularly) as a pharmaceutical composition. Examples of oral administration preparations include tablets (sugar-coated tablets,
Film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions and the like. This formulation for oral administration contains additives commonly used in the field of formulation,
It can be produced according to a known method. Examples of such additives include lactose, mannitol, excipients such as anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, methyl cellulose, binders such as polyvinylpyrrolidone, starch, disintegrants such as carboxymethyl cellulose, magnesium stearate, A lubricant such as talc is used.

Examples of preparations for parenteral administration include injections. Such an injection is produced by a known method, for example, by dissolving the compound of the general formula (1) or a pharmaceutically acceptable salt thereof in water for injection by the Pharmacopoeia of Japan. If necessary, an isotonic agent such as sodium chloride and the like, and a buffering agent such as sodium hydrogen phosphate and sodium monohydrogen phosphate may be added. The compound of general formula (1) and a pharmaceutical composition thereof include, for example, an agent for preventing or treating diabetes (eg, insulin-dependent diabetes, non-insulin-dependent diabetes, gestational diabetes, etc.), hyperlipidemia (eg, hypertriglyceride) , Hypercholesterolemia, hypoHDL bloodemia, etc.), the above-mentioned diabetes and hyperlipidemia preventive and therapeutic agents, insulin sensitivity enhancers, insulin sensitizers, impaired glucose tolerance (IGT)
Can be used as a prophylactic / therapeutic agent and a transition inhibitor from glucose intolerance to diabetes. Further, the compound of the general formula (1) and a pharmaceutical composition thereof include, for example, diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, etc.), obesity, osteoporosis, evil Fluid (eg, cancer cachexia, diabetic cachexia, etc.), fatty liver, hypertension, kidney disease (eg, diabetic nephropathy, glomerulonephritis, etc.), myocardial infarction, angina, cerebral infarction, insulin resistance Syndrome, Syndrome X, sensory impairment in hyperinsulinemia, tumor (eg, prostate cancer, etc.), inflammatory disease (eg, rheumatoid arthritis, spondyloarthropathy, etc.), arteriosclerosis (eg, atherosclerosis) Etc.) can also be used as a prophylactic / therapeutic agent.

The daily dose of the compound of the formula (1) per adult may vary depending on the patient's condition, body weight, age, type of compound, administration route and the like. 1 to 1,000 mg is suitable, and about 1 to 100 mg is preferred. In the case of parenteral administration, one-tenth to one-half the amount of oral administration may be administered. These dosages can be appropriately increased or decreased depending on the patient's condition, body weight, age and the like.

[0055]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited thereto. [Example 1] 3- [4- [2- [3- (2,4-difur
Orophenyl) -1-n-heptylureido] ethoxy
[S] phenyl] -2- (4-isopropylphenoxy)
-2-Methylpropionic acid (a) 3- [4- (tert-butyldimethylsilyloxy) phenyl] -2- (4-isopropylphenoxy)
Ethyl-2-methylpropionate Under argon atmosphere, to a solution of 0.74 mL of isopropylcyclohexylamine in 5 mL of tetrahydrofuran (hereinafter referred to as THF) was added 3.0 mL of a 1.5 mol / L n-butyllithium hexane solution at -78 ° C, 3 at the same temperature
Stirred for 0 minutes. Then, at -78 ° C, 708 mg of ethyl 2- (4-isopropylphenoxy) propionate in THF
A 5 mL solution was added, and the mixture was stirred at the same temperature for 45 minutes. Next, -7
At 8 ° C., a solution of 1.43 g of 4- (tert-butyldimethylsilyloxy) benzyl iodide in 10 mL of THF was added, and the mixture was stirred at −78 ° C. for 55 minutes and at 0 ° C. for 1 hour and 55 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate-hexane = 1: 20) to give the title as a pale yellow oil. 996 mg of the compound were obtained. IRνmax (neat): 2957, 1731, 1608, 1507, 1471, 137
^{. 5,1260,1109,1016,916,838,781,689,534 cm -1 1 H-NMR} (CDCl 3) δ: 0.19 (6H, s), 0.98 (9H, s), 1.
20 (6H, t, J = 7.0Hz), 1.21 (3H, t, J = 7.1Hz), 1.
36 (3H, s), 2.83 (1H, quint, J = 7.0Hz), 3.08 (1
H, d, J = 13.7 Hz), 3.23 (1H, d, J = 13.7 Hz), 4.19
(2H, q, J = 7.1Hz), 6.74 (2H, d, J = 8.6Hz), 6.76
(2H, d, J = 8.6Hz), 7.05 (2H, d, J = 8.6Hz), 7.12
(2H, d, J = 8.6Hz).

(B) 3- (hydroxyphenyl) -2-
Ethyl (4-isopropylphenoxy) -2-methylpropionate 3- [4- (tert-butyldimethylsilyloxy) phenyl] -2- (4-isopropylphenoxy) -2-
797 mg of ethyl methyl propionate in 12 mL of THF
To the solution was added 2.0 mL of a 1.0 mol / L tetra-n-butylammonium fluoride THF solution at 0 ° C.
Stirred at C for 17 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate-hexane = 1: 4) to give the title as a pale yellow oil. 532 mg of compound were obtained. IRνmax (neat): 3445, 2960, 1715, 1652, 1615, 155
7, 1540, 1507, 1455, 1374, 1110, 1016, 949, 831, 4
18cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 7.0 Hz), 1.22 (3
H, t, J = 7.2 Hz), 1.37 (3H, s), 2.83 (1H, quint, J =
7.0Hz), 3.09 (1H, d, J = 13.8Hz), 3.23 (1H, d, J
= 13.8Hz), 4.20 (2H, q, J = 7.2Hz), 6.75 (4H, d,
J = 8.6Hz), 7.05 (2H, d, J = 8.3Hz), 7.13 (2H, d,
J = 8.6Hz).

(C) 3- [4- (2-aminoethoxy)
Phenyl] -2- (4-isopropylphenoxy) -2
-Ethyl methyl propionate Ethyl 3- (hydroxyphenyl) -2- (4-isopropylphenoxy) -2-methylpropionate 696m
g of benzene 40 mL of a solution of N- (tert-butoxycarbonyl) ethanolamine 492 mg of benzene 1
0 mL solution, 618 mg of tri-n-butylphosphine in 10 mL of benzene and 1,1′-azobis (N, N-
Dimethylformamide) 527 mg of benzene 10 mL
The solution was added and stirred at room temperature overnight. Add water to the reaction solution,
After extraction with ethyl acetate, the extract was washed with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography.
(Ethyl acetate-hexane = 1: 3) to give 3- [4- (2-tert-butoxycarbonylaminoethoxy) phenyl] -2- (4 as a pale yellow oil.
There was obtained 764 mg of ethyl -isopropylphenoxy) -2-methylpropionate. To a solution of 764 mg of this compound in 20 mL of ethanol was added 20 mL of an ether solution saturated with hydrogen chloride at 0 ° C., and the mixture was stirred at room temperature for 21 hours and 30 minutes. After evaporating the solvent under reduced pressure, the residue was added with saturated NaHCO 3 at 0 ° C.
₃ After adding an aqueous solution to make it alkaline, extract with ethyl acetate,
Wash with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (chloroform-methanol = 10: 1) to obtain 479 mg of the title compound as a pale yellow oil. Was. IRνmax (neat): 3371, 2960, 1731, 1609, 1507, 137
4, 1301, 1110, 1022, 834, 533, 418 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.18 (6H, d, J = 7.0 Hz), 1.22 (3H,
t, J = 7.2 Hz), 1.36 (3H, s), 2.82 (1H, quint, J = 7.0H
z), 3.09 (1H, d, J = 13.8Hz), 3.15−3.25 (2.5H, m),
3.55-3.65 (0.5H, m), 4.02 (1H, t, J = 2.1Hz), 4.10 (1H
H, t, J = 2.1 Hz), 4.18 (2H, q, J = 7.2 Hz), 6.74 (2H,
d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J
= 8.6Hz), 7.14 (2H, d, J = 8.6Hz).

(D) Ethyl 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate 3- [4- (2-aminoethoxy) phenyl ] -2-
To a solution of 900 mg of ethyl (4-isopropylphenoxy) -2-methylpropionate in 20 mL of ethanol was added n-
A solution of 267 mg of heptanal in 5 mL of ethanol and 5
% Palladium-carbon (500 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 3 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (chloroform: methanol = 30: 1 to 15: 1) to give a pale brown oil. As a result, 853 mg of the title compound was obtained. IRνmax (neat): 2926, 1731, 1611, 1582, 1507, 145
5,1375,1242,1178,1114,1023,948,830,775,59
1,534 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 7.0 Hz), 1.20 (6H, d,
J = 6.8Hz), 1.22 (3H, t, J = 7.2Hz), 1.22-1.40 (8H,
m), 1.36 (3H, s), 1.50-1.60 (2H, m), 2.71 (2H, t, J =
7.3Hz), 2.83 (1H, quint, J = 6.8Hz), 3.03 (2H, t, J = 5.
2Hz), 3.10 (1H, d, J = 13.7Hz), 3.24 (1H, d, J = 13.7H)
z), 4.09 (2H, t, J = 5.2Hz), 4.20 (2H, q, J = 7.2Hz), 6.
75 (2H, d, J = 8.8 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.06 (2
H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.5 Hz).

(E) 3- [4- [2- [3- (2,4-
Ethyl difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- Chloroform 15m of 720 mg of ethyl (4-isopropylphenoxy) -2-methylpropionate
To the L solution was added a solution of 254 mg of 2,4-difluorophenyl isocyanate in 5 mL of chloroform at 0 ° C, and the mixture was stirred at room temperature for 2 hours. To the reaction solution, 398 mg of tris (2-aminoethyl) amine polystyrene (hereinafter, referred to as PS-trisamine) (3.75 mmol / g) was added, and the mixture was stirred for 2 hours. Then, PS-trisamine was removed by filtration. Further, after washing the PS-trisamine with chloroform, the combined filtrate was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate-ethyl acetate).
Separation and purification with hexane = 1: 4) gave 936 mg of the title compound as a colorless oil. IRνmax (neat): 3745, 3374, 2931, 2865, 1886, 173
5,1673,1612,1515,1461,1234,1106,1041,960,
902, 840, 752, 586 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.9 Hz), 1.20 (6H,
d, J = 7.0 Hz), 1.22 (3H, t, J = 7.2 Hz), 1.20-1.37 (11
H, m), 1.39 (3H, s), 1.60-1.70 (2H, m), 2.83 (1H, qu
int, J = 7.0Hz), 3.10 (1H, d, J = 13.8Hz), 3.26 (1H, d,
J = 13.8Hz), 3.38 (2H, t, J = 7.7Hz), 3.75 (2H, t, J = 4.7
Hz), 4.16 (2H, t, J = 4.7Hz), 4.20 (2H, q, J = 7.2Hz),
6.75 (2H, d, J = 8.6Hz), 6.80-6.90 (2H, m), 6.87 (2H,
d, J = 8.6Hz), 7.06 (2H, d, J = 8.6Hz), 7.20 (2H, d, J =
8.6Hz), 7.95-8.05 (1H, m).

(F) 3- [4- [2- [3- (2,4-
Difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid 3- [4- [2- [3- (2,4-difluorophenyl)- Ethyl 1-n-heptylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate 936 mg of ethanol 24 mL
To the solution was added 12 mL of a 10% aqueous potassium hydroxide solution at 0 ° C., and at room temperature for 21 hours, a further 15 mL of THF was added to the solution.
Stirred at C for 3 hours. After evaporating the solvent under reduced pressure, 2 mol
The mixture was acidified by adding / L hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (chloroform-methanol = 30: 1) to give 743 mg of the title compound as a colorless amorphous. Obtained. IRνmax (KBr): 3367, 2931, 1735, 1612, 1515, 1234,
960,840,755,578 cm ^{- 1. 1} H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.8 Hz), 1.21 (6H,
d, J = 7.0Hz), 1.25-1.40 (8H, m), 1.42 (3H, s), 1.60-
1.70 (2H, m), 2.86 (1H, quint, J = 7.0 Hz), 3.13 (1H,
d, J = 14.2Hz), 3.26 (1H, d, J = 14.2Hz), 3.37 (2H, t, J
= 7.8Hz), 3.74 (2H, t, J = 4.6Hz), 4.16 (2H, t, J = 4.6H)
z), 6.80-6.90 (6H, m), 7.12 (2H, d, J = 8.3Hz), 7.23
(2H, d, J = 8.3Hz), 7.95-8.05 (1H, m). MS m / z (ESI-): 609 (M-H) ^- .

Example 2 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-heptylu
[Reid] ethoxy] phenyl] -2- (4-isopropyl
Rufenoxy) -2-methylpropionate sodium 3- [4- [2- [3- (2,4-
After dissolving 67 mg of difluorophenyl) -1-n-heptylureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid in 7.5 mL of a THF-ethanol (1: 2) mixed solution, 0
At 75 ° C., add 75 mg of sodium ethoxide, and add
Stirred for minutes. The solvent was distilled off under reduced pressure to obtain 65 mg of the title compound as a pale yellow powder. IRνmax (KBr): 3370, 2931, 2865, 1666, 1604, 1515,
1461, 1400, 1230, 1137, 1099, 960, 840, 725, 574c
m ^-1 . ¹ H-NMR (CDCl ₃ −CD ₃ OD) δ: 0.87 (3H, t, J = 7.0 Hz), 1.1
5 (6H, d, J = 7.0 Hz), 1.20-1.40 (11H, m), 1.60-1.70
(2H, m), 2.78 (1H, quint, J = 7.0Hz), 2.98 (1H, d, J
= 13.9Hz), 3.26 (1H, d, J = 13.9Hz), 3.37 (2H, t, J =
7.8Hz), 3.73 (2H, t, J = 4.5Hz), 4.13 (2H, t, J = 4.5H)
z), 6.75-6.90 (6H, m), 7.00 (2H, d, J = 8.4Hz), 7.19
((2H, d, J = 8.4 Hz), 7.90-8.00 (1H, m) MS m / z (ESI-): 609 (M-Na) ^- .

Example 3 3- [4- [2- [3- (4
-Chlorophenyl) -1-n-heptylureido] etho
[Xy] phenyl] -2- (4-isopropylphenoxy)
B) -2-Methylpropionic acid ethyl 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 1 (d) And 4
Example 1 using -chlorophenyl isocyanate
The title compound was obtained in the same manner as in (e) and (f). IRνmax (KBr): 3374, 2931, 1727, 1639, 1511, 1230,
1118, 910, 825, 736, 586 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 7.6 Hz), 1.21 (6
H, d, J = 6.9 Hz), 1.15-1.35 (8H, m), 1.40 (3
H, s), 1.55-1.70 (2H, m), 2.85 (1H, quint, J
= 6.9Hz), 3.13 (1H, d, J = 13.9Hz), 3.27 (1H, d,
J = 13.9Hz), 3.36 (2H, t, J = 7.6Hz), 3.72 (2H,
t, J = 4.6 Hz), 4.17 (2H, t, J = 4.6 Hz), 6.83 (2H,
d, J = 8.4 Hz), 6.85 (2H, d, J = 8.4 Hz), 7.11 (2H,
d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.25 (2H,
d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 Hz). MS m / z (ESI-): 607 (M-H) ^- .

Example 4 3- [4- [2- [3-
(3,4-dichlorophenyl) -1-n-heptyluree
Id] ethoxy] phenyl] -2- (4-isopropyl
Phenoxy) -2-methylpropionate sodium 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid obtained in Example 1 (d) The title compound was synthesized in the same manner as in Example 1 (e), (f) and Example 2 using ethyl and 3,4-dichlorophenyl isocyanate. IRνmax (KBr): 3356, 2927, 2862, 1651, 1589, 1512,
1473, 1408, 1300, 1230, 1134, 1041, 822, 571c
m ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.6 Hz), 1.03 (6H,
brs), 1.20 (3H, s), 1.26-1.29 (8H, m), 1.59-1.68
(2H, m), 2.67 (1H, brs), 2.87 (1H, brs), 3.11 (1H, br
s), 3.30 (2H, t, J = 7.3 Hz), 3.63 (2H, brs), 4.04 (2
H, brs), 6.72 (4H, d, J = 7.0Hz), 6.84 (2H, d, J = 7.0Hz)
Hz), 7.13 (2H, d, J = 7.0Hz), 7.13 (1H, d, J = 8.6H)
z), 7.24 (1H, d, J = 8.6Hz), 7.63 (2H, brs). MS m / z (ESI +): 665 (M + H) ^<+> .

Example 5 3- [4- [2- [3-
(2,3-dichlorophenyl) -1-n-heptyluree
Id] ethoxy] phenyl] -2- (4-isopropyl
Phenoxy) -2-methylpropionate sodium 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionic acid obtained in Example 1 (d) The title compound was obtained in the same manner as in Example 1 (e), (f) and Example 2 using ethyl and 2,3-dichlorophenyl isocyanate. IRνmax (KBr): 3436, 3367, 2927, 2862, 1674, 1585,
1512, 1458, 1412, 1230, 1227, 1176, 1049, 903, 83
3,775,532 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 7.1 Hz), 1.03 (6H,
d, J = 6.1 Hz), 1.26 (8H, brs), 1.31 (3H, s), 1.66-
1.74 (2H, m), 2.65 (1H, quint, J = 6.1Hz), 2.84 (1H,
d, J = 12.1 Hz), 3.12 (1H, d, J = 12.1 Hz), 3.36 (2H,
t, J = 6.9 Hz), 3.68 (2H, brs), 4.05 (2H, brs), 6.68 (2
H, d, J = 7.5 Hz), 6.74 (2H, d, J = 7.5 Hz), 6.83 (2H,
d, J = 7.5 Hz), 7.05 (2H, d, J = 7.5 Hz), 7.06 (1H, d, J
= 7.9Hz), 7.11 (1H, t, J = 7.9Hz), 7.65 (1H, brs), 8.
14 (1H, d, J = 7.9Hz). MS m / z (ESI +): 665 (M + H) ^<+> .

Example 6 3- [4- [2- (3-cyclyl)
Rohexyl-1-n-heptylureido) ethoxy] f
Enyl] -2- (4-isopropylphenoxy) -2-
Sodium methyl propionate Ethyl 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 1 (d) and cyclohexyl isocyanate Example 1 using
The title compound was obtained in the same manner as in (e), (f) and Example 2. IRνmax (neat): 3379, 2927, 2858, 1890, 1616, 151
2,1458,1400,1230,1176,1115,1045,899,829,5
48 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.8 Hz), 1.05 (6H,
d, J = 6.8 Hz), 1.08-1.34 (14H, m), 1.26 (3H, s), 1.54
-1.67 (4H, m), 1.88-1.92 (2H, m), 2.66 (1H, quint,
J = 6.8Hz), 2.87 (1H, d, J = 14.1Hz), 3.15 (1H, d, J = 14.
1Hz), 3.20 (2H, t, J = 7.3Hz), 3.53 (2H, brs), 3.51-
3.60 (1H, m), 3.97 (2H, brs), 4.80 (1H, brd, J = 7.3H
z), 6.69 (2H, d, J = 8.5Hz), 6.70 (2H, d, J = 8.5Hz), 6.
84 (2H, d, J = 8.5Hz), 7.08 (2H, d, J = 8.5Hz). MS m / z (ESI +): 603 (M + H) ⁺ .

Example 7 3- [4- [2- (3-Fe
Nyl-1-n-heptylureido) ethoxy] phenyi
2-] (4-isopropylphenoxy) -2-methyl
Sodium rupropionate Ethyl 3- [4- (2-n-heptylaminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 1 (d) and phenyl isocyanate Example 1 (e),
The title compound was obtained in the same manner as in (f) and Example 2. IRνmax (KBr): 3371, 2927, 2866, 1647, 1601, 1508,
1450, 1404, 1304, 1234, 1173, 1115, 1061 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.5 Hz), 1.02-1.
36 (17H, m), 1.51-1.70 (2H, brm), 2.64 (1H, qu
int, J = 6.8 Hz), 2.86 (1H, d, J = 13.7 Hz), 3.15 (1
H, d, J = 13.7 Hz), 3.29 (2H, t, J = 7.7 Hz), 3.60
(2H, m), 3.99 (2H, t, m), 6.65−7.43 (13H,
m). MS m / z (ESI-): 573 (M-Na) ^- .

Example 8 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-decyluree
Id] ethoxy] phenyl] -2- (4-isopropyl
Sodium phenoxy) -2-methylpropionate Ethyl 3- [4- (2-aminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 1 (c) and n -The title compound was obtained in the same manner as in Examples 1 (d), (e), (f) and Example 2 using decanal. IRνmax (neat): 3375, 2927, 2858, 1666, 1604, 151
6,1461,1400,1230,1138,1099,960,841,567cm
^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.8 Hz), 1.02 (6
H, d, J = 6.8 Hz), 1.00-1.29 (14H, m), 1.43 (3H,
s), 1.61 (2H, bs), 2.62 (1H, quint, J = 6.8Hz), 2.
84 (1H, d, J = 13.9Hz), 3.16 (1H, d, J = 13.9Hz), 3.2
7−3.32 (2H, m), 3.44 (2H, bs), 3.99 (2H, bs), 6.64
−6.83 (8H, m), 7.04 (2H, d, J = 8.1Hz), 7.47 (1H, b
s), 7.90-7.95 (1H, m). MS m / z (ESI-): 652 (M-Na) ^- . mp: 196-200 ℃

Example 9 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-pentyl
[Reid] ethoxy] phenyl] -2- (4-isopropyl
Rufenokishi) -2-methyl obtained in acid Example 1 (c) 3- [4- (2-aminoethoxy) phenyl] -2- (4-isopropyl-phenoxy) -2-methylpropionic acid ethyl and n -The title compound was obtained in the same manner as in Examples 1 (d), (e) and (f) using pentanal. IRνmax (KBr): 3370, 2858, 1731, 1612, 1511, 1230,
1114, 960, 910, 840, 732, 647, 586 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 6.7 Hz), 1.21 (6
H, d, J = 6.8 Hz), 1.21-1.40 (4H, m), 1.41 (3H, s),
1.60-1.70 (2H, m), 2.86 (1H, quint, J = 6.8Hz), 3.13
(1H, d, J = 14.1Hz), 3.27 (1H, d, J = 14.1Hz), 3.38 (2
H, t, J = 7.7 Hz), 3.75 (2H, t, J = 4.6 Hz), 4.16 (2H,
t, J = 4.6 Hz), 6.80-6.90 (6H, m), 7.11 (2H, d, J = 8.
6Hz), 7.23 (2H, d, J = 8.3Hz), 7.95−8.05 (1H, m).

Example 10 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-isopropylphenoxy) -2
Example 1 Using sodium 3-methylpropionate obtained using ethyl 3- [4- (2-aminoethoxy) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 1 (c). The title compound was obtained in the same manner as in 1 (e), (f) and Example 2. IRνmax (KBr): 3343, 2958, 1570, 1242 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.12 (6H, d, J = 7.2 Hz), 1.15 (3
H, s), 2.76 (1H, quint, J = 7.2Hz), 2.95 (1H, d, J =
13.8Hz), 3.09 (1H, d, J = 13.8Hz), 3.45 (2H, t, J = 5.3
Hz), 3.97 (2H, t, J = 5.3Hz), 6.76 (2H, d, J = 8.4H
z), 6.80 (2H, d, J = 8.4Hz), 6.92 (2H, d, J = 8.6H)
z), 7.09 (2H, d, J = 8.6Hz), 7.21 (1H, bs), 8.03-8.
05 (1H, m), 8.59 (1H, bs). MS m / z (ESI-): 511 (M-Na) ^- . mp: 164-166 ° C

Example 11 3- [4- [2- [1-
[2- (2-chloro-6-fluorophenyl) ethyl]
-3- (2,3-Dichlorophenyl) ureido] ethoxy
[S] phenyl] -2- (4-isopropylphenoxy)
Sodium 2-methylpropionate (a) 3- [4- [2- [2- (2-chloro-6-fluorophenyl) acetylamino] ethoxy] phenyl]
Ethyl-2- (4-isopropylphenoxy) -2-methylpropionate Under an argon atmosphere, PS-carbodiimide (1.05 m
(mol / g) A solution of 2.5 mg of 2-chloro-6-fluorophenylacetic acid in 5 mL of dichloromethane was added to a solution of 2.5 g of 30 mL of dichloromethane. After stirring at room temperature for 1 hour, 3- [4- (2-aminoethoxy) phenyl]-
A solution of 500 mg of ethyl 2- (4-isopropylphenoxy) -2-methylpropionate in 5 mL of dichloromethane was added, and the mixture was further stirred for 15 hours. The reaction solution is collected by filtration, and P
The S-carbodiimide residue was washed four times with 25 mL of chloroform and the solvent was distilled off to obtain 719 mg of the title compound as a colorless oil. IRνmax (neat): 3367,3324,3070,2958,2873,1732,1666,
^{. 1608,1581,1512,1458,1377,1242,1180,1111,1061 cm -1 1 H-NMR} (CDCl 3) δ: 1.20 (6H, d, J = 6.6Hz), 1.23 (3
H, t, J = 7.2 Hz), 1.37 (3H, s), 2.83 (1H, quin
t, J = 6.6 Hz), 3.10 (1H, d, J = 16.7 Hz), 3.25 (1
H, d, J = 16.7 Hz), 3.62-3.67 (2H, m), 3.77 (2H,
d, J = 1.2 Hz), 4.00 (2H, t, J = 5.2 Hz), 4.20 (2H,
q, J = 7.2 Hz), 5.94 (1H, m), 6.74 (2H, d, J = 2.4
Hz), 6.77 (2H, d, J = 2.4Hz), 6.98−7.08 (3H,
m), 7.15-7.23 (4H, m).

(B) 3- [4- [2- [2- (2-chloro-6-fluorophenyl) ethylamino] ethoxy]
Phenyl] -2- (4-isopropylphenoxy) -2
-Ethyl methyl propionate Under an argon atmosphere, 3- [4- [2- [2- (2-chloro-6-fluorophenyl) acetylamino] ethoxy] phenyl] -2- (4-isopropylphenoxy)
719 mg of ethyl 2-methylpropionate in THF
6.5 mL was cooled to 0 ° C., and borane of 1.0 mol / L was added.
2.6 mL of a THF complex solution was added, and the mixture was stirred at 0 ° C. for 1.5 hours. Further, 2.6 mL of a 1.0 mol / L borane-THF complex solution was added, and the mixture was stirred at room temperature for 5 hours. 5 mL of water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate-hexane = 1: 5-1: 1).
By separating and purifying in 2), 254 mg of the title compound was obtained as a colorless oil. IRνmax (neat): 3394, 2958, 2866, 1736, 1612, 151
^{. 2,1458,1385,1230,1180,1115,1080 cm -1 1 H-NMR} (CDCl 3) δ: 1.19-1.28 (9H, m), 1.36 (3
H, s), 2.83 (1H, quint, J = 6.6 Hz), 3.
00−3.42 (6H, m), 3.69−3.87 (2H, m), 4.11−
4.24 (3H, m), 4.39 (1H, t, J = 5.1Hz), 6.7
2-6.88 (4H, m), 7.00-7.17 (7H, m), 10.09 (1
H, br).

(C) 3- [4- [2- [1- [2- (2
-Chloro-6-fluorophenyl) ethyl] -3-
(2,3-Dichlorophenyl) ureido] ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-
Sodium methyl propionate 3- [4- [2- [2- (2-Chloro-6-fluorophenyl) ethylamino] ethoxy] phenyl] -2-
The title compound was obtained in the same manner as in Examples 1 (e), (f) and 2 using ethyl (4-isopropylphenoxy) -2-methylpropionate and 2,3-dichlorophenyl isocyanate. IRνmax (KBr): 3413, 3375, 2958, 2873, 1674, 1585,
1512, 1454, 1404, 1292, 1230, 1192, 1126, 1049 cm
^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.15 to 1.28 (9H, brm), 2.81 (1H, qui
nt, J = 7.0Hz), 2.96 (1H, d, J = 13.8Hz), 3.15-3.19
(3H, brm), 3.58 (2H, brm), 3.68 (2H, brm), 3.94 (2H,
brm), 6.72-7.14 (12H, m), 7.49 (1H, br), 7.95 (1H, b
rm). MS m / z (ESI-): 699 (M-Na) ^- .

Example 12 3- [4- [2- [1-
[2- (2-chloro-6-fluorophenyl) ethyl]
-3- (2,4-Difluorophenyl) ureido] etho
[Xy] phenyl] -2- (4-isopropylphenoxy)
B) Sodium 2-methylpropionate 3- [4- [2- [2-] obtained in Example 11 (b)
(2-chloro-6-fluorophenyl) ethylamino]
Example 1 using ethyl [ethoxy] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate and 2,4-difluorophenyl isocyanate.
The title compound was obtained in the same manner as in (e), (f) and Example 2. IRνmax (KBr): 3371, 2958, 2873, 1674, 1604, 1516,
1458, 1396, 1230, 1180, 1041 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.15 to 1.28 (9H, brm), 2.81 (1H, qui
nt, J = 7.0Hz), 2.96 (1H, d, J = 13.8Hz), 3.15-3.19
(3H, brm), 3.58 (2H, brm), 3.68 (2H, brm), 3.94 (2H,
brm), 6.72-7.14 (12H, m), 7.49 (1H, br), 7.95 (1H, b
rm). MS m / z (ESI-): 667 (M-H) ^- .

Example 13 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-heptylu
Raido] ethoxy] phenyl] -2-methyl-2-fe
Example 1 using sodium 2-hydroxypropionate 2-ethyl phenoxypropionate
The title compound was obtained in the same manner as in (a) to (f) and Example 2. IRνmax (KBr): 3367, 2927, 1662, 1593, 1520, 140
0, 1234, 960, 841, 756, 571 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.87 (3H, t, J = 6.6 Hz), 1.20-1.
33 (8H, m), 1.40 (3H, s), 1.65 (2H, bs), 3.01 (H,
d, J = 14.3 Hz), 3.28-3.39 (3H, m), 3.73 (2H, t, J =
4.6Hz), 4.14 (2H, t, J = 4.6Hz), 6.81−6.90 (6H,
m), 6.98 (1H, t, J = 7.2Hz), 7.19 (4H, d, J = 8.3Hz),
7.89−7.97 (1H, m). MS m / z (ESI-): 567 (M-Na) ^- .

Example 14 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-heptylu
[Reid] ethoxy] phenyl] -2- (4-isopropyl
Rufenoxy ) sodium propionate WO 99/18066, 3- [4-
Using ethyl (2-aminoethoxy) phenyl] -2- (4-isopropylphenoxy) propionate, the title compound was prepared in the same manner as in Examples 1 (d), (e), (f) and Example 2. Obtained. IRνmax (KBr): 3371, 2927, 1608, 1516, 1408, 1234,
960, 833 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 6.2 Hz), 1.09 (6
H, d, J = 6.8 Hz), 1.22-1.30 (8H, m), 1.62 (2H, b
s), 2.72 (1H, quint, J = 6.8Hz), 2.97 (1H, d, J = 13.
8Hz), 3.10 (1H, d, J = 13.8Hz), 3.33 (2H, t, J = 8.1H)
z), 3.68 (2H, t, J = 4.6Hz), 4.06 (2H, t, J = 4.6H)
z), 4.48−4.52 (1H, m), 6.70 (2H, d, J = 8.4Hz), 6.77
−6.84 (4H, m), 6.95 (2H, d, J = 8.4Hz), 7.16 (2H, d,
J = 8.4Hz), 7.89−7.97 (1H, m). MS m / z (ESI-): 595 (M-Na) ^- . mp: 244-245 ° C

Example 15 3- [3- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-isopropylphenoxy) -2
Example 1 (a), (b), using sodium methylpropionate and ethyl 2- (4-isopropylphenoxy) propionate and 3- (tert-butyldimethylsilyloxy) benzyliodide.
The title compound was obtained in the same manner as in (c), (e), (f) and Example 2. IRνmax (KBr): 2958, 2877, 1662, 1569, 1508, 1400,
1249, 1091, 960, 844 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.08 (6H, dd, 6.8 Hz), 1.17 (3H,
s), 2.70 (1H, quint, J = 6.8Hz), 2.95 (1H, d, J = 14.3)
Hz), 3.05 (1H, d, J = 14.3Hz), 3.43 (2H, brs), 3.84 (2
H, brs), 6.54-6.71 (4H, m), 6.63 (2H, d, J = 7.9H
z), 6.83 (2H, d, J = 7.9 Hz), 6.92 (1H, s), 7.00 (1H, d
d, J = 7.5, 7.7 Hz), 7.82 (1H, brs). MS m / z (ESI-): 511 (M-Na) ^- .

Example 16 3- [3- [2- [3-
(2,4-difluorophenyl) -1-n-heptylu
[Reid] ethoxy] phenyl] -2- (4-isopropyl
Examples 1 (a) to (f) and Examples 1 (a) to (f) using ruphenoxy ) -2-methylpropionate sodium 2- (4-isopropylphenoxy) propionate and 3- (tert-butyldimethylsilyloxy) benzyliodide. The title compound was obtained in the same manner as in Example 2. IRνmax (KBr): 2931, 2865, 1666, 1604, 1519, 1400,
1253, 1095, 960, 844 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, t, J = 5.5 Hz), 1.03 (6H,
dd, 6.8 Hz), 1.12 (3H, s), 1.19-1.27 (8H, m), 1.59 (2
H, brs), 2.64 (1H, quint, J = 6.8 Hz), 2.93 (1H, d, J
= 13.9Hz), 3.19 (1H, d, J = 13.9Hz), 3.25 (2H, brs),
3.58 (2H, brs), 3.97 (2H, brs), 6.68−6.83 (9H, m),
7.05 (1H, dd, J = 6.6, 7.7Hz), 7.85-8.00 (1H, m). MS m / z (ESI-): 609 (M-Na) ^- .

Example 17 3- [4- [2- [3-
(2,4-difluorophenyl) -1-n-heptylu
[Reid] ethyl] phenyl] -2- (4-isopropyl
Sodium phenoxy) -2-methylpropionate (a) ethyl 3- (4-bromophenyl) -2- (4-isopropylphenoxy) -2-methylpropionate ethyl 2- (4-isopropylphenoxy) propionate and The title compound was obtained in the same manner as in Example 1 (a) using -bromobenzyl bromide. IRνmax (neat): 2962, 1735, 1608, 1508, 1376, 123
0, 1180, 1110, 1018, 948, 840, 728 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.8 Hz), 1.21 (3H,
t, J = 7.2 Hz), 1.37 (3H, s), 2.83 (1H, quint, J = 6.8H
z), 3.09 (1H, d, J = 13.6Hz), 3.27 (1H, d, J = 13.6H
z), 4.20 (2H, q, J = 7.2Hz), 6.73 (2H, d, J = 8.6Hz),
7.06 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.3Hz), 7.41
(2H, d, J = 8.3Hz).

(B) 3- [4- [2- (phthalimide)
Ethyl vinylene] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate Ethyl 3- (4-bromophenyl) -2- (4-isopropylphenoxy) -2-methylpropionate 1.5
g, 21 mg of palladium acetate, 91 mg of tri-o-tolylphosphine and 641 mg of N-vinylphthalimide were dissolved in a 3 mL solution of acetonitrile, and 0.84 mL of diisopropylethylamine was added at 0 ° C.
For 43 hours and 30 minutes. After adding chloroform to the reaction solution under ice cooling, the reaction solution was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate-hexane = 1: 30) to give the title compound as a yellow oil. 1.5 g were obtained. IRνmax (neat): 2962, 1727, 1508, 1380, 1226, 110
6, 1018, 956, 894, 848, 755, 717, 628 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.8 Hz), 1.23 (3H,
t, J = 7.2 Hz), 1.39 (3H, s), 2.83 (1H, quint, J = 6.8H
z), 3.16 (1H, d, J = 13.6Hz), 3.32 (1H, d, J = 13.6H
z), 4.21 (2H, q, J = 7.2 Hz), 6.76 (2H, d, J = 8.3 Hz),
7.06 (2H, d, J = 8.3Hz), 7.25 (2H, d, J = 8.1Hz), 7.34
(1H, d, J = 15.0Hz), 7.40 (2H, d, J = 8.1Hz), 7.63 (1
H, d, J = 15.0 Hz), 7.72-7.78 (2H, m), 7.87-7.92 (2
H, m).

(C) 3- [4- (2-phthalimidoethyl) phenyl] -2- (4-isopropylphenoxy)
Ethyl-2-methylpropionate 1.5 g of ethyl 3- [4- [2- (phthalimido) vinylene] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate was added to a mixed solution of 18 mL of THF and 3 mL of ethanol. After dissolution, 200 mg of tris (triphenylphosphine) rhodium chloride was added, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 66 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (ethyl acetate-hexane = 1: 8 to 1:
By separating and purifying in 6), 1.49 g of the title compound was obtained as a yellow oil. IRνmax (neat): 2958, 1770, 1716, 1612, 1508, 145
4, 1392, 1234, 1110, 1018, 840, 717 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.18 to 1.26 (9H, m), 1.33 (3H, s),
2.83 (1H, quint, J = 7.2Hz), 2.92−3.01 (2H, m), 3.10
(1H, d, J = 13.5Hz), 3.27 (1H, d, J = 13.5Hz), 3.91 (2
H, m), 4.19 (2H, q, J = 7.2 Hz), 6.73 (2H, d, J = 8.8H
z), 7.05 (2H, d, J = 8.8 Hz), 7.17 (4H, s), 7.68 (2H, d
d, J = 5.3, 3.1 Hz), 7.81 (2H, dd, J = 5.3, 3.1 Hz).

(D) 3- [4- (2-aminoethyl) phenyl] -2- (4-isopropylphenoxy) -2-
Ethyl methyl propionate 3- [4- (2-phthalimidoethyl) phenyl] -2
A solution of 1.49 g of ethyl-(4-isopropylphenoxy) -2-methylpropionate in 30 mL of ethanol was dissolved in 0%.
Hydrazine monohydrate (0.3 mL) was added at 0 ° C, and the mixture was stirred at 100 ° C for 40 minutes and further at room temperature for 7 hours. The precipitated colorless solid was removed by filtration, and the filtrate and the colorless solid washed with ethyl acetate and diethyl ether were combined and distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (chloroform-methanol = 20: 1 to 10: 1 to
5: 1) to give 625 mg of the title compound as a colorless oil. IRνmax (neat): 3444, 3374, 2962, 1735, 1608, 150
8, 1457, 1376, 1234, 1184, 1110, 1022, 944, 898, 8
36,759 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.8 Hz), 1.21 (3H,
t, J = 7.2 Hz), 1.38 (3H, s), 1.68 (2H, brs), 2.75 (2
H, t, J = 6.8 Hz), 2.83 (1H, quint, J = 6.8 Hz), 2.97 (2
H, brs), 3.14 (1H, d, J = 13.5Hz), 3.28 (1H, d, J = 1
3.5Hz), 4.20 (2H, q, J = 7.2Hz), 6.75 (2H, d, J = 8.6H
z), 7.05 (2H, d, J = 8.6Hz), 7.11 (2H, d, J = 7.9Hz),
7.19 (2H, d, J = 7.9 Hz).

(E) 3- [4- [2- [3- (2,4-
Difluorophenyl) -1-n-heptylureido] ethyl] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate sodium 3- [4- (2-aminoethyl) phenyl] -2- (4
Examples 1 (d) to (f) and Example 2 using ethyl- (isopropylphenoxy) -2-methylpropionate
The title compound was obtained in the same manner as in. IRνmax (KBr): 2927, 2861, 1658, 1604, 1519, 1430,
1396, 1226, 1184, 1133, 1091, 960, 844, 725 cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (3H, t, J = 6.8 Hz), 1.09 −
1.30 (17H, m), 1.40-1.52 (2H, m), 2.72-2.81 (3H,
m), 2.95 (1H, d, J = 13.5Hz), 3.12-3.21 (3H, m), 3.4
6 (2H, t, J = 7.7Hz), 6.75 (2H, d, J = 8.4Hz), 6.96 (1
H, brs), 6.97 (2H, d, J = 8.4Hz), 7.09 (4H, s), 7.20
(1H, m), 7.37 (1H, m), 7.94 (1H, s). MS m / z (ESI-): 593 (M-Na) ^- . mp: 189-192 ° C.

Example 18 3- [4- [3- [3-
(2,4-difluorophenyl) -1-n-heptylu
Raido] propyl] phenyl] -2- (4-isopropyl)
Ruphenoxy) -2-methylpropionate sodium (a) 3- [4- [3- (phthalimido) propenylene] phenyl] -2- (4-isopropylphenoxy)
Ethyl-2-methylpropionate Using ethyl 3- (4-bromophenyl) -2- (4-isopropylphenoxy) -2-methylpropionate obtained in Example 17 (a) and N-allylphthalimide, The title compound was obtained in the same manner as in Example 17 (b). IRνmax (neat): 2962, 1775, 1712, 1612, 1511, 146
^1, 1392, 1110, 952, 844, 721 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.18 (6H, d, J = 7.0 Hz), 1.20 (3H,
t, J = 7.2 Hz), 1.34 (3H, s), 2.82 (1H, quint, J = 7.0H
z), 3.11 (1H, d, J = 13.3Hz), 3.27 (1H, d, J = 13.3H
z), 4.18 (2H, q, J = 7.2 Hz), 4.44 (2H, dd, J = 6.4, 1.
1Hz), 6.23 (1H, dt, J = 15.9, 6.4Hz), 6.64 (1H, d, J
= 15.9Hz), 6.72 (2H, d, J = 8.6Hz), 7.04 (2H, d, J =
8.4Hz), 7.18 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.6H)
z), 7.70-7.74 (2H, m), 7.84-7.88 (2H, m).

(B) Ethyl 3- [4- (3-phthalimidopropyl) phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate 3- [4- [3- (phthalimido) propenylene] phenyl] The title compound was obtained in the same manner as in Example 17 (c) using ethyl 2- (4-isopropylphenoxy) -2-methylpropionate. IRνmax (neat): 2962, 1775, 1716, 1612, 1508, 145
7, 1396, 1234, 1106, 1022, 844, 717 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.18 to 1.24 (9H, m), 1.34 (3H, s),
1.97−2.08 (2H, m), 2.66 (2H, t, J = 7.2) Hz), 2.82 (1
H, quint, J = 6.8 Hz), 3.09 (1H, d, J = 13.3 Hz), 3.23
(1H, d, J = 13.3Hz), 3.74 (2H, t, J = 7.2Hz), 4.18 (2
H, q, J = 7.2 Hz), 6.73 (2H, d, J = 8.6 Hz), 7.05 (2H,
d, J = 8.6 Hz), 7.09-7.16 (4H, m), 7.69 (2H, dd, J =
5.5, 2.9 Hz), 7.82 (2H, dd, J = 5.5, 2.9 Hz).

(C) 3- [4- (3-aminopropyl)
Phenyl] -2- (4-isopropylphenoxy) -2
-Ethyl methyl propionate 3- [4- (3-phthalimidopropyl) phenyl]-
The title compound was obtained in the same manner as in Example 17 (d) using ethyl 2- (4-isopropylphenoxy) -2-methylpropionate. IRνmax (neat): 3440, 2958, 1735, 1608, 1508, 146
^1, 1376, 1234, 1184, 1110, 1018, 948, 833 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.18 to 1.24 (9H, m), 1.37 (3H, s),
1.77 (2H, quint, J = 7.4Hz), 2.63 (2H, t, J = 7.4Hz),
2.73 (2H, t, J = 7.4Hz), 2.82 (1H, quint, J = 7.0Hz),
3.13 (1H, d, J = 13.5Hz), 3.27 (1H, d, J = 13.5Hz), 4.
19 (2H, q, J = 7.2 Hz), 6.75 (2H, d, J = 8.6 Hz), 7.05
(2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.1Hz), 7.17 (2
H, d, J = 8.1 Hz).

(D) 3- [4- [3- [3- (2,4-
Difluorophenyl) -1-n-heptylureido] propyl] phenyl] -2- (4-isopropylphenoxy) -2-methylpropionate sodium 3- [4- (3-aminopropyl) phenyl] -2-
The title compound was obtained in the same manner as in Examples 1 (d) to (f) and Example 2 using ethyl (4-isopropylphenoxy) -2-methylpropionate. IRνmax (KBr): 2927, 2861, 1646, 1604, 1515, 1400,
1226, 1137, 1099, 964, 844 cm ^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 0.83 (3H, t, J = 7.0 Hz), 1.08 (3
H, s), 1.12-1.30 (14H, m), 1.45-1.52 (2H, m), 1.74
-1.86 (2H, m), 2.50-2.58 (2H, m), 2.70-2.79 (1H,
m), 2.94 (1H, d, J = 13.5Hz), 3.10 (1H, d, J = 13.5H)
z), 3.14−3.42 (4H, m), 6.74 (2H, d, J = 8.8Hz), 6.92
−7.10 (7H, m), 7.14−7.23 (1H, m), 7.39 (1H, dt, J =
8.8, 6.2Hz), 7.92 (1H, s). MS m / z (ESI-): 607 (M-Na) ^- . mp: 162-165 ° C.

Example 19 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Sodium phenyl] -2-methyl-2-phenoxypropionate Ethyl 3- [4- (2-aminoethoxy) phenyl] -2-methyl-2-phenoxypropionate and 2,4-
Example 1 using difluorophenyl isocyanate
The title compound was obtained in the same manner as in (e), (f) and Example 2. IRνmax (KBr): 3336, 1662, 1589, 1508, 1242, 84
5,756,548 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.22 (3H, s), 2.99 (1H, d, J =
13.8Hz), 3.23 (1H, d, J = 13.8Hz), 3.52 (2H, t, J =
5.3Hz), 4.00 (2H, t, J = 5.3Hz), 6.77−6.93 (7H,
m), 7.09 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6H)
z), 7.82-7.88 (1H, m). MS m / z (ESI +): 493 (M + H) ^<+> . mp: 145-147 ° C

Example 20 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- [4- (pyrrol-1-yl) phenoxy] propionate sodium 3- [4- (2-aminoethoxy) phenyl] -2-
Using ethyl [4- (pyrrol-1-yl) phenoxy] propionate and 2,4-difluorophenyl isocyanate, the title compound was prepared in the same manner as in Example 1 (e), (f) and Example 2. Obtained. IRνmax (KBr): 3321, 2931, 1655, 1604, 1562, 151
6,1423,1327,1296,1242,1068,960,829,725cm
^-1 . ¹ H-NMR (DMSO-d ₆ ) δ: 2.89 (1 H, dd, J = 14.7, 8.8 H
z), 3.04 (1H, d, J = 14.7Hz), 3.26-3.47 (2H,
m), 3.95 (2H, brs), 4.19 (1H, d, J = 8.8Hz), 6.16
(2H, d, J = 1.9Hz), 6.77 (2H, d, J = 8.2Hz), 6.82-
6.88 (1H, m), 6.83 (2H, d, J = 7.2Hz), 6.95 (1H, b
rt, J = 7.9Hz), 7.12 (2H, d, J = 1.9Hz), 7.18 (2H,
d, J = 8.2Hz), 7.17-7.27 (1H, m), 7.28 (2H, d, J =
7.2Hz), 7.99-8.07 (1H, m), 8.43 (1H, s). MS m / z (ESI-): 520 (M-Na) ^- . mp:> 300 ℃

Example 21 3- [4- [2- (3-phenylureido) ethoxy] phenyl] -2- [4-
Sodium (pyrrole-1-yl) phenoxy] propionate 3- [4- (2-aminoethoxy) phenyl] -2-
Using ethyl [4- (pyrrol-1-yl) phenoxy] propionate and phenyl isocyanate, the title compound was obtained in the same manner as in Example 1 (e), (f) and Example 2. IRνmax (KBr): 3340, 3136, 3055, 2931, 2873, 165
8, 1604, 1554, 1512, 1435, 1408, 1315, 1234, 111
5, 1068, 922, 829, 729 cm ^-1 . ^{1 H-NMR (DMSO-d} 6) δ: 2.89 (1H, dd, J = 13.3,8.9H
z), 3.05 (1H, d, J = 13.3Hz), 3.38−3.44 (2H,
m), 3.94 (2H, t, J = 4.9Hz), 4.29 (1H, brd, J = 8.9H)
z), 6.16 (2H, d, J = 2.0Hz), 6.78-6.86 (6H, m),
7.12 (2H, d, J = 2.0Hz), 7.12-7.14 (2H, m), 7.18
(2H, d, J = 7.2Hz), 7.29 (2H, d, J = 7.2Hz), 7.38
(2H, d, J = 7.7Hz), 8.96 (1H, s). MS m / z (ESI-): 484 (M-Na) ^- . mp:> 250 ℃

Example 22 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Sodium phenyl] -2- (4-dimethylaminophenoxy) propionate (a) 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-
Dimethylaminophenoxy) malonate 3- [4- (2-aminoethoxy) phenyl] -2-
Diethyl (4-benzylphenoxy) malonate and 2,
The title compound was obtained in the same manner as in Example 1 (e) using 4-difluorophenyl isocyanate. IRνmax (KBr): 3357, 2981, 2925, 2852, 2801, 174
1, 1655, 1611, 1543, 1512, 1430, 1285, 1242, 120
0, 1057, 960, 847, 819, 757 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.15 (6H, t, J = 7.2 Hz), 2.88 (6
H, s), 3.52 (2H, s), 3.65 (2H, brq, J = 4.8Hz),
4.03 (2H, t, J = 4.8Hz), 4.14 (4H, q, J = 7.2Hz), 5.
12 (1H, brt, J = 4.8Hz), 6.46 (1H, brs), 6.62 (2
H, d, J = 9.3 Hz), 6.77 (2H, d, J = 8.6 Hz), 6.80-6.8
7 (2H, m), 6.92 (2H, d, J = 9.3 Hz), 7.15 (2H, d, J
= 8.6Hz), 7.91−7.97 (1H, m).

(B) 3- [4- [2- [3- (2,4-
Difluorophenyl) ureido] ethoxy] phenyl]
2- (4-Dimethylaminophenoxy) propionic acid diethyl 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-dimethylaminophenoxy) malonate 105.4m
2.0 mL of 2-methoxyethanol and 0.2 m of water
To the L solution, 58 mg of 85% potassium hydroxide was added, and 13
Stir at 0 ° C. for 1.5 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and ice water and 1 mol / L hydrochloric acid were added to add acidic (pH 2 to 2).
After 3), extract with ethyl acetate three times and wash with saturated saline. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound as a brown oil.
1 mg was obtained. ¹ H-NMR (CD ₃ OD) δ: 3.03 (6H, s), 3.12 (1H, dd, J =
14.1, 8.0Hz), 3.20 (1H, dd, J = 14.1, 4.5Hz), 3.56
(2H, t, J = 5.3Hz), 4.03 (2H, t, J = 5.3Hz), 4.79
(1H, dd, J = 8.0, 4.5Hz), 6.82−6.99 (2H, m), 6.8
8 (2H, d, J = 8.6Hz), 6.89 (2H, d, J = 9.0Hz), 7.15
(2H, d, J = 9.0Hz), 7.23 (2H, d, J = 8.6Hz), 7.85-
7.93 (1H, m).

(C) 3- [4- [2- [3- (2,4-
Difluorophenyl) ureido] ethoxy] phenyl]
Sodium 2- (4-dimethylaminophenoxy) propionate 3- [4- [2- [3- (2,4-difluorophenyl) ureido] ethoxy] phenyl] -2- (4-dimethylaminophenoxy) propionic acid Example 2 using
The title compound was obtained using a method similar to IRνmax (KBr): 3348, 3074, 2935, 2881, 2800, 161
2,1562,1512,1423,1331,1292,1238,1138,106
1,957,822 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 2.75 (6H, s), 3.01 (1H, dd, J =
14.1, 9.0Hz), 3.10 (1H, dd, J = 14.1, 3.8Hz), 3.56
(2H, t, J = 5.1Hz), 4.03 (2H, t, J = 5.1Hz), 4.38
(1H, dd, J = 9.0, 3.8Hz), 6.72 (4H, s), 6.84-6.9
8 (2H, m), 6.85 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J
= 8.4Hz), 7.86−7.94 (1H, m). MS m / z (ESI-): 498 (M-Na) ^- . mp: 257-258 ℃

Example 23 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-benzoylphenoxy) propionate sodium 3- [4- (2-aminoethoxy) phenyl] -2-
Using diethyl (4-benzoylphenoxy) malonate and 2,4-difluorophenyl isocyanate,
The title compound was obtained in the same manner as in Example 22. IRνmax (KBr): 3356, 3074, 2935, 1601, 1512, 142
7, 1315, 1250, 1176, 1061, 960, 933, 849, 741, 70
2,629 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 3.12 (1 H, dd, J = 14.2, 9.0 Hz),
3.21 (1H, dd, J = 14.2, 3.8Hz), 3.57 (2H, t, J = 5.0H
z), 4.04 (2H, t, J = 5.0Hz), 4.62 (1H, dd, J = 9.0,
3.8Hz), 6.84-6.95 (2H, m), 6.86 (2H, d, J = 8.6H)
z), 6.94 (2H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.6H)
z), 7.45-7.68 (5H, m), 7.69 (2H, d, J = 8.8Hz),
7.86-7.94 (1H, m). MS m / z (ESI-): 559 (M-Na) ^- . mp: 193-195 ℃

Example 24 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-benzylphenoxy) propio
Sodium 3- [4- (2-aminoethoxy) phenyl] -2-
Diethyl (4-benzylphenoxy) malonate and 2,
The title compound was obtained in the same manner as in Example 22 using 4-difluorophenyl isocyanate. IRνmax (KBr): 3329, 3066, 3032, 2927, 1612, 156
2, 1508, 1419, 1331, 1292, 1238, 1138, 1099, 106
1,960,841,725,698 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 3.03 (1 H, dd, J = 14.1, 9.0 Hz),
3.11 (1H, dd, J = 14.1, 3.9Hz), 3.55 (2H, t, J = 5.3H
z), 3.82 (2H, s), 4.02 (2H, t, J = 5.3Hz), 4.44
(1H, dd, J = 9.0, 3.9Hz), 6.73 (2H, d, J = 8.8Hz),
6.84 (2H, d, J = 8.6Hz), 6.88−6.97 (2H, m), 6.97
(2H, d, J = 8.8Hz), 7.09 (1H, brs), 7.11 (2H, d,
J = 7.2Hz), 7.19 (2H, d, J = 7.2Hz), 7.24 (2H, d, J =
8.6Hz), 7.85-7.93 (1H, m). MS m / z (ESI-): 545 (M-Na) ^- . mp:> 300 ℃

Example 25 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-isopropylphenylthio) propionate sodium 3- [4- (2-aminoethoxy) phenyl] -2-
Using dimethyl (4-isopropylphenylthio) malonate and 2,4-difluorophenyl isocyanate, the title compound was obtained in the same manner as in Example 22. IRνmax (KBr): 3348, 3074, 2962, 2873, 1658, 157
7, 1508, 1427, 1392, 1242, 1138, 1095, 960, 822, 5
44 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 1.20 (6H, d, J = 7.0 Hz), 2.79−
2.89 (2H, m), 3.13 (1H, dd, J = 13.6, 8.3Hz), 3.56
(2H, t, J = 5.2Hz), 3.77 (1H, dd, J = 8.3, 6.5Hz),
4.01 (2H, t, J = 5.2Hz), 6.81 (2H, d, J = 8.6Hz), 6.
85−6.99 (2H, m), 7.10 (2H, d, J = 8.2Hz), 7.13 (2
H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.86-7.9
5 (1H, m). MS m / z (ESI-): 513 (M-Na) ^- . mp: 145-147 ° C

[Example 26] 3- [4- [2- [3-
(2,4-difluorophenyl) ureido] ethoxy]
Phenyl] -2- (4-fluorobenzyloxy) propionate sodium 3- [4- (2-aminoethoxy) phenyl] -2-
Using ethyl (4-fluorobenzyloxy) propionate and 2,4-difluorophenyl isocyanate, the title compound was obtained in the same manner as in Example 1 (e), (f) and Example 2. IRνmax (KBr): 3345, 1655, 1609, 1511, 1246, 109
^{. 4,825cm -1 1 H-NMR (} CDCl 3) δ: 2.81 (1H, dd, J = 9.5,14.1Hz),
2.98 (1H, dd, J = 3.9, 14.1Hz), 3.59 (2H, t, J = 5.0H
z), 3.84 (1H, dd, J = 3.9, 9.5Hz), 4.06 (2H, t, J =
5.0Hz), 4.20 (1H, d, J = 11.6Hz), 4.62 (1H, d, J = 1
1.6Hz), 6.85 (2H, d, J = 8.6Hz), 6.88−6.91 (3H,
m), 6.96 (1H, ddd, J = 2.8, 8.6, 11.3Hz), 7.09 (2
H, dd, J = 5.7, 8.6Hz), 7.16 (2H, d, J = 8.6Hz), 7.8
7-7.96 (1H, m). MS m / z (ESI-): 487 (M-Na) ^- .mp: 120.2-125.8 ° C

Example 27 3- [4- [3- (2,4
-Difluorophenyl) ureidomethyl] benzyloxy
[S] -2- (4-isopropylphenoxy) propion
Sodium (a) 4- [3-hydroxy-2- (4-isopropylphenoxy) propoxymethyl] benzonitrile Under an argon atmosphere, 896 mg of 2- (4-isopropylphenoxy) propane-1,3-diol in THF4
170 mg of 60% oily sodium hydride at 0 ° C in 0 mL
Was added and stirred at room temperature for 1 hour. Next, 835 mg of 4-cyanobenzyl bromide was added at 0 ° C, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. Next, N, N-dimethylformamide (5.0 mL) was added, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction solution at 0 ° C., extracted with ethyl acetate, and washed with saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate-hexane =
1: 3-4: 1) to give 731.6 mg of the title compound as a yellow oil. IRνmax (neat): 3503, 3032, 2959, 2927, 2871, 222
8, 1609, 1508, 1238, 1179, 1102, 1050, 820, 548 cm
^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.0 Hz), 1.95 (1
H, t, J = 6.5Hz), 2.87 (1H, quint, J = 7.0Hz), 3.75
(2H, d, J = 5.2Hz), 3.83-3.95 (2H, m), 4.50 (1
H, quint, J = 5.2Hz), 4.61 (2H, s), 6.90 (2H, d, J
= 8.5Hz), 7.14 (2H, d, J = 8.5Hz), 7.40 (2H, d, J =
8.5Hz), 7.62 (2H, d, J = 8.5Hz).

(B) 1- (2,4-difluorophenyl)
) -3- [4- [3-Hydroxy-2- (4-isoprop)
Ropirphenoxy) propoxymethyl] benzyl] uree
A. Under an argon atmosphere, 4- [3-hydroxy-2- (4-
Isopropylphenoxy) propoxymethyl] benzoni
88 mg of tolyl and 129 of cobalt (II) chloride hexahydrate
90% hydrogenated borohydride at 0 ° C in 3 mL of methanol
Add 114 mg of sodium hydrogen chloride and stir at the same temperature for 1 hour.
Was. Water and 10% aqueous sodium hydroxide solution
After adding basic (pH 8-9), acetic acid
Extracted with ethyl and washed with saturated saline. Organic layer anhydrous sulfur
After drying over sodium acid, the solvent was distilled off under reduced pressure. Residue
To a 2 mL solution of chloromethane was added 2,4-difluoro
Add 88.9 mg of phenyl isocyanate, and add for 30 minutes
Stirred. PS-trisamine (3.75 mm
ol / g) 120 mg, and the mixture was stirred overnight.
Lithamine was removed by filtration. The filtrate was concentrated under reduced pressure,
The obtained crude product is subjected to silica gel column chromatography.
-(Ethyl acetate-hexane = 1: 3 to 1: 1)
To give the title compound as a colorless powder (48.1 m).
g was obtained. IRνmax (KBr): 3495, 3314, 2960, 2925, 2874, 163
6, 1566, 1511, 1469, 1427, 1362, 1286, 1244, 117
9,1140,1109,1049,963,845,831,635,570c
m ^-1.¹ H-NMR (DMSO-d₆) Δ: 1.15 (6H, d, J = 6.8Hz), 2.80
(1H, quint, J = 6.8Hz), 3.54 (2H, d, J = 5.0Hz), 3.
56 (1H, dd, J = 10.5, 5.7Hz), 3.64 (1H, dd, J = 10.
5, 5.0Hz), 4.28 (2H, d, J = 5.9Hz), 4.36 (1H, quin
t, J = 5.0Hz), 4.48 (2H, s), 4.82 (1H, t, J = 5.7H)
z), 6.87 (2H, d, J = 8.5Hz), 6.95−7.00 (2H, m),
7.10 (2H, d, J = 8.5Hz), 7.22 (1H, td, J = 9.2, 2.9H
z), 7.25 (4H, s), 8.06 (1H, td, J = 9.2, 6.1Hz),
8.32 (1H, s).

(C) 1- (2,4-difluorophenyl) -3- [4- [2- (4-isopropylphenoxy) -3-oxopropoxymethyl] benzyl] urea 4-Difluorophenyl) -3- [4- [3-hydroxy-2- (4-isopropylphenoxy) propoxymethyl] benzyl] urea in a 8 mL solution of dimethylsulfoxide in 35 mL of dimethylsulfoxide at 0 ° C. 247 mg of benziodooxol-3 (1H) -one 1-oxide was added, and the mixture was stirred at room temperature overnight. At 0 ° C., water and ethyl acetate were added to the reaction solution, which was filtered through celite. After the filtrate was extracted with ethyl acetate, it was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate-hexane = 1: 1) to give the title compound as a yellow powder. 235.8 mg were obtained. IRνmax (KBr): 3308, 3033, 2958, 2925, 2871, 272
8, 1737, 1638, 1610, 1571, 1510, 1500, 1431, 128
5,1242,1141,1107,1054,963,847,826,636c
m ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 2.86 (1
H, quint, J = 7.0Hz), 3.91 (2H, d, J = 4.3Hz), 4.42
(2H, d, J = 5.7Hz), 4.54 (1H, d, J = 12.0Hz), 4.60
(1H, d, J = 12.0Hz), 4.63 (1H, td, J = 4.3, 1.5H
z), 5.06 (1H, brs), 6.38 (1H, s), 6.79-6.85 (1
H, m), 6.84 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6
Hz), 7.16-7.27 (1H, m), 7.26 (4H, s), 7.95 (1
H, td, J = 9.5, 6.0 Hz), 9.77 (1H, d, J = 1.5 Hz).

(D) 3- [4- [3- (2,4-difur
Orophenyl) ureidomethyl] benzyloxy] -2-
(4-Isopropylphenoxy) propionic acid Under an argon atmosphere, 1- (2,4-difluorophenyi)
) -3- [4- [2- (4-isopropylphenoxy)
B) -3-oxopropoxymethyl] benzyl] urea
31.6 mg of 231.6 mg of 2-methyl-2-propanol
1.5 mL of 2-methyl-2-butene at 0 ° C.
1.5 mL aqueous solution of 217 mg of sodium citrate and phosphorus
1.5 mL of 225 mg of sodium dihydrogen acid dihydrate
An aqueous solution was added, and the mixture was stirred at room temperature overnight. Water and vinegar for the reaction solution
Ethyl acetate was added, extracted with ethyl acetate, and washed with saturated saline.
Was cleaned. After drying the organic layer over anhydrous sodium sulfate, the solvent was removed.
The title compound 18 was obtained as a colorless powder by evaporation under reduced pressure.
1.4 mg were obtained. IRνmax (KBr): 3314, 2959, 2925, 2872, 1752, 163
7, 1570, 1512, 1469, 1430, 1356, 1284, 1249, 118
1,1140,1095,1038,963,847,831,631,530c
m ^-1.¹ H-NMR (DMSO-d₆) Δ: 1.16 (6H, d, J = 6.8Hz), 2.81
(1H, quint, J = 6.8Hz), 3.82 (1H, dd, J = 11.0, 4.3H
z), 3.87 (1H, dd, J = 11.0, 4.3Hz), 4.30 (2H, d, J
= 5.7Hz), 4.53 (1H, d, J = 12.3Hz), 4.58 (1H, d, J =
12.3Hz), 4.89 (1H, t, J = 4.3Hz), 6.80 (2H, d, J =
8.6 Hz), 6.96−7.01 (2H, m), 7.13 (2H, d, J = 8.6H)
z), 7.20-7.31 (1H, m), 7.28 (4H, s), 8.06 (1
H, td, J = 9.3, 6.3 Hz), 8.34 (1H, s).

(E) 3- [4- [3- (2,4-difur
Orophenyl) ureidomethyl] benzyloxy] -2-
(4-Isopropylphenoxy) sodium propionate
3- [4- [3- (2,4-difluorophenyl) uree
Idmethyl] benzyloxy] -2- (4-isopropyl
Phenoxy) propionic acid (144.7 mg)
In the same manner as in Example 2, the title compound 1 was obtained as a colorless powder.
37.3 mg were obtained. IRνmax (KBr): 3310, 3031, 2959, 2926, 2871, 163
8, 1611, 1569, 1512, 1467, 1431, 1362, 1288, 124
4,1141,1092,1051,964,848,829,670,565c
m ^-1.¹ H-NMR (DMSO-d₆) Δ: 1.15 (6H, d, J = 7.0Hz), 2.79
(1H, quint, J = 7.0Hz), 3.39-3.60 (1H, m), 3.71
(1H, dd, J = 10.8, 7.1Hz), 3.77 (1H, dd, J = 10.8,
2.7Hz), 4.28 (2H, d, J = 5.3Hz), 4.50 (2H, s), 6.
73 (2H, d, J = 8.6Hz), 6.97 (1H, brt, J = 8.9Hz), 7.
06 (2H, d, J = 8.6Hz), 7.12 (1H, t, J = 5.3Hz), 7.18
−7.30 (1H, m), 7.27 (4H, s), 8.05 (1H, td, J = 9.
2,6.4Hz), 8.44 (1H, s). MS m / z (ESI-): 497 (M-Na)^-.

[Test Example] Hypoglycemic effect in mice
Fine blood lipid (triglyceride) lowering action test compound powder diet (F-2, CLEA Japan) to 0.0
08%, and mixed with male KKA ^y mice (6 weeks old, group 5), which are obesity and non-insulin-dependent diabetes models.
) Were given 7 days ad libitum. During this time, water was given ad libitum. Blood is collected from the tail vein under anesthesia and glucose and triglyceride (hereinafter referred to as TG) are enzymatically analyzed using plasma selected by centrifugation using L-type Wako Glu2 (Wako Pure Chemical) and L-type. Wako T
Quantification was performed using GH (Wako Pure Chemical Industries, Ltd.). The value of each test compound administration group was determined by the following formula and is shown in [Table 1]. Blood glucose lowering rate (%) = [(control group blood glucose level−test compound administration group blood glucose level) / control group blood glucose level] × 100 Blood lipid lowering effect (%) = [(control group TG value−test compound administration group TG) Value) / control group TG value] × 100

[0103]

[Table 1]

[0104]

INDUSTRIAL APPLICABILITY The present invention provides a drug having an excellent blood glucose lowering action and blood lipid lowering action, especially
An agent for preventing or treating diseases such as hyperlipidemia and glucose intolerance can be provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 275/26 C07C 275/26 C07D 207/333 C07D 207/333 (72) Inventor Yoshiaki Watanabe Fukushima, Fukushima No. 1 Tanaka, Yuno, Iizaka-cho, TOA-AIYO Co., Ltd., Fukushima Research Laboratory (72) Inventor Hidenori Yamada 2-293-3, Amanuma-cho, Saitama-shi, Saitama Prefecture TOA-AIYO Co., Ltd. Tokyo Research Laboratory (72) Inventor, Shinichi Kazayama Saitama Saitama 2-293-3 Amanuma-cho, Tokyo, Japan Toa Ayo Corporation Tokyo Research Laboratory (72) Inventor Miho Asai 2-293-3 Amanuma-cho, Saitama City, Saitama Prefecture Toa Ayo Corporation Tokyo Research Laboratory F-term (reference) 4C069 AC06 BB08 BB16 4C086 AA01 AA02 AA03 BC05 MA01 MA04 NA14 ZC33 ZC35 4C206 AA01 AA02 AA03 HA29 HA30 MA01 MA 04 NA14 ZC33 ZC35 4H006 AA01 AB27

Claims (5)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ represents a cycloalkyl group or a phenyl group which may be substituted with a halogen atom, R ² represents a hydrogen atom,
A linear or branched alkyl group having 1 to 15 carbon atoms, or an aralkyl group which may have a halogen atom on the phenyl ring, R ³ represents a hydrogen atom or a lower alkyl group; ⁴ represents a hydrogen atom, a lower alkyl group, a benzoyl group, a benzyl group, a halogen atom, an optionally substituted amino group or a monocyclic heterocyclic group, X represents a single bond or an oxygen atom, Y represents an oxygen atom or Z represents a sulfur atom;
-CH ₂ is - or -CH ₂ -O-CH ₂ - indicates, m is 0
Or an integer of 1 and n represents an integer of 1 to 4], or a pharmaceutically acceptable salt thereof. 2. A medicament comprising the ureacarboxylic acid derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. A hypoglycemic agent comprising the ureacarboxylic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A blood lipid lowering agent comprising the ureacarboxylic acid derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 5. An agent for lowering blood sugar and blood lipid comprising the ureacarboxylic acid derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.