RU2144533C1 - Derivatives of tetrazole, method of their synthesis and pharmaceutical compositions based on them - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention describes the novel derivatives of tetrazole of the general formula (I)

Description

 The invention relates to a new derivative of tetrazole having the effect of lowering blood sugar and lipid levels, as well as to an agent containing it for use in the treatment of diabetes and hyperlipemia.

 Various biguanide compounds and sulfonylureas are used as agents for treating diabetes. However, the use of biguanide compounds is currently difficult, because they cause milk acidosis, and sulfonylureas, which have a strong effect on lowering blood sugar, often cause severe hypoglycemia and require special attention when used. Derivatives of tetrazole with substituents at position 5 are known. For example, in Journal of Medicinal Chemistry, 35, p. 944 (1992) describe a number of tetrazole derivatives substituted at position 5 with an effect on lowering blood glucose. However, the activity of these compounds is unsatisfactory.

 An object of the present invention is to search for 5-substituted tetrazole derivatives having a stronger effect on lowering blood glucose and lipid levels. It has been found that the introduction of a phenyl group or a pyridyl group substituted with an alkoxy group containing an optionally substituted tetracyclic residue as a substituent at position 5 significantly increases activity. Thus, the aim of the invention is to increase the activity of tetrazole derivatives.

где n = 1, 2, 3; A - необязательно замещенный гетероциклический остаток; Y - бивалентный углеводородный остаток; а X представляет CH или N, или их фармацевтически приемлемые соли. Данные соединения позволяют значительно снизить содержание сахара и липида сахара в крови и могут использоваться в новом средстве для лечения диабета или гиперлипемии, содержащем в качестве эффективного компонента производное тетразола с формулой I или его фармацевтически приемлемую соль.The goal is achieved by these derivatives of tetrazole of the formula I

where n = 1, 2, 3; A is an optionally substituted heterocyclic radical; Y is a bivalent hydrocarbon residue; and X represents CH or N, or their pharmaceutically acceptable salts. These compounds can significantly reduce blood sugar and sugar lipid levels and can be used in a new drug for the treatment of diabetes or hyperlipemia containing, as an effective component, a tetrazole derivative with the formula I or a pharmaceutically acceptable salt thereof.

где каждый символ имеет определенное выше значение, с азидом металла.Derivatives of tetrazole and formula I are prepared by reacting a compound of formula II

where each symbol has the same meaning as above, with metal azide.

In the formula I, it is preferable that the benzene ring or the pyridine ring be substituted with the A- (CH ₂ ) _n —O— fragment in the para position relative to the point of attachment of the —Y— fragment.

 In the above formulas I and II, a heterocyclic residue represented by the symbol A, which 1) represents a five-membered ring, 2) represents a heterocyclic ring containing at least one nitrogen atom, 3) represents an aromatic ring, is preferred a ring with an unsaturated bond, 4) optionally contains, as a ring forming atom, two or more nitrogen atoms, and in addition to nitrogen atoms, optionally contains heteroatoms such as an oxygen atom and a sulfur atom, and 5 ) may optionally have a substituent at possible positions in the ring. Examples of the heterocyclic residue represented by A include pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl), triazolyl (1,2,3-triazol-4-yl, 1, 2,4-triazol-3-yl), tetrazolyl, oxazolyl (2-oxazolyl, 4-oxazolyl) and thiazolyl-2- (thiazolyl, 4-thiazolyl).

 These heterocyclic residues may optionally have one or more substituents at possible ring positions. Substituents may be hydrocarbon residues, heterocyclic compound residues or amino groups, which may optionally contain additional substituents.

These hydrocarbon residues include aliphatic hydrocarbon residues, alicyclic hydrocarbon residues, alicyclic-aliphatic hydrocarbon residues, aromatic-aliphatic hydrocarbon residues, and aromatic hydrocarbon residues. Examples of these aliphatic hydrocarbon residues include saturated aliphatic hydrocarbon residues with 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl , hexyl, isohexyl, heptyl and octyl; as well as residues of C _2-8 unsaturated aliphatic hydrocarbons with 2-8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1 pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethenyl , 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentenyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiinyl 5-hexynyl, 1-heptinyl and 1-octynyl. Among them, aliphatic hydrocarbons with a carbon number of not more than 4 are preferred. Examples of said residues or alicyclic hydrocarbons include residues of saturated alicyclic hydrocarbons with a carbon number of 3 to 7, as well as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as residues C _5-7 unsaturated alicyclic hydrocarbon residues with 5-7 carbon atoms, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-tsiklogeksenil, 1-cycloheptenyl, 2-tsiklog ptenil, 3-cycloheptenyl and 2,4-cycloheptadienyl. Among them, residues of alicyclic hydrocarbons with 5 and 6 carbon atoms are preferred. Examples of alicyclic-aliphatic hydrocarbon residues include, together with the residues formed by bonding the above alicyclic hydrocarbon residues to aliphatic hydrocarbon residues, residues with 4 to 9 carbon atoms such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethylmethyl 3 , cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl and cycloheptylethyl. Examples of these aromatic aliphatic hydrocarbon residues include phenylalkyls having 7 to 9 carbon atoms such as benzyl, phenethyl, 1-phenylethyl, 3-phenyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; and also naphthylalkyl having 11 to 13 carbon atoms such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl and β-naphthylethyl. Examples of these aromatic hydrocarbon residues include phenyl and naphthyl (α-naphthyl, β-naphthyl).

 The specified heterocyclic group is a 5-6 membered ring, which in addition to carbon atoms contains 1-3 atoms selected from N, O and S as atoms forming a ring bonded through carbon atoms. Specific examples of the heterocyclic group include heterocyclic groups such as thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (2 -thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrimidinyl (2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl and 6-pyridazinyl); as well as a saturated heterocyclic group such as piperidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (2-morpholinyl) and tetrahydrofuryl (2-tetrahydrofuryl, 3-tetrahydrofuryl, etc.).

 An amino group may be substituted. By a substituted amino group is meant an N-monosubstituted amino group and an N, N-disubstituted amino group.

 "N-monosubstituted amino group" means an amino group with one substituent. Examples of substituents include a lower alkyl group (e.g., a group with 1-4 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, etc.), a cycloalkyl group (e.g., from 3-7 carbon atoms such as cyclopentyl, cyclohexyl, etc.), an aryl group (e.g. phenyl, naphthyl, etc.), an aromatic heterocyclic group (e.g. pyridyl, thienyl, furyl, oxazolyl, thiazolyl, etc. ), a non-aromatic heterocyclic group (e.g. piperidinyl, pyrrolidinyl, morpholinyl, etc.), an arylalkyl group (e.g. benz l, phenethyl, etc.), an acyl group (e.g., acetyl, propionyl, etc.), a carbamoyl group, an N-monosubstituted carbamoyl group (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, etc. d.), N, N-disubstituted carbamoyl group (e.g. N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N, N-diethylcarbamoyl, etc.), lower alkoxycarbonyl group (e.g., from 2-5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a hydroxy group, a lower alkoxy group (for example, a group with 1-4 carbon atoms, such as labels si, ethoxy, propoxy, butoxy, etc.), as well as an arylalkyloxy group (for example, benzyloxy, phenethyloxy, naphthyloxy, etc.).

 "N, N-disubstituted amino group" means an amino group with two substituents. Examples of substituents include, on the one hand, mainly those indicated for the aforementioned “N-monosubstituted amino group”, and on the other hand, an alkyl group, a cycloalkyl group, an aryl group and an arylalkyl group. In addition, in some cases, two substituents can form a cyclic amino group, closed through a nitrogen atom. Examples of such a cyclic amino group include 1-azetidini-, 1-pyrrolidino-, piperidino-, morpholino-, piperazino-group, as well as a piperazino-group containing in position 4, for example, a lower alkyl group (for example, with 1-4 carbon atoms, such as methyl , ethyl, propyl, etc.), an arylalkyl group (e.g., benzyl, phenethyl, naphthylmethyl, etc.) or an aryl group (e.g., phenyl, naphthyl, etc.).

 The aforementioned hydrocarbon residue or the residue of the heterocyclic ring as substituents in the heterocyclic residue A may have a substituent or substituents at possible positions. When the hydrocarbon residue contains an alicyclic group or when the heterocyclic ring residue is saturated, each of them may contain from one to three lower alkyl groups with 1-3 carbon atoms (e.g. methyl, ethyl, propyl and isopropyl) at the ring (including ring atoms) . In addition, when the hydrocarbon residue contains an aromatic hydrocarbon residue or when the heterocyclic group is unsaturated, they may contain from 1 to 4 identical or different substituents. These substituents include halogens (fluorine, chlorine, iodine), hydroxy, cyano, nitro, trifluoromethyl groups, lower alkoxy groups (for example, groups with 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and butoxy), a lower alkyl group (for example, groups with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl), a lower alkoxycarbonyl group (for example, groups with 2-4 carbon atoms, such as methoxycarbonyl , ethoxycarbonyl and propoxycarbonyl), lower alkylthio group (for example, groups with 1-3 carbon atoms kind, such as methylthio, ethylthio, propylthio and isopropylthio), and a lower alkylamino group (e.g., a group having 1-4 carbon atoms such as methylamino, ethylamino and dimethylamino).

When the heterocyclic residue depicted by A contains two or more hydrocarbon residues as substituents, and when these hydrocarbon residues are located at adjacent positions of the aromatic 6 membered heterocyclic ring, they can be joined together to form a fused ring. This means that two hydrocarbon residues bind to each other with the formation of a saturated or unsaturated bivalent linear hydrocarbon residue with 3-5 carbon atoms. Specific examples of a linear hydrocarbon residue include —CH ₂ CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -, —CH = CHCH ₂ -, —CH = CH -CH = CH-, -CH = CH-CH = CH-CH ₂ and -CH = CH-CH ₂ CH ₂ CH ₂ -.

где B¹ представляет атом серы, атом кислорода или группу NR [где R обозначает водород, низшую алкильную группу (например, группы с 1-3 атомами углерода, такие как метил и этил) или арилалкильную группу (например, бензильную группу и фенэтил)]; а B² представляет атом азота или -C-R² {(R² - водород или низшая алкильная группа, необязательно замещенная гидроксильной группой); R¹ - водород, необязательно замещенный углеводородный остаток или гетероциклический остаток; при условии, что R¹ и R² могут быть объединены друг с другом и образовывать конденсированное кольцо, если R¹ соединен с одним из образующих кольцо атомов углерода, соседним с атомом углерода, при котором находится заместитель R²}. Углеводородный остаток, гетероциклический остаток, изображенный как R¹ и заместители в этих группах те же, что были описаны выше для 5-членного гетероциклического остатка.Of the heterocyclic residues represented by the symbol A, those represented by the formula are preferred.

where B ¹ represents a sulfur atom, an oxygen atom or an NR group [where R is hydrogen, a lower alkyl group (for example, groups with 1-3 carbon atoms such as methyl and ethyl) or an arylalkyl group (for example, a benzyl group and phenethyl)] ; and B ² represents a nitrogen atom or —CR ² {(R ² is hydrogen or a lower alkyl group optionally substituted with a hydroxyl group); R ¹ is hydrogen, an optionally substituted hydrocarbon residue or a heterocyclic residue; provided that R ¹ and R ² can be combined with each other and form a condensed ring if R ^{1 is} connected to one of the ring-forming carbon atoms adjacent to the carbon atom at which the substituent R ² } is located. The hydrocarbon residue, the heterocyclic residue depicted as R ¹ and the substituents in these groups are the same as described above for the 5-membered heterocyclic residue.

Examples of a lower alkyl group designated R ² are groups containing from 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and pentyl; preference is given to groups containing 1-3 carbon atoms. Although this alkyl group may contain a hydroxy group in one of the possible positions, the α-position is particularly preferred. When B ² is CR ² and R ² is hydrogen, the ring may be substituted with R ¹ at position B ² . This heterocyclic residue is bonded via a suitable ring atom, and a group bonded via a carbon atom adjacent to the nitrogen atom is preferred. For example, when B ¹ is NR, B ² is CR ² and R ² is hydrogen, a group (III) linked via B is also a preferred example.

[где R¹ и R² имеют указанные выше значения; каждый из R³ и R⁴ представляет водород, необязательно замещенный углеводородный остаток или необязательно замещенный гетероциклический остаток, и они могут путем связывания друг с другом образовывать конденсированное кольцо; B - атом кислорода или серы] . Углеводородный остаток или гетероциклический остаток, изображенные как R³ или R⁴, а также заместители в них те же, что описанные выше для остатка ароматического 5-членного гетероциклического кольца, R³ и R⁴ могут образовывать конденсированное кольцо, такое же, как конденсированное кольцо, образованное остатком ароматического 5-членного гетероциклического кольца, имеющего два углеводородных остатка как заместители в соседних положениях.Among the heterocyclic groups represented by the above formula, thiazolyl or oxazolyl represented by the formula are particularly preferred.

[where R ¹ and R ² have the above meanings; each of R ³ and R ⁴ represents hydrogen, an optionally substituted hydrocarbon residue or an optionally substituted heterocyclic residue, and they can form a fused ring by bonding to each other; B is an oxygen or sulfur atom]. The hydrocarbon residue or heterocyclic residue depicted as R ³ or R ⁴ , as well as their substituents, are the same as those described above for the residue of the aromatic 5-membered heterocyclic ring, R ³ and R ⁴ can form a fused ring, the same as a fused ring formed by the residue of an aromatic 5-membered heterocyclic ring having two hydrocarbon residues as substituents in neighboring positions.

 The ring containing X as its constituent atom is a benzene ring when X is CH, or a pyridine ring when X is N. Preferably X is CH. The symbol n = 1, 2, 3, preferably 1 or 2. The bivalent hydrocarbon residue represented by the Y symbol may be linear or branched, may be saturated or unsaturated, and typically includes alkylenes and alkenylenes containing from 1 to 5 carbon atoms. Alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,3-propylene, 1-methyl-1,2-ethylene and 1,4-butylene. Alkenylene include -CH = CH-CH = CH-, etc. Among them, 1,3-propylene and 1,4-butylene are preferred.

 Compound I of the present invention contains an acidic nitrogen atom in its tetrazole ring or a basic nitrogen atom when it contains a pyridine ring, and thus includes salts with acids and bases. As such salts, pharmaceutically acceptable salts are preferred, examples of which are salts with inorganic bases, salts with organic bases, salts with organic acids and salts with basic or acid amino acids. Preferred examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt or magnesium salt; as well as aluminum salt and ammonium salt. Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N-dibenzylethylenediamine. Preferred examples of salts include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid. Preferred examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or para-toluenol. Preferred examples of salts with a basic amino acid include salts with arginine, lysine or ornithine, and preferred examples of salts with an acid amino acid include salts with aspartic acid or glutamic acid.

 Compound I of the present invention or pharmaceutically acceptable salts thereof have hypoglycemic activity and low toxicity. For example, when the compound of Example 1 was orally administered to mice for 4 days in an amount of 15 mg / kg, there were no changes in body weight or in liver weight compared to control trials. In addition, none of the test animals was killed with the oral administration of the compound obtained in example 14, with a dose of 100 mg / kg or with its intraperitoneal administration with a dose of 50 mg / kg. The compounds of this invention can be used as therapeutic agents for diabetes and hyperlipemia in mammals, including humans. Compound I can be used orally or non-orally in the form of solid compositions, such as tablets, capsules, granules or powders, or as liquid compositions, such as syrups or injectable preparations prepared using pharmaceutically acceptable carriers.

 As pharmaceutically acceptable carriers, conventional organic or inorganic carriers for pharmaceutical preparations are used, more specifically, for example, fillers, lubricants, binders, and disintegrants for solid preparations, as well as solvents, solubilizers, suspending agents, isotonic agents, buffering agents and local agents anesthesia. In addition, additives, such as antiseptics, antioxidants, tinting agents and sweeteners, are additionally used if necessary. Preferred examples of fillers include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light silica. Preferred examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silicon dioxide. Preferred examples of binders include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Preferred examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium salt, crosscarmellose sodium and carboxymethyl starch derivative sodium. Preferred examples of solvents include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, tri-ethanolamine, sodium carbonate and sodium citrate. Preferred examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzetonium chloride, glycerol monostearate, as well as hydrophilic polymers, polyvinyl hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose and methyl cellulose hydroxymethyl cellulose cellulose hydroxymethyl cellulose methyl sulfonate hydroxyethyl cellulose and hydroxypropyl cellulose. Preferred examples of isotonic agents include sodium chloride, glycerin and D-mannitol. Preferred examples of buffering agents include buffers of phosphates, acetates, carbonates and citrates. Preferred examples of local anesthetics include benzyl alcohol. Preferred examples of antiseptics include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydrate acid and sorbic acid. Preferred examples of antioxidants include sulfites and ascorbic acid.

 Compound I is usually used orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders and granules, however, in a number of possible cases, it can be used in a way different from the oral method in the form of, for example, injectable preparations, suppositories or balls. The daily oral dose for adults is in the range of 0.05 to 10 mg / kg; it is preferable to divide it into one to three daily doses.

 Compounds I of the present invention are prepared as follows.

(Method A)
The tetrazole derivative I is obtained by reacting a nitrile derivative II with an azide compound. The reaction of converting compound II to compound I is carried out, for example, in accordance with the method described in Journal of American Chemical Society, 80, p. 3908 (1958), by reacting compound II with sodium azide and ammonium chloride in N, N-dimethylformamide. The corresponding amounts of ammonium chloride and sodium azide are in the range from 1 to 7 mol, preferably from 1 to 5 mol, based on 1 mol of compound II. This reaction is carried out at temperatures ranging from 50 to 180 ^o C for 1-50 hours. In addition, the reaction of the conversion of compound II to compound I can also be carried out, for example, in accordance with the method described in Journal of Organic chetistru, 56, p . 2395 (1991) by reacting compound II with trimethyltin azide or tributyltin azide, followed by acid treatment.

 The tetrazole derivatives thus obtained and their salts can be isolated and purified by known separation and purification means, such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer and chromatography.

[где Y¹ - ненасыщенный бивалентный углеводородный остаток, Y² - насыщенный бивалентный углеводородный остаток, а остальные символы имеют описанные выше значения].(Method B)

[where Y ¹ is an unsaturated bivalent hydrocarbon residue, Y ² is a saturated bivalent hydrocarbon residue, and the remaining symbols have the meanings described above].

An unsaturated bivalent hydrocarbon residue depicted as Y ¹ is an unsaturated residue depicted as Y, and a saturated bivalent hydrocarbon residue depicted as Y is a saturated residue depicted as Y.

In this method, compound II among the compounds obtained by method A is reduced to form compound I-2. Although this reduction reaction can be carried out per se in a known manner, it is advantageous to carry out it by catalytic hydrogenation using a metal catalyst. In accordance with a conventional method, this catalytic hydrogenation is carried out in a solvent in the presence of a catalyst in a hydrogen atmosphere at a pressure of from 1 to 150 atmospheres. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane, ethyl acetate, acetic acid or a mixture of these solvents. For a favorable reaction, a transition metal such as palladium, platinum or rhodium, for example, is used as a catalyst. The reaction temperature ranges from 0 to 100 ^o C, preferably from 10 to 80 ^o C, and the reaction time is from 0.5 to 50 hours

 The tetrazole derivatives thus obtained and their salts can be isolated and purified using conventional means such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer and chromatography.

 Nitrile derivatives II used as starting material in the method of this invention can be obtained, for example, as follows.

[в формуле IV Z обозначает атом галогена, в формуле VIII-1 Q обозначает удаляемую группу, а остальные символы имеют определенные выше значения].(Method B)

[in formula IV, Z represents a halogen atom, in formula VIII-1 Q represents a leaving group, and the remaining symbols have the same meanings as above].

 By a halogen atom represented by Z is meant fluoro, chloro, bromo and iodo. By the leaving group represented by the symbol Q, among others are meant, for example, methanesulfonyloxy and para-toluenesulfonyloxy groups, in addition to halogen atoms, including chlorine, bromine and iodine.

 The preparation steps, including the condensation of compound III with compound IV to give compound V, which is then converted to the aldehyde derivative VI-1, are carried out in accordance with methods described, for example, in Chemical and Pharmacentical Bulletin, 39, p. 1440 (1991) and Journal of Medicinal Chemistry, 35, p. 2817 (1992).

After this, compound VI-1 is reduced to give alcohol VII-1. This reduction can be carried out by a known method, for example, reduction using a metal hydride, reduction using a metal hydride complex, reduction using diborane and substituted by boron, as well as catalytic hydrogenation. In other words, this reaction is carried out by treating compound VI-1 with a reducing agent. Examples of reducing agents include, but are not limited to, a metal hydride complex such as an alkali metal borohydride (eg, sodium borohydride and lithium borohydride); a metal hydride complex such as lithium aluminum hydride; a metal hydride such as sodium hydride; a metal or metal salt, such as an organotin compound (e.g. triphenyltin hydride), a nickel compound and a zinc compound; a catalytic reducing agent using a transition metal catalyst such as palladium, platinum and rhodium, and hydrogen; as well as diborane. This reaction is carried out in an organic solvent which does not affect the reaction. Use a solvent adequately selected depending on the types of reducing agent from, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; amides, such as N, N-dimethylformamide; or mixtures of these solvents. The reaction temperatures range from -20 to 150 ^° C., particularly preferably from 0 to 100 ^° C. The reaction time is from about 1 to 24 hours.

Thereafter, compound VII-1 is reacted with a halogenating agent or with a sulfonating agent to obtain compound VII-1. As the halogenating agent, it is preferable to use, for example, hydrochloric acid, thionyl chloride and phosphorus tribromide; in this case, compound VIII-1 is obtained, where Q is chloro or bromo. This reaction is carried out in a suitable inert solvent (for example, benzene, toluene, xylene, chloroform and dichloromethane) or an excessive amount of halogenating agent is used as a solvent at temperatures in the range from -10 to 80 ^° C. The amount of halogenating agent used is 1-20 mol relative to compound VII-1. As the sulfonating agent, it is preferable to use, for example, methanesulfonyl chloride, paratosyl chloride and benzenesulfonyl chloride; Compound VIII-1 is obtained, where Q is methanesulfonyloxy, para-toluenesulfonyloxy and benzenesulfonyloxy, respectively. This reaction is carried out in a suitable inert solvent (e.g. benzene, toluene, xylene, diethyl ether, ethyl acetate, tetrahydrofuran, chloroform and dichloromethane) in the presence of a base (e.g. triethylamine, N-methylmorpholine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate ) at temperatures from -10 to 30 ^o C. the Amount of sulfonating agent and the base are in the range from 1 to 2 mol with respect to 1 mol of compound VIII-1, respectively. By carrying out the reaction, 1 mol of compound VIII-1, where Q is chloro, bromo or sulfonyloxy, with 1-1.5 mol of sodium iodide or potassium iodide, compound VIII-1 can also be obtained, where Q is iodine. In this case, the reaction can be carried out in a solvent such as acetone, methyl ethyl ketone, methanol and ethanol at temperatures in the range from 20 to 80 ^° C. After this, the reaction of compound VIII-1 with potassium cyanide or sodium cyanide gives compound II-1. The reaction is usually carried out in a solvent (for example, ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, methanol, ethanol, ethyl acetate, acetone, 2-butanone, N, N-dimethylformamide and dimethyl sulfoxide) 0 to 100 ^o C. The amount of potassium cyanide or sodium cyanide used is from 1 to 8 mol with respect to 1 mol of compound VIII-1.

 The nitrile derivative II-1 thus obtained can be isolated and purified using conventional isolation and purification procedures, for example, concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer and chromatography.

[где J - водород или низшая алкильная группа, R⁵ - низшая алкильная группа, q = 0 или 1, а остальные символы имеют определенное выше значение].(Method D)

[where J is hydrogen or a lower alkyl group, R ⁵ is a lower alkyl group, q = 0 or 1, and the remaining symbols have the same meaning as defined above].

Examples of the lower alkyl group designated as J or R ⁵ include groups containing 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc.

In this method, the aldehyde derivative VI-2 is reacted with an ester derivative of cyanomethylphosphonic acid XX and an unsaturated nitrile derivative II-2 is obtained. According to a conventional method, the reaction of compound VI-2 with compound IX is carried out in a suitable solvent in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and a mixture of these solvents. Examples of bases include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbate, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine, N, N-dimethylaniline; metal hydrides such as sodium hydride and potassium hydride; sodium ethoxide, sodium methoxide and potassium tert-butoxide, and the amount of these bases used varies from 1 to 5 molar equivalents with respect to compound VI-2. The amount of compound IX used varies from 1 to 5 molar equivalents, preferably from about 1 to 3 molar equivalents, relative to compound VI-2. This reaction is usually carried out at temperatures ranging from -50 to 150 ^° C., preferably from about -10 to 100 ^° C. The reaction time varies from 0.5 to 30 hours. By reducing the compound II-2 thus obtained, compound II- 3. This recovery is carried out mainly in the same way as in method B.

 The nitrile derivatives thus obtained can be isolated and purified using conventional isolation and purification procedures, such as concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer and chromatography.

[где R⁶ и R⁷ независимо представляют низшую алкильную группу, q = 0 или 1; а остальные символы имеют определенное выше значение].(Method D)

[where R ⁶ and R ⁷ independently represent a lower alkyl group, q = 0 or 1; and the remaining characters have the meaning defined above].

Examples of the lower alkyl group designated as R ⁶ and R ⁷ include groups containing 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc.

According to this method, the aldehyde or ketone derivative VI-3 is first reacted with a phosphonoacetic acid derivative or a γ-phosphonocrotonic acid derivative X to form an unsaturated ester derivative XI. The reaction of compound VI-3 with compound X is carried out essentially the same as the reaction of compound VI-2 with compound IX according to method D. After this, compound XI is reduced and the alcohol derivative VII-2 is obtained. This reduction reaction can be carried out by itself in a known manner, for example, reduction with a metal hydride, reduction with a metal hydride complex and reduction with diborane and substituted borane. In other words, this reaction is carried out by treating compound XI with a reducing agent. As the reducing agent, mention is made, for example, of a metal hydride complex, such as an alkali metal borohydride (for example, sodium borohydride and lithium borohydride) and lithium aluminum hydride, as well as diborane; in the best way, the reaction is carried out using diisobutylaluminium hydride. This reaction is carried out in an organic solvent which does not affect the reaction. Use a solvent adequately selected depending on the types of reducing agent from, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; amides, such as N, N-dimethylformamide; or a mixed solvent thereof. Reaction temperatures range from -20 to 150 ^° C., particularly preferably from 0 to 100 ^° C. The reaction time is from about 1 to 24 hours. After the reduction of compound VII-2, compound VII-3 is obtained. This reduction reaction is carried out basically in the same way as in method B. Compound VII-3 is treated basically the same as in method B, including the conversion of compound VII-1 to compound VIII-2 and then to compound II-1 to obtain nitrile derivative II-4.

 The nitrile derivatives II-1 thus obtained can be isolated and purified using conventional isolation and purification procedures, such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, phase transfer and chromatography.

 The pyridine aldehyde derivatives VI-4, which are used in method D and method D, can be obtained, for example, by method E.

[в формуле XV Z' - хлор, бром или иод, а остальные символы имеют определенные выше значения].(Method E)

[in the formula XV Z 'is chlorine, bromine or iodine, and the remaining symbols have the meanings defined above].

In this method, first 2-chloro-5-nitropyridine XII is reacted with the alcohol derivative III to give compound XIII. Compound XII is reacted in a conventional manner with compound XIII in a suitable solvent in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane; as well as a mixed solvent thereof. Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbate, sodium carbonate and sodium bicarbonate; amines such as pyridine, triethylamine and N, N-dimethylaniline; metal hydrides such as sodium hydride and potassium hydride; potassium tert-butoxide, etc .; the amount of these bases used is preferably about 1-5 molar equivalents with respect to compound III. This reaction is usually carried out at temperatures ranging from -50 to 150 ^° C., preferably from about -10 to 100 ^° C. The reaction time varies from 0.5 to 30 hours. After this, compound XIII is reduced and the amine derivative XIV-1 is obtained. Although this reduction can be carried out by itself in a known manner, it is better to carry out it by catalytic hydrogenation using a metal catalyst. In accordance with the usual method, catalytic hydrogenation is carried out in a solvent in the presence of a catalyst in a hydrogen atmosphere at 1-150 atm. Examples of solvents include alcohols such as methanol, ethanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachloroethane, ethyl acetate, acetic acid; or a mixture thereof. A favorable reaction is facilitated by the use, for example, of a metal compound, such as nickel, as well as a transition metal catalyst, such as palladium, platinum and rhodium. The reaction temperature ranges from 0 to 100 ^° C., preferably from 10 to 80 ^° C., the reaction time ranges from 0.5 to 50 hours. After this, compound XIV-1 is introduced into the known Sandmeyer reaction as such and a halogenated derivative is obtained Xi. In this reaction, compound XIV-1 is first diazotized by adding dropwise an aqueous solution of sodium nitrite (NaNO ₂ ) in a solvent in the presence of hydrochloric acid, hydrobromic acid or hydroiodic acid, followed by reaction with an aqueous solution of sodium halide or potassium halide to obtain compound XV. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; ethers such as dioxane and tetrahydrofuran; acetone, 2-butanone or a mixture thereof. The reaction temperatures range from -80 to 100 ^° C, preferably from -50 to 60 ^° C, the reaction time is from 0.5 to 50 hours. After this, compound XV is treated, for example, with butyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium or phenylmagnesium bromide to give a lithium compound, which is then reacted with N, N-dimethylformamide (DMF) to give compound VI-4.

[в формулах XVI-1 и II-5 G обозначает цианогруппу (CN) или COOR⁷; а остальные символы имеют значения, определенные выше].(Method G)

[in formulas XVI-1 and II-5, G denotes a cyano group (CN) or COOR ⁷ ; and the remaining characters have the meanings defined above].

The reaction converting compound XIV-2 to compound XVI-1 is carried out according to the method described in Journal of Medicinal Chemistry, 35, p. 2617 (1992). More specifically, compound XIV-2 is introduced into the so-called Meerwein arylation reaction, which involves the diazotization of compound XIV-2 in the presence of hydrohalic acid (HZ '), which is then reacted with an acid ester (CH ₂ = CHCOOR ⁷ ) or acrylonitrile (CH ₂ = CHCN) in the presence of a copper catalyst (for example, copper (I) oxide, copper (II) oxide, copper (I) chloride, copper (II) chloride, copper bromide (I and copper (II) bromide). After this compound XVI-1 was subjected to dehydrohalogenation to give compound II-5. This dehydrohalogenation reaction was carried out a suitable solvent in the presence of a base Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; ethyl acetate, acetonitrile, pyridine, N, N dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone and 2-butanone; as well as mixed solvents based on them. Examples of the base include inorganic bases such as alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxide (e.g. magnesium hydroxide and calcium hydroxide), alkali metal carbonate (e.g. sodium carbonate and potassium carbonate), alkaline earth metal carbonate
(e.g. magnesium carbonate and calcium carbonate), alkali metal hydrogen carbonate (sodium hydrogen carbonate and potassium hydrogen carbonate) and alkali metal acetate (sodium acetate and potassium acetate); and organic bases such as trialkylamine (eg, trimethylamine and triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2 , 2,2] non-5-ene and 1,8-diazabicyclo [5.4.0] -7-undeken. The amount of these bases used is preferably in the range of from about 1 to 5 molar equivalents with respect to compound XVI-1. Usually this reaction is carried out at temperatures in the range from -20 to 150 ^o C, preferably from about -10 to 120 ^o C.

[где каждый символ имеет значение, определенное выше].(Method H)

[where each character has the meaning defined above].

 In this method, the α-halogenopropionitrile derivative XVI-2 is reduced and the propionitrile derivative II-6 is obtained. This method can be carried out, for example, by catalytic reduction basically in the same way as by method B, or in the usual way using zinc or iron and acetic acid.

(где каждый символ имеет значение, определенное выше).(Method I)

(where each character has the meaning defined above).

In this method, the condensation reaction of compound VI-2 and the cyanoacetic acid ester derivative is first carried out to give compound XVII. This condensation reaction is carried out in a solvent in the presence of a base. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran; pyridine, N, N-dimethylformamide, dimethyl sulfoxide and acetic acid. Examples of bases used include sodium alkoxide (e.g., sodium methoxide and sodium ethoxide), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, or secondary amines such as piperazine, pyrrolidine, morpholine, diethylamine and diisopropylamine, etc. The amount used the base is in the range from 0.01 to 5 molar equivalents, preferably from 0.05 to 2 molar equivalents relative to compound VI-2. This reaction is carried out in a temperature range from 0 to 150 ^° C., preferably from 20 to 120 ^° C. for a period of 5 to 30 hours. After this, compound XVII is reduced to give compound XVIII. This reduction reaction can be carried out per se by a known method, for example, reduction using a metal hydride, reduction using a metal hydride complex or catalytic hydrogenation. In other words, this reaction is carried out by treating compound XVII with a reducing agent. Examples of reducing agents include, but are not limited to, a metal hydride complex such as an alkali metal borohydride (eg, sodium borohydride and lithium borohydride); methyl hydride complex, such lithium aluminum hydride; a metal hydride such as sodium hydride; a metal or metal salt, such as an organotin compound (e.g. triphenyltin hydride), a nickel compound, and a zinc compound; a catalytic reducing agent using a transition metal catalyst such as palladium, platinum and rhodium, and hydrogen; as well as diborane. The use of alkali metal borohydride (for example, sodium borohydride and lithium borohydride), among others, contributes to a better reaction. This reaction is carried out in an organic solvent which does not affect the reaction. Use a solvent appropriately selected depending on the types of reducing agent from, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; amides, such as N, N-dimethylformamide; or mixtures of these solvents. The reaction temperatures range from -20 to 150 ^° C., particularly preferably from 0 to 100 ^° C. The reaction time is from 1 to 24 hours. After this, compound XVIII is hydrolyzed and then decarboxylated to give compound II-3. The hydrolysis is carried out in a known manner in an aqueous solution in the presence of an acid or base. The carboxylic acid derivative XIX thus obtained is subjected to decarboxylation after isolation or without isolation to give compound II-3. This decarboxylation reaction is carried out in a solvent with heating. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; amides such as N, N-dimethylformamide; chlorobenzene, o-dichlorobenzene and pyridine; as well as their mixture. The reaction temperature is in the range from 50 to 250 ^o C, particularly preferably from 70 to 160 ^o C. The reaction time is from 1 to 24 hours

 The nitrile derivative can also be obtained by method K or method L.

(где каждый символ имеет вышеуказанное значение).(Method K)

(where each character has the above meaning).

In this method, the nitrile derivative II-5 can be obtained by reacting compound XX with compound XXI. This method is carried out in a suitable solvent in the presence of a base. Solvents include aromatic hydrocarbons, such as benzene, toluene, xylene, etc., ethers, such as dioxane, tetrahydrofuran, dimethoxyethane, etc., alcohols, such as methanol, ethanol, propanol, etc., halogenated. hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., N, N-dimethylformamide, dimethyl sulfoxide, or a mixture of two or more of the above solvents. Alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc., amines such as pyridine, triethylamine, N, N-dimethylaniline, etc., hydride are used as bases. a metal, such as sodium hydride, potassium hydride, etc., a metal alkoxide, such as sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc. The base is used in an amount of from 1 to 5 mol per 1 mol of compound III. This reaction is carried out at a temperature ranging from -50 to 150 ^° C., preferably from -10 to 100 ^° C. The reaction time is usually from 0.5 to 10 hours.

По данному способу вначале соединение XX и производное соединения XXII реагируют с образованием сложноэфирного производного XXIII. Эту реакцию осуществляют так же, как для соединения XX и соединения XXI по способу К. После этого соединение XIII превращают в спиртовое производное VII-4 методом, аналогичным реакции, превращающей соединение XI в соединение VII-2 по способу Д. Соединение VII-4 превращают в соединение VIII-3 методом, аналогичным реакции, превращающей соединение VII-3, в соединение VIII-2 по способу Д. Соединение VIII-3 превращают в соединение II-6 методом, аналогичным реакции, превращающей соединение VIII-2 в соединение II-4 по способу Д.

In this method, first, compound XX and a derivative of compound XXII are reacted to form an ester derivative XXIII. This reaction is carried out in the same way as for compound XX and compound XXI according to method K. After this, compound XIII is converted to the alcohol derivative VII-4 by a method similar to the reaction converting compound XI to compound VII-2 according to method D. Compound VII-4 is converted to compound VIII-3 by a method similar to the reaction converting compound VII-3 to compound VIII-2 by method D. Compound VIII-3 is converted to compound II-6 by a method similar to the reaction converting compound VIII-2 to compound II-4 by method D.

 Compound I according to this invention has a hypoglycemic and hypolipidemic effect. The experimental results confirming these actions are given below.

Experimental example
Hypoglycemic and hypolipidemic effects in mice
The test compound, mixed with powdered food (CE-2, Japan Clea) in a ratio of 0.01% or 0.005%, is used for non-forced feeding of mice KKA ^y (age 9-14 weeks) for 4 days. During this time, animals have free access to water. Blood is taken from the orbital plexus of the veins, and the plasma levels of glucose and triglyceride are quantitatively determined by the enzymatic method using the Iatrochem equipment GZU (A) and Iatro-MA 701 TG (Iatron), respectively. Relative values are given as the percentage reduction in comparison with the group without the dosage of the drug (table 1).

 As stated above, the tetrazole I derivatives of the present invention exhibit excellent hypoglycemic and lipid-lowering effects and can be used as a therapeutic agent for the treatment of diabetes mellitus, hyperlipemia, hypertension and the like diseases.

 Reference Example 1

To a solution of 2-chloro-5-nitropyridine (25 g) and 2- [5-methyl-2-phenyl-4-oxazolyl] ethanol (32.1 g) in THF (250 ml) sodium hydride (60%) is added in small portions. in oil, 6.92 g) and the mixture is stirred. The reaction mixture was further stirred at room temperature for 15 hours, poured into water and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The remaining crystals are collected by filtration, and then recrystallized from ethanol; get 2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-nitropyridine (25.4 g, 49%) as yellowish-brown crystals, so pl. 110.5 - 111.5 ^o C.

 Reference Example 2

A mixture of 2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-nitropyridine (13.4 g), palladium carbon (5%, 1.5 g) and ethyl acetate (200 ml) - methanol (150 ml) is subjected to catalytic hydrogenation at room temperature at a pressure of 1 ATM. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to the remaining crystals. The crystals were collected by filtration to give 5-amino-2 [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (11.4 g 93%), which was recrystallized from ethyl acetate-hexane to give brown crystals, t .pl. 107-108 ^o C.

 Reference Example 3

To a mixture of 5-amino-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (10.0 g), concentrated hydrochloric acid (8.47 ml) and acetone (100 ml) at at temperatures of 10 ^° C. or lower, a solution of sodium nitrite (NaNO ₂ ) (2.46 g) in water (10 ml) is added dropwise. The mixture was stirred for 30 minutes at 10 ^° C. and a solution of potassium iodide (KI) (2.46 g) in water (10 ml) was added dropwise thereto. The reaction mixture is stirred for one hour at 30-35 ^o C and one hour at 35-40 ^o C, after which concentration is carried out under reduced pressure. The residue was poured into water, from which extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure to an oily product, which was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1: 3, v / v), 5-iodo-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (7.22 g, 52%) was obtained ), which is recrystallized from a mixture of ethyl acetate-hexane to form colorless crystals, so pl. 105-106 ^o C.

 Reference Example 4

To a solution of 5-iodo-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (2.5 g) in tetrahydrofuran (40 ml) at -65 ^° C. under a nitrogen stream was added dropwise a solution of n-butyllithium in hexane (1.6 M, 4.61 ml). The mixture was stirred for 15 minutes at the same temperature, and then N, N-dimethylformamide (0.71 ml) was added dropwise thereto. The cooling bath was removed and the reaction mixture was further stirred for 30 minutes, then a saturated aqueous solution of ammonium chloride (6 ml) was added to it. The reaction mixture was poured into water and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure to the residue 5-formyl-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (1.5 g , 79%), which is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless crystals, so pl. 99-100 ^o C.

 Reference Example 5

Sodium borohydride (0.473 g) was added to a solution of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (7.0 g) in ethanol (100 ml) under ice-cooling, and the mixture was stirred 2 h at room temperature. Acetic acid (2 ml) was added to the reaction mixture, then it was poured into an ice-water mixture, after which the resulting crystalline precipitate was collected by filtration; After further recrystallization from ethyl acetate-hexane, 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl alcohol (6.9 g, 88%) was obtained as colorless plates, mp. 112-113 ^o C
Reference Example 6

To a solution of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl alcohol (6.8 g) in chloroform (100 ml) was added thionyl chloride (3.1 g), and the mixture was stirred with saturated an aqueous solution of sodium bicarbonate and then with water, after which it is dried (MgSO ₄ ). The solvent was distilled off to the residue 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl chloride (6.5 g, 90%) as colorless needles, mp. 93-94 ^o C.

 Reference Example 7

A mixture of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl chloride (6.4 g), powdered potassium cyanide (4.0 g) and N, N-dimethylformamide (50 ml) stirred for two hours at 60 ^° C. The reaction mixture was poured into water and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off to obtain 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl cyanide (5.2 g, 81%). The product was recrystallized from ethyl acetate-hexane to give colorless needle crystals, mp. 109-110 ^o C.

 Reference Example 8

To a solution of diethyl cyanomethylphosphonate (8.2 g) in tetrahydrofuran (150 ml) at 0 ^° C) sodium hydride (60% in oil, 2.0 g) was added in small portions. The mixture was stirred for about 15 minutes, 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (13.0 g) was added thereto, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, from which extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off; 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamononitrile (11.8 g, 85%) remained. The product was recrystallized from ethyl acetate-hexane to give colorless needle crystals, mp. 112-113 ^o C.

 Examples for reference 9-15.

 The compounds shown in table 2 were obtained basically the same as described in example 8.

 Note 1 (to table. 2).

 A mixture of (E) - and (2) - compounds in a ratio of 3: 1.

NMR (δ ppm in CDCl ₃ ): 1.2 - 2.1 (10H, m), 2.24 (3H, s), 2.6 - 2.8 (1H, m), 2.89 (2H, t, J = 7 Hz), 5.28 (d, J = 12 Hz) and 5.70 (d, J = 1, 16.5 Hz) (total 1H), 6.88 and 6.91 (total 2H, each d, J = 9 Hz), 7.02 (d, J = 12 Hz) and 7.32 (d, J = 16.5 Hz) (total 1H), 7.37 and 7.76 (total 2H, each d, J = 9 Hz).

 Note 2 (to table. 2).

 Used for subsequent reaction without isolation.

 Note 3 (to table. 2).

 A mixture of (E) - and (Z) - compounds in a ratio of 5: 2.

NMR (δ ppm in CDCl ₃ ): 2.24 (3H, s), 2.38 (3H, s), 2.88 (2H, t, J = 7 Hz), 4.21 and 4, 23 (d, J = 7 Hz) (total 2H), 5.28 (d, J = 12 Hz) and 5.71 (d, J = 16.5 Hz) (total 1H), 6.89 and 6, 93 (total 2H, each d, J = 9 Hz), 7.02 (d, J = 12 Hz) and 7.32 (d, J = 16.5 Hz) (total 1H), 7.37 and 7, 77 (total 2H, each d, J = 9 Hz).

 Reference Example 16

A mixture of 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamononitrile (4.0 g), palladium carbon (5%, 0.5 g) and ethyl acetate (50 ml) was subjected to catalytic hydrogenation at room temperature at a pressure of 1 atm. The catalyst was filtered off and the filtrate was concentrated under reduced pressure; 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propionitrile (3.7 g, 93%) remained. The product was recrystallized from ethyl acetate-hexane to give colorless needle crystals, mp. 109-110 ^o C.

 Reference Examples 17-21.

 The compounds shown in table 3, obtained basically the same as described in example 16.

 Note 1 (to table. 3).

NMR (δ ppm in CDCl ₃ ): 1.2 - 2.1 (10H, m), 2.24 (3H, s), 2.57 (2H, t, J = 7.5 Hz), 2.69 (1H, t, J = 11.5, 3.5 Hz), 2.87 (2H, t, J = 7 Hz), 2.89 (2H, t, J = 7.5 Hz), 4.14 (2H, t, J = 7 Hz), 6.84 (2H, d, J = 8 Hz), 7.12 (2H, d, J = 8.5 Hz).

 Note 2 (to table. 3).

 The total yield of the corresponding benzaldehyde.

 Note 3 (to table. 3).

NMR (δ ppm in CDCl ₃ ): 2.59 (2H, t, J = 7 Hz), 2.91 (2H, t, J = 7 Hz), 3.55 (3H, s), 5 00 (2H, d, J = 1 Hz), 6.46 (1H, t, J = 1 Hz), 6.97 (2H, d, J = 8.5 Hz), 7.15 (2H, d , J = 8.5 Hz), 7.2 - 7.5 (5H, m).

 Reference Example 22

To a solution of triethylphosphonoacetate (11.2 g) in tetrahydrofuran (200 ml) at 0 ^° C. sodium hydride (60% in oil, 2.2 g) was added in small portions, and the mixture was stirred for 15 minutes at the same temperature. Then 4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde (14.0 g) was added to the mixture, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was neutralized with 2 n HCl. The resulting crystalline precipitate was collected by filtration, recrystallized from ethyl acetate-hexane and ethyl 4- [2- (5-methyl-2-phenyl-4-oxazolyl) - ethoxy] cinnamate (15.1 g, 88%). Colorless needles, mp 114-115 ^o C.

 Reference Example 23

To a suspension of ethyl 4- [2- [5-methyl-2-phenyl-4-oxazolyl) ethoxy] cinnamate (15.0 g) in toluene (200 ml) at 0 ^° C. was added dropwise a toluene solution of diisobutylaluminum hydride (1 5 M, 67 ml). The mixture was stirred for 2 hours at room temperature and 2 N HCl (200 ml) was added thereto under ice-cooling. The organic layer was washed with water, dried (MgSO ₄ ) and concentrated; get (E) -3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] -2-propen-1-ol (12.0 g, 90%), which is recrystallized from ethyl acetate with the formation of colorless prisms, so pl. 127-128 ^o C.

 Reference Example 24

A mixture of (E) -3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] -2-propen-1-ol (3.1 g), palladium carbon (5 %, 0.5 g) and ethyl acetate (50 ml) were subjected to catalytic hydrogenation at a pressure of 1 atm at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure; 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propan-1-ol (2.8 g, 90%) was obtained, which was recrystallized from ethyl acetate-hexane with obtaining colorless needle crystals, so pl. 99-100 ^o C.

 Reference Example 25

To a mixture of 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propan-1-ol (2.6 g) and benzene (50 ml) is added phosphorus tribromide ( 2.1 g) and the mixture was stirred for 2 hours at 70 ^° C. The reaction mixture was poured into water, from which extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off; there remains 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propyl bromide (0.98 g, 32%), which is recrystallized from ethyl acetate-hexane to give colorless needle crystals, so pl. 78-79 ^o C.

 Reference Example 26

To a mixture of 5-amino-2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] pyridine (9.1 g), an aqueous solution of HBr (47%, 14.2 ml) and acetone (150 ml) at a temperature not exceeding 10 ^° C., a solution of sodium nitrite (NaNO ₂ ) (2.33 g) in water (10 ml) is added dropwise. The mixture was stirred for 30 minutes at 10 ^° C. and Acrylonitrile (CH ₂ = CHCN) (12.1 ml) was added. With vigorous stirring, copper (I) oxide (Cu ₂ O) (0.1 g) was added to the mixture. The reaction mixture is stirred for another hour at a temperature in the range of 30 to 35 ^° C. and then concentration is carried out under reduced pressure. The concentrate was poured into water, which was made basic using a concentrated aqueous solution of ammonia, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The remaining oily product is subjected to silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1: 1, v / v), 2-bromo-3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl is obtained ] propionitrile (6.11 g, 48%), which is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless crystals, so pl. 93-94 ^o C.

 Reference Example 27

A mixture of 2-bromo-3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] propionitrile (2.0 g), palladium carbon (5%, 0, 2 g) and dioxane (30 ml) are subjected to catalytic reduction at a pressure of 1 atm at room temperature. The catalyst is filtered off, after which the filtrate is concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography. From fractions eluted with ethyl acetate-hexane (2: 3, v / v), 3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] propionitrile (1 , 3 g, 78%), which is recrystallized from a mixture of ethyl acetate-hexane and get colorless crystals, so pl. 105-106 ^o C.

 Reference Example 28

A mixture of 2-bromo-3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] propionitrile (4.5 g), lithium bromide (LiBr) (1, 14 g), lithium carbonate (Li ₂ CO ₃ ) (2.17 g) and N, N-dimethylformamide (50 ml) were stirred for 2.5 hours at 120 ^° C. The reaction mixture was poured into water, from which ethyl acetate was extracted. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure; there remains (E) -3- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] acrylonitrile (3.2, 89%), which is recrystallized from ethyl acetate-hexane and get pale yellow crystals, so pl. 116-117 ^o C.

 Reference Example 29

A mixture of 4- [2- [2- (2-chlorophenyl-5-methyl-4-oxazolyl) ethoxy] benzaldehyde (2.0 g), ethyl cyanoacetate (0.795 g), pyridine (0.15 g) and pyridine (30 ml) was stirred for 2 hours at 100-110 ^° C. The reaction mixture was poured into water. The resulting crystalline precipitate was collected by filtration and recrystallized from dichloromethane-ethanol; ethyl 4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] -α-cyanocinnamate (2.45 g, 96%) was obtained in the form of colorless needles; 120-121 ^o C.

 Reference Example 30

To a mixture of ethyl 4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] -α-cyanocinnamate (2.25 g) and dioxane (30 ml) -ethanol (30 ml ) While cooling with ice, sodium borohydride (0.06 g) is added. The mixture is stirred for one hour at the same temperature. The reaction mixture was poured into ice-water, which was acidified, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. Ethyl 3- [4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] phenyl was obtained from the fractions eluted with chloroform-methanol (50: 1, v / v) ] -2-cyanopropionate (2.25 g, quant.) As an oily product.

NMR (δ ppm in CDCl ₃ ): 1.27 (3H, t, J = 7 Hz), 2.39 (3H, s), 3.00 (2H, t, J = 6.5 Hz) , 3.12 (1H, dd, J = 14 and 8 Hz), 3.22 (1H, dd, J = 14 and 6 Hz), 3.66 (1H, dd, J = 8 and 6 Hz), 4 22 (2H, q, J = 7 Hz), 4.24 (2H, t, J = 6.5 Hz), 6.87 (2H, d, J = 9 Hz), 7.17 (2H, d , J = 9 Hz), 7.25 - 7.5 (3H, m), 7.85 - 8.0 (1H, m).

 Reference Example 31

A mixture of ethyl 3- [4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] phenyl] -2-cyanopropionate (2.24 g), 1 n NaOH (15 ml ) and ethanol (50 ml) was stirred for one hour at room temperature. The reaction mixture was poured into water and acidified, extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure; there remains a crystalline product, which is added to the mixture of pyridine (5 ml) -o-dichlorobenzene (50 ml), and the mixture is heated for 2 hours under reflux. The reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography. From fractions eluted with chloroform, 3- [4- [2- [2- (2-chlorophenyl) -5-methyl-4-oxazolyl] ethoxy] phenyl} propionitrile (1.5 g, 80%) is obtained, which is recrystallized from mixtures of dichloromethanisopropyl ether and get pale yellow crystals, so pl. 88 - 89 ^o C.

 Reference Example 32

Ethyl 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamate is prepared essentially as described in Example 22, recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 145 - 146 ^o C.

 Reference Example 33

(E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ol was obtained essentially as described in Reference Example 23, recrystallized from ethyl acetate -hexane with the formation of colorless prisms, so pl. 134 - 135 ^o C.

 Reference Example 34

To a solution of (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ol (3.7 g) in dichloromethane (80 ml) was added activated manganese dioxide. (MnO ₂ ) (9.0 g); the mixture is stirred for one hour at room temperature. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) -cinnamaldehyde (2.6 g, 70%), which was recrystallized from ethyl acetate-hexane to give colorless prisms, mp . 114 - 115 ^o C.

 Reference Example 35

To a solution of diethyl cyanomethylphosphonate (1.3 g) in tetrahydrofuran (50 ml) at 0 ^° C. sodium hydride (60% in oil, 0.32 g) was added in small portions. The mixture was stirred for 15 minutes at the same temperature, and then) 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamaldehyde (2.0 g) was added, after which the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was poured into water, from which extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), then concentrated to obtain (E, E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadiene nitrile (1, 5 g, 68%). Recrystallization of the product from ethyl acetate-hexane gave colorless needles, mp. 120 - 121 ^o C.

 Reference Example 36

Basically, as described in Example 24, 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propen-1-ol was obtained, which was recrystallized from ethyl acetate-hexane to give colorless prisms. , mp 72 - 73 ^o C.

 Reference Example 37

Basically, as described in Example 25, 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl bromide was obtained, which was recrystallized from diethyl ether-hexane to give colorless prisms, mp . 80 - 81 ^o C.

 Reference Example 38

A mixture of 3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl bromide (1.5 g), powdered potassium cyanide (1.52 g) and N, N-dimethylformamide (30 ml ) stirred for 3 hours at 80 ^° C. The reaction mixture was poured into water, from which extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), and then concentrated; 4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyronitrile (1.2 g, 92%) was obtained. Recrystallization of the product from ethyl acetate-hexane led to colorless needles, mp. 73 - 74 ^o C.

 Reference Example 39

Basically, as described in Example 38, 4- [4- [2- (5-methyl-2-phenyl-4-oxazolyl] ethoxy] phenyl] butyronitrile was obtained, which was recrystallized from diethyl ether-hexane to give colorless needles, mp 69 - 70 ^o C.

 Reference Example 40

According to the method described in Example 22, 4- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamaldehyde is reacted with triethylphosphonoacetate to give ethyl (E, E) -5- [4- (5- methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienoate; subsequent recrystallization from a mixture of ethyl acetate-hexane gave colorless prisms, so pl. 137 - 138 ^o C.

 Reference Example 41

In accordance with the method described in example 16, ethyl- (E, E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienoate is subjected to catalytic hydrogenation to form ethyl -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] valerate. Recrystallization from hexane gives colorless rod-shaped crystals, mp. 57 - 58 ^o C.

 Reference Example 42

To a suspension of lithium aluminum hydride (LiAlH ₄ ) (0.247 g) in ether (40 ml) was added dropwise a solution of ethyl 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] valerate (2) under ice-cooling. , 55 g) in ether (20 ml). The mixture was stirred for 15 minutes while cooling with ice, after which water (2 ml) was added. The insoluble solid is filtered off and the filtrate is concentrated; 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1-pentanol (2.15 g, 94%) was obtained, which was recrystallized from ethyl acetate-hexane to give colorless rod-shaped crystals, i.e. pl. 78 - 79 ^o C.

 Reference Example 43

According to the method described in Example 25, 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1-pentanol is reacted with phosphorus tribromide to give 5- [4- (5- methyl-2-phenyl-4-oxazolylmethoxy) phenyl] pentyl bromide. Recrystallization from a mixture of ether-hexane gives colorless needles, so pl. 58 - 59 ^o C.

 Reference Example 44

According to the method described by way of example for reference 38, a reaction of 5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] pentyl bromide with potassium cyanide to produce 5- [4- (5-methyl- 2-phenyl-4-oxazolylmethoxy) phenyl] hexanenitrile. Recrystallization from a mixture of ether-hexane gives colorless prisms, so pl. 76 - 77 ^o C.

 Reference Example 45

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 g), para-hydroxyacetophenone (7.95 g), potassium carbonate (6.73 g) and N, N-dimethylformamide (DMF) (100 ml) stirred for 2.5 hours at temperatures ranging from 70 to 80 ^° C. The reaction mixture was poured into water and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off; 4 '- (5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone (11.6 g, 85%) was obtained. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 126 - 127 ^o C.

 Reference Example 46

According to the method described for Example 22, 4 - '(5-methyl-2-phenyl-4-oxazolylmethoxy) acetophenone is reacted with trimethylphosphonoacetate to form methyl- (E) -3- [4- (5-methyl- 2-phenyl-4-oxazolylmethoxy) phenyl] -2-butenoate. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 125 - 126 ^o C.

 Reference Example 47

According to the method described for Example 23, methyl- (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-butenoate is reduced with diisobutylaluminium hydride to give (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-butene-1-ol. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 126 - 127 ^o C.

 Reference Example 48

According to the method described for example 34, (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-ol is oxidized with activated manganese dioxide to form (E ) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-al. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 94 - 95 ^o C.

 Reference Example 49

According to the method described for example 35, (E) -3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-buten-1-al is reacted with diethylcyanomethylphosphonate to form ( E, E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-hexadiene nitrile. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 134 - 136 ^o C.

 Reference Example 50

According to the method described for Example 45, 4-chloromethyl-5-methyl-2-phenyloxazole is reacted with methahydroxybenzaldehyde to form 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde. Recrystallization from a mixture of ethanol leads to colorless prisms, so pl. 67 - 68 ^o C.

 Reference Example 51

 According to the method described for example 22, 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzaldehyde is reacted with triethylphosphonoacetate to form ethyl 3- (5-methyl-2-phenyl-4-oxazolylmethoxy) cinnamon.

 Reference Example 53

According to the method described for example 34, (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ol is oxidized with activated manganese dioxide to form (E ) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-ala. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 103 - 104 ^o C.

 Reference Example 54

 According to the method described for example 35, (E) -3- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2-propen-1-al is reacted with diethylcyanomethylphosphonate to form ( E, E) -5- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienitrile in the form of an oily product.

 Reference Example 55

According to the method described for Example 45, 2-chloromethyl-5-methyl-4-phenylthiazole is reacted with para-hydroxybenzaldehyde to form 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) benzaldehyde. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 81 - 82 ^o C.

 Reference Example 56

According to the method described for Example 22, 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) benzaldehyde is reacted with trimethylphosphonoacetate to form methyl 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) cinnamon. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 142 - 143 ^o C.

 Reference Example 57

According to the method described for Example 23, methyl 4- (5-methyl-4-phenyl-2-thiazolylmethoxy) cinnamate is reduced with diisobutylaluminum hydride to form (E) -3- [4- (5-methyl-4-phenyl- 2-thiazolylmethoxy) phenyl] -2-propen-1-ol. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 125 - 126 ^o C.

 Reference Example 58

According to the method described for example 34, (E) -3- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2-propen-1-ol is introduced into the oxidation reaction with activated manganese dioxide with the formation of (E) -3- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2-propen-1-al. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 116 - 117 ^o C.

 Reference Example 59

According to the method described by way of example for reference 35, (E) -3- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2-propen-1-al is reacted with diethyl cyanomethylphosphonate with the formation of (E, E) -5- [4- (5-methyl-4-phenyl-2-thiazolylmethoxy) phenyl] -2,4-pentadiene nitrile. Recrystallization from a mixture of ethyl acetate and ether leads to colorless prisms, so pl. 108 - 109 ^o C.

 Reference Example 60

According to the method described by way of example for reference 45, 2-chloromethyl-5-methyl-4-phenyloxazole is reacted with para-hydroxybenzaldehyde to form 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 90 - 91 ^o C.

 Reference Example 61

According to the method described for example 22, 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde is reacted with trimethylphosphonoacetate to form methyl 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamon. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 109 - 110 ^o C.

 Reference Example 62

According to the method described for Example 23, methyl 4- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamate is reduced with diisobutylaluminum hydride to give (E) -3- [4- (5-methyl-4-phenyl- 2-oxazolylmethoxy) phenyl] -2-propen-1-ol. Recrystallization from a mixture of chloroform-isopropyl ether leads to colorless prisms, so pl. 154 - 155 ^o C.

 Reference Example 63

According to the method described for example 34, (E) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ol is oxidized with activated manganese dioxide to form (E ) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ala. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 144 - 146 ^o C.

 Reference Example 64

In accordance with the method described for example 35, (E) -3- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al is reacted with diethylcyanomethylphosphonate to form ( E, E) -5- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienitrile. Then, in accordance with the method described for example 16, (E, E) -5- [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienitrile is subjected to catalytic reduction to form 5 - [4- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] valeronitrile. Recrystallization from a mixture of ethyl acetate-ether-hexane leads to colorless prisms, so pl. 65 - 66 ^o C.

 Reference Example 65

According to the method described for Example 45, 4-chloromethyl-5-methyl-2- (2-naphthyl) oxazole was reacted with para-hydroxybenzaldehyde to form 4- [5-methyl-2- (2-naphthyl) - 4-oxazolylmethoxy] benzaldehyde. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 163 - 164 ^o C.

 Reference Example 66

According to the method described for Example 22, 4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] benzaldehyde is reacted with trimethylphosphonoacetate to form methyl 4- [5-methyl-2- (2 naphthyl) -4-oxazolylmethoxy] cinnamate. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 185 - 186 ^o C.

 Reference Example 67

According to the method described for Example 23, methyl 4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] cinnamate is reduced with diisobutylaluminum hydride to give (E) -3- [4- [5-methyl- 2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-propen-1-ol. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 159 - 160 ^o C.

 Reference Example 68

According to the method described for example 34, (E) -3- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-propen-1-ol is oxidized with activated manganese dioxide with the formation of (E) -3- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-propen-1-ala. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 179 - 180 ^o C.

 Reference Example 69

In accordance with the method described for example 35, (E) -3- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2-propen-1-al is reacted with diethyl cyanomethylphosphonate to form (E, E) -5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] -2,4-pentadiene nitrile. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 159 - 160 ^o C.

 Reference Example 70

According to the method described for Example 45, 4-chloromethyl-5-methyl-2- (2-naphthyl) oxazole was reacted with 4- (4-hydroxyphenyl) butyronitrile to form 4- [4- [5-methyl- 2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] butyronitrile. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 149 - 151 ^o C.

 Reference Example 71

In accordance with the method described for example 45, 4-chloromethyl-5-methyl-3- (2-naphthyl) oxazole is reacted with methyl 5- (4-hydroxyphenyl) valerate to form methyl 5- [4- [ 5-methyl-2- [2-naphthyl-4-oxazolylmethoxy] phenyl] valerate. Then, in accordance with the method described for example 42, methyl-5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] valerate is reduced with lithium aluminum hydride to give 5- [4- [ 5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy} phenyl] pentan-1-ol. Recrystallization from a mixture of ethyl acetate-ether leads to colorless needles, so pl. 128 - 129 ^o C.

 Reference Example 72

To a mixture of 5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] pentan-1-ol (1.1 g), triethylamine (0.333 g) and dichloromethane (40 ml ) while cooling with ice, methanesulfonyl chloride (0.345 g) is added dropwise. The mixture was stirred for two hours at room temperature, washed with water and dried (MgSO ₄ ). The solvent was distilled off, and 5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] pentylmethanesulfonate (1.21 g, 92%) remained. Recrystallization from a mixture of dichloromethane-ether leads to colorless needles, so pl. 132 - 133 ^o C.

 Reference Example 73

According to the method described for example 38, 5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] pentylmethanesulfonate is reacted with potassium cyanide to form 6- [4- [5 methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] hexannitrile. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 116 - 117 ^o C.

 Reference Example 74

According to the method described for example 35, 4- [3- [5-methyl-2-4-oxazolyl) propoxy] benzaldehyde is reacted with diethyl cyanomethyl phosphonate with diethyl cyanomethyl phosphonate to form 4- [3- [5-methyl-2- phenyl-4-oxazolyl) propoxy] cinnamonitrile. Recrystallization from a mixture of ethyl acetate-isopropyl ether-hexane leads to colorless prisms, so pl. 97 - 98 ^o C.

 Reference Example 75

According to the method described for Example 45, 2-chloromethyl-5-methyl-4-phenyloxazole is reacted with orthohydroxybenzaldehyde to form 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 95 - 96 ^o C.

 Reference Example 76

According to the method described for example 22, 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) benzaldehyde is reacted with trimethylphosphonoacetate to form methyl 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamon. Recrystallization from a mixture of ethyl acetate-chloroform-ether leads to colorless prisms, so pl. 128 - 129 ^o C.

 Reference Example 77

According to the method described for example 23, methyl 2- (5-methyl-4-phenyl-2-oxazolylmethoxy) cinnamate is reduced with diisobutylaluminum hydride to give (E) -3- [2- (5-methyl-4-phenyl- 2-oxazolylmethoxy) phenyl] -2-propen-1-ol. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 128 - 129 ^o C.

 Reference Example 78

According to the method described for example 34, (E) -3- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ol is oxidized with activated manganese dioxide to form (E ) -3- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-ala. Recrystallization from a mixture of chloroform-isopropyl ether leads to colorless prisms, so pl. 112 - 113 ^o C.

 Reference Example 79

In accordance with the method described for example 35, (E) -3- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2-propen-1-al is reacted with diethylcyanomethylphosphonate to form ( E, E) -5- [2- (5-methyl-4-phenyl-2-oxazolylmethoxy) phenyl] -2,4-pentadienitrile. Recrystallization from a mixture of ethanol-chloroform leads to colorless prisms, so pl. 128 - 129 ^o C.

 Reference Example 80

According to the method described for example 45, 2- (benzo [b] furan-2-yl) -4-chloromethyl-5-methyloxazole was reacted with 4- (4-hydroxyphenyl) butyronitrile to form 4- [4- [2- (Benzo [b] furan-2-yl) -5-methyl-4-oxazolylmethoxy] phenyl] butyronitrile. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to colorless prisms, so pl. 118 - 119 ^o C.

 Reference Example 81

 In accordance with the method described for example 45, 4-chloromethyl-2- (furan-2-yl) -5-methyloxazole is reacted with 4- (4-hydroxyphenyl) butyronitrile to form 4- [4- [2- ( furan-2-yl) -5-methyl-4-oxazolylmethoxy] phenyl] butyronitrile as an oily product.

NMR (δ ppm in CDCl ₃ ): 1.85 - 2.05 (2H, m), 2.31 (2H, t, J = 7 Hz), 2.42 (3H, s), 2, 72 (2H, t, J = 7.5 Hz), 4.97 (2H, s), 6.52 (1H, dd, J = 3.5 Hz and 2 Hz), 6.9 - 7.0 ( 3H, m), 7.10 (1H, d, J = 9 Hz), 7.53 (1H, dd, J = 2 and 1 Hz).

 Reference Example 82

According to the method described for example 45, 3-chloromethyl-1-methyl-5-phenyl-1,2,4-triazole is reacted with 4- (4-hydroxyphenyl) butyronitrile to form 4- [4- (1 methyl 5-phenyl-1,2,4-triazol-3-ylmethoxy) phenyl] butyronitrile. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to colorless prisms, so pl. 106 - 107 ^o C.

 Reference Example 83

Basically, as in Example 1, 2- (5-methyl-2-phenyl-4-oxazolylmethoxy-5-nitropyridine was obtained by reacting 2-chloro-5-nitropyridine with 5-methyl-2-phenyl-4-oxazolylmethanol The yield is 84%. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to pale yellow prisms, so pl. 142 - 143 ^o C.

 Reference Example 84

Basically, as in example 2, by catalytic hydrogenation of 2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-nitripyridine, 5-amino-2- (5-methyl-2-phenyl-4- oxazolylmethoxy) pyridine. The yield is 81%. Recrystallization from a mixture of methanol-isopropyl ether leads to colorless prisms, so pl. 106 - 107 ^o C.

 Reference Example 85

To a mixture of 5-amino-2- (5-methyl-2-phenyl-4-oxazolylmethoxy) pyridine (4.00 g), 47% HBr (12.2 g) and acetone (80 ml) at temperatures below 5 ^o C was added dropwise a solution of sodium nitrite (NaNO ₂ ) (1.08 g) in water (2 ml). After stirring for 30 minutes, methyl acrylate (6.12 g) was added to the mixture, followed by copper (I) oxide (0.20 g) at 10-20 ^° C. The mixture was stirred for another hour at room temperature, followed by concentration under reduced pressure. The concentrate is diluted with concentrated ammonia and extraction is carried out with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The remaining oily product is chromatographed on silica gel. From fractions eluted with ethyl acetate-hexane (1: 5, v / v), 2-bromo-3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propionate was obtained (2, 27 g, 37%) as an oily substance.

NMR (δ ppm in CDCl ₃ ): 2.48 (3H, s), 3.18 (1H, dd, J = 14.5 and 7 Hz), 3.39 (1H, dd, J = 14 5 and 8 Hz), 3.76 (3H, s), 4.34 (1H, dd, J = 8 and 7 Hz), 5.28 (2H, s), 6.78 (1H, d, J = 8.5 Hz), 7.35 - 7.5 (4H, m), 7.95 - 8.1 (3H, m).

 Reference Example 86

A mixture of 2-bromo-3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propionate (4.00 g), 1,8-diazabicyclo [5.4.0] -7 -undeken (1.41 g) and toluene (80 ml) was stirred for 2 hours at 90-100 ^° C. The reaction mixture was poured into water and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off under reduced pressure. The remaining oily product is chromatographed on silica gel. From the fractions eluted with ethyl acetate-hexane (1: 3, v / v), methyl- (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] acrylate ( 2.71 g, 83%). Recrystallization from a mixture of diethyl ether-isopropyl ether leads to colorless prisms, so pl. 116 - 117 ^o C.

 Reference Example 87

In the same manner as in Example 23, by reduction of methyl- (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] acrylate with diisobutylaluminum hydride, (E) -3 was obtained - [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl-2-pyridyl-2-propen-1-ol. The yield is 76%. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to colorless prisms, so pl. 116 - 117 ^o C.

 Reference Example 88

In the same manner as in Example 34, by the oxidation of (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propen-1-ol with manganese dioxide, (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl-2-propen-1-al. The yield is 92%. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to colorless prisms, so pl. 147 - 148 ^o C.

 Reference Example 89

Basically the same as in Example 24, by catalytic hydrogenation of (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propen-1-ol, obtained 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propanol. The yield is 82%. Recrystallization from a mixture of diethyl ether-isopropyl ether leads to colorless needles, so pl. 89 - 90 ^o C.

 Reference Example 90

 Basically the same as in Example 72, 3- [2- (5-methyl-2-phenyl-) was obtained by methanesulfonation of 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propanol 4-oxazolylmethoxy) pyridyl / propylmethanesulfonate. The yield is 89%.

NMR (δ ppm in CDCl ₃ ): 1.95 - 2.15 (2H, m), 2.48 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.01 (3H, s), 4.24 (2H, t, J = 5.5 Hz), 5.28 (2H, s), 6.78 (1H, d, J = 8.5 Hz), 7.35 - 7.5 (4H, m); 7.95 - 8.1 (3H, m).

 Reference Example 91

 Basically, as in example 38, by the reaction of 3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propylmethanesulfonate with potassium cyanide, 4- [2- (5-methyl- 2-phenyl-4-oxazolylmethoxy) pyridyl] butyronitrile as an oily product. The yield is 95%.

NMR (δ ppm in CDCl ₃ ): 1.85 - 2.05 (2H, m), 2.35 (2H, t, J = 7 Hz), 2.48 (3H, s), 2, 73 (2H, t, J = 7.5 Hz), 5.28 (2H, s), 6.80 (1H, d, J = 8.5 Hz), 7.35 - 7.5 (4H, m ), 7.95-8.1 (3H, m).

 Reference Example 92

 Basically the same as in Example 64, by reaction of (E) -3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] -2-propen-1-al with diethyl cyanomethylphosphonate with Subsequent catalytic hydrogenation, 5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] valeronitrile was obtained. The yield is 96%.

NMR (δ ppm in CDCl ₃ ): 1.55 - 1.85 (4H, m), 2.37 (2H, t, J = 6.5 Hz), 2.48 (3H, s), 2.59 (2H, t, J = 7.5 Hz), 5.27 (2H, s), 6.77 (1H, d, J = 8.5 Hz), 7.35 - 7.5 (4H , m), 7.95 - 8.1 (3H, m).

 Example 1

A mixture of 3- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] propionitrile (0.7 g), sodium azide (0.411 g), ammonium chloride (0.337 g) and N, N-dimethylformamide (15 ml) was stirred for 24 hours at 120 ^° C. The reaction mixture was poured into water and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water and dried, after which the solvent was distilled off; there remains 5- [2- [4- [2- (5-methyl-2-phenyl-oxazolyl) ethoxy] phenyl] ethyl] tetrazole (0.38 g, 48%), which is recrystallized from ethyl acetate-hexane to give colorless prisms, so pl. 143 - 144 ^o C.

 Examples 2-14.

 The compounds shown in table 4 and table 5 were obtained essentially the same as in example 1.

 Note 1 (to table. 5).

Elemental analysis for C ₁₆ H ₁₈ N ₅ O ₂ Na • 1/2 H ₂ O:
Calculated,%: C 55.81; H 5.56; N, 20.34
Found,%: C 56.01; H 5.82; N, 20.68
Example 15

A mixture of (E) -5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) styryl] tetrazole (1.0 g), palladium carbon (5%, 0.5 g) and dioxane (100 ml) subjected to catalytic hydrogenation at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure; 5- [2- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] ethyl] -tetrazole (0.81 g, 81%) was obtained, which was recrystallized from methanol-chloroform to give colorless plates, so pl. 203 - 204 ^o C.

 Example 16

Basically, as in Example 15, 5- [4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole is subjected to catalytic hydrogenation with the formation of 5- [4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyl] tetrazole, which is recrystallized from a mixture of ethyl acetate-hexane to give colorless prisms, so pl. 116 - 117 ^o C.

 Examples 17-27.

 The compounds shown in table 6 and table 7, obtained in the same manner as in example 1.

 Example 28

According to the method described for Example 1, (E, E) -5- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienitrile is reacted with sodium azide and chloride ammonium to form 5- [4- [3- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole. Recrystallization from methanol leads to colorless prisms, so pl. 201 - 202 ^o C.

 Example 29

According to the method described for Example 1, (E, E) -5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -2,4-pentadienitrile is reacted with sodium azide and chloride ammonium to form 5- [4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] -1,3-butadiene-1-yl] tetrazole. Recrystallization from a mixture of dichloromethane-methanol leads to colorless prisms, so pl. 192 - 193 ^o C.

 Examples 30-35.

 The compounds shown in table 8, obtained by the method described in example 15.

 1) Oil (to table. 8).

NMR (δ ppm in CDCl ₃ ): 1.15 (3H, d, J = 7 Hz), 1.35 - 1.85 (4H, m), 2.47 (3H, s), 2, 47 - 2.68 (1H, m), 2.68 - 2.95 (2H, m), 4.91 (2H, s), 6.73 (2H, d, J = 8.8 Hz), 6 92 (2H, d, J = 8.8 Hz), 7.35 - 7.52 (3H, m), 7.90 - 8.05 (2H, m).

 Example 36

Basically the same as in Example 1, 5- [3- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] propyl] -1H-tetrazole was obtained by the reaction 4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] butyronitrile with sodium azide and ammonium chloride. The yield is 45%. Recrystallization from a mixture of methanol-ethyl acetate leads to colorless prisms, so pl. 137 - 138 ^o C.

 Example 37

In the same manner as in Example 1, 5- [4- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] butyl] -1H-tetrazole was obtained by the reaction 5- [2- (5-methyl-2-phenyl-4-oxazolylmethoxy) -5-pyridyl] valeronitrile with sodium azide and ammonium chloride. The yield is 46%. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 104 - 105 ^o C.

Example composition 1 (preparation of tablets)
(1) 5- [2- [4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] ethyl] tetrazole (compound obtained in example 1), g - 10
(2) Lactose, g - 50
(3) Corn starch, g - 15
(4) Calcium salt of carboxymethyl cellulose, g - 44
(5) Magnesium stearate, g - 1 - 1000 tablets 120 g
All amounts of the above components (1), (2) and (3), as well as 30 g of component (4), are triturated with water, dried in a vacuum, and then granulated. The powder thus granulated is mixed with 14 g of component (4) and 1 g of component (5), after which tablets are formed using a tablet preparation device; 1000 tablets were obtained, each of which contains 10 mg of component (1).

Example composition 2 (preparation of tablets)
(1) 5- [3- [4- [2- (5-Methyl-2-phenyl-4-osazolyl) ethoxy] phenylpropyl] tetrazole (the compound obtained in example 7), g - 30
(2) Lactose, g - 50
(3) Corn starch, g - 15
(4) Calcium salt of carboxymethyl cellulose, g - 44
(5) Magnesium stearate, g - 1 - 1000 tablets 140 g
All amounts of the above components (1), (2), and (3), as well as 30 g of component (4), are triturated with water, dried in a vacuum, and then granulated. The powder thus granulated is mixed with 14 g of component (4) and 1 g of component (5), after which tablets are formed using a tablet preparation device; 1000 tablets were obtained, each of which contains 30 mg of component (1).

Claims (21)

1. Derivatives of tetrazole of the formula I

where n = 1, 2, 3;
A is an aromatic 5 membered cyclic residue of the formula

where B ¹ is S, O or NR, where R is a lower alkyl group;
B ² is N or CR ² where R ² is hydrogen or lower alkyl;
R ¹ - C ₁ - C ₈ alkyl, phenyl unsubstituted or substituted with halogen or C ₁ - C ₄ alkyl, naphthyl, C ₃ - C ₇ cyclic alkyl, thienyl, furyl, benzo (b) furanyl, an amino group substituted with C ₁ - C ₄ alkyl and phenyl;
Y is alkylene or alkenylene containing 1 to 5 carbon atoms;
X is CH or N,
or their pharmaceutically acceptable salts. 2. The compound according to claim 1, where A is a group

where R ¹ - C ₁ - C ₈ alkyl, phenyl, which is optionally substituted with halogen or C ₁ - C ₄ alkyl, naphthyl, C ₃ - C ₇ cyclic alkyl, thienyl, furyl, benzo (b) furanyl, an amino group substituted with C ₁ - C ₄ alkyl and phenyl;
R ² is hydrogen or a lower alkyl group;
B is O or S,
or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where A is a group of the formula

where B is O or S;
R ³ is phenyl;
R ⁴ is C ₁ -C ₈ alkyl;
or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, where B ¹ is O, S or NR, where R is a lower alkyl group;
B ² - N, or a pharmaceutically acceptable salt thereof.  5. The compound according to claim 1, where n = 1 or 2, or its pharmaceutically acceptable salt.  6. The compound of claim 1, wherein X is CH, or a pharmaceutically acceptable salt thereof.  7. The compound according to claim 1, where Y is alkylene with 1 to 5 carbon atoms, or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1, where Y is —CH ₂ CH ₂ CH ₂ - or —CH ₂ CH ₂ CH ₂ CH ₂ -, or a pharmaceutically acceptable salt thereof.  9. The compound of claim 1, which is 5- [2- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] ethyl] tetrazole, or a pharmaceutically acceptable salt thereof.  10. The compound according to claim 1, which is 5- [2- [2- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] -5-pyridyl] ethyl] tetrazole, or a pharmaceutically acceptable salt thereof .  11. The compound according to claim 1, which is 5- [3- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] propyl] tetrazole, or a pharmaceutically acceptable salt thereof.  12. The compound according to claim 1, which is 5- [4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] butyl] tetrazole, or a pharmaceutically acceptable salt thereof.  13. The compound according to claim 1, which is 5- [5- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) phenyl] pentyl] tetrazole, or a pharmaceutically acceptable salt thereof.  14. The compound according to claim 1, which is 5- [3- [4- (5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] propyl] tetrazole, or a pharmaceutically acceptable salt thereof.  15. The compound according to claim 1. representing 5- [5- [4- [5-methyl-2- (2-naphthyl) -4-oxazolylmethoxy] phenyl] pentyl] tetrazole, or a pharmaceutically acceptable salt thereof.  16. The compound according to claim 1, which is 5- [3- [4- [5-methyl-2- (2-furyl) -4-oxazolylmethoxy] phenyl] propyl] tetrazole or a pharmaceutically acceptable salt thereof.  17. The compound according to claim 1, which is 5- [3- [4- (1-methyl-5-phenyl-1,2,4-triazol-3-ylmethoxy) phenyl] propyl] tetrazole, or a pharmaceutically acceptable salt thereof .  18. The compound according to claim 1, which is 5- [3- [4- [5-methyl-2- (benzo (b) furan-2-yl) -4-oxazolylmethoxy] phenyl] propyl] tetrazole, or its pharmaceutically acceptable salt. 19. A pharmaceutical composition having a hypoglycemic effect, comprising an active ingredient and an inert excipient, characterized in that it contains a compound of formula I as an active ingredient

where A, X, Y and n have the meanings indicated in claim 1,
or a pharmaceutically acceptable salt thereof in an effective amount. 20. A pharmaceutical composition having a hypolipedic effect, comprising an active ingredient and an inert excipient, characterized in that the compound of formula I is contained as an active ingredient

where A, X, Y, and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof in an effective amount. 21. A method of obtaining a compound of formula I

where A, X, Y and n have the meanings indicated in claim 1,
characterized in that the reaction of the compounds of formula

where each character has the meaning defined above,
with metal azide.

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