JP2591345B2 - Tetrazole derivatives and pharmaceuticals - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to the following general formula [I] [Where A represents-(O) _m- (CH (R ⁴ ) _n- (R ⁴ represents hydrogen or alkyl, and m and n represent 0 or 1). Oxygen or —S (O) _p — (p is 0 to 2
Represents ). R ¹ represents hydrogen, lower alkyl, lower alkoxy, halogen, halogenoalkyl, or hydroxy. R ² represents a substituted or unsubstituted alkyl, alkenyl or aralkyl. R ⁸ represents hydrogen, lower alkoxy, or halogen. R ³ represents hydrogen, lower alkyl, lower alkoxy, lower acyloxy, halogen, nitro, hydroxy. R ¹⁰ represents hydrogen or lower alkyl. And a pharmacologically acceptable salt thereof.

The compound according to the present invention exhibits antiallergic and antiinflammatory effects, improves allergic symptoms such as bronchial asthma, urticaria, allergic rhinitis, atopic dermatitis, cardiovascular disorder, cerebrovascular disorder, inflammation, arthritis, etc. It is useful as a remedy for

BACKGROUND ART Various chemical mediators are released from the lungs and other tissues and contract biological tissues such as bronchial muscles and pulmonary blood vessels, and enhance the permeability of skin blood vessels, thereby damaging living tissues. It is considered that allergic asthma, atopic disease and the like develop.

Histamine and SRS among such chemical mediators
-A is regarded as the most important. Recently, the main body of the SRS-A has been elucidated that a peptide leukotrienes LTC _4, LTD ₄ and LTB _4, relevance to various physiological actions and conditions possessed by these leukotrienes (LT) has been extensively studied . Originally, SRS-A, which is a metabolite of arachidonic acid by lipoxygenase, is regarded as important as a substance involved in the onset or refractory disease of bronchial asthma and other diseases based on immediate allergic reactions. .

In fact, LTC ₄ and LTD ₄ are excised trachea guinea pig and human is strongly contracted and the like to enhance mucus secretion from human airway in vitro, are of particular interest is involvement in bronchial asthma.

In an actual disease state, a concentration of LT that has a physiological effect on sputum of a patient such as bronchitis is detected. Furthermore, in children with bronchial asthma, the blood levels of LTC ₄ is also reported to correlate well with the severity.

In addition to asthma, LT is also used for ischemic diseases such as allergic rhinitis and dermatitis, myocardial infarction, cardiac anaphylaxis,
Its involvement has also been suggested in endotoxin shock, psoriasis, and the like.

Therefore, the development of drugs that suppress or antagonize SRS-A production has attracted attention.

For example, FPL-55712, SKF-104353, WY-45911, ONO
-1078 and the like are known as LT antagonists. However, none has yet been commercialized [Tohn H. Msser et.
al., New development concerning Leukotriene Antagon
ists.Agents and Actions, 18 (3/4) 332 (1986), Drugs
of the Future, 13 (4) 317 (1988)].

JP-A-62-198652 describes a group of compounds similar to the compounds according to the present invention and that some of the compounds have 5α-reductase inhibitory activity. According to the description of the claims in the specification of the application, it is considered that the compound of the present invention is indicated, but there is no specific disclosure of the compound having a tetrazolyl group anywhere in the specification. . Further, there is no description suggesting the pharmacological action of the compound of the present invention as a feature thereof. It has been found that the compound of the present invention has no 5α-reductase inhibitory activity at all.

DISCLOSURE OF THE INVENTION The present inventors have a compound which has SRS-A production inhibitory or antagonistic activity, and is superior in efficacy, safety and sustainability to conventionally known antiallergic agents and antiinflammatory agents. A study was conducted to obtain The object of the present invention is therefore:
An object of the present invention is to obtain a novel compound having an excellent antiallergic action and antiinflammatory action.

The gist of the present invention lies in the structure itself of the compound represented by the general formula [I].

The compound according to the present invention is a novel compound that has not been described in the literature, exhibits excellent pharmacological action, bioavailability, and sustainability as described below, has low toxicity, and is useful as a pharmaceutical.

The compound of the present invention represented by the general formula [I] will be described in detail.

Examples of the halogen represented by R ¹ in the general formula [I] include chlorine, fluorine, bromine and iodine.

As the lower alkyl, a straight-chain or branched C 1 -C 1
4 are preferred, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.
-Butyl and the like.

As the lower alkoxy, a linear or branched C 1 -C 1
~ 4 are preferable, for example, methoxy, ethoxy,
Examples thereof include n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the like.

As the halogenoalkyl, a linear or branched carbon number 1
It is preferable that at least one of the alkyls of the formulas (1) to (4) is substituted with at least one of fluorine, chlorine, bromine and iodine. Butyl and the like can be mentioned.

The alkyl represented by R ² preferably has 1 to 10 carbon atoms, and in addition to the above, for example, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoptyl and the like can be mentioned.

As the alkenyl, a linear or branched C2-C10
Are preferred, for example, vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-butenyl,
Pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl and the like can be mentioned.

The aralkyl preferably has 7 to 12 carbon atoms, and examples thereof include benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, and naphthylmethyl.

Examples of the alkyl substituent include —COOR ³ (R ³ is hydrogen,
Or, unsubstituted or ^{-CON (R 6) R 7 (} R 6, R 7 are the same or different and each represents. Hydrogen or lower alkyl) alkyl of been 1 to 6 carbon atoms substituted with. ) Hydroxy group,
—CON (R ⁶ ) R ⁷ (R ⁶ and R ⁷ are the same or different and represent hydrogen or lower alkyl), or a heterocyclic group. Examples of such a heterocyclic ring include unsubstituted or halogen-substituted quinoline and tetrazole.

Examples of the alkyl represented by R ⁴ include the alkyls exemplified for R ¹ above.

Examples of the lower alkoxy represented by R ⁸ include the alkoxys exemplified for R ¹ above. The halogen, halogen as exemplified above R ^1.

Examples of the lower alkyl, lower alkoxy and halogen represented by R ⁹ include the alkyl, alkoxy and halogen exemplified for R ¹ above.

The lower acyloxy is preferably a straight-chain or branched one having 2 to 5 carbon atoms, and examples thereof include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy and isovaleryloxy.

Examples of the lower alkyl represented by R ¹⁰ include the lower alkyls exemplified for R ¹ above.

Examples of the salt include an alkali salt such as a sodium salt and a calcium salt or an alkaline earth metal salt, and an organic amine salt, an amino acid salt or an ammonium salt.

The compound of the present invention can be produced, for example, by the following method.

Here ^{A, B, R 1, R} 2, R 8, R 9, R 10 are the same as defined above.

Method A [I] can be produced by reacting a aniline derivative [II] with a reactive derivative of a benzoic acid derivative [III] or [III].

This acylation reaction can be performed by a method known per se.

For example, a reactive derivative of [III], for example, a benzoyl halide derivative (eg, benzoyl chloride derivative, benzoyl bromide derivative, etc.), a lower alkyl ester or an active ester (eg, p-nitrophenyl ester,
a method of appropriately reacting p-nitrobenzyl ester, p-chlorophenyl ester, etc.), imidazolide or mixed acid anhydride (eg, lower alkyl carbonic acid mixed acid anhydride, lower alkyl phosphoric acid mixed acid anhydride) and the like, or [II] And [II
I] can be directly bonded using a condensing agent.

When using a benzoyl halide derivative, usually in a solvent inert to the reaction, in the presence or absence of an organic base-
The benzoyl halide derivative is reacted with [II] at 5 ° C to 120 ° C. As the solvent, for example, diethyl ether,
Ether solvents such as tetrahydrofuran and dioxane,
Halogenated hydrocarbon solvents such as methylene chloride and chloroform, hydrocarbon solvents such as benzene, toluene and xylene, aprotic solvents such as N, N-dimethylformamide, and mixtures thereof can be used.

As the organic base, for example, tertiary organic bases such as pyridine, triethylamine, tributylamine, and dimethylaniline can be used.

The reaction time varies depending on the type of the starting material, the base used, and the solvent, but is usually appropriate for 30 minutes to 12 hours.

Usually, the benzoyl halide derivative and the base are preferably used in an amount of 1 to 3 moles per 1 mole of [II].

In the case of direct bonding using a condensing agent, [II] and [III] are usually reacted at -20 to 80 ° C in a solvent inert to the reaction in the presence of the condensing agent. As the solvent, those described above can be used.

Examples of the condensing agent include carbodiimides such as dicyclohexylcarbodiimide, quaternary pyridinium salts such as 2-chloro-N-methylpyridinium iodide, and 2-methanesulfonyloxy-N-methylpyridinium iodide, diphenylphosphoryl azide, diethyl Phosphoryl cyanide, or triphenylphosphine and carbon tetrachloride can be used.

The reaction time varies depending on the type of the starting material, the condensing agent and the solvent used, but is usually appropriate for 30 minutes to 12 hours.

The amount of [III] and the condensing agent is usually preferably 1 to 3 moles per 1 mole of [II].

Method B [I] can be produced by reacting a compound [IV] containing a cyano group with hydrazoic acid or a salt thereof.

Examples of the salt of hydrazide include, for example, salts of hydrazide with alkali metals such as sodium azide, potassium azide and lithium azide, and salts of hydrazide with alkali metals such as calcium azide and magnesium azide. Salts with earth metals,
Alternatively, a salt with another metal capable of forming a salt with hydrazoic acid such as aluminum azide or tin azide, or a salt with an organic base such as tetramethylguanidinium azide can be used.

As the salt of hydrazoic acid of the present invention, in addition to using these salts alone, an alkali metal salt of hydrazoic acid (eg, sodium azide) and a Lewis acid (eg, aluminum chloride, stannic chloride, Zinc chloride, titanium chloride, BF ₃
-Diethyl ether, etc.), ammonium salts (e.g., ammonium chloride, di-n-butylammonium chloride, benzeneammonium chloride, tetramethylammonium chloride, etc.), sulfonic acids (e.g., ethanesulfonic acid),
In the presence of an alkali metal halide (eg, lithium chloride) or an amine salt (eg, triethylamine hydrochloride, pyridine hydrochloride, etc.) in a solvent inert to the reaction, from 0 to 200
[I] can be produced by reacting at ℃. As the solvent, N, N-dimethylformamide, dimethyl sulfoxide, aprotic solvents such as N-methylpyrrolidone,
Tetrahydrofuran, dioxane, methyl cellosolve,
Ethers such as ethyl cellosolve and hydrocarbons such as benzene, toluene and petroleum ether can be used.

The amount of the azide to be used is 1 mol to 10 mol per 1 mol of compound [IV]. The reaction time varies depending on the type of the starting material, the salt used, and the solvent, but is generally 30 minutes to 48 hours.

When the compound obtained as described above is an ester (R ³ =
Alkyl)), whereby the target compound in which R ³ is hydrogen can be obtained. This hydrolysis reaction is carried out in a suitable solvent (eg, alcohols such as methanol and ethanol, glycols such as ethylene glycol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,2-dimethoxyethane, acetone, methyl ethyl ketone and the like). (Ketones, water or a mixture thereof), the reaction is easily carried out using an alkali at 0 to 100 ° C. for 30 minutes to 5 hours.

As the alkali, hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and carbonates such as sodium carbonate and potassium carbonate can be used. The amount of the alkali to be used is 2 to 6 mol, preferably 3 to 4 mol, per 1 mol of the ester. The carboxylic acid (R ³ ＨH) produced by this method can be converted to an ester (R ³ア ル キ ル alkyl) if necessary. This esterification reaction is carried out by a known esterification, for example, diazomethane, alcohol and acid (eg, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, etc.),
Alternatively, the reaction can be performed using thionyl chloride and an alcohol.

In addition, [I] obtained by the above method may be mixed with a pharmacologically acceptable organic amine, alkali metal hydroxide or ammonia by a conventional method, and reacted by a method known per se such as heating. Thus, an organic amine salt, an amino acid salt, an alkali metal salt or an ammonium salt corresponding to the compound [I] can be obtained.

For example, in the case of an alkali metal salt, a salt can be formed by heating a compound produced by the above method with sodium hydroxide or the like in an alcohol or aqueous alcohol.

The oxidation reaction of the sulfur atom can be performed by a method known per se.

The reaction is performed using an oxidizing agent, for example, perbenzoic acid, ozone, phenyldichloroiodide, hydrogen peroxide, sodium metaperiodate, sodium hypochlorite, or the like. Especially,
m-Chloroperbenzoic acid is preferred. Usually, when 1 equivalent is used for the compound [I] (p = 0), sulfoxide (p = 1) is obtained, and when 2 or more equivalents are used, sulfone (p = 2) is used. can get.

The reaction is usually carried out in an inert solvent such as methylene chloride, chloroform or carbon tetrachloride at −30 to 60 ° C., and the reaction time is about 3 minutes to 3 hours for sulfoxide and about 3 hours for sulfone. 1 to 48 hours.

Some of the compounds of the present invention have an asymmetric carbon, but each of the optical isomers and mixtures thereof are included in the present invention. The optical isomer is obtained from the mixture obtained as described above, by utilizing the acidity of the mixture and using an optically active base (brucine, quinine, α-methylbenzylamine, etc.) by a method known per se. The optically active compounds [II] to [I
V] as a raw material.

The target compound [I] thus produced can be isolated and purified by a means known per se, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, fractionation, chromatography and the like. Can be.

Starting materials [II] and [IV] can be produced as in Reference Examples.

When the compound of the present invention is administered as a medicament, the compound of the present invention is used alone or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.01% to 99.5%, preferably 0.5%.
~ 90% as a pharmaceutical composition administered to animals, including humans.

As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered intravenously, orally, intraosseously, topically (eg, nasal or ophthalmic) or rectally. Needless to say, the composition is administered in a dosage form suitable for these administration methods. Oral or inhalation administration is particularly preferred.

It is desirable to set the dose as an antiallergic or anti-inflammatory agent in consideration of the patient's condition such as age and weight, the administration route, the nature and extent of the disease, etc. As the amount of the active ingredient of the invention, in the case of oral administration per day, in the range of 1 to 1000 mg / human, preferably 1 to 100 mg
In the case of inhalation administration, the range is generally 0.01 to 100 mg / human. In some cases, less is sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

For oral administration, solid or liquid dosage units, such as powders,
Powders, tablets, sugar coatings, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets and other forms can be used.

Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as starch, edible carbohydrates such as mannitol, and the like. If necessary, flavoring agents, preservatives, dispersants, coloring agents, fragrances and the like may be mixed.

Capsules are produced by first filling powdered powders, powders or granules as described in the section of tablets as described above into a capsule shell such as a gelatin capsule. You. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, and the like may be mixed with the powdered state, and then the filling operation may be performed. it can. Disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium,
Addition of sodium carboxystarch, calcium carbonate, sodium carbonate can improve the efficacy of the medicine when the capsule is taken.

Further, the fine powder of the product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped with a gelatin sheet to form a soft capsule. Tablets are made by preparing a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and pressing. The powder mixture is prepared by mixing the appropriately powdered material with the diluent or base described above and, if necessary, a binder (e.g., sodium carboxymethylcellulose,
Hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, polyvinylalcohol, etc.), dissolution retardant (eg, paraffin, wax, hydrogenated castor oil, etc.), resorbent (eg, quaternary salt) and adsorbent (For example, bentonite, kaolin, dicalcium phosphate, etc.) may also be used in combination. The powder mixture can be first moistened with a binder such as syrup, starch paste, gum arabic, a cellulose solution or a polymer solution, and then forced through a sieve to form granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules.

The granules thus prepared can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and the like as a lubricant. The lubricated mixture is then tableted.

The uncoated tablets thus produced can be coated with a film or coated with sugar.

Alternatively, the drug may be directly tableted after being mixed with a fluid inert carrier without going through the steps of granulation and slag formation as described above. Transparent or translucent protective coating consisting of shellac sealing coating, coating of sugar or polymer material, and
Such as a wax topcoat may also be used.

Other oral dosage forms such as solutions, syrups, elixirs and the like can also be made in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg,
Ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, peppermint oil, saccharin) and the like can also be added as necessary.

Where necessary, dosage unit formulations for oral administration may be microencapsulated. The formulations can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes, and the like.

Administration into tissues can be carried out by using liquid dosage unit forms for subcutaneous / muscular or intravenous injection, for example, solutions and suspensions. These are prepared by suspending or dissolving a fixed amount of the compound in a non-toxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily medium, and then sterilizing the suspension or solution. You. Alternatively, an aliquot of the compound may be placed in a vial and the vial and its contents sterilized and sealed thereafter.
Spare vials or carriers may be provided with the powdered or lyophilized active ingredient for dissolving or mixing immediately prior to administration. A non-toxic salt or salt solution may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination.

Rectal administration is carried out by using a suppository containing a compound soluble or insoluble in water having a low melting point, such as polyethylene glycol, cocoa butter, higher esters (for example, myristyl palmitate), and a mixture thereof. Can be.

Inhalation administration, in addition to the method using a vapor inhaler, for example,
It can be carried out in the form of a spray using a pressure vessel or a nebulizer.

When using a nebulizer, dissolve the compound of the present invention in an aqueous solvent or an oily solvent such as water, physiological saline, or hydroalcohol, put the nebulizer in the nebulizer, and blow the air strongly to apply it in a mist to the throat or nasal cavity. Can be.
If necessary, an auxiliary agent such as a solubilizing agent may be blended. A single dose can be determined by adjusting the air flow.

When using a pressure vessel, two-phase system, three-phase system (two-liquid layer system,
It can be applied to the throat or nasal cavity in the form of a mist, a foam, a jet stream, or a paste using a liquefied gas propellant in the form of an emulsified or suspended gas or a compressed gas propellant.
A single dose as a propellant can be determined by using a valve to deliver a metered amount.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, Test Examples, and Production Examples of the medicament of the present invention.

Reference Example 1 2- [3- [1- (1H-tetrazol-5)
Il) ethoxy] phenoxy] aniline Step 1 3- (2-nitrophenoxy) anisole 3-methoxyphenol 19.9 g and potassium hydroxide 9.1 g
Was added to 150 ml of dimethyl sulfoxide, and the mixture was heated to 70 to 80 ° C. to obtain a homogeneous solution. Add 2-chloronitrobenzene 2
1.1 g was added and the mixture was stirred at 100 ° C for 4 hours. The reaction solution was diluted with water and extracted with ether, and the ether layer was washed with a 10% sodium hydroxide solution and then with a saturated saline solution. After drying over magnesium sulfate, the ether was distilled off to obtain 31.9 g of the desired product as a pale yellow solid.

Step 2 3- (2-Nitrophenoxy) phenol A mixture of 28.8 g of 3- (2-nitrophenoxy) anisole and 68 g of pyridine hydrochloride is heated to 160 to 170 ° C. to form a homogeneous solution, and then at 195 to 205 ° C. for 1 hour. The mixture was heated and stirred. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried and concentrated.
23.8 g were obtained as a pale brown oil.

Step 3 Ethyl 2- [3- (2-nitrophenoxy)
[Phenoxy] propionate 3- (2-nitrophenoxy) phenol 8.0 g and 2-
7.5 g of ethyl bromopropionate was dissolved in 120 ml of acetone, 7.2 g of potassium carbonate was added, and the mixture was heated under reflux for 5 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was concentrated to obtain 11.6 g of the desired product as a pale brown oil.

Step 4 Ethyl 2- [3- (2-nitrophenoxy) phenoxy] propionate 6.7 g of 2- [3- (2-nitrophenoxy) phenoxy] propionate is dissolved in 100 ml of ethanol, and 1.6 g of sodium hydroxide in water (10 ml). The solution was added and stirred at room temperature for 1 hour. After distilling off the ethanol, the mixture was diluted with water. The mixture was acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried and concentrated to obtain 6.2 g of the desired product as a pale yellow oil.

Step 5 2- [3- (2-Nitrophenoxy) phenoxy] propionamide Dissolve 6.15 g of 2- [3- (2-nitrophenoxy) phenoxy] propionic acid and 4.2 g of triethylamine in 100 ml of methylene chloride and distill at 0 ° C. or lower. 2.5 g of ethyl formate was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes, and then poured into an ice-cooled ammonia gas saturated methylene chloride (120 ml) solution, and then returned to room temperature and stirred for 30 minutes. The methylene chloride layer was washed with water (twice), dried and concentrated, and the obtained residue was crystallized from methanol and isopropyl ether to give 3.3 g of the desired product.

Step 6 2- [3- (2-nitrophenoxy) phenoxy] propionitrile 4.52 g of 2- [3- (2-nitrophenoxy) phenoxy] propionamide is added to 12 ml of pyridine and 35 ml of dioxane.
Suspended under ice-cooling and stirring.
6 g was added dropwise. After the addition, the mixture was stirred at the same temperature for 30 minutes, ice water was added, and the mixture was extracted with ether. The ether layer was washed with dilute hydrochloric acid and then with a sodium bicarbonate solution, dried and concentrated to obtain 4.3 g of the desired product as a pale yellow oil.

Step 7 2.0 g of 5- [1- [3- (2-nitrophenoxy) phenoxy] ethyl] -1H-tetrazole 2- [3- (2-nitrophenoxy) phenoxy] propionitrile is added to 25 ml of N, N-dimethylformamide
0.92 g of sodium azide and ammonium chloride
0.76 g was added, and the mixture was heated and stirred at 115 ° C. for 80 minutes. The reaction mixture was poured into ice water containing 3 ml of concentrated hydrochloric acid and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried and concentrated to obtain 2.4 g of the desired product as a pale brown oil.

Step 8 Dissolve 2- [3- [1- (1H-tetrazol-5-yl) ethoxy] phenoxy] aniline 5- [1- [3- (2-nitrophenoxy) phenoxy] ethyl] 1H-tetrazole in 30 ml of ethanol. Then, 0.3 g of palladium carbon was added, and catalytic hydrogenation was performed at normal temperature and normal pressure. After the reaction, the catalyst was removed by filtration, and the filtrate was concentrated to give 2.
1 g was obtained as a brown oil.

In the same manner as in Reference Example 1, 2- [3- (1H-tetrazol-5-ylmethoxy) phenoxy] aniline was produced.

Reference Example 2 2- [3- (1H-tetrazol-5-yl)
Phenoxy] aniline Step 1 3- (2-nitrophenoxy) benzonitrile 5.0 g of 3-cyanophenol and 5.93 g of 2-fluoronitrobenzene are dissolved in 50 ml of N, N-dimethylformamide,
8.71 g of potassium carbonate was added, and the mixture was heated and stirred at 100 ° C. for 2 hours.
After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed three times with water, dried and concentrated. The residue was crystallized from diisopropyl ether to give 9.63 g of the desired product as pale yellow crystals.

Step 2 4.0 g of 5- [3- (2-nitrophenoxy) phenyl] -1H-tetrazole 3- (2-nitrophenoxy) benzonitrile
It was dissolved in N, N-dimethylformamide (40 ml), sodium azide (2.28 g) and ammonium chloride (1.88 g) were added, and the mixture was stirred at 110 ° C. for 4 hours. After cooling, the reaction solution was acidified by adding diluted hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried and concentrated. The residue was crystallized from a mixed solvent of ethyl acetate and benzene to give 3.6 g of the desired product as pale brown crystals.

Step 3 2- [3- (1H-tetrazol-5-yl) phenoxy] aniline 5- [3- (2-nitrophenoxy) phenyl] -1H
1.5 g of tetrazole was dissolved in a mixed solvent of 18 ml of ethanol and 9 ml of N, N-dimethylformamide, 0.3 g of palladium carbon was added, and the mixture was subjected to catalytic hydrogenation at room temperature and pressure. After the reaction, the catalyst was filtered, and the filtrate was concentrated to give 1.3 g of the desired product as a colorless oil.

Reference Example 3 N- [2- [2-cyanophenoxy] phenyl] -4-hexyloxybenzamide Step 1 2- (2-aminophenoxy) benzonitrile 2- (2-nitrophenoxy) benzonitrile (Reference Example 2 Step 1 2.5 g) was dissolved in 50 ml of ethyl acetate, 0.5 g of palladium carbon was added, and the mixture was subjected to catalytic hydrogenation at normal temperature and normal pressure. After the reaction, the catalyst was filtered, the filtrate was concentrated, and the obtained residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 2.0 g of the desired product as a colorless oil.

Step 2 N- [2- [2-cyanophenoxy] phenyl] -4-hexyloxybenzamide 2.0 g of 2- (2-aminophenoxy) benzonitrile was dissolved in 20 ml of ether, and 2.04 g of triethylamine was added.
Under ice-cooling and stirring, 4-hexyloxybenzoyl chloride 2.
67 g was dissolved in 5 ml of ether and added dropwise. After the addition, the mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with dilute hydrochloric acid and then with a sodium bicarbonate solution, dried and concentrated. The residue was subjected to silica gel column chromatography, purified by eluting with a mixed solvent of ethyl acetate and n-hexane, and then crystallized from diisopropyl ether to obtain 3.05 g of the desired product as white crystals.

In the same manner as in Reference Example 3, ethyl 4- [2- (4-
Cyanophenix) phenylcarbamoyl] phenoxyacetate was prepared.

Reference Example 4 (B) -N- [2- (2-cyanophenylthio) phenyl] -4- (2-heptenyloxy) benzamide Step 1 Ethyl 2- (2-nitrophenylthio) benzoate 15.4 g of thiosalicylic acid was added to N , N-dimethylformamide 10
The mixture was dissolved in 0 ml, potassium carbonate (42 g) and 2-fluoronitrobenzene (14.8 g) were added, and the mixture was stirred at 100 ° C. for 3 hours. After the temperature of the reaction mixture was returned to room temperature, 18.7 g of ethyl iodide was added, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ether. The ether layer was washed twice with water, dried and concentrated. The residue was crystallized from ethanol to give 25.5 g of the desired product as yellow crystals.

Step 2 Ethyl 2- (2-aminophenylthio) benzoate Ethyl 2- (2-nitrophenylthio) benzoate 22.5
g was suspended in 130 ml of ethanol and stannic chloride dihydrate 5
A solution of 8.7 g in concentrated hydrochloric acid (70 ml) and ethanol (45 ml) was added all at once. After stirring for 3 hours at room temperature, the reaction mixture is
Under cooling and stirring, the mixture was poured into a mixture of 600 ml of a 10% aqueous sodium hydroxide solution and 500 ml of ether. Separate the ether layer,
The extract was washed with water and saturated saline and dried, and ether was distilled off to obtain 20.5 g of the desired compound as a pale yellow oil.

Step 3 (E) Ethyl 2- (2-aminophenylthio) benzoate 2.1 g of 2- [2- [4- (2-heptenyloxy) benzoylamino] phenylthio] benzoic acid
And 1.8 g of ethylamine were dissolved in 30 ml of methylene chloride, and 2.2 g of (E) -4- (2-heptenyloxy) benzoyl chloride was added dropwise under ice-cooling and stirring. After stirring at room temperature for 10 hours, methylene chloride was distilled off, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with dilute hydrochloric acid and a saturated sodium bicarbonate solution, dried, and the ether was distilled off. Ethanol residual oil
Dissolved in 50 ml, added 7 ml of 10% aqueous sodium hydroxide solution and heated on a water bath for 40 minutes. After cooling, the mixture was acidified with hydrochloric acid, diluted with water, and the precipitated crystals were collected by filtration, washed with water and then with aqueous ethanol to obtain 2.8 g of the desired product as white crystals.

Step 4 (E) -2- [2- [4- (2-Heptenyloxy) benzoylamino] phenylthio] benzamide (E) -2- [2- [4- (2-Heptenyloxy)
2.8 g of benzoylamino] phenylthio] benzoic acid are suspended in 40 ml of benzene, and N, N'-carbonyldiimidazole is suspended.
1.2 g was added and stirred at room temperature for 2 hours. Ammonia gas was introduced into the obtained solution under ice-cooling and stirring for 20 minutes, and then left at room temperature for 2 hours. The precipitated crystals were collected by filtration and washed with ethyl acetate to obtain 2.6 g of the desired product as white crystals.

Step 5 (E) -N- [2- (2-cyanophenylthio) phenyl] -4- (2-heptenyloxy) benzamide (E) -2- [2- [4- (2-heptenyloxy)
2.5 g of benzoylamino] phenylthio] benzamide was suspended in a mixture of 5 ml of pyridine and 50 ml of dioxane, and 2.2 g of trifluoroacetic anhydride was added dropwise with stirring under ice-cooling. After the dropwise addition, the mixture was further stirred at room temperature for 3 hours, ice water was added, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.4 g of the desired product as white crystals.

 The following compounds were produced in the same manner as in Reference Example 4.

N- [2- (3-cyanomethylphenoxy) phenyl] -4-hexyloxybenzamide N- [2- (2-cyanomethylphenoxy) phenyl] -4-hexyloxybenzamide (E) -N- [3-chloro -2- (2-cyanophenylthio) phenyl] -4- (2-heptenyloxy) benzamide (E) -N- [4-methoxy-2- (2-cyanophenylthio) phenyl] -4- (2-heptenyloxy )
Benzamide N- [2- (2-cyanophenylthio) phenyl]-
4- (4-phenylbutoxy) benzamide N- [3-chloro-2- (2-cyanophenylthio)
Phenyl] -4- (4-phenylbutoxy) benzamide N- [2- (2-cyanophenylthio) -3-fluorophenyl] -4- (4-phenylbutoxy) benzamide N- [2- (2-cyanophenyl Thio) phenyl]-
4-pentyloxybenzamide N- [2- (2-cyanophenylthio) phenyl]-
4-heptyloxybenzamide (E) -N- [2- (2-cyanophenylthio) phenyl] -4- (2-hexenyloxy) benzamide Reference Example 5 N- [2- (2-cyanophenylthio) phenyl] -4-hexyloxybenzamide Step 1 2- (2-nitrophenylthio) benzoic acid thiosalicylic acid 30.8 g, 2-fluoronitrobenzene 2
8.2 g, potassium carbonate 69.0 g in N, N-dimethylformamide
The suspension was suspended in 300 ml and heated and stirred at 10 ° C. for 2 hours. After cooling, water was added, the mixture was acidified with hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water.
The crystals were dissolved in ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The precipitated crystals were collected by filtration and dried to obtain 42.6 g of the desired product as yellow prism crystals. Melting point 169 ~
Step 2 2- (2-nitrophenylthio) benzamide 20.0 g of 2- (2-nitrophenylthio) benzoic acid and 40 ml of thionyl chloride were suspended in 200 ml of benzene and heated under reflux for 6 hours. The solvent and excess thionyl chloride are distilled off under reduced pressure to give 2- (2-nitrophenylthio) benzoic acid chloride
22 g were obtained as yellow crystals. This was dissolved in a mixture of 200 ml of ether and 100 ml of methylene chloride without further purification, and ammonia gas was introduced under ice-cooling for 15 minutes. After the mixture was stirred at room temperature for 1 hour, the crystals were collected by filtration, washed with water and washed with hot ethanol to give 18.4 g of the desired product as pale yellow crystals. Step 3 2- (2-nitrophenylthio) benzonitrile 8.8 g of 2- (2-nitrophenylthio) benzamide is suspended in a mixture of 12.7 g of pyridine and 80 ml of dioxane.
Under ice cooling, 10.1 g of trifluoroacetic anhydride was added dropwise thereto,
Stir for 1 hour. Water was added, and the precipitated crystals were collected by filtration, washed with water, washed with hot ethanol, and dried. Object as yellow crystals
7.84 g was obtained. Melting point 166-167 [deg.] C.

Step 4 2- (2-aminophenylthio) benzonitrile 6.6 g of 2- (2-nitrophenylthio) benzonitrile
Was suspended in 40 ml of concentrated hydrochloric acid, 60 ml of methanol and 40 ml of N, N-dimethylformamide, and 8.64 g of iron powder was added thereto all at once, followed by stirring at 60 ° C. for 1 hour. Dilute the reaction mixture with water,
The precipitate was extracted with ether. The extract was washed with aqueous sodium hydrogen carbonate, washed with water and dried over magnesium sulfate. The solvent is distilled off, and the residue is subjected to column chromatography (Wakogel C200)
And eluted with ethyl acetate-n-hexane (1: 4).
The obtained crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 4.8 g of the desired product as white crystals. Melting point 86 ~
89 ° C. Step 5 N- [2- (2-cyanophenylthio) phenyl] -4-hexyloxybenzamide 1.03 g of 4-hexyloxybenzoic acid is added to 2 ml of thionyl chloride
And heated under reflux for 1 hour. Excess thionyl chloride was distilled off and dried under reduced pressure to obtain 4-hexyloxybenzoyl chloride. Separately, 2- (2-aminophenylthio)
1.00 g of benzonitrile and 0.89 g of triethylamine were dissolved in 10 ml of ether, stirred under ice-cooling, and 4-hexyloxybensoyl chloride dissolved in 5 ml of ether was added thereto. The mixture was stirred overnight. Water was added, followed by aqueous sodium bicarbonate, and the precipitate was extracted with ethyl acetate.
The extract was dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to obtain 1.27 g of the desired product as white prism crystals.

 The following compounds were produced in the same manner as in Reference Example 5.

(E) -N- [5-chloro-2- (2-cyanophenylthio) phenyl] -4- (2-heptenyloxy) benzamide N- [5-chloro-2- (2-cyanophenylthio)
Phenyl] -4-hexyloxybenzamide Reference Example 6 Methyl 4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxyacetate Step 1 N- [2- (2-cyanophenylthio) phenyl] -4-hydroxy 2.6 g of benzamide 2- (2-aminophenylthio) benzonitrile (prepared in Step 4 of Reference Example 5) and 2.8 g of pyridine were added to ether 60.
The resulting mixture was dissolved in the same solution, and a solution of 2.7 g of 4-acetoxybenzoyl chloride in ether was added dropwise with stirring under ice-cooling. Room temperature after dropping 10
After stirring for an hour, ether was distilled off, and ethanol was added to the residue, and the precipitated crystals were collected by filtration and washed with ethanol. The crystals were suspended in 70 ml of ethanol, 7 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified by adding concentrated hydrochloric acid, diluted with water, and the precipitated crystals were collected by filtration and dried to obtain 3.3 g of the desired product as white crystals.

Step 2 Methyl 4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxyacetate N- [2- (2-cyanophenylthio) phenyl]-
1.0 g of 4-hydroxybenzamide and methyl bromoacetate
0.49 g was dissolved in N, N-dimethylformamide (10 ml), potassium carbonate (0.6 g) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, and the precipitated crystals were collected by filtration, washed with water and then with aqueous ethanol to give 1.2 g of the desired product as white crystals.

 The following compounds were produced in the same manner as in Reference Example 6.

N- [2- (2-cyanophenylthio) phenyl]-
4- (2-quinolylmethoxy) benzamide N- [2- (2-cyanophenoxy) phenyl] -4
-(2-quinolylmethoxy) benzamide N- [2- (2-cyanophenylthio) phenyl]-
4- (7-chloro-2-quinolylmethoxy) benzamide N- [2- (2-cyanophenylthio) phenyl]-
4- (6-hydroxyhexyloxy) benzamide ethyl 4- [4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxy] butyrate ethyl 6- [4- [2- (2-cyanophenylthio) phenylcarbamoyl ] Phenoxy] hexanoate ethyl 4- [2- (2-cyanophenoxy) phenylcarbamoyl] phenoxyacetate N- [2- (2-cyanophenylthio) phenyl]-
4-heptyloxybenzamide N- [2- (2-cyanophenylthio) phenyl]-
4-pentyloxybenzamide N- [2- (2-cyanophenylthio) phenyl]-
4- (5-oxohexyloxy) benzamide N- [2- (2-cyanophenylthio) phenyl]-
4-cyanomethoxybenzamide ethyl 2- [4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxy] propionate ethyl 2-methyl-2- [4- [2- (2-cyanophenylthio) phenylcarbamoyl] Phenoxy] propionate N- [2- (2-cyanophenoxy) phenyl] -4
-(6-hydroxyhexyloxy) benzamide N- [2- (2-cyanophenoxy) phenyl] -4
-(5-oxohexyloxy) benzamide ethyl 4- [4- [2- (2-cyanophenoxy)
Phenylcarbamoyl] phenoxy] butyrate ethyl 6- [4- [2- (2-cyanophenoxy)
Phenylcarbamoyl] phenoxy] hexanate Reference Example 7 2- [2- (1H-tetrazol-5-yl)
Phenylthio] aniline 2.4 g of 2- (2-aminophenylthio) benzonitrile (manufactured in Step 4 of Reference Example 5), 3.4 g of sodium azide and 1.7 g of ammonium chloride are suspended in 25 ml of DMF and heated to 110 to 120 ° C.
For 5 hours. After cooling, the mixture was diluted with water, acidified with acetic acid, and extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the residue was crystallized from ethyl acetate and isopropyl ether to give 1.9 g of the desired product as a white powder. Melting point
153 to 156 ° C The following compound was produced in the same manner as in Reference Example 7.

5-chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] aniline 5-methoxy-2- [2- (1H-tetrazol-5-
Yl) phenylthio] aniline 3-fluoro-2- [2- (1H-tetrazole-5-
Yl) phenylthio] aniline 5-methyl-2- [2- (1H-tetrazol-5-yl) phenylthio] aniline 2- [2- (1H-tetrazol-5-yl) phenylthio] -5-trifluoromethylaniline 5 -Fluoro-2- [2- (1H-tetrazol-5-
Yl) phenylthio] aniline 4-methyl-2- [2- (1H-tetrazol-5-yl) phenylthio] aniline 3-chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] aniline 4- [ 2- (1H-tetrazol-5-yl) phenylthio] aniline 2- [4- (1H-tetrazol-5-yl) phenylthio] aniline 2- [3-chloro-2- (1H-tetrazol-5-yl) phenylthio ] Aniline 2- [4-chloro-2- (1H-tetrazol-5-yl) phenylthio] aniline 2- [3-methoxy-2- (1H-tetrazol-5-
Yl) phenylthio] aniline 2- [5-methoxy-2- (1H-tetrazole-5
Yl) phenylthio] aniline 2- [3-methyl-2- (1H-tetrazol-5-yl) phenylthio] aniline 4-chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] aniline 4-methoxy -2- [2- (1H-tetrazol-5-
Yl) phenylthio] aniline 4-hydroxy-2- [2- (1H-tetrazole-5)
-Yl) phenylthio] aniline 5-hydroxy-2- [2- (1H-tetrazole-5
-Yl) phenylthio] aniline 2- [2- (1H-tetrazol-5-yl) phenylthio] -N-methylaniline Reference Example 8 N- [2- (2-cyanophenylthio) phenyl] -4- (5- (Hydroxyhexyloxy) benzamide N- [2- (2-cyanophenylthio) phenyl]-
3.33 g of 4- (5-oxohexyloxy) benzamide (prepared by the method of Reference Example 6, step 2) was added to tetrahydrofuran 3
The mixture was suspended in 0 ml, a methanol solution of 0.31 g of sodium borohydride was added, and the mixture was stirred for 1 hour. Chloroform was added to the reaction solution, washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate-n-hexane to give 3.15 g of the desired product as white crystals.

 The following compounds were produced in the same manner as in Reference Example 8.

N- [2- (2-cyanophenoxy) phenyl] -4
-(5-hydroxyhexyloxy) benzamide Reference Example 9 Ethyl 4- [2- (2-cyanophenylsulfinyl) phenylcarbamoyl] phenoxyacetate Ethyl 4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxyacetate (Example 6: prepared by the method of step 2)
A solution of 0.87 g of% metachloroperbenzoic acid in 20 ml of chloroform was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 1.3 g of the desired product as white crystals. Melting point: 128-130 ° C. The following compound was produced in the same manner as in Reference Example 9.

Ethyl 4- [4- [2- (2-cyanophenylsulfenyl) phenylcarbamoyl] phenoxy] butyrate Ethyl 6- [4- [2- (2-cyanophenylsulfinyl) phenylcarbamoyl] phenoxy] hexanate N- [2- (2-Cyanophenylsulfinyl) phenyl] -4- (6-hydroxyhexyloxy) benzamide N- [2- (2-cyanophenylsulfinyl) phenyl] -4- (5-hydroxyhexyloxy) benzamide Reference Example 10 ethyl 4 -[2- (2-cyanophenylsulfonyl) phenylcarbamoyl] phenoxyacetate ethyl 4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxyacetate (prepared by the method of Step 2 in Reference Example 6) (1.51 g) In a chloroform 5 ml solution, 70
A solution of 1.73 g of% metachloroperbenzoic acid in 30 ml of chloroform was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to obtain 1.51 g of the desired product as white crystals.
131-132 ° C.

 The following compounds were produced in the same manner as in Reference Example 10.

Ethyl 4- [4- [2- (2-cyanophenylsulfonyl) phenylcarbamoyl] phenoxy] butyrate Ethyl 6- [4- [2- (2-cyanophenylsulfonyl) phenylcarbamoyl] phenoxy] hexanate N- [2- ( 2-cyanophenylsulfonyl) phenyl] -4- (6-hydroxyhexyloxy) benzamide N- [2- (2-cyanophenylsulfonyl) phenyl] -4- (5-hydroxyhexyloxy) benzamide Reference Example 11 2- ( Separate production method of 2-aminophenylthio) benzonitrile (product of Step 4 of Reference Example 5) Dissolve 1.25 g of orthoaminothiophenol in 10 ml of DMF, add 1.38 g of potassium carbonate, preheat to 100 ° C, and add 1.45 g of chlorobenzonitrile was added, and the mixture was stirred at 100 ° C. for 1 hour under an argon stream. Ice water was added to the reaction mixture, extracted with ethyl acetate, washed twice with water, dried over magnesium sulfate, and the solvent was distilled off. The residue was crystallized from n-hexane and isopropyl ether to give 1.91 g of the desired product as white crystals. 88-90 ° C.

The following compounds were produced in the same manner as in Reference Example 11.

2- (2-aminophenylthio) -6-chlorobenzonitrile 2- (2-aminophenylthio) -5-chlorobenzonitrile 2- (2-aminophenylthio) -6-methoxybenzonitrile 2- (2- Aminophenylthio) -4-methoxybenzonitrile 2- (2-aminophenylthio) -6-methylbenzonitrile Reference Example 12 3- (2-aminophenylthio) -2- (1H
-Tetrazol-5-yl) phenol 2- [3-methoxy-2- (1H-tetrazol-5-
Yl) phenylthio] aniline (prepared by the method of Reference Example 7).
It was dissolved in 14 ml of a dimethylformamide solution and heated under reflux for 6 hours. Ice water was added to the reaction solution, and the mixture was made weakly acidic with dilute hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate, and concentrated. The residue obtained was subjected to silica gel column chromatography and eluted with 5% methanol-chloroform to obtain 0.2 g of the desired product as white crystals. Melting point 220-2
25 ° C (decomposition) The following compound was produced in the same manner as in Reference Example 12.

3- (2-aminophenylthio) -4- (1H-tetrazol-5-yl) phenol Reference Example 13 2- [2- (methylamino) phenylthio]
Benzonitrile Step 1 2- [2- (trifluoroacetylamino) phenylthio] benzonitrile 2- (2-aminophenylthio) benzonitrile (prepared by the method of Reference Example 5, Step 4) 2.3 g and triethylamine 1.
1 g was dissolved in 25 ml of methylene chloride, and 2.2 g of trifluoroacetic anhydride was added dropwise under ice cooling and stirring. After the dropwise addition, the mixture was stirred for 2 hours under ice-cooling, then the solvent was distilled off, and the residue was crystallized from 50% aqueous ethanol to obtain 2.8 g of the desired product as white crystals.

Step 2 2- [2- (N-methyl-N-trifluoroacetylamino) phenylthio] benzonitrile 2.8 g of 2- [2- (trifluoroacetylamino) phenylthio] benzonitrile is dissolved in 20 ml of N, N-dimethylformamide And methyl iodide 2.4 g, potassium carbonate 2.4 g
Was added, and the mixture was stirred at room temperature for 2 hours and diluted with water.
The precipitated crystals were collected by filtration, washed with water, and washed with aqueous ethanol to give 2.8 g of the desired product as white crystals.

Step 3 2- [2- (methylamino) phenylthio] benzonitrile 2.8 g of 2- [2- (N-methyl-N-trifluoroacetylamino) phenylthio] benzonitrile is suspended in 20 ml of ethanol, and 10% sodium hydroxide is added. 4 ml of an aqueous solution was added and heated on a water bath for 5 minutes. After cooling, the precipitated crystals were collected by filtration and washed with 50% aqueous ethanol to obtain 1.8 g of the desired product as white crystals.

Example 1 N- [2- [3- [1- (1H-tetrazol-5-yl) ethoxy] phenoxy] phenyl] -4-
Hexyloxybenzamide 2- [3- [1- (1H-tetrazol-5-yl) ethoxy] phenoxy] aniline 2.1 g and triethylamine
2.2 g was dissolved in 30 ml of methylene chloride, and a solution of 1.7 g of 4-hexyloxybenzoic acid chloride in benzene was added dropwise under ice cooling and stirring. After stirring at room temperature overnight, the mixture was heated under reflux for 1 hour.
The reaction mixture was acidified by adding ice water and subsequently dilute hydrochloric acid, and the methylene chloride layer was separated. After drying over magnesium sulfate,
The oil obtained by concentration was subjected to silica gel column chromatography, and eluted with chloroform / methanol (100: 1) to obtain 2.2 g of the desired compound as a pale yellow oil.

Nuclear magnetic resonance spectra _{(CDC1 3) δ; 0.7~1.9 (} 14H, m), 3.91 (2H, t, J = 6Hz), 5.70 (1H,
q, J = 7Hz), 6.4 ~ 7.3 (10H, m), 7.56 (2H, d, J = 9Hz),
8.1-8.4 (2H, m), 11 (1H, br) Example 2 N- [2- [3- [1- (1H-tetrazol-5-yl) ethoxy] phenoxy] phenyl] -4-
Sodium salt of hexyloxybenzamide 2.0 g of N- [2- [3- [1- (1H-tetrazol-5-yl) ethoxy] phenoxy] phenyl] -4-hexyloxybenzamide is dissolved in 30 ml of ether, and 90 mg of sodium is dissolved. After the addition of the ethanol solution, the mixture was concentrated to dryness under reduced pressure. The obtained foamy solid was added with isopropyl ether, pulverized, collected by filtration and dried, 1.9 g of sodium salt
Was obtained as an amorphous white powder.

Elemental analysis value (as C ₂₈ H ₃₀ N ₅ O ₄ · Na · H ₂ O) Theoretical value (%) C: 62.10 H: 5.96 N: 12.93 Actual value (%) C: 62.54 H: 6.57 N: 13.09 Example 3 N- [2- [3- (1H-tetrazole-5-
Yl) methoxyphenoxy] phenyl] -4-hexyloxybenzamide 1.5 g of N- [2- (3-cyanomethoxyphenoxy) phenyl] -4-hexyloxybenzamide was dissolved in 15 ml of N, N-dimethylformamide (DMF), Add 0.44 g of sodium chloride and 0.37 g of ammonium chloride, and add 105 to 110
Stirred at C for 1 hour. After cooling, the mixture was diluted with ice water to make it acidic with hydrochloric acid, and the precipitate was collected by filtration and recrystallized from ethanol.
1.35 g of the desired compound were obtained as white crystals.

Mp one hundred fifty-eight to one hundred fifty-nine ° C. Elemental analysis (C ₂₇ H ₂₉ N ₅ as O ₄₎ theory (%) C: 66.51 H: 6.00 N: 14.36 Found (%) C: 66.67 H: 6.20 N: 14.42 Example 4 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4- (4-phenylbutoxy) benzamide N- [2- (2-cyanophenylthio) phenyl]-
1.35 g of 4- (4-phenylbutoxybenzamide, 0.55 g of sodium azide and 0.46 g of ammonium chloride in DMF 20m
and stirred at 110-115 ° C for 5 hours. Add 0.18 g of sodium azide and 0.15 g of ammonium chloride, 110-1
Stirred at 15 ° C. for a further 2 hours. Ice water was added, the mixture was neutralized with dilute hydrochloric acid, and the precipitate was collected by filtration and recrystallized from ethanol to obtain 0.95 g of the desired compound. Mp 156-159 ° C.

Elemental analysis value (as C ₃₀ H ₂₇ N ₅ O ₂ S) Theoretical value (%) C: 69.08 H: 5.22 N: 13.43 Actual value (%) C: 68.93 H: 5.45 N: 13.32 Example 5 Methyl 4- [ 2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate methyl 4- [2- (2-cyanophenylthio) phenylcarbamoyl] phenoxyacetate (1.1 g), sodium azide (0.85 g), and ammonium chloride (0.7 g) are suspended in DMF (10 ml) and heated and stirred at 110 to 120 ° C. for 8 hours. did. After cooling, the mixture was acidified with concentrated hydrochloric acid, diluted with water, and the precipitate was collected by filtration. This was subjected to silica gel column chromatography (chloroform → chloroform / ethanol = 50: 1) to obtain 0.4 g of the desired compound as white crystals. 204-205 ° C.

Elemental analysis _{(C 23 H 19 N 5 O} 4 as S) theory (%) C: 59.86 H: 4.15 N: 15.18 Found (%) C: 59.95 H: 4.23 N: 15.22 IR cm -1 (KBr) 3380,3100-2200,1760,1680,1600,15
80,1500,1440,1300,1220 Example 6 4- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenylcarbamoyl] phenoxyacetate methyl 4- [2- [2- (1H-tetrazole-5-
0.38 g of yl) phenylthio] phenylcarbamoyl] phenoxyacetate was suspended in 10 ml of ethanol, 1 ml of 10% sodium hydroxide was added, and the mixture was heated on a water bath for 10 minutes.
After cooling, the mixture is acidified with concentrated hydrochloric acid, diluted with water, and the precipitate is collected by filtration. Wash with water, ethanol and then ethyl acetate,
0.32 g of the target compound was obtained as white crystals.

Melting point 252-253 ° C Elemental analysis value (as C ₂₂ H ₁₇ N ₅ O ₄ S) Theoretical value (%) C: 59.05 H: 3.83 N: 15.65 Actual value (%) C: 58.93 H: 4.06 N: 15.43 7 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4-hexyloxybenzamide N- [2- (2-cyanophenylthio) phenyl]-
1.20 g of 4-hexyloxybenzamide was dissolved in 20 ml of DMF, 0.36 g of sodium azide and 0.30 g of ammonium chloride were added, and the mixture was stirred at 120 ° C. for 3 hours. Add the same amount of sodium azide and ammonium chloride twice every 3 hours. The mixture was acidified with dilute hydrochloric acid, and the crystals were collected by filtration and washed with water. It was dissolved in chloroform, dried over magnesium sulfate, and the solvent was distilled off. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 1.1 g of the desired compound as white crystals. Melting point 154
156156 ° C. Elemental analysis value (as C ₂₆ H ₂₇ N ₅ O ₂ S) Theoretical value (%) C: 65.94 H: 5.75 N: 14.79 Actual value (%) C: 66.01 H: 6.03 N: 14.78 Example 8N -[2- [2- (1H-tetrazol-5-
Yl) phenylsulfinyl] phenyl] -4-hexyloxybenzamide N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4-hexyloxybenzamide 2.5 g of 80% metachloroform in a 30 ml chloroform solution 1.5 g of perbenzoic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and ethyl acetate-chloroform was added to the residue, and the precipitated crystals were collected by filtration. Recrystallization from a mixed solution of ethanol-chloroform yielded 0.67 g of the target compound as white crystals. Mp 206 to 210 ° C. (decomposition) Elemental analysis _{(C 26 H 27 N 5 O} 3 S · 1 / 4H 2 O as) theory (%) C: 63.20 H: 5.61 N: 14.17 Found value (%) C: 63.12 H: 5.74 N: 14.25 Example 9 N- [2- [2- (1H-tetrazol-5-
Yl) phenylsulfonyl] phenyl] -4-hexyloxybenzamide 80% metachloroform in a solution of 2.0 g of N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4-hexyloxybenzamide in 20 ml of chloroform 2.0 g of perbenzoic acid was added, and the mixture was stirred at room temperature for 20 hours. The precipitated crystals were washed with chloroform. The crystals were recrystallized from ethanol-chloroform to give 1.44 g of the desired compound as white crystals. Mp 203 - 205 ° C. (decomposition) Elemental analysis _{(C 26 H 27 N 5 O} 4 as S) theory (%) C: 61.77 H: 5.38 N: 13.85 Found (%) C: 61.57 H: 5.42 N: 13.67 The following compounds were obtained in the same manner.

Example 10 N- [2- [3- (1H-tetrazol-5)
Yl) methoxyphenoxy] phenyl] -4-heptyloxy benzamide mp 154 to 156 ° C. Elemental analysis (C ₂₈ H ₃₁ N ₅ as O ₄₎ theory (%) C: 67.05 H: 6.23 N: 13.96 Found (% C: 67.04 H: 6.46 N: 13.67 Example 11 N- [2- [3- (1H-tetrazol-5-)
Yl) phenoxy] phenyl] -4-hexyloxy benzamide melting one hundred and seventy-two to one hundred seventy-three ° C. Elemental analysis (C ₂₆ H ₂₇ N ₅ as O ₃₎ theory (%) C: 68.25 H: 5.95 N: 15.31 Found (%) C: 68.38 H: 5.94 N: 15.34 Example 12 N- [2- [3- (1H-tetrazole-5-
Yl) methylphenoxy] phenyl] -4-hexyloxy benzamide melting from 99 to 104 ° C. Elemental analysis (as _{C 27 H 29 N 5 O 3} ) theory (%) C: 68.77 H: 6.20 N: 14.85 Found (% C: 68.75 H: 6.38 N: 14.70 Example 13 N- [2- [2- (1H-tetrazol-5)
Yl) methylphenoxy] phenyl] -4-hexyloxy benzamide mp 142-143 ° C. Elemental analysis (as _{C 27 H 29 N 5 O 3} ) theory (%) C: 68.77 H: 6.20 N: 14.85 Found (% C) 68.76 H: 6.25 N: 14.61 Example 14 (E) -N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4- (2-
Heptenyloxy) benzamide mp 154-155 ° C. Elemental analysis _{(C 27 H 27 N 5 O} 2 as S) theory (%) C: 66.78 H: 5.60 N: 14.42 Found (%) C: 66.82 H: 5.54 N: 14.31 Example 15 (E) -N- [3-chloro-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenyl]
4- (2-heptenyloxy) benzamide mp 149-150 ° C. Elemental analysis _{(C 27 H 25 C1N 5 O} 2 as S) theory (%) C: 62.36 H: 5.04 N: 13.47 Found value (%) C: 62.14 H: 5.49 N: 13.04 Example 16 (E) -N- [5-chloro-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenyl]
4- (2-heptenyloxy) benzamide mp one hundred and eighty-seven to one hundred and eighty-eight ° C. Elemental analysis _{(C 27 H 26 C1N 5 O} 2 as S) theory (%) C: 62.36 H: 5.04 N: 13.47 Found value (%) C: 62.31 H: 5.08 N: 13.38 Example 17 (E) -N- [4-methoxy-2- [2-
(1H-tetrazol-5-yl) phenylthio] phenyl] -4- (2-heptenyloxy) benzamide Melting point 156-158 ° C. Elemental analysis (as C ₂₈ H ₂₉ N ₅ O ₃ S) Theoretical value (%) C: 65.22 H: 5.67 N: 13.58 Found (%) C: 65.22 H: 5.64 N: 13.20 Example 18 N- [3-chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4 −
(4-phenyl-butoxy) benzamide mp 145-147 ° C. Elemental analysis _{(C 30 H 26 CIN 5 O} 2 S · 1 / 2H 2 O as a) the theoretical value (%) C: 63.76 H: 4.82 N: 12.39 Found ( %) C: 63.50 H: 4.75 N: 12.07 Example 19 N- [3-Fluoro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4-
(4-phenyl-butoxy) benzamide mp one hundred and seventy-five to one hundred and seventy-seven ° C. Elemental analysis _{(C 30 H 26 FN 5 O} 2 as S) theory (%) C: 66.77 H: 4.86 N: 12.98 Found (%) C: 66.93 H : 4.89 N: 12.51 Example 20 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4-bench oxy benzamide mp 170-171 ° C. Elemental analysis _{(C 25 H 25 N 5 O} 2 as S) theory (%) C: 65.34 H: 5.48 N: 15.24 Found ( %) C: 65.46 H: 5.49 N: 15.00 Example 21 N- [5-Chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4-hexyloxybenzamide Melting point 191-193C elemental analysis _{(C 26 H 26 C1N 5 O} 2 as S) theory (%) C: 61.47 H: 5.16 N: 13.79 Found (%) C: 61.51 H: 5.39 N: 13.69 example 22 N-[2 -[2- (1H-tetrazol-5-
Yl) phenylthio] phenyl] -4-heptyloxy benzamide melting one hundred fifty-seven to one hundred fifty-eight ° C. Elemental analysis _{(C 27 H 29 N 5 O} 2 as S) theory (%) C: 66.50 H: 5.99 N: 14.36 Found (% ) C: 66.66 H: 5.84 N: 14.26 Example 23 (E) -N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4- (2-
Hexenyloxy) benzamide mp 177-178 ° C. Elemental analysis _{(C 26 H 25 N 5 O} 2 as S) theory (%) C: 66.22 H: 5.34 N: 14.85 Found (%) C: 66.39 H: 5.42 N : 24.91 Example 24 N- [2- [2- (1H-tetrazole-5-
Yl) phenoxy] phenyl] -4-hexyloxy benzamide mp 159-161 ° C. Elemental analysis (as _{C 28 H 27 N 5 O 3} ) theory (%) C: 68.25 H: 5.95 N: 15.31 Found (%) C: 68.55 H: 6.22 N: 15.20 Example 25 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4- (quinoline-2
- ylmethoxy) benzamide mp 198-200 ° C. Elemental analysis _{(C 30 H 22 N 5 O} 2 as S) theory (%) C: 67.91 H: 4.18 N: 15.84 Found (%) C: 67.86 H: 4.49 N : 15.70 Example 26 N- [2- [2- (1H-tetrazol-5)
Yl) phenoxy] phenyl] -4- (quinoline-2-
Ylmethoxy) benzamide mp 224 to 226 ° C. Elemental analysis _{(C 30 H 22 N 6 O} 3 · 1 / 4H 2 O as) theory (%) C: 69.42 H: 4.37 N: 16.19 measured value (%) C: 69.50 H: 4.76 N: 15.82 Example 27 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4- (7-chloroquinolin-2-ylmethoxy) benzamide Melting point: 224-226 ° C Elemental analysis (as C ₃₀ H ₂₁ CIH ₆ O ₂ S) Theoretical value (%) C: 63.77 H: 3.75 N: 14.87 measured value (%) C: 63.33 H: 3.77 N: 14.59 Example 28 4- [4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] butyric acid Melting point 188 ° C Elemental analysis value (as C ₂₄ H ₂₁ N ₅ O ₄ S) Theoretical value (%) C: 60.62 H: 4.45 N: 14.73 Measurement value (%) C: 60.65 H: 4.71 N: 14.78 Example 29 N− [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4- (6-hydroxy-hexyloxy) benzamide mp one hundred ninety-two to one hundred ninety-three ° C. Elemental analysis _{(C 26 H 27 N 5 O} 3 as S) theory (%) C: 63.78 H: 5.56 N: 14.30 measured value (%) C: 63.76 H: 5.51 N: 14.23 Example 30 4- [2- [2- (1H-tetrazole-5-)
Yl) phenoxy] phenylcarbamoyl] phenoxyacetic acid mp 123 to 125 ° C. Elemental analysis _{(C 22 H 17 N 5 O} 5 · 1 / 2H 2 O as a) the theoretical value (%) C: 59.99 H: 4.12 N: 15.90 measurements (%) C: 60.23 H: 4.20 N: 15.94 Example 31 6- [4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] hexanoic acid Melting point 185-186 ° C Element analysis _{(C 26 H 25 N 5 O} 4 as S) theory (%) C: 62.01 H: 5.00 N: 13.91 measured value (%) C: 61.97 H: 4.97 N: 13.84 example 32 ethyl 4- [4 -[2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] butyrate Melting point 173-175 ° C IRcm ^-1 (KBr) 3375,3100-2300,1735,1680,1600,158
0,1500,1435,1250 Example 33 Ethyl 6- [4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] hexanate Melting point 137-138 ° C IRcm ^-1 (KBr) 3380,3200-2300,1730,1680,1600,157
5,1500,1435,1245 Example 34 N- [2- [2- (1H-tetrazole-5-
Yl) phenoxy] phenyl] -4- (6-hydroxyhexyloxy) benzamide Melting point 174-175 ° C Elemental analysis (as C ₂₆ H ₂₇ N ₅ O ₄ ) Theoretical value (%) C: 65.95 H: 5.75 N: 14.79 Measured value (%) C: 66.01 H: 5.64 N: 14.91 Example 35 6- [4- [2- [2- (1H-tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxy] hexanoic acid Melting point 153 to 154 ℃ elemental analysis (C ₂₆ H ₂₅ N ₅ as O ₅₎ theory (%) C: 64.32 H: 5.19 N: 14.42 measured value (%) C: 63.99 H: 5.22 N: 14.32 example 36 4- [4 - [2- [2- (1H- tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxy] butyric acid mp one hundred ninety-seven to one hundred and ninety-eight ° C. elemental analysis (C ₂₄ H ₂₁ N ₅ as O ₅₎ theory (%) C: 62.74 H: 4.61 N: 15.24 measured value (%) C: 62.82 H: 4.75 N: 15.11 Example 37 N- [2- [2- (1H-tetrazol-5-
Yl) phenoxy] phenyl] -4- (5-hydroxy-hexyloxy) benzamide mp 142-144 ° C. Elemental analysis _{(C 26 H 27 N 5 O} 4 · 1 / 4H 2 O as) theory (%) C: 65.33 H: 5.80 N: 14.65 measured value (%) C: 65.39 H: 5.75 N: 14.59 Example 38 N- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenyl] -4- (5-hydroxy-hexyloxy) benzamide mp 161 to 163 ° C. Elemental analysis _{(C 26 H 27 N 5 O} 3 as S) theory (%) C: 63.78 H: 5.56 N: 14.30 measured value (%) C: 63.40 H: 5.56 N: 14.04 Example 39 N- [2- [2- (1H-tetrazol-5-
Yl) phenylsulfinyl] phenyl] -4- (6-
Hydroxyhexyloxy) benzamide mp 196-198 ° C. Elemental analysis _{(C 26 H 27 N 5 O} 4 as S) theory (%) C: 61.77 H: 5.38 N: 13.85 measured value (%) C: 61.63 H: 5.45 N: 13.87 example 40 6- [4- [2- [2- (1H- tetrazol-5-yl) phenylsulfinyl] phenylcarbamoyl] phenoxy] hexanoic acid mp two hundred and thirty-five to two hundred thirty-six ° C. (decomposition) elemental analysis (C ₂₆ H ₂₅ N ₅ O ₅ as S) theory (%) C: 60.10 H: 4.85 N: 13.48 measured value (%) C: 59.70 H: 4.82 N: 13.24 example 41 4- [4- [2- [2 -(1H-tetrazol-5-yl) phenylsulfinyl] phenylcarbamoyl] phenoxy] butyric acid Melting point 254 to 255 ° C (decomposition) Elemental analysis (as C ₂₄ H ₂₁ N ₅ O ₅ S 1 / 4H ₂ O) Theoretical value (%) C: 58.11 H: 4.37 N: 14.12 Measurement value (%) C: 58.02 H: 4.31 N: 14.20 Example 42 4- [2- [2- (1H-tetrazole-5-)
Yl) phenylsulfinyl] phenylcarbamoyl]
Phenoxyacetic acid mp two hundred seventy-two to two hundred seventy-four ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 5 S · 1 / 4H 2 O as) theory (%) C: 56.47 H: 3.77 N: 14.97 found (%) C: 56.45 H: 3.95 N: 15.04 Example 43 N- [2- [2- (1H-tetrazole-5-
Yl) phenylsulfinyl] phenyl] -4- (5-
Hydroxyhexyloxy) benzamide mp one hundred ninety-five to one hundred ninety-eight ° C. Elemental analysis _{(C 26 H 27 N 5 O} 4 S · 1 / 4H 2 O as) theory (%) C: 61.22 H: 5.43 N: 13.73 found (%) C: 61.16 H: 5.48 N: 13.76 Example 44 N- [2- [2- (1H-tetrazole-5-
Yl) phenylsulfonyl] phenyl] -4- (6-hydroxyhexyloxy) benzamide Melting point 182-184 ° C Elemental analysis (as C ₂₆ H ₂₇ N ₅ O ₅ S) Theoretical value (%) C: 59.87 H: 5.22 N : 13.43 Measurement value (%) C: 59.76 H: 5.38 N: 13.13 Example 45 6- [4- [2- [2- (1H-tetrazol-5-yl) phenylsulfonyl] phenylcarbamoyl] phenoxy] hexanoic acid 219-221 ° C Elemental analysis (as C ₂₆ H ₂₅ N ₅ O ₆ S) Theoretical value (%) C: 58.31 H: 4.70 N: 13.08 Measured value (%) C: 58.22 H: 4.69 N: 12.98 Example 46 4- [4- [2- [2- ( 1H- tetrazol-5-yl) phenylsulfonyl] phenylcarbamoyl] phenoxy] butyric acid mp two hundred thirty-eight to two hundred thirty-nine ° C. (decomposition) elemental analysis _{(C 24 H 21 N 5 O} 6 S As) Theoretical value (%) C: 56.80 H: 4.17 N: 13.80 Measured value (%) C: 56.76 H: 4.08 N: 14.06 Example 47 4- [2- [2- (1H-tetrazole-5
Yl) phenylsulfonyl] phenylcarbamoyl] phenoxyacetic acid mp 222-224 ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 6 as S) theory (%) C: 55.11 H: 3.57 N: 14.61 found ( %) C: 54.97 H: 3.55 N: 14.40 Example 48 N- [2- [2- (1H-tetrazole-5-
Yl) phenylsulfonyl] phenyl] -4- (5-hydroxyhexyloxy) benzamide Melting point 170-171 ° C Elemental analysis (as C ₂₆ H ₂₇ N ₅ O ₅ S) Theoretical value (%) C: 59.87 H: 5.22 N : 13.43 Measurement value (%) C: 59.74 H: 5.35 N: 13.28 Example 49 4- [2- [4- (1H-tetrazole-5-)
Yl) phenoxy] phenylcarbamoyl] phenoxyacetic acid mp two hundred sixty-eight to two hundred and seventy ° C. (decomposition) Elemental analysis (C ₂₂ H ₁₇ N ₅ O as ₅₎ theory (%) C: 61.25 H: 3.97 N: 16.23 found (%) C: 60.88 H: 4.33 N: 15.97 Example 50 2- [4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] propionic acid Melting point 207-209 ° C Elemental analysis ( C ₂₃ H ₁₉ N ₅ O ₄ as S) theory (%) C: 59.86 H: 4.15 N: 15.18 measured value (%) C: 59.61 H: 4.36 N: 15.02 example 51 2-methyl-2- [4 -[2- [2- (1H-
Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] propionic acid Melting point 186-188 ° C (decomposition) Elemental analysis (as C ₂₄ H ₂₁ N ₅ O ₄ S 1 / 4H ₂ O) Theoretical value (%) C : 60.05 H: 4.51 N: 14.59 Measurement value (%) C: 60.25 H: 4.69 N: 14.28 Example 52 Ethyl-4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate Melting point 202-203 ° C Elemental analysis (as C ₂₄ H ₂₁ N ₅ O ₄ S) Theoretical value (%) C: 60.62 H: 4.45 N: 14.73 Measurement value (%) C: 60.57 H: 4.53 N: 14.71 example 53 propyl 4- [2- [2- (1H- tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide diacetate mp 174-176 ° C. elemental analysis (as _{C 25 H 23 N 5 O 4} S) Theoretical value (%) C: 61.34 H: 4.74 N: 14.31 Measurement value (%) C: 61.56 H: 4.84 N: 14.31 Example 54 Isoamyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] ] phenylcarbamoyl] phenoxyacetamide diacetate mp 120 to 122 ° C. elemental analysis _{(C 27 H 27 N 5 O} 4 as S) theory (%) C: 62.65 H: 5.26 N: 13.53 measured value (%) C: 62.83 H : 5.43 N: 13.62 Example 55 Ethyl 4- [2- [2- (1H-tetrazol-5-yl) phenylsulfinyl] phenylcarbamoy ] Phenoxyacetamide diacetate mp 215-216 ° C. (decomposition) IRcm ^-1 (KBr) 3700~2200,1725,1605,1495,1435,1250 Example 56 Ethyl 4- [2- [2- (1H- tetrazol-5 Yl) phenylsulfonyl] phenylcarbamoyl] phenoxyacetate Melting point 162-163 ° C IRcm ^-1 (KBr) 3700-2200,1740,1680,1600,1500,131
Example 57 Ethyl 4- [4- [2- [2- (1H-tetrazol-5-yl) phenylsulfinyl] phenylcarbamoyl] phenoxy] butyrate Melting point 204-206 ° C (decomposition) IRcm ^-1 (KBr) 3700-2200,1730,1635,1600,1300,1255 Example 58 Ethyl 4- [4- [2- [2- (1H-tetrazol-5-yl) phenylsulfonyl] phenylcarbamoyl] phenoxy] butyrate Melting point 182-184 ° C IRcm ^-1 (KBr) 3700-2200,3360,1740,1670,1580,150
5,1325,1255 Example 59 Ethyl 6- [4- [2- [2- (1H-tetrazol-5-yl) phenylsulfinyl] phenylcarbamoyl] phenoxy] hexanate Melting point 188-189 ° C IRcm ^-1 (KBr) 3700 ~ 2200,1730,1640,1605,1580,152
0,1500,1440,1255 Example 60 Ethyl 6- [4- [2- [2- (1H-tetrazol-5-yl) phenylsulfonyl] phenylcarbamoyl] phenoxy] hexanate Melting point 180-181 ° C IRcm ^-1 (KBr ) 3700-2200,3360,1725,1670,1605,158
0,1505,1320,1255 Example 61 Ethyl 4- [4- [2- [2- (1H-tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxy] butyrate Melting point 162-164 ° C IRcm ^-1 (KBr) 3700-2300,3360,1730,1640,1610,151
0,1280,1260 Example 62 Ethyl 6- [4- [2- [2- (1H-tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxy] hexanate Melting point 140-141 ° C IRcm ^-1 (KBr) 3700- 2500,3350,2950,1725,1640,160
5,1500,1260,1250 Example 63 Ethyl 2- [4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] propionate Melting point 157-158 ° C IRcm ^-1 (KBr) 3700-2200,3380,1725,1680,1600,158
5,1500,1435,1300,1240 Example 64 ethyl 2-methyl-2- [4- [2- [2
-(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxy] propionate Melting point 157-158 ° C IRcm ^-1 (KBr) 3700-2200,3350,1720,1640,1600,149
0,1470,1255 Example 65 Ethyl 4- [2- [4- (1H-tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxyacetate Melting point 206-208 ° C (decomposition) IRcm ^-1 (KBr) 3700- 2200,3420,1750,1625,1605,150
5,1450,1220 Example 66 Ethyl 4- [2- [2- (1H-tetrazol-5-yl) phenoxy] phenylcarbamoyl] phenoxyacetate Melting point 162-163 ° C IRcm ^-1 (KBr) 3355,3200-2200 , 1745,1625,1600,149
5,1470,1260,1220 Example 67 butyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate 2- [2- (1H-tetrazol-5-yl) phenylthio] aniline (5.3 g) in pyridine (6 ml) and methylene chloride (80 ml)
And 5.4 g of butyl 4-chloroformylphenoxyacetate was added dropwise. After stirring overnight, the solvent was distilled off and the residue was crystallized from aqueous ethanol. Recrystallization from ethyl acetate gave 8.1 g of the desired product as white crystals. Mp 133-135 ° C. Elemental analysis _{(C 26 H 25 N 5 O} 4 as S) theory (%) C: 62.01 H: 5.00 N: 13.91 measured value (%) C: 61.98 H: 5.09 N: 13.87 Example The following compounds were produced in the same manner as in 67.

Example 68: ethyl 4- [5-chloro-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 206-208 ° C IRcm ^-1 (KBr) 3370,3100-2300,1745,1680,1600,156
5,1500,1410,1220 Example 69 Ethyl 4- [5-methoxy-2- [2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 195-197 ° C IRcm ^-1 (KBr) 3380,3200-2300,1755,1680,1600,157
5,1500,1450,1200 Example 70 Ethyl 4- [3-fluoro-2- [2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 208-209 ° C IRcm ^-1 (KBr) 3390,3200-2300,1760,1680,1600,158
0,1500,1465,1220 Example 71 ethyl 2-methoxy-4- [2- [2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 179-181 ° C IRcm ^-1 (KBr) 3380,3100-2300,1730,1680,1580,150
0,1435,1270,1210 Example 72 butyl 4- [5-methyl-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 146-148 ° C IRcm ^-1 (KBr) 3380,3200-2300,1740,1680,1600,157
0,1500,1450,1210 Example 73 butyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] -5-trifluoromethyl] phenylcarbamoyl] phenoxyacetate Melting point 190-192 ° C IRcm ^{− 1} (KBr) 3380,3200-2300,1760,1605,1580,153
0,1505,1430,1335 Example 74 butyl 4- [5-fluoro-2- [2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 177-179 ° C IRcm ^-1 (KBr) 3360,3200-2300,1740,1680,1585,152
0,1500,1430,1250 Example 75 butyl 4- [4-methyl-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 161-162 ° C IRcm ^-1 (KBr) 3380,3200-2300,1740,1680,1600,150
0,1300,1210 Example 76 ethyl 4- [3-chloro-2- [2- (1H
-Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 180-182 ° C IRcm ^-1 (KBr) 3360,3200-2300,1760,1670,1605,157
0,1500,1450,1210,1180 Example 77 Ethyl 3- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate Melting point 130-133 ° C IRcm ^-1 (KBr) 3370,3200-2200,1740,1675,1575,1525 Example 78 Ethyl 2- [2- [2- (1H-tetrazol-5-yl) phenylthio] Phenylcarbamoyl]
Phenoxyacetate Melting point 145-146 ° C IRcm ^-1 (KBr) 3700-2200,1760,1635,1575,1520 Example 79 Ethyl 4- [4- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl ]
Phenoxyacetate Melting point 232-234 ° C (decomposition) IRcm ^-1 (KBr) 3200-2200,1780,1650,1605,1505 Example 80 Ethyl 3- [4- [2- (1H-tetrazol-5-yl) phenylthio] ] Phenylcarbamoyl]
Phenoxyacetate Melting point 176-179 ° C (decomposition) IRcm ^-1 (KBr) 3270,3700-2200,1740,1650,1585 Example 81 Ethyl 2- [4- [2- (1H-tetrazol-5-yl) phenylthio] ] Phenylcarbamoyl]
Phenoxyacetate Melting point 97-99 ° C IRcm ^-1 (KBr) 3320,3700-2200,1750,1655,1585,1525 Example 82 Ethyl 4- [2- [3- (1H-tetrazol-5-yl) phenoxy] Phenylcarbamoyl] phenoxyacetate Melting point 165-166 ° C IRcm ^-1 (KBr) 3700-2200,1755,1600,1500,1445 Example 83 Ethyl 4- [2- [4- (1H-tetrazol-5-yl) phenylthio] ] Phenylcarbamoyl]
Phenoxyacetate Melting point 148-149 ° C IRcm ^-1 (KBr) 3380,3200-2200,1750,1670,1605,158
0,1520,1500,1435,1300 Example 84 Ethyl 3- [2- [4- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate Melting point 88-90 ° C IRcm ^-1 (KBr) 3370,3200-2200,1745,1680,1650,158
0,1520,1490,1440,1310,1200 Example 85 Ethyl 2- [2- [4- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl]
Phenoxyacetate Melting point 155-157 ° C IRcm ^-1 (KBr) 3450,3200-2200,1755,1635,1600,158
0,1520,1490,1420,1315,1205 The following compounds were produced in the same manner as in Example 6.

Example 86 4- [5-Chloro-2-[2-(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp 217-220 ° C. Elemental analysis _{(C 22 H 16 CIN 5 O} 4 S · (As 7 / 4H ₂ O) Theoretical value (%) C: 51.46 H: 3.83 N: 13.64 Measurement value (%) C: 51.59 H: 3.97 N: 13.35 Example 87 4- [5-methoxy-2- [2-] (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 244-246 ° C. Elemental analysis (as C ₂₃ H ₁₉ N ₅ O ₅ S) Theoretical value (%) C: 57.85 H: 4.01 N: 14.67 Measured value (%) C: 57.63 H: 4.29 N: 14.37 Example 88 4- [4- [2- (1H-tetrazole-5-)
Yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred fifty to two hundred and fifty-one ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 4 as S) theory (%) C: 59.05 H: 3.83 N: 15.65 found (% ) C: 59.02 H: 3.63 N: 15.45 Example 89 2- [4- [2- (1H-tetrazole-5-)
Yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp 257-259 ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 4 S · 1 / 4H 2 O as) theory (%) C: 58.46 H: 3.90 N : 15.50 Measurement value (%) C: 58.43 H: 3.98 N: 15.49 Example 90 3- [2- [2- (1H-tetrazole-5-)
Yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp from 214.5 to 215.5 ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 4 as S) theory (%) C: 59.05 H: 3.83 N: 15.65 found (% ) C: 59.13 H: 3.84 N: 15.61 Example 91 4- [3-Fluoro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 225-227 ° C Elemental analysis ( _{C 22 H 16 FN 5 O 4} S · 1 / 4H 2 O as) theory (%) C: 56.23 H: 3.54 N: 14.90 measured value (%) C: 56.08 H: 3.84 N: 14.98 example 92 2- Methoxy-4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 218-220 ° C. Elemental analysis (as C ₂₃ H ₁₉ N ₅ O ₅ S) Theoretical value (%) ) C: 57.85 H: 4.01 N: 14.67 Measurement value (%) C: 57.72 H: 4.28 N: 14.62 Example 93 3- [4- [2- (1H-tetrazole-5-)
Yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred thirty-three to two hundred and thirty-four ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 4 as S) theory (%) C: 59.05 H: 3.83 N: 15.65 found (% C: 58.85 H: 3.60 N: 15.60 Example 94 4- [5-Methyl-2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 246-247 ° C Elemental analysis ( _{C 23 H 19 N 5 O 4} S · 1 / 5H 2 O as) theory (%) C: 59.40 H: 4.20 N: 15.06 measured value (%) C: 59.40 H: 4.11 N: 15.06 example 95 4- [2- [3- (1H-tetrazole-5-
Yl) phenoxy] phenylcarbamoyl] phenoxyacetic acid mp one hundred and seventy-nine to one hundred eighty-three ° C. Elemental analysis _{(C 22 H 17 N 5 O} 5 S · 1 / 4H 2 O as) theory (%) C: 60.62 H: 4.06 N: 16.07 Measurements Value (%) C: 60.49 H: 4.28 N: 15.77 Example 96 2- [2- [2- (1H-tetrazole-5-
Yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 191-193 ° C (decomposition) Elemental analysis (as C ₂₂ H ₁₇ N ₅ O ₄ S) Theoretical (%) C: 59.05 H: 3.83 N: 15.65 Measured (% C: 58.84 H: 3.84 N: 15.46 Example 97 4- [2- [2- (1H-tetrazole-5-)
Yl) phenylthio-5-trifluoromethyl] phenylcarbamoyl] phenoxyacetic acid mp two hundred and seventy-five to two hundred seventy-seven ° C. Elemental analysis _{(C 23 H 16 F 3 N} 5 O 4 S · 7 / 4H 2 O as) theory (%) C: 50.50 H: 3.59 N: 12.80 Found (%) C: 50.43 H: 3.43 N: 12.83 Example 98 4- [5-Fluoro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred eighteen to two hundred twenty ° C. elemental analysis _{(C 22 H 16 FN 5 O} 4 S · 1 / 2H 2 O as a) the theoretical value (%) C: 55.69 H: 3.61 N: 14.76 measured value (%) C: 55.83 H: 3.87 N: 14.71 example 99 4- [4-methyl-2-[2-(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred forty-six to two hundred forty-eight ° C. elemental analysis (C ₂₃ H ₁₉ N ₅ O ₄ S 1 / 4H ₂ O) Theoretical value (%) C: 59.28 H: 4.22 N: 15.03 Measurement value (%) C: 59.25 H: 4.37 N: 14.99 Example 100 4- [2- [ 4- (1H-tetrazole-5
−yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 252 to 253 ° C. (decomposition) Elemental analysis value (as C ₂₂ H ₁₇ N ₅ O ₄ S) Theoretical value (%) C: 59.05 H: 3.83 N: 15.65 Measurement value ( %) C: 58.99 H: 3.88 N: 15.55 Example 101 3- [2- [4- (1H-tetrazole-5)
- yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred eighty-five to two hundred eighty-eight ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 4 S · 3 / 2H 2 O as a) the theoretical value (%) C: 55.69 H: 4.25 N: 14.76 measured value (%) C: 55.88 H: 4.00 N: 15.06 Example 102 2- [2- [4- (1H-tetrazole-5)
−yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 253 to 254 ° C. (decomposition) Elemental analysis value (as C ₂₂ H ₁₇ N ₅ O ₄ S) Theoretical value (%) C: 59.05 H: 3.83 N: 15.65 Measurement value ( %) C: 58.98 H: 3.65 N: 15.45 Example 103 N- [2- [2- (1H-tetrazole-5)
-Yl) phenylthio] phenyl] -4-[(1H-tetrazol-5-yl) methoxy] benzamide N- [2- (2-cyanophenylthio) phenyl]-
0.77 g of 4-cyanomethoxybenzamide (produced in the same manner as in Reference Example 6) is dissolved in 10 ml of N, N-dimethylformamide, and 0.91 g of sodium azide and 0.27 g of ammonium chloride are dissolved.
Was added and the mixture was heated and stirred at 120 ° C. for 7 hours. After cooling, the mixture was acidified with diluted hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.7 g of the desired product as white crystals.

Mp 240 - 242 ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 8 O} 2 as S) theory (%) C: 56.04 H: 3.63 N: 26.74 measured value (%) C: 56.20 H: 3.70 N: 26.47 Example 104 N, N-Dimethylcarbamoylmethyl 4-
[2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid (Example) 6) 1.2 g of N, N-dimethylformamide 1
The solution was dissolved in 5 ml, and 0.44 g of N, N'-carbonyldiimidazole was added under ice cooling and stirring. After stirring for 20 minutes under ice-cooling, 0.42 g of NN-dimethylglycolamide was added, and the mixture was stirred at room temperature overnight. After acidification by adding acetic acid, the mixture was diluted with water, and the precipitated crystals were collected by filtration and recrystallized from a mixture of N, N-dimethylformamide and ethyl acetate to obtain 0.55 g of the desired product as white crystals.

Mp two hundred and five to two hundred and six ° C. Elemental analysis _{(C 26 H 24 N 6 O} 5 as S) theory (%) C: 58.64 H: 4.54 N: 15.78 measured value (%) C: 58.36 H: 4.70 N: 15.66 In analogy The following compounds were prepared.

Example 105 N, N-diethylcarbamoylmethyl 4-
[2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 137-139 ° C. Elemental analysis (as C ₂₈ H ₂₈ N ₆ O ₅ S) Theoretical value (%) C: 59.99 H: 5.03 N: 14.99 measured value (%) C: 59.75 H: 5.19 N: 14.93 Example 106 4- [2- [2- (1H-tetrazole-5)
-Yl) phenylthio] phenylcarbamoyl] phenoxyacetamide 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid (prepared in Example 6) 0.63 g was converted to N, N-dimethylformamide
Dissolve in 6 ml, N, N'-carbonyldiimidazole 0.24 g
Was added. After stirring at room temperature for 1 hour, the solution was poured into 28% aqueous ammonia and stirred for 1 hour. Water was added to the reaction solution, and concentrated hydrochloric acid was added to make the solution acidic, and the precipitated crystals were collected by filtration and washed with water. The crude crystals were recrystallized from a mixture of N, N-dimethylformamide and ethanol to give 0.52 g of the desired product as white crystals.

Mp two hundred twenty-nine to two hundred thirty-one ° C. (decomposition) Elemental analysis _{(C 22 H 18 N 6 O} 3 as S) theory (%) C: 59.18 H: 4.06 N: 18.82 measured value (%) C: 58.89 H: 4.11 N: 18.46 The following compounds were prepared in a similar manner.

Example 107 N, N-diethyl--4- [2- [2- (1H- tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide mp 176-178 ° C. Elemental analysis _{(C 26 H 25 N 6 O} 3 S · 1 / 2H ₂ as O) theory (%) C: 61.22 H: 5.34 N: 16.47 measured value (%) C: 61.27 H: 5.38 N: 16.26 example 108 N, N-dimethyl-4- [2 - [2- (1H- tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide mp 189-190 ° C. elemental analysis _{(C 24 H 22 N 6 O} 3 as S) theory (%) C: 60.75 H: 4.67 N: 17.71 measured value (%) C: 60.97 H: 4.67 N: 17.90 Example 109 ethyl 4- [2- [3-chloro-2- (1
H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 220-222 ° C (decomposition) Elemental analysis (as C ₂₄ H ₂₀ CIN ₅ O ₄ S) Theoretical value (%) C: 54.83 H: 3.35 N: 14.53 measured value (%) C: 54.97 H: 3.52 N: 14.45 Example 110 butyl 4- [2- [4-chloro-2- (1
H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 156-157 ° C IRcm ^-1 (KBr) 3370,3200-2200,1730,1675,1600,157
Example 111 111 butyl 4- [2- [3-methoxy-2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 216-217 ° C. Elemental analysis (as C ₂₇ H ₂₇ N ₅ O ₅ S) Theoretical value (%) C: 60.77 H: 5.10 N: 13.12 measured value (%) C: 60.51 H: 5.15 N: 13.06 Example 112 butyl 4- [2- [5-methoxy-2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 169-171 ° C IRcm ^-1 (KBr) 3375,3200-2200,1755,1680,1605,158
0,1500,1435,1300 Example 113 butyl 4- [2- [3-methyl-2- (1
H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 150-151 ° C Elemental analysis (as C ₂₇ H ₂₇ N ₅ O ₅ S) IRcm ^-1 (KBr) 3375,3200-2200,1750, 1680,1605,158
0,1500,1435,1300 Example 114 ethyl 2-chloro-4- [2- [2- (1
H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 208-209 ° C (decomposition) Elemental analysis (as C ₂₄ H ₂₀ CIN ₅ O ₄ S) Theoretical value (%) C: 56.53 H: 3.95 N: 13.73 measured value (%) C: 56.34 H: 4.03 N: 13.72 Example 115 butyl 4- [4-methoxy-2- [2-
(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate Melting point 152-154 ° C. Elemental analysis (as C ₂₇ H ₂₇ N ₅ O ₅ S) Theoretical value (%) C: 60.77 H: 5.10 N: 13.12 measured value (%) C: 60.73 H: 4.93 N: 12.99 Example 116 butyl 4- [4-chloro-2- [2- (1
H- tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide diacetate mp 168-170 ° C. Elemental analysis _{(C 26 H 24 CIN 5 O} 4 as S) theory (%) C: 58.04 H: 4.50 N: 13.02 Measured value (%) C: 58.06 H: 4.49 N: 12.99 Example 117 butyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl-N-methylcarbamoyl] phenoxyacetate Melting point 148- 150 ° C IRcm ^-1 (KBr) 3200-2300,1760,1610,1560,1475,120
0.1118 Example 118 ethyl 4- [2- [3-hydroxy-2
-(1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate 3- (2-aminophenylthio) -2- (1H-tetrazol-5-yl) phenol (prepared in Reference Example 12) 0.63
g was suspended in 10 ml of toluene, 2 ml of a toluene solution of 0.58 g of ethyl 4-chloroformylphenoxyacetate was added, and the mixture was heated under reflux for 2 hours. The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, and eluted with 0.5% methanol / chloroform to obtain 0.66 g of the desired product as white crystals. Melting point 155 ~ 157 ℃ IRcm ^-1 (KBr) 3430,3700 ~ 2200,1750,1650,1600,158
0,1500,1440,1300 The following compounds were produced in the same manner as in Example 118.

Example 119: butyl 4- [4-hydroxy-2- [2
- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide diacetate mp 162 to 165 ° C. Elemental analysis _{(C 26 H 25 N 5 O} 5 as S) theory (%) C: 60.10 H: 4.85 N : 13.48 Measurement value (%) C: 60.03 H: 4.80 N: 13.24 Example 120 butyl 4- [5-hydroxy-2- [2
- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide diacetate mp 207 to 209 ° C. Elemental analysis _{(C 26 H 25 N 5 O} 5 S · 1 / 2C 2 H as ₅ OH) Theoretical value (% C) 59.77 H: 5.20 N: 12.91 found (%) C: 59.81 H: 5.41 N: 13.15 Example 121 ethyl 4- [2- [5-hydroxy-2]
- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetamide diacetate mass spectrometry _{(C 24 H 21 N 5 O} 5 S) M +: 491 The following compounds were prepared in the same manner as in Example 6.

Example 122 4- [2- [3-chloro-2-(-5-1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred and forty-five to two hundred forty-seven ° C. (decomposition) Elemental analysis (C ₂₂ H ₁₆ CIN ₅ O _{(As 4} S) Theoretical value (%) C: 54.83 H: 3.35 N: 14.53 Measured value (%) C: 54.97 H: 3.52 N: 14.45 Example 123 4- [2- [4-Chloro-2- (1H- Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 300 ° C. or higher Elemental analysis value (as C ₂₂ H ₁₆ CIN ₅ O ₄ S.2H ₂ O) Theoretical value (%) C: 51.02 H: 3.89 N: 13.52 Measured value (%) C: 51.31 H: 3.72 N: 13.85 Example 124 4- [2- [3-Methoxy-2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point: 255 to 256 ° C. (decomposition) elemental analysis _{(C 23 H 13 N 5 O} 5 as S) theory (%) C: 57.85 H: 4.01 N: 14.67 found (%) C: 57.80 H: 4.08 N: 14.47 Example 125 4- [2- [5-Methoxy-2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 235-237 ° C (decomposition) Elemental analysis value _{(C 23 H 13 N 5 O} 5 as S) theory (%) C: 57.85 H: 4.01 N: 14.67 measured value (%) C: 57.64 H: 4.20 N: 14.55 example 126 4- [2- [ 3-methyl-2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 230-232 ° C (decomposition) Elemental analysis value (as C ₂₃ H ₁₃ N ₅ O ₄ S 1 / 4H ₂ O ) Theoretical value (%) C: 59.28 H: 4.22 N: 15.03 Measured value (%) C: 59.34 H: 4.20 N: 14.82 Example 127 4- [3-Chloro-2- [2- (1H-tetrazol-5) - yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp 118 to 122 ° C. elemental analysis _{(C 22 H 16 C1N 5 O} 4 S · 5 / 4H 2 O as) theory (%) C: 52.3 8 H: 3.70 N: 13.88 Found (%) C: 52.39 H: 3.68 N: 13.93 Example 128 2-Chloro-4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp 252 to 254 ° C. elemental analysis _{(C 22 H 16 C1N 5 O} 4 as S) theory (%) C: 54.83 H: 3.35 N: 14.53 measured value (%) C: 54.83 H: 3.48 N: 14.36 Example 129 4- [4-Chloro-2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 200 ° C. Elemental analysis (C ₂₂ H ₁₆ C1N ₅ O ₄ S · 3 / 4H ₂ O as) theory (%) C: 53.34 H: 3.56 N: 14.14 measured value (%) C: 53.34 H: 3.48 N: 14.10 example 130 4- [4-methoxy-2-[2-(IH -Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 244 to 246 ° C Elemental analysis (as C ₂₃ H ₁₉ N ₅ O ₅ S) Theoretical value (%) C: 57.85 H: 4.01 N: 14.67 measured value (%) C: 57.79 H: 4.12 N: 14.65 Example 131 4- [2- [2- (1H-tetrazole-5)
- yl) phenylthio] phenyl -N- methylcarbamoyl] phenoxyacetic acid mp two hundred forty-eight to two hundred fifty ° C. Elemental analysis _{(C 23 H 19 N 5 O} 4 as S) theory (%) C: 59.86 H: 4.15 N: 15.18 measurements (%) C: 59.95 H: 4.12 N: 15.06 Example 132 4- [4-hydroxy-2- [2- (1H-
Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp two hundred and twenty-eight to two hundred and thirty ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 5 S · 3 / 4H 2 O as) theory (%) C: 55.40 H: 3.91 N: 14.68 measured value (%) C: 55.65 H: 3.84 N: 14.57 Example 133 4- [5-hydroxy-2- [2- (1H-
Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid mp 272 - 275 ° C. (decomposition) Elemental analysis _{(C 22 H 17 N 5 O} 5 S · 1 / 3H 2 O as a) the theoretical value (%) C: 56.28 H: 3.76 N: 14.92 Measured value (%) C: 56.52 H: 3.74 N: 14.64 Example 134 4- [2- [3-hydroxy-2- (1H-
Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Melting point 240-242 ° C (decomposition) Elemental analysis (as C ₂₂ H ₁₇ N ₅ O ₅ S) Theoretical value (%) C: 57.01 H: 3.70 N: 15.11 Measured value (%) C: 56.82 H: 3.74 N: 14.92 Example 135 4- [2- [5-hydroxy-2- (1H-
Tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid Mass spectrometry _{(C 22 H 17 N 5 O} 5 S) M +: 463 results of pharmacological tests showing the usefulness for the representative examples of the compounds of the present invention in the following Test Examples Is shown.

Test Method 1) leukotriene _{D 4 (leukotriene D 4: LTD} 4) was prepared from ³ H-LTD ₄ and guinea pig lung receptors binding inhibition experiments 0.2 pmol 1
After incubating with the membrane fraction of 00 μg for 1 hour at 25 ° C., the reaction solution was filtered with a glass filter. It bound to the remaining membrane on the glass filter. The radioactivity of ³ H-LTD ₄ was measured, and this value was defined as the total binding amount (total).

Similarly, the presence of a membrane fraction of 100μg and ³ H-LTD ₄ 0.2 pmol with a large excess of cold LTD ₄ (0.1 nmol) 1 at 25 ° C.
After incubation for ³ hours, ³ H-LTD ₄
Was measured for radioactivity, and this was measured for non-specific binding (non spec
ific binding: NSB).

³ H-LTD ₄ the amount of specifically bound (specific binding: S
B) was calculated by the equation (1).

Study of SB = total-NSB --- (1 ) Effect of the test substance to the receptor binding of LTD ₄ is
The test substance was added at the time of measuring the total binding amount (total), and the binding amount (total ') in the presence of the test substance was determined. The inhibition rate was determined from equation (2).

(Total-total ') / SB × 100 --- (2) 2) Shultz-Dale (SD) reaction anti-bovine serum albumin (BSA)
A guinea pig passively sensitized with rabbit serum was exsanguinated and killed, the trachea was excised, and a chain specimen was prepared according to the method of Takagi et al.
K., Takayanagi, I. and Fujie, K .: Chem. Pharm. Bull., 6 ,
716-720 (1958)].

The tracheal muscle specimen was suspended in a Magnus apparatus containing 10 ml of Tyrode's solution kept at 37 ° C, and after stabilization, histamine 10 ^-5 M
Was measured.

After washing and stabilizing, test substance and mepyramine 10 ^-5 M
Antigen contraction was measured in the presence. Histamine 10 ^-5 M
From the percentage of contraction due to the antigen-antibody reaction with respect to the contraction due to, the inhibition rate relative to the control value was determined.

3) Effect of endogenous leukotriene (LT) on experimental asthma Mepiramine (5 mg / kg), propranolol (0.1 mg / kg) in guinea pigs passively sensitized with anti-BSA rabbit serum
And indomethacin (1 mg / kg) were intravenously administered, and 5 minutes later, the antigen (BSA) was intravenously administered. The airway constriction response produced by the Konchet-Wrestler method (Knzett-Rossler) [Kon
zett, H. and Rossler, R .: Naunyn Schmiedebergs Arch. B
xp. Pathol. Pharmax., 195 , 71-74 (1940)].

The test substance was suspended in 0.5% methylcellulose and orally administered 3 hours before the antigen administration. The case where the airway cannula was completely obstructed by Klemme was defined as 100% contraction, and the percentage of the maximum response of airway contraction due to the antigen-antibody reaction was determined.

From this value, the inhibition rate of the test substance relative to the control was determined.

4) Effects on experimental asthma Anti-benzylpenicilloylated bovine gamma globulin (be
Antigen (benzyl penicilloyl-bovine serum albumin: benzyl penicilloyl-bov) on guinea pigs passively sensitized with nzyl penicilloyl-bovine gammaglobulin guinea pig serum
Inine serum albumin) was intravenously administered and the airway constriction reaction produced was measured by the Konzett-Rossler method.

The test substance was suspended in 0.5% methylcellulose and orally administered. After 3 hours, the airway contraction reaction due to the antigen-antibody reaction was measured. The case where the airway cannula was completely obstructed by Klemme was defined as 100% contraction, and the percentage of the maximum response of airway contraction due to the antigen-antibody reaction was determined. From this value, the inhibition rate of the test substance relative to the control was determined.

The results are shown in the following table. The effect of the compound of the present invention is clear.

5) Acute toxic effect A 6-week-old ddy mouse was used after fasting for 24 hours. A physiological saline suspension containing 0.5% methylcellulose of the compound of the present invention of Example 7 was orally administered, and thereafter, the animals were bred normally and observed for general symptoms and appearance of death cases for 2 weeks.

As a result, the compound of the present invention of Example 7 was low in toxicity and had an LD ₅₀ value of 1 g / kg or more.

Formulation Example 1 2 g of the compound of the present invention of Example 6 was taken and uniformly mixed with 70 g of lactose and 30 g of corn starch, and 25 ml of a 16% hydroxypropylcellulose solution was added thereto, followed by stirring and granulation. After drying, this was sized, 2 g of magnesium stearate and 2 g of talc were added and mixed, and made into a tablet with a rotary tableting machine (1 mg of a tablet, 110 mg of the compound of the present invention of Example 6, 2 mg of lactose). 70 mg, corn starch 30 mg, hydroxypropylcellulose 4 mg, magnesium stearate 2 mg, talc 2 mg).

Formulation Example 2 In a manner similar to Formulation Example 1, in 1 tablet, 110 mg of the compound of the present invention of Example 7, 2 mg of lactose, 30 mg of corn starch,
Tablets containing 4 mg of hydroxypropylcellulose, 2 mg of magnesium stearate, and 2 mg of talc.

Formulation Example 3 In a manner similar to Formulation Example 1, in 1 tablet (110 mg), the compound of the present invention of Example 67 was 2 mg, lactose was 70 mg, corn starch was 30 mg,
Tablets containing 4 mg of hydroxypropylcellulose, 2 mg of magnesium stearate, and 2 mg of talc.

Formulation Example 4 Lactose (990 mg) was added to 10 mg of the compound of the present invention in Example 6 and mixed uniformly to give a powder containing 0.1% of the compound of the present invention in Example 6.

Formulation Example 5 In the same manner as in Formulation Example 4, 0.1% of the compound of the present invention of Example 7 was added.
% Powder.

Formulation Example 6 In the same manner as in Formulation Example 4, 0.1% of the compound of the present invention of Example 67 was added.
% Powder.

Claims (2)

(57) [Claims] 1. A tetrazole derivative represented by the following general formula [I] and a pharmacologically acceptable salt thereof. Here, A represents-(O) _m- (CH (R ⁴ )) _n- (R ⁴ represents hydrogen or alkyl, and m and n represent 0 or 1). B is oxygen or -S (O) _p- (p is 0 to 2;
Represents ). R ¹ represents hydrogen, lower alkyl, lower alkoxy, halogen, halogenoalkyl, or hydroxy. R ² represents a substituted or unsubstituted alkyl, alkenyl or aralkyl. R ⁸ represents hydrogen, lower alkoxy, or halogen. R ⁹ represents hydrogen, lower alkyl, lower alkoxy, lower acyloxy, halogen, nitro, hydroxy. R ¹⁰ represents hydrogen or lower alkyl. 2. An antiallergic agent comprising a tetrazole derivative represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as a main component. Here, A represents-(O) _m- (CH (R ⁴ )) _n- (R ⁴ represents hydrogen or alkyl, and m and n represent 0 or 1). B is oxygen or -S (O) _p- (p is 0 to 2;
Represents ). R ¹ represents hydrogen, lower alkyl, lower alkoxy, halogen, halogenoalkyl, or hydroxy. R ² represents a substituted or unsubstituted alkyl, alkenyl or aralkyl. R ⁸ represents hydrogen, lower alkoxy, or halogen. R ⁹ represents hydrogen, lower alkyl, lower alkoxy, lower acyloxy, halogen, nitro, hydroxy. R ¹⁰ represents hydrogen or lower alkyl.