JPH11130753A - Phenylcarboxylic derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel compound that has the action of inhibiting simultaneously fatty acid biosynthesis and cholesterol biosynthesis, can simultaneously lower both levels of triglyceride and cholesterol in blood with high safety and is useful for treatment of hyperlipemia. SOLUTION: This compound is a phenylcarboxylic acid derivative represented by formula I [A is a lower alkyl or the like; Q is formula II (R<3> and R<4> are each H or the like); B is O or the like; R<1> is H or the like; R<2> is H or the like; n is 1 or 2; m is 0 or 1] or its salt, typically 1-(4-chlorophenyl)-5- methyl-4-(4'-ethoxycarbonylphenoxy)methylpyrazole. The compound of formula I is prepared, for example, by reducing a compound of the formula: A- Q-(CH2 )n-1 -CO2 C2 H5 , for example, 1-(4-chlorophenyl)-5-methyl-4- ethoxycarbonylpyrazole, chlorinating the product and allowing the chlorinated product to react with a compound of formula III, preferably at about 0-50 deg.C for 1-12 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel phenylcarboxylic acid derivative or a pharmaceutically acceptable salt thereof. The phenylcarboxylic acid derivative or a salt thereof has an effect of simultaneously inhibiting fatty acid biosynthesis and cholesterol biosynthesis, and is useful as an antihyperlipidemic agent or the like.

[0002]

2. Description of the Related Art It has recently been revealed that the onset of coronary artery disease can be reduced by reducing serum lipid triglyceride (hereinafter abbreviated as TG) or low-density lipoprotein-cholesterol. For example, United Airline Trial using Clofibrate, a TG-lowering agent (Kra
sno, LR and Kidera, GJ: Journal of the American
Medical Association, 219 , 845, 1972) demonstrated that myocardial infarction could be significantly reduced. A West of Scotland coronary using pravastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor that lowers cholesterol
Prevention Study (West of Scotland Coronar)
y Prevention Study) (Shepherd, J., etc .: New England J
ournal of Medicine, 333 , 1301, 1995), which has been shown to reduce coronary artery disease and reduce mortality.

Therefore, if TG and cholesterol can be simultaneously and strongly reduced, it is expected that coronary artery disease and mortality can be reduced.

[0004] Conventionally, compounds that inhibit fatty acid biosynthesis to lower TG and at the same time inhibit cholesterol biosynthesis are disclosed in, for example, JP-A-2-56452, JP-A-3-275666, Kaihei 4-111
773, JP-A-4-242287, JP-A-4-243228, JP-A-5-519129, JP-A-5-507962, JP-A-5-140
No. 826, etc., but no useful drug has been reported yet.

[0005]

SUMMARY OF THE INVENTION The main object of the present invention is to:
By having the action of simultaneously inhibiting fatty acid biosynthesis and cholesterol biosynthesis, it is possible to simultaneously reduce triglyceride and cholesterol in the blood, and to obtain novel compounds that have not been published in literatures that are useful as highly safe pharmaceuticals. To provide.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, have found that a phenylcarboxylic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof is: They have found that they have both a fatty acid biosynthesis inhibitory action and a cholesterol biosynthesis inhibitory action, and have completed the present invention.

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

[0008]

Embedded image

Wherein A is a lower alkyl group; or a substituent is selected from a halogen atom, a lower alkyl group, a lower alkoxy group and an amino group in which a hydrogen atom on a nitrogen atom is substituted by a lower alkyl group. May have a group,
Represents an optionally substituted phenyl group or an optionally substituted pyridyl group, and Q is

[0010]

Embedded image

(Wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a lower alkyl group, an amino group or a pyrrole group in which a hydrogen atom on a nitrogen atom may be substituted with a lower alkyl group) , R ⁵ and R ⁶ each represent a hydrogen atom or a lower alkyl group), B represents an oxygen atom or NR ⁷ (wherein R ⁷ represents a hydrogen atom or a lower alkyl group), R ¹ represents a hydrogen atom, a halogen atom or a lower alkoxy group, R ² represents a hydrogen atom or a lower alkyl group, n represents 1 or 2, and m represents 0 or 1.
Is shown. ) Or a salt thereof.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I), A, R ² ,
Examples of the lower alkyl group represented by R ³ , R ⁴ , R ⁵ , R ^6, and R ⁷ include a linear or branched alkyl group having 1 to 4 carbon atoms, and specifically, a methyl group , Ethyl group,
Examples thereof include an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group.

Examples of the halogen atom represented by A and R ¹ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the lower alkoxy group represented by A and R ¹ include a straight-chain alkoxy group having 1 to 4 carbon atoms, and specific examples include a methoxy group, an ethoxy group, an n-propoxy group and an n-propoxy group. Butoxy groups and the like can be exemplified.

The amino group in which a hydrogen atom on the nitrogen atom represented by R ³ and R ⁴ may be substituted with a lower alkyl group includes, in addition to the amino group, one of two hydrogen atoms of the amino group. And two or more amino groups substituted with the above lower alkyl group, and specifically, N-methylamino, N, N-dimethylamino, N-ethylamino, N,
N-diethylamino, N- (n-propyl) amino,
Examples thereof include N, N-di (n-propyl) amino, N- (n-butyl) amino, and N, N-di (n-butyl) amino group.

The substituent represented by A may have a group selected from a halogen atom, a lower alkyl group, a lower alkoxy group and an amino group in which a hydrogen atom on a nitrogen atom is substituted by a lower alkyl group. An optionally substituted phenyl group or an optionally substituted pyridyl group "
Examples of the substituents of the phenyl group and the pyridyl group include the same halogen atoms, lower alkyl groups and lower alkoxy groups as described above, and amino groups in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group. be able to. As the phenyl group which may be substituted and the pyridyl group which may be substituted, more specifically, phenyl, 2-chlorophenyl, 3-chlorophenyl,
-Chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3
-Bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2
-Methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4
-Ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 4-aminophenyl, 3-aminophenyl, 2-aminophenyl, 4-
(N-methyl) aminophenyl, 3- (N-methyl) aminophenyl, 2- (N-methyl) aminophenyl,
-(N, N-dimethyl) aminophenyl, 3- (N, N
-Dimethyl) aminophenyl, 2- (N, N-dimethyl) aminophenyl, 4- (N-ethyl) aminophenyl, 3- (N-ethyl) aminophenyl, 2- (N-ethyl) aminophenyl, 4- (N, N-diethyl) aminophenyl, 3- (N, N-diethyl) aminophenyl, 2- (N, N-diethyl) aminophenyl, 4-
(N- (n-propyl)) aminophenyl, 3- (N-
(N-propyl)) aminophenyl, 2- (N- (n-
Propyl)) aminophenyl, 4- (N, N-di (n-
Propyl)) aminophenyl, 3- (N, N-di (n-
Propyl)) aminophenyl, 2- (N, N-di (n-
Propyl)) aminophenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2- (n-propoxy) phenyl, 3- (n
-Propoxy) phenyl, 4- (n-propoxy) phenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-chloro-2- Pyridyl, 4-fluoro-2-pyridyl, 4-bromo-2-
Examples thereof include a pyridyl group.

Among the phenylcarboxylic acid derivatives of the present invention represented by the general formula (I), preferred compounds are those wherein A is a halogen atom, a lower alkyl group, a lower alkoxy group or a hydrogen atom on a nitrogen atom as a substituent. May have a group selected from an amino group substituted with a lower alkyl group,
A phenyl group which may be substituted, wherein Q is

[0018]

Embedded image

[0019] (wherein, R ³ and R ⁴ are the same - or different and each represents a hydrogen atom or a lower alkyl group, R ⁵ and R
⁶ represents a lower alkyl group. ), B is an oxygen atom, R ¹ is a hydrogen atom, R ² is a hydrogen atom or a lower alkyl group, n is 1 and m is 0.

Further, a more preferred phenylcarboxylic acid derivative (I) is the above-mentioned preferred compound, wherein A is a phenyl group or a phenyl group substituted with a halogen atom, and Q is

[0021]

Embedded image

(Wherein, R ³ represents a methyl group, R ⁴ represents a hydrogen atom, and R ⁵ represents a methyl group).

Particularly preferred phenylcarboxylic acid derivatives (I) are the compounds described above as more preferred compounds, wherein A is a phenyl group or 4-chlorophenyl group, and R ² is a hydrogen atom, a methyl group or an ethyl group. It is.

Specific examples of particularly preferred phenylcarboxylic acid derivatives (I) include, for example, the following compounds.

1-phenyl-5-methyl-4- (4 '
-Methoxycarbonylphenoxy) methylpyrazole 1- (4-chlorophenyl) -5-methyl-4-
(4'-ethoxycarbonylphenoxy) methylpyrazole 1- (4-chlorophenyl) -5-methyl-4-
(4'-carboxyphenoxy) methylpyrazole 1- (4-chlorophenyl) -5-methyl-3-
(4'-methoxycarbonylphenoxy) methyl-1,
2,4-Triazole The salt of the phenylcarboxylic acid derivative represented by the above general formula (I) is not particularly limited, but may be an acid addition salt obtained by reacting a pharmaceutically acceptable acid and / or basic compound, and And / or base salts. Examples of the acid addition salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, p-acetic acid, and the like. -Salts with organic acids such as toluenesulfonic acid and methanesulfonic acid can be exemplified. Examples of the base salt include salts with alkali metals such as sodium, potassium, magnesium and calcium, alkaline earth metals and the like; salts with amines such as ammonia, methylamine, dimethylamine, piberidine, cyclohexylamine and triethylamine. Can be illustrated.

The phenylcarboxylic acid derivative (I) of the present invention
Can be produced, for example, by a synthesis route shown in the following reaction scheme.

[0027]

Embedded image

(Wherein A, Q, B, R ¹ , R ² , n and m are the same as above.) Among the phenylcarboxylic acid derivatives of the general formula (I),
But,

[0029]

Embedded image

The compound of the formula (I) can be obtained by, for example, using the known raw material (II) in the above reaction scheme, using the following steps: (Step 1) → (Step 2) → (Step 3) → (Step 1)
→ (Step 4) → (Step 5) → Route of general formula (I) or (Step 1) → (Step 6) → Route of general formula (I).

In the phenylcarboxylic acid derivative of the general formula (I), Q is

[0032]

Embedded image

The compound of the formula (III) can be prepared by, for example, using the known raw material (IV) in the above reaction scheme, using the route of (Step 3) → General formula (I), or using the known compound (III) Can be synthesized by taking the route of (Step 6) → General formula (I) using

Each step in the above reaction scheme is carried out in more detail as follows.

(Step 1) The compound represented by the general formula (III) can be produced by reducing the known compound represented by the general formula (II). The reducing agent used in this reaction is not particularly limited, but lithium aluminum hydride (LiAlH ₄ ), sodium borohydride (NaBH ₄ ), lithium borohydride (LiB
H _4), dihydrobis (2-methoxyethoxy) aluminum hydride _{(NaAlH 2 (OCH 2 CH 2} OC
H ₃ ) ₂ ), a system of sodium borohydride and a Lewis acid, a system of lithium aluminum hydride and a Lewis acid, and the like. The Lewis acid is not particularly limited, but examples thereof include aluminum chloride, zinc chloride, and boron trifluoride / diethyl etherate (BF ₃ -Et ₂ O). This reaction is usually performed in a suitable solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme. The reducing agent is used in an amount of 0.5 to 1 mol of the compound of the general formula (II).
It is appropriate to use about 3 molar equivalents. The reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 10 ° C to 50 ° C.
It is about ° C. The reaction time is about 0.1 to 6 hours,
Preferably, it is about 0.5 to 2 hours.

The compound of the general formula (III) obtained by this reaction can be used in Step 2, Step 4 and Step 6 without isolation.

(Step 2) The compound represented by the general formula (IV) is produced by reacting the compound represented by the general formula (III) with a chlorinating agent without solvent or in a suitable solvent. be able to. The solvent is not particularly limited as long as it does not participate in the reaction.Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; and halogenated hydrocarbons such as dichloromethane and chloroform. An aprotic polar solvent such as hydrogen or acetonitrile can be used. The chlorinating agent used in this reaction is not particularly limited, and examples thereof include chlorine gas, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride. The chlorinating agent is used in an amount of 1 to 1 mol of the compound of the general formula (III).
It is good to use about 10 molar equivalents, preferably about 1 to 1.5 molar equivalents. The reaction temperature may be about -10 ° C to about the boiling point of the solvent, preferably about 0 to 50 ° C. The reaction time is about 0.1 to 6 hours, preferably 0.5 to 6 hours.
About 2 hours.

The compound of the general formula (IV) obtained by this reaction can be used in Step 3 without isolation or without isolation.

(Step 3) The compound represented by the above general formula (IV) and the compound of the general formula (V) wherein R ² is lower alkyl are reacted with a basic compound in a suitable solvent to obtain A compound in which R ² is a lower alkyl in the general formula (I) can be produced. As the solvent,
There is no particular limitation as long as it does not participate in the reaction, for example, benzene, toluene, aromatic hydrocarbons such as xylene,
Ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and chloroform, and aprotic polar solvents such as acetonitrile, dimethylformamide, dimethylacetamide and dimethylsulfoxide can be used. Examples of the basic compound include organic basic compounds such as tertiary amines such as triethylamine and pyridine; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. And inorganic basic compounds such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metals such as sodium and potassium, and alkali metal hydrides such as sodium hydride. The compound represented by the general formula (V) is used in an amount of 0.1 to 1 mol of the compound of the general formula (IV).
It is good to use about 9 to 2 molar equivalents, preferably about 1 to 1.2 molar equivalents. The basic compound is used in an amount of about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound of the general formula (IV). The reaction temperature is about 0 ° C to about the boiling point of the solvent, preferably about 0 to 50 ° C. The reaction time is about 0.5 to 48 hours, preferably about 1 to 12 hours.

(Step 4) The compound represented by the general formula (VI) can be produced by reacting the compound represented by the general formula (III) with an oxidizing agent in a suitable solvent. The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, ethers such as dioxane,
Halogenated hydrocarbons such as dichloromethane and chloroform; alkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and dimethyl sulfoxide; Can be exemplified. The oxidizing agent is not particularly limited, and various oxidizing agents can be used. As an oxidizing agent using chromic acid,
For example, chromic acid, pyridinium chlorochromate, pyridinium dichromate and the like can be exemplified. In an oxidizing agent using an electrophile and dimethyl sulfoxide, for example, acetic anhydride, trifluoroacetic anhydride, phosphorus pentoxide, sulfur trioxide-pyridine complex, oxalyl chloride, etc. can be used as the electrophile. Manganese dioxide can be exemplified as an oxidizing agent using manganese. Further, an oxidizing agent such as hypochlorous acid or dimethyl sulfide-N-chlorosuccinimide can also be used. The oxidizing agent is used in an amount of about 1 to 50 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound of the formula (III). The reaction temperature is-
It is about 78 to 30 ° C. The reaction time is about 0.1 to 48 hours, preferably about 0.5 to 12 hours.
The compound of the general formula (VI) obtained by this reaction can be used in Step 5 without isolation or without isolation.

(Step 5) The compound represented by the above general formula (VI) and the compound represented by the general formula (V), wherein R ² is lower alkyl, are reacted with a reducing agent in a suitable solvent to give a general compound. Compounds of the formula (I) wherein R ² is lower alkyl can be prepared. The solvent used here is not particularly limited as long as it does not participate in the reaction,
Examples thereof include alcohols such as methanol, ethanol, propanol and isopropanol, organic acids such as formic acid and acetic acid, aromatic hydrocarbons such as benzene, toluene and xylene, and ethers such as diethyl ether, tetrahydrofuran and dioxane. One type may be used alone, or two or more types may be used in combination. Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, a pyridine borane complex, a piperidine borane complex and the like.
The compound of the general formula (V) is used in an amount of about 0.9 to 2 molar equivalents, preferably 1 to 2 mol, per 1 mol of the compound of the general formula (VI).
The reducing agent is preferably used in an amount of about 1.2 molar equivalents. The reducing agent is used in an amount of about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound of the general formula (VI).
The reaction temperature is about 0 to 50 ° C. Reaction time is 0.1 ~
It is about 8 hours, preferably about 0.5 to 2 hours.

(Step 6) The compound represented by the general formula (III) and the compound represented by the general formula (V) wherein R ² is lower alkyl is reacted with a condensing agent in a suitable solvent. And a compound of the formula (I) wherein R ² is lower alkyl. The solvent used here is not particularly limited as long as it does not participate in the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, dichloromethane, chloroform and the like. Examples thereof include halogenated hydrocarbons, alkyl ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, and aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Examples of the condensing agent include triphenylphosphine-diethylazodicarboxylate. The compound of the general formula (V) is used in an amount of about 0.9 to 2 molar equivalents, preferably about 1 to 1.2 molar equivalents, per 1 mol of the compound of the general formula (III). The condensing agent is used in an amount of about 1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound of the formula (III). The reaction temperature is about 0 ° C to 50 ° C. The reaction time is about 1 to 48 hours, preferably about 1 to 8 hours.

Further, the compound in which R ² is a hydrogen atom in the general formula (I) can be obtained by converting the compound in which R ² is a lower alkyl in the general formula (I) obtained by the above-mentioned method into an alkali in a suitable solvent. It can be produced by hydrolysis. As the solvent, water alone or a mixture of water and an organic solvent can be used. The organic solvent is not particularly limited as long as it does not participate in the reaction,
For example, aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane and chloroform; aprotons such as acetonitrile, dimethylformamide, dimethylacetamide, and dimethylsulfoxide. A polar solvent and the like can be exemplified. Examples of the alkali compound include alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and inorganic metals such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Examples thereof include an alkali compound. The alkali compound is used in an amount of about 0.1 to 10 molar equivalents, preferably about 1 to 2 molar equivalents, per 1 mol of the compound in which R ² is lower alkyl in the general formula (I). The reaction temperature is about 0 ° C. to the boiling point of the solvent. Reaction time is 0.5-4
It is about 8 hours, preferably about 1 to 12 hours.

The phenylcarboxylic acid derivative (I) of the present invention obtained by the above method can be used after isolation and purification by usual separation means, for example, column chromatography, recrystallization and the like.

The phenylcarboxylic acid derivative (I) or a salt thereof of the present invention thus obtained has a fatty acid biosynthesis inhibitory action and a cholesterol biosynthesis inhibitory action. It is useful as an agent for preventing and treating sclerosis, an antiobesity agent, a drug for reducing coronary artery disease and the like.

[0046]

EXAMPLES Reference examples, examples and test examples are shown below.
The present invention will be described in more detail.

Reference Example 1 1- (4-chlorophenyl) -5-methyl-4-ethoxy
Synthesis of cyclocarbonylpyrazole N, N-dimethylformamide dimethyl acetal (51.6 g, 0.39 mol) was added to ethyl acetoacetate (51.6 g, 0.39 mol).
(5.7 g, 0.46 mol) was added dropwise at 100 ° C.
The mixture was heated and stirred for an hour. After the reaction, the mixture was cooled, concentrated under reduced pressure, and the residue obtained was distilled under reduced pressure to give 63.7 g of ethyl N, N-dimethylaminomethyleneacetoacetate (yield: 8).
7%: 156 ° C./0.2 Torr). This compound (1
2.2 g, 66.3 mmol), 4-chlorophenylhydrazine hydrochloride (11.8 g, 66.3 mmol),
It was added to a mixed solution of ethanol (100 ml) and acetic acid (1.9 g), and the mixture was heated and stirred at 60 ° C. for 12 hours. After cooling, the residue obtained by concentration was extracted with ethyl acetate-water. The organic layer was washed with 1N hydrochloric acid, water, 1M aqueous potassium carbonate, brine, and water, and then dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure is
n-Hexane (500 ml) was added, and the precipitated crystals were collected by filtration to obtain 130 g (yield 74%) of the title compound.

Reference Example 2 1- (4-chlorophenyl) -4-ethoxycarbonyl
Synthesis of pyrazole ethoxycarbonylmalonaldehyde (7.2 g, 50
mmol) in ethanol (50 ml) was added dropwise a solution of 4-chlorophenylhydrazine (8.5 g, 60 mmol) in diethyl ether (200 ml) under ice-cooling. After stirring at room temperature for 3 hours, the solvent was distilled off, and ethanol was added to the obtained residue for crystallization. The precipitated crystals were collected by filtration to obtain 8.3 g (yield 66%) of the title compound.

Reference Example 3 1-chlorophenyl-5-dimethylamino-4-ethoxy
Synthetic ethoxymethylene cyanoacetate ethyl ester of cyclocarbonylpyrazole (1.69
g, 10 mmol) in ethanol (50 ml).
4-chlorophenylhydrazine (1.7 g, 12 mmol
l) was added and the mixture was stirred under reflux for 12 hours. After the reaction, diethyl ether was added to the residue obtained by distilling off the solvent to cause crystallization. The precipitated crystals were collected by filtration and 1-chlorophenyl-5-amino-4-ethoxycarbonylpyrazole.
2 g (82% yield) were obtained. This compound (1.3 g, 5
mmol) in tetrahydrofuran solution (20 ml),
Under ice cooling, 60% -sodium hydride (0.44 g) was added and stirred. After stirring for 30 minutes, methyl iodide (1.7 g,
12 mmol) and stirred at room temperature for 12 hours. After the reaction, ethyl acetate-aqueous sodium hydrogen carbonate solution was added for extraction. The organic layer was washed with brine and water, and dried over magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was recrystallized from ether to give 1.4 g (yield 95%) of the title compound.

Reference Example 4 1-chlorophenyl-3-dimethylamino-4-ethoxy
Synthesis of Cycarbonylpyrazole In a solution of phenylhydrazine (10.8 g, 0.1 mol) in xylene (80 ml), benzaldehyde (10.
6 g, 0.1 mol) and stirred at room temperature. After crystal deposition, ethoxymethylene cyanoacetate ethyl ester (2
(0.3 g, 0.12 mol) and stirred under reflux for 3 days. After dissolving once, the precipitated crystals were collected by filtration and washed with diethyl ether to obtain white crystals (25 g). The crystals were added to a mixed solvent of concentrated hydrochloric acid (10 ml) and ethanol (60 ml), and the mixture was stirred under reflux for 15 minutes. After the reaction, 10% aqueous potassium hydroxide (200 ml) was added to the residue obtained by evaporating the solvent under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with brine and water, and dried over magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure is
Recrystallization from ether gave 1-chlorophenyl-3-amino-4-ethoxycarbonylpyrazole (7.8 g, yield 37%). This compound (6.2
g, 30 mmol) in tetrahydrofuran (50 m
l), 60% -sodium hydride (2.6) under ice-cooling
g) was added and stirred. After stirring for 30 minutes, methyl iodide (1
(0.2 g, 72 mmol) and stirred at room temperature for 12 hours. After the reaction, ethyl acetate-aqueous sodium hydrogen carbonate solution was added for extraction. The organic layer was washed with brine and water, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 7.0 g (yield 90%) of the title compound.

Reference Example 5 1- (4-chlorophenyl) -5-methyl-4-hydro
Synthesis of xymethylpyrazole lithium aluminum hydride (1 g, 26.4 mmol
In a solution of 1) in tetrahydrofuran (50 ml) at room temperature, 1- (4-chlorophenyl) -5- obtained in Reference Example 1 was added.
Methyl-4-ethoxycarbonylpyrazole (10 g,
37.8 mmol) of tetrahydrofuran (50 ml)
The solution was added dropwise. After stirring at room temperature for 30 minutes, the reaction solution was
After adding little by little into ice-cooled diluted hydrochloric acid, ethyl acetate was added for extraction. The organic layer was washed with brine and water, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was added with 20 ml of diethyl ether, and the precipitated crystals were collected by filtration to give 6.46 g of the title compound (yield 7).
7%).

Reference Example 6 1- (4-Chlorophenyl) -3-hydroxymethyl-
Synthesis of 5-methyl-1,2,4-triazole Lithium aluminum hydride (319 mg, 8.4 mm
ol) in a solution of tetrahydrofuran (15 ml) under ice-cooling with 1- (4-chlorophenyl) -3-ethoxycarbonyl-5-methyl-1,2,4-triazole (3.1).
9 g, 12 mmol) of tetrahydrofuran (15 m
l) After the solution was added dropwise and stirred for 2 hours, the reaction solution was added little by little to ice-cooled 1N hydrochloric acid, and then ethyl acetate was added for extraction. The organic layer was washed with brine and water, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was added with 20 ml of diethyl ether,
The precipitated crystals were collected by filtration, and the title compound (1.5 g, yield 5) was obtained.
7%).

Example 1 1- (4-chlorophenyl) -5-methyl-4- (4 '
- methoxycarbonyl Fe phenoxy) obtained in Reference Example 5 methyl pyrazole (Compound 1) 1- (4-chlorophenyl) -5-
Methyl-4-hydroxymethylpyrazole (6 g, 27
mmol) in tetrahydrofuran (25 ml).
Under ice cooling, thionyl chloride (3.2 g, 27 mmol
A solution of l) in tetrahydrofuran (5 ml) was added dropwise.
After stirring at room temperature for 30 minutes, the reaction solution was added little by little to ice-cooled saturated sodium bicarbonate water, and then ethyl acetate was added for extraction. After washing the organic layer with saline and water,
It was dried over anhydrous magnesium sulfate. After filtration, 1- (4-chlorophenyl) -5-methyl-4-chloromethylpyrazole obtained by concentration under reduced pressure was used for the next reaction without purification. A solution of this crude product in dimethylformamide (10 ml) was added to a dimethylformamide mixed solution (70 ml) of p-hydroxybenzoic acid methyl ester (4.1 g, 27 mmol) and potassium carbonate (4.47 g, 32.3 mmol). In addition, 2 at 25 ° C
Stir for 4 hours. After the reaction, ethyl acetate was added, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. In the residue obtained, water:
Methanol (40 ml, 1: 1) was added, and the mixture was heated and stirred, cooled with ice, and the obtained crystals were collected by filtration and dried under reduced pressure to obtain 6.4 g (yield 67%) of the title compound.

[0054] Melting point: 142-143 ° C. (Example 2) 1- (4-chlorophenyl) -5-methyl-4- (N-
Methyl-N-4'-ethoxycarbonylphenyl) ami
Synthesis of Nomethylpyrazole (Compound 16) 1- (4-chlorophenyl) -5 obtained in Reference Example 5
Methyl-4-hydroxymethylpyrazole (10 g, 4
4.9 mmol) in a solution of chloroform (300 ml) in activated manganese dioxide (100 g, 1.15 mol).
Was added and stirred at room temperature. After the reaction, the insolubles were filtered through celite, and the filtrate was concentrated to obtain 1- (4-chlorophenyl) -5-methyl-4-formylpyrazole, which was used for the next reaction without purification. Acetic acid (1 ml) and p-aminobenzoic acid ethyl ester (7.4 g, 44.9 m) were added to an ethanol solution (30 ml) of this crude product.
mol), and sodium cyanoborohydride (2.8 g, 44.9 mmol) was added little by little under ice-cooling.
After the reaction, 97% aqueous formalin (5 ml) was further added, and sodium cyanoborohydride (2.8 g, 4 g) was added.
4.9 mmol) were added in small portions. After the reaction, the residue obtained by concentration under reduced pressure was extracted by adding ethyl acetate-aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and water, and dried over magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was recrystallized from ethanol to obtain 11.2 g (yield 65%) of the title compound.

[0055] Melting point: 79-80 ° C (Example 3) 1- (4-pyridyl) -5-methyl-4- (4'-methoate)
Xycarbonylphenoxy) methylpyrazole (compound
1- (4-pyridyl) obtained in the same manner as in Synthesis Reference Example 5 of 7 )
-5-methyl-4-hydroxymethylpyrazole (1.
7 g, 8.99 mmol) and p-hydroxybenzoic acid methyl ester (1.67 g, 11 mmol)
l) in tetrahydrofuran (50 ml) was added to a solution of triphenylphosphine (2.35 g, 8.99 mmol).
l), diethyl azodicarboxylate (3.9 ml,
40% toluene solution, 9 mmol) and add
Stir for 4 hours. After the reaction, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 1: 4). The residue obtained by concentrating the corresponding fraction was crystallized from diethyl ether to give 1.2 g of the title compound (41% yield).
I got

[0056] Melting point: 171-172 ° C. (Example 4) Compounds 2 to 6, 8 to 15 and 17 to 19 shown in the following table were synthesized in the same manner as in Examples 1 to 3.

Example 5 1- (4-chlorophenyl) -5-methyl-3- (4 '
-Methoxycarbonylphenoxy) methyl-1,2,4
Synthesis of 1- (4-chlorophenyl) -3- obtained from Reference Example 6 of triazole (compound 29)
Hydroxymethyl-5-methyl-1,2,4-triazole (2.24 g, 10 mmol) and p-hydroxybenzoic acid methyl ester (1.52 g, 10
mmol) in a solution of tetrahydrofuran (30 ml).
Triphenylphosphine (3.15 g, 12 mmo
l), diethyl azodicarboxylate (5.22 g,
(40% toluene solution, 12 mmol) was added and the mixture was stirred at room temperature for 14 hours. After the reaction, the residue obtained by concentration under reduced pressure was extracted with ethyl acetate. The organic layer was saline,
After washing with water, it was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate: n-hexane =
1: 1). The residue obtained by concentrating the corresponding fraction was crystallized from diethyl ether,
2.6 g (74% yield) of the title compound was obtained.

[0058] Melting point: 139-140 ° C. (Example 6) 2- (4-chlorophenyl) -4- (2- (4′-method)
(Xycarbonylphenoxy) ethyl) thiazole (compound
Synthesis of compound 32) 2- (4-chlorophenyl) -4- (2-hydroxyethyl) thiazole (1 g, 4.18 mmol) and p-hydroxybenzoic acid methyl ester (699)
mg, 4.59 mmol) of tetrahydrofuran (50
ml) solution, triphenylphosphine (1 g, 5.
02 mmol), diethyl azodicarboxylate (2.2 ml, 40% toluene solution, 5.02 mmol)
l) was added and the mixture was stirred at room temperature for 14 hours. After the reaction, the residue obtained by concentration under reduced pressure was extracted with ethyl acetate and water. The organic layer was washed with a 1N-NaOH aqueous solution and a saturated saline solution, and then dried with magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was crystallized from methanol to give 1.1 g (yield 70%) of the title compound.

[0059] Melting point: 155-156 ° C (Example 7) 2- (4-chlorophenyl) -4- (4'-methoxyca)
Rubonylphenoxy) methylthiazole (compound 31)
Synthesis of p-chlorothiobenzamide (5 g, 29.1 mmol)
l) and α, α'-dichloroacetone (3.7 g, 29.
(1 mmol) in acetone (50 ml) was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration and the crude product washed with acetone was refluxed and stirred with methanol (50 ml) for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 2-
The crude product of (4-chlorophenyl) -4-chloromethylthiazole was used for the next reaction without purification. A solution of this crude product in dimethylformamide (10 ml) was added to p-hydroxybenzoic acid methyl ester (3.8
g, 25 mmol) and potassium carbonate (5.2 g, 37.
7 mmol) mixed solution of dimethylformamide (70 m
l) and stirred at room temperature for 24 hours. After the reaction, the residue concentrated under reduced pressure was extracted with ethyl acetate and water.
The organic layer was washed with 1N aqueous NaOH, water and brine, and dried over magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was crystallized from methanol to obtain 6.2 g (yield 61%) of the title compound.

[0060] Melting point: 118-120 ° C. (Example 8) Compound 33 shown in the following table was synthesized in the same manner as in Examples 6 and 7.

Example 9 1- (4-chlorophenyl) -5-methyl-4- (4 '
-Carboxyphenoxy) methylpyrazole (Compound 2
Synthesis of 0) In a solution of the compound of Example 1 (5.1 g, 14.9 mmol) in methanol: dioxane (200 ml, 1: 1), 0.2N-NaOH aqueous solution (100 ml) was added.
The mixture was heated and stirred at 70 ° C. for 5 hours. After the reaction, the solvent was distilled off, cold diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and water, and dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentration under reduced pressure was added with 20 ml of diethyl ether, and the precipitated crystals were collected by filtration and dried to give 4.99 g (yield 97.3%) of the title compound.

[0062] Melting point: 201-202 ° C. (Example 10) Compounds 21 to 28, 30, 34 and 35 shown in the following table were synthesized in the same manner as in Example 9.

[0063]

[Table 1]

[0064]

[Table 2]

[0065]

[Table 3]

[0066]

[Table 4]

[0067]

[Table 5]

[0068]

[Table 6]

[0069]

[Table 7]

[0070]

[Table 8]

[0071]

[Table 9]

[0072]

[Table 10]

[0073]

[Table 11]

[0074]

[Table 12]

[0075]

[Table 13]

[0076]

[Table 14]

[0077]

[Table 15]

[0078]

[Table 16]

[0079]

[Table 17]

[0080]

[Table 18]

Test Example The effect on the sterol and fatty acid biosynthesis system using rat liver slices and the effect of lowering triglyceride and cholesterol using rats were examined by the following methods.

Test Example 1 Effect on sterol and fatty acid biosynthesis system using rat liver slices (in vitro test) A test was carried out according to the following procedure with reference to the following literature.

Endo, A., Tsujita, Y., Kuroda, M. and T
anzawa, K., Eur. J. Biochem., 77 , 31-36 (1977).

That is, male S. D. Rat (weight about 200)
g) Immediately after the decapitation to death, the liver was removed and perfused sufficiently with ice-cooled Krebs-Ringer Bicarbonate buffer. [1- ¹⁴ C] acetate (74kBq / 2
liver sections in 1 ml of Krebs-Ringer bicarbonate buffer containing test compounds prepared at various concentrations.
mg in a mixed gas of 95% O ₂ -5% CO _2.
The reaction was performed at 7 ° C. for 2 hours. After cooling, petroleum ether 2
The sterol fraction was extracted by shaking, and concentrated to 1%.
1 ml of digitonin solution was added. After standing, the sterol fraction obtained as a sediment by centrifugation was washed several times with an organic solvent, dissolved in 1 ml of acetic acid, and radioactivity was determined. The radioactivity of the control group excluding the test compound was 50%.
The concentration (IC ₅₀ ) of the test compound that inhibited the% was determined.

The radioactivity of the fatty acid fraction obtained from the lower layer of petroleum ether in the above operation by hydrochloric acid treatment was determined in the same manner.

The results obtained are shown in the table below.

[0087]

[Table 19]

Test Example 2 Triglyceride and cholesterol lowering action using rats (in vivo test) D. Rats (5 weeks old, 8 rats)
A solution of 30 mg / 5 ml of a 0.5% aqueous solution of hydroxypropylmethylcellulose / kg was administered by oral gavage for 7 consecutive days. On the other hand, to the control group (male SD rats, 5 weeks old, 8 rats), only the hydroxypropyl methylcellulose aqueous solution was similarly administered. 16 hours after the final administration, blood was collected from the abdominal vena cava under ether anesthesia, and serum lipid items (total cholesterol (TC), high-density lipoprotein cholesterol (HDL
C), phospholipid (PL), triglyceride (TG))
Was measured.

The ultra-low density lipoprotein cholesterol ((V) LDL · C), the arteriosclerosis index (AI) and the rate of change were calculated by the following equations.

(V) LDL · C = TC−HDL · C AI = (V) LDL · C / HDL · C Rate of change (%) = {(actual value of drug administration group / actual value of control group) −1 } × 100 The obtained results are shown in the following table.

[0091]

[Table 20]

[0092]

The phenylcarboxylic acid derivative (I) of the present invention or a salt thereof has a fatty acid biosynthesis inhibitory action and a cholesterol biosynthesis inhibitory action as shown in the above in vitro test results. As shown in the in vivo test results, blood triglyceride (TG) and ultra-low-density lipoprotein cholesterol ((V) LDL-C, bad cholesterol) were simultaneously reduced, while high-density lipoprotein cholesterol ( HDL · C, good cholesterol) can be reduced, and the arteriosclerosis index can be reduced. Therefore, the phenylcarboxylic acid derivative (I) or a salt thereof of the present invention is useful as a drug for treating hyperlipidemia, preventing and treating arteriosclerosis, an antiobesity drug, reducing coronary artery disease and the like.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 403/04 207 C07D 403/04 207 417/04 213 417/04 213 // A61K 31/41 A61K 31/41 31/415 ADN 31/415 ADN 31/425 31/425 31/44 AED 31/44 AED (72) Inventor Akira Yamamoto 1-35-1 Fudohoncho, Tokushima City, Tokushima Prefecture (72) Inventor Haruo Yamada 6-Chome Sumiyoshi, Tokushima City, Tokushima 6-33-503 (72) Inventor Hidekazu Miyake 5-4 Nakashiki, Ushikaino Higashi Ushikaino, Matsushige-cho, Itano-gun, Tokushima

Claims (3)

[Claims] 1. A compound of the general formula (I) (In the formula, A is a lower alkyl group; or as a substituent, a group selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and an amino group in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group. Represents an optionally substituted phenyl group or an optionally substituted pyridyl group, wherein Q is (Wherein, R ³ and R ⁴ are the same or different and are each a hydrogen atom,
A lower alkyl group, an amino group or a pyrrole group in which a hydrogen atom on a nitrogen atom may be substituted with a lower alkyl group, and R ⁵ and R ⁶ each represent a hydrogen atom or a lower alkyl group. ) Indicates, B is oxygen atom or NR ⁷ (wherein, R ⁷ represents a a hydrogen atom or a lower alkyl group.), R ¹ represents a hydrogen atom, a halogen atom or a lower alkoxy group, R ² Represents a hydrogen atom or a lower alkyl group, n represents 1 or 2, m represents 0 or 1. Or a salt thereof. 2. A may have, as a substituent, a group selected from a halogen atom, a lower alkyl group, a lower alkoxy group and an amino group in which a hydrogen atom on a nitrogen atom is substituted by a lower alkyl group. A phenyl group which may be substituted, wherein Q is Wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom or a lower alkyl group, and R ⁵ and R ⁶ each represent a lower alkyl group; and B is an oxygen atom; R
¹ is a hydrogen atom, R ² is a hydrogen atom or a lower alkyl group, n is 1, phenyl carboxylic acid derivative or its salt according to claim 1, wherein m is 0. 3. A is a phenyl group or a phenyl group substituted with a halogen atom, and Q is (Wherein, R ³ represents a methyl group, R ⁴ represents a hydrogen atom,
R ⁵ represents a methyl group. 3. The phenylcarboxylic acid derivative or a salt thereof according to claim 2, wherein