WO2002032883A1 - Novel 4-benzyloxyphenyl derivative and use thereof - Google Patents

Abstract

A 4-benzyloxyphenyl derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof: (I) wherein R1 and R2 are the same or different and each represents hydrogen, halogeno, nitro, cyano, or lower alkyl and R3 represents a structure represented by (II) or (III) (wherein R4 represents hydrogen, hydroxyalkyl, phenyl substituted by amino, or aminoalkyl; R5 represents hydrogen or lower alkyl; R6 represents hydrogen or lower alkyl; n is an integer of 0 to 3; and m is an integer of 0 or 1), provided that when R3 is a group containing a piperazine ring and n is 0, then at least one of R1 and R2 is halogeno, nitro, cyano, or lower alkyl. They are useful as an Na+/Ca2+ exchange inhibitor.

Description

 Description New 4-Benenyl Derivatives and Their Applications

 The present invention relates to a novel 4-benzyloxyphenyl derivative or a pharmacologically acceptable salt thereof and use thereof. Background art

The Na ⁺ / Ca ²⁺ exchange system (abbreviation: NCX) is one of the ion transport mechanisms to maintain the regulation of intracellular sodium ion concentration and potassium ion concentration. Normally, C acts as a pathway (forward mode) for pumping intracellular Ca ²⁺ mobilized during stimulation to the outside of the cell (forward mode). For example, in the case of myocardial ischemia ゃ ischemia reperfusion, Na ⁴ / H ⁺ exchange mechanism Activation and activation of Na ⁺ channels increase the intracellular Na ⁺ concentration and act as a pathway (reverse mode) for influx of extracellular Ca ²⁺ . This Ca ²⁺ influx is excessive, it is known to cause myocardial cell damage becomes Ca ²⁺ overload. Therefore, compounds that inhibit NCX can be used as drugs against various disorders induced by intracellular Ca ²⁺ overload. At present, three genes have been identified in NCX (NCX 1, NCX 2, NCX 3), NCX 1 is ubiquitously expressed mainly in various organs including myocardium, and NCX 2 is mainly expressed in brain, It is expressed in skeletal muscle, smooth muscle, kidney, etc., and NCX 3 is specifically expressed mainly in brain and skeletal muscle. In addition, NCX has been found to be present in the cornea, retina, and lens.

Compounds that selectively inhibit NCX include, for example, JP-A-7-41465 (quinazolidine derivatives), JP-A-9-167336 (isothioperia derivatives), and JP-A-10-218844 (2-phenoxyaniline derivatives). Compounds disclosed in JP-A-10-245336 (2- (4-benzyloxyphenoxy) aniline), JP-A-10-265460 (phenoxypyridine derivative) and the like are known. Have been. On the other hand, 1,6-disubstituted isochroman for migraine treatment The published international publication (W097 / 02259) states that 1,4- (4-benzyloxyphenyl) pidazine, which is considered to be closest to the compound of the present invention, synthesizes 1,6-disubstituted isochromans. (Example 9), but does not disclose any NCX inhibitory activity.

 Under the above circumstances, the present inventors have conducted various studies, and as a result, have created novel 41-benzyloxyphenyl derivatives and pharmacologically acceptable salts thereof, and these compounds have excellent NCX. They have found that they have an inhibitory effect, and have further studied to complete the present invention. That is, the present invention provides a novel 4-benzyloxyphenyl derivative having an NCX inhibitory action and its use. Disclosure of the invention

 The present invention

 (1) The following equation (I)

(Wherein, R and R ₂ are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a cyano group or a lower alkyl group, R ₃ represents any of the above structures, R ₄ represents hydrogen R ₅ represents a hydrogen atom or a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and n represents 0 or a hydrogen atom or a lower alkyl group substituted with an atom, a hydroxyalkyl group, or an amino group. Represents an integer of 3, and m represents an integer of 0 or 1, provided that R ₃ is piperazine A group containing a ring, when n is 0, and at least one of R ₂ is a halogen atom, a nitro group, a cyano group or a lower alkyl group. 4) Benzyloxyphenyl derivative or a pharmaceutically acceptable salt thereof,

(2) In the formula (I), and R ₂ both represent the same halogen atom, or one of them represents a halogen atom, the other represents a hydrogen atom, and R ₃ represents the above-mentioned piperazine ring. R ₄ represents a hydrogen atom, a hydroxyalkyl group, a phenyl group or an aminoalkyl group substituted with an amino group, R ₅ represents a hydrogen atom or a lower alkyl group, and n is an integer of 0 to 3. A 4-benzyloxyphenyl derivative or a pharmaceutically acceptable salt thereof according to the above (1),

(3) In the formula (I), R and R ₂ both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R ₃ represents a group containing the above thiazolidine ring. R ₆ represents a hydrogen atom or a lower alkyl group; m represents an integer of 0 or 1; the 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to the above (1) ,

(4) In the formula (I), R and R ₂ both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R ₃ represents the above-mentioned pyrazine ring. R ₄ represents a hydrogen atom, R ₅ represents a hydrogen atom, and n represents an integer of 0 to 3. The 4-benzyloxyphenyl derivative or (4) according to the above (1), Its pharmacologically acceptable salts,

(5) In formula (I), and R ₂ both represent a cyano group, one of them represents a cyano group, the other represents a hydrogen atom, and R ₃ represents a group containing the above-mentioned pyrazine ring. Wherein R ₄ represents a hydrogen atom, R ₅ represents a hydrogen atom, and n represents an integer of 0 to 3. The 4-benzyloxyphenyl derivative or the pharmacological thereof according to the above (1) Acceptable salts,

(6) In the formula (I), R and R _{2 each} represent a lower alkyl group, or one of them represents a lower alkyl group, the other represents a hydrogen atom, and R ₃ represents the above-mentioned piperazine R ₄ represents a hydrogen atom; R ₅ represents a hydrogen atom; n represents an integer of 0 to 3; 4-benzylo according to the above (1) A xylenyl derivative or a pharmaceutically acceptable salt thereof,

 (7) 1- [4- (4-nitrobenzyloxy) phenyl] piperazine, 1- [4- (4-fluorobenzyloxy) phenyl] piperazine, 1- [4—

(4-cyanobenzyloxy) phenyl] piperazine, 1— {2- (4- (4-fluorobenzyloxy) phenyl] ethyl} piperazine, 1-1 {3-—4 ( 4—Fluorobenzyloxy) phenyl] propyl} piperazine, 1—

[4- (4-Nitrobenzyloxy) benzyl] thiazolidine—4-ethyl ethyl ester, 2- [4- (4-nitrobenzyloxy) phenyl] thiazolidine—4-carboxylic acid, 1— [ 4- (3-Fluorobenzyloxy) phenyl] piperazine, 1- [4- (2-Fluorobenzyloxy) phenyl] piperazine, 1 _ [4- (4 Benzyloxy) phenyl] piperazine,

1- [4- (4-Methylbenzyloxy) phenyl] piperazine, 1- {4- [4- (4-fluorobenzyloxy) phenyl] piperazinyl} ethanol,

2-U— [4- (4-Fluorobenzyloxy) phenyl] piperazinyl} aniline, 1- [4— (3,4-dichlorobenzyloxy) phenyl] piperazine, 1— [4— (2 , 3-Dichloro mouth benzyloxy) phenyl] pidazine, 1-1 [4- (2,4-dichlorobenzyloxy) phenyl] pidazine, 1- [4-1 (2,5-dichlorobenzyloxy) phenyl ] Piperazine, 1-1 [4- (2,6-Dichroic benzyloxy) phenyl] Piperazine, 1-1 [4- (3,5-Dichrolic benzyloxy) phenyl] piperazine, 2-{4 -[4- (3,4-Dichlorobenzyloxy) phenyl] piperazinyl} ethylamine and 1- {2- [4- (4- (4-cyclobenzyloxy) phenyl] ethyl] ethyl-1,3-dimethylpiperazine; 4) Benzyloxyphenyl derivative according to the above (1) or a drug thereof Histological acceptable salts,

 (8) A pharmaceutical composition comprising the 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), and a pharmaceutically acceptable carrier,

(9) Intracellular Ca "perfume comprising the 4-benzyloxyphenyl derivative or a pharmacologically acceptable salt thereof according to any one of the above (1) to (7). Prevention and treatment of diseases induced by overload

(10) Intracellular administration comprising administering to a mammal an effective amount of the 4-benzyloxyphenyl derivative or a pharmaceutically acceptable salt thereof according to any of (1) to (7) above. For preventing or treating diseases induced by overload of Ca ²⁺ , and

(11) The 4_benzyloxyphenyl derivative according to any one of (1) to (7) above, for the manufacture of a prophylactic or therapeutic agent for a disease induced by intracellular Ca ²⁺ overload. Or the use of a pharmacologically acceptable salt thereof. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the infrared absorption spectrum (IR) of the compound synthesized in Example 2.

 FIG. 2 shows the infrared absorption spectrum (IR) of the compound synthesized in Example 6. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the halogen atom of and R ₂ in the formula (I) of the compound of the present invention include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom.

The lower alkyl group for R, R ₂ and R ₅ means a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. Specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, pentyl group, isopentyl group, Neopentyl group, tert-pentyl group, 1-ethylpentyl pill group, 4-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,2-dimethylbutyl group, 2-ethylbutyl group, Examples thereof include a clopentyl group, a hexyl group, a cyclohexyl group, a heptyl group, an isoheptyl group, an octyl group, an isooctyl group, a nonyl group, an isononyl group, a decyl group, and an isodecyl group. Preferably, it is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (methyl group, ethyl group, propyl group, isopropyl group). Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethyl pill, 4-methylpentyl, 1 , 1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,2-dimethylbutyl group, 2-ethylbutyl group, hexyl group), and more preferably 1-3 linear or branched alkyl groups ( A methyl group, an ethyl group, a propyl group and an isopropyl group), and particularly preferably a methyl group.

The alkyl group in the hydroxyalkyl group for R _{4 has} the same meaning as the lower alkyl group for R ₂ and R ₅ described above. Preferred hydroxyalkyl groups include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1-methylethyl group, Hydroxycyclopropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 1-hydroxybutyl Hydroxypentyl group,

2-hydroxypentyl group, 3-hydroxypentyl group, 5-hydroxypentyl group,

3-hydroxy-1-methylpropyl group, 3-hydroxy-1-ethylpropyl group, 4-hydroxy-1-methylbutyl group, 4-hydroxy-2-methylbutyl group, 4-hydroxy-3-methylbutyl group, 4-hydroxypentyl group And the like. More preferred hydroxyalkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and particularly preferably 2-hydroxyethyl.

As the phenyl group substituted by the amino group for R _4, the amino group may be located at any position of the phenyl group.

The alkyl group in the aminoalkyl group for R _{4 has} the same meaning as the lower alkyl group for R ₂ and R ₅ described above. Preferred aminoalkyl groups include an aminomethyl group, a 1-aminoethyl group, a 2-aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group, a 3-aminopropyl group, a 2-amino-1-methylethyl group, and an aminocyclo group. Propyl, 1-aminobutyl, 2-amino Butyl, 3-aminobutyl, 4-aminobutyl, 2-amino-2-methylpropyl, 2-amino-1,1-dimethylethyl, 1-aminopentyl,

2-aminopentyl, 3-aminopentyl, 5-aminopentyl, 3-amino-1-methylpropyl, 3-amino-1-ethylpropyl, 4-amino-1-methylbutyl, 4-amino-2-methylbutyl, 4 Amino

3-methylbutyl group, 4-aminopentyl group, and the like. More preferred aminoalkyl groups are an aminomethyl group, a monoaminoethyl group and a 2-aminoethyl group, particularly preferably a 2-aminoethyl group.

 Pharmaceutically acceptable salts of this compound include acid addition salts such as salts with inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and salts with organic acids such as acetic acid, citric acid, and tartaric acid. Any of the pharmacologically acceptable salts can be appropriately used for the purpose of the present invention.

 This compound can be appropriately synthesized, for example, by the following synthesis method or according to the method. The method for producing this compound will be described in the following three cases.

(1) When R ₃ in the formula (I) is a group containing a piperazine ring (n = 0)

(2) When R ₃ in the formula (I) is a group containing a piperazine ring (n = l to 3)

(3) When R ₃ in the formula (I) is a group containing a thiazolidine ring (HO, 1) When R ₃ in the formula (I) is a group containing a piperazine ring and n = 0 The production method of the present compound is as follows.

)

In the above formula, R, R ₂ , R ₄ and R ₅ are as defined above, and X is a halogen atom. Examples of the halogen atom for X include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.

尸 5 Dissolve the 4-hydroxyphenylpiperazine derivative (Π) in ethanol or the like, add alkali carbonate (such as potassium carbonate or sodium carbonate) and R _1; R _2- substituted benzyl halide (III), and add methyl ethyl ketone. After heating and stirring in a solvent such as for about 8 to 10 hours, the solvent is distilled off, the residue is extracted with ethyl acetate, etc., and the target compound can be produced by distilling off. When R _{4 of the} 4-hydroxyphenylpiperazine derivative (II) is hydrogen, for example, di-t-butyl dicarbonate or benzyloxycarbonyl chloride is added to R ₄ to introduce a urethane-type protecting group or the like. The above reaction can be performed by using N-protected form. The N-protected compound is dissolved in acetone or alcohol (methanol or ethanol), deprotected with an acid, and then recrystallized from, for example, methanol / acetone or methanol / ethyl acetate to form the acid addition salt of the target compound. Get. Examples of the acid for deprotection include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as acetic acid and trifluoroacetic acid. When R ₃ in the formula (I) is a group containing a piperazine ring and n = l to 3, the production method of the present compound is as follows.

Society 5

HN N— R ₄

(I) In the above formula, R ₂ , R ₄ , R ₅ and X have the same meanings as described above, and n = 1 to 3.

Add the corresponding commercially available hydroxyalkylphenol (V) to an alkali carbonate (carbonic acid or sodium carbonate) and RR _2- substituted benzyl halide (IV), and heat and stir in a solvent such as methyl ethyl ketone for about 8 to 10 hours. after distilling off the solvent medium, and extracted like with acetic Echiru it was distilled off, to obtain R ₂ substituents base Njiruoki Schiff enyl alkyl alcohols body (VI). Next, this and methanesulfonyl halide are stirred in a solvent such as pyridine for 1 to 3 hours under ice-cooling to room temperature, extracted with ethyl acetate, and distilled off to obtain an alkylsulfonyl ester (VII). Next, the piperazine derivative (VI II) is dissolved in 1,4-dioxane and the like, and a tertiary amine such as triethylamine is added. Then, the alkylsulfonyl ester form (VI I) is added, and the mixture is heated and stirred for 8 to 15 hours. The solvent is distilled off, the residue is extracted with ethyl acetate and the like, and the target compound can be produced by distilling off the solvent. In the case R ₄ of piperazine down derivative (VI II) is hydrogen, for example, was substituted with a protecting group of hydrogen, using a 1 one (3-butoxycarbonyl) R ₅ substituted piperidines Rajin derivatives,, R ₂ substituted Benzyloxyphenylalkylpiperazinyl N-protected. Next This is dissolved in acetone or alcohol (methanol or ethanol), deprotected with an acid, and then recrystallized from methanol / acetone or methanol / ethyl acetate to obtain an acid addition salt of the target compound. As the acid for deprotection, those described above can be used.

On the other hand, when R ₃ in the formula (I) is a group (ΠΡΟ, 1) containing a thiazolidine ring, the production method of the present compound is as follows.

HS— CH ₂ CH (NH ₂ ) —COOR ₆

 (I)

In the above formula, R ₂ , R ₆ and X have the same meanings as described above, and m = 0 or 1.

In the same manner as above, 4 dissolved-hydroxy alkyl phenols (V) such as Mechirue ethyl ketone, and alkali carbonate (such as potassium carbonate or sodium carbonate acid) thereto, R ₂ disubstituted base Njiruharaido (IV) is added methyl after about 8-10 hours heating and stirring in a solvent such as Echiruketon, the solvent was evaporated, and extracted with a solvent such as acetic acid Echiru was distilled off,, R ₂ substituted base Njiruokishifue two Le alkyl alcohols body (VI ') obtain. Next, this is dissolved in methylene chloride and oxidized with an oxidizing agent such as pyridinium chromate (PCC) or manganese dioxide to obtain an aldehyde (IX). The aldehyde compound and cysteine alkyl ester hydrochloride or cysteine are added at room temperature for 2 to 15 hours in pyridine or the like. After stirring for a while, evaporate the solvent and extract with ethyl acetate. After evaporating the solvent, recrystallize from ethyl acetate / isopropyl ether / dimethylformamide / acetone to obtain the desired compound.

The compound thus obtained is a novel compound that has not been published in the literature, inhibits NCX and suppresses Ca ²⁺ overload, and is therefore useful in mammals (for example, horses, horses, dogs, horses, mice are useful rat, as a preventive and therapeutic agent for various diseases induced by Ca ^w excess load such as human Bok). Specific diseases induced by Ca ²⁺ overload include ischemic heart disease such as myocardial infarction, ischemic brain disease such as cerebral infarction or ischemic renal disease, hypertension, heart failure, or circulatory system such as arrhythmia. Disease, glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, diabetic retinopathy, and the like. '

 When the present compound is used as a pharmaceutical composition, one or more of the present compounds can be appropriately combined and contained according to the purpose and necessity.

 The present compound is appropriately used orally or parenterally as a pharmaceutical composition for various diseases as described above. The preparation can be prepared by any known method, for example, into solid preparations such as tablets, granules, powders and capsules or liquid preparations such as injections and eye drops. These preparations contain commonly used excipients, binders, thickeners, dispersants, resorption accelerators, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizing agents. Various additives such as an agent and a pH adjuster may be appropriately used.

 This compound has the characteristics, for example, of remarkably inhibiting NCX 1 and being soluble in water. Among these compounds, the compound of Example 6 described below is particularly excellent in NCX1 inhibitory activity, and the compound of Example 4 is particularly excellent in water solubility (0. g / 0.5 mi or more).

The dosage of the compound when used as a pharmaceutical composition varies depending on the type of the compound used, the weight and age of the patient, the type and condition of the disease to be treated, the method of administration, and the like. For example, when applying to injections or cardiovascular diseases, for example, for injections, about lmg to about 30mg for adults once a day, for oral administration, for adults several times a day, about 1mg to about 100mg per dose Is good. Also> when applied to eye diseases, Adults Several times a day, 1 time drop> It is preferable to administer an eyedrop having a concentration of about 0.01 to 5 (w / v). Pharmaceutical compositions containing the present compound may be used unless they violate the purpose of the present invention. It may optionally contain other NCX inhibitors or other kinds of pharmaceutically active ingredients.

 Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples, and Formulation Examples, but the scope of the present invention is not limited thereto.

Reference Example 11 1- (tert-butyloxycarbonyl) -4-1 (4-hydroxyphenyl) piperazine (compound represented by formula (Π) as an intermediate of this compound)

 8 g of 11- (4-hydroxyphenyl) piperazine was dissolved in 200 ml of ethanol, and 24 g of di-tert-butyl dicarbonate was added dropwise thereto, followed by stirring at room temperature for 3 hours. After the solvent was distilled off, the obtained residue was extracted with ethyl acetate, washed with water, and then the ethyl acetate was distilled off. The residue was recrystallized from ethyl acetate-isopropyl ether to obtain 23.3 g of the desired compound having a melting point of 160 to 162 ° C.

Example 11 1- [4- (4-nitrobenzyloxy) phenyl] pidazine dihydrochloride

Dissolve 8.4 g of 1- (tert-butyloxypropyl) piperazine obtained in Reference Example 1 in 100 ml of acetone, add 4.2 g of carbon dioxide, and add it at room temperature. After stirring for 30 minutes, 7.8 g of 412g benzylbutamide was added, and the mixture was heated under reflux for 14 hours. After filtering the insoluble matter, the solvent was distilled off, and the obtained residue was extracted with chloroform, washed with water and the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate-isopropyl ether to give 1- [4- (4-nitrobenzyloxy) phenyl] 141- (tertiary-butyloxyl-propionyl) piperazine having a melting point of 145-148 ° C. 9.3 g was obtained. This 4.lg was dissolved in 100 ml of acetone, 20 ml of 2N hydrochloric acid was added thereto, and the mixture was heated and stirred at about 50 ° C for 2 hours. After distilling off the solvent, the obtained residue was washed with ethyl acetate. After washing with water and recrystallizing from water, 3.5 g of the target compound having a melting point of 209 to 211 ° C (decomposition) was obtained.

Elemental analysis _{C 17 H 19 N 3 0 3} - 2HC 1 - as 1. 5H ₂ 0

Theoretical value: C, 49.40 H, 5.85 N, 10.17

Found: C, 49.60 H, 5.82 N, 10.19

Example 2 1- [4- (4-Fluorobenzyloxy) phenyl] piperazinni hydrochloride

 1- (tert-butyloxycarbonyl) 1-41- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 2.8 g, 4-fluorophenylbenzyl chloride 3.0 g, potassium carbonate 1.4 g, methyl The reaction and treatment were carried out in the same manner as in Example 1 using 30 ml of ethyl ketone, and recrystallized from isopropyl ether to give 1- [4- (4-fluorobenzyloxy) phenyl having a melting point of 124 to 126 ° C. 2.3 g of 4- (tert-butyloxycarbonyl) pidazine was obtained. 1.9 g of this compound was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-ethyl acetate to obtain 1.7 g of the desired compound having a melting point of 195 to 197 ° C (decomposition).

As _{C 17 H 19 N 2 0F '} 2HC1: Elemental analysis

Theoretical value: C, 56.83 H, 5.89 N, 7.80

Found: C, 56.61 H, 5.89 N, 7.76

参考例 1で得た 1— (第三ブチルォキシ力ルポニル）一 4— (4ーヒドロキ シフエニル）ピぺラジン 2. 8g、4一シァノフエニルベンジルブ口マイド 2. 2g、 炭酸カリウム 1. 4g、 メチルェチルケトン 30ml を用いて実施例 1 と同様に 反応および処理を行い、 酢酸ェチルーイソプロピルェ一テルから再結晶し 融点 151〜153°Cの 1— [4一 （4一シァノベンジルォキシ） フエニル] 一 4 一 （第三ブチルォキシカルボニル） ピぺラジンを 2. lg得た。 このもの 2. Og を実施例 1 と同様に塩酸処理をしてメタノール—酢酸ェチルから再結晶し 融点 231〜233°C (分解） の目的化合物 1. 7gを得た。 Example 3 1- [4- (4-Cyanobenzyloxy) phenyl] pidazine dihydrochloride

1- (tert-butyloxyl-propionyl) -1-4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 2.8 g, 2.2 g of 4-cyanophenylbenzylbutamide, 1.4 g of potassium carbonate, methyl The reaction and treatment were carried out in the same manner as in Example 1 using 30 ml of ethyl ketone, and the product was recrystallized from ethyl acetate-isopropyl ether to give 1- [4- (4-cyanobenzyloxy) having a melting point of 151 to 153 ° C. 2.) [Phenyl] 1.4g (tert-butyloxycarbonyl) pidazine was obtained in an amount of 2.lg. This Og was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-ethyl acetate to obtain 1.7 g of the desired compound having a melting point of 231 to 233 ° C (decomposition).

Elemental analysis: as _{C 18 H I 9 N 3 0} '2HC1' H 2 0

Theoretical value: C, 56.26 H, 6.03 N, 10.93

Found: C, 56.38 H, 6.08 N, 10.64

Example 4 11 {2- [4- (4-fluorobenzyloxy) phenyl] ethyl} piperazine dihydrochloride

It was prepared from 6.2 g of 2- (4-hydroxyphenyl) ethyl alcohol and 7.8 g of 4-fluorobenzoyl chloride by a method according to JP-A-50-148357. Dissolve 4.9 g of benzylbenzyloxy) phenyl alcohol in 100 ml of pyridine, add 2.7 g of methanesulfonyl chloride dropwise under ice cooling, stir for a while, and then stir at room temperature for 2 hours. went. The solvent was distilled off, and the obtained residue was extracted with ethyl acetate. After washing with acid and water, the solvent was distilled off to obtain a colorless oil. This was dissolved in dioxane, to which was added 3.7 g of 11- (tert-butyloxyl-propionyl) piperazine and 2.4 g of triethylamine, and the mixture was heated under reflux for 15 hours. The residue obtained by distilling off the solvent was extracted with ethyl acetate, washed with water, and the solvent was distilled off. The obtained residue was recrystallized from isopropyl ether-hexane to give 1- {2- [4- (4-fluorobenzyloxy) phenyl] ethyl} 1-41 with a melting point of 89-92 ° C. Tributyloxycarbonyl) piperazine 4. lg was obtained. 3.9 g of this compound was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-ethyl acetate to obtain 3.4 g of the desired compound having a melting point of 249 to 250 ° C (decomposition).

Elemental analysis: C ₁₉ H ₂₃ N ₂ 0F '2HC or 0.75¾0

Theoretical value: C, 56.93 H, 6.66 N, 6.99

Found: C, 56.97 H, 6.74 N, 7.03

Example 5 1- {3- [4- [4-fluorobenzyloxy) phenyl] propyl} piperazine dihydrochloride

3- [4-hydroxyphenyl) propyl alcohol prepared from 5.Og and 9.5 g of 4-fluorobenzyl chloride by a method according to Japanese Patent Application Laid-Open No. 50-U8357. The reaction and treatment were carried out in the same manner as in Example 4 using 3.9 g of phenyl] propyl alcohol and 2.lg of methanesulfonyl chloride to obtain an oil. This was reacted and treated with 1.1 (tertiary butyloxycarbonyl) pidazine (2.8 g), triethylamine (1.8 g) and dioxane (100 ml) in the same manner as in Example 4, and the resulting residue was purified from hexane. Recrystallized and has a melting point of 80-82 ° C. {3- {4- (4-fluorobenzyloxy) phenyl] propyl} -14- (tert-butyloxycarbonyl) piperazine 3.4g Obtained. 3.4 g of this product was treated with hydrochloric acid in the same manner as in Example 1 to give methanol-acetate. Recrystallization from ton gave 2.2 g of the target compound having a melting point of 240 to 241 ° C (decomposition). As _{C 20 H 25 N 2 0F '} 2HC 1: Elemental analysis

Theoretical value: C, 59.85 H, 6.78 N, 6.98

Found: C, 59.51 H, 6.92 N, 7.01

Example 6 2- [4- (4-Nitrobenzyloxy) benzyl] thiazolidine-4th-yl ethyl ester of rubonic acid

 It was prepared from 6.2 g of 2- (4-hydroxyphenyl) ethyl alcohol and 7.8 g of 412 trobenzirubide by a method according to JP-A-50-148357. Benzoxy) phenyl] ethyl alcohol 4. lg was dissolved in 200 ml of methylene chloride, and 6.5 g of pyridinium chromate (PCC) was added thereto, followed by stirring at room temperature for 2 hours. After filtration of the insoluble matter, the solvent was distilled off to obtain 2.8 g of a yellow oily [4-1 (4-nitrobenzyloxy) phenyl] acetaldehyde. This was dissolved in 1.7 g of pyridine and 30 ml of pyridine, to which 1.9 g of cysteineethyl ester hydrochloride was added, followed by stirring at room temperature for 2 hours. The residue obtained by distilling off the solvent was neutralized with 2 N sodium hydroxide, extracted with ethyl acetate, washed with water and distilled off the solvent. The obtained residue was recrystallized from ethyl acetate-isopropyl ether to obtain 1.5 g of the desired compound having a melting point of 116 to 117 ° C.

As _{C 20 H 22 N 2 0 5} S · 0. 25H 2 0: Elemental analysis

Theoretical value: C, 59.03 H, 5.57, 6.88

Found: C, 58.97 H, 5.18 N, 7.03

Example 7 2- [4- (4-nitrobenzyloxy) phenyl] thiazolidine-14-carboxylic acid

 4- [4- (4-nitrobenzyloxy) phenyl] methanol prepared from 10.4 g of 4-hydroxybenzyl alcohol 5.Og and 4,12-trobenzylbutane by a method according to JP-A-50-148357 7.4 g was dissolved in 200 ml of methylene chloride, and 21 g of manganese dioxide was added thereto, followed by stirring at room temperature for 1 week. After filtration of the insolubles, the solvent was distilled off to obtain 7. Ig of [4- (4-nitrobenzyloxy) phenyl] acetaldehyde. 2.6 g of this product was dissolved in 30 ml of pyridine, and 1.2 g of cysteine and 1.Og of triethylamine were added thereto, followed by stirring at room temperature for 15 hours. The solvent was distilled off, water was added to the obtained residue, and insoluble crystals were collected by filtration and recrystallized from dimethylformamide-acetone to obtain 1.6 g of the desired compound having a melting point of 171 to 173 ° C (decomposition).

As _{C 17 H 16 N 2 O 5} S'0.5H 2 0: Elemental analysis

Theoretical value: C, 55.28 H, 4.64 N, 7.58

Found: C, 55.59 H, 4.31, 7.97

Example 8 1- [4- (3-fluorobenzyloxy) phenyl] piperazinni hydrochloride

参考例 1で得た 1一 （第三ブチルォキシカルボニル） 一 4— (4ーヒドロ キシフエニル） ピぺラジン 2.8g、 3—フルオロフェニルベンジルクロライ ド 4.3g、 炭酸カリウム 1.4g、 メチルェチルケトン 100ml を用いて実施例 1 と同様に反応および処理を行いカラム （シリカゲル 酢酸ェチル：へキサ ン = 1 : 4) 精製し、 へキサンから再結晶し融点 89〜91°Cの 1一 [4— (3— フルォロベンジルォキシ）フエニル]一 4一（第三ブチルォキシカルボニル）

11- (tert-butyloxycarbonyl) -1- (4-hydroxyphenyl) piperazine obtained in Reference Example 1 2.8 g, 3-fluorophenylbenzyl chloride 4.3 g, potassium carbonate 1.4 g, methylethylketone The reaction and treatment were carried out in the same manner as in Example 1 using 100 ml, and the column (silica gel ethyl acetate: hexane) was used. 1: 4) Purified, recrystallized from hexane and melted at 89-91 ° C with 1- [4- (3-fluorobenzyloxy) phenyl] 1-4 (tert-butyloxycarbonyl)

 3.I got LG. This 3.lg was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from pill alcohol to obtain 2.5 g of the target compound having a melting point of 195 to 199 ° C (decomposition).

As C ₁₇ H ₁₉ N ₂ OF'2HC There 0.5H ₂ 0: Elemental analysis

Theoretical value: C, 55.44 H, 6.02 N, 7.61

Found: C, 55.40 H, 6.17 N, 7.55

Example 9 1- [4- (2-Fluorobenzyloxy) phenyl] piperazinni hydrochloride

参考例 1で得た 1— (第三ブチルォキシ力ルポニル） 一 4一 （4—ヒドロ キシフエニル） ピぺラジン 7.0g、 2—フルオロフェニルベンジルクロライ ド 10.8g、 炭酸カリウム 3.5g、 メチルェチルケトン 100ml を用いて実施例 1 と同様に反応および処理を行いカラム （シリカゲル 酢酸ェチル：へキ サン = 1 : 4) 精製し、 イソプロピルエーテル—へキサンから再結晶し融点 81〜83°Cの 1一 [4— (2—フルォロベンジルォキシ） フエニル] 一 4一 （第 三ブチルォキシカルボニル） ピぺラジンを 8. lg得た。 このもの 3. lgを実 施例 1 と同様に塩酸処理をしてイソプロピルアルコールから再結晶し、 融 点 205〜207°C (分解） の目的化合物 2. lgを得た。

1- (tert-butyloxyl-propyl) obtained in Reference Example 1 4- (4-hydroxyphenyl) piperazine 7.0 g, 2-fluorophenylbenzyl chloride 10.8 g, potassium carbonate 3.5 g, methylethylketone The reaction and treatment were carried out in the same manner as in Example 1 by using 100 ml, and the column (silica gel: ethyl acetate: hexane = 1: 4) was purified, recrystallized from isopropyl ether-hexane, and melted at a melting point of 81-83 ° C. 8. 4-lg of [4- (2-fluorobenzyloxy) phenyl] 141- (tert-butyloxycarbonyl) pidazine was obtained. This 3.lg was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from isopropyl alcohol to obtain 2.lg of the desired compound having a melting point of 205 to 207 ° C (decomposition).

As _{C 17 H I9 N 2 OF-} 2HC1-0.5H 2 0: Elemental analysis

Theoretical value: C, 55.44 H, 6.02 N, 7.61

Found: C, 55.35 H, 6.15 N, 7.53

参考例 1で得た 1一 （第三ブチルォキシカルボニル） —4— (4ーヒドロ キシフエニル） ピぺラジン 2. 8g、 4—クロ口べンジルクロライド 4. 8g、 炭 酸カリウム 1. 3g、 メチルェチルケトン 100mlを用いて実施例 1 と同様に反 応ぉよび処理を行いィソプ口ピルエーテルから再結晶し融点 139〜 U3°C の 1— [4一 （4一クロ口ベンジルォキシ） フエニル] 一 4一 （第三プチルォ キシカルボニル） ピぺラジンを 3. lg得た。 このもの 2. Ogを実施例 1 と同 様に塩酸処理をしてイソプロピルアルコールから再結晶し、 融点 280〜 283°C (分解） の目的化合物 1. 4gを得た。 Example 101- [4- (4-chlorobenzyloxy) phenyl] piperazine: acid salt

11- (tert-butyloxycarbonyl) -4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 2.8 g, 4-chloropentyl chloride 4.8 g, potassium carbonate 1.3 g, The reaction and treatment were carried out in the same manner as in Example 1 using 100 ml of methyl ethyl ketone, and the product was recrystallized from isopropyl ether at the isobutate to give 1- [4- (4-monobenzyloxy) phenyl] having a melting point of 139 to U3 ° C. 1.41 g of (tertiary butyloxycarbonyl) pidazine was obtained. This 2.Og was treated with hydrochloric acid as in Example 1 and recrystallized from isopropyl alcohol to give 1.4 g of the desired compound having a melting point of 280 to 283 ° C (decomposition).

Elemental _{analysis: C, 7 H 19 N 2} 0C1 -HC1 - as 0. 25H ₂ 0

Theoretical value: C, 59.40 H, 6.01 N, 8.15

Found: C, 59.66 H, 6.02 N, 8.1

Example 1 1 1 _ [4- (4-methylbenzyloxy) phenyl] piperazine

Example 1 using 3.0 g of 4- (4-hydroxyphenyl) pidazine 1- (ethoxycarbonyl) piperazine, 4.8 g of 4-cyclopentyl benzyl chloride, 1.3 g of potassium carbonate, and 100 ml of methyl ethyl ketone. The reaction and treatment were carried out in the same manner as described above to obtain 2.6 g of 4- [4- (4-methylbenzyloxy) phenyl] -41- (ethoxycarbonyl) pidazine. This was dissolved in 2.6 g of ethanol (50 ml), a solution of lithium hydroxide (0.5 g) in water (10 ml) was added, and the mixture was heated under reflux for 15 hours. The solvent was distilled off, 2N sodium hydroxide (20 ml) was added to the obtained residue, and the precipitated crystal was recrystallized from water to obtain 1.6 g of the target compound having a melting point of 94 to 97 ° C (decomposition).

As C ₁₈ H ₂₂ N ₂ 0: Elemental analysis

Theoretical value: C, 76.56 H, 7.85 N, 9.92

Found: 76. 14 H, 7.93 N, 10.13

Example 12-22- {4- [4- (4-fluorobenzyloxy) phenyl] piperazinyl} ethanol

 3.6 g of the compound of Example 2 was dissolved in 100 ml of ethanol, and 3.7 g of bromoethanol and 3.0 g of triethylamine were added thereto, followed by heating under reflux for 5 hours. The residue obtained by evaporating the solvent was extracted with chloroform, washed with water, dried and concentrated. The obtained residue was recrystallized from ethyl acetate to obtain 2.2 g of the desired compound having a melting point of 130 to 133 ° C (decomposition).

As _{C 19 H 23 N 2 0 2} F '0. 25H 2 0: Elemental analysis

Theoretical value: C, 68.14 H, 7.07 N, 8.36

Obtained values: C, 68.19H, 7.06N, 8.44

Example 1 32-2- {4- [4- (4-fluorobenzyloxy) phenyl] piperazinyl} aniline

実施例 1の化合物 3. 8gをジォキサン 10ml に溶解させ、 これに 0—二ト 口フルォロベンゼン 1Λも及び炭酸カリウム 1. 8gを加えて加熱還流を 15 時間行った。 溶媒を留去し得られた残渣をクロロフオルムで抽出し、 水で 洗浄した後、 乾燥させ濃縮した。 得られた残渣をェチルェ一テルから再結 晶し、融点 U9〜152°Cの 1一 [4— (4一フルォロベンジルォキシ）フエニル] - 4- (2—二トロフエニル） ピぺラジン 3. 2gを得た。 これを 3. Ogェタノ —ルに溶解させ、 さらに鉄 2. 2g及び塩化アンモニゥム 0. 3gを溶解させた 水溶液 2mlを加えて加熱還流を 15時間行った。不溶性なものを濾過して濾 液を濃縮した。得られた残渣をクロロフオルムで抽出し、水で洗浄した後、 乾燥させ濃縮した。 得られた残渣を酢酸ェチルから再結晶し、 融点 193〜 196°C (分解） の目的化合物を 1. 3g得た。

3.8 g of the compound of Example 1 was dissolved in 10 ml of dioxane, to which was added 0-to-two-neck fluorobenzene and 1.8 g of potassium carbonate, and the mixture was heated under reflux for 15 hours. The residue obtained by evaporating the solvent was extracted with chloroform, washed with water, dried and concentrated. The obtained residue was recrystallized from ethyl ether to give 4- [4- (4-fluorobenzyloxy) phenyl] -4- (2-nitrophenyl) pyrazine having a melting point of U9 to 152 ° C. 3.2 g was obtained. This was dissolved in 3. ethanol, and 2 ml of an aqueous solution in which 2.2 g of iron and 0.3 g of ammonium chloride were dissolved was added, followed by heating and refluxing for 15 hours. The insoluble matter was filtered and the filtrate was concentrated. The obtained residue was extracted with chloroform, washed with water, dried and concentrated. The obtained residue was recrystallized from ethyl acetate to give 1.3 g of the desired compound having a melting point of 193 to 196 ° C (decomposition).

As C ₂₃ H ₂₄ N ₃ 0F: Elemental analysis

Theoretical value: C, 73.19 H, 6.41, 1 1.13

Obtained values: C, 72.96 H, 6.45 N, 1 1.15

Example 1 41- [4- (3,4-dichlorobenzyloxy) phenyl] pi dihydrochloride

11- (tert-butyloxyl-propyl) obtained in Reference Example 1 14- (4-hydroxyphenyl) pidazine 2.8 g, acetone 50 ml, 3,4-dichlorobenzyl chloride 2.9 g, potassium carbonate 1.4 g The reaction and treatment were carried out in the same manner as in Example 1 and the obtained crystals were recrystallized from isopropyl ether to obtain white crystals of 4-[(3-, 4-dichlorobenzenebenzyloxyphenyl)]. 3.9 g of 14- (tert-butyloxyl-propionyl) -piperazine was obtained, and 3.7 g of this was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-isopropyl ether to give the target compound as white 3. Crystals (melting point: gradually decomposed from 186 ° C) were obtained. As _{C 17 H 18 N 2 0C 1} 2 · 2HC1: elemental analysis

Theoretical value: C, 49.78 H, 4.91 N, 6.83

Found: C, 49.51 H, 5.21, 6.82

Example 1 5 1— [4- (2,3-diclo-benzyloxy) phenyl] piperazine dihydrochloride:

 2.8 g of 1- (tert-butyloxycarbonyl) -4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 and 50 ml of acetone, 2.9 g of 2,3-dichlorobenzyl chloride, 2.9 g of potassium carbonate The reaction and treatment were carried out in the same manner as in Example 1 using 1.4 g, and the resulting residue was purified by column chromatography (silica gel) (ethyl acetate: hexane = 1: 4) and recrystallized from isopropyl ether. 3.7 g of 1- [4- (2,3-dichlorobenzyloxyphenyl) —4- (tert-butyloxycarbonyl) -piperazine, a red-light colored crystal, was obtained, and this 3.3 g was carried out. The mixture was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-acetone to obtain 2.9 g of the target compound as white crystals (melting point: gradually decomposed from 207 ° C).

As _{C 17 H IS N 2 0C1 2} · 2HC1 · 0. 75H 2 0: Elemental analysis

Theoretical value: C, 48.19H, 5.11N, 6.61

Found: C, 47.83 H, 5.48 N, 6.51

Example 16 1- [4- (2,4-dichloro mouth benzyloxy) phenyl] piperazine dihydrochloride

1-1 (tert-butyloxycarbonyl) 1-41 (4-hydroxyphenyl) piperazine obtained in Reference Example 1 2.8 g and acetone 50 ml, 2,4-dichlorobenzene The reaction and treatment were carried out in the same manner as in Example 1 using 2.9 g of chlorochloride and 1.4 g of potassium carbonate, and the obtained crystals were recrystallized from isopropyl ether to give 1- [4-1- (2) , 4-Dichlorobenzyloxyphenyl] —4- (tert-butyloxycarbonyl) -piperazine (2.8 g) was obtained, which was then treated with hydrochloric acid in the same manner as in Example 1. The crystals were recrystallized from methanol-acetone to obtain 2.3 g of white crystals of the target compound having a melting point of 210 to 211 ° C (decomposition).

As _{C 17 H 18 N 2 0C1 2} · 2HC 1 · 0. 5H 2 0: Elemental analysis

Theoretical value: C, 48.71H, 5.05N, 6.68

Found: C, 48.47 H, 5.15 N, 6.57

Example 17 1 1- [4- (2,5-dichlorobenzyloxy) phenyl] piperazine dihydrochloride

 1- (tert-butyloxypropyl) -4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 4.2 g and acetone 50 ml, 2,5-dichlorobenzenebenzyl chloride 4.4 g, potassium carbonate 2. Reaction and treatment were carried out using lg in the same manner as in Example 1, and the resulting residue was subjected to column chromatography (silica gel).

(Ethyl acetate: hexane = 1: 4) to give colorless oil 1- [4- (2,5-dichlorobenzyloxyphenyl) -4-1- (tert-butyloxycarbonyl) -piperazine as 6 Next, this 5.Og was treated with hydrochloric acid as in Example 1 and recrystallized from methanol-acetone to obtain white crystals of the target compound having a melting point of 237 to 238 ° C (decomposition). 3 g were obtained.

As _{C I7 H I8 N 2 0C1 2} · 2HC1: elemental analysis

Theoretical value: C, 49.78 H, 4.91 N, 6.83

Found: C, 49.45 H, 4.69 N, 6.68

Example 18 1- [4- (2,6-dichlorobenzyloxy) phenyl] pi Razine dihydrochloride

 2.8 g of 1- (tert-butyloxycarbonyl) 1-4- (4-hydroxyphenyl) pidazine obtained in Reference Example 1 and 50 ml of acetone, 2.9 g of, 6-dichlorobenzyl chloride, 2.9 g of potassium carbonate 1. The reaction and treatment were carried out in the same manner as in Example 1 by using 4 g, and the obtained residue was purified by column chromatography (silica gel) (ethyl acetate: hexane = 1: 5) to give a colorless oily substance. 4.2 g of 1- (2,6-dichlorobenzyloxyphenyl) -4-1-1 (tert-butyloxyl-propionyl) -piperazine was obtained, and this 4.0 g was treated with hydrochloric acid in the same manner as in Example 1 to give methanol. The crystals were recrystallized from acetone to give 2.5 g of white crystals of the target compound having a melting point of 234 to 236 ° C (decomposition).

As _{C 17 H 1S N 2 0C 1} 2 · 2HC1: elemental analysis

Theoretical value: C, 49.78 H, 4.91 N, 6.83

Found: C, 49.42 H, 4.92 N, 6.69

Example 19 9 1- [4- (3,5-dichlorobenzyloxy) phenyl] pi dihydrochloride

1- (tert-butyloxycarbonyl) 1-14- (4-hydroxyphenyl) piperazine obtained in Reference Example 1 2.8 g, acetone 50 ml, 3,5-dichlorobenzyl chloride 2.9 g, potassium carbonate 1 Using 4 g, the reaction and treatment were carried out in the same manner as in Example 1, and the obtained residue was purified by column chromatography (silica gel) (ethyl acetate: hexane = 1: 5) to give a colorless oil. 4 one (3, 5— 4.3 g of dichlorobenzyloxyphenyl] 1- (tert-butyloxycarbonyl) -piperazine were obtained. Next, 3.9 g of this was treated with hydrochloric acid in the same manner as in Example 1 and recrystallized from methanol-acetone to obtain 3.4 g of white crystals of the target compound having a melting point of 210 to 213 ° C (decomposition).

Elemental analysis: _CH) as _{8 N 2 0Cl 2 · 2HC 1} · 0. 75H 2 0

Theoretical value: C, 48.19H, 5.11N, 6.61

Found: C, 47.88 H, 4.93 N, 6.35

Example 20 2- {4- [4- (4- (3,4-diclo-benzyloxy) phenyl] piperazinyl} ethylamine trihydrochloride

Dissolve 4.4 g of N- (2-chloroethyl) -N- (tert-butyloxycarbonyl) amine and 5.3 g of 1_ (4-hydroxyphenyl) pidazine and 3.Og of triethylamine in 100 ml of ethanol, Heating reflux was performed overnight. Thereafter, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed successively with 2N—NaOH and sat. NaCl, concentrated and dried to obtain 2.3 g of a brown oil. This was dissolved in 50 ml of acetonitrile, 2.lg of 3,4-dichlorobenzyl chloride and l.Og of potassium carbonate were added thereto, and the mixture was heated under reflux for 15 hours. Thereafter, the solvent was distilled off, and the obtained residue was extracted with ethyl acetate, washed with 2N—NaOH and sat. NaCl in that order, concentrated, and the obtained residue was subjected to column chromatography (silica gel) (silica gel). Purification with ethyl acetate: hexane = 1: 1) yielded 1.6 g of white crystals. Next, this was dissolved in 1.2 g of acetone, and 30 ml of acetone was added thereto. Then, 5 ml of 6N-HC1 was added thereto, and the mixture was stirred at room temperature for a while. Then, 10 ml of water was added, followed by heating and stirring (at an external temperature of about 40 ° C.) for 10 hours. After cooling, acetone was added thereto, and the precipitated crystals were collected by filtration to obtain l.lg of white crystals (melting point: gradually decomposed from 218 ° C). As _{C 19 H 23 N 3 0C1 2} · 3HC1: elemental analysis

Theoretical value: C, 46.60 H, 5.35 N, 8.58

Found: C, 46.68 H, 5.48 N, 8.38

Example 21 1- {2- [4 -— (4-cyclobenzyloxy) phenyl] ethyl} -1,3-dimethylbiperazine dihydrochloride

1.7 g of acid 2- [4- (4-cyclobenzyloxy) phenyl] ethyl ester and 0.63 g of 1,2,6-dimethylbiperazine were dissolved in 50 ml of ethanol, and the mixture was heated under reflux overnight. After the solvent was distilled off, the obtained residue was extracted with ethyl acetate, washed sequentially with 2N-NaOH and sat. NaCl, dried and concentrated. The obtained residue was dissolved in acetone, and 2N-HC1 was added thereto and concentrated to obtain a hydrochloride. This was recrystallized from methanol / ethyl acetate to obtain 0.77 g of white crystals of the target compound having a melting point of 267 to 269 ° C (decomposition). Elemental analysis: C ₂₁ H ₂₇ N _{2 0} C1 · 2HC1

Theoretical value: C, 58.41 H, 6.77 N, 6.49

Found: C, 58.40 H, 7.05 N, 6.26

 [Formulation Example 1] Tablet

Compound lOOmg of Example 5, 7, 10 or 12

Lactose 80mg

17mg starch

Magnesium stearate 3mg

 The above is formed into tablets by a conventional method as a material for one tablet.

 [Formulation Example 2] Injection

Compound lOOmg of Example 2, 3, 4 or 5 Mannitol 5. Og

 IN Sodium hydroxide solution

Distilled water 100ml

 pH 5.0

 The above components are made into injections by a conventional method.

 [Formulation Example 3] Eye drops

500 mg of the compound of Examples 2, 3, 4 or 5

1.5g boric acid

Borax 0.3g

 P-Methoxy benzoate 0.026g

 Propyl oxybenzoate 0.014g

100 ml of sterilized purified water

 The above is prepared by an ordinary method to prepare eye drops.

 [Formulation Example 4] Eye drops

Compounds of Examples 8 and 9 lOOmg

1.5g boric acid

Borax 0.3g

 P-Methoxy benzoate 0.026g

Propyl oxybenzoate 0.014g

100 ml of sterilized purified water

 The above is prepared by an ordinary method to prepare eye drops.

[Test Example 1] Inhibitory effect of present compound on excessive accumulation of Ca ²⁺ in cells- 1 The inhibitory effect of the present compound on excessive accumulation of Ca "in cells was examined.

 (Test method)

 NCX1-expressing CCL-39 cells were cultured to confluence, and then replaced with a culture medium without fetal calf serum.

Three hours later, remove the culture solution and prepare a Na + loading solution containing the test substance at the target concentration (10 mM HEPES / Tris buffer, 146 mM NaCl, mM KC1, 2 mM MgCl ₂ , The solution was replaced with 0.05 mM CaCl ₂ , lmM Ouabain (10 × M Monensin), and incubated at 37 ° C. for 30 minutes.

After incubation for 30 minutes, the Na + loading solution is removed, and the target concentration of test substance and Na-containing Ca ²⁺ uptake solution containing about 50 kilobecquerel (kBq) / ml of ⁴⁵ Ca (lOtnMHEPES / Tris buffer, 146 mM aCl , 4 mM KC1, ₂ mM MgCl ₂ , 0.05 mM CaCl ₂ , lmM perbain) or about 50 kBq / ml Na-free Ca ²⁺ uptake solution containing ⁴⁵ Ca (10πl MHEPES / Tris buffer, U6 mM choline chloride, 4 mM KC1, 2 mM MgCl ₂ , 0.05 mM CaCl ₂ , lmM perbain) were exchanged and incubated at 37 C for 30 seconds.

After a 30-second incubation, the Na-containing Ca ²⁺ uptake solution or the Na-free Ca ²⁺ uptake solution was removed, and the cells were washed three times with ice-cold physiological saline containing 10 mM LaCl ₃ .

 After washing, IN NaOH was added and the cells were solubilized by incubating at 37 ° C.

The amount of ⁴⁵ Ca in the solubilized cell solution was measured using a liquid scintillation counter.

 All test substances were dissolved in dimethylsulfoxide (DMS0) to a concentration of 10 mM and added to each solution to a final concentration of 5 M.

(Test results)

Na ⁺ The difference obtained by subtracting the uptake in Na ⁺ presence than uptake in the absence and uptake of Ca "into cells by NCX1,% relative to the amount uptake in the absence the test substance (Ca ² incorporation rate).

 Table 1 shows the results.

Table 1 Inhibitory effect of this compound on Ca ²⁺ excessive accumulation in cells

Test compound Ca ²⁺ uptake rate

 Compound of Example 1

 Compound of Example 2

 Compound of Example 4 43.0%

 Compound of Example 5

 Compound of Example 6

Compound of Example 8 Compound of Example 9 73.n

 Compound of Example 10 21.5¾

 Compound of Example 11 1 44. \%

 Compound of Example 1 2 30.2%

As is clear from Table 1, it was found that the present compound effectively suppressed Ca ²⁺ overload in cells.

The inhibitory effect of the compound on an excess accumulation of Ca ²⁺ to Test Example 2 suppressive action one 2 in cells of the present compounds against excessive accumulation of Ca ²⁺ into the cells was examined in the same manner as in Test Example 1 .

 Table 2 shows the results.

Table 2 Inhibitory effect of this compound on excessive accumulation of Ca ^{2+ in} cells

As is evident from Table 2, this compound was found to effectively suppress intracellular Ca ²⁺ overload.

 [Test Example 3] Effect of this compound on renal ischemia model

 The effect of the compound on a renal ischemia model was tested.

 (Test method)

Animals: Six-week-old male S.D. rats (Nippon S.L.C.) were used.

 Rats fasted for 2 hours were anesthetized by intraperitoneal administration of clonal hydrate. Evoked renal ischemia-reperfusion injury.

 The right and left renal veins were closed with disposable clips (AM-1.60 g, BEAR) for 45 minutes, and the clips were removed for reperfusion.

 Blood was collected 24 hours after reperfusion, and urea nitrogen in serum was measured. The test substance was administered intraperitoneally 30 minutes before ischemia (dose: 10 mg / 5 ml / kg). They fasted for 48 hours until blood collection.

 Table 3 shows the results.

Table 3 Effect of the compound on renal ischemia model

Test compound Urea nitrogen (mg / dl) Inhibition rate (%) Saline 47 8+ 15 5

Compound of Example 2 24.1 Sat 9.4 * ¹ 49.6 Compound of Example 4 23.6 Sat 5.0 * ¹ 50.6 Compound of Example 6 25.4 Sat 6.2 * ² 46.9 Compound of Example 10 21.4 Sat 6.1 * ² 55.2 Sham operation group

The values indicate Mean S. D. (n = 5-6). * 1 0.05, * 2 <0.01, significant difference from control group.

 From these results, it was confirmed that the present compound is useful for ischemic renal disease. Industrial applicability

The 4-benzyloxyphenyl derivative and the pharmacologically acceptable salt thereof of the present invention have NCX inhibitory activity, and are diseases induced by Ca ²⁺ overload, for example, ischemic heart such as myocardial infarction. Disease, ischemic brain disease such as cerebral infarction or ischemic renal disease, hypertension, cardiovascular disease such as heart failure or arrhythmia, glaucoma, retinitis pigmentosa, macular degeneration, ischemic optic neuropathy, iris ciliary body It is useful as a prophylactic and therapeutic agent for inflammation, retinal artery occlusion, and diabetic retinopathy. While some of the embodiments of the present invention have been described in detail, those skilled in the art will recognize that the particular embodiments illustrated are capable of reading various aspects without departing substantially from the novel teachings and advantages of the present invention. Since it is possible to make modifications and changes, all such modifications and changes are intended to be included within the spirit and scope of the invention as defined by the following claims.

 This application is based on a patent application No. 2000-317807 filed in Japan, the contents of which are incorporated in full herein.

Claims

 The scope of the claims  The following equation (I)

(Wherein, R _t and R ₂ are the same or different and represent a hydrogen atom, a halogen atom, a nitro group, a cyano group or a lower alkyl group, R ₃ represents any of the above structures, and R ₄ represents hydrogen R ₅ represents a hydrogen atom or a lower alkyl group, R ₆ represents a hydrogen atom or a lower alkyl group, and n represents 0 or a hydrogen atom or a lower alkyl group substituted with an atom, a hydroxyalkyl group, or an amino group. And m represents an integer of 0 or 1. However, when R ₃ is a group containing a piperazine ring and n is 0, and at least one of R _{2 is} a halogen atom or a nitro group. 4) benzyloxyphenyl derivative or a pharmacologically acceptable salt thereof represented by the formula: 2. In the formula (I), and R ₂ both represent the same halogen atom, or one of them represents a halogen atom, the other represents a hydrogen atom, and R ₃ represents the above-mentioned pyrazine ring. R ₄ represents a hydrogen atom, a hydroxyalkyl group, a phenyl group or an aminoalkyl group substituted with an amino group, R ₅ represents a hydrogen atom or a lower alkyl group, and n is an integer of 0 to 3. 4. The 4-benzyloxyphenyl derivative according to claim 1, or a pharmaceutically acceptable salt thereof. 3. In the formula (I), R and R ₂ both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R ₃ represents the above thiazolidine ring. Wherein R ₆ represents a hydrogen atom or a lower alkyl group, and m represents an integer of 0 or 1, wherein the 4-benzyloxyphenyl derivative or pharmacologically thereof according to claim 1. Acceptable salt. 4. In the formula (0, R and R ₂ both represent a nitro group, or one of them represents a nitro group, the other represents a hydrogen atom, and R ₃ represents a pyrazine ring. R ₄ represents a hydrogen atom, R ₅ represents a hydrogen atom, and n represents an integer of 0 to 3, wherein the 4_benzyloxyphenyl derivative according to claim 1 or Its pharmacologically acceptable salts. 5. In formula (I), R and R ₂ both represent a cyano group, or one of them represents a cyano group, the other represents a hydrogen atom, and R ₃ represents the above-mentioned pyrazine ring. R ₄ represents a hydrogen atom, R ₅ represents a hydrogen atom, and n represents an integer of 0 to 3, wherein 4 is a benzyloxyphenyl derivative or Its pharmacologically acceptable salts. 6. In the formula (I), R and R ₂ both represent a lower alkyl group, or one of them represents a lower alkyl group, the other represents a hydrogen atom, and R ₃ represents the above-mentioned piperazine ring. R ₄ represents a hydrogen atom, R ₅ represents a hydrogen atom, and n represents an integer of 0 to 3, wherein the 4-benzyloxyphenyl derivative or the drug thereof according to claim 1, Physically acceptable salts.  7. (1) 1- [4- (4-nitrobenzyloxy) phenyl] piperazine (2) 1- [4- (4-Fluorobenzyloxy) phenyl] piperazine (3) 1- [4- (4-cyanobenzyloxy) phenyl] pidazine (4) 1— {2- [4- (4-fluorobenzyloxy) phenyl] ethyl} piperazine  (5) 1 1 {3-[4- (4-fluorobenzyloxy) phenyl] propyl} (6) 2- [4- (4-nitrobenzyloxy) benzyl] thiazolidine 4-ethyl ether ester (7) 2- [4- (4- (12-nitrobenzyloxy) phenyl] thiazolidine-1 4-rubonic acid (8) 1-one [4- (3-fluorobenzyloxy) phenyl] pidazine (9) 1- [4- (2-fluorobenzyloxy) phenyl] pidazine (10) 1- [4- (4-chlorobenzyloxy) phenyl] pidazine (1 1) 1- [4- (4-Methylbenzyloxy) phenyl] pidazine (1) 2-{4- [4- (4-fluorobenzyloxy) phenyl] piperazinyl} ethanol  (13) 2-{4-[4- (4-fluorobenzyloxy) phenyl] piperazinyl} aniline  (14) 1- [4- (3,4-Dichloro-mouth benzyloxy) phenyl] pidazine (15) 1- [4- (2,3-Dichloro-mouth benzyloxy) phenyl] pidazine (16) 1-[4-1 (2,4-dichloro mouth benzyloxy) phenyl] piperazine (17) 1- [4- (2,5-Dichroic benzyloxy) phenyl] pidazine (18) 1— [4- (2,6-dichlorobenzyloxy) phenyl] pidazine (19) 1- [4- (3,5-Dichrolic benzyloxy) phenyl] piperazine (20) 2--4- [4- (4- (3,4-Dichrolic benzyloxy) phenyl] piradinyl} ethylamine  (21) 1 1 {2- [4- (4-chlorobenzyloxy) phenyl] ethyl} ― 3,5-dimethylpiperazine The 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:  8. A pharmaceutical composition comprising the 4-benzyloxyphenyl derivative according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. 9. Prevention of a disease induced by intracellular Ca ^w overload comprising the 4-benzyloxyphenyl derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. Therapeutic agent. ^10. Diseases induced by intracellular Ca ²⁺ overload are ischemic heart disease, ischemic brain disease or ischemic renal disease, hypertension, circulatory disease of heart failure or arrhythmia, glaucoma, retinitis pigmentosa 10. The preventive and therapeutic agent according to claim 9, wherein the agent is macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, or diabetic retinopathy. 11. An intracellular Ca comprising administering to a mammal an effective amount of the 4-benzyloxyphenyl derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7. ^A method for preventing or treating a disease induced by ²⁺ overload. 1 2. Diseases induced by intracellular Ca overload are ischemic heart disease, ischemic brain disease or ischemic kidney disease, hypertension, heart failure or arrhythmia cardiovascular disease, glaucoma, retinitis pigmentosa, 12. The method according to claim 11, wherein the disease is macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, or diabetic retinopathy. 13. The 4-benziloxyphenyl derivative or its derivative according to any one of claims 1 to 7, for the manufacture of a prophylactic or therapeutic agent for a disease induced by intracellular Ca "overload". Use of pharmacologically acceptable salts. 1 4. Disease is ischemic heart disease induced by Ca ²⁺ overload in cells, ischemic brain disease or ischemic renal diseases, hypertension, circulatory failure or arrhythmia diseases, glaucoma, retinitis pigmentosa The use according to claim 13, wherein the disease is macular degeneration, ischemic optic neuropathy, iridocyclitis, retinal artery occlusion, or diabetic retinopathy.