JPH09124631A - Benzofuran derivative and medicine composition containing it - Google Patents

Abstract

PURPOSE: To obtain a new benzofuran derivative having ω-(4-phenylpiperadinyl) acyl side chain on the benzene ring side, useful as a medicine capable of improving a ratio causing cardiac infarction or unexpected death, especially an antihypertensive agent.

CONSTITUTION: This benzofuran derivative is represented by formula I [R¹ is H, a halogen, an alkyl or an N'-1-6C alkylcarbohydrazonomethyl; X is H, a halogen, a 1-6C alkyl or a 1-6C alkoxy; (n) is 0-10], e.g. 5-[4-(2-methoxyphenyl) piperazinylcarbonyl]benzofuran. The compound of formula I, e.g. the compound of formula I in which (n) is 0 is obtained by reacting a bromophenol of formula II with a bromoacetoaldehydediethylacetal of formula III under alkaline conditions, cyclizing the resultant compound to afford bromobenzofuran of formula IV, changing bromo group to cyano group to provide cyanobenzofuran, hydrolyzing the compound to afford a carboxylic acid of formula V and finally condensing the carboxylic acid of formula V with N-phenylpiperazine.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzofuran derivative, and a pharmaceutical composition containing the same, and more particularly to a lipid-lowering antihypertensive agent.

[0002]

2. Description of the Related Art Various medicines for circulatory organs containing a benzofuran derivative as an active ingredient have been developed. Among them, there are some reports regarding a benzofuran derivative-based antihypertensive agent (hypotensive agent) having a 4-phenylpiperazinyl group.

For example, JP-A-60-202872, JP-A-61-218582 and the like disclose an α-blocking action and C
The benzofuran derivative represented by the general formula of the following Chemical Formula 2 is described as an antihypertensive agent having an antagonistic effect.

[0004]

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(In the formula, R represents an acetyl group, a carbamoyl group, a cyano group, a lower alkoxycarbonyl group, a carboxyl group, or a 1-hydroxyethyl group, and Y represents a hydrogen atom, a lower alkoxy group, a lower alkyl group, or a halogen. Further, JP-A-64-70480 also describes a benzofuran derivative including a kerinone derivative having a 4-phenylpiperazinyl group as an antihypertensive agent having a Ca antagonistic action.

[0006] Although hypertension is an important risk factor for cardiovascular diseases, it is now relatively easy to reduce blood pressure in hypertensive patients by developing various antihypertensive agents such as those mentioned above. However, the current situation is that even if an antihypertensive agent is administered, the rate of myocardial infarction and sudden death is not so much improved.

Therefore, development of an antihypertensive agent capable of improving these rates has been awaited. On the other hand, as a compound similar to the compound of the present invention, for example, a substance having a central action,
Indian J. Chem., Sect. B, 28B (5), 385 (1989) or Acta.
2 of benzofuran ring in Pol. Pharm., 44 (6), 497 (1987)
There are some known compounds having a ω- (4-phenylpiperazinyl) acyl side chain on the-or 3-position, that is, on the furan ring side, but the 4-, 5-, 6-, or 7-positions, That is, a compound having a ω- (4-phenylpiperazinyl) acyl side chain on the benzene ring side is not known.

[0008]

SUMMARY OF THE INVENTION The present invention has been made from the above point of view, and a benzene ring side which can be effectively used as a drug capable of improving the rate of myocardial infarction and sudden death, particularly as an antihypertensive agent. ω- (4-phenylpiperazinyl)
An object is to provide a novel benzofuran derivative having an acyl side chain.

[0009]

[Means for Solving the Problems] The present inventors have noticed that it is necessary to develop an antihypertensive agent having a lipid lowering effect in order to improve the rate of myocardial infarction and sudden death. As a result of repeated improvement studies on a benzofuran derivative known as an agent, ω- (4 at the benzene ring side of the benzofuran ring, that is, at the 4-, 5-, 6-, or 7-position.
A novel benzofuran derivative having a -phenylpiperazinyl) acyl side chain has a ω- (4-phenylpiperazinyl) acyl side chain in the conventional furan ring side of the benzofuran ring, i.e. in the 2- or 3-position. The present invention has been completed by finding that it also has a lipid-lowering action that was not found at all in benzofuran derivative antihypertensive agents.

That is, the present invention provides a benzofuran derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[0011]

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(Wherein R ¹ is a hydrogen atom, a halogen atom,
Represents a C ₁ -C ₆ alkyl group or an N′-C ₁ -C ₆ alkylcarbohydrazonomethyl group, X represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or C ₁ -C ₆ And an n represents an integer of 0 to 10. The present invention also provides a pharmaceutical composition containing a benzofuran derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which is particularly useful as a hypolipidemic antihypertensive agent. is there.

Hereinafter, the present invention will be described in detail. The benzofuran derivative of the present invention is a compound represented by the above general formula (I), and details of the group to which the substituent R ¹ ; X in the general formula (I) is bonded are as follows.

<Regarding Substituent R ¹ > R ¹ is a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or N′-C _1- .
It represents a C ₆ alkylcarbohydrazonomethyl group, and among them, a hydrogen atom, a halogen atom, or an N′-C ₁ -C ₆ alkylcarbohydrazonomethyl group is preferable.

When R ¹ is a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkyl group, the benzene ring side of the benzofuran ring, that is, 4-, 5-,
Substitution at the 6- or 7-position is preferred. In addition, R ¹ is represented by an N′-C ₁ -C ₆ alkylcarbohydrazonomethyl group [—CH═NNHCOR ² (R ² is a C ₁ -C ₆ alkyl group). ], The furan ring side of the benzofuran ring, that is, the 2- or 3-position of the benzofuran ring is preferably substituted, and further the 2-position of the benzofuran ring is more preferably substituted.

When R ¹ is a halogen atom, the halogen atom may be a chlorine atom, a bromine atom or a fluorine atom, and among them, a chlorine atom is preferable. R ¹ is C ¹ ~
When it is a C ⁶ alkyl group, the alkyl group includes a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group. , N-hexyl group and the like.

[0017] When R ¹ is a N'-C ₁ ~C ₆ alkyl carboxymethyl hydrazonomethyl group, the alkyl group of the C ₁ -C _6, as in the case of R ^1, a methyl group, an ethyl radical, n
-Propyl group, i-propyl group, n-butyl group, sec
-Butyl group, tert-butyl group, n-pentyl group, n
A hexyl group and the like.

<Substituent X> When X is a halogen atom, the halogen atom is a chlorine atom, a bromine atom,
Alternatively, it may be either a fluorine atom, but a chlorine atom is preferred.

When X is a C ₁ -C ₆ alkyl group, the alkyl group may be a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group or a tert group. -Butyl group, n-pentyl group, n-hexyl group and the like.

When X is a C ₁ -C ₆ alkoxy group,
Examples of the C ₁ -C ₆ alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group and an n-hexoxy group. Groups and the like.

X is o-, relative to the piperazinyl group.
It may be substituted at either the m- or p-position, but it is preferably substituted at the o-position. n is 0 to 1
It is an integer of 0, preferably 0, 1 or 2, and more preferably 0 or 2.

A substituent to which X is bonded, that is, the following chemical formula 4
The piperazinylcarbonyl group of is a benzofuran ring 4
It may be substituted at any of the-, 5-, 6-, or 7-positions, but among them, it is preferable that the 5-, 7-position is substituted.

[0023]

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In the present invention, the salt of the benzofuran derivative represented by the general formula (I) is a pharmaceutically acceptable salt of a mineral acid or an organic acid, for example, hydrochloride, sulfate, nitrate, acetate or oxalate. , Tartrate, citrate, lactate and the like.

The benzofuran derivative represented by the general formula (I) of the present invention can be produced, for example, by the following methods A to D. In addition, in each method, the amount of the reactant directly involved in the reaction is not described, but all of them are stoichiometric amounts.

<Method for Producing Compound of General Formula (I)> (1) Method A: This method is represented by the following chemical formula 5.
Bromophenol (II) and bromoacetaldehyde diethyl acetal (III) are reacted under alkaline conditions, the reaction product is cyclized to bromobenzofuran (IV), and the bromo group of bromobenzofuran is converted to a cyano group to produce a cyano group. This is a method of obtaining benzofuran (V), then hydrolyzing this to give carboxylic acid (VI), and finally condensing this carboxylic acid with N-phenylpiperazine to obtain target compound (VII).

[0027]

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(In the formula, R ¹ is a hydrogen atom, a halogen atom,
Alternatively, it represents a C _{1 to} C ₆ alkyl group, and X represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, or a C _{1 to} C ₆ alkoxy group. ) In this method, first, bromobenzofuran (IV)
It is manufactured in two stages.

In the first step, bromophenol (II) is reacted with bromoacetaldehyde diethyl acetal (III) for acetalization. This reaction is usually performed in an organic solvent in the presence of a base. Examples of the base used here include sodium hydroxide, potassium hydroxide, thorium carbonate, potassium carbonate, sodium hydride, triethylamine and the like. Examples of the organic solvent include acetonitrile, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, ethanol and the like.

The reaction temperature and reaction time in the first step are not particularly limited, and usually 15 at any temperature from ice cooling to reflux.
The reaction may be performed for about minutes to 24 hours. This reaction product is used for the next reaction after being isolated or purified by an ordinary treatment means such as extraction with a solvent, separation by chromatography, crystallization, distillation and the like. In addition, although not particularly described, the reaction products obtained in the following steps or steps are to be isolated or purified by the same treatment means (methods B to
The same applies to D).

In the second step, the obtained reaction product (acetal) is cyclized in a suitable organic solvent or neat in the presence of an acid catalyst. As the organic solvent, for example, benzene, toluene, xylene, etc. are usually used.

The reaction temperature and reaction time of the second step are not particularly limited, and usually, the reaction may be carried out at any temperature from ice cooling to 300 ° C. for about 15 minutes to 24 hours. Next, cyanobenzofuran (V) is obtained by reacting this bromobenzofuran (IV) with a metal cyanide compound in a suitable organic solvent or in a neat state. Here, as the metal cyanide compound,
For example, potassium cyanide, sodium cyanide, copper cyanide and the like can be mentioned, and among them, copper cyanide is preferable.
Examples of the organic solvent include pyridine, quinoline, N, N
-Dimethylformamide, N-methylpyrrolidone, hexamethylphosphoramide (HMPA) and the like can be used.

The reaction temperature and reaction time in this step are not particularly limited, and usually, the reaction may be carried out at any temperature from ice cooling to 300 ° C. for about 15 minutes to 24 hours. Next, the carboxylic acid (VI) is obtained by hydrolyzing the cyanobenzofuran (V) with an acid or an alkali. Examples of the acid used here include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid, formic acid and the like, and examples of the alkali include sodium hydroxide, potassium hydroxide, barium hydroxide and the like. These acids or alkalis include water, lower alcohols (methanol, ethanol, isopropanol, propanol, etc.), dioxane, tetrahydrofuran, organic acids (however, in the case of acid hydrolysis, for example, carboxylic acid, sulfonic acid, etc.) and mixtures thereof. Used by dissolving in a solvent.

The reaction temperature and reaction time in this step are not particularly limited, and usually 1 at any temperature from ice cooling to reflux.
The reaction may be performed for about 5 minutes to 24 hours. The final target compound, 4-phenylpiperazinylcarbonylbenzofuran (VII), is obtained by condensing this carboxylic acid (VI) with N-phenylpiperazine.

In this condensation reaction, the carboxylic acid (VI) is once converted into a carboxylic acid derivative such as an acid chloride, an acid anhydride, an ester or an amide and then reacted with an amine, or directly dehydrated with an amine. By doing so.

(2) Method B: In this method, bromosalicylaldehyde (VIII) and diethyl bromomalonate (IX) are reacted under alkaline conditions and then hydrolyzed to bromo as shown in the following chemical formula 6. After obtaining the benzofurancarboxylic acid (X), the bromo group of this carboxylic acid is converted to a cyano group, and further decarboxylated to give a cyano compound (XI),
Then, this is a method similar to the final step of Method A to obtain the same target compound (VII) as Method A.

[0037]

[Chemical 6]

(In the formula, R ¹ is a hydrogen atom, a halogen atom,
Alternatively, it represents a C _{1 to} C ₆ alkyl group, and X represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, or a C _{1 to} C ₆ alkoxy group. ) In this method, first, carboxylic acid (X) is bromosalicylaldehyde (VIII) and diethyl bromomalonate (IX).
And are usually reacted in an organic solvent in the presence of a base,
It is obtained by hydrolyzing the reaction product (carboxylic acid ester). The base, organic solvent, and reaction conditions used here are the first step in Method A (bromobenzofuran (I
It may be the same as the first step (reaction of bromophenol and bromoacetaldehyde diethyl ether) in the production step (V).

Next, the carboxylic acid ester is hydrolyzed with an acid or an alkali to give a carboxylic acid (X). The acid or alkali used in this hydrolysis reaction, the solvent, and the reaction conditions may be the same as those in the hydrolysis reaction of Method A above.

Next, cyanobenzofuran (V) can be produced by the same method as the conversion reaction of the bromo benzofuran carboxylic acid (X) from the bromo compound (IV) to the cyano compound (V) in the above method A. . However, in the conversion reaction in the case of Method B, the decarboxylation reaction occurs at the same time and the desired cyano compound (V) is obtained. The metal cyano compound, organic solvent, and reaction conditions used in the conversion reaction of Method B may be the same as those in Method A.

The subsequent steps until the final target compound (VII) is obtained are the steps of producing benzofurancarboxylic acid (VI) by the hydrolysis reaction of cyanobenzofuran (V) of Method A, and the carboxylic acid (VI) and N- It is carried out in the same manner as in the production process of 4-phenylpiperazinylcarbonylbenzofuran (VII) by condensation reaction with phenylpiperazine.

(3) Method C: In this method, as shown in Chemical formula 7 below, benzofuran-2 obtained by reacting bromosalicylaldehyde (VIII) with diethyl bromomalonate (IX) under alkaline conditions. -The bromo group of ethyl carboxylate (XI) is converted to a cyano group to give a cyano compound (XII), the 2-carboxylic acid ester of this compound is derivatized to the 2-aldehyde derivative (XIII), and then ethylene glycol, etc. And acetalized with acetal (XI
V) and then hydrolyze the cyano group to produce a carboxylic acid (X
IV), which is then amidated with N-phenylpiperazine to give an amide (XV), and then the acetal group of this amide is hydrolyzed to an aldehyde (XVI), which is then treated with a suitable hydrazine compound to give the desired compound. Hydrazide (XVI
I) is the way to get.

[0043]

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(Wherein R ² represents a C _{1 to} C ₆ alkyl group, X represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, or a C _{1 to} C ₆ alkoxy group, Further, Z represents an ethylene or propylene chain which may be substituted, respectively.) In this method, the cyclization and hydrolysis in the first step are the same as those in the first step of Method B (step of producing bromobenzofurancarboxylic acid (X)). It can be done in a similar way. The cyanation in the second step can be carried out by the same method as the step of converting the bromo group to a cyano group described in methods A and B.

The 2-carboxylic acid ester (XII) thus obtained can be converted into the 2-aldehyde derivative (XIII) by the usual method as described below. For example, an ester (XII) is reduced to a metal alkoxide with a metal hydride and then directly hydrolyzed to an aldehyde (XIII), or is once reduced to an alcohol with a metal hydride and then oxidized to an aldehyde (XIII). Alternatively, it can be hydrolyzed to a carboxylic acid, then reduced to an alcohol with a metal hydride and further oxidized to an aldehyde (XIII). Examples of the metal hydride used here include lithium aluminum hydride, sodium aluminum hydride, lithium trimethoxy aluminum hydride, lithium triethoxy hydride aluminum, and aluminum hydride. These metal hydrides can be used in organic solvents such as tetrohydrofuran. In the method of reducing a carboxylic acid to an alcohol like the method of 1, it is preferable to use lithium aluminum hydride in tetrohydrofuran. In the method of passing through a carboxylic acid like the other method, it may be advantageous to induce the carboxylic acid into a mixed acid anhydride and then reduce the alcohol.

The hydrolysis can be carried out in the same manner as in the method B in which the carboxylic acid ester is hydrolyzed. Examples of the oxidizing agent used in the oxidizing step include manganese dioxide, chromic acid, organic peroxides, DMSO.
(Dimethyl sulfoxide) and the like.

In the next fourth step, the aldehyde group of the thus-obtained 2-aldehyde compound (XIII) is converted into a cyclic acetal (XI
In this step, the cyano group is hydrolyzed after being induced to V) and protected.

The first step of acetalizing the aldehyde group is usually carried out in an organic solvent in the presence of an acid catalyst and a diol. Examples of the acid catalyst used here include p-
Toluenesulfonic acid, hydrochloric acid, sulfuric acid, formic acid, acetic acid, cation exchange resin and the like can be mentioned. Examples of the diol include glycerol, 1,3-propanediol, 2,2-di and the like. Examples of the organic solvent include benzene, toluene, xylene, tetrahydrofuran, dioxane, acetonitrile, chloroform and the like.

The reaction temperature and reaction time in this first step (acetalization) are not particularly limited, and it is usually sufficient to carry out the reaction for about 15 minutes to 24 hours at any temperature from ice cooling to reflux. The second stage of hydrolysis of the next acetal is usually
It is carried out in the presence of an acid catalyst in a solvent. Examples of the acid catalyst used here include hydrochloric acid, sulfuric acid, nitric acid, perchloric acid,
Examples thereof include acetic acid, formic acid, oxalic acid and the like. As the solvent,
For example, water, methanol, ethanol, isopropanol, propanol, dioxane, tetrahydrofuran or the like can be used.

The fifth step is a step of hydrolyzing the acetal of the amide (XV) to return it to the aldehyde (XVI). This step is carried out in the same manner as the hydrolysis in the second step of the previous step.

The final step is to remove the aldehyde (XV
In this step, I) is reacted with an alkyl-substituted acylhydrazine to obtain an acylhydrazine (XVII). Examples of the organic solvent used here include acetic acid, methanol, ethanol, N, N-dimethylformamide, pyridine and the like.

The reaction temperature and reaction time in this step are not particularly limited, and are usually 1 at any temperature from ice cooling to reflux.
The reaction may be performed for about 5 minutes to 24 hours.

(4) Method D: In this method, the 2-ethoxycarbonylbenzofuran derivative (XVIII) is acylated to the corresponding acyl compound (XIX) as shown in Chemical formula 8 below, and the 2-position of this acyl compound is obtained. After the ester of is hydrolyzed, it is decarboxylated to give an acyl compound (XX), and finally, the acyl compound (XX) is reacted with N-phenylpiperazine and formaldehyde (or paraformaldehyde) by Mannich reaction to give the desired compound (XXI). It is a manufacturing method.

[0054]

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(In the formula, R ¹ is a hydrogen atom, a halogen atom,
Alternatively, it represents a C _{1 to} C ₆ alkyl group, and X represents a hydrogen atom, a halogen atom, a C _{1 to} C ₆ alkyl group, or a C _{1 to} C ₆ alkoxy group. ) In this method, the acylation in the first step is usually carried out by Friedel-Crafts reaction of a 2-ethoxycarbonylbenzofuran derivative (XVIII) with an acid chloride or an acid anhydride in the presence of an acid catalyst in an organic solvent. Be seen. Examples of the acid catalyst used here include aluminum chloride, iron chloride,
Examples thereof include titanium trichloride, tin chloride, zinc chloride, hydrogen fluoride, sulfuric acid, polyphosphoric acid and the like. Examples of the organic solvent include nitrobenzene, carbon disulfide, dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like.

The reaction temperature and reaction time in the first step are not particularly limited, and usually 15 at any temperature from ice cooling to reflux.
The reaction may be performed for about minutes to 24 hours. Next, the carboxylic acid ester of the acyl compound (XIX) thus obtained is hydrolyzed and then decarboxylated to give the corresponding acyl compound (XX). The hydrolysis in this step can be performed in the same manner as in the hydrolysis step of Method A (the step of hydrolyzing cyanobenzofuran (V) to produce benzofurancarboxylic acid (VI)). The carboxylic acid obtained is subsequently decarboxylated, usually in the presence of a copper catalyst in an organic solvent. Examples of the organic solvent used here include N, N-dimethylformamide, quinoline and the like. The reaction temperature in the decarboxylation step is preferably a high temperature above room temperature, and particularly preferably a heating reflux temperature. The reaction time in this case is not particularly limited,
It is usually about 15 minutes to 24 hours.

Finally, the acyl compound (XX) is reacted with N-phenylpiperazine and formaldehyde or paraformaldehyde in a solvent, usually under Mannich reaction conditions, to produce the desired compound (XXI). Examples of the solvent used here include water, methanol, ethanol, n-propanol, n-butanol, dioxane and the like. The reaction temperature and reaction time of this Mannich reaction are not particularly limited, and are usually 1 at any temperature from ice cooling to reflux.
The reaction may be performed for about 5 minutes to 24 hours.

The benzofuran derivative of the present invention produced as described above is a novel compound and has an excellent antihypertensive action and a lipid lowering action due to the pharmacological action described later. Therefore, a novel lipid lowering antihypertensive agent Is useful as

When the compound of the present invention is used as a medicine, it can be made into a preparation depending on the administration method together with a usual preparation carrier. For example, in the case of oral administration, it is prepared in the form of tablets, capsules, granules, powders, liquids and the like. When preparing a solid preparation for oral administration, conventional excipients, binders, lubricants, coloring agents, disintegrating agents and the like can be used. Examples of excipients include lactose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose (CM
C), glycerin, sodium alginate, gum arabic and the like. Examples of the binder include polyvinyl alcohol (PVA), polyvinyl ether, ethyl cellulose, gum arabic, shellac and sucrose.
Examples of the lubricant include magnesium stearate, talc and the like. Examples of the colorant include food yellow No. 4 aluminum lake (tartrazine). Examples of the disintegrant include hydroxypropyl cellulose, carboxymethyl cellulose, starches and the like.
When used as a tablet, the compound of the present invention may be coated by a known method such as dipping, spraying or coating. Liquid formulations include aqueous or oily suspensions, solutions,
It may be a syrup, an elixir or the like, and is prepared by a conventional method. In the case of an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to the compound of the present invention to prepare a subcutaneous, intramuscular or intravenous injection according to a conventional method. You can In the case of suppositories, oils and fats such as cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, Witepsol (registered trademark of Dynamite Nobel) and the like can be used as a base.

The dose of the preparation thus prepared varies depending on the patient's symptoms, body weight, age and the like and cannot be decided unconditionally, but in the case of an adult, the amount of the compound of the present invention is usually about 10 per day.
An amount in the range of up to 2000 mg is preferred. In this case, it is usually preferable to administer the drug in 1 to 4 divided doses per day.

[0061]

EXAMPLES Hereinafter, a method for producing a benzofuran derivative of the general formula (I) which is a compound of the present invention and a lipid-lowering antihypertensive agent containing this compound will be described in more detail with reference to Examples.

[0062]

Example 1 Preparation of 5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 1)

(1) Production of 5-bromobenzofuran 35.0 g of 5-bromophenol and 40.0 g of bromodiethyl acetal were added to N, N-dimethylformamide 1
The solution dissolved in 00 ml was put into a suspension of 8.9 g of sodium hydride in 100 ml of N, N-dimethylformamide under ice cooling. The resulting reaction solution was heated under reflux for 6 hours, cooled to room temperature, and water was added. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 45 g of polyphosphoric acid was added to the obtained residue.
And benzene (500 ml) were added and the mixture was heated under reflux for 2 hours.
After cooling the obtained reaction solution to room temperature, the supernatant was decanted and the residue was washed with n-hexane and combined with the supernatant,
It was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using n-hexane as an eluent to obtain 28.0 g (yield 70%) of 5-bromobenzofuran as an oily substance.

NMR δ (CDCl ₃ ): 6.72 (1
H, dd), 7.24 (1H, dd), 7.42 (1H,
d), 7.57 (1H, d), 7.63 (1H, d)

(2) Production of 5-cyanobenzofuran 5-bromobenzofuran 18.0 obtained in the above (1)
g and 9.6 g of copper cyanide in 50 ml of N, N-dimethylformamide were refluxed for 6 hours. The obtained reaction liquid was cooled to room temperature, water was added, and the precipitated solid was collected by filtration and washed with water. 30 ml of water and 18 ml of ethylenediamine were added to this solid, and the aqueous layer was washed with chloroform to 3
Extracted twice and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 10: 1) as an eluent. Then, the fraction containing the target substance was concentrated under reduced pressure to obtain 9.1 g (yield 72%) of 5-cyanobenzofuran as precipitated crystals.

Melting point: 87-88 ° C. NMR δ (CDCl ₃ ): 6.72-6.73 (1H,
dd), 7.26 (2H, S), 7.42 (1H, d
d), 7.96 (1H, d)

(3) Production of 5-benzofurancarboxylic acid 5-cyanobenzofuran 13.0 obtained in the above (2)
100 ml of ethylene glycol and 100 ml of water were added to a mixture of g and 12.0 g of potassium hydroxide, and the mixture was heated under reflux for 2 hours. The obtained reaction solution was cooled to room temperature, acidified with concentrated hydrochloric acid, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 5-benzofurancarboxylic acid crystals 1.
3.5 g (yield 91%) was obtained.

Melting point: 168-172 ° C. NMR δ (CDCl ₃ ): 6.88 (1H, d), 7.
57 (1H, d), 7.71 (1H, d), 8.10 (1
H, d), 8.45 (1H, d)

(4) Preparation of 5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 5-benzofurancarboxylic acid obtained in (3) above.
0 g of N, N-dimethylformamide (0.1 ml) and thionyl chloride (1.8 g) were added to a suspension of 1,2-dichloroethane (10 ml), and the mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, dichloromethane was added to the residue to give a solution, and the solution was 2.8 g of 1- (2-methoxyphenyl) piperazine and 1.6 g of triethylamine.
Was dissolved in 10 ml of dichloromethane under ice-cooling and stirred at room temperature for 1 hour. Water was added to the obtained reaction solution, this was extracted with ethyl acetate, the organic layer was washed with saturated saline, and then dried with magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 2: 1) as an eluent, and then the n-hexane-ethyl acetate mixed Recrystallization from the solvent gave 3.5 g of 5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (yield 86%).

Melting point: 121 to 124 ° C. NMR δ (CDCl ₃ ): 3.08 (4H, br
s), 3.69 (2H, brs), 3.87 (3H,
s), 4.00 (2H, brs) 6.81 (1H, d), 6.81-6.92 (3H,
m), 6.92-6.94 (1H, m), 7.37 (1
H, d), 7.42 (1H, d), 7.72 (1H, d)

[0071]

Example 2 Preparation of 5- (4-phenylpiperazinylcarbonyl) benzofuran (compound 2) -hydrochloride hydrochloride 600 mg of 5-benzofurancarboxylic acid and 1- (2
-Methoxyphenyl) piperazine instead of 2.8 g 1
Using 540 mg of -phenylpiperazine, 610 mg of 5- (4-phenylpiperazinylcarbonyl) benzofuran (yield 64%) was produced in the same manner as in (4) of Example 1.

Next, 610 mg of this 5- (4-phenylpiperazinylcarbonyl) benzofuran was dissolved in ethyl acetate to give a solution. To this solution was added a 7% hydrogen chloride-containing ethyl acetate solution, and the precipitated solid was collected by filtration. 5- (4-phenylpiperazinylcarbonyl) benzofuran hydrochloride 6
90 mg was obtained.

Melting point: 170-172 ° C. NMR δ (DMSO-d ₆ ): 3.35 (4H, br
s), 3.72 (4H, brs), 7.03 (2H,
m), 7.33-7.44 (5H, m) 7.68 (1H, d), 7.99 (1H, d), 8.0
9 (1H, d)

[0074]

Example 3 Preparation of 5- [4- (3-chlorophenyl) piperazinylcarbonyl] benzofuran (Compound 3) -hydrochloride hydrochloride 600 mg of 5-benzofurancarboxylic acid and 1- (2
-Methoxyphenyl) piperazine instead of 2.8 g 1
Using 5- (3-chlorophenyl) piperazine (650 mg) and in the same manner as in (4) of Example 1, 5- [4- (3-
Chlorophenyl) piperazinylcarbonyl] benzofuran (460 mg, yield 41%) was produced.

Next, 460 mg of this 5- [4- (3-chlorophenyl) piperazinylcarbonyl] benzofuran
Was dissolved in ethyl acetate to give a solution, to this solution was added a 7% hydrogen chloride-containing ethyl acetate solution, and the precipitated solid was collected by filtration to give 5- [4- (3-chlorophenyl) piperazinylcarbonyl] benzofuran / hydrochloric acid. 510 mg of salt was obtained.

Melting point: 168 to 170 ° C. NMR δ (DMSO-d ₆ ): 3.24 (4H, br
s), 3.60 (4H, brs), 6.84 (1H,
d), 6.94-7.02 (3H, m) 7.19 (1H, t), 7.38 (1H, dd), 7.
67 (1H, d), 7.76 (1H, d), 8.09
(1H, d)

[0077]

Example 4 Preparation of 5- [4- (4-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 4) 0.95 g of 5-benzofurancarboxylic acid and 1- (2
-Methoxyphenyl) piperazine instead of 2.8 g 1
Using 5- (4-methoxyphenyl) piperazine (1.20 g) in the same manner as in (4) of Example 1, 5- [4- (4
1.30 g (yield 73%) of -methoxyphenyl) piperazinylcarbonyl] benzofuran was produced.

Melting point: 125 to 126 ° C. NMR δ (CDCl ₃ ): 3.09 (4H, br
s), 3.77 (3H, s), 3.84 (4H, br)
s), 6.81-6.94 (5H, m) 7.40 (1H, dd), 7.55 (1H, d), 7.
71 (1H, dd)

[0079]

Example 5 Production of 5- [4- (2-chlorophenyl) piperazinylcarbonyl] benzofuran (Compound 5) 2.5 g of 5-benzofurancarboxylic acid and 1- (2-
Methoxyphenyl) piperazine instead of 2.8 g 1-
5- [4- (2-chlorophenyl) piperazinylcarbonyl] benzofuran 5 was prepared in the same manner as in (4) of Example 1 using 3.0 g of (2-chlorophenyl) piperazine.
00 mg (36% yield) was produced.

Melting point: 175 to 176 ° C. NMR δ (CDCl ₃ ): 3.06 (4H, br
s), 3.71 (2H, brs), 3.96 (2H, b)
rs), 6.82 (1H, d), 6.82-7.01
(2H, m), 7.01-7.21 (2H, m), 7.
24-7.27 (2H, m), 7.36-7.42 (2
H, m), 7.56 (1H, dd), 7.69 (1H,
d), 7.71 (1H, d)

[0081]

Example 6 Preparation of 7- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 6)

(1) Production of 7-Bromobenzofuran: 2-Bromophenol (25.0 g) and bromodiethyl acetal (2) were used instead of 5-bromophenol (35.0 g).
In the same manner as in (1) of Example 1 using 8.6 g.
16.1 g (yield 58%) of -bromobenzofuran was obtained as an oil.

NMR δ (CDCl ₃ ): 6.83 (1
H, d), 7.11 (1H, dd), 7.46 (1H,
d), 7.53 (1H, d), 7.68 (1H, d)

(2) Production of 7-cyanobenzofuran 15.0 g of 7-bromobenzofuran obtained in the above (1) instead of 18.0 g of 5-bromobenzofuran
And 8.0 g of copper cyanide in the same manner as in (2) of Example 1 with 9.8 g of 7-cyanobenzofuran (yield 9
0%).

Melting point: 57 to 58 ° C. NMR δ (CDCl ₃ ): 6.88 (1H, d), 7.
32 (1H, dd), 7.61 (1H, dd), 7.76
(1H, d), 7.85 (1H, dd)

(3) Preparation of 7-benzofurancarboxylic acid The same procedure as in (3) of Example 1 except that 9.8 g of 7-cyanobenzofuran obtained in (2) above was used instead of 13.0 g of 5-cyanobenzofuran. By various methods, 10.3 g of 7-benzofurancarboxylic acid (yield 92%) was produced.

Melting point: 160-161 ° C. NMR δ (DMSO-d ₆ ): 7.08 (1H, d),
7.38 (1H, dd), 7.88 (1H, d), 7.9
4 (1H, d), 8.13 (1H, d), 13.20 (1
H, brs)

(4) Preparation of 7- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 500 m of the 7-benzofurancarboxylic acid obtained in the above (3) in place of 2.0 g of 5-benzofurancarboxylic acid
g in the same manner as in (4) of Example 1
730 mg (yield 70%) of [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran was produced.

Melting point: 91 to 92 ° C. NMR δ (CDCl ₃ ): 3.04 (2H, brs),
3.21 (2H, brs), 3.55 (2H, brs),
3.87 (3H, s), 4.09 (2H, brs), 6.8
2 (1H, d), 6.88-7.05 (4H, m), 7.
30 (1H, dd), 7.41 (1H, d), 7.66-
7.68 (2H, m)

[0090]

Example 7 Preparation of 5-chloro-7- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 7) (1) Preparation of 5-chloro-7-bromobenzofuran-2-carboxylic acid 2-bromo-5-chloro-2-hydroxybenzaldehyde 25.0 g, diethyl bromomalonate 50.7
g and 44.0 g of potassium carbonate were heated to reflux in 110 ml of methyl ethyl ketone for 5 hours. After cooling, the precipitated salt was filtered off and the filtrate was distilled off under reduced pressure to obtain 54 g of a residue.
300 ml of 10% sulfuric acid water and 300 m of ethyl acetate
It is sequentially extracted with 1 and the aqueous layer is further diluted with 150 ml of ethyl acetate to 2 times.
Extracted times. The ethyl acetate layer was washed with 375 ml of saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain 80 g of a residue. To this, an ethanolic 10% potassium hydroxide aqueous solution 2
After adding 50 ml and heating and refluxing for 1 hour, ethanol was distilled off under reduced pressure. Further, 3 liters of water was added thereto, and the mixture was heated and dissolved, then concentrated hydrochloric acid was added while hot, and the precipitated crystals were collected by filtration.
The crystals were washed with 625 ml of water, collected by filtration, and dried to give 5-
Chloro-7-bromobenzofuran-2-carboxylic acid 2
4.2 g (yield 83%) was obtained.

Melting point: 204 to 205 ° C. NMR δ (DMSO-d ₆ ): 7.69 (1H, s),
7.87 (2H, s)

(2) Preparation of 5-chloro-7-cyanobenzofuran The 5-chloro-7-bromobenzofuran-2-carboxylic acid obtained in (1) above was replaced with 18.8.0 g of 5-bromobenzofuran. 0g and copper cyanide 8.2g
Was used in the same manner as in (2) of Example 1 to obtain 6.6 g (yield 57%) of 5-chloro-7-cyanobenzofuran.

Melting point: 133-134 ° C. NMR δ (CDCl ₃ ): 6.84 (1H, d),
7.58 (1H, d), 7.80 (1H, d), 7.82
(1H, d)

(3) Preparation of 5-chloro-7-benzofurancarboxylic acid Carried out using 5.8 g of 5-chloro-7-cyanobenzofuran obtained in the above (2) instead of 13.0 g of 5-cyanobenzofuran. In the same manner as in (3) of Example 1, 5-
Chloro-7-benzofurancarboxylic acid 5.8 g (yield 9
0%).

Melting point: 215 to 216 ° C. NMR δ (DMSO-d ₆ ): 7.04 (1H, d),
7.76 (1H, d), 8.01 (1H, d), 8.18
(1H, d), 13.51 (1H, brs)

(4) Preparation of 5-chloro-7- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 5-Benzofurancarboxylic acid In place of 2.0 g of 5-, obtained in the above (3) 670 mg of the target 5-chloro-7- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran was obtained in the same manner as in (4) of Example 1 using 500 mg of chloro-7-benzofurancarboxylic acid.
(Yield 71%) was produced.

Melting point: 139-141 ° C. NMR δ (CDCl ₃ ): 3.03 (2H, brt),
3.19 (2H, brt), 3.54 (2H, brt),
3.87 (3H, s), 4.06 (2H, brt), 6.7
8 (1H, d), 6.87-7.08 (4H, m), 7.
38 (1H, d), 7.63 (1H, d), 7.69 (1
H, d)

[0098]

Example 8 Preparation of 2- (N′-acetylhydrazono) methyl-5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 8)

(1) Preparation of 5-bromo-2-ethoxycarbonylbenzofuran 5-bromo-2-hydroxybenzaldehyde 25.0
g, 50.0 g of diethyl bromomalonate, and 51.4 g of potassium carbonate were heated to reflux in 100 ml of methyl ethyl ketone for 5 hours. After cooling, the precipitated salt was filtered off, the filtrate was distilled off under reduced pressure, and the resulting residue was treated with 10% sulfuric acid water 300 m.
1 and 300 ml of ethyl acetate successively, and the aqueous layer was further extracted twice with 150 ml of ethyl acetate. The ethyl acetate layer was washed with 375 ml of saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated under reduced pressure, and the obtained residue was separated by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 20: 1) as an eluent to obtain 5 -Bromo-2-ethoxycarbonylbenzofuran 28.2 g (yield 90%)
I got

Melting point: 59-60 ° C. NMR δ (CDCl ₃ ): 1.42 (3H, t), 4.
44 (2H, q) 7.45 (1H, s), 7.46 (1H, d) 7.53 (1H, dd), 7.81 (1H, d)

(2) Preparation of 5-cyano-2-ethoxycarbonylbenzofuran 13.0 g of 5-bromo-benzofuran-2-ethoxycarbonylbenzofuran obtained in the above (1) was substituted for 18.0 g of 5-bromobenzofuran. And 5.1 g of copper cyanide in the same manner as in (2) of Example 1 to give 5-cyano-2-ethoxycarbonylbenzofuran 1
1.1 g (yield 47%) was obtained as an oil.

NMR δ (CDCl ₃ ): 1.44 (3
H, t), 4.47 (2H, q), 7.57 (1H,
s), 7.71 (2H, m), 8.07 (1H, d)

(3) Production of 5-cyano-2-hydroxymethylbenzofuran 11.1 g of 5-cyano-2-ethoxycarbonylbenzofuran obtained in (2) above and sodium hydroxide 2.
50 ml of water and 50 ml of ethanol were added to 1 g, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled to room temperature, ethanol was distilled off, and the residue was dissolved in water. After adding concentrated hydrochloric acid to this solution, it was extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated saline and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 10.0 g of a residue. Triethylamine (12.3 ml) and tetrahydrofuran (200 ml) were added to the residue, and ethyl chlorocarbonate was appropriately added under ice cooling, followed by stirring at room temperature for 30 minutes. The precipitated triethylamine hydrochloride was removed by filtration, and the filtrate (tetrahydrofuran solution) was added with 6.1 g of sodium borohydride.
The solution was appropriately added to a 200 ml solution of water under ice-cooling and stirred at room temperature for 3 hours. 300 ml of 1N hydrochloric acid was appropriately added to the obtained reaction solution under ice cooling, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate (volume ratio 1: 1) as an eluent to give 5-cyano-2-hydroxymethylbenzofuran. 5.8 g (yield 62%) was obtained.

Melting point: 105 to 108 ° C. NMR δ (CDCl ₃ ): 2.06 (1H, brs),
4.82 (2H, s), 6.74 (1H, s), 7.55
(1H, s), 7.90 (1H, s)

(4) 2- (1,3-dioxolane-2-
Il) -5-benzofurancarboxylic acid production 20.0 g of chromic acid was added to a solution of 32 ml of pyridine in 400 ml of dichloromethane, and 15 minutes later, 5.8 g of 5-cyano-2-hydroxymethylbenzofuran obtained in the above (3) was added. , Stirred at room temperature for 15 minutes. The supernatant was decanted, the residue was washed with dichloromethane, and the solution was combined with the supernatant and washed successively with 1N sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated saline, and then with sulfuric acid. It was dried with magnesium. The solvent was distilled off, and 100 ml of toluene, 3.10 g of ethylene glycol and 100 p-toluenesulfonic acid were added to the obtained residue.
mg was added, and the mixture was heated under reflux for 2 hours while removing water with a Dean Stark trap. The obtained reaction solution was washed with a saturated aqueous sodium hydrogencarbonate solution and dried over magnesium sulfate. The solvent was distilled off, and 60 ml of ethylene glycol, 60 ml of water, and 6.60 potassium hydroxide were added to the obtained residue.
g was added and the mixture was heated under reflux for 1 hour. The obtained reaction solution was acidified with 1N hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, the solvent was evaporated, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to give 2- (1,3-dioxolan-2-yl) -5. −
4.30 g (yield 55%) of benzofurancarboxylic acid was obtained.

Melting point: 300 ° C. or higher NMR δ (CDCl ₃ ): 4.10-4.21 (4H,
m), 6.11 (1H, s), 6.91 (1H, s),
7.54 (1H, d)

(5) 2- (1,3-dioxolane-2-
Iyl) -5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 2- (1,3-dioxolane-2 obtained in the above (4)
Carbodiimidazole (410 mg) was added to (5-yl) -5-benzofurancarboxylic acid (590 mg), and the mixture was stirred at room temperature for 1 hour and then 1- (2-methoxyphenyl) piperazine 49 was added.
0 mg was added, and the mixture was further stirred at room temperature for 1 hour. Ethyl acetate was added to the obtained reaction solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 1: 1) as an eluent to give 2- (1,3-dioxolane-). 2-yl) -5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 430 mg
(Yield 43%) was obtained as an oil.

NMR δ (CDCl ₃ ): 3.02 (4
H, brs), 3.63 (2H, brs), 3.88 (3
H, s), 3.98 (2H, brs), 4.09-4.2.
0 (4H, M), 6.10 (1H, s), 6.85-6.
94 (3H, M), 7.02-7.10 (1H, m),
7.40 (1H, d), 7.53 (1H, d), 7.69
(1H, S)

(6) 2- (N'-acetylhydrazono)
Production of methyl-5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 2- (1,3-dioxolane-2 obtained in (5) above.
-Yl) -5- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (430 mg) was added with ethanol (20 ml) and 1N hydrochloric acid (10 ml), heated at 50 ° C for 1 hour, and then the solvent was distilled off to obtain saturated hydrogen carbonate. Aqueous sodium solution was added slowly. The aqueous layer was extracted with ethyl acetate, then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 90 mg of acetylhydrazine was added to the obtained residue, and the mixture was heated under reflux in 5 ml of ethanol for an hour. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography using a dichloromethane-methanol mixed solvent (volume ratio of 20: 1) as an eluent to obtain the desired 2- (N'- Acetylhydrazono) methyl-5- [4- (2-methoxyphenyl)
300 mg (60% yield) of piperazinylcarbonyl] benzofuran was obtained.

Melting point: 194-195 ° C. NMR δ (CDCl ₃ ): 1.65 (3H, s), 2.
44 (3H, s), 3.10 (4H, brs), 3.65
(2H, brs), 4.02 (2H, brs), 6.88
-7.02 (5H, m), 7.48 (1H, d), 7.5
4 (1H, d), 7.72 (1H, s), 7.82 (1
H, s), 10.01 (1H, brs)

[0111]

Example 9 Preparation of 5- [3- {4- (2-methoxyphenyl) piperazinyl} propionyl] benzofuran (Compound 9) (1) Preparation of 5-acetyl-2-ethoxycarbonylbenzofuran 2-ethoxycarbonylbenzofuran 10 0.0g and 41.0g of acetyl chloride in 100m of dichloromethane
The solution 1 was put under ice cooling in a suspension of 53.0 g of aluminum chloride in 200 ml of dichloromethane, stirred for 1 hour at room temperature, and then heated under reflux for 12 hours. The obtained reaction solution was gradually added to ice water. The reaction solution was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 10: 1) as an eluent.
-Acetyl-2-ethoxycarbonylbenzofuran 1
1.0 g was obtained as an oil.

NMR δ (CDCl ₃ ): 1.45 (3
H, t), 2.68 (3H, s), 4.47 (2H,
q), 7.60 (1H, s), 7.64 (1H, s),
8.09 (1H, d), 8.33 (1H, d)

(2) Production of 5-Acetylbenzofuran 15 ml of ethanol and 15 ml of water were added to 3.15 g of 5-acetyl-2-ethoxycarbonylbenzofuran obtained in (1) above and 1.14 g of sodium hydroxide, and the mixture was stirred for 1 hour. Heated to reflux. The obtained reaction solution was acidified with 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. Copper powder (100 mg) and quinoline (10 ml) were added to the crystals and the mixture was heated under reflux for 1 hour. After cooling the obtained reaction solution, ethyl acetate was added, and the organic layer was washed with 6N hydrochloric acid three times and then with saturated saline.
It was washed twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 10: 1) as an eluent to give 850 mg of 5-acetylbenzofuran crystals. Obtained.

Melting point: 39-41 ° C. NMR δ (CDCl ₃ ): 2.66 (3H, s), 6.
86 (1H, s), 7.54 (1H, d), 7.69 (1
H, s), 7.95 (1H, d), 8.26 (1H, s)

(3) Preparation of 5- [3- {4- (2-methoxyphenyl) piperazinyl} propionyl] benzofuran To a solution of 1.70 g of 1- (2-methoxyphenyl) piperazine in 10 ml of ethanol was added 1.5 ml of concentrated hydrochloric acid. In addition, after stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. 600 mg of paraformaldehyde and 0.02 m of concentrated hydrochloric acid were added to the obtained residue.
1, and a solution of 1.08 g of 5-acetylbenzofuran obtained in (2) above in 10 ml of 95% ethanol,
The mixture was heated under reflux for 10 hours. After cooling the obtained reaction solution,
The solvent was distilled off, the residue was diluted with 1N sodium hydroxide,
It was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography using an n-hexane-ethyl acetate mixed solvent (volume ratio 2: 1) as an eluent to obtain the desired 5- [3-]. {4
1.45 g (yield 69%) of crystals of-(2-methoxyphenyl) piperazinyl} propionyl] benzofuran were obtained.

Melting point: 132-133 ° C. NMR δ (CDCl ₃ ): 2.77 (4H, brs),
2.96 (2H, t), 3.13 (4H, brs), 3.3
1 (2H, t), 3.87 (3H, s), 6.85-6.9
2 (2H, m), 6.94-7.03 (3H, m), 7.5
6 (1H, d), 7.70 (1H, d), 7.98 (1H,
dd), 8.29 (1H, d) On the other hand, as a reference example, a benzofuran derivative (conventional product) in which the substituent of Chemical formula 4 was bonded to the 2- or 3-position was produced as follows.

[0117]

Reference Example 1 Preparation of 2- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran (Compound 10) shown below

[0118]

Embedded image

Instead of 2.0 g of 5-benzofurancarboxylic acid, 810 mg of 2-benzofurancarboxylic acid, 1-
Example 1 using 1.23 g of (2-methoxyphenyl) piperazine and methanol as the recrystallization solvent.
2- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran 1.54 by a method similar to that of (4).
g (92% yield) were produced.

Melting point: 161-163 ° C

[0121]

Reference Example 2 Preparation of 2- [3- {4- (2-methoxyphenyl) piperazinyl} propionyl] benzofuran dihydrochloride (Compound 11) of the following chemical formula 10

[0122]

Embedded image

As in Example 9 (3), except that 1.26 g of 1- (2-methoxyphenyl) piperazine, 800 mg of 2-acetylbenzofuran instead of 1.08 g of 5-acetylbenzofuran, and 440 mg of paraformaldehyde were used. 2- [3- {4- (2-methoxyphenyl) piperazinyl} propionyl] benzofuran was prepared by various methods and then treated with a hydrogen chloride-containing ethyl acetate solution to give 1.17 g of dihydrochloride crystals (yield: 59%).

Melting point: 185 to 187 ° C.

[0125]

[Reference Example 3] Production of 3- [4- (2-methoxyphenyl) piperazinylcarbonyl] benzofuran hydrochloride (Compound 12) shown below

[0126]

Embedded image

Instead of 2.0 g of 5-benzofurancarboxylic acid, 370 mg of 3-benzofurancarboxylic acid, 1-
520 mg of (2-methoxyphenyl) piperazine was used and 3- [4- (2-
Methoxyphenyl) piperazinylcarbonyl] benzofuran was produced and then treated with a hydrogen chloride-containing ethyl acetate solution to obtain 720 mg (yield 85%) of crystals of hydrochloride.

Melting point: 205 to 207 ° C. Next, the following tests were conducted on the antihypertensive action and lipid lowering action of the benzofuran derivative obtained as described above.

[0129]

[Test Example 1] Test of antihypertensive effect On the day before the test, spontaneously hypertensive rats (S
A polyethylene catheter for measuring blood pressure was inserted into the abdominal aorta from the tail artery of (HR) and then placed in an individual cage to fix the tail. Under anesthesia, blood pressure was measured in a semi-restrained state using a pressure transducer (TP-400T; manufactured by Nihon Kohden). Heart rate is measured from the blood pressure veins by a heart rate monitor (AT-60
1G; manufactured by Nihon Kohden Co., Ltd.).

The test compound was suspended in a 1.5% aqueous solution of Tween 80 (trade name of a surfactant manufactured by Sigma Co.) and 10
SHR was administered orally at a dose of ml / kg. Table 1 shows the results
Shown in

[0131]

[Table 1] * Amount of change ± 0 before administration, with the mean value ± S. E. FIG.

As can be seen from this table, the test compound of the present invention lowered the blood pressure of SHR in a dose-dependent manner.

On the other hand, the compounds 10, 11 and 12 of the reference examples, which are 2- or 3-substituted compounds, are known compounds, but even at a dose of 100 mg / kg, it does not change the blood pressure of SHR. could not.

[0134]

[Test Example 2] Test of hyperlipidemia action A 6-week-old Golden Syrian hamster was used in groups of 6 to 8 to test the hyperlipidemia action. A diet containing 1% cholesterol and 0.5% cholic acid (manufactured by Oriental Yeast Co., Ltd.) was given to the administration group to which the test compound was administered and the control group to which the test compound was not administered to cause hyperlipidemia. As a non-treated control group, a group fed with normal solid feed [MF (Oriental Yeast Co., Ltd.)] was prepared.

The test compound was suspended in a 1.5% aqueous solution of Tween80. The solvent or the test compound was changed to the cholesterol-containing feed, and the administration was started at the same time, and 10 times once a day.
It was orally administered at a dose of mg / kg for 5 days. After the last dose,
Blood was collected from the abdominal descending vena cava under Nembutal anesthesia at 3 hours, and serum was collected to collect total cholesterol (T
C) was measured by an enzymatic method using an assay kit (manufactured by Kyowa Medex Co., Ltd.), and the TC increase suppression rate was calculated from the following formula.

[0136]

(Equation 1)

Table 2 shows the results.

[0138]

[Table 2]

As can be seen from this table, the test compounds of the present invention suppressed TC increase in a dose-dependent manner.

[0140]

INDUSTRIAL APPLICABILITY The benzofuran derivative of the present invention has not only an excellent antihypertensive effect but also a high lipid lowering effect, so that it is not only an excellent antihypertensive agent, but also an ischemic disease such as angina, myocardial infarction and heart failure. It is useful as a preventive or therapeutic drug.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C07D 307/81 C07D 307/81 (72) Inventor Akiko Uchida 1000 Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa (72) Inventor Chirei Miyajima, 1000, Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Mitsubishi Kasei Co., Ltd. (72) Hisao Takayanagi, 1000, Kamoshida-cho, Midori-ku, Yokohama, Kanagawa Mitsubishi Kasei Co., Ltd., Research Institute (72) Inventor Xie Ming, 20 Xihuamen, Xi'an, Xi'an, People's Republic of China, Shaanxi, China Institution of Pharmaceutical Research (72) Incheon Yu Yuan, 20 Xihuamen, Xi'an, Xi'an, China Province of China Pharmaceutical Research Institute (72) Inventor Xu Qi, No. 20 Xihuamen, Xi'an, People's Republic of China Shaanxi Province China Medicine Research Institute (72) Inventor Wang Changtai People Republic of Xi'an NishiHanamon No. 20 Shaanxi in the pharmaceutical research hospital

Claims (8)

[Claims] 1. A benzofuran derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof. Embedded image (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, or an N′-C ₁ -C ₆ alkylcarbohydrazonomethyl group, and X represents a hydrogen atom, a halogen atom, C ₁
To C ₆ alkyl group or C _{1 to} C ₆ alkoxy group, and n represents an integer of 0 to 10. ) 2. 4-, 5-, 6 wherein R ¹ is a benzofuran ring
-, or 7-position to replace a hydrogen atom, a halogen atom, or a compound of claim 1, wherein the alkyl group of C ₁ -C _6. 3. The compound according to claim 1, wherein R ¹ is substituted on the 2- or 3-position of the benzofuran ring and represents an N′-C ₁ -C ₆ alkylcarbohydrazonomethyl group. 4. The compound according to claim 3, wherein R ¹ is substituted at the 2-position of the benzofuran ring. 5. The compound according to claim 1, wherein n represents an integer of 0-2. 6. The compound according to any one of claims 1 to 4, wherein n is 0 or 2. 7. A pharmaceutical composition comprising a benzofuran derivative represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 8. The pharmaceutical composition according to claim 7, which is used as a lipid-lowering antihypertensive agent.