JP3352184B2 - Piperazine unsaturated fatty acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention has excellent antiallergic activity despite its weak antihistamine activity, and is useful as a therapeutic agent for bronchial asthma, allergic rhinitis, atopic dermatosis, urticaria, etc. The present invention relates to a novel piperazine unsaturated fatty acid derivative and a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art Many compounds having an anti-allergic effect, an anti-asthmatic effect and the like have hitherto been known. As piperazine derivatives similar to the present invention, for example, JP-A-3-246287 discloses that the following compound (A) and the like are useful as antiallergic agents and antiasthmatics. Not listed.

Embedded image Also, JP-A-59-62577 discloses a compound represented by the formula:

Embedded image It has been reported that 4- (diphenylmethyl) -1-piperazinyl- (2-butenoic acid) ethyl ester represented by is useful as a cardiovascular pharmaceutical composition. However,
A compound having the same structure as the compound of the present invention and having the same pharmacological action is not known.

[0003] Many antihistamines have been developed and used as therapeutic drugs for allergic skin diseases, rhinitis and the like, but as side effects of strong antihistamine action,
It had the drawback of having symptoms such as drowsiness and sedation due to the central depressant effect. Various studies have been made to overcome these drawbacks, but at present it is still insufficient. The present inventors have conducted intensive studies in view of the above-mentioned circumstances, and as a result, have an excellent antiallergic effect, have a weak antihistamine effect as compared with a control drug, and have low toxicity as compared with existing drugs, and have extremely low synthesis. The present inventors have found a novel piperazine unsaturated fatty acid derivative which is easy and have completed the present invention.

[0004]

That is, the piperazine unsaturated fatty acid derivative of the present invention has the following general formula [I]:

Embedded image [Wherein, R ₁ is a C1-C4 alkyl group, a C1-C4 alkoxy group, halogen, —CF ₃ , —NO ₂ ; R ₂ is —OH,
C1-C8 alkoxy group, C3-C6 cycloalkyl-
C1-C4 alkoxy group, C3-C6 cycloalkyloxy group, C1-C4 alkoxy-C1-C4 alkoxy group, C1-C4 hydroxyalkoxy group, 4-N-diphenylmethylpiperidinyloxy group, C1-C4 alkylamino group _{, -O (CH 2) nCH 2} -R 3 group (R ₃ is a phenyl group which may have a substituent selected from C1~C4 alkoxy group or a methylenedioxy group on the phenyl ring); a is phenyl Group, 1 or 2-naphthyl group, 2-
An aromatic ring group selected from a thienyl group or a 2-pyridyl group, and these aromatic ring groups may have a substituent selected from halogen on the ring; Y is at least one or more double bonds Or a C3 to C6 alkylene group having a triple bond; n represents 0 to 3], or a pharmaceutically acceptable salt thereof.

In the general formula [I] of the present invention, the C ₁ -C 4 alkyl group represented by R ₁ is methyl, ethyl, n-
Propyl, n-butyl; C1-C4 alkoxy as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy; halogen as chlorine, bromine, fluorine, iodine. Represented by R _2, C1 to C8
Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, n-pentyloxy, iso-pentyloxy, n-hexyloxy, iso-hexyloxy; C3 to C6 cycloalkyl- C1-C4 alkoxy as cyclopropylmethyloxy; C3-C6 cycloalkyloxy as cyclohexyloxy; C1-C4 alkoxy-C
1~C4 methoxyethoxy as alkoxy group, ethoxyethoxy, methoxypropoxy, ethoxypropoxy group; the C1～C ₅ hydroxyalkoxy group -OCH
_{2 CH 2 OH, -OCH 2 CH} 2 CH 2 OH, -OCH 2 CH
_{(OH) CH 2 OH, -OCH} 2 CH 2 OCH 2 CH 2 OH
A C1-C4 alkylamino group as methylamino;
Examples include ethylamino, propylamino, iso-propylamino, dimethylamino, and diethylamino groups.

[0006] represented by _{R 2, -O (CH 2)} nCH 2 -R 3
Represented by by R ₃ in; the C1~C4 alkoxy or methylenedioxy phenyl group which may be substituted with a group 3,4-methylenedioxyphenyl, 3,4,5-trimethoxyphenyl group and the like . As the phenyl group substituted by halogen represented by A, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl group, p-chlorophenyl
Examples include fluorophenyl, m-fluorophenyl, and o-fluorophenyl groups.

[0007] represented by Y, a double bond or The C3~C6 alkylene group having at least 1 or more triple bonds _{-CH = CH -, - CH 2} C≡C -, - CH 2 CH =
_{CH -, - CH 2 CH 2} CH = CH -, - CH 2 CH = C
HCH _2- ,

Embedded image Is mentioned.

The compound represented by the above general formula [I] of the present invention can be converted into a pharmacologically acceptable salt, or a base or acid can be liberated from the formed salt, if desired. . As the pharmacologically acceptable salt of the compound represented by the general formula [I] of the present invention, an acid addition salt or an alkali addition salt is provided. Examples of the acid addition salt include hydrochloric acid, hydrobromic acid and the like. Mineral salts such as sulfuric acid, nitric acid, phosphoric acid,
Lower alkyl sulfonates such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid, aryl sulfonates such as benzenesulfonic acid, acetic acid, maleic acid, fumaric acid, citric acid, malic acid, oxalic acid, Organic acid salts such as lactic acid and tartaric acid, and alkali addition salts include, for example, metal salts such as sodium, potassium and calcium, ammonium salts, organic bases such as methylamine, ethylamine, dimethylamine, triethylamine, ethanolamine and piperidine. Salts.

In the general formula [I], there are an E, Z coordination isomer based on a double bond portion and an optical isomer based on an asymmetric carbon atom, and the present invention relates to these stereoisomers and their stereoisomers. It also includes mixtures. The novel piperazine unsaturated fatty acid derivative represented by the general formula [I] of the present invention can be produced by the following various methods.

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[0010]

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[0011]

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Embedded image In the above formula, R ₁ , R ₂ , R ₅ , A, X, Y and n are as defined above.

Method A is a method for producing the compound [I] of the present invention. According to Method A, a piperazine derivative having the general formula [II] is reacted with a halogen compound represented by the general formula [III] in the absence of a solvent or in a solvent in the presence of a base as a deoxidizing agent to obtain a compound [ I] can be produced. The organic solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction.Examples include methanol, ethanol, iso-propanol, alcohol solvents such as n-butanol, tetrahydrofuran, dioxane, acetone, Examples include aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and the like, and the reaction is carried out in a range from under cooling to the reflux temperature of the solvent.
Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like.

Method B is a method for producing the compound [Ia] of the present invention. According to Method B, a piperazine derivative having the general formula [II] is reacted with a halogen compound having an E-coordination represented by the general formula [IV] in the absence of a solvent or in a solvent in the presence of a base as a deoxidizing agent. By this, compound [Ia] can be produced. The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction, for example, methanol, ethanol,
alcohol solvents such as iso-propanol and n-butanol; aprotic polar solvents such as tetrahydrofuran, dioxane, acetone, acetonitrile, N, N-dimethylformamide and dimethylsulfoxide; To the reflux temperature. Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like.

Method C is a method for producing the compound [Ib] of the present invention. According to the method C, the first step is a general formula [V]
A halogenated butyric acid derivative having a
ar) By catalytic reduction in the presence of a catalyst, the general formula [V
I] to produce a Z-coordinated halogenated butenoic acid derivative. The organic solvent used in the reduction reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, alcohols such as methanol, ethanol, iso-propanol, and n-butanol, tetrahydrofuran, dioxane, acetone, Acetonitrile,
Examples include polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, and nonpolar solvents such as benzene, toluene, xylene and chloroform. The reaction is carried out in a range from under cooling to the reflux temperature of the solvent. The pressure of the hydrogen gas used in the present production method is in a range from normal pressure to 10 atm.

As the second step, Z represented by the general formula [VI]
The compound [Ib] can be produced by reacting a coordinated halogen compound with a piperazine derivative having the general formula [II] without a solvent or in a solvent in the presence of a base as a deoxidizing agent. The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction.
Alcohol solvents such as -propanol and n-butanol, aprotic polar solvents such as tetrahydrofuran, dioxane, acetone, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide;
The reaction is carried out in a range from under cooling to the reflux temperature of the solvent. Further, as the base used as the dehydrohalogenating agent, for example, potassium carbonate, sodium carbonate,
Examples include potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like.

Method D is another method for producing the compound [Ib] of the present invention. According to Method D, compound [Ib] can be produced by catalytically reducing the compound represented by the general formula [Ic] in the presence of a Lindlar catalyst. The organic solvent used in the reduction reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, alcohols such as methanol, ethanol, iso-propanol, and n-butanol, tetrahydrofuran, dioxane, acetone, Polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide,
Non-polar solvents such as benzene, toluene, xylene and chloroform are mentioned, and the reaction is carried out in a range from under cooling to the reflux temperature of the solvent. The pressure of the hydrogen gas used in the present production method is in a range from normal pressure to 10 atm.

Method E is a method for producing a compound [Id] in which Y is -CH = CH- among the compounds represented by the above general formula [I]. According to Method E, compound [Id] can be produced by reacting a piperazine derivative having the general formula [II] with a propiolic acid derivative represented by the general formula [VII] without or in a solvent. The organic solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction.Examples include methanol, ethanol, iso-propanol, alcohol solvents such as n-butanol, tetrahydrofuran, dioxane, acetone, Examples include aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and the like, and the reaction is carried out in a range from under cooling to the reflux temperature of the solvent.

Method F is a method for producing the compound [If] of the present invention. According to the method F, a piperazine derivative represented by the general formula [Ie] or an acid addition salt thereof and a general formula [VIII]
Is reacted in the presence of an acid as a dehydrating agent to produce compound [If]. In the formula [VIII], R ₅ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec
-Butyl, n-pentyl, iso-pentyl, sec-pentyl, n-heptyl, iso-heptyl, cyclopropylmethyl, cyclohexyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl , 4-hydroxybutyl, 5-hydroxypentyl, 2,3-dihydroxypropyl, or _{- (CH 2) nCH 2 -R} 6 group (R ₆ is 3,4
A methylenedioxyphenyl or 3,4,5-trimethoxyphenyl group, n represents 0 to 3).

The reaction can be carried out by using an excess of the general formula [Ie] and the hydroxy derivative or by using a non-polar solvent which does not inhibit the condensation reaction thereof with 1 to 2 molar equivalents of the hydroxy derivative. The non-polar solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction, and examples thereof include benzene solvents such as benzene, toluene, and xylene, chloroform, dichloromethane, carbon tetrachloride, and ethyl ether. And aprotic non-polar solvents such as iso-propyl ether, tetrahydrofuran, and dioxane. The reaction is carried out under cooling to the reflux temperature of the solvent. Dilute sulfuric acid, concentrated sulfuric acid, dry hydrochloric acid gas and the like can be used as the acid as a dehydrating agent used in the condensation reaction in the present production method.

Method G is a method for producing the compound of the present invention represented by the general formula [Ih]. According to Method G, the compound [Ih] can be produced by reacting the piperazine derivative having the general formula [Ig] with the alkyl halide derivative represented by the general formula [IX] without or in a solvent. In the formula [Ig], Z represents sodium, potassium, calcium or the like; in the formula [IX], X represents chlorine, bromine, iodine; R ₇ represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- -Butyl, sec-butyl, n-pentyl,
iso-pentyl, sec-pentyl, n-heptyl, iso-heptyl, cyclopropylmethyl, cyclohexyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, - hydroxypentyl or _{- (CH 2) nCH 2 -R} 6 group (R ₆ is 3,4-methylenedioxyphenyl or 3,4,5-trimethoxyphenyl group, n represents 0 to 3) represents a. The organic solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, methanol, ethanol, iso-propanol, alcohol solvents such as n-butanol, tetrahydrofuran, dioxane, acetone, Acetonitrile, N, N-dimethylformamide,
Examples include a polar solvent such as dimethyl sulfoxide and a non-polar solvent such as benzene, toluene, xylene and chloroform, and the reaction is carried out at room temperature to the reflux temperature of the solvent.

Method H is a method for producing a compound [Ie] wherein R ₂ is —OH among the compounds represented by the general formula [I]. According to the method H, in the general formula [I], R ₂ is C1 to C4
The compound [Ie] can be produced by hydrolyzing a compound which is an alkoxy group without a solvent or in a solvent with an acid or a base. In this production method, hydrochloric acid, sulfuric acid or the like is used as an acid used for the hydrolysis, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like is used as a base, and water is used as a reaction solvent. , Methanol, ethanol, acetone, tetrahydrofuran and the like.
Performed in the range of ° C.

Method I is a method for producing the compound [Ii] of the present invention. According to the method I, as a first step, a piperazine derivative having the general formula [II] is combined with a halogenated propyne represented by the general formula [X] without solvent or in a solvent,
By reacting in the presence of a base as a deoxidizing agent,
A propynylpiperazine derivative represented by the general formula [XI] is produced. The organic solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, methanol, ethanol, iso-propanol, alcohol solvents such as n-butanol, tetrahydrofuran, dioxane, acetone, Examples include aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, and the like, and the reaction is carried out in a range from under cooling to the reflux temperature of the solvent.
Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like. In the second step, the general formula [X
I] is reacted with a C1-C4 alkyllithium or a lithium amide of a secondary amine in a nonpolar solvent under a stream of argon gas or nitrogen gas, and further carbon dioxide gas is added to the resulting reaction mixture. By reacting, compound [Ii] can be produced.

The C1-C4 alkyllithium in the present production method includes methyllithium, ethyllithium, n-propyllithium, iso-propyllithium, n-butyllithium, iso-butyllithium, sec-butyllithium, tert-butyllithium.
Butyl lithium. Examples of the lithium amide of the secondary amine include lithium diisopropylamide. The nonpolar solvent used in the condensation reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, n-hexane, ethyl ether,
Examples include aprotic non-polar solvents such as iso-propyl ether, tetrahydrofuran, and dioxane. The reaction is carried out under cooling, preferably in the range of -78 ° C to room temperature.

Method J is a method for producing the compound [Ig] of the present invention. By reacting a piperazine derivative having the general formula [Ie] with an inorganic base according to Method J,
Compound [Ig] can be produced. General formula [Ig]
In the formula, Z represents sodium, potassium, calcium and the like.
As the inorganic base used in the reaction in the present production method,
Examples include potassium hydroxide, sodium hydroxide, calcium hydroxide, acidic potassium carbonate, acidic sodium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and the like.

The compound represented by the general formula [II] used as a starting material in the process for producing the compound of the present invention, except for a part thereof, is, for example, Journal of Pharmaceutical Science (Journal of Pharmaceutical Sciences).
l Sience) Vol. 67, p. 900, 1978 and the like, and can be produced by the method represented by the following reaction formula.

Embedded image General formula [III] (and the following formula [II included therein)
Compounds represented by Ia]) are, for example, jars, with some exceptions.
Null of American Chemical Society (Journ
al of American Chemical Society) Vol. 73, 309
This compound is described in, for example, page 1, 1951, and can be produced by the method represented by the following reaction formula.

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Embedded image In the formula [IIIa] in the first method, R ₅ represents the same as described above, and in the second method, Q represents methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec. -Butanol, n-pentanol, iso-pentanol, sec-pentanol, n-heptanol, iso-heptanol, cyclopropylmethanol,
Cyclohexanol, methoxyethanol, methoxy propanol, ethoxy ethanol, ethoxy propanol, 2-hydroxy ethanol, 3-hydroxy-propanol, 4-hydroxy-butanol, 5-hydroxy-pentanol, 2,3-dihydroxy-propanol or HO (CH ₂₎ nCH, ₂ -R ₆ group (R ₆ and n are as defined above) represents an amine such as alcohols or ammonia, methylamine, ethylamine, n- propylamine, iso- propylamine and the like.

The novel piperazine-unsaturated fatty acid derivative represented by the above general formula [I] and the pharmaceutically acceptable salt thereof of the present invention have excellent antiallergic action despite their weak antihistamine action. It is useful as a therapeutic agent for bronchial asthma, allergic rhinitis, atopic dermatosis, urticaria and the like. In addition, the compound of the present invention also has an antibacterial effect, and in allergic diseases, especially in atopic dermatitis, the condition usually progresses as red spots, pruritus, disintegration, moistening, infection, and severe disease. Therefore, the compound of the present invention having antibacterial action is extremely useful clinically as an antiallergic agent. When the compound of the present invention is used as a drug, it can be administered orally or parenterally. Examples of the dosage form for oral administration include tablets, capsules, powders, fine granules, granules, solutions, and syrups. Examples of dosage forms for parenteral administration include injections and sprays. Preparations, eye drops, patches, suppositories and the like. In the preparation of these preparations, pharmacologically and pharmaceutically acceptable additives can be added, and excipients, disintegrants or disintegration aids, binders, lubricants, coating agents and pigments Are used.

In an oral preparation, excipients include glucose, lactose, D-mannitol, starch, crystalline cellulose and the like; disintegrants and disintegrants include carboxymethylcellulose, starch, carboxymethylcellulose calcium and the like. A binder such as hydroxypropylcellulose, hydroxymethylcellulose, polyvinylpyrrolidone and gelatin; a lubricant such as magnesium stearate and talc; a coating agent such as hydroxypropylmethylcellulose, sucrose and titanium oxide; . On the other hand, injections include water for injection, physiological saline, propylene glycol and the like as solubilizers or solubilizers that can constitute aqueous or ready-to-use injections; glucose, sodium chloride, D -Mannitol, glycerin and the like; As a pH adjuster, pharmaceutical ingredients such as inorganic acids, organic acids or inorganic bases and organic bases can be used. The dose of the compound of the present invention to a treated patient is generally 0.1 mg to 300 mg per day in the case of an adult by oral administration,
It can be increased or decreased as appropriate depending on age, symptoms, and the like.

[0028]

EXAMPLES The present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 Production of 4-bromobutenoic acid iso-propylamide i) 4-bromobutenoic acid: A solution of 10.57 g (0.055 mol) of 4-bromobutenoic acid ethyl ester in 20 ml of absolute ethanol was cooled to -15 ° C and stirred. Bottom, 20m
of 5N-KOH aqueous solution is gradually added dropwise and stirred for 1.5 hours. After further stirring at 0 ° C. for 2 hours, the reaction solution was concentrated under reduced pressure.
The residue was washed with ether, the aqueous layer was acidified with 10% diluted sulfuric acid under cooling, extracted with ether and dried, the solvent was distilled off, and anhydrous magnesium sulfate was added to the residue. Shake with ligroin and decant the supernatant. This operation was repeated several times, and the whole was combined and cooled to obtain the desired product, prismatic crystals, melting point 63-69 ° C, yield 3.4 g (37.5%). NMR δ (CDCl ₃ ) ppm 3.91-4.25
(M, 2H), 5.80-6.33 (d, J = 15H
z, 1H), 6.82-7.41 (m, 1H), 9.5
5 (s, 1H). Mass spec EI-MS m / z 164 (M ⁺ ) CI-MS m / z 165 (M ⁺ +1).

Ii) 4-bromobutenoic acid chloride: 8.
46 g (0.051 mol) of 4-bromobutenoic acid
5.4 ml (0.4 ml) of the anhydrous chloroform solution was cooled.
(077 mol) of thionyl chloride was added dropwise, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was distilled under reduced pressure, and the target substance was a yellow oily substance, boiling point 82-87 ° C / 21 mmHg, yield 4.16.
g (49%). iii) 4-bromobutenoic acid iso-propylamide: 0.8
3 g (0.013 mol) of iso-propylamine, 1.9
ml (0.013 mol) of triethylamine and 4 ml of anhydrous chloroform solution were gradually cooled under ice-cooling with 25 g (0.014 mol) of 4-bromobutenoic acid chloride in 8 ml of anhydrous chloroform, and heated at room temperature for 5 hours. Reflux. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform) to obtain the desired product as pale yellowish white prism crystals, melting point 67-70 ° C. , Yield 2.04
g (76.4%).

Reference Example 2 Production of [(4-acetoaminophenyl) phenylmethyl] piperazine i) 4-Acetaminobenzophenone: 10 g (0.0
51 mol) of 4-aminobenzophenone and an equimolar amount of triethylamine are suspended in 50 ml of anhydrous chloroform, and a solution of 4.4 g (0.056 mol) of acetyl chloride in 20 ml of anhydrous chloroform is added dropwise under ice-cooling. Stir overnight. The reaction solution is washed with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off to obtain 13.81 g (quantitative) of pale yellow crystals. The obtained crude crystals were recrystallized from ethyl acetate to give 7.87 g (64.5%),
The desired product at 148 ° C. is obtained. ii) 4-acetaminobenzhydrol: 7.87 g
(0.033 mol) of 4-acetaminobenzophenone is suspended in anhydrous ethanol, an equimolar amount of sodium borohydride is added little by little, and the mixture is stirred at room temperature for 3.5 hours. After completion of the reaction, the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product, 4-acetoaminobenzhydrol 8.1.
5 g (quantitative) of pale yellow crystals with a melting point of 126 DEG-132 DEG C. are obtained.

Iii) (4-acetoaminophenyl) phenylmethyl chloride: 1.2 g (0.005 mol) of 4-
Acetaminobenzhydrol is dissolved in anhydrous chloroform, 0.55 ml (0.0075 mol) of thionyl chloride is added dropwise under ice cooling, and the mixture is refluxed for 1.5 hours. After completion of the reaction, the solvent is distilled off and used for the next reaction without purification. iv) [(4-acetoaminophenyl) phenylmethyl]
Piperazine: 2.58 g (0.03 mol) of anhydrous piperazine and an equimolar amount of triethylamine are suspended in 12 ml of anhydrous chloroform, and 1.29 g (0.005 mol) under ice-cooling.
13 ml of 4-acetaminobenzhydryl chloride
An anhydrous chloroform solution is added dropwise, and the mixture is stirred at room temperature overnight. After completion of the reaction, the reaction solution was washed with water, extracted with 5% hydrochloric acid, neutralized with saturated sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.47 g (95% ) To obtain a deep yellow amorphous target product. NMR δ (CDCl ₃ ) ppm 2.07 (s, 3
H), 2.18-3.25 (m, 9H), 4.20
(S, 1H), 6.95-7.68 (m, 9H), 8.
02 (s, 1H). Mass spec EI-MS m / z 309 (M ⁺ ) CI-MS m / z 310 (M ⁺ +1).

Reference Example 3 Preparation of 6-bromo-2,4-hexadienoic acid ethyl ester 32.4 g (0.23 mol) of sorbic acid ethyl ester, 40.6 g (0.228 mol) of N-bromosuccinimide ( NBS) and 0.53 g of benzoyl peroxide in 14
Suspend in 0 ml of benzene and reflux for 20 hours. The reaction solution is cooled, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate: hexane = 1: 50) to obtain 10.45 g (26.8%) of a pale yellow oil. NMR δ (CDCl ₃ ) ppm 1.15 to 1.50
(T, J = 6.6 Hz, 3H), 3.97-4.45
(M, 4H), 5.80-6.49 (m, 3H), 7.
05-7.53 (m, 1H). Mass spec EI-MS m / z 218 (M ⁺ ) CI-MS m / z 219 (M ⁺ +1).

Reference Example 4 Preparation of 1- (diphenylmethyl) -4- (2-propynyl) piperazine 2.52 g (0.010 mol) of 1- (diphenylmethyl) piperazine and 1.01 g (0.010 mol) Was dissolved in 40 ml of methanol, and 1.19 g (0.010 mol) of 3-bromo-1-amine was dissolved at room temperature.
Add propyne. The reaction solution is refluxed for 4 hours, cooled and concentrated, and the residue is dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane) to concentrate the target fraction.
Recrystallization with propanol gives 1.67 g (58%) of the desired product, mp 88-90 ° C. NMR δ (CDCl ₃ ) ppm 2.22 (t, J =
2.4Hz, 1H), 2.35-2.64 (m, 8H),
3.25 (d, J = 2.4 Hz, 2H), 4.23 (s,
1H), 7.10-7.51 (m, 10H). Mass spec EI-MS m / z 290 (M ⁺ ) CI-MS m / z 291 (M ⁺⁺ 1).

Reference Example 5 1-[(4-chlorophenyl) phenylmethyl] -4-
Preparation of (2-propynyl) piperazine 14.3 g (0.050 mol) of 1- (4-chlorobenzhydryl) piperazine and 5.56 g (0.055 mol) of triethylamine were dissolved in 200 ml of benzene and iced. Under cooling 6.54 g (0.055 mol) of 3-bromo-1-propyne are added. The reaction solution is refluxed for 1 hour, cooled and concentrated, and the residue is dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane: methanol = 50: 1) to obtain 13.6 g (84%) of the desired product as a yellow oil. obtain. NMR δ (CDCl ₃ ) ppm 2.18 (t, J =
2.4Hz, 1H), 2.34-2.58 (m, 8H),
3.20 (d, J = 2.4 Hz, 2H), 4.12 (s,
1H), 7.02-7.35 (m, 9H).

Example 1 (Method A) 4- [4-[(4-chlorophenyl) phenylmethyl] -1
Preparation of [-Piperazinyl] -2-butenoic acid ethyl ester dihydrochloride (Compound No. 5) 4.3 g (0.015 mol) of 1- (4-chlorobenzhydryl) piperazine were suspended in 40 ml of benzene. ,
5.01 g (0.02 mol) of ethyl 4-bromocrotonate and an equimolar amount of triethylamine are added, and the mixture is refluxed for 5 hours. The reaction solution is cooled, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 10
0: 1) to give 4.67 g (78.1%) of a yellow oil. The resulting oil was converted to the hydrochloride salt with methanolic hydrochloric acid (16%), and the obtained crude crystals were recrystallized from ethanol to give a melting point of 191-196 ° C and a yield of 2.84 g (47.5 g).
%) To obtain the desired product.

Example 2 (Method B) (E) of 4- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -2-butenoic acid ethyl ester dihydrochloride (Compound No. 83) Preparation 28.5 g (0.25 mol) of (E) -2-butenoic acid ethyl ester, 44.5 g (0.25 mol) of N-bromosuccinimide, 0.1 g of benzoyl peroxide, and 100 ml of dry benzene Is refluxed for 6 hours. After cooling, the mixture is filtered, and the filtrate is successively washed with a 0.5% aqueous solution of sodium hydrogen sulfate, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated. The resulting residue is distilled to give a boiling point of 84-85 ° C./10 mmHg, 29.8.
g (62%) of (E) -4-bromo-2-butenoic acid ethyl ester are obtained. Next, 8.6 g (0.03 mol) of 1- (4-chlorobenzhydryl) piperazine was added to 50 m.
The mixture is suspended in 1 benzene, 6.36 g (0.033 mol) of (E) -4-bromo-2-butenoic acid ethyl ester and an equimolar amount of triethylamine are added, and the mixture is refluxed for 1 hour. The reaction solution is cooled, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: dichloromethane: methanol = 3)
0: 1), the resulting yellow oil was converted to the hydrochloride salt with methanolic hydrochloric acid (16%) and the resulting crude crystals were recrystallized from 2-propanol to give a melting point of 196-200 ° C. and a yield of 5.76 g (41%). %) To obtain the desired product.

Example 3 (Method C) Preparation of (Z) -4- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -2-butenoic acid ethyl ester maleate (Compound No. 95) Preparation 14.6 g (0.1 mol) of 4-chloro-2-butyric acid ethyl ester are dissolved in 100 ml of acetone,
The catalytic hydrogenation-reduction reaction is carried out at room temperature under a hydrogen pressure of 1 atm for 18 hours in the presence of 1.1 g of Lindlar catalyst. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: hexane: acetone = 30: 1) to give (Z) -4-chloro-2-butenoic acid ethyl ester. 98 g are obtained as a colorless oil. This compound is used for the next reaction without further purification. 1.48 g (0.01 mol) of this compound and 1.
43 g (0.005 mol) of 1- (4-chlorobenzhydryl) piperazine are dissolved in 30 ml of benzene,
Reflux for 12 hours in the presence of 1.01 g (0.01 mol) of triethylamine and one drop of DMF. After cooling, the mixture was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane: methanol =
50: 1) twice to give 0.43 g of a yellow oil. This compound was converted into a maleic acid salt by a conventional method, and recrystallized twice from ethyl acetate / methanol to give the target compound having a melting point of 164-166 ° C and white crystals in 0.0%.
9 g are obtained.

Example 4 (Method D) Preparation of (Z) -4- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] -2-butenoic acid ethyl ester maleate (Compound No. 95) Production 2.41 g (0.0067 mol) of 4- [4-[(4-
Chlorophenyl) phenylmethyl] -1-piperazinyl] -2-butyric acid ethyl ester was dissolved in 50 ml of acetone and, in the presence of 0.16 g of Lindlar catalyst,
The catalytic hydrogenation-reduction reaction is performed at room temperature under a hydrogen pressure of 1 atm. The reaction was terminated after 7 hours, the reaction solution was filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: dichloromethane: methanol = 50:
1) to give a pale yellow oil. This was converted to a maleate by a conventional method, and recrystallized twice from ethyl acetate / methanol to give a melting point of 164-166.
0.81 g (26%) of the desired product is obtained.

Example 5 (Method E) 3- [4-[(4-chlorophenyl) phenylmethyl] -1
Preparation of ethyl 2-piperazinyl] -2-propenoate (Compound No. 1) 2.87 g (0.01 mol) of 1- (4-chlorobenzhydryl) piperazine was dissolved in 7 ml of ethanol, and cooled under ice-cooling. A mixture of .29 g (0.013 mol) of ethyl propiolate and 7 ml of ethanol was added dropwise. After leaving for a while, the precipitated crystals are collected by filtration to obtain 2.5 g (65.8%) of white crystals. The obtained crude crystals were recrystallized from ethanol to give a melting point of 106-108 ° C and a yield of 1.95 g (51.3%).
To get the target.

Example 6 (Method F) 4- [4-[(4-chlorophenyl) phenylmethyl] -1
Preparation of 1-piperazinyl] -2-butenoic acid iso-propyl ester dihydrochloride (Compound No. 7) 1 g (0.003 mol) of 4- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl] Dissolve 2-butenoic acid in 100 ml of iso-propanol, add dropwise 1 ml of concentrated sulfuric acid under ice cooling, and reflux overnight. The solvent is distilled off under reduced pressure while leaving a small amount, water is added to the residue, neutralized with sodium carbonate, and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.1 g (quantitative) of a pale yellow oil. The obtained oil was converted into a hydrochloride with a methanol solution of hydrochloric acid (9.9%), and the obtained crude crystals were recrystallized from ethanol to give a melting point of 195-199 ° C and a yield of 0.7.
1 g (64.5%) of the desired product were obtained as colorless needles.

Example 7 (Method G) 4- [4-[(4-chlorophenyl) phenylmethyl] -1
Preparation of 3-piperazinyl] -2-butenoic acid 3-hydroxypropyl ester dihydrochloride (Compound No. 17) 1.17 g (0.003 mol) of 4- [4-[(4-chlorophenyl) phenylmethyl] -1 -Piperazinyl]
Sodium 2-butenoate was dissolved in 15 ml of absolute ethanol, 0.27 ml (0.003 mol) of 3-bromo-1-propanol was added, and the mixture was refluxed for 70 hours. After evaporating the solvent, the residue is dissolved in ethyl acetate, washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography.
(Eluent: chloroform: methanol = 50: 1) to give 0.32 g (25%) of a yellow oil. The resulting oil was converted into the hydrochloride salt with methanolic hydrochloric acid (9.9%), and 0.28 g (21.9%) of the desired product was obtained as a pale yellow amorphous substance.

Reference Example 6 (Method H) 4- [4- (diphenylmethyl) -1-piperazinyl] -2-
Preparation of butenoic acid (Compound No. 56) 4.4 g (0.012 mol) of 4- [4- (diphenylmethyl) -1-piperazinyl] -2-butenoic acid ethyl ester was dissolved in 43 ml of 5% hydrochloric acid, Reflux for 2.5 hours. After cooling, pH 7.2 with saturated sodium bicarbonate solution
And extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 10: 1) to give 1.68 g (4
2%) of white crystals are obtained. The obtained crude crystals were recrystallized from methanol to give a melting point of 108-110 ° C and a yield of 1.07 g.
(26.7%) to give the desired product.

Reference Example 7 (Method I) 4- [4- (diphenylmethyl) -1-piperazinyl]
Preparation of 2-butyric acid (Compound No. 57) 1.45 g (0.005 mol) of 1- (diphenylmethyl) -4- (2-propynyl) piperazine was dissolved in 50 ml of anhydrous ether, and the mixture was dissolved under nitrogen. At 78 ° C
3.8 ml of n-butyllithium / n-hexane solution (1.6M)
ml (0.006 mol) are added dropwise. After stirring for 30 minutes, an excess amount of carbon dioxide gas is injected, and the temperature is slowly raised to room temperature. Carefully add 30 ml of water, wash with ether and separate the aqueous layer. The aqueous layer is made weakly acidic with 10% aqueous hydrochloric acid and extracted twice with dichloromethane. After drying over anhydrous magnesium sulfate, the organic layer was concentrated, and the residue was recrystallized with a mixed solvent of ethanol and methanol to give a residue having a melting point of 1: 1.
12-115 ° C, 0.82 g (49%) of the desired product as white prism crystals.

Example 8 (Method J) 4- [4-[(4-chlorophenyl) phenylmethyl]-
Preparation of 1-piperazinyl] -2-butenoic acid sodium salt (Compound No. 60) 0.2 g (0.0005 mol) of 4- [4-[(4-chlorophenyl) phenylmethyl] -1-piperazinyl]-
2-butenoic acid is dissolved by heating in 8 ml of ethanol, and after cooling, 2 ml of an equimolar sodium hydroxide solution in ethanol is added dropwise through a filter paper. The solvent is distilled off to give a melting point of 21.
4-222 DEG C., yield 0.23 g (quantitative) of white crystals.

Using methods similar to those described in the above examples, the compounds shown in the following table are prepared.

[Table 1]

[0046]

[Table 2]

[0047]

[Table 3]

[0048]

[Table 4]

[0049]

[Table 5]

[0050]

[Table 6]

[0051]

[Table 7]

[0052]

[Table 8]

[0053]

[Table 9]

[0054]

[Table 10]

[0055]

[Table 11]

[0056]

[Table 12]

[0057]

[Table 13]

[0058]

[Pharmacological test] Next, a pharmacological test method for the compound of the present invention and the results thereof will be described. Test Example 1: Passive cutaneous anaphylaxis (PCA) inhibitory effect This test was performed by the method of Tada and Okumura [Tada, T. and Okumura, T .:
J. Immunol., 106, 1002-1011, 1971]. Anti-DNP-produced according to the method of Tada and Okumura at four sites in the back skin of male Wistar rats (weight 150-200 g)
0.05 ml of a 1000-fold diluted solution of Ascaris serum
/ Site for passive sensitization. 48 hours later,
0.5% E containing 0.25 mg of DNP-Ascaris
vans blue physiological saline solution 0.5ml / 100
g was injected intravenously under anesthesia to elicit a reaction. 40
After a minute, bang the head and kill the blood, then peel off the skin,
Leakage dye at the injection site was extracted and quantified. The test compound was orally administered 1 hour before the induction of the reaction. The inhibition rate was compared with the case where a 0.7% aqueous solution of methylcellulose was orally administered as a control. Table 14 shows the results. As shown in the table, all the compounds showed stronger effects than the compound A. In addition, ketotifen used as a control drug showed the same action as described in the literature.

[0059]

[Table 14]

Test Example 2: Antihistamine Action The head of a Hartley female guinea pig (body weight: 500 to 650 g) was blown to death by exsanguination, and then about 10 to 2 from the ileocecal part.
A 5 cm ileum was removed and a 3 cm long specimen was prepared.
The specimen was subjected to Ty under a 95% O ₂ +5 CO ₂ % gas mixture.
0.5 into a Magnus tube filled with a rode solution (30 ± 1 ° C).
g and suspended. The sample was allowed to stand for about 60 minutes, and after the specimen was stabilized, a single application of histamine (3 × 10 −7 M) was performed. The contraction was measured and recorded isotonic using an isotonic transducer. After the contraction was fixed, the test compound was pretreated for 3 minutes to examine the inhibitory effect. The results were expressed as EC50 values. Table 15 shows the results. As shown in Table 15, all of the compounds showed weaker antihistamine action than Compound A and ketotifen used as the control.

[0061]

[Table 15]

Test Example 3: Konzett & Rossler
Method test 10% ovalbumi in Hartley female guinea pigs
n was sensitized by injecting 1 ml intraperitoneally and subcutaneously. Approximately 3 weeks after sensitization, guinea pigs were anesthetized with urethane, tracheal cannula with side branches were intubated, and connected to a ventilator. g
Immobilized by intravenous injection of allamine and artificial respiration was performed. Challenge the antigen when respiration is stable,
Respiratory anaphylaxis (IgG dependent histamine spasm)
Was induced, and the change in airway pressure at that time was measured for 10 minutes by Kotzett & Wrestler method. The test compound was orally administered one hour before the antigen challenge. As a result, the inhibition rate at the time of drug treatment was expressed in%, with the area under the one-hour curve of airway pressure change in sensitized guinea pigs to which the solvent was administered as 100%. Table 16 shows the results. As shown in Table 16, all the compounds exhibited the same or better effects as Compound A. In addition, ketotifen used as a control drug showed the same action as described in the literature.

[0063]

[Table 16] ★: 30μg / kg-po

Test Example 4: Toxicity test ICR male mice fasted overnight (weight 25-35 g)
Was orally administered with a test compound, and the survival or death up to 24 hours was determined. The results are shown as the minimum lethal dose. Table 17 shows the results. As shown in Table 17, all compounds showed lower toxicity than the existing drug, ketotifen, which was used as a control. Therefore, the compounds of the present invention are extremely safe compounds, and can be used for a long term as pharmaceuticals.

[Table 17]

[0065]

The piperazine unsaturated fatty acid derivative of the present invention
[I] and its addition salts show excellent effects in tests against various allergic effects. In addition, the antibacterial activity of the present compound was examined for Staphylococcus aureus and the like, and as a result, it was shown to have antibacterial activity. It is generally assumed that the progression of the pathology in allergic diseases, particularly in atopic dermatitis, progresses through erythema, pruritus, disintegration, moistening, infection, and seriousness. The piperazine unsaturated fatty acid derivative of the present invention [I ] And its addition salts have an antibacterial effect and are therefore particularly clinically useful agents. Therefore, the compound of the present invention has excellent antiallergic action and antiasthmatic action despite its weak antihistamine action, has low toxicity, and is useful as a therapeutic agent for allergic diseases or asthma.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 37/08 37/08 C07D 213/61 C07D 213/61 295/14 295/14 A 333/20 333/20 333/28 333/28 (72) Inventor Yasuko Bonshihara 2 Mishimacho, Ibaraki City, Osaka Prefecture 1-808 Ibaraki Laurel Heights 1-808 Inventor Fumitsuki Iwakura 2-13-7 Toyosato, Higashiyodogawa-ku, Osaka City, Osaka Prefecture Grand Heights Onishi 406 (72) Inventor Yoshinobu Akimoto 3-1-15 Sakae, Kumiyama-cho, Kuse-gun, Kyoto (72) Inventor Hirohiko Sakamoto Approximately 766, Ikaruga-cho, Ikoma-gun, Nara Prefecture 200-27 Nishiki Tsujicho Shintani Building 3F (72) Inventor Takeshi Takeno 1-24-2 Shibacho, Takatsuki-shi, Osaka Sanheim 303 (72) Inventor Akihide Eda 3-8-20 Fukumitsuhigashi, Gifu City, Gifu Prefecture (72) Inventor Hiroi Nagai Gifu, Gifu Mayor Ryo Ryuhigashi 3-55 (56) References JP-A-3-246287 (JP, A) JP-A-59-62577 (JP, A) Jerry March, Advanced Organic Chemistry, 3rd Edition, p. 433-434 (1985) Jerry March, Advanced Organic Chemistry, 3rd Edition, p. 691-700 (1985) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/00-31/496 C07D 213 / 00-213/75 C07D 295/00-295/14 C07D 333/00-333/42 CA (STN) REGISTRY (STN) CAOLD (STN)

Claims (9)

(57) [Claims] 1. A compound of the general formula [I]: [Wherein, R ₁ is a C1-C4 alkyl group, a C1-C4 alkoxy group, halogen, —CF ₃ , —NO ₂ ; R ₂ is —OH,
C1-C8 alkoxy group, C3-C6 cycloalkyl-
C1-C4 alkoxy group, C3-C6 cycloalkyloxy group, C1-C4 alkoxy-C1-C4 alkoxy group, C1-C4 hydroxyalkoxy group, 4-N-diphenylmethylpiperidinyloxy group, C1-C4 alkylamino group _{, -O (CH 2) nCH 2} -R 3 group (R ₃ is a phenyl group which may have a substituent selected from C1~C4 alkoxy group or a methylenedioxy group on the phenyl ring); a is phenyl Group, 1 or 2-naphthyl group, 2-
An aromatic ring group selected from a thienyl group or a 2-pyridyl group, and these aromatic ring groups may have a substituent selected from halogen on the ring; Y is at least one or more double bonds Or a C3-C6 alkylene group having a triple bond; n represents 0 to 3] or a pharmacologically acceptable salt thereof. 2. The piperazine unsaturated fatty acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is a C3-C6 alkylene group having at least one or more E-coordinate double bond. 3. The piperazine unsaturated fatty acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein Y is a C3-C6 alkylene group having at least one or more Z-coordinate double bond. 4. A compound of the general formula [I]: [Wherein, R ₁ is a C1-C4 alkyl group, a C1-C4 alkoxy group, halogen, —CF ₃ , —NO ₂ ; R ₂ is —OH,
C1-C8 alkoxy group, C3-C6 cycloalkyl-
C1-C4 alkoxy group, C3-C6 cycloalkyloxy group, C1-C4 alkoxy-C1-C4 alkoxy group, C1-C4 hydroxyalkoxy group, 4-N-diphenylmethylpiperidinyloxy group, C1-C4 alkylamino group _{, -O (CH 2) nCH 2} -R 3 group (R ₃ is a phenyl group which may have a substituent selected from C1~C4 alkoxy group or a methylenedioxy group on the phenyl ring); a is phenyl Group, 1 or 2-naphthyl group, 2-
An aromatic ring group selected from a thienyl group or a 2-pyridyl group, and these aromatic ring groups may have a substituent selected from halogen on the ring; Y is at least one or more double bonds Or a C3-C6 alkylene group having a triple bond; n represents 0 to 3], or one or more pharmaceutically acceptable salts of a piperazine unsaturated fatty acid represented by the following formula: Allergic disease therapeutic agent. 5. The agent for treating an allergic disease according to claim 4, comprising one or more of the piperazine unsaturated fatty acid derivative according to claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient. . 6. A bronchial asthma or allergic, which comprises, as an active ingredient, at least one of the piperazine unsaturated fatty acid derivative or the pharmaceutically acceptable salt thereof according to any one of claims 2 and 3. Prophylactic or therapeutic agent for rhinitis, atopic skin disease, urticaria. 7. A general formula: And a compound represented by the general formula: A compound represented by the general formula: [In the above formulas, X is a leaving group, and R ₁ , A, R ₂ and n have the same meanings as in claim 1.] and a pharmaceutically acceptable derivative thereof. Method for producing salt. 8. A general formula obtained by catalytically reducing a compound represented by the formula X—CH ₂ C≡CCOO—R ₂ in the presence of a Lindlar catalyst: A compound represented by the general formula: Wherein the compound is reacted with a compound represented by the following formula: [In the above formulas, X is a leaving group, and R ₁ , A, R ₂ and n have the same meanings as in claim 1.] and a pharmaceutically acceptable derivative thereof. Method for producing salt. 9. A compound of the general formula: A compound represented by the general formula: which is obtained by reacting a compound represented by the following formula with carbon dioxide in the presence of alkyl lithium. Is represented by the general formula: R ₅ —OH wherein R ₅ is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, iso- Pentyl, sec-pentyl, n-heptyl, i
so-heptyl, cyclopropylmethyl, cyclohexyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 2,3-dihydroxypropyl, or _{- (CH 2) nCH 2 -R} 6 group (R ₆ is 3,4-methylenedioxyphenyl or 3,4,5-trimethoxyphenyl group,
n represents 0 to 3)] and a compound represented by the general formula: Wherein a compound represented by the formula is synthesized and further subjected to catalytic reduction in the presence of a Lindlar catalyst, characterized by the general formula: [Wherein R ₁ , A, R ₂ and n are as defined in claim 1], and a method for producing a piperazine unsaturated fatty acid derivative and a pharmacologically acceptable salt thereof.