JPH0283375A - 2-substituted piperazinyl-2-(1,2-benzisoxazol-3-yl)acetic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 2-substituted piperazinyl-2-(1,2-benzisoxazol-3-yl)acetic acid derivative shown by formula I (R1 is H, halogen, lower alkoxy; R2, R3 and R4 are the same or different and H, halogen, lower alkoxy or two adjoining substituent groups of of R1-R4 are bonded to form methylenedioxy; X is single bond, -O-, -CH=CH-, C=O; n is 1-3: Y is H, cyano, -COOR5 or -CONR6R7; R5 is lower alkyl, etc.; R6 and R7 are H, lower alkyl, cycloalkyl, etc.) or an acid addition salt thereof. EXAMPLE:Isoamyl 2-[4-(3,4-methylenedioxybenzyl)piperazino]-2-(1,2-benzisoxazol-3- yl)acetate. USE:A remedy for alimentary disease. PREPARATION:A compound shown by formula II (Hal is halogen) is reacted with a compound shown by formula III to give a compound shown by formula I.

Description

Detailed Description of the Invention The compound of the present invention is a 2-substituted biverazinyl compound which has an antispasmodic effect as a medicine and is useful as a therapeutic agent for gastrointestinal diseases.
This invention relates to 2-(1,2-benzisoxazol-3-yl)acetic acid derivatives.

The and Akira try to solve - Until now, many compounds with anti-acetylcholine (antimuscarinic) effects have been used clinically as antispasmodics, but anti-acetylcholine effects such as mydriasis, tachycardia, urinary retention, etc. (antimuscarinic)
The problem of side effects due to its action remains, and the development of more useful antispasmodics is desired.

As a means to reduce the side effects of antispasmodics based on antiacetylcholine effects, G. Toson et al.
.

Forsch. It states that all side effects on the circulatory system are reduced.

The present invention provides an excellent anti-spasmodic effect that has both excellent anti-acetylcholine effect and white muscle action in a well-balanced manner.
Substituted biverazinyl-2-(1,2-benzisoxazol-3-yl)acetic acid derivatives are provided.

and the general formula [wherein, R8 means a hydrogen atom, a halogen atom or a lower alkoxy group, and R2, R3 and R4 are the same or different and mean a hydrogen atom, a halogen atom or a lower alkoxy group, or It means a methylenedioxy group in which two adjacent substituents are combined, and X means a single bond, -0-, -CH=CH-, or a group represented by C=O.

n means 0, 1.2 or 3, Y is hydrogen atom, cyan group, GOOR5 or -CON
R, means a group represented by IR7, where R5 means a lower alkyl group or a cycloalkyl group, and R8 or R7 are the same or different and are a hydrogen atom, a lower alkyl group,
Cycloalkyl group or phenylethyl group, or R6
and R7 taken together mean a saturated heterocyclic group containing a nitrogen atom. ] 2-Substituted biperazinyl- having analgesic effect represented by
The present invention relates to 2-(1,2-benzisoxazol-3-yl)acetic acid derivatives and physiologically acceptable addition salts and quaternary ammonium salts thereof.

As the addition salt of the compound represented by formula (1), physiologically acceptable salts are preferable, such as inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. acid salts, and oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates,
Formula 0 (which includes organic acid salts such as methanesulfonate)
Physiologically acceptable quaternary ammonium salts of the compound I) include, for example, methyl iosito, methyl bromide, ethyl iosito, lower alkyl halogenides such as ethyl bromide, allyl alkyl halides such as benzyl bromide, methyl methyl sulfate, Lower alkyl like methyl ethyl sulfate Lower alkyl sulfate, methyl methanesulfonate, ethyl
Examples include quaternary ammonium salts with lower alkyl sulfonates such as methanesulfonate, lower alkyl arylsulfonates such as methyl p-)luenesulfonate, and particularly preferred as the anion component are bromide or ioside.

The compound of formula (1), its acid addition salts and quaternary ammonium salts have one or more asymmetric carbon atoms and therefore stereoisomers exist. The present invention includes these stereoisomers, mixtures and racemates thereof. Furthermore, since compound (I) can exist as a hydrate or solvate,
Hydrates and solvates thereof are also included in the compounds of the present invention.

Terms used in this specification will be explained below.

"Lower" means 1 to 1 carbon atom, unless otherwise specified.
It means 6 things. The lower alkyl group may be linear or branched. "Halogen atom" refers to fluorine, chlorine,
Means bromine and iodine.

"Lower alkyl group" refers to 1 such as methyl and ethyl.

Examples include propyl and isopropyl. "Lower alkoxy group" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, etc., with methoxy being preferred; "cycloalkyl group" has 3 to 8 carbon atoms.
For example, cyclopropyl, cyclobutyl, cyclopentyl.

Examples include cyclohexyl. When Rs and R7 are taken together, "a saturated heterocyclic group containing a nitrogen atom" means, for example, piperidino, pyrrolidinyl, hexamethyleneimino,
Examples include morpholino.

Compound (I) of the present invention can be produced, for example, by the following method.

(Left below) A compound represented by the general formula (II) (wherein, Hal means a halogen atom such as chlorine, bromine, or iodine, and R8 and Y have the same meanings as above) or It can be obtained by reacting the acid addition salt thereof with a compound represented by the general formula % (% formula %) (wherein R21R3, R4, n and X have the same meanings as above).

The reaction between the compound of formula (II) and the compound of formula (III) is usually carried out in a solvent, and specific examples of the solvent include halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, diethyl ether, and dichloromethane. Propyl ether, tetrahydrofuran.

Ethers such as dioxane, benzene, toluene,
Formula (III) includes aromatic hydrocarbons such as xylene, dialkyl and ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, esters such as ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof. The compound is usually 1 (
II) in a molar amount or in a slightly excess amount (
The reaction is preferably carried out in the presence of an acid acceptor, and a specific example of an acid acceptor is a single molar amount. Examples include alkali bicarbonates such as sodium carbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N-methylmorpholine. The reaction temperature is usually 0-150°C, preferably 20-70°C.
C, and one reaction time is usually 5 minutes to 24 hours.

The compound of formula (I) is isolated and purified by conventional methods. Compound (I) can be obtained in the form of free or acid addition salt depending on the type of starting compound, reaction and treatment conditions. Acid addition salts can be prepared using conventional methods, such as alkali carbonates.

It can be converted to the free state by treatment with a base such as ammonia. On the other hand, the free base is
Acid addition salts can be obtained by treatment with various physiologically acceptable inorganic or organic acids using conventional methods.

Inorganic acids used for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, phosphoric acid, nitric acid, sulfuric acid, and organic acids include, for example, citric acid, oxalic acid, and fumaric acid.

Maleic acid, lactic acid, succinic acid, malic acid, tartaric acid.

Examples include methanesulfonic acid.

Since the compound of formula (I) has one or more asymmetric carbon atoms, it can be obtained in the form of a racemate or a mixture of stereoisomers, but it can be separated into each stereoisomer by a conventional method.

The quaternary ammonium salt of formula (I) is a compound of formula (1) and general formula (IV) R, -Z (IV) (wherein R8 means an alkyl group or a benzyl group, and 2
means an anionic moiety such as a halide, lower alkyl sulfate, lower alkyl sulfonate, substituted or unsubstituted benzene sulfonate or nidrade. ) can be obtained by reacting with the compound represented by

This reaction can be carried out according to a conventional method for producing quaternary ammonium salts, and is carried out by reacting both compounds without a solvent or in a solvent. Specific examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as tetrahydrofuran and dioxane.

Dialkyl ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, lower alcohols such as methanol, ethanol, isopropyl alcohol, acetonitrile, dimethylformamide or mixtures thereof, etc. 0 reaction temperature 1 reactant (I),
Compound (IV).

It varies depending on the type of reaction solvent, but usually 10 to 130°C
The reaction time is usually 72 hours per 1O min.

Among the raw material compounds (II) of the present invention, the raw material compounds in which Y is other than a hydrogen atom are novel compounds, and can be produced, for example, by the following method.

(V) (Vl) (V) (VIII) (X) (wherein, Y” is -〇〇OR,, -CONR, R7 or -
Means a group represented by ON, R,,R,.

R, 3, R7 and l1al have the same meanings as defined above. ) The compound of formula (VII), which is the raw material compound of the present invention, can be produced by carrying out the reaction between the compound of formula (V) and the compound of formula (Vl) under normal esterification reaction conditions.

Furthermore, the compound of formula (IX), which is the raw material compound of the present invention, can be produced by carrying out the reaction between the compound of formula (V) and the compound of formula (VIII) under normal amidation reaction conditions. .

The compound of formula (V) may be used as it is, or may be converted into a reactive derivative such as an acid halide, mixed acid anhydride, or active ester.

Esterification and amidation reactions are carried out without solvent or in a solvent,
Examples of the reaction solvent, which is carried out in the presence of an acid or a base if necessary, include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as tetrahydrofuran and dioxane, and halogen carbonization such as dichloromethane, chloroform, and dichloroethane. Examples include hydrogens, acetonitrile, dimethylformamide, and the like. The reaction temperature is usually -20 to 150 °C, depending on whether the compound (V) is used, but the reactive derivative thereof is used.
The reaction time is usually 1 to 24 hours.

Alternatively, a compound of formula (II') can be obtained by reacting a compound of formula (VKf), formula (IX) or formula (X) with a substantially equimolar amount of a halogenating agent.

This reaction is usually carried out in a solvent, and specific examples of solvents include:
Examples include halogenated hydrocarbons such as dichloromethane and chloroform, carbon disulfide, dioxane, acetic acid, and mixtures thereof. Specific examples of halogenating agents include:
Halogens such as chlorine and bromine, N- such as monochlorinated iodine, N-promosuccinimide, N-chlorsuccinimide, etc.
Examples include halogen adducts such as halogenamides, pyridine/verpromide, and dioxane/dibromide.

The reaction temperature varies depending on the type of halogenating agent, but is usually 20 to 130°C. The reaction time is usually 1 to 24 hours. The compound of formula (11') may be purified by recrystallization etc. It can also be used in the next step in its crude form.

The compound of formula (I) and its physiologically acceptable addition salts and quaternary ammonium salts have a strong antispasmodic effect and have weak side effects such as mydriasis, salivation, and tachycardia, so they are used as antispasmodic drugs. It is useful as

Below, the results of pharmacological tests on representative compounds of the present invention are shown.

Acts on the cone W, D, M using pieces of ileum removed from guinea pigs.

Paton's method [Br, J. Pharmacol, .
12.119 (1957)].

Transmural stimulation (0.1m5ec, 20V.

The concentration (rn, o) of the test compound that inhibited contraction by 50% at 5 Hz (125 ec) was calculated. The test results are shown in Table 1.

(Margin below) Table 1 Antispasmodic effect *Means the compound of Example 1 (the same applies below).

(Left below) The compound of formula (I) and its physiologically acceptable acid addition salts and quaternary ammonium salts are usually administered orally, parenterally or in the form of a preparation prepared by mixing it with a pharmaceutical carrier. Administered rectally. These formulations may also contain other therapeutically valuable ingredients; examples of formulations include tablets, capsules, granules, granules, powders, syrups.

Examples include injections. These formulations are prepared by conventional methods.

The clinical dosage of the compound of formula (1) and its physiologically acceptable acid addition salts and quaternary ammonium salts varies depending on the type of compound, administration method, patient's symptoms and age, etc. 40 H/kg 7 days, preferably 0
．． 1 to 20 g/kg/day.

The present invention will be explained in more detail with reference to the following reference examples and examples, but the present invention is not limited to these examples.The identification of compounds may be performed using elemental analysis, mass spectroscopy ( MS), IR spectrum, NMR spectrum, etc.

Further, in the following Reference Examples and Examples, the following abbreviations may be used to simplify the description.

A: Ethanol AC: Acetone E Nidiethyl ether EA: Ethyl acetate Et: Ethyl group IPE: Isopropyl ether M: Methanol Me: Methyl group ox: Oxalate W: Water (white space below) Reference [Isoamyl 2-(1,2) -Benzisoxazole-3
-yl) Acetate Production: 1.100011 isoamyl alcohol and 1 ml of concentrated sulfuric acid were added to 17.7 g of 2-benzisoxazole-3-acetic acid, and the mixture was refluxed for 2 hours. After the isoamyl alcohol was distilled off under reduced pressure, the residue was dissolved in toluene, and the toluene layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 24 g of the target product as an oil.

η vs. isopropyl 2-(1,2-benzisoxazole-
Production of 3-yl) acetate: 17.7 g of 1.2-benzisoxazole-3-acetic acid was dried in dioxane 60
11 g of triethylamine was added under water cooling, and a solution of 13.6 g of isopropyl chlorocarbonate dissolved in 20 ml of dioxane was added dropwise to this solution over 1.5 hours. After the addition, the reaction solution was stirred at room temperature for 1.5 hours, and then 12 g of isopropyl alcohol was added to this solution while cooling with water.
A solution prepared by dissolving the above in 20 ml of dioxane was added dropwise. After further stirring the reaction solution at room temperature for 1.5 hours, the precipitate was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in toluene. The toluene layer was washed with a 5% aqueous sodium bicarbonate solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5 g of the target product IEi as an oil.

1 Evidence-1 Production of cyclohexyl 2-(1,2-benzisoxazol-3-yl) acetate: 1. Dioxane 10 by drying 8.9 g of 2-benzisoxazole-3-acetic acid
Dissolve in 0 ml p-)luenesulfonic acid chloride 1
0.5 g of triethylamine was added thereto, and a solution of 5.5 g of triethylamine dissolved in 20 ml of dioxane was slowly added dropwise under water cooling. The reaction solution was stirred for 85 hours, and an additional 5.5 g of triethylamine was added under water cooling, followed by 10 g of cyclohexanol. A solution prepared by dissolving this in 10 ml of dioxane was added dropwise. After stirring the reaction solution overnight at room temperature, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, the chloroform layer was washed with water, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After subjecting the residue to silica gel column chromatography, the chloroform eluate was combined, and the solvent was distilled off under reduced pressure to obtain 3.5 g of the target product as an oil.

1 Evidence-1 Production of isoamyl 2-bromo-2-(1,2-benzisoxazol-3-yl) acetate: Isoamyl
After dissolving 2.5 g of 2-(1,2-benzisoxazol-3-yl) acetate in 20 ml of acetic acid, 10 ml of a solution of 2.4 g of bromine dissolved in 10 ml of acetic acid was added dropwise at 80"C. The mixture was further heated for 0.5 hour.

The reaction solution was concentrated under reduced pressure, then dissolved in chloroform, the chloroform layer was washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3 g of the target product as an oil.

Reference 1 - Production of N-isopropyl-2-(1,2-benzisoxazol-3-yl)acetamide = 100 ml of dioxane obtained by drying 8.9 g of 1.2-benzisoxazole-3-acetic acid Dissolved in triethylamine 5.5% under water cooling.
g and further p-)luenesulfonic acid chloride9.
5 g was added little by little and stirred for 0.5 hour. Furthermore, under water cooling, add 30 g of isopropylamine to 20 ml of dioxane.
The reaction mixture was stirred under water cooling for 1 hour and then at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform, and the chloroform layer was washed with 5% aqueous sodium bicarbonate solution, then water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and insoluble materials were collected by filtration to obtain 4.0 g of the desired product.

Reference side-1 Production of cyclohexyl-2-(1,2-benzisoxazol-3-yl)acetamide = Dioxane 3 obtained by drying 3.6 g of 1.2-benzisoxazole-3-acetic acid
A suspension of 4.1 g of dicyclohexylcarbodiimide dissolved in 1 ml of dioxane and 10 ml of tetrahydrofuran was added dropwise under water cooling. After further stirring for 1 hour under water cooling, 2.0 g of cyclohexylamine
A solution prepared by dissolving the above in 10 ml of dioxane was added dropwise. After stirring overnight at room temperature.

The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the chloroform layer was washed with 5% aqueous sodium bicarbonate solution, then water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 50 ml of heated toluene was added to the residue, and insoluble matter was filtered off to obtain 1.4 g of the target product.

Concept - Production of UN-phenylethyl-2-(1,2-benzisoxazol-3-yl)acetamide: 1. 3.6 g of 2-benzisoxazole-3-acetic acid was dried in dioxane 50 ml, 2.3 g of N-hydroxysuccinimide was added thereto, and a solution of 4.1 g of dicyclohexylcarbodiimide dissolved in 40 ml of dioxane was added dropwise under water cooling. After further stirring for 4 hours, the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 4.9 g. 1.8g of this crystal
was dissolved in 30 ml of chloroform, 0.8 g of phenethylamine was added, and the reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The chloroform eluates were combined, and the solvent was removed under reduced pressure. The residue was distilled off to obtain 1.7 g of the desired product as colorless crystals.

Reference I Preparation of N-isopropyl-2-bromo-2-(1,2-benzisoxazol-3-yl)acetamide: N-isopropyl-2-(1,2-benzisoxazol-3-yl) 0.5g of acetamide in 1 part of chloroform
A solution of 0.4 g of bromine dissolved in 5 ml of chloroform was added at room temperature and stirred overnight. The reaction solution was washed with water, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. N-hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain 0.55 g of the desired product.

1. Production of 2-bromo-(1,2-benzisoxazol-3-yl)acetonitrile: 1.2-Benzisoxazole-3-acetonitrile 1
．． 57 g was heated and dissolved in 40 ml of carbon tetrachloride, and a solution of 1.8 g of bromine dissolved in 10 ml of carbon tetrachloride was added dropwise. After the dropwise addition, the mixture was heated for 15 minutes with stirring, and the reaction solution was concentrated under reduced pressure. The mixture was dried to obtain 2.4 g of an oily target product.

Production of Isoamyl 2-[4-(3,4-methylenedioxybenzyl)piperazino]-2-(1,2-benzisoxazol-3-yl)acetate: Isoamyl 2-bromo-2- (1,2-benzisoxazol-3-yl)acetate 2g to toluene 30g
ml, add 0.74 g of triethylamine,
Furthermore, 1.8 g of 4-(3,4-methylenedioxybenzyl)piperazine was added and stirred overnight at room temperature. Water was added to the reaction mixture, extracted with toluene, the toluene layer was extracted with dilute hydrochloric acid, and the aqueous layer was diluted with ammonia. The mixture was made alkaline with water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the chloroform eluates were combined, and the solvent was distilled off under reduced pressure. The residue was treated with hydrobromic acid in a conventional manner and recrystallized from ethanonyl-diethyl ether to obtain 1.2 g of the desired dihydrobromide salt in the form of colorless crystals. Melting point: 198-198°C Inujinghan-yu N-isopropyl-2-[4-(3,4-methylenedioxybenzyl)piperazino]-2-(1°2-benzisoxazol-3-yl)acetamide Production: Dissolve 0.5 g of N-isopropyl-2-bromo-2-(1,2-benzisoxazol-3-yl)acetamide in 15 ml of toluene and add 0.34 g of triethylamine.
0.37 g of 4-(3,4-methylenedioxybenzyl)piperazine was added and stirred overnight at room temperature. The reaction solution was extracted with diluted hydrochloric acid, the aqueous layer was made alkaline with concentrated aqueous ammonia, and extracted with chloroform. did. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the chloroform eluates were combined, and the solvent was distilled off under reduced pressure. The residue was treated with hydrochloric acid in a conventional manner and recrystallized from ethanol-diethyl ether to obtain 0.34 g of the hydrochloride salt of the target product as colorless crystals. Melting point 148-154°C
-yl)acetonitrile = 2-bromo-2-(1
, 2-benzisoxazol-3-yl)acetonitrile was dissolved in 40 ml of toluene, 1 g of triethylamine was added, and further 1.1 g of 4-(3,4-methylenedioxybenzyl)piperazine was added. °
After heating at C for 1 hour with stirring, the washed product was filtered off. Dilute hydrochloric acid was added to the filtrate to separate the resulting candy-like precipitate, and the precipitate was made alkaline by adding cold aqueous ammonia, followed by extraction with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the chloroform eluates were combined, and the solvent was distilled off under reduced pressure. The residue was treated with hydrochloric acid in a conventional manner and recrystallized from ethanol to obtain 0.6 g of the desired hydrochloride as colorless crystals. Melting point 202-208°C
, 2-benzisoxazol-3-yl) methylbiperazine: 3-bromomethyl-1,2-benzisoxazole Ig
was dissolved in 30 IIll of chloroform, 0.57 g of triethylamine was added thereto, 10 ml of a chloroform solution containing Ig of 4-(3,4-methylenedeoxybenzyl)piperazine was added, and the mixture was refluxed for 1 hour.

After cooling, add 100 ml of 5% sodium carbonate aqueous solution,
Extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated with hydrochloric acid in a conventional manner and recrystallized from ethanol-diethyl ether to obtain 0.65 g of the desired dihydrochloride as colorless crystals.

Melting point: 208-212°C Compounds of Examples 5-40 shown in Table 2 were obtained by reacting and treating the corresponding piperazines in the same manner as in Examples 1-4. Obtained.

(Margins below) Table 2 Table 2 (Continued) Table 2 (Continued) Table 2 (Continued) (Margins below) Table 2 (Continued) (Margins below) Ability side -11 4-(3,4 -methylenedioxybenzyl)-4-methyl-1-[isoamyloxycarbonyl-(1,2-benzisoxazol-3-yl)]methylpiperazinium Yosito production: isoamyl 2-[4-(3 ,4
-methylenedioxybenzyl)piperazino] -2-(
Dissolve 0.72 g of 1,2-benzisoxazol-3-yl) acetate in 10 ml of acetone, and dissolve methyl
Yoshit Ig was added and left at room temperature overnight. After concentrating the reaction solution under reduced pressure, it was left in a cool place for 20 hours, and the precipitated crystals were collected by filtration to obtain 0.55 g of the desired product.

Melting point 148-153℃ -42-45 Reaction and reaction in the same manner as in Example 41 using the corresponding raw materials.
The compounds of Examples 42-45 shown in Table 3 were obtained upon processing.

(Margin below)

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 means a hydrogen atom, a halogen atom, or a lower alkoxy group, and R_2, R_3 and R_4 are the same or different and are hydrogen atoms, It means a halogen atom or a lower alkoxy group, or a methylenedioxy group in which two adjacent substituents are combined, and X is a single bond, -O-, -CH=CH-, or means a group represented by C=O, n means 0, 1, 2 or 3, Y is a hydrogen atom, a cyano group, -COOR_5 or -CON
means a group represented by R_6R_7, where R_
5 means a lower alkyl group or a cycloalkyl group, R
_6 and R_7 are the same or different and mean a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a phenylethyl group, or R_6 and R_7 taken together mean a saturated heterocyclic group containing a nitrogen atom. ] A 2-substituted piperazinyl-2-(1,2-benzisoxazol-3-yl)acetic acid derivative represented by these, and physiologically acceptable acid addition salts and quaternary ammonium salts thereof.