JPH08325241A - Piperazine derivative - Google Patents

Abstract

PURPOSE: To obtain a new compound having excellent antiallergic action, thus useful for treating, as an antiallergic agent, allergic diseases such as bronchial asthma, pollinosis, allergic rhinitis and endocarditis. CONSTITUTION: This new compound (salt) is expressed by formula I (R1 is benzene ring, naphthalene ring, etc.; R2 and R3 are each H or a lower alkyl), e.g. 3-[4-(2-carboethoxyphenyl)piperazinyl]-1-(2-t-butyl-4-methoxyphenyl)pr opan-2- ol. The compound of formula I is obtained by condensation reaction under heating between a 2,3epoxypropanol derivative of formula II and a 4-(2- carboalkoxyphenyl)piperazine of formula III through reflux under heating in the presence of an organic amine in a solvent. The compound of formula II is prepared, for example, from a compound of the formula R1 OH and a halomethyl oxirane. The compound of formula III is prepared, for example, by reaction between N-monobenzylpiperazine and an o-halobenzoic acid lower alkyl ester followed by catalytic reduction.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel and useful piperazine derivative, a method for producing the same, a drug containing the same as an active ingredient and an antiallergic agent.

[0002]

BACKGROUND OF THE INVENTION The present inventors have already succeeded in synthesizing a propanolamine derivative represented by the following formula, and have found that these compounds are useful as antihypertensive agents and antiglaucoma agents (Japanese Patent Application No. Hei 10 (1999) -135242). 6-11844).

[0003]

Embedded image

[Wherein R ₁ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ₂ represents an isopropylamino group, a tert-butylamino group or a 2- (2-methoxyphenyl) ethyl-1-amino group. , 4- (2-methoxyphenyl) -1-piperazinyl group or 4-piperonyl-1
Represents a piperazinyl group. However, when R ₁ is a hydrogen atom, R ₂ is not an isopropylamino group and a tert-butylamino group, and when R ₁ is a methyl group, R ₂ is not an isopropylamino group. ]

[0005]

DISCLOSURE OF THE INVENTION The present inventors have further conducted earnest research on the synthesis and drug efficacy of these related compounds. As a result, they have succeeded in synthesizing novel piperazine derivatives and found that these compounds are useful as antiallergic agents. The present invention has been completed through further studies based on these new findings.

[0006]

That is, the present invention is
(1) The following formula (I)

[0007]

[Chemical 4]

[Wherein R ₁ represents a benzene ring, naphthalene ring, quinoline ring, indole ring or chroman ring which may be substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group or an amino group, and R ₂ and R ₃ represents a hydrogen atom or a lower alkyl group. ] The piperazine derivative represented by these, or its pharmacologically acceptable salt (henceforth this compound), (2) The following formula (II) [In Formula, R < ₁ > is synonymous with the above. ] The 2,3-epoxy propanol derivative represented by the following formula (III) [in the formula,
R ₂ and R ₃ are as defined above. ] 4-represented by
A method for producing a piperazine derivative or a pharmaceutically acceptable salt thereof according to (1) above, which comprises heat-condensing (2-carboalkoxyphenyl) piperazine or further hydrolyzing these compounds;

[0009]

Embedded image

(3) A drug comprising as an active ingredient the piperazine derivative or the pharmaceutically acceptable salt thereof described in (1) above, and (4) the piperazine derivative or pharmacologically thereof described in (1) above. The present invention relates to an anti-allergic agent containing a salt acceptable as an active ingredient as an active ingredient.

Specific examples of the present compound include the following compounds and pharmaceutically acceptable salts thereof. (1) 3- [4- (2-Carboethoxyphenyl) piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol (2) 3- [4- (2-carboxyphenyl) ) Piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol (3) 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (4-hydroxyphenoxy) propane -2-ol (4) 3- [4- (2-carboxyphenyl) piperazinyl] -1- (4-hydroxyphenoxy) propan-2-ol (5) 3- [4- (2-carboethoxyphenyl) piperazinyl ] -1-Phenoxypropan-2-ol (6) 3- [4- (2-Carboxyphenyl) piperazinyl] -1-phenoxypropan-2-o (7) 3- [4- (2-Carboethoxyphenyl) piperazinyl] -1- (1-naphthyl) propan-2-ol (8) 3- [4- (2-Carboxyphenyl) piperazinyl] -1- ( 1-naphthyl) propan-2-ol (9) 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol (10) 3- [4 -(2-Carboxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol (11) 3- [4- (2-carboxyethoxyphenyl) -2-methylpiperazinyl] -1 -(2-tert-Butyl-4-methoxyphenyl) propan-2-ol (12) 3- [4- (2-carboxyphenyl) -2
-Methylpiperazinyl] -1- (2-tert-butyl-4-
Methoxyphenyl) propan-2-ol (13) 3- [4- (2-carboxyethoxyphenyl) piperazinyl] -1- (3,4-methylenedioxyphenoxy) propan-2-ol (14) 3- [4 -(2-Carboxyphenyl) piperazinyl] -1- (3,4-methylenedioxyphenoxy) propan-2-ol (15) 3- [4- (2-carboethoxyphenyl)
Piperazinyl] -1- (α-tocopherol-6-yl) propan-2-ol (16) 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (α-tocopherol-6-yl) propan-2 -Ol (17) 3- [4- (2-carboxyphenyl) piperazinyl] -1- (4-aminophenoxy) propane-
2-ol (18) 3- [4- (2-carboxyphenyl) piperazinyl] -1- (3-tert-butyl-4-hydroxyphenoxy) propan-2-ol

The lower alkyl group represented by R ₂ and R _{3 in} the formula is preferably linear, branched or cyclic and has 1 to 5 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, iso-propyl group, cyclopropyl group, n-butyl group, tert-butyl group, se
Examples thereof include a c-butyl group, an n-pentyl group, a 1-ethylpropyl group and an iso-pentyl group.

In the formula, a benzene ring of R ₁ , a naphthalene ring,
The quinoline ring, indole ring or chroman ring may be substituted on the ring with a lower alkyl group, a lower alkoxy group, a hydroxyl group or an amino group, and the lower alkyl group has the same meaning as described above. The lower alkoxy group on the ring is preferably linear, branched or cyclic and has 1 to 5 carbon atoms. Specifically, methoxy group, ethoxy group, propoxy group, iso-propoxy group, n-butoxy group, iso-butoxy group, tert-
Examples thereof include butoxy group, n-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group and 1-ethylpropoxy group.

This compound is represented by the formula (II)
-The compound can be synthesized by reacting an epoxypropanol derivative and 4- (2-carboalkoxyphenyl) piperazine represented by the formula (III). Hereinafter, the method for producing the present compound will be described in detail.

[0015]

[Chemical 6]

The raw material is represented by the formula (II) 2,
The 3-epoxypropanol derivative can be synthesized by a known method, for example, as follows. That is, R ₁ OH [R ₁ has the same meaning as described above. ] And the following formula [X shows halogen atoms, such as a chlorine atom, a bromine atom, and an iodine atom. ] It can be obtained by heating a halogenated methyloxirane represented by the following in a solvent such as acetone or methyl ethyl ketone in the presence of an alkali carbonate.

[0017]

[Chemical 7]

The other starting material, 4- (2-carboalkoxyphenyl) piperazine represented by the formula (III), can be synthesized by a known method, for example, as follows. That is, N-monobenzylpiperazine and o-halogenated benzoic acid lower alkyl ester are heated in an organic solvent or in the absence of a solvent to give [1-benzyl-4- (2-carboxyalkyl)] piperazine (IV). Then, the compound can be obtained by catalytic reduction with palladium carbon (Pd-C) or the like. R ₂ and X in the formula are as defined above.

[0019]

Embedded image

The compound (II) and the compound (III) thus obtained are heated to reflux in a solvent such as dioxane in the presence of an organic amine such as triethylamine to obtain the compound (I). You can
This reaction is completed under heating under reflux for about 5 to 6 hours. The solvent used in this reaction is preferably dioxane or the like, but any solvent that does not inhibit this reaction can be used. The organic amine is preferably triethylamine or tributylamine. Further, among the present compounds, a compound in which R ₂ is a hydrogen atom can be obtained by saponifying (ester hydrolysis reaction) a compound in which R ₂ is a lower alkyl group with an alkaline compound such as sodium hydroxide.

The present compound thus obtained may be obtained as a pharmacologically acceptable salt by a known method. For example, the obtained compound is added to a suitable solvent with a substance that gives an alkali metal ion or an alkaline earth metal ion such as hydroxide, carbonate or hydrogen carbonate, or the reaction solution is treated with an acid. By making it acidic, the target salt can be obtained. The conversion to a salt may be performed after the compound is once isolated from the reaction solution, or may be performed without isolation from the reaction solution.

The present compound thus obtained can be purified and isolated by subjecting it to silica gel chromatography or recrystallization from an appropriate solvent such as methyl alcohol or ethyl alcohol.

The present compound thus obtained is a novel compound which has not been published in the literature and has an excellent anti-allergic action, and thus is an extremely useful compound.

The present compound used in the antiallergic agent of the present invention, whether it is a free compound or a pharmacologically acceptable salt thereof, can be appropriately used for the purpose of the present invention. . As the pharmacologically acceptable salt,
Examples thereof include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt. In addition, inorganic salts such as hydrochlorides, sulfates and nitrates or acetates, and organic salts such as maleates and tartaric acid are exemplified. Any salt other than these may be appropriately used as long as it is a pharmacologically acceptable salt.

Examples of the allergic disease treated by the antiallergic agent of the present invention include bronchial asthma,
Hay fever, allergic rhinitis, dietary allergic gastritis,
Allergic diarrhea, ulcerative colitis, stomatitis, periarteritis nodosa, endocarditis obliterans, endocarditis, urticaria, eczema,
Examples include contact dermatitis, fructene, sympathetic ophthalmitis, allergic conjunctivitis and allergic keratitis.

The antiallergic agent of the present invention is appropriately used orally or parenterally for the treatment of the above-mentioned various allergic diseases. As the form of the preparation, for example, solid preparations such as tablets, granules, powders, capsules and ointments, or liquid preparations such as eye drops, nasal drops and syrups are appropriately prepared by known methods. be able to. These formulations include commonly used excipients, binders, disintegrants, thickeners, dispersants, reabsorption promoters, buffers, surfactants, preservatives, isotonic agents, stabilizers and Various additives such as a pH adjuster may be used as appropriate.

When the present compound is used as an anti-allergic agent, the dose of the present compound varies depending on the kind of the compound used, the kind of target disease, the weight of the patient, the age and the indication symptoms and the administration method. For example, in the case of an injection, it is preferable to administer about 0.1 mg to about 30 mg once a day for an adult, and for an oral preparation, it is preferable to administer a dose of about 1 mg to about 100 mg once a day for an adult. When used as an eye drop, it is advisable to instill a substance having a concentration of about 0.01 (w / v)% to 0.5 (w / v)% once a few times and several times a day.

In the antiallergic agent of the present invention, one kind or two or more kinds of the present compounds can be used in an appropriate combination depending on the purpose and need.

[0029]

The present invention will be described in more detail below with reference to Examples and Formulation Examples.

Reference Example 1 Ethyl 2-piperazinyl benzoate monoacetate 11.5 g of ethyl 2-bromobenzoate, 17.6 g of N-monobenzylpiperazine and 6.91 g of potassium carbonate were mixed together, and the mixture was mixed at 220 ° C. for 2 minutes. Heat and stir for hours. After the reaction, the reaction mixture is cooled, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over sodium sulfate. After distilling off the solvent, the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1: 3) to obtain 10.5 g of a colorless oily substance. 10.5 g of the oil thus obtained was added to 10
% Palladium carbon 2.5 g, acetic acid 100 as a reaction solvent
ml, dioxane 100 ml, water 50 ml
The mixture is catalytically reduced under normal pressure for 2 hours to obtain 8.0 g of ethyl 2-piperazinyl benzoate monoacetate.

Reference Example 2 2-tert-butyl-4-methoxyphenoxymethyloxirane 4-hydroxy-3-tert-butylanisole 4.5 g
(0.025 mol) and chloromethyloxirane 8.
0 g is dissolved in 150 ml of methyl ethyl ketone, 7.0 g of anhydrous potassium carbonate is added thereto, the mixture is heated under reflux for 8 hours, inorganic salts are filtered off, and the filtrate is concentrated. The residual oily matter was extracted with ethyl acetate, washed with a 1% sodium hydroxide solution and water in this order, and the ethyl acetate was distilled off to obtain about 5 g of 2-tert-butyl-4-methoxyphenoxymethyloxirane as an oily matter.

Example 1 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (2-tert-butyl-
4-Methoxyphenyl) propan-2-ol 2.94 g of 2-piperazinyl ethyl benzoate monoacetate obtained in Reference Example 1 and 2-tert-butyl-4-obtained in Reference Example 2
2.36 g of methoxyphenoxymethyloxirane was dissolved in 100 ml of dioxane, 1.7 ml of triethylamine was added dropwise thereto, and the mixture was refluxed with heating for 6 hours. After the reaction, the solvent was distilled off, the residue was extracted with ethyl acetate, diluted hydrochloric acid,
Wash sequentially with water and saturated saline, and dry with mirabilite. After distilling off the solvent, the residue was recrystallized from benzene and isopropyl ether to give 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propane-2-. Obtain all 2.5g.
2.0 g of the compound thus obtained was further added to 3 ml of 30 ml of 2N sodium hydroxide and 10 ml of ethyl alcohol.
After heating under reflux for a period of time, the mixture is made neutral with acetic acid and the solvent is distilled off. The residue is dissolved in ethyl alcohol, water is added, and the precipitated crystals are collected by filtration to obtain 1.7 g of the desired compound having a melting point of 171 ° C to 172 ° C. Elemental analysis Theoretical value (%) as C ₂₅ H ₃₄ N ₂ O ₅ : C, 67.85; H, 7.74;
N, 6.33 Found (%): C, 67.78; H, 7.71;
N, 6.38

Example 2 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (4-hydroxyphenoxy) propan-2-ol Ethyl 2-piperazinyl benzoate monoacetate 1 obtained in Reference Example 1 0.54 g, 4-benzyloxyphenoxymethyloxirane obtained by the same reaction treatment as in Reference Example 2.
97 g, dioxane 50 ml, triethylamine 1.7 ml
Is heated to reflux for 5 hours. After the reaction, the mixture was treated in the same manner as in Example 1, and the residue was subjected to silica gel chromatography using chloroform to give 3- [4- (2-
Carboethoxyphenyl) piperazinyl] -1- (4-
Benzyloxyphenoxy) propan-2-ol 2.
6 g are obtained. 2.6 g of the compound thus obtained was subjected to catalytic reduction under atmospheric pressure using 1.5 g of 10% palladium-carbon, 80 ml of dioxane as a reaction solvent, and 20 ml of water.
[4- (2-carboethoxyphenyl) piperazinyl]
1.6 g of -1- (4-hydroxyphenoxy) propan-2-ol are obtained. 1.2 g of this compound was hydrolyzed and treated in the same manner as in Example 1, and the residue was converted into a hydrochloride, followed by recrystallization from ethyl alcohol to give a melting point of 235 ° C.
1.0 g of the target compound at 237 ° C. is obtained. Elemental analysis Theoretical value (%) as C ₂₀ H ₂₄ N ₂ O ₅ .HCl: C, 58.75; H, 6.16;
N, 6.85 Found (%): C, 58.55; H, 6.15;
N, 7.02

Example 3 3- [4- (2-Carboxyphenyl) piperazinyl] -1-phenoxypropan-2-ol 2.94 g of ethyl 2-piperazinylbenzoate monoacetate obtained in Reference Example 1 was used as a reference. Phenoxymethyloxirane (1.5 g) obtained by reacting in the same manner as in Example 2, 1.7 ml of triethylamine, and 80 ml of dioxane are heated to reflux for 5 hours. After the reaction, the mixture was treated in the same manner as in Example 1, and the residue was subjected to silica gel chromatography using ethyl acetate and hexane (1: 2) to give 3- [4- (2
2.8 g of -carboethoxyphenyl) piperazinyl] -1-phenoxypropan-2-ol are obtained. 2.0 g of the compound thus obtained was hydrolyzed and treated in the same manner as in Example 1 to give the residue as a hydrochloride salt, which was then recrystallized from methyl alcohol to give the desired compound having a melting point of 235 ° C. to 237 ° C. 1.6 g are obtained. Elemental analysis Theoretical value (%) as C ₂₀ H ₂₄ N ₂ O ₄ .HCl: C, 61.14; H, 6.41;
N, 7.13 Found (%): C, 61.12; H, 6.40;
N, 6.99

Example 4 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (1-naphthyl) propan-2-ol Ethyl 2-piperazinyl benzoate monoacetate obtained in Reference Example 1. 47 g, 1.0 g of 1-naphthylmethyloxirane obtained by the reaction treatment in the same manner as in Reference Example 2, 0.8 ml of triethylamine, and 50 ml of dioxane are heated to reflux for 4 hours. After the reaction, the reaction mixture was treated in the same manner as in Example 1, and the residue was subjected to silica gel chromatography using ethyl acetate and hexane (1: 3) to give a brown oil 3- [4- (2-
Carboethoxyphenyl) piperazinyl] -1- (1-
1.3 g of naphthyl) propan-2-ol are obtained. 1.3 g of the compound thus obtained was hydrolyzed and treated in the same manner as in Example 1, and the residue was converted into a hydrochloride, which was dissolved in methyl alcohol, and ether was further added to precipitate crystals. , 0.9 g of the desired compound having a melting point of 215 ° C. to 218 ° C. are obtained. Elemental analysis As C ₂₄ H ₂₆ N ₂ O ₄ .2HCl Theoretical value (%): C, 60.13; H, 5.89;
N, 5.84 Found (%): C, 60.42; H, 6.00;
N, 5.70

Example 5 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol Ethyl mono-2-piperazinyl benzoate obtained in Reference Example 1 2.34 g of acetate, 4- (2,3-epoxypropoxy) indole obtained by reacting in the same manner as in Reference Example 1.
The reaction and treatment were carried out in the same manner as in Example 1 using 89 g and 50 ml of dioxane to give 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol. 2.58 g are obtained. 2.58 g of the compound thus obtained are hydrolyzed and treated in the same manner as in Example 1, and the residue is subjected to silica gel chromatography to obtain 1.25 g of the desired compound having a melting point of 163 ° C to 165 ° C. Elemental analysis Theoretical value (%) as C ₂₂ H ₂₅ N ₃ O ₄ : C, 66.82; H, 6.37;
N, 10.63 Found (%): C, 66.73; H, 6.27;
N, 10.46

Example 6 3- [4- (2-carboxyphenyl) -2-methylpiperazinyl] -1- (2-
Tert-Butyl-4-methoxyphenyl) propan-2-ol 6.87 g of 2-bromobenzoic acid, 6.01 g of 2-methylpiperazine, 4.15 g of potassium carbonate Reference Example 1
The reaction is carried out in the same manner as described above to give a yellow oil 3- [4- (2-carboxyethoxyphenyl) -2-methylpiperazinyl] -1- (2-tert-butyl-4-methoxyphenyl)
8.8 g of propan-2-ol are obtained. 3.08 g of the compound thus obtained, 2.36 g of 2-tert-butyl-4-methoxyphenoxymethyloxirane obtained in Reference Example 2, 2.8 ml of triethylamine, dioxane 1
Heat to reflux with 00 ml for 5 hours. Then hydrolyzed and treated as in Example 1, melting point 205 ° C. to 20 ° C.
0.7 g of the target compound at 8 ° C. is obtained. Elemental analysis C ₂₆ H ₃₆ N ₂ O ₅・ 2HCl ・ 1 / 2H ₂
Theoretical value as O (%): C, 57.99; H, 7.30;
N, 5.20 Found (%): C, 58.22; H, 7.09;
N, 5.11

Example 7 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (3,4-methylenedioxyphenoxy) propan-2-ol 2-piperazinylbenzoic acid obtained in Reference Example 1 2.5 g of ethyl monoacetate, 3,4-obtained in the same manner as in Reference Example 2
Using 1.94 g of methylenedioxyphenoxyoxirane, 90 ml of dioxane, 1.7 ml of triethylamine, 5
Heat to reflux for hours. The mixture was treated as in Example 1, and the residue was subjected to silica gel chromatography using ethyl acetate and hexane (1: 1) to give 3- [4- (2
-Carboethoxyphenyl) piperazinyl] -1-
(3,4-methylenedioxyphenoxy) propane-2
-Obtain 2.6 g of all. 2.0 g of the compound thus obtained was hydrolyzed and treated in the same manner as in Example 1, and the residue was converted into a hydrochloride, which was then recrystallized from ethyl alcohol to give the desired compound having a melting point of 229 ° C to 231 ° C. 1.6 g
Get. Elemental analysis Theoretical value (%) as C ₂₁ H ₂₄ N ₂ O ₆ .HCl: C, 57.73; H, 5.77;
N, 6.41 Found (%): C, 57.68; H, 5.76;
N, 6.36

Example 8 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (α-tocopherol-6-yl) propan-2-ol Ethyl mono-2-piperazinyl benzoate obtained in Reference Example 1 Using 2.94 g of acetate, 4.87 g of α-tocopherol oxirane obtained by reacting in the same manner as in Reference Example 2, 100 ml of dioxane, and 1.8 ml of triethylamine, the mixture is heated under reflux for 4 hours. Thereafter, the mixture was treated in the same manner as in Example 1, and the residue was subjected to silica gel chromatography using ethyl acetate and hexane (1: 2) to give 3- [4-
(2-Carboethoxyphenyl) piperazinyl] -1-
2.5 g of (α-tocopherol-6-yl) propan-2-ol are obtained. Compound 2.
After hydrolyzing and treating 2 g in the same manner as in Example 1, the crystals were recrystallized from methyl alcohol-water to give a melting point of 94 ° C to 96 ° C.
1.4 g of the target compound of Elemental analysis C ₄₃ H ₆₈ N ₂ O ₅ and a theoretical (%): C, 74.52; H, 9.89;
N, 4.04 Found (%): C, 74.22; H, 10.08;
N, 3.97

Example 9 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol Ethyl 2-piperazinyl benzoate monoacetate 7 obtained in Reference Example 1 .24 g, 4-nitrophenyloxirane 4.80 g obtained by the reaction treatment in the same manner as in Reference Example 2, dioxane 200 ml, and triethylamine 6.8 ml were used.
Heat to reflux for hours. Thereafter, the same treatment as in Example 1 was carried out, and the residue was subjected to silica gel chromatography using ethyl acetate to give 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (4-nitrophenoxyl as a yellow oil. ) 2.5 g of propan-2-ol are obtained. 2.0 g of the compound thus obtained was hydrolyzed and treated in the same manner as in Example 1 to give the residue as a hydrochloride salt, which was then recrystallized from ethyl alcohol-ethyl acetate to give a melting point of 175 ° C. to 1
3- [4- (2-Carboxyphenyl) piperazinyl] -1- (4-nitrophenoxy) propane-2 at 78 ° C
-Obtain 1.0 g of all-2 hydrochloric acid. Next, 1.0 g of the obtained compound is dissolved in a mixed solution of 50 ml of dioxane and 50 ml of water, and catalytic reduction is performed using 10% palladium carbon. After completion of the reaction, the solvent is distilled off, and the obtained crystals are recrystallized from acetone to obtain 0.8 g of the desired compound having a melting point of 260 ° C to 263 ° C. Elemental analysis _{C 20 H 25 N 3 O 4} · 2HCl · 1.25H
Theoretical value (%) as ₂ O: C, 51.45; H, 6.37;
N, 9.00 Found (%): C, 51.24; H, 6.03;
N, 8.82

Example 10 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (3-tert-butyl-4-hydroxyphenoxy) propan-2-ol 2-piperazinyl obtained in Reference Example 1 1.47 g of ethyl benzoate monoacetate, 1.56 g of 4-benzyloxy-3-tert-butyl-phenoxyoxirane obtained by the reaction treatment as in Reference Example 2, 100 ml of dioxane and 1.4 ml of triethylamine were used. Heat to reflux for hours. Thereafter, the mixture was treated in the same manner as in Example 1, and the residue was subjected to silica gel chromatography using ethyl acetate and hexane (1: 2) to give 3- [4- (2-carboethoxyphenyl) piperazinyl] as a pale yellow oil. -1- (4-benzyloxy-
1.32 g of 3-tert-butyl-phenoxy) propan-2-ol are obtained. Compound 1.
32 g was hydrolyzed and treated in the same manner as in Example 1 to give the residue as a hydrochloride, and then recrystallized from acetone to give 3- [4
-(2-Carboxyphenyl) piperazinyl] -1-
(4-benzyloxy-3-tert-butyl-phenoxy)
1.10 g of propan-2-ol are obtained. 1.10 g of the obtained compound is dissolved in a mixed solvent of 50 ml of dioxane and 50 ml of water, and catalytic reduction is performed using 10% palladium carbon. After completion of the reaction, the solvent was distilled off, and the obtained crystals were recrystallized from methanol-acetone to give a melting point of 236 ° C-23
0.4 g of the target compound at 8 ° C. is obtained. Elemental analysis C ₂₄ H ₃₂ N ₂ O ₅ · HCl · 0.75H ₂
Theoretical value as O (%): C, 60.24; H, 7.27;
N, 5.85 Found (%): C, 60.45; H, 7.17;
N, 5.88

[Example 11] Effect of this compound on rat eyelid passive skin anaphylactic reaction (PCA reaction) The effect of this compound on rat eyelid PCA reaction was tested.

(Test substance) 3- [4- (2-carboxyphenyl) piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl)
Propan-2-ol (Compound of Example 1) 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol (Compound of Example 5)

(Method) In this test, a male Wistar rat weighing about 120 g, purchased from Japan SLC, was used. Antiserum (32-fold dilution) under the conjunctiva of rat right eye
25 μl was injected using a microsyringe under pentobarbital anesthesia. 48 hours after the injection of antiserum, 5 ml / kg of a mixed solution of 2% ovalbumin and 1% Evans blue was intravenously administered to the tail vein to induce a PCA reaction. The rat was sacrificed 30 minutes after the induction of the PCA reaction, the dye leakage site of the right eyelid was cut off, and the dye was extracted with 5 ml of formamide. The dye amount was measured at a wavelength of 625 nm. The test substance was orally administered 100 mg / 5 ml / kg 60 minutes before the induction of the PCA reaction.
As a control, 0.5% carboxymethyl cellulose (CM
C) Oral administration of 5 ml / kg. As a positive control, diphenhydramine hydrochloride 10 which is a commercially available antihistamine
0 mg / 5 ml / kg was orally administered.

(Results) The results are shown in Tables 1 and 2. As is clear from these results, this compound was found to be useful as an antiallergic agent.

[0046]

[Table 1] Effect of the present compound on rat eyelid PCA reaction Group Absorbance suppression rate (%) Control 0.662 ± 0.112-Compound of Example 1 0.299 ± 0.056 ^{* 2} 54.8 Diphenhydramine hydrochloride 0.413 ± 0.126 ^{* 1} 37.6

Each value represents an average ± standard deviation (n = 5). Significant difference from control group ^{* 1} ; p <0.05, ^{* 2} ; p <
0.001. The test is based on student-t.

[0048]

[Table 2] Effect of the present compound on rat eyelid PCA reaction Group Absorbance suppression rate (%) Control 0.486 ± 0.093- Compound of Example 5 0.276 ± 0.048 ^{* 1} 43.2

Each value represents an average ± standard deviation (n = 6). Significantly different from control group ^{* 1} ; p <0.001. The test is based on student-t.

[Formulation Example 1] Oral tablet Compound of Example 1 30 mg Lactose 80 mg Starch 17 mg Magnesium stearate 3 mg

[Formulation Example 2] Ophthalmic solution Compound of Example 5 100 mg Boric acid 700 mg Borax 400 mg Sodium chloride 500 mg Methyl p-oxybenzoate 26 mg Propyl p-oxybenzoate 14 mg Sterilized purified water Total amount 100 ml

[0052]

INDUSTRIAL APPLICABILITY Since the piperazine derivative of the present compound and the pharmacologically acceptable salt thereof have an excellent antiallergic action, they can be advantageously used for the treatment of various allergic diseases.

[Brief description of drawings]

1 shows an infrared absorption spectrum (IR) of the compound synthesized in Example 1. FIG.

FIG. 2 shows an infrared absorption spectrum (IR) of the compound synthesized in Example 4.

FIG. 3 shows an infrared absorption spectrum (IR) of the compound synthesized in Example 6.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display area A61K 31/495 ADA A61K 31/495 ADA C07D 215/20 C07D 215/20 295/14 295/14 A 311/58 311/58 317/58 317/58 403/12 209 403/12 209

Claims (22)

[Claims] 1. The following formula (I): [Wherein R ₁ is a lower alkyl group, a lower alkoxy group,
It represents a benzene ring, naphthalene ring, quinoline ring, indole ring or chroman ring which may be substituted with a hydroxyl group or an amino group, and R ₂ and R ₃ represent a hydrogen atom or a lower alkyl group. ] The piperazine derivative represented by these, or its pharmacologically acceptable salt. 2. A piperazine derivative or a derivative thereof according to claim 1, which is 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol. A pharmacologically acceptable salt. 3. 3- [4- (2-carboxyphenyl)
The piperazine derivative according to claim 1, which is piperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol, or a pharmaceutically acceptable salt thereof. 4. A piperazine derivative according to claim 1, which is 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (4-hydroxyphenoxy) propan-2-ol, or a pharmaceutically acceptable derivative thereof. salt. 5. 3- [4- (2-carboxyphenyl)
The piperazine derivative according to claim 1, which is piperazinyl] -1- (4-hydroxyphenoxy) propan-2-ol, or a pharmaceutically acceptable salt thereof. 6. The piperazine derivative according to claim 1, which is 3- [4- (2-carboethoxyphenyl) piperazinyl] -1-phenoxypropan-2-ol, or a pharmaceutically acceptable salt thereof. 7. 3- [4- (2-carboxyphenyl)
The piperazine derivative according to claim 1, which is piperazinyl] -1-phenoxypropan-2-ol, or a pharmaceutically acceptable salt thereof. 8. 3- [4- (2-Carboethoxyphenyl) piperazinyl] -1- (1-naphthyl) propane-
The piperazine derivative according to claim 1, which is 2-ol, or a pharmaceutically acceptable salt thereof. 9. 3- [4- (2-carboxyphenyl)
Piperazinyl] -1- (1-naphthyl) propane-2-
The piperazine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is all. 10. 3- [4- (2-Carboethoxyphenyl) piperazinyl] -1- (1H-indole-4-
2. The piperazine derivative according to claim 1, which is yloxy) propan-2-ol, or a pharmaceutically acceptable salt thereof. 11. A piperazine derivative according to claim 1, which is 3- [4- (2-carboxyphenyl) piperazinyl] -1- (1H-indol-4-yloxy) propan-2-ol, or a pharmacologically equivalent thereof. Acceptable salt. 12. The compound according to claim 1, which is 3- [4- (2-carboxyethoxyphenyl) -2-methylpiperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol. A piperazine derivative or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 1, which is 3- [4- (2-carboxyphenyl) -2-methylpiperazinyl] -1- (2-tert-butyl-4-methoxyphenyl) propan-2-ol. A piperazine derivative or a pharmaceutically acceptable salt thereof. 14. A piperazine derivative or pharmacology thereof according to claim 1, which is 3- [4- (2-carboethoxyphenyl) piperazinyl] -1- (3,4-methylenedioxyphenoxy) propan-2-ol. Acceptable salt. 15. The piperazine derivative according to claim 1, which is 3- [4- (2-carboxyphenyl) piperazinyl] -1- (3,4-methylenedioxyphenoxy) propan-2-ol, or a pharmacological agent thereof. Acceptable salt. 16. 3- [4- (2-Carboethoxyphenyl) piperazinyl] -1- (α-tocopherol-6
-Yl) propan-2-ol, The piperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1. 17. 3- [4- (2-Carboxyphenyl) piperazinyl] -1- (α-tocopherol-6-
2. The piperazine derivative according to claim 1, which is yl) propan-2-ol, or a pharmaceutically acceptable salt thereof. 18. The piperazine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is 3- [4- (2-carboxyphenyl) piperazinyl] -1- (4-aminophenoxy) propan-2-ol. . 19. A piperazine derivative or a drug thereof according to claim 1, which is 3- [4- (2-carboxyphenyl) piperazinyl] -1- (3-tert-butyl-4-hydroxyphenoxy) propan-2-ol. A physically acceptable salt. 20. The following formula (II) [wherein, R ₁ has the same meaning as defined above. ] The 2,3-epoxy propanol derivative represented by the following formula and the following formula (III) [wherein, R ₂ and R ₃ have the same meanings as described above]. ] The 4- (2-carboalkoxyphenyl) piperazine represented by these is heat-condensed, or these compounds are further hydrolyzed, The piperazine derivative of Claim 1 or its pharmacologically acceptable. Salt production method. Embedded image 21. A drug comprising the piperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 22. An anti-allergic agent comprising the piperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.