RU2115648C1 - Tetrazole derivatives and antiallergic composition - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: present invention describes tetrazole derivatives of general formula I:

wherein A is single bond or oxygen, alkenyl having 2-7 carbon atoms, phenylalkyl having 7-10 carbon atoms or alkyl having 1-6 carbon atoms optionally substituted with -COOR² in which R² is hydrogen or alkyl having 1-6 carbon atoms optionally substituted with CONR³R⁴ in which R³ and R⁴ are the same or different and each is hydrogen or alkyl having 1-4 carbon atoms, or pharmaceutically acceptable salts thereof. The present invention also describes antiallergic composition which comprises compound of formula I in effective amount. Compounds have antiallergic and antiinflammatory activities and are useful as therapeutic agent for treating bronchial asthma, allergic rhenite, or the like. Besides, compounds are low toxic. EFFECT: improved properties of the antiallergic composition. 9 cl, 135 ex, 1 tbl

Description

 The invention relates to the production of tetrazole of the following general formula (I) or a pharmacologically acceptable salt thereof.

в которой A - одинарная связь или кислород; R' - алкенил с 2 - 7 атомами углерода, фенилалкил с 7 - 10 атомами углерода или алкил с 1 - 6 атомами углерода, необязательно замещенный группой -COOR², в которой R² - водород или алкил с 1 - 6 атомами углерода, необязательно замещенный группой -CONR³R⁴, в которой R³ и R⁴ являются одинаковыми или различными и каждый представляет водород или алкил с 1 - 4 атомами углерода.

in which A is a single bond or oxygen; R 'is alkenyl with 2 to 7 carbon atoms, phenylalkyl with 7 to 10 carbon atoms or alkyl with 1 to 6 carbon atoms, optionally substituted with a -COOR ² group, in which R ² is hydrogen or alkyl with 1 to 6 carbon atoms, optionally substituted by the group —CONR ³ R ⁴ in which R ³ and R ⁴ are the same or different and each represents hydrogen or alkyl with 1 to 4 carbon atoms.

 The compounds of the present invention have anti-allergic and anti-inflammatory activities and are useful for alleviating or alleviating allergic symptoms such as bronchial asthma, burning, allergic rhinitis and displaced deriatitis, or as a therapeutic agent for treating cardiovascular disorders, cerebrovascular disorders, fever, arthritis and other diseases.

 It is generally believed that allergic asthma and atopic diseases are caused by a large number of chemical mediators as they separate from the lung and other tissues and contract smooth muscles such as the bronchial muscle and pulmonary blood vessels or increase the permeability of the blood vessels of the skin, resulting in various disorders of various tissues.

Among these chemical mediators, histamine and SRS-A are believed to be of the greatest importance. It has recently been found that SRS-A is a mixture of the ITC ₄ , ITD ₄ and ITE ₄ leukotrienes, which are peptides, and an extensive study of the multidisciplinary physiological effect of such leukotrienes (IT) and their association with various pathological conditions has been conducted. By its origin, SRS-A is a lipoxygenase-catalyzed metabolite of arachidonic acid and the role played by such a compound as a substance involved in the nucleation and development of processes of resistance to bronchial asthma and other diseases arising from contact-type allergic reactions has caused great interest.

In fact, ITC ₄ and ITD ₄ greatly reduce the isolated trachea of guinea pigs and humans and increase the secretion of mucus from the human respiratory tract in vitro. In this regard, special attention was paid to the participation of such substances in the disease of bronchial asthma.

In clinical conditions, it was found that IT is contained in the sputum of patients, for example, with a diagnosis of bronchitis, in concentrations sufficient to implement physiological changes. It was also reported that in children with bronchial asthma, the level of ITC ₄ in the blood correlates well with the severity of this disease.

 In addition to asthma, it is assumed that the action of IT is associated with allergic rhinitis and deriatitis and even with ischemic diseases such as myocardial infarction, etc., cardiac anaphylaxis, endotoxin shock, psoriasis, etc.

 In connection with the aforementioned, of considerable interest is the development of drugs that can inhibit the production of SRS-A or serve as antagonists of SRS-A.

 For example, among other substances, known IT antagonists are FRI-55712, SKF-104353, WY-45911 and ONO-1078. However, at present, none of these substances is commercially available (Ton G. Musser et al. New advances in the field of leukotriene antagonists. Agents and their effects. 18 (3/4) 332 (1986). Medications of the future, 13 (4) 317 (1988).

 Japanis Kokai Tokkio Kokho Patent Publication No. 62-198652 describes a group of compounds having some relation to the compound of the present invention, and it is noted that some of these compounds have 5a-reductase inhibitory activity. From the claims of the corresponding description, it can be assumed that the compound of the present invention belongs to the same category, however, no compound with a tetrazoyl group is specifically disclosed elsewhere in the description. In addition, there are no suggestions about the pharmacological action characteristic of the compounds of the invention. It was accidentally proved that the compound of the present invention generally does not have 5a-reductase activity.

 The authors of the present invention conducted a large study aimed at obtaining compounds that would have the property to inhibit the production of SRS-A or antagonist of SRS-A and at the same time superior to the known anti-allergic and anti-inflammatory drugs in efficacy, reliability and duration of action. Thus, the aim of the present invention is to develop a new compound with improved anti-allergic and anti-inflammatory activities.

 The essence of the present invention lies in the special structure of the compounds corresponding to General formula (I).

 The compound developed in the present invention is not only a new substance not described in the literature, but also a substance with excellent pharmacological activity, good bioavailability, long duration of action and low toxicity, as will be demonstrated below, in connection with which the substance is a valuable medicine.

 The following is a detailed description of the compounds of the present invention corresponding to the general formula (I).

As for the radical R ¹ , alkyl is preferably a group containing 1 to 6 carbon atoms. As such groups, in addition to the above-mentioned alkyl groups, other groups such as pentyl, isopentyl, hexyl, isohexyl and the like may be mentioned.

 Alkenyl is preferably a straight or branched group containing 2 to 7 carbon atoms, such as vinyl, allyl, isopropenyl, 2-metal, 2-butenyl, 3-butenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl and t .P.

 Phenylalkyl is preferably a group containing 7 to 10 carbon atoms, such as benzyl, phenethyl, phenylpropyl, phenylbutyl and the like.

Among the substituents for said alkyl are -COOR ² (R ² is hydrogen or C ₁ -C ₆ alkyl, which may be unsubstituted or substituted by a group -CON (R ³ ) R ⁴ (R ³ and R ⁴ may have the same or different values and each represents hydrogen or C ₁ -C ₄ lower alkyl).

 The compound of the present invention can be obtained in accordance with the following and other methods.

Процесс B

В указанных выше формулах A и R' имеют указанные выше значения.Process a

Process b

In the above formulas, A and R 'have the above meanings.

 Method A.

 The aniline derivative (II) is reacted with a benzoic acid derivative (III) or a reactive derivative (III) to produce compound (I).

 Such an acylation reaction itself can be carried out by known methods.

 For example, you can use a method that uses a reactive derivative of compound (III) such as a benzoyl halide derivative (e.g., benzoyl chloride derivative, benzoyl bromide derivative, etc.), lower alkyl ester or active ester (e.g., n nitrophenyl ether, n-nitrobenzyl ether, n-chlorophenyl ether, etc.), imidzolid or mixed acid anhydride (for example, mixtures of anhydrides and lower alkyl carbonates or lower alkyl phosphates), or a method involving direct condensation of the compound (II) with compound (III) in the presence of a condensation agent.

When using a benzoyl halide derivative, usually such a derivative reacts with compound (II) in the presence or absence of an organic base, in an inert solvent medium at a temperature of -5 ^° C to 120 ^° C. An inert solvent for this reaction includes, among other substances, such esters such as diethyl ether, tetrahydrofuran, dioxane and the like, halogenated hydrocarbons such as methylene chloride, chloroform and the like. hydrocarbons such as benzene, toluene, xylene and the like, aprotic solvents such as N, N-dimethylformamide and the like. and various mixtures of such solvents.

 Organic bases, among others, include tertiary organic bases such as pyridine, triethylamine, tributylamine, dimethylaniline, etc.

 The reaction time may vary depending on the nature of the starting materials, the base and the solvent used, but usually ranges from 30 minutes to 12 hours.

 Preferred ratios between these benzoyl halide derivatives and the base are usually 1 to 3 mol / mol of compound (II).

In the case when the direct condensation reaction is carried out using a condensation agent, compound (II) is reacted with compound (III) in the presence of a condensing agent, usually in an inert solvent, at a temperature of -20 - 80 ^o C. As the solvent, the above compounds can be used .

 Carbodiimides such as dicyclohexylcarbodiimide and the like, quaternary pyridinine salts such as 2-chloro-N-methylpyridinium iodide, 2-methanesulfonyloxy-N-methylpyridinium iodide and the like, diphenyl can be used as a condensing agent among other substances. phosphoryl azide, diethyl phosphoryl cyanide or triphenylphosphine and carbon tetrachloride.

 The reaction time, which may vary depending on the nature of the starting materials, the condensing agent used and the solvent used, can usually be in the range of 30 minutes to 12 hours.

 Preferred ratios between the compound (III) and the condensing agent are 1 to 3 mol per mol of the compound (II).

 Method B.

 Compound (IV) containing a cyano group reacts with nitric acid or its salt to form compound (I).

 As salts of nitric acid, alkali metal salts of nitric acid can be used, for example, sodium azide, potassium azide, lithium azide and the like, alkaline earth metal salts such as calcium azide, magnesium azide, etc., salts of other metals, capable of forming salts with nitric acid, for example, aluminum azide, tin azide, and the like. or salts with organic bases, for example tetramethylguanidium azide and the like.

In accordance with the present invention, such salts of nitric acid can be used as such. However, as an alternative, compound (I) can be obtained by carrying out the reaction in an inert solvent in the presence of such an alkali metal salt of nitric acid (e.g. sodium azide) and Lewis acid (e.g. aluminum chloride, tin (IV) chloride, zinc chloride, titanium chloride, BF ₃ - diethyl ether, etc.), ammonium salts (e.g. ammonium chloride, di-n-butylammonium chloride, benzene ammonium chloride, tetramethyl ammonium chloride, etc.), sulfuric acid (e.g. ethanesulfonic acid) halide an alkali metal (e.g. lithium chloride) or an amine salt (e.g. triethylamine hydrochloride, pyridine hydrochloride, etc.) and a temperature of 0-200 ^° C. The solvent used, among other substances, may be aprotic solvents such as N , N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like, ethers such as tetrahydrofuran, dioxane, methyl cellulosolve, ethyl cellosolve and the like, hydrocarbons such as benzene, toluene, petroleum ether and the like.

 The amount of azide compound is 1 to 10 moles per mole of compound (IV). The duration of the reaction may vary depending on the nature of the compound, salt and solvent used, but usually ranges from 30 minutes to 48 hours.

In the case where the substance thus obtained is an ester (R ² = alkyl), it can be hydrolyzed to the target compound in which R ² is hydrogen. This hydrolysis reaction can be easily carried out in an appropriate solvent medium (for example, in alcohols, such as methanol, ethanol, etc., glycols, such as ethylene glycol, 2-methoxyethanol, etc., ethers, such as tetrahydrofuran, 1 , 2-dimethoxyethane and the like, ketones, such as acetone, methyl ethyl ketone and the like, in water or in mixtures of the listed substances) in the presence of alkali at a temperature of 0-100 ^o C for a period of 30 minutes to 5 hours .

 Alkalis that can be used include hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and carbonates such as sodium carbonate, potassium carbonate and the like. The amount of said alkali is usually 2 to 6 moles and preferably 3 to 4 moles per mole of ether.

The carboxylic acid thus obtained (R ² = H), if necessary, can be converted into an ester (R ² = alkyl). This complex esterification reaction can be carried out by methods of esterification known to it, for example, using diazomethane, alcohol and acid (for example, hydrogen chloride, sulfuric acid, p-toluenesulfonic acid, etc.) or thionyl chloride and alcohol.

 The compound (I) obtained according to the above can be reacted with a pharmaceutically acceptable organic amine, alkali metal hydroxide or ammonia in a manner known per se, for example by mixing and heating them to obtain the corresponding organic amine salt, amino acid salt, alkali metal salt or ammonium salt of compound (I).

 In the case of an alkali metal salt, the compound obtained by the aforementioned method can be reacted, for example, with sodium hydroxide in an alcohol medium or in an aqueous solution of alcohol by heating to obtain a salt.

 In the case where a particular compound of the present invention contains an asymmetric carbon atom, all its corresponding optical isomers and racemic mixtures are covered by the scope of the present invention. The isolation of the optical isomers from the obtained ratichymic mixture can be carried out using their acidity, for example, using optical cleavage using an optically active base (brucine, quinine, a-methylbenzylamine, etc.), which is carried out in a conventional manner. Such optical isomers can also be obtained from the optical active compounds (II) through compound (IV).

 Thus obtained target compound (I) can be isolated and purified per se by known methods, for example, by concentration, pH adjustment, redistribution, solvent extraction, recrystallization, fractional distillation, chromatography, etc.

 The starting compounds (II) and (IV) can be obtained by the method described in the following reference examples.

 The compound of the present invention in the form of a medicament for humans or animals may be used as such, or it may be preformed into a pharmaceutical composition containing 0.01 to 99.5%, preferably 0.5 to 90% of the compound in a pharmaceutically applicable, non-toxic and inert excipient.

 As the above excipient, one or more solid, semi-solid, or liquid diluents, fillers, and / or other forming aids can be used. Such a pharmaceutical composition is preferably used in unit dosage forms. The pharmaceutical composition of the present invention can be applied intravenously, orally, into tissues, nasally (by instillation into the nose or eyes) or rectally. Of course, dosage forms suitable for the respective routes of use should be used. Particularly preferred is oral administration or inhalation.

 The dosage of an anti-allergic or anti-inflammatory drug should be selected in accordance with the patient's age, body weight and other characteristics, type of application and the nature and severity of the disease. Typically, the recommended dosage for oral use by adults is 1-1000 mg / body weight / day, preferably 1-100 mg / body weight / day, and for inhalation, 0.01-100 mg / body weight / day. Depending on the specific case, the required dosage may exceed the indicated values or be lower than them. The pharmaceutical composition may also be administered in 2 or 3 divided doses.

 For oral administration, solid or liquid dosage forms may be provided, for example, undiluted powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and the like.

 Pure powders are obtained by grinding the active substance to a certain size. Powders are obtained by grinding the active substance to a certain size and mixing the resulting pure powder with a pharmaceutical excipient such as edible carbohydrate, for example, starch, mannitol, etc., which can also be pre-ground. If necessary, a flavoring agent, preservative agent, dispersant, coloring agent, fragrance, and the like can be added to the composition.

 Capsules can be formed by preparing pure or formed powders by the above method, or granules in accordance with the method described below for tablets, followed by filling gelatin or other capsule shells with powders or granules. Before the filling operation, a lubricating or fluidizing agent, for example, colloidal silicon oxide, talc, magnesium stearate, calcium stearate, solid polyethylene glycol, and the like can be added to these granules in a crushed form. An improved drug effect can be achieved by adding a disintegrant or solubilizer, for example, carboxymethyl cellulose, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxy starch, calcium carbonate, sodium carbonate and the like.

 Soft capsules can be prepared by suspending the finely divided drug powder in a mixture of vegetable oil, polyethylene glycol, glycerol and a surface agent, and plugging the suspension in a flexible gelatin shell. Tablets can be created by preparing a powder composition, processing it into granules or slag, and compressing the mixture after adding a disintegrator or lubricant.

 A powdered composition can be prepared by mixing the finely divided drug with the indicated diluent and base, in the absence or addition of a binding agent (e.g. sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinyl pyrrolidone, polyvinyl alcohol, etc.) , paraffin, wax, hydrogenated castor oil, etc.), a reabsorption agent (e.g., a quaternary salt) and / or an adsorbent (e.g., bentonite, kaolin, wild ltsy phosphate and the like). The powder composition can be granulated by wetting with a binder, for example, syrup, starch paste, gum arabic, cellulose or polymer solution and the like. followed by passing through a sieve under the action of force. Instead of such a granulation process, the composition can first be tabletted and the resulting crude tablets are crushed into granules.

 To the granules obtained by this method, to prevent their internal adhesion, an appropriate lubricant, for example, stearic acid, stearates, talc, mineral oil, etc. can be added. The lubricated compositions thus obtained are then subjected to compression molding.

 Deprived tablet coatings thus obtained can be coated with a film or sugar coating.

 Deprived tablet coatings thus obtained can be coated with a film or sugar coating.

 Instead of performing the indicated granulation and tabletting steps, the drug can be mixed with a free-flowing inert carrier and directly subjected to compression molding. You can also use a transparent or translucent protective coating consisting of a hermetically sealed shellac film, sugar or a polymer coating, or use a polished wax coating.

 Other oral dosage forms, for example, solutions, syrups and elixirs, can also be carried out in unit dosage forms so that the drug can be distributed in constant amounts. Syrups can be prepared by dissolving the compound in an appropriate aqueous odorant, while elixirs are prepared using non-toxic alcoholic vehicles. Suspensions may be formed by dispersing the compound in a non-toxic carrier. If necessary, solubilizers and emulsifiers (for example, ethoxylated isostearyl alcohol, polyoxyethylene (sorbitol ether), preservatives, perfumes (for example, peppermint oil, saccharin) and other agents can be added.

 If desired, such a unit dosage form for oral administration may be microencapsulated. The unit dosage can also be coated with polymer or wax, or introduced into them in order to provide a prolonged action or delayed release.

 For use in tissues, liquid unit dosage forms for subcutaneous, intramuscular or intravenous use, for example, such as solutions and suspensions, can be used. For example, such preparations can be prepared by suspending or dissolving a certain amount of the active compound in an injectable non-toxic liquid carrier, for example, in an aqueous or oil medium with sterilization resulting from a suspension or solution. Another technique is to fill the ampoules with a certain amount of the active compound, sterilize the filled ampoules and seal them. In case of unplanned formulation or mixing, a spare ampoule and a carrier may be provided to accompany the powdered or lyophilized preparation of the active ingredient. For the purpose of isotonization, a non-toxic salt or salt solution may be added to the composition to be injected. In addition, stabilizers, preservatives, emulsifiers and the like may also be used.

 For rental use, suppositories may be provided which are prepared by mixing the active compound with a low melting water-soluble or water-insoluble solid, such as polyethylene glycol, cocoa butter or a higher ester (e.g. myristyl palmitate) or mixtures thereof.

 For the use of inhalation, a steam inhaler may be used. A pressure-resistant container or nebulizer associated with a spray preparation or aerosol may also be used.

 When using a nebulizer, the drug can be used in the form of fog in the larynx or nasal cavity as a result of filling the nebulizer with a solution of a compound of the invention in an aqueous or oil carrier, such as water, saline or aqueous alcohol, and forcing it into the air nebulizer. If necessary, auxiliary agents such as a solubilizer can be used. A single dosage can be controlled by adjusting the air volumetric velocity.

 When using a pressure-resistant container, a system can be formed with liquefied or compressed gas of the double or triple type (binary liquid-phase emulsion) or suspension type and can be applied locally in the form of fog, foam, stream or paste in the larynx or nasal cavity. A single dose of such a spray preparation can be adjusted using a regulatory dosing valve.

 The best method of carrying out the invention.

 The following reference examples, working examples, test examples, and preparation examples of a compound of the invention are intended to more fully describe the invention.

 Reference Example 1. 2- / 3- / 1- (1H-tetrazol-5-yl) ethoxy / phenoxy / aniline.

 Stage 1. 3- (2-nitrophenoxy) anisole.

To 150 ml of dimethyl sulfoxide were added 19.9 g of 3-methoxyphenol and 9.1 g of potassium hydroxide and the resulting mixture was heated to 70 - 80 ^o C to obtain a homogeneous solution. To this solution, 21.1 g of 2-chloronitrobenzene was added and the resulting mixture was stirred for 4 hours at 100 ^° C. Then the reaction mixture was diluted with water and extracted with ether, and the ether extract was washed successively with 10% sodium hydroxide solution and saturated sodium chloride solution. The washed extract was dried over magnesium sulfate, and the ether was distilled off to obtain 31.9 g of the target compound as a pale yellow solid.

 Step 2: 2- (2-nitrophenoxy) phenol.

A mixture of 28.8 g of 3- (2-nitrophenoxy) anisole and 68 g of pyridine hydrochloride was heated to 160 - 170 ^o C to obtain a homogeneous solution, which was further heated at 195 - 205 ^o C with stirring for one hour. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated, and the obtained residue was passed through silica gel and eluted with chloroform to obtain 23.8 g of the target compound as a light brown oil.

 Stage 3. Ethyl 2- / 3- (2-nitrophenoxy) phenoxy / propionate.

 8.0 g of 3- (2-nitrophenoxy) phenol and 7.5 g of ethyl 2-bromopropionate were dissolved in 120 ml of acetone, followed by 7.2 g of potassium carbonate. The resulting mixture was heated for 5 hours under reflux and, after cooling, the precipitate was filtered. The filtrate was concentrated to obtain 11.6 g of the target compound as a light brown oil.

 Stage 4. 2- / 3- (2-nitrophenoxy) phenoxy / propionic acid.

 6.7 g of ethyl 2- / 3- (2-nitrophenoxy) propionate was dissolved in 100 ml of ethanol, followed by the addition of a solution of 1.6 g of sodium hydroxide in 10 ml of water, and the resulting mixture was stirred at room temperature for 1 h. Then, ethanol was distilled off and the residue was diluted with water, acidified with hydrochloric acid and extracted with chloroform. The chloroform layer was dried and concentrated to give 6.2 g of the target compound as a pale yellow oil.

 Stage 5. 2- / 3- (3-nitrophenoxy) phenoxy / propionamide.

6.15 g of 2- / 3- (2-nitrophenoxy) phenoxy / propionic acid and 4.2 g of triethylamine were dissolved in 100 ml of methylene chloride, after which 2.5 g of ethyl chloroformate were added dropwise at a temperature not exceeding 0 ^o C and the resulting mixture additionally stirred for 30 min at the same temperature. The reaction mixture was poured into pre-ice-cooled methylene chloride (120 ml) saturated with ammonium gas, and the resulting mixture was further stirred at room temperature for 30 minutes. The methylene chloride layer was washed with water (twice), dried and concentrated, and the residue was recrystallized from both methanol and isopropyl ether to give 3.3 g of the target compound.

 Stage 6. 2- / 3- (2-nitrophenoxy) phenoxy / propionitrile.

 In a mixture of 12 ml of pyridine and 35 ml of dioxane, 4.55 g of 2- / 3- (2-nitrophenoxy) phenoxy / propionamide was suspended, and then 3.6 g of trifluoroacetic anhydride were added dropwise with ice-cooling and stirring. Then the mixture was stirred at the indicated temperature for 30 minutes, and after adding a mixture of ice-water, extraction was carried out with ether. The ether extract was washed with dilute hydrochloric acid and a solution of sodium hydrogencarbonate, dried and concentrated to give 4.3 g of the target compound as a pale yellow oil.

 Step 7. 5- (1- / 3- (2-nitrophenoxy) phenoxy / ethyl / -1H-tetrazole.

2 g of 2- / 3- (2-nitrophenoxy) phenoxy / propionitrile was dissolved in 25 ml of N, N-dimethylformamide, followed by the addition of 0.92 g of sodium azide and 0.76 g of ammonium chloride, and the mixture was stirred at 115 ^° C. for 80 min The reaction mixture was then poured into a mixture of ice and water containing 3 ml of concentrated hydrochloric acid, and was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated, giving 2.4 g of the target compound as a light brown oil.

 Step 8. 2- / 3- / 1- (1H- / tetrazol-5-yl) ethoxy / phenoxy / aniline.

 5- / 1- / 3- (2-nitrophenoxy) phenoxy / ethyl / -1H-tetrazole was dissolved in 30 ml of ethanol, and catalytic hydrogenation was carried out in the presence of 0.3 g of palladium on carbon at atmospheric temperature and pressure. After the reaction, the catalyst was filtered off, and the filtrate was concentrated, giving 2.1 g of the target compound as a brown oil.

 2- / 3- (1P-tetrazol-5-ylmethoxy) phenoxy aniline was obtained in the same manner as in Reference Example 1.

 Reference Example 2. 2- / 3- (1H-tetrazol-5-yl) phenoxy / aniline.

 Stage 1. 3- (2-nitrophenoxy) benzonitrile.

5.0 g of 3-cyanophenol and 5.93 g of 2-fluoronitrobenzene were dissolved in 50 ml of N, N-dimethylformamide, followed by 8.71 g of potassium carbonate, and the mixture was stirred under heating at 100 ^° C for 2 hours. After cooling the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed 3 times with water and concentrated. The residue crystallized from diisopropyl ether, giving 9.63 g of the target compound as pale yellow crystals.

 Step 2.5. 5- / 3- (2-nitrophenoxy) phenyl / -1H-tetrazole.

4.0 g of 3-2-nitrophenoxybenzonitrile was dissolved in 40 ml of N, N-dimethylformamide, after which 2.28 g of sodium azide and 1.68 g of ammonium chloride were added, and the resulting mixture was stirred at 110 ^° C. for 4 hours. After cooling the reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried and concentrated. The residue was recrystallized from ethyl acetate-benzene to give 3.6 g of the target compound as light brown crystals.

 Step 3.2: 2- / 3- (1H-tetrazol-5-yl) phenoxy aniline.

 In a mixture of 18 ml of ethanol and 9 ml of N, N-dimethylformamide, 1.5 g of 5- / 3- (2-nitrophenoxy) phenyl / -1H-tetrazole was dissolved and catalytic hydrogenation was carried out in the presence of 0.3 g of palladium on charcoal at a temperature ambient air and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to form 1.3 g of the target compound as a colorless oil.

 Reference Example 3. N- [2- [2-cyanophenoxy / phenyl] -4-hexyloxobenzamide.

 Stage 1. 2- (2-aminophenoxy) benzonitrile.

 2.5 g of (2- (2-nitrophenoxy) benzonitrile prepared in accordance with Reference Example 2, stage 1, were dissolved in 50 ml of ethyl acetate, and catalytic hydrogenation was carried out in the presence of 0.5 g of palladium on carbon at ambient temperature and pressure. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated, and the residue was passed through a silica gel column using chloroform as eluent to give 2.0 g of the target compound as a colorless oil.

 Stage 2. N- / 2- / 2-cyanophenoxy / phenyl / -4-hexyloxybenzamide.

 2.0 g of 2- (2-aminophenoxy) benzonitrile was dissolved in 20 ml of ether, followed by the addition of 2.04 g of triethylamine. Then, while cooling the system with ice and stirring, a solution of 2.67 g of 4-hexyloxybenzoyl chloride in 5 ml of ether was added dropwise. The mixture was further stirred at the same temperature for 1 hour. Then, the reaction mixture was washed with dilute hydrochloric acid and an aqueous solution of sodium hydrogencarbonate, dried and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate-n-hexane as an eluent, and the desired fractions were recrystallized from diisopropyl ether to obtain 3.05 g of the target compound as white crystals.

 Ethyl 4- / 2- (4-cyanophenoxy) phenylcarbamoyl / phenoxyacetate was obtained in the same manner as described in Reference Example 3.

 Reference Example 4. (E) -N- / 2-cyanophenylthio) phenyl / -4- (2-heptenyloxy) benzamide.

 Stage I. Ethyl 2- (2-nitrophenylthio) benzoate.

15.4 g of thiosalicylic acid were dissolved in 100 ml of N, N-dimethylformamide, after which 42 g of potassium carbonate, 14.8 g of fluoronitrobenzene were added and the resulting mixture was stirred for 3 hours at 100 ^° C. After completion of the reaction, the mixture was cooled to room temperature 18.7 g of ethyl iodide was added and the mixture was further stirred for 3 hours at room temperature. Then the reaction mixture was poured into a mixture of ice water and extraction was carried out with ether. The ether layer was washed twice with water, dried and concentrated. Finally, the residue was recrystallized from ethanol to give 25.5 g of the target compound as yellow crystals.

 Stage 2. Ethyl 2- (2-aminophenylthio) benzoate.

 22.5 g of ethyl 2- (2-nitrophenylthio) benzoate was suspended in 130 ml of ethanol, and then a solution of 58.7 g of tin (IV) chloride dihydrate in a mixture of 70 ml of concentrated hydrochloric acid and 45 ml of ethanol was added en bloc. The resulting mixture was stirred at room temperature for 3 hours, after which it was poured into a mixture of 600 ml of a 10% aqueous sodium hydroxide solution and 500 ml of ether while cooling and stirring the mixture. The ether layer was separated, washed with water and a saturated aqueous solution of sodium chloride, and dried. Finally, the ether was distilled off to obtain 20.5 g of the target compound as a pale yellow oil.

 Stage 3. (E) - / 2- / 2- (4- (2-heptenyloxy) benzoylamino / - phenylthio / benzoic acid.

 2.1 g of ethyl 2- (2-aminophenylthio) benzoate and 1.8 g of triethylamine were dissolved in 30 ml of methylene chloride, after which 2.2 g of (E) -4- (2-heptenyloxy) benzoyl chloride were added dropwise with cooling and stirring. system. The resulting mixture was stirred at room temperature for 10 hours, after which methylene chloride was distilled off. The residue was diluted with water and extracted with ether. The ether layer was washed with dilute hydrochloric acid and a saturated solution of sodium hydrogencarbonate and dried, after which the ether was distilled off. The oily residue was dissolved in 50 ml of ethanol, followed by the addition of 7 ml of a 10% aqueous sodium hydroxide solution, and the resulting mixture was heated in a water bath for 40 minutes. After cooling, the reaction mixture was acidified with hydrochloric acid and diluted with water, and the obtained crystals were collected by filtration and washed with water and an aqueous solution of ethanol to obtain 2.8 g of the target compound as white crystals.

 Stage 4. (E) -2- / 2- / 4- (2-heptenyloxy) benzoylamino / phenylthio / benzamide.

 2.8 g of (E) -2- / 2- / 4- (2-heptenyloxy) benzoylamino / phenylthio / benzoic acid were suspended in 40 ml of benzene, after which 1.2 g of N, N-carbonyldiimidazole was added and the resulting mixture was stirred at room temperature for 2 hours. Ammonia gas was introduced into the mixture while cooling the system with ice and stirred for 20 minutes and the resulting mixture was allowed to stand at room temperature for 2 hours. The crystals were isolated and collected by filtration and washed with ethyl acetate to obtain 2.6 g of the target compounds in the form of white crystals.

 Step 5. (E) -N- / 2- (2-cyanophenylthio) phenyl / -4- (2-heptenyloxy) benzamide.

 In a mixture of 5 ml of pyridine and 50 ml of dioxane, 2.5 g of (E) -2- / 2- / 4- (2-heptenyloxy) benzoylamino / phenylthio / benzamide were suspended, after which 2.2 g of anhydride were added dropwise. trifluoroacetic acid while cooling the system with ice and stirring. After the completion of the dropping, the mixture was stirred at room temperature for 3 hours. Then, a mixture of ice-water was added and the separated crystals were collected by filtration, washed with water and dried to obtain 2.4 g of the target compound as white crystals.

 Following the procedure of Reference Example 4, the following compounds were prepared.

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-cyanophenylthio) 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.

 Stage 1. 2- (2-nitrophenylthio) benzoic acid.

30.8 g of thiosalicylic acid, 28.2 g of 2-fluoronitrobenzene and 69.0 g of potassium carbonate were suspended in 300 ml of N, N-dimethylformamide, and the resulting mixture was stirred for 2 hours at 100 ^° C. After cooling, water was added and acidification was carried out hydrochloric acid and the precipitated crystals were collected by filtration and washed with water. Next, the crystals were dissolved in ethyl acetate and the resulting solution was dried over magnesium sulfate and filtered. The filtrate was concentrated and the precipitated crystals were collected by filtration and dried to obtain 42.6 g of the target compound as yellow prisms, so pl. 169 - 171 ^o C.

 Stage 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 the resulting suspension was heated for 6 hours under reflux. The solvent and excess thionyl chloride were distilled off under reduced pressure, whereby 22 g of 2- (2-nitrophenylthio) benzoyl chloride were obtained as yellow crystals. Without further purification, this product was dissolved in a mixture of 200 ml of ether and 100 ml of methylene chloride and ammonia gas, bubbled through the solution for 15 minutes while cooling the system with ice. Then the mixture was stirred for one hour at room temperature, after which the precipitated crystals were collected by filtration, washed with water and hot ethanol to obtain 18.4 g of the target compound as yellow crystals, so pl. 166 - 167 ^o C.

 Stage 3. 2- (2-nitrophenylthio) benzonitrile.

In a mixture of 12.7 g of pyridine and 80 ml of dioxin, 8.8 g of 2- (2-nitrophenylthio) benzamide was suspended, after which 10.1 g of trifluoroacetic anhydride were added dropwise while cooling the system with ice, and the resulting mixture was stirred for 1 h. water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water and hot ethanol, and dried. The result was 7.84 g of the target compound in the form of yellow crystals, so pl. 166 - 167 ^o C.

 Stage 4. 2- (2-aminophenylthio) benzonitrile.

In a mixture of 40 ml of concentrated hydrochloric acid, 60 ml of methanol and 40 ml of N, N-dimethylformamide, 6.6 g of 2- (2-nitrophenylthio) benzonitrile was suspended, followed by 8.64 g of iron powder en bloc. and the resulting mixture was stirred for 1 h at 60 ^o C. Then the reaction mixture was diluted with water and the precipitate was extracted with ether. The extract was washed with an aqueous solution of sodium hydrogencarbonate and water, and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (Vacogel C200) using ethyl acetate-n.hexane (1: 4) as an eluent. The obtained crystals were recrystallized from a mixture of ethyl acetate - N. hexane to obtain 4.8 g of the target compound in the form of white crystals, so pl. 86 - 89 ^o C.

 Step 5. N- / 2- (2-cyanophenylthio) phenyl / -4-hexyloxybenzamide.

 1.03 g of 4-hexyloxybenzoic acid was dissolved in 2 ml of thionyl chloride, and the resulting solution was heated under reflux for 1 h. The excess thionyl chloride was distilled off and the residue was dried in vacuo to give 4-hexyloxybenzoyl chloride. Separately, 1.00 g of 2- (2-aminophenylthio) benzonitrile and 0.89 g of triethylamine were dissolved in 10 ml of ether, and a solution of the above 4-hexyloxybenzoyl chloride in 5 ml of ether was added while stirring the resulting solution with ice cooling. The resulting mixture was stirred overnight. The next morning, water and an aqueous solution of sodium hydrogencarbonate were added, and the resulting precipitate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate - n. Hexane to obtain 1.27 g of the target compound as white prisms.

 Following the procedure of Reference Example 5, the following compounds were prepared.

(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.

 Stage 1. N- / 2- (2-cyanophenylthio) phenyl / -4-hydroxybenzamide.

 2.6 g of 2- (2-aminophenylthio) benzonitrile (prepared in accordance with Reference Example 5, step 4) and 2.8 g of pyridine were dissolved in 60 ml of ether, after which a solution of 2.7 g of 4-acetoxybenzoyl chloride in ether was added dropwise. while cooling the system with ice and stirring. After completion of the dropwise addition, the mixture was stirred at room temperature for 10 hours. The ether was distilled off and ethanol was added to the residue. The resulting crystals were collected by filtration and washed with ethanol. Then the crystals were suspended in 70 ml of ethanol, and after adding 7 ml of a 10% aqueous sodium hydroxide solution, the mixture was stirred at room temperature for 1 h. The reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The separated crystals were collected by filtration and dried to form 3.3 g of the target compound as white crystals.

 Stage 2. Methyl 4- / 2- (2-cyanophenylthio) phenylcarbamoyl / phenoxyacetate.

 1.0 g of N- / 2- (2-cyanophenylthio) phenyl / -4-hydroxybenzamide and 0.49 g of methyl bromoacetate were dissolved in 100 ml of N, N-dimethylformamide, after which 0.6 g of potassium carbonate was added and the resulting mixture was stirred for 4 hours at room temperature. Then, the reaction mixture was diluted with water, and the precipitated crystals were collected by filtration and washed with water with aqueous ethanol to obtain 1.2 g of the target compound as white crystals.

 Following the procedure of Reference Example 6, the following compounds were prepared.

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-quinallylmethoxy) benzamide;
N- / 2-cyanophenylthio) phenyl / -4- (6-hydroxyhexyloxy) benzamide;
ethyl 4- / 4- / 2- (2-cyanophenylthio) phenylcarbamoyl / phenoxy / butyrate;
ethyl 6- / 4- / 2- (2-cyanophenylthio) phenylcarbamoyl / phenoxy / hexanate;
ethyl 4- / 2- (2-cyanophenoxy) phenylcarbamoyl / phenoxyacetate;
N- / 2- (2-cyanophenoxy) 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 (prepared according to the procedure of Reference Example 5, step 4), 3.4 g of sodium azide and 1.7 g of ammonium chloride were suspended in 25 ml of DMF, and the resulting suspension was stirred for 5 hours at 110-120 ^° C. After cooling the system, the reaction 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 recrystallized from ethyl acetate and isopropyl ether to obtain 1.9 g of the target compound in the form of white crystals, so pl. 153 - 156 ^o C.

 Following the same procedure as described in Reference Example 7, the following compounds were prepared.

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-tetrazol-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-tetrazol-5-yl) phenylthio / aniline;
2- / 3-methyl-2- (1H-ttrazol-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-tetrazol-5-yl) phenylthio / aniline;
5-hydroxy-2- / 2- (1H-tetrazol-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.

 3.33 g of N- / 2- (2-cyanophenylthio) phenyl / -4- (5-oxohexyloxy) benzamide (prepared according to Reference Example 6, step 2) was suspended in 30 ml of tetrahydrofuran, after which a solution of 0.31 was added. g of sodium borohydride in methanol and the resulting mixture was stirred for 1 hour. Chloroform was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate - n. hexane to obtain 3.15 g of the target compound in the form of white crystals.

 In the same manner as described in Reference Example 8, the following compounds were prepared.

 N- / 2- (2-cyanophenoxy) phenyl / -4- (5-hydroxyhexyloxy) benzamide.

 Reference Example 9. Ethyl 4- / 2- (2-cyanophenylsulfinyl) phenylcarbamoyl / phenoxyacetate.

To a solution of 1.51 g of ethyl 4- / 2- (2-cyanophenylthio) phenylcarbamoyl) phenoxyacetate (prepared according to the procedure of Reference Example 6, step 2) in 5 ml of chloroform was added a solution of 0.87 g of 70% m-chloroperbenzoic acid in 20 ml of chloroform and the resulting mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate, after which the solvent was distilled off. The residue was recrystallized from ethyl acetate - n. hexane to obtain 1.3 g of the target compound in the form of white crystals, so pl. 128 - 130 ^o C.

 In the same manner as described in Reference Example 9, the following compounds were prepared.

Ethyl 4- / 4- / 2- (2-cyanophenylsulfinyl) 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 / phenylcarbamoyl / phenoxyacetate.

To a solution of 1.51 g of ethyl 4- / 2- (2-cyanophenylthio) phenylcarbamoyl / phenoxyacetate (prepared according to Reference Example 6, step 2) in 5 ml of chloroform was added a solution of 1.73 g of 70% m-chlorobenzoic acid in 30 ml of chloroform and the resulting mixture was stirred overnight at room temperature. Then the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate, and then the solvent was distilled off. The residue was recrystallized from ethyl acetate - n. hexane to obtain 1.51 of the target compound in the form of white crystals, so pl. 131 - 132 ^o C.

 In the same manner as described in Reference Example 10, the following compounds were prepared.

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. An alternative method of obtaining 2- (2-aminophenylthio) benzonitrile (product of reference example 5, stage 4).

1.25 g of orthoaminothiophenol was dissolved in 10 ml of DMF, followed by the addition of 1.38 g of potassium carbonate. The mixture was preheated at 100 ^° C and, after adding 1.45 g of o-chlorobenzonitrile, it was stirred under argon for 1 h at 100 ^° C. A mixture of ice-water was added to the reaction mixture, and the resulting mixture was extracted in the presence of ethyl acetate. The extract was washed twice with water and dried over magnesium sulfate, after which the solvent was distilled off. The residue was recrystallized from a mixture of n. hexane - isopropyl ether to obtain 1.91 g of the target compound in the form of white crystals, so pl. 88 - 90 ^o C.

 In the same manner as described in Reference Example 11, the following compounds were prepared.

2- (2-aminophenylthio) -6-chlorobenzonitrile;
2- (2-aminophenylthio) -5-chlorobenzonitrile;
2- (2-aminophenylthio) -6-methoxybenzonitrile;
2- (2-aminophenylthio) -4-methoxybenzonitrile;
2- (2-aminophenylthio) -6-methylbenzonitride.

 Reference Example 12. 3- (2-Aminophenylthio) -2- (1H-tetrazol-5-yl) phenol.

0.6 g of 2- / 3-methoxy-2- (1H-tetrazol-5-yl) phenylthio / aniline (obtained by the method described in the reference) was dissolved in a 14 ml of a 1.4 M solution of sodium ethylthiolate in N, N-dimethylformamide Example 7) and the resulting solution was heated under reflux for 6 hours. A mixture of ice-water was added to the reaction mixture, and the resulting mixture was slightly acidified with dilute hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column using 5% methanol chloroform as an eluent to obtain 0.2 g of the target compound as white crystals, mp. 220 - 225 ^o C (decomp.)
In the same manner as described in Reference Example 12, the following compounds were prepared.

 3- (2-aminophenylthio) -4- (1H-tetrazol-5-yl) phenol.

 Reference Example 13. 2- / 2- (Methylamino) phenylthio / benzonitrile

 Stage 1. 2- / 2- (trifluoroacetylamino) phenylthio / benzonitrile.

 2.3 g of 2- (2-aminophenylthio) benzonitrile (prepared in accordance with Reference Example 5, step 4) and 1.1 g of triethylamine were dissolved in 25 ml of methylene chloride, after which 2.2 g of trifluoroacetic anhydride were added dropwise while cooling the system ice and stirring. After completion of the dropwise addition, the mixture was stirred under ice-cooling for 2 hours, after which the solvent was distilled off, and the residue was recrystallized from 50% aqueous ethanol to obtain 2.8 g of the target compound as white crystals.

 Step 2.2: 2- / 2- (N-methyl-N-trifluoroacetylamino) phenylthio / benzonitride.

 2.8 g of 2- / 2- (trifluoroacetylamino) phenylthio) benzonitrile was dissolved in 20 ml of N, N-dimethylformamide, followed by 2.4 g of methyl iodide and 2.4 g of potassium carbonate, and the resulting mixture was stirred at room temperature for 2 h, after which the reaction mixture was diluted with water. The precipitated crystals were collected by filtration, washed with water and aqueous ethanol to obtain 2.8 g of the target compound as white crystals.

 Stage 3. 2- / 2- (methylamino) phenylthio / benzonitride.

 2.8 2- / 2- (N-methyl-N-trifluoroacetylamino) phenylthio / benzonitrile was suspended in 20 ml of ethanol, followed by the addition of 4 ml of a 10% sodium hydroxide solution, and the mixture was heated in a water bath for 5 minutes. After cooling, the crystals were collected by filtration and washed with 50% aqueous ethanol to obtain 1.8 g of the target compound as white crystals.

 Example 1. N- / 2- / 3- / 1- (1H-tetrazol-5-yl) ethoxy / phenoxy / phenyl / -4-hexyloxybenzamide.

 2.1 g of 2- / 3- / 1- (1H-tetrazol-5-yl) ethoxy / phenoxy / aniline and 2.2 g of triethylamine were dissolved in 30 ml of methylene chloride, after which a solution of 1.7 g of 4-hexayloxybenzoyl was added dropwise. chloride in benzene while cooling the system with ice and stirring. The resulting mixture was stirred overnight at room temperature and heated under reflux for 1 h. A mixture of water and ice was added to the reaction mixture, and after the mixture was acidified with dilute hydrochloric acid, the methylene chloride layer was separated. The methylene chloride solution was dried over magnesium sulfate and concentrated, and the oily residue was purified by silica gel column chromatography using a chloroform-methanol mixture (100: 1) as an eluent to obtain 2.2 g of the target compound as a light yellow oil.

NMR spectrum (CDCl ₃ ): 0.7-1.9 (14H, multiplet) 3.91 (2H, triplet, 1 = 6 Hz) 5.70 (1H, quartet, 1 = 7 Hz), 6.4-7.3 (1- H, multiplet), 7.56 (2H, doublet, 1 = 9 Hz), 8.1-8.4 (2H, multiplet), 11 (1H, broad).

 Example 2. N- / 2-3- / 1- (1H tetrazol-5-yl) ethoxy / -phenoxy / phenyl / -4-hexyloxybenzamide, sodium salt.

 2.0 g of N- / 2- / 3- / 1- (1H-tetrazol-5-yl) ethoxy / phenoxy / phenyl / -4-hexyloxybenzamide was dissolved in 30 ml of ether, followed by the addition of a solution of 90 mg of sodium in ethanol and the resulting the mixture was concentrated in vacuo. After adding isopropyl ether, the resulting foamed solid was crushed, filtered and dried to obtain 1.9 g of sodium salt as a white amorphous powder.

Elemental analysis for C ₂₈ H ₃₀ N ₅ O ₄ NaH ₂ O.

 Calculated,%: C - 62.10, H - 5.96, N - 12.93.

 Found,%: C - 62.54, H - 6.57, N - 13.09.

 Example 3. N- / 2- / 3- (1H-tetrazol-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), followed by the addition of 0.44 g of sodium azide and 0.37 g of ammonium chloride and the resulting the mixture was stirred for 1 h at 105-110 ^o C. After cooling, the reaction mixture was diluted with ice-water and acidified with hydrochloric acid. The resulting residue was collected by filtration and recrystallized from ethanol to obtain 1.35 g of the target compound in the form of white crystals, so pl. 158-159 ^o C.

Elemental analysis for C ₂₇ H ₂₉ N ₅ O ₄ .

 Calculated,%: 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-tetrazol-5-yl) phenylthio / phenyl / -4- (4-phenylbutoxy) benzamide.

1.35 g of N- / 2- (2-cyanophenylthio) phenyl / -4- (4-phenylbutoxy) benzamide, 0.55 g of sodium azide and 0.46 g of ammonium chloride were dissolved in 20 ml of DMF, and the mixture was stirred for 5 s at 110 115 ^° C. Then, 0.18 g of sodium azide and 0.15 g of ammonium chloride were added and the mixture was stirred for 2 hours at 110-115 ^° C. After adding an ice-water mixture, the reaction 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 target compound, so pl. 156-159 ^o C.

Elemental analysis for C ₃₀ H ₂₇ N ₅ O ₂ S.

 Calculated,% C - 69.08, H - 5.22, N - 13.43.

 Found,%: C - 68.93, H - 5.45, N - 13.32.

 Example 5. Methyl 4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

1.1 g of methyl 4- / 2- (2-cyanophenylthio) phenylcarbomoyl / phenoxyacetate, 0.85 g of sodium azide and 0.7 g of ammonium chloride were suspended in 10 ml of DMF and the resulting mixture was stirred for 8 hours at 110-120 ^° C. After cooling the reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The resulting precipitate was subjected to chromatographic purification on a column of silica gel (chloroform-ethanol = 50: 1) to obtain 0.4 g of the target compound in the form of white crystals, so pl. 204-205 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S.

 Calculated,%: C - 59.86, H - 4.15, N - 15.18.

 Found,%: C - 59.95, H - 4.23, N - 15.22.

IR spectrum, cm ^-1 (KBr): 3380, 3100-2200, 1760, 1680, 1600, 1580, 1500, 1440, 1300, 1220.

 Example 6. 4- (2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

0.38 g of methyl 4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / -n-phenoxyacetate was suspended in 10 ml of ethanol, followed by the addition of 1 ml of 10% sodium hydroxide solution and the mixture was heated in a water bath within 10 minutes After cooling, the reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The precipitate was collected by filtration and washed with water, ethanol and this acetate to obtain 0.32 g of the target compound in the form of white crystals, so pl. 252-253 ^o C.

Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated%: C: 59.05 H: 3.83 N 15.65.

 Found%: C: 58.93 H: 4.06 N: 15.43.

 Example 7. N- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenyl / -4-hexyloxybenzamide.

1.20 g of N- / 2- (2-cyanophenylthio) phenyl / -4-hexyloxybenzamide was dissolved in 20 ml of DMF, followed by the addition of 0.36 g of sodium azide and 0.30 g of ammonium chloride, and the resulting mixture was stirred at 120 ^° C. within 3 hours. Then the same amounts of sodium azide and ammonium chloride as indicated above were added twice with an interval of 3 hours. Then the reaction mixture was acidified with dilute hydrochloric acid and the resulting crystals were collected by filtration and washed with water. Such crystals were dissolved in chloroform and dried over magnesium sulfate and the solvent was distilled off. The crystals thus obtained were recrystallized from ethyl acetate-n. Hexane to obtain 1.1 g of the target compound as white crystals, mp. 154-156 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₂ S.

 Calculated,%: C: 65.94 H: 5.75 N: 14.79.

 Found,%: C: 66.01 H: 6.03 N: 14.78.

 Example 8. N- / 2- / 2- (1H-tetrazol-5-yl) phenylsulfinyl / phenyl / -4-hexyloxybenzamide.

To a solution of 2.5 g of N- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenyl / -4-hexyloxybenzamide in 30 ml of chloroform was added 1.5 g of 80% m-chlorobenzoic acid and the resulting mixture was stirred for 2 hours at room temperature and then the solvent was distilled off. Then, ethyl acetate - chloroform was added to the residue, and the resulting crystals were collected by filtration and recrystallized from ethanol - chloroform to obtain 0.67 g of the target compound as white crystals, mp. 206-210 ^o C (decomp.)
Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₃ S • 1/4 H ₂ O:
Calculated,%: C: 63.20 H: 5.61 N: 14.17.

 Found,%: C: 63.12 H: 5.74 N: 14.25.

 Example 9. N- / 2- / 2- (1H-tetrazol-5-yl) phenylsulfonyl / phenyl-4-hexyloxybenzamide.

To a solution of 2.0 g of N- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenyl / -4-hexyloxybenzamide in 20 ml of chloroform was added 2.0 g of 80% m-chloroperbenzoic acid and the resulting mixture was stirred for 20 hours at room temperature. The resulting crystals were washed with chloroform and recrystallized from ethanol-chloroform to give 1.44 g of the target compound as white crystals, mp. 203-205 ^o C (decomp.)
Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₄ S:
Calculated,%: 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 a similar manner.

 Example 10. N- / 2- / 3- (1H-tetrazol-5-yl) methoxyphenoxy / phenyl / -4-heptyloxybenzamide.

Melting point: 154-156 ^o C.

Elemental analysis for C ₂₈ H ₃₁ N ₅ O ₄ :
Calculated,%: 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-hexyloxybenzamide.

Melting point: 172-173 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₃ :
Calculated,%: 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-tetrazol-5-yl) methylphenoxy / phenyl-4-hexyloxybenzamide.

Melting point: 99-104 ^o C.

Elemental analysis for C ₂₇ H ₂₉ N ₅ O ₃ :
Calculated,%: 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-hexyloxybenazamide.

Melting point: 142-143 ^o C.

Elemental analysis for C ₂₇ H ₂₉ N ₅ O ₃ :
Calculated,%: 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.

Melting point: 154-155 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₅ O ₂ S:
Calculated,%: C: 66.78 H: 5.60 N: 14.42.

 Found,%: C: 66.82 H: 5.54 N: 14.31.

 Example 15. (E) - / 3-chloro-2 - / - 2 (1H-tetrazol-5-yl) phenylthio / - phenyl / 4- (2-heptenyloxy) benzamide.

Melting point: 149-150 ^o C.

Elemental analysis for C ₂₇ H ₂₆ ClN ₅ O ₂ S:
Calculated,%: C: 62.36 H: 5.04 N: 13.47.

 Found,%: 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.

Melting point: 187-188 ^o C.

Elemental analysis for C ₂₇ H ₂₆ ClN ₅ O ₂ S:
Calculated,%: C: 62.36 H: 5.04 N: 13.47.

 Found,%: 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 ^o C.

Elemental analysis for C ₂₈ H ₂₉ N ₅ O ₃ S:
Calculated,%: 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-phenylbutoxy) benzamide.

Melting point: 145-147 ^o C.

Elemental analysis for C ₃₀ H ₂₆ ClN ₅ O ₂ S • 1/2 H ₂ O.

 Calculated,%: 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-phenylbutoxy / benzamide.

Melting temperature; 175-177 ^o C.

Elemental analysis for C ₃₀ H ₂₆ FN ₅ O ₂ S:
Calculated,% 6 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-tetrazol-5-yl) phenylthio / phenyl / -4-pentyloxybenzamide.

Melting point: 170-171 ^o C.

Elemental analysis for C ₂₅ H ₂₅ N ₅ O ₂ S:
Calculated,%: 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-tetrachol-5-yl) phenylthio / phenyl / 4-hexyloxybenzamide.

Melting point: 191-193 ^o C.

Elemental analysis for C ₂₆ H ₂₆ ClN ₅ O ₂ S:
Calculated,%: 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-heptyloxybenzamide.

Melting point: 157-158 ^o C.

Elemental analysis for C ₂₇ H ₂₉ N ₅ O ₂ S:
Calculated,%: 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-hexenyloxy / benzamide.

Melting point: 177-178 ^o C.

Elemental analysis for C ₂₆ H ₂₅ H ₅ O ₂ S:
Calculated,%: C: 66.22 H: 5.34 N: 14.85.

 Found%: C: 66.39 H: 5.42 N: 14.91.

 Example 24. N- / 2- / 2- (1H-tetrazol-5-yl) phenoxy / phenyl / -4-hexylbenzamide.

Melting point: 159-161 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₃ :
Calculated,%: 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-tetrazol-5-yl) phenylthio / phenyl / -4- (quinolin-2-ylmethoxy / benzamide.

Melting point: 198-200 ^o C.

Elemental analysis for C ₃₀ H ₂₂ N ₆ O ₂ S:
Calculated,%: C: 67.91 H: 4.18 N: 15.85.

 Found,%: C: 67.86 H: 4.49 N: 15.70.

 Example 26. N-2- / 2- (1H-tetrazol-5-yl) phenoxy / phenyl / -4- (quinolin-2-ylmethoxy / benzamide.

Melting point: 244-226 ^o C.

Elemental analysis for C ₃₀ H ₂₂ N ₆ O ₃ • 1/4 H ₂ O.

 Calculated%: C: 69.42 H: 4.37 N: 16.19.

Found%: C: 69.50 H: 4.76 N: 15.82 /
Example 27. N- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenyl / -4- (7-chloroquinoline -2-ylmethoxy / benzamide.

Melting point: 225-226 ^o C.

Elemental analysis for C ₃₀ H ₂₁ CIN ₆ O ₂ S:
Calculated%: C: 63.77 H: 3.75 N: 14.87.

 Found,%: C: 63.33 H: 3.77 N: 14.59.

 Example 28. 4- / 4- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbaioml / phenoxy / butanoic acid.

Melting point: 188 ^o C.

Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₄ S:
Calculated,%: C: 60.62 H: 4.45 N: 14.73.

 Found,%: C: 60.65 H: 4.71 N: 14.78.

 Example 29. N- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenyl / -4 -6 (-hydroxyhexyloxy) benzamide.

Melting point: 192-193 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₃ S:
Calculated,%: C: 63.78 H: 5.56 N: 14.30.

 Found,%: C: 63.76 H: 5.51 N: 14.23.

 Example 30. 4- / 2- / 2- (IH-tetrazol-5-yl) phenoxy / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 123-125 ^o C.

Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ • 1/2 H ₂ O:
Calculated,%: C: 59.99 H: 4.12 N: 15.90.

 Found,%: C: 60.23 H: 4.20 N: 15.94.

 Example 31. 6- / 4- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxy / hexanoic acid.

Melting point: 185-186 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₄ S:
Calculated,%: C: 62.01 H: 5.00 N: 13.91.

 Found,%: C: 61.97 H: 4.97 N: 13.84.

 Example 32. Ethyl 4- / 4- / 2- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxy / butyrate.

Melting points: 173-175 ^o C.

IR spectrum, cm ^-1 (KBr): 3375, 3100-2300, 1735, 1680, 1600, 1580, 1500, 1435, 1250.

 Example 33. Ethyl 6- / 4- (2- / 2- (2H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxy / hexanate.

Melting point: 137-138 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2300, 1730, 1680, 1600, 1575, 1500, 1435, 1245.

 Example 34. N- / 2- / 2- (IH-tetrazol-5-yl) phenoxy / phenyl-4 -5-hydroxyhexyloxy) benzamide.

Melting point: 175-175 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₄ :
Calculated,%: C: 65.95 H: 5.75 N: 14.79.

 Found,%: C: 66.01 H: 5.64 N: 14.91.

 Example 35. 6- / 4- / 2- / 2- (IH-tetrazol-5-yl) phenoxy / phenylcarbamoylphenoxy / hexanoic acid.

Melting point: 153-154 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₅ :
Calculated,%: C: 64.32 H: 5.19 N: 14.42.

 Found,%: C: 63.99 H: 5.22 N: 14.32.

 Example 36. 4- / 4- / 2- / 2- [IH-tetrazol-5-yl / phenoxy / phenylcarbamoli / phenol-xybutanoic acid.

Melting point: 197-198 ^o C.

Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₅ .

 Calculated,%: C: 62.74 H: 4.61 N: 15.24.

 Found%: C: 62.82 H: 4.75 N: 15.11.

 Example 37. N- (2- (2- / IH-tetrazol-5-yl) phenoxy / phenyl / -4 -5-hydroxyhexyloxy / benzamide.

Melting point: 142-144 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₄ • 1/4 H ₂ O:
Calculated,%: C: 65.33 H: 5.80 N: 14.65.

 Found,%: C: 65.39 H: 5.75 N: 14.59.

 Example 38. N- (2- / 2- / IH-tetrazol-5- / phenylthio / phenyl / -4- / 5-hydroxyhexyloxy / benzamide.

Melting point: 161-163 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₃ S:
Calculated,%: C: 63.78 H: 5.56 N: 14.30.

 Found,% C: 63.40 H: 5.56 N: 14.04.

 Example 39. N- (2- / 2- / IH-tetrazol-5-yl) phenylsulfinyl / phenyl-4- / 6-hydroxyhexyloxy / benzamide.

Melting point: 196-198 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₄ S:
Calculated,%: C: 61.77 H: 5.38 N: 13.85.

 Found,% C: 61.33 H: 5.45 N: 13.87.

 Example 40. 6- (4- (2- / 2- / IH-tetrazol-5-yl) phenylsulfinyl / phenylcarbamoyl / phenoxy / hexanoic acid.

Melting point: 235-236 ^o C (decomposition).

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₅ S:
Calculated,% C: 60.10 H: 4.85 N: 13.48.

 Found,%: C: 59.70 H: 4.82 N: 13.24.

 Example 41. 4 - / - / 2- / 2- / IH-tetrazol-5-yl / phenylsulfinyl-phenylcarbamoyl / phenoxy / butyric acid.

Melting point: 254-255 ^o C (div.)
Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₅ S • 1/4 H ₂ O:
Calculated,%: C: 58.11 H: 4.37 N: 14.12.

 Found,%: C: 58.02 H: 4.31 N: 14.20.

 Example 42. 4- (2- (2- / IH-tetrazol-5-yl) phenylsulfinyl / phenyl-carbamoyl / phenoxyacetic acid.

Melting point: 272-274 ^o C.

Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ S • 1/4 H ₂ O:
Calculated,%: C: 56.47 H: 3.77 N: 14.97.

 Found,%: C: 56.45 H: 3.95 N: 15.04.

 Example 43. N- (2- (2- / IH-tetrazol-5-yl) phenylsulfinyl / phenyl / -4- / 5-hydroxyhexyloxy / benzamide.

Melting point: 195-195 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₄ S • 1/4 H ₂ O.

 Calculated,%: C: 61.22 H: 5.43 N: 13.73.

 Found,%: C: 61.16 H: 5.48 N: 13.76.

 Example 44. N- [2- / 2- [IH-tetrazol-5-yl] phenylsulfonyl / phenyl-4- / 6-hydroxyhexyloxy / benzamide.

Melting point: 182-184 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₅ S:
Calculated,%: C: 59.87 H: 5.22 N: 13.43.

 Found,%: C: 59.76 H: 5.38 N: 13.13.

 Example 45. 6- (4- (2- / 2- / IH-tetrazol-5-yl) phenylsulfonyl-phenylcarbamoyl / phenoxy / hexanoic acid.

Melting point: 219-221 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₆ S:
Calculated,%: C: 58.31 H: 4.70 N: 13.08.

 Found,%: C: 58.22 H: 4.69 N: 12.98.

 Example 46. 4- (4- (2- / 2- / IH-tetrazol-5-yl) phenylsulfonyl-phenylcarbamoyl / phenoxy / butyric acid.

Melting point: 238-239 ^o C (decomp.)
Elemental analysis for C ₂₆ H ₂₁ N ₅ O ₆ S:
Calculated,%: C: 56.80 H: 4.17 N: 13.80.

 Found,%: C: 56.76 H: 4.08 N: 14.06.

 Example 47. 4- (2- (2- / IH-tetrazol-5-yl) phenylsulfonyl / phenyl-carbamoyl / phenoxyacetic acid.

Melting point: 222-224 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₆ S:
Calculated,%: C: 55.11 H: 3.57 N: 14.61.

 Found,%: C: 54.97 H: 3.55 N: 14.40.

 Example 48. N- [2- / 2- [IH-tetrazol-5-yl] phenylsulfonyl / phenyl / 4- / 5-hydroxyhexyloxy / benzamide.

Melting point: 170-171 ^o C.

Elemental analysis for C ₂₆ H ₂₇ N ₅ O ₅ S:
Calculated,%: C: 59.87 H: 5.22 N: 13.43.

 Found,%: C: 59.74 H: 5.35 N: 13.28.

 Example 49. 4- (2- (4-) IH-tetrazol-5-yl / phenoxy / phenylcarbamoyl-phenoxyacetic acid.

Melting point: 268-270 ^o C (decomp.).

Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ :
Calculated,%: 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- / IH-tetrazol-5-yl) phenylthio / phenylcarb-molyfetoxy / propionic acid.

Melting point: 207-209 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S:
Calculated,%: C: 59.86 H: 41.15 N: 15.18.

 Found,%: C: 59.61 H: 4.36 N: 15.02.

 Example 51. 2-methyl-2- / 4- / 2- / 2- / IH-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxy // propionic acid.

Melting point: 186-188 ^° C (decomp.).

Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₄ S • 1/4 H ₂ O:
Calculated,%: C: 60.05 H: 4.51 N: 14.59.

 Found,%: C: 60.25 H: 4.69 N: 14.28.

 Example 52. Ethyl 4- / 2- (2- / IH-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 202-203 ^o C.

Elemental analysis for C ₂₄ H ₂₁ N ₅ O ₄ S:
Calculated,% 6 C: 60.62 H: 4.45 N: 14.73.

 Found,%: C: 60.57 H: 4.53 N: 14.71.

 Example 53. Propyl 4-2- / 2- / IH-tetrazol-5-yl / phenylthio / phenyl-carbamoyl / phenoxyacetate.

Melting point: 174-176 ^o C.

Elemental analysis for C ₂₅ H ₂₃ N ₅ O ₄ S:
Calculated,%: C: 61.34 H: 4.74 N: 14.31.

 Found,% C: 61.56 H: 4.84 N: 14.31.

 Example 54. Isoamyl 4- / 2- / 2-1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 120-122 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₅ O ₄ S:
Calculated,%: C: 62.65 H: 5.26 N: 13.53.

 Found,% C: 62.83 H: 5.43 N: 13.62.

 Example 55. Ethyl 4- (2- (2- / 1H-tetrazol-5-yl) phenylsulfinyl / phenylcarbamoyl / phenoxyacetate.

Melting point 215-216 ^o C (decomp.)
IR spectrum, cm ^-1 (KBr): 3700-2200, 1725, 1605, 1495, 1435, 1250.

 Example 56. Ethyl 4- (2- (2- / 1H-tetrazol-5-yl) phenylsulfonyl / phenylcabamoyl / phenoxyacetate.

Melting point: 162-163 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 1740, 1680, 1600, 1500, 1315, 1220.

 Example 57. Ethyl 4- / 4- / 2- / 2- / 1H-tetrazol-5-yl / phenylsulfinyl / phenylcarbamoyl / phenoxy / butyrate.

Melting point: 204-206 ^o C (decomp.)
IR spectrum, cm ^-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 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 3360, 1740, 1670, 1580, 1505, 1325, 1255.

 Example 59. Ethyl 6- / 4- (2- / 2- / 1H-tetrazol-5-yl / phenylsulfinyl / phenylcarbamoyl / phenoxy / hexanoate.

Melting point: 188-189 ^o C.

IR spectrum, cm ^-1 : 3700-2200, 1730, 1640, 1605, 1580, 1520, 1500, 1440, 1255.

 Example 60. Ethyl 6- / 4- / 2- / 2- / 1H-tetrazol-5-yl / phenylsulfonyl / phenylcarbamoyl / phenoxy / hexanoate.

Melting point: 180-181 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 3360, 1725, 1670, 1605, 1580, 1550, 1320, 1255.

 Example 61. Ethyl 4- / 4- (2- / 2- / 1H-tetrazol-5-yl / phenoxy / phenylcarbamoyl / phenoxy / butyrate.

Melting point: 162-164 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2300, 3360, 1730, 1640, 1610, 1510, 1280, 1260.

 Example 62. Ethyl 6- / 4- / 2- / 2- / 1H-tetrazol-5-yl / phenoxy / phenylcarbamoyl / phenoxy / hexanoate.

Melting point: 140-141 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2500, 3350, 2950, 1725, 1640, 1605, 1500, 1260, 1250.

 Example 63. Ethyl 2- / 4- / 2- / 2- / 1H-tetrazol-5-yl (phenylthio / phenylcarbamoyl / phenoxy / propionate.

Melting point: 157-158 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 3380, 1725, 1680, 1600, 1580, 1500, 1435, 1240.

 Example 64. Ethyl 2-methyl-2- / 4- / 2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxy / propionate.

Melting point: 157-158 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 3350, 1720, 1640, 1600, 1490, 1470, 1255.

 Example 65. Ethyl 4- (2- (4- / 1H-tetrazol-5-yl) phenoxy / phenylcarbamoyl / phenoxyacetate.

Melting point: 206-208 ^o C (decomp.)
IR spectrum, cm ^-1 (KBr): 3700-2200, 3420, 1750, 1625, 1605, 1505, 1450, 1220.

 Example 66. Ethyl 4- (2- (2- / 1H-tetrazol-5-yl) phenoxy / phenylcarbamoyl / phenoxyacetate.

Melting point: 162-163 ^o C.

IR spectrum, cm ^-1 (KBr): 3355, 3200-2200, 1745, 1625, 1600, 1495, 1470, 1260, 1220.

 Example 67. Butyl 4- / 2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

5.3 g of 2- / 2- / 1H-tetrazol-5- / phenylthio / aniline was dissolved in a mixture of 6 ml of pyridine and 80 ml of methylene chloride, followed by dropwise addition of 5.4 g of butyl 4-chloroformylphenoxyacetate and the resulting mixture was stirred for nights. Then the solvent was distilled off and the residue was recrystallized from aqueous ethanol, after which it was recrystallized from ethyl acetate to obtain 8.1 g of the target compound as white crystals, mp. 133-135 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₄ S:
Calculated,%: C: 62.01 H: 5.00 N: 13.91.

 Found,%: C: 61.98 H: 5.09 N: 13.87.

 In the same manner as in Example 67, the following compounds were prepared.

 Example 68. Ethyl 4- / 5-chloro-2- [2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 206-208 ^o C.

IR spectrum, cm ^-1 (KBr): 3370, 3100-2300, 1745, 1680, 1600, 1565, 1500, 1410, 1220.

 Example 69. Ethyl 4- / 5-methoxy-2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 195-197 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2300, 1755, 1680, 1600, 1575, 1500, 1450, 1200.

 Example 70. Ethyl 4- / 3-fluoro-2- / 2- / 1H-tetrazol-5-yl / phenylthiro / phenylcarbamoyl / phenoxyacetate.

Melting point: 208-209 ^o C.

IR spectrum, cm ^-1 (KBr): 3390, 3200-2300, 1760, 1680, 1600, 1580, 1500, 1465, 1220.

 Example 71. Ethyl 2-methoxy-4- / 2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 179-181 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3100-2300, 1730, 1680, 1580, 1500, 1435, 1270, 1210.

 Example 72. Butyl 4- / 5-methyl-2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 146-148 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2300, 1740, 1685, 1600, 1570, 1500, 1450, 1210.

 Example 73. Butyl 4- / 2- (2- (1H-tetrazol-5-yl) phenylthio / -5-trifluoromethyl / phenylcarbamoyl / phenoxyacetate.

Melting point: 190-192 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2300, 1760, 1605, 1580, 1530, 1505, 1430, 1325.

 Example 74. Butyl 4- / 5-fluoro-2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 177-179 ^o C.

IR spectrum, cm ^-1 (KBr): 3360, 3200-2300, 1740, 1680, 1585, 1520, 1500, 1430, 1250.

 Example 74. Butyl 4- / 5-fluoro-2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 161-162 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2300, 1740, 1680, 1600, 1500, 1300, 1210.

 Example 76. Ethyl 4- / 3-chloro-2- [2- / 1H-tetrazol-5-yl / phenylthiophenylcarbamoyl / phenoxyacetate.

Melting point: 180-182 ^o C.

IR spectrum, cm ^-1 (KBr): 3360, 3200-2300, 1760, 1670, 1605, 1570, 1500, 1450, 1210, 1180.

 Example 77. Ethyl 3- (2- (2- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 130-133 ^o C.

IR spectrum, cm ^-1 (KBr): 3370, 3200-2200, 1740, 1675, 1575, 1525.

 Example 78. Ethyl 2- / 2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenyl-carbamoyl / phenoxyacetate.

Melting point: 145-146 ^o C.

IR spectrum, cm ^-1 (KBr): 3700-2200, 1760, 1635, 1575, 1520.

 Example 79. Ethyl 4- / 4- (2- / 1H-tetrazol-5-yl / phenylthio / phenyl-carbamoyl / phenoxyacetate.

Melting point: 232-234 ^o C (decomp.)
IR spectrum, cm ^-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 ^o C (decomp.)
IR spectrum, cm ^-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 ^o C.

IR spectrum, cm ^-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 ^o C.

IR spectrum, cm ^-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 ^o C.

IR spectrum, cm ^-1 (KBr): 3380, 3200-2200, 1750, 1670, 1605, 1580, 1520, 1500, 1435, 1300.

 Example 84. Ethyl 3- (2- (4- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 88-90 ^o C.

IR spectrum, cm ^-1 (KBr): 3370, 3200-2200, 1745, 1680, 1650, 1580, 1520, 1490, 1440, 1310, 1200.

 Example 85. Ethyl 2- / 2- / 4- [1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 155-157 ^o C.

IR spectrum, cm ^-1 (KBr): 3450, 3200-2200, 1755, 1635, 1600, 1580, 1520, 1490, 1420, 1315, 1205.

 In the same manner as described in example 6, the following compounds were obtained.

 Example 86. 4- / 5-chloro-2- / 2- [1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 217-220 ^o C.

Elemental analysis for C ₂₂ H ₁₆ ClN ₅ O ₄ • 7/4 H ₂ O:
Calculated,%: C: 51.46 H: 3.83 N: 13.64.

 Found,%: 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 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₅ S:
Calculated,%: C: 57.85 H: 4.01 N: 14.67.

 Found,%: C: 57.63 H: 4.29 N: 14.37.

 Example 88. 4- (4- (2- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 250-251 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: 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-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 257-259 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S • 1/4 H ₂ O:
Calculated,%: C: 58.46; H: 3.90; N: 15.50.

 Found,%: C: 58.43 H: 3.98 N: 15.49.

 Example 90. 3- (2- (2- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 214.5 - 215.5 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: C: 59.05; H: 3.83; N: 5.65.

 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 ^o C.

Elemental analysis for C ₂₂ H ₁₆ FN ₅ O ₄ S • 1/4 H ₂ O:
Calculated,%: C: 56.23 H: 3.54 N: 14.90.

 Found,%: 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 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₅ S:
Calculated,%: C: 57.85 H: 4.01 N: 14.67.

 Found,%: C: 57.72 H: 4.28 N: 14.62.

 Example 93. 3- (4- (2- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 233-234 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: 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 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S • 1/5 H ₂ O.

 Calculated,%: C: 59.40; H: 4.20; N: 15.06.

 Found,%: C: 59.40; H: 4.11; N: 15.06.

 Example 95. 4- (2- (3- / 1H-tetrazol-5-yl) phenoxy / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 179-183 ^o C.

Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ • 1/4 H ₂ O.

 Calculated,%: C: 60.62 H: 4.06 N: 16.07.

 Found,%: C: 60.49 H: 4.28 N: 15.77.

 Example 96. 2- / 2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 191-193 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: C: 59.05; H: 3.83; N: 15.65.

 Found,%: C: 58.84 H: 3.84 N: 15.46.

 Example 97. 4- (2- (2- / 1H-tetrazoyl-5-yl) phenylthio-5-trifluoromethyl / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 275-277 ^o C.

Elemental analysis for C ₂₃ H ₁₆ F ₃ N ₅ O ₄ S • 7/4 H ₂ O.

 Calculated%: 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.

Melting point: 218 - 220 ^o C.

Elemental analysis for C ₂₂ H ₁₆ FN ₅ O ₄ S • 1/2 H ₂ O.

 Calculated,%: C: 55.69 H: 3.61 N: 14.76.

 Found,%: C: 55.83 H: 3.87 N: 14.71.

 Example 99. 4- / 4-methyl-2- / 2- / 1H-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 246 - 248 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S • 1/4 H ₂ O.

 Calculated,%: C: 59.28 H: 4.22 N: 15.03.

 Found,%: C: 59.25 H: 4.37 N: 14.99.

 Example 100. 4- (2- (4- / 1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 252 - 253 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: C: 59.05 H: 8.83 N: 15.65.

 Found,%: C: 58.99 H: 3.88 N: 15.55.

 Example 101. 3- (2- / 4- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 285 - 288 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S • 3/2 H ₂ O.

 Calculated,%: C: 55.69 H: 4.25 N: 14.76.

 Found,%: C: 55.88 H: 4.00 N: 15.06.

 Example 102. 2- / 2- / 4- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 253 - 254 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₄ S:
Calculated,%: C: 59.05 H: 3.83 N: 15.65.

 Found,%: C: 58.98 H: 3.65 N: 15.45.

 Example 103. N- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenyl / -4 - / (1H-tetrazol-5-yl) methoxy / benzamide.

0.77 g of N- / 2- (2-cyanophenylthio) phenyl / -4-cyanomethoxybenzamide (obtained by the method described in Reference Example 6) was dissolved in 10 ml of N, N-dimethylformamide, after which 0.91 g of sodium azide was added and 0.27 g of ammonium chloride and the resulting mixture was stirred for 7 hours at 120 ^° C. After cooling, the reaction mixture was acidified with dilute hydrochloric acid and the precipitated crystals were collected by filtration and washed with water. The crystals thus obtained were recrystallized from ethanol to obtain 0.7 g of the target compound as white crystals, mp. 240 - 242 ^o C (div.)
Elemental analysis for C ₂₂ H ₁₇ N ₉ O ₂ S:
Calculated,%: C: 56.04 H: 3.63 N: 26.74.

 Found,%: C: 56.20 H: 3.70 N: 26.47.

 Example 104. N, N-dimethylcarbamoylmethyl-4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

 1.2 g of 4- / 2- / 2- (1H-tetrazoyl-5-yl) phenylthio / phenylcarbomoyl / phenoxyacetic acid (obtained in Example 6) was dissolved in 15 ml of N, N-dimethylformamide, after which 0.44 g was added. N, N-carbonyldiimidazole while cooling the system with ice and stirring. The resulting mixture was stirred under ice-cooling for 20 minutes, then 0.42 g of N, N-dimethyl glycolamide was added, and the resulting mixture was stirred overnight at room temperature. This reaction was acidified with acetic acid and diluted with water, and the precipitated crystals were collected by filtration, after which it was recrystallized from N, N-dimethylformamide-ethyl acetate to obtain 0.55 g of the target compound as white crystals.

Melting point: 205 - 206 ^o C.

Elemental analysis for C ₂₆ H ₂₄ N ₆ O ₅ S:
Calculated,%: C: 58.64 H: 4.54 N: 15.78.

 Found,%: C: 58.36 H 4.70 N: 15.66.

 The following compound was obtained in the same manner.

 Example 105. N, N-diethylcarbamoylmethyl 4- / 2- / 2- (1H-tetrazol-5-yl) phenyltyl / phenylcarbamoyl / phenoxyacetate.

Melting point: 137 - 139 ^o C.

Elemental analysis for C ₂₈ H ₂₈ N ₆ O ₅ S:
Calculated,%: C: 59.99 H: 5.03 N: 14.99.

 Found,%: C: 59.75 H: 5.19 N: 14.98.

 Example 106. 4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetamide.

 0.53 g of 4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid (obtained in Example 6) was dissolved in 6 ml of N, N-dimethylformamide, after which 0.24 g was added. N, N-carbonyldiimidazole. The resulting mixture was stirred at room temperature for one hour and then poured into a 28% aqueous ammonia solution and the mixture was stirred for 1 hour. The reaction mixture was diluted with water and then acidified with concentrated hydrochloric acid and the separated crystals were collected by filtration and washed with water. The crude crystals thus obtained were recrystallized from a mixture of N, N-dimethylformamide-ethanol to obtain 0.52 g of the target compound as white crystals.

Melting point: 229 - 231 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₈ N ₆ O ₃ S:
Calculated,%: C: 59.18 H: 4/06 N: 18.82.

 Found,%: C: 58.89 H: 4.11 N: 18.46.

 The following compounds were obtained in the same manner.

 Example 107. N, N-diethyl-4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl, phenoxyacetamide.

Melting point: 176 - 178 ^o C.

Elemental analysis for C ₂₆ H ₂₆ N ₆ O ₃ S • 1/2 H ₂ O.

 Calculated,%: C: 61.22 H: 5.34 N: 16.47.

 Found,%: C: 61.27 H: 5.38 N: 16.26.

 Example 108. N, N-dimethyl-4- / 2- / 2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetamide.

Melting point: 189 - 190 ^o C.

Elemental analysis for C ₂₄ H ₂₂ N ₆ O ₃ S.

 Calculated,%: C: 60.75 H: 4.67 N: 17.71.

 Found,%: C: 60.97 H: 4.67 N: 17.90.

 Example 109. Ethyl 4- / 2- / 3-chloro-2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 220 - 222 ^o C (decomp.)
Elemental analysis for C ₂₄ H ₂₀ ClN ₅ O ₄ S:
Calculated,%: C: 54.83 H: 3.35 N: 14.53.

 Found,%: C: 54.97 H: 3.52 N: 14.45.

 Example 110. Butyl 4- / 2- / 4-chloro-2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 156 - 157 ^o C.

IR spectrum, cm ^-1 (KBr): 3370, 3200 - 2200, 1730, 1675, 1600, 1575, 1525, 1495, 1430.

 Example 111. Butyl 4- / 2- / 3-methoxy-2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 216 - 217 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₅ O ₅ S:
Calculated,%: C: 60.77 H: 5.10 N: 13.12.

 Found,%: 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 ^o C.

IR spectrum, cm ^-1 (KBr): 3375, 3200 - 2200, 1755, 1680, 1605, 1580, 1500, 1435, 1300.

 Example 113. Butyl 4- / 2- / 3-methyl-2- (1H-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 150 - 151 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₅ O ₅ S:
IR spectrum, cm ^-1 (KBr): 3375, 3200 - 2200, 1750, 1680, 1605, 1580, 1500, 1435, 1300.

 Example 114. Ethyl 2-chloro-4- / 2 - / - 2 (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 208-209 ^o C (decomp.).

Elemental analysis for C ₂₄ H ₂₀ CIN ₅ O ₄ S:
Calculated,%: C: 56.53 H: 3.95 N: 13.73.

 Found,%: C: 56.34 H: 4.03 N: 13.72.

 Example 115. Butyl 4- / 4-methoxy-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 152-154 ^o C.

Elemental analysis for C ₂₇ H ₂₇ N ₅ O ₅ S:
Calculated,%: C: 60.77 H: 5.10 N: 13.12.

 Found,%: C: 60.73 H: 4.93 N: 12.99.

 Example 116. Butyl 4- / 4-chloro-2- / 2- (IH-tetrazol-5-yl) phenylthiophenylcarbamoyl / phenoxyacetate.

Melting point: 168-170 ^o C.

Elemental analysis for C ₂₆ H ₂₄ CIN ₅ O ₄ S:
Calculated,%: C: 58.04 H: 4.50 N: 13.02.

 Found,%: C: 58.06 H: 4.49 N: 12.99.

 Example 117: Butyl 4- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenyl-N-methylcarbamoyl / phenoxyacetate.

Melting point: 148-150 ^o C.

IR spectrum, cm ^-1 (KBr): 3200-2300, 1760, 1610, 1560, 1475, 1200, 1170.

 Example 118. Ethyl 4- / 2- / 3-hydroxy-2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

0.63 g of 3- (2-aminophenylthio) -2- (IH-tetrazol-5-yl) phenol (prepared according to Reference Example 12) was suspended in 10 ml of toluene, followed by the addition of a solution containing 0.58 g of 4 -chloroformylphenoxyacetate in 2 ml of toluene and the resulting mixture was heated under reflux for 2 hours. Then the solvent was distilled off and the residue was subjected to silica gel column chromatography using 0.5% methanol-chloroform mixture to obtain 0.66 g of the target compounds in the form of white crystals, so pl. 155-157 ^o C.

IR spectrum, cm ^-1 (KBr): 3430, 3700-2200, 1750, 1650, 1600, 1580, 1500, 1440, 1300.

 In the same manner as described in Example 118, the following compounds were prepared.

 Example 119. Butyl 4- / 4-hydroxy-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 162-165 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₅ S.

 Calculated,%: C: 60.10 H: 4.85 N: 13.48.

 Found,% 6 C: 60.03 H: 4.80 N: 13.24.

 Example 120. Butyl 4- / 5-hydroxy-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Melting point: 207-209 ^o C.

Elemental analysis for C ₂₆ H ₂₅ N ₅ O ₅ S 1 / 2C ₂ H ₅ OH:
Calculated,%: 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- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetate.

Mass spectrum (C ₂₄ H ₂₁ N ₅ O ₅ S) M ⁺ : 491.

 In the same manner as described in example 6, the following compounds were obtained.

 Example 122. 4- / 2- / 3-chloro-2- / IH-tetrazol-5-yl / phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 245-247 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₆ CIN ₅ O ₄ S:
Calculated,%: C: 54.83 H: 3.35 N: 14.53.

 Found,%: C: 54.97 H: 3.52 N: 14.45.

 Example 123. 4- / 2- / 4-chloro-2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: not lower than 300 ^o C.

Elemental analysis for C ₂₂ H ₁₆ CIN ₅ O ₄ S • 2H ₂ O:
Calculated% C: 51.02 H: 3.89 N: 13.52
Found% C: 51.31 H: 3.72 N: 13.85
Example 124. 4- / 2- / 3-methoxy-2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 255-256 ^o C (decomp.)
Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₅ S
Calculated,%: 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- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 235-237 ^o C (decomp.)
Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₅ S:
Calculated,%: C: 57.85 H: 4.01 N: 14.67.

 Found,%: C: 57.67 H: 4.20 N: 14.55.

 Example 126. 4- / 2- / 3-methyl-2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 230-232 ^o C (decomp.)
Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S • 1/4 H ₂ O:
Calculated,%: C: 59.28 H: 4.22 N: 15.03.

 Found,%: C: 59.34 H: 4.20 N: 14.82.

 Example 127. 4- / 3-chloro-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 118-122 ^o C.

Elemental analysis for C ₂₂ H ₁₆ ClN ₅ O ₄ S • 5/4 H ₂ O:
Calculated,%: C: 52.38 H: 3.70 N: 13.88.

 Found,%: C: 52.39 H: 3.68 N: 13.93.

 Example 128. 2-chloro-4- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 252-254 ^o C.

Elemental analysis for C ₂₂ H ₁₆ ClN ₅ O ₄ S:
Calculated,%: C: 54.83 H: 3.35 N: 14.53.

 Found,%: C: 54.83 H: 3.48 N: 14.36.

 Example 129. 4- / 4-chloro-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 200 ^o C.

Elemental analysis for C ₂₂ H ₁₆ ClN ₅ O ₄ S • 3/4 H ₂ O:
Calculated,%: C; 53.34 H: 3.56 N: 14.14.

 Found,%: 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: 244-246 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₅ S:
Calculated,%: C: 57.85 H: 4.01 N: 14.67.

 Found,%: C: 57.79 H: 4.12 N: 14.65.

 Example 131. 4- / 2- / 2- (IH-tetrazol-5-yl) phenylthio / phenyl-N-methyl-carbamoyl / phenoxyacetic acid.

Melting point: 248-250 ^o C.

Elemental analysis for C ₂₃ H ₁₉ N ₅ O ₄ S:
calculated,%: C: 59.86 H: 4.15 N: 15.18.

 Found,%: C: 59.95 H: 4.12 N: 15.06.

 Example 132. 4- / 4-hydroxy-2- / 2- (IH-tetrazol-5-yl) phenylthiophenylcarbamoyl / phenoxyacetic acid.

Melting point: 228-230 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ S • 3/4 H ₂ O.

 Calculated,%: C: 55.40 H: 3.91 N: 14.68.

 Found,%: C: 55.65 H: 3.84 N: 14.57.

 Example 133. 4- / 5-hydroxy-2- / 2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 272-275 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ S • 1/3 H ₂ O:
Calculated,%: C: 56.28 H: 3.76 N: 14.92.

 Found,%: C: 56.52 H: 3.74 N: 14.64.

 Example 134. 4- / 2- / 3-hydroxy-2- (IH-tetrazol-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Melting point: 240-242 ^o C (decomp.)
Elemental analysis for C ₂₂ H ₁₇ N ₅ O ₅ S:
Calculated,%: C: 57.01 H: 3.70 N: 15.11.

 Found,%: C: 56.82 H: 3.74 N: 14.92.

 Example 135. 4- / 2- / 5-hydroxy-2- (1H-tetrazod-5-yl) phenylthio / phenylcarbamoyl / phenoxyacetic acid.

Mass spectrum (C ₂₂ H ₁₇ N ₅ O ₅ S) M ⁺ : 463.

 The following pharmacological test data are intended to illustrate the usefulness of some representatives of the compounds of the present invention.

 Test methods.

1) Leukotriene D ₄ binding assay (ITD ₄ ).

Initially, 0.2 pmol of ³ H-ITD ₄ and 100 μg of the membrane fraction obtained from light guinea pigs were incubated at 25 ^° C for 1 h and then the reaction mixture was filtered through a glass filter. The radioactivity of ³ H-ITD ₄ bound to the membrane remaining on the glass filter was measured and the obtained value was considered as total binding (total).

Similarly, 100 μg of the membrane fraction was incubated in the presence of 0.2 pmol of ³ H-ITD ₄ in the presence of a large excess of cold ITD (0.1 nmol) at 25 ^° C for 1 h and the radioactivity of ³ H-ITD ₄ bound to the membrane was determined, which was considered as non-specific binding (NSB).

The specific binding of (SB) ³ H-ITD _{4 was} calculated in accordance with expression (1).

B = total -NSB (1)
In order to study the effect of the test substance on the binding of the ITD ₄ receptor, the test compound was added in the determination of total binding and the total binding was determined in the presence of the test substance (total '). Percent inhibition was calculated according to expression (2).

(General - General ') / SB x 100
2) Schulz-Dale Reaction (SD).

 In a passive state, guinea pigs were immunized with anti-BSA serum albumin (BSA), rabbit serum, after which they were killed by bleeding and the trachea was removed. Samples of the tracheal chain were prepared according to the method of Takagi et al. (K. Takagi, I. Takayanagi, and K. Fuji: Chem Pharm Bull, 6, 716-720 (1958).

Each tracheal muscle sample was suspended in a Magnus bath containing 10 ml Tyrode solution at 37 ^° C and, after stabilization, the contractions induced by 10 ^-5 M histamine were measured.

After washing and stabilization, the contractions induced by the antigen in the presence of the test compound and 10 ^-5 M mepiramine were measured. From the percentage of the number of contractions under the antigen-antibody reaction, the number of contractions under the antigen-antibody reaction and the number of contractions induced by the action of 10 ^-5 M histamine, the percent inhibition relative to the control value was determined.

 (3) Effect on experimental asthma caused by the action of endogenous leukotriene (IT).

 Mepiramine (5 mg / kg), propranolol (0.1 mg / kg) or indomethacin (1 mg / kg) was administered intravenously in guinea pigs passively immunized with rabbit anti-BSA, and antigen (BSA) was administered intravenously after 5 minutes. The resulting respiratory contraction reaction was determined by the Konzette-Rossler method (N. Konzet and R. Rossler: R .: Naunyn Schmiederbergs Arch Exp. Pathol Pharmak. 195, 71 - 74 (1940).

 The test compound was suspended in 0.5% methylcellulose and administered orally 3 hours after antigen administration. Taking the reaction of the complete attenuation of the respiratory cannula when it is closed with a clamp for 100 contractions, we determined the percentage of the maximum contractions under the action of the antigen-antibody reaction.

 From the obtained value, the percent inhibition under the action of the test compound relative to the control value was calculated.

 (4) Effect on experimental asthma.

 The reaction of breathing difficulties to the intravenous use of benzylpenicilloyl antigen - bovine serum albumin in guinea pigs passively immunized with anti-benzylpenicillol-bovine gamma globulin guinea pig serum was determined by the Konzett-Rossler method.

 The test compound was suspended in 0.5% methylcellulose and administered orally, and after 3 hours, the breathing difficulties caused by the antigen-antibody reaction were determined. Based on the reaction of complete blockage of the air cannula under the action of the clamp, which was evaluated as 100%, the maximum blockage of the blockage of respiration (in percent) under the influence of the antigen-antibody reaction was determined. From the obtained value, the percent inhibition under the action of the test compound was determined in comparison with the control value. The results are presented in the following table. From these results, it is clear that the conclusion about the effectiveness of the compounds of the present invention.

 5) Acute toxicity.

 Six week old ddy mice were used after fasting for 24 hours. A suspension of the compound of Example 7 of the present invention in physiological saline containing 0.5% methylcellulose was administered orally. After that, the animals were kept under regular conditions of the agricultural compound and the general symptoms of the disease and mortality were observed for 2 weeks.

The results show that the compound of Example 7 of the present invention is moderately toxic with an ID ₅₀ value of at least 1 g / kg.

 Two grams of the compound of Example 6 of the present invention was weighed and thoroughly mixed with 70 g of lactose and 30 g of corn starch. After this, 25 ml of a 16% hydroxypropyl cellulose solution was added with stirring, and the mixture was granulated. The granules were dried and sampled by size. Then 2 g of magnesium stearate and 2 g of talc were added and mixed with granules, after which the resulting composition was subjected to compression molding on a tabletting machine to obtain tablets (each containing 2 mg of the compound of Example 6 of the present invention, 70 mg of lactose, 30 mg corn starch, 4 mg of hydroxypropyl cellulose, 2 mg of magnesium stearate and 2 mg of talcum based on a total tablet weight of 110 mg).

 Preparative Example 2. In the same manner as in Preparative Example 1, tablets were prepared, each containing 2 mg of the compound of Example 7 of the present invention, 70 mg of lactose, 30 mg of wheat starch, 4 mg of hydroxypropyl cellulose, 2 mg of magnesium stearate and 2 mg of talc per 100 mg.

 Preparative Example 3. In the same manner as in Preparative Example 1, tablets were prepared, each containing 2 mg of the compound of Example 67 of the present invention, 70 mg of lactose, 30 mg of wheat starch, 4 mg of hydroxypropyl cellulose, 2 mg of magnesium stearate and 2 mg of talc in 100 mg of the substance.

 Preparative Example 4. A powder containing 0.1% of the compound of Example 6 of the present invention was obtained by mixing 990 mg of lactose with 10 mg of the compound.

 Preparative Example 5. A powder containing 0.1% of the compound of Example 7 of the present invention was obtained in the same manner as described in Preparative Example 4.

 Preparative Example 6. A powder containing 0.1% of the compound of Example 67 of the present invention was obtained in the same manner as described in Preparative Example 4.

Claims (8)

1. Derivatives of tetrazole of General formula I

in which A is a single bond or oxygen;
R ¹ is alkenyl with 2 to 7 carbon atoms, phenylalkyl with 7 to 10 carbon atoms or alkyl with 1 to 6 carbon atoms, optionally substituted with a —COOR ² group, in which R ² is hydrogen or alkyl with 1 to 6 carbon atoms, optionally substituted by the group —CONR ³ R ⁴ in which R ³ and R ⁴ are the same or different and each represents hydrogen or alkyl with 1 to 4 carbon atoms;
or their pharmaceutically acceptable salts.  2. The compound according to claim 1, which is 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetic acid.  3. The compound of claim 1, which is N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4- (4-phenylbutoxy) benzamide.  4. The compound according to claim 1, which is N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4-hexyloxybenzamide.  5. The compound according to claim 1, which is (E) -N- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenyl] -4- (2-heptenyloxy) benzamide.  6. The compound according to claim 1, which is butyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate.  7. The compound according to claim 1, which is N, N-diethylcarbamoylmethyl 4- [2- [2- (1H-tetrazol-5-yl) phenylthio] phenylcarbamoyl] phenoxyacetate.  8. An antiallergic composition comprising an active agent and a pharmaceutically acceptable excipient, characterized in that as the active agent it contains a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof in an effective amount. Priority on points and signs:
06.22.90 A is a single bond or oxygen; R ¹ is alkenyl, phenylalkyl or alkyl optionally substituted with —COOR ² , where R ² is hydrogen or alkyl;
01/31/91 for PP. 2-5: R ¹ is alkyl substituted with —COOR ² , where R ² is alkyl, substituted with —CONR ³ R ⁴ , where R ³ and R ⁴ are the same or different and each represents hydrogen or alkyl, and claims 6 and 7.1

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