Derivatives tetrazole, method for their production and pharmaceutical compositions based on them

 

(57) Abstract:

Describes the new derivatives tetrazole General formula I, where the values of A, X, Y, n listed in paragraph 1 of the claims that have effect in reducing blood sugar and lipid in the blood. Also describes the method of production thereof and pharmaceutical compositions based on them. 4 C. and 17 C.p. f-crystals, 8 PL.

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia.

As a means for treating diabetes using different biguanide compounds and compounds sulfonylureas. However, the application of biguanide compounds currently difficult because they cause lactic acidosis, and connection sulfonylureas, has a strong effect in reducing the blood sugar, often cause severe hypoglycemia and require special attention when applying. Known derivatives tetrazole with substituents in position 5. For example, in the Journal of Medicinal Chemistry, 35, p. 944 (1992) describes several derivatives of tetrazole, substituted in position 5 with action to reduce altoadige of the invention is the search for 5-substituted derivatives of tetrazole, with a stronger effect in reducing glucose and lipid in the blood. Found that the introduction of phenyl groups or peredelnoj group, substituted alkoxygroup containing optionally substituted tetracyclic residue as a substituent in position 5 significantly increases the activity. Thus, the aim of the invention is to increase the activity of derivative tetrazole.

This goal is achieved in these derivatives tetrazole formula I

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

Derivatives tetrazole and formula I is produced by interaction of the compounds of formula II

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where each symbol is defined above significance, with a metal azide.

In the formula I preferably benzene to which the accession of the fragment-Y-.

In the above formulas I and II is preferred heterocyclic residue represented by the symbol A, which 1) is five-membered ring, 2) represents a heterocyclic ring containing as atoms forming the ring, at least one nitrogen atom, 3) is a ring, which is aromatic ring with an unsaturated bond, 4) optionally contains as atoms forming the ring, two or more nitrogen atoms, and in addition to nitrogen atoms optionally contains heteroatoms, such as oxygen atom and sulfur atom, and 5) optional may have a substituent at any possible position in the ring. Examples of the heterocyclic residue represented by the symbol A, include pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (2-imidazolyl, 4-imidazolyl), triazolyl (1,2,3-triazole-4-yl, 1,2,4-triazole-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 any possible positions of the ring. Substituents may be the remains of hydrocarbon residues of heterocyclic compounds or amino group, which may optionally contain additional samestate alicyclic hydrocarbons, the remains of the alicyclic-aliphatic hydrocarbon residues, aromatic-aliphatic hydrocarbons and residues of aromatic hydrocarbons. Examples of these residues of aliphatic hydrocarbons include balances of saturated aliphatic hydrocarbons having 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; and the remains of the C2-8unsaturated aliphatic hydrocarbon of 2-8 carbon atoms, such as ethynyl, 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, ethynyl, 1-PROPYNYL, 2-PROPYNYL, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl. Among them, preferred aliphatic hydrocarbons having a number of carbon atoms does not exceed 4. Examples of these balances or alicyclic hydrocarbons include balances saturated alicyclic hydrocarbons with the number of carbon atoms from 3 to 7, as well as cyclopropyl,glendorado with 5-7 carbon atoms, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadiene. Among them, preferred residues alicyclic hydrocarbons with 5 and 6 carbon atoms. Examples of residues, alicyclic-aliphatic hydrocarbon includes, along with the remnants formed by the above-mentioned residues, alicyclic hydrocarbon with the remnants of the aliphatic hydrocarbon residue with 4 to 9 carbon atoms, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, 3-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylmethyl, cycloheptylmethyl and cycloheptylmethyl. Examples of these aromatic residues of aliphatic hydrocarbons include phenylalkyl with 7-9 carbon atoms, such as benzyl, phenethyl, 1-phenylethyl, 3-phenyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl; and nafcillin from 11 to 13 carbon atoms, such as-naphthylmethyl-naphtalate-naphthylmethyl and-naphtalate. Examples of these residues of aromatic hydrocarbons include phenyl and naphthyl ( -naphthyl, -NAF is Yes contains 1-3 atom, selected from N, O and S as atoms forming a ring linked through carbon atoms. Specific examples of the heterocyclic group include aromatic 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); and saturated heterocyclic group such as piperidinyl (2-pyrrolidinyl, 3-pyrrolidinyl), morpholinyl (2-morpholinyl) and tetrahydrofuran (2-tetrahydrofuryl, 3-tetrahydrofuryl and so on).

The amino group may be substituted. Under the substituted amino group mean N-monosubstituted amino group and N,N-disubstituted amino group.

"N-monosubstituted amino group" means an amino group with one substituent. Examples of substituents include a lower alkyl group (for example, a group with 1-4 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, and so on), cycloalkyl group (for example, with 3-7 carbon atoms, tsiklicheskaya group (for example, pyridyl, thienyl, furyl, oxazolyl, thiazolyl and so on), non-aromatic heterocyclic group (for example, piperidinyl, pyrrolidinyl, morpholinyl and so on), arylalkyl group (for example, benzyl, phenetyl and so on), acyl group (e.g. acetyl, propionyl and so on), carnemolla group, N-monosubstituted carnemolla group (for example, N-methylcarbamoyl, N-ethylcarbazole, N-propellerblades and so on), N,N-disubstituted carnemolla group (for example, N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbazole, N,N-diethylcarbamoyl and so on), the lower alkoxycarbonyl group (for example, with 2-5 carbon atoms, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and so on), the hydroxy-group, the lowest alkoxygroup (for example, a group with 1-4 carbon atoms, such as methoxy, ethoxy-, propoxy-, butoxypropan and so on), as well as arylalkylamine (for example, benzyloxy, penetrate, naphthyloxy and so on).

"N,N-disubstituted amino group" means an amino group with two substituents. Examples of substituents include, on the one hand, mostly listed for the above-mentioned "N-monosubstituted amino group", and on the other hand is an alkyl group, cycloalkyl group, aryl group and arylalkyl group. In addition, some what aka cyclic amino group include 1-azetidine-, 1-pyrrolidino-, piperidino, morpholino, piperazinone and piperazinone containing in position 4, for example, a lower alkyl group (for example, from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and so on), arylalkyl group (for example, benzyl, phenetyl, naphthylmethyl and so on) or aryl group (e.g. phenyl, naphthyl and so on).

The above-mentioned hydrocarbon residue or heterocyclic residue rings as substituents in the heterocyclic residue And may have a Deputy or deputies in possible positions. When the hydrocarbon residue contains alicyclic group, or when the remainder of the heterocyclic ring is saturated, each of them can contain from one to three lower alkyl groups with 1-3 carbon atoms (e.g. methyl, ethyl, propyl and isopropyl) in the ring (including the atoms of the ring). In addition, when the remainder of the hydrocarbon contains a residue of aromatic hydrocarbon or when the heterocyclic group is unsaturated, they can contain from 1 to 4 identical or different substituents. Among these substituents include halogen (fluorine, chlorine, iodine), hydroxy-, cyano-, nitro-, triptorelin group, lower alkoxygroup (for example, groups with 1-4 carbon atoms the group with 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl), lower alkoxycarbonyl group (for example, groups with 2-4 carbon atoms, such as methoxycarbonyl, etoxycarbonyl and propoxycarbonyl), the lowest allylthiourea (for example, groups with 1-3 carbon atoms, such as methylthio, ethylthio, propylthio and isopropylthio), and the lowest alkylamino (for example, a group with 1-4 carbon atoms, such as methylamino, ethylamino and dimethylaminopropyl).

When the heterocyclic residue represented by the symbol A, contains two or more hydrocarbon residue as substituents, and when these hydrocarbon residues are located in adjacent positions of the aromatic 6-membered heterocyclic rings, they can be joined together to form a condensed ring. This means that the two hydrocarbon residue linked to each other to form a saturated or unsaturated bivalent linear hydrocarbon residue with 3 to 5 carbon atoms. Specific examples of the linear hydrocarbon residue include-CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH= CHCH2-, -CH=CH-CH=CH-, -CH=CH-CH= CH-CH2and-CH=CH-CH2CH which is represented by the formula

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where B1represents a sulfur atom, an oxygen atom or a group NR [where R denotes hydrogen, a lower alkyl group (for example, groups with 1-3 carbon atoms, such as methyl and ethyl) or arylalkyl group (for example, benzyl group and phenethyl)]; and B2represents a nitrogen atom or C-R2{(R2is hydrogen or a lower alkyl group, optionally substituted hydroxyl group; R1is hydrogen, optionally substituted hydrocarbon residue or heterocyclic residue; provided that R1and R2can be combined with each other to form a condensed ring, if R1connected with one of the forming ring carbon atoms adjacent to the carbon atom, which is the substituent R2}. Hydrocarbon residue, a heterocyclic residue represented as R1and the substituents in these groups are the same as those described above for the 5-membered heterocyclic residue.

Examples of the lower alkyl groups denoted by R2are 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 atoms pleactale is - position. When B2represents C-R2and R2is hydrogen, the ring may be substituted by R1in position B2. This heterocyclic residue is linked via a suitable atom of the ring, and preferred is a group linked through a carbon atom adjacent to the nitrogen atom. For example, when B1represents NR, B2represents C-R2and R2is hydrogen, a preferred example is group (III), connected through B.

Among the heterocyclic groups represented by the above formula, especially preferred are thiazolyl or oxazolyl represented by the formula

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[where R1and R2have the values indicated above; each of R3and R4represents hydrogen, optionally substituted hydrocarbon residue or an optionally substituted heterocyclic residue, and they can by linking with each other to form a condensed ring; B is an oxygen atom or sulfur] . Hydrocarbon residue or heterocyclic residue represented as R3or R4and the substituents in them are the same as described above for the remainder of the aromatic 5-membered heterocyclic ring, R3and R4can about the who 5-membered heterocyclic ring, having two hydrocarbon residue as substituents in adjacent positions.

The ring containing X as a component of its atom is a benzene ring, when X represents CH, or pyridine ring, when X is N. Preferably, X was CH. The symbol n = 1, 2, 3, preferably 1 or 2. Bivalent hydrocarbon residue represented by the symbol Y may be linear or branched, may be saturated or unsaturated and usually includes alkylene and alkeneamine 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. Alkeneamine include-CH= CH-CH=CH -, and so on, Among them the preferred 1,3-propylene and 1,4-butylene.

Compound I according to this 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, the preferred pharmaceutically acceptable salts, examples of which include salts with inorganic bases, salts with organic bases, salts with organic acids and salts with basic or acidic amino acids. Predoctor and potassium salt; salts of alkaline earth metals such as calcium salt or magnesium salt; and 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-dibenziletilendiaminom. Preferred examples of the 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, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonate, benzosulfimide or para-toluensulfonate. Preferred examples of salts with basic amino acid include salts with arginine, lysine or ornithine, and preferred examples of salts with acidic amino acid include salts with aspartic acid or glutamic acid.

Compound I according to this invention or its pharmaceutically acceptable salts have hypogly is correctly applied to mice in amounts of 15 mg/kg, there have been no changes in body weight or liver weight compared to the control trials. In addition, none of the test animals was not killed in oral administration of the compound obtained in example 14, with a dose of 100 mg/kg or intraperitoneal administration of 50 mg/kg of the Compounds according to this invention can be used as therapeutic agents in the treatment of diabetes and hyperlipemia for mammals, including humans. Compound I can be used orally or neironalna in the form of solid compositions such as tablets, capsules, granules or powders or in the form of liquid compositions, such as syrups or injections prepared using pharmaceutically acceptable carriers.

As pharmaceutically acceptable carriers using conventional organic or inorganic carriers for pharmaceuticals, more specifically, for example, fillers, lubricants, binders and disintegrators for solid preparations, and solvents, soljubilizatory, suspendresume agents, isotonic means, buffer agents and means of local anesthesia. In addition, if necessary, further use of such fillers include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicon dioxide. Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc and colloidal silicon dioxide. Preferred examples of binders include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone. Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium salt croscarmellose and sodium salt carboxymethyllysine starch. Preferred examples of solvents include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of solubilization include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, Tris-aminomethane, cholesterol, tri-ethanolamine, sodium carbonate and sodium citrate. Preferred examples suspendida agents include surfactants such as steartrimonium, sodium lauryl sulfate, lauramidopropyl, lecithin, benzalkonium chloride, chloride benzene, glycerol monostearate, and gelosi, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Preferred examples of isotonic means include sodium chloride, glycerin and D-mannitol. Preferred examples of the buffer agent include buffer solutions of phosphates, acetates, carbonates and citrates. Preferred examples of local anaesthetics include benzyl alcohol. Preferred examples of the antiseptics include esters of para-oksibenzoynoy acid, chlorbutanol, benzyl alcohol, finitely alcohol, dehydrator acid and sorbic acid. Preferred examples of the antioxidants include sulfites and ascorbic acid.

The connection I usually use in oral form, such as tablets, capsules (including soft capsules and microcapsules), powders and granules, but in some possible cases, it can be used other than oral method in the form of, for example, injections, suppositories or balls. Daily dose for oral administration for adults is in the range from 0.05 to 10 mg/kg; preferably divided into one to three daily doses.

The compounds I according to this invention was prepared as follows.

(Saccio conversion of compound II to compound I spend, for example, in accordance with the method described in Journal of American Chemical Society, 80, p. 3908 (1958), by reacting the compound (II) with sodium azide and ammonium chloride in N,N-dimethylformamide. Appropriate amounts of ammonium chloride and sodium azide are in the range from 1 to 7 mol, preferably from 1 to 5 mol per 1 mol of compound (II). This reaction is carried out at temperatures in the range from 50 to 180oC for 1-50 hours in Addition, the reaction conversion of compound II to compound I can also be, for example, in accordance with the method described in Journal of Organic chetistru, 56, p. 2395 (1991), by reaction of compound II with azide trimacinolone or azide anti-followed by treatment with acid.

Thus obtained derivative of tetrazole and their salts can be isolated and purified by known means of separation and purification such as concentration, concentration under reduced pressure, crystallization, recrystallization, phasic transfer and chromatography.

(Method B)

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[where Y1unsaturated bivalent hydrocarbon residue, Y2- saturated bivalent hydrocarbon residue, and other symbols have the above meanings].

Nanosystem as Y, and a saturated bivalent hydrocarbon residue represented as Y is a saturated residue represented as y

In this way the connection I-I from among the compounds obtained by the method A, is subjected to recovery with the formation of compound I-2. Although this reaction may also be conducted by per se known method, it is advantageous to carry out by catalytic hydrogenation using a metal catalyst. In accordance with the usual method is 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 ATM. 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-tetrachlorethane, ethyl acetate, acetic acid or a mixture of these solvents. For a favorable reaction as the catalyst used, for example, a transition metal, such as palladium, platinum or rhodium. The reaction temperature lies in>/P>Thus obtained derivative of tetrazole and their salts can be isolated and purified using conventional means such as concentration, concentration under reduced pressure, crystallization, recrystallization, phasic transfer and chromatography.

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

(The way IN)

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[in the formula IV, Z denotes a halogen atom, in the formula VIII-1 Q denotes the deleted group, and other symbols are as defined above values].

Under the halogen atom represented by the symbol Z, is meant fluorine, chlorine, bromine and iodine. Under the deleted group, represented by the symbol Q, among other means, for example, methanesulfonate - and para-toluensulfonate, in addition to atoms of Halogens, including chlorine, bromine and iodine.

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

oC, particularly preferably from 0 to 100oC. the reaction Time is from about 1 to 24 hours

After this connection VII-1 is introduced into a reaction with a halogenation agent or sulfurous agent to obtain compound VII-1. As the halogenation agent is preferable to use, for example, hydrochloric acid, thionyl chloride and tribromide phosphorus; in this case, get the connection VIII-1, where Q is chlorine or bromine. This reaction is carried out in a suitable inert solvent (e.g. benzene, toluene, xylene, chloroform and dichloromethane), or use an excessive amount of halogenation agent as the solvent at temperatures in the range from -10 to 80oC. the Amount of halogenation agent is 1-20 mol relative to compound VII-1. As sulfurous agent, it is preferable to use, for example, methanesulfonate, para-taillored and benzosulphochloride; obtained compound VIII-1, where Q denotes methansulfonate-pair-toluensulfonate and benzosulfimide is e, xylene, diethyl ether, ethyl acetate, tetrahydrofuran, chloroform and dichloromethane) in the presence of a base (e.g. triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate) at temperatures from -10 to 30oC. Number sulfureuse agent and the base are in the range from 1 to 2 mol relative to 1 mol of compound VIII-1, respectively. By carrying out the reaction of 1 mol of compound VIII-1, where Q is chlorine, bromine or sulfonyloxy, 1-1,5 mol of sodium iodide or potassium iodide can also obtain compound VIII-1, 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 80oC. After carrying out the reaction of compound VIII-1 with potassium cyanide or sodium cyanide obtain compound II-1. The reaction is usually conducted in a solvent (e.g. ether, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, methanol, ethanol, ethyl acetate, acetone, 2-butanone, N,N-dimethylformamide and dimethyl sulfoxide) at temperatures in the range from 0 to 100oC. the amount of potassium cyanide or sodium cyanide is from 1 to 8 mol against the stop using the normal procedures for isolation and purification, for example, concentration, concentration under reduced pressure, crystallization, recrystallization, phase transfer and chromatography.

(Method D)

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[where J is hydrogen or a lower alkyl group, R5- lower alkyl group, q = 0 or 1, and the remaining symbols are defined above value].

Examples of lower alkyl groups, designated as J, or R5include groups containing 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc.

In this way aldehyde derivative VI-2 is introduced into the reaction with the ester derivative cyanomethylphosphonate acid XX and receive unsaturated nitrile derivative II-2. In accordance with the conventional method, the reaction of the 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, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and a mixture of these solvents. Examples of bases include salts of alkaline met the ins, such as pyridine, triethylamine, N,N-dimethylaniline; metal hydrides such as sodium hydride and potassium hydride; ethoxide sodium, sodium methoxide and tert-piperonyl potassium, and the number of these used grounds varies from 1 to 5 molar equivalents relative to the compound VI-2. The amount used of the compound IX is changed 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 in the range from -50 to 150oC, preferably from about -10 to 100oC. the reaction Time varies from 0.5 to 30 hours By restoring the thus obtained compound (II-2 to obtain compound II-3. This recovery is carried out in much the same way as in method B.

Thus obtained nitrile derivatives can be extracted and cleaned using normal procedures of separation and purification such as concentration, concentration under reduced pressure, crystallization, recrystallization, phasic transfer and chromatography.

(Method D)

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[where R6and R7independently represent a lower alkyl group, q = 0 or 1; and the remaining symbols are defined above value].

carbon such as methyl, ethyl, propyl, isopropyl, butyl, etc.

According to this method, first aldehyde or ketone derivative VI-3 is introduced into reaction with a derivative phosphonooxy acid or derivative - phosphonocrotonate acid X and polyunsaturated complex ether derivative XI. The reaction of the compound VI-3 with compound X is carried out in much the same way as the reaction of the compound VI-2 connection IX according to the method, then the connection XI restore and get alcohol derivative VII-2. This reduction can be carried out per se known method, for example, the recovery of the metal hydride, the metal hydride recovery and restoration of the DIBORANE and substituted borane. In other words, this reaction is performed by treating compound XI reducing agent. As the reductant will mention, for example, metal hydride complex such as alkali metal borohydride (e.g. sodium borohydride and lithium borohydride) and sociallyengaged, and DIBORANE; best reaction is carried out using diisobutylaluminium. This reaction is carried out in an organic solvent which does not affect the reaction. Using solvent, adequac benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachlorethane; 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 combination of these solvents. The reaction temperature range from -20 to 150oC, particularly preferably from 0 to 100oC. the reaction Time is from about 1 to 24 hours After the reconnection VII-2 receives the connection VII-3. This reduction is carried out in much the same way as in method B. Compound VII-3 is treated in much the same way as in the method, including the conversion of compound VII-1 in compound VIII-2 and then to compound II-1 to obtain the nitrile derivative (II-4.

Thus obtained nitrile derivative (II-1 can be extracted and cleaned using normal procedures of separation and purification such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, phasic transfer and chromatography.

Pyridine aldehyde derivative VI-4, which are used in sposobem or iodine, and other symbols are as defined above values].

In this method first 2-chloro-5-nitropyridine XII injected into the reaction with the alcohol derivative III and get a connection XIII. The usual method of conducting a reaction of the compound XII with the 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, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane; and of them mixed solvent. Examples of the base include alkali metal salts, such as sodium hydroxide, potassium hydroxide, carbamate potassium, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine and N, N-dimethylaniline; metal hydrides such as sodium hydride and potassium hydride; tert-piperonyl potassium and so on; the amount of these bases is preferably about 1-5 molar equivalents, relative to compound III. This reaction is usually carried out at temperatures in the range from -50 to 150oC, preferably from about -10 to 100oC. the reaction Time varies from 0.5 to 30 hours After saudino yourself in a known manner, better to spend it by the catalytic hydrogenation using a metal catalyst. In accordance with the usual method of catalytic hydrogenation is carried out in a solvent in the presence of a catalyst in an atmosphere of hydrogen at 1-150 atmospheres. Examples of the 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-tetrachlorethane, ethyl acetate, acetic acid, or their mixture. Favorable reaction promotes the use as a catalyst, for example, compounds of metal, such as Nickel, and a catalyst based on a transition metal, such as palladium, platinum and rhodium. The reaction temperature ranges from 0 to 100oC, preferably from 10 to 80oC, the reaction time ranges from 0.5 to 50 hours After compound XIV-1 is entered in per se known reaction Sandmeyer and get a halogenated derivative of XI. In this reaction, the first compound XIV-1 diazotised by adding dropwise to n the ne acid or idiscovered acid, followed by reaction with aqueous solution of sodium halide or potassium halide to obtain the 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 their mixture. The reaction temperature range from -80 to 100oC, preferably from -50 to 60oC, the reaction time is from 0.5 to 50 hours After compound XV is treated with, for example, butyllithium, tert-butyllithium, methyllithium, phenyllithium or phenylmagnesium obtaining lithium compound, which is then injected into the reaction with N,N-dimethylformamide (DMF) and get a connection VI-4.

(Way W)

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[in the formula XVI-1 and II-5 G denotes a cyano (CN) or COOR7; and other symbols have the meanings given above].

The reaction converting compound XIV-2 in compound XVI-1 is performed according to the method described in Journal of Medicinal Chemistry, 35, p. 2617 (1992). More specifically, the connection of the XIV-2 is introduced into the so-called reaction arilirovaniya of Meerwein, which involves the diazotization of compound XIV-2 in the presence of halogen acids (HZ'), which is then introduced into the reaction with ether acid (CH
(for example, magnesium carbonate and calcium carbonate, a bicarbonate of an alkali metal (sodium bicarbonate and potassium bicarbonate) and an acetate of an alkali metal (sodium acetate and potassium acetate); and organisationally, 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-undecene. The amount of these bases is preferably lies in the range from about 1 to 5 molar equivalents relative to the compound XVI-1. Typically this reaction is carried out at temperatures in the range from -20 to 150oC, preferably from about -10 to 120oC.

(Method C)

< / BR>
[wherein each symbol has the meaning given above].

This process is halogenopyrimidines derived XVI-2 restore and get propionitrile derived II-6. This method may be implemented, for example, by catalytic regeneration in much the same way as in method B, or in the usual way using zinc or iron and acetic acid.

(Method)

< / BR>
(wherein each symbol has the meaning given above).

In this method first by the condensation reaction of compound VI-2 and derived complex ester tsianuksusnogo acid and get a connection 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; aromaticheskimi, dioxane and tetrahydrofuran; pyridine, N,N-dimethylformamide, dimethylsulfoxide and acetic acid. Examples of bases include sodium alkoxide (e.g. sodium methoxide and ethoxide sodium), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate, or secondary amines, such as piperazine, pyrrolidine, morpholine, diethylamine and Diisopropylamine, etc., the Amount of base ranges 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 150oC, preferably from 20 to 120oC for a time from 5 to 30 hours After this connection XVII restore and get the connection XVIII. This reduction can be conducted by per se known method, for example, the restoration of using metal hydride, recovery using metal hydride or by catalytic hydrogenation. In other words, this reaction is carried out by treating compound XVII reducing agent. Examples of reducing agents, among others, include a metal hydride complex such as alkali metal borohydride (e.g. sodium borohydride and bolide or salt of the metal, such as ORGANOTIN compound (for example, hydride triphenylamine), a compound of Nickel and a compound of zinc; a catalytic reducing agent, using a catalyst based on a transition metal, such as palladium, platinum and rhodium, and hydrogen; and DIBORANE. The use of alkali metal borohydride (e.g. 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 of a solvent properly selected depending on the types of the reducing agent from among, 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-tetrachlorethane; 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 temperature range from -20 to 150oC, particularly preferably from 0 to 100oC. the reaction Time is from 1 to 24 hours After compound XVIII hydrolyzing, and then evaluation of the ora in the presence of acid or base. Thus obtained carboxylic acid derivative XIX subjected to decarboxylation after isolation or without isolation, and obtain compound II-3. This decarboxylation reaction is carried out in a solvent under 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-tetrachlorethane; 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; and their mixture. The reaction temperature is in the range from 50 to 250oC, particularly preferably from 70 to 160oC. the reaction Time is from 1 to 24 hours

Nitrile derivative can also be obtained by the method or by the method L

(How TO)

< / BR>
(wherein each symbol has the above value).

In this way nitrile derivative (II-5 can be obtained by reaction of compound XX with a compound XXI. This method is carried out in a suitable solvent in the presence of a base. R as dioxane, tetrahydrofuran, dimethoxyethane and so on, alcohols, such as methanol, ethanol, propanol and so on, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane etc., N, N-dimethylformamide, dimethylsulfoxide or a mixture of two or more solvents from the number given. As the bases used alkali metal salts, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., amines, such as pyridine, triethylamine, N, N-dimethylaniline, etc., a metal hydride such as sodium hydride, potassium hydride, etc., metal alkoxide, such as ethoxide sodium, sodium methoxide, tert-piperonyl potassium and so on, 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 150oC, preferably from -10 to 100oC. the reaction Time is usually from 0.5 to 10 hours

< / BR>
In this method first the connection of the XX and derived compounds XXII react with the formation of ester derivative XXIII. This reaction is carried out in the same way as for compound XX and connections XXI according to the method of K. then the compound XIII is turned into alcohol derivative VII-4 method, similar to the I-3 method a similar reaction converting compound VII-3, compound VIII-2 according to the method of D. Compound VIII-3 is transformed into compound II-6 by a method similar to the reaction converting compound VIII-2 in compound II-4 according to method D.

Compound I according to this invention possesses hypoglycemic and hypolipidemic effect. Experimental results confirming these steps below.

Experimental example

Hypoglycemic and hypolipidemic effect in mice

The test compound mixed with turned into powder food (CE-2, Japan Clea) at a ratio of 0.01% or 0.005% of the use in non-feeding mice ADCy(ages 9-14 weeks) for 4 days. During this time the animals had free access to water. From the orbital plexus of veins take the blood, and the amount of content in plasma glucose and triglyceride quantify enzymatic method using respectively the equipment Iatrochem - GZU (A) and Iatro-MA 701 TG (Iatron). Relative values are given as percent reduction compared with the group without medication dosage (table 1).

As stated above, the derivatives of tetrazole I of the present invention showing the second agent for the treatment of diabetes, hyperlipemia, hypertension and related diseases.

Referential 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) in small portions add sodium hydride (60% in oil, 6,92 g) and the mixture is stirred. The reaction mixture is additionally stirred at room temperature for 15 hours, poured into water and then the extraction is carried out with ethyl acetate. An ethyl acetate layer is washed with water and dried (MgSO4), after which the solvent is distilled off under reduced pressure. The remaining crystals are collected by filtration, 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 - 111,5oC.

Referential 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 under a pressure of 1 ATM. The catalyst is filtered off and the filtrate is concentrated under reduced pressure until the remaining crystals. The crystals are collected by filtration and receive 5-amino-2[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy, the.sq. 107-108oC.

Reference example 3.

To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (10.0 g), conc. hydrochloric acid (of 8.47 ml) and acetone (100 ml) at temperatures of 10oC or below added dropwise a solution of sodium nitrite (NaNO2) (2,46 g) in water (10 ml). The mixture is stirred for 30 min at 10oC and add dropwise a solution of potassium iodide (KI) (2,46 g) in water (10 ml). The reaction mixture is stirred for one hour at 30-35oC and one hour at 35-40oC, followed by concentration under reduced pressure. The residue is poured into water, from which the extraction is carried out with ethyl acetate. An ethyl acetate layer is washed with water and dried (MgSO4), after which the solvent is distilled under reduced pressure before formation of an oily product, which was subjected to column chromatography on silica gel. From the faction elyuirovaniya a mixture of ethyl acetate-hexane (1:3, V/V) obtained 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (7,22 g, 52%) which is recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless crystals, so pl. 105-106oC.

Reference example 4.

To a solution of 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (2.5 g) in T1 ml). The mixture is stirred for 15 min at the same temperature and then added dropwise N,N-dimethylformamide (0,71 ml). Remove the cooling bath and the reaction mixture is additionally stirred for 30 min, then to it was added a saturated aqueous solution of ammonium chloride (6 ml). The reaction mixture was poured into water and the extraction is carried out with ethyl acetate. An ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled off under reduced pressure to a residue of 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 get colorless crystals, so pl. 99-100oC.

Reference example 5.

To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzaldehyde (7.0 g) in ethanol (100 ml) under cooling with ice add sodium borohydride (0,473 g) and the mixture is stirred for 2 h at room temperature. To the reaction mixture are added acetic acid (2 ml), then poured into a mixture of ice-water, and then collected by filtration the resulting crystalline precipitate; after further recrystallization from a mixture of ethyl acetate-hexane obtained 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzyl alcohol (6,9 g, 88%) as colourless plates, so pl. 112-11 the mouth (6.8 g) in chloroform (100 ml) is added thionyl chloride (3.1 g), and the mixture is stirred saturated aqueous sodium bicarbonate and then with water, then dried (MgSO4). The solvent is distilled to a residue of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylchloride (6.5 g, 90%) as colourless needles, so pl. 93-94oC.

Reference example 7.

A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylchloride (6.4 g), powdered potassium cyanide (4.0 g) and N,N-dimethylformamide (50 ml) is stirred for two hours at 60oC. the Reaction mixture was poured into water and the extraction is carried out with ethyl acetate. The ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled off and receive a 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -benzylcyanide (5,2 g, 81%). The product is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless needle crystals, so pl. 109-110oC.

Reference example 8.

To a solution of citizen.metropolitan (8,2 g) in tetrahydrofuran (150 ml) at 0oC) in small portions add sodium hydride (60% in oil, 2.0 g). The mixture is stirred for about 15 min, there was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzaldehyde (13,0 g), and the mixture is stirred for 30 min at room temperature. The reaction mixture is poured into SMEs>), after which the solvent is distilled off; it's 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] cinnamonitrile (11.8 g, 85%). The product is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless needle crystals, so pl. 112-113oC.

Examples for reference 9-15.

Compounds in table 2 were obtained in much the same way as described in example 8.

Note 1 (PL. 2).

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

NMR ( M. D. in CDCl3): 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 to 7.32 (d, J = 16.5 Hz) (total 1H), 7,37 and 7,76 (total 2H, each d, J = 9 Hz).

Note 2 (PL. 2).

Used for the subsequent reaction without isolation.

Note 3 (PL. 2).

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

NMR ( M. D. in CDCl3): of 2.24 (3H, s), of 2.38 (3H, s), is 2.88 (2H, t, J = 7 Hz), 4,21 and to 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 in and 6,93 (total 2H, each d, J = 9 Hz), 7,02 (d, J = 12 Hz) and to 7.32 (d, J = 16.5 Hz) (total 1H), 7,37 and to 7.77 (total 2H, each d, J = 9 Hz).

Reference example 16.

A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamonitrile (4,0 temperature at a pressure of 1 ATM. The catalyst is filtered off and the filtrate is concentrated under reduced pressure; remains 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-phenyl]propionitrile (3.7 g, 93%). The product is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless needle crystals, so pl. 109-110oC.

Reference examples 17-21.

Compounds shown in table 3, obtained in much the same way as described in example 16.

Note 1 (PL. 3).

NMR ( M. D. in CDCl3): 1,2 - 2,1 (10H, m), 2,24 (3H, s), to 2.57 (2H, t, J = 7.5 Hz), 2,69 (1H, TT, 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), at 6.84 (2H, d, J = 8 Hz), 7,12 (2H, d, J = 8,5 Hz).

Note 2 (PL. 3).

The overall yield from the corresponding benzaldehyde.

Note 3 (PL. 3).

NMR ( M. D. in CDCl3): at 2.59 (2H, t, J = 7 Hz), only 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), to 7.15 (2H, d, J = 8.5 Hz), 7,2 - 7,5 (5H, m).

Reference example 22.

To a solution of triethylphosphate (11.2 g) in tetrahydrofuran (200 ml) at 0oC small portions add sodium hydride (60% in oil, 2.2 g) and the mixture stirred for 15 min at the same temperature. Then added to the mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzaldehyde (14.0 g), and cm is transouth 2 n HCl, The resulting crystalline precipitate is collected by filtration, recrystallized from a mixture of ethyl acetate-hexane and get ethyl-4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy] cinnamate (15,1 g, 88%). Colorless needles, so pl. 114-115oC.

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 0oC added dropwise toluene solution diisobutylaluminium hydride (1.5 M, 67 ml). The mixture is stirred for 2 h at room temperature and to it was added 2 n HCl (200 ml) under cooling with ice. The organic layer is washed with water, dried (MgSO4) and concentrate; 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. 127-128oC.

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) is subjected to catalytic hydrogenation at a pressure of 1 ATM at room temperature. The catalyst is filtered off and the filtrate is concentrated under reduced pressure; the resulting 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]phenyl] propan-1-ol (2.8 g, 90%), KotoroC.

Reference example 25.

To the mixture 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-phenyl]-propan-1-ol (2.6 g) and benzene (50 ml) add tribromide phosphorus (2.1 g) and the mixture is stirred 2 h at 70oC. the Reaction mixture was poured into water, which make the extraction with ethyl acetate. An ethyl acetate layer is washed with water and dried (MgSO4), after which the solvent is distilled off; remains 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] propyl bromide (0,98 g, 32%) which is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless needle crystals, so pl. 78-79oC.

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%, of 14.2 ml) and acetone (150 ml) at a temperature not exceeding 10oC added dropwise a solution of sodium nitrite (NaNO2) (2,33 g) in water (10 ml). The mixture is stirred for 30 min at 10oC and added Acrylonitrile (CH2=CHCN) (12.1 ml). With vigorous stirring to the mixture, copper oxide (I) (Cu2O) (0.1 g). The reaction mixture was stirred for further one hour at a temperature in the range from 30 to 35oC and followed by concentration under reduced pressure. The concentrate was poured into water, which ptom. An ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled off under reduced pressure. The remaining oily product is subjected to column chromatography on silica gel. Faction buervenich a mixture of ethyl acetate-hexane (1:1, V/V), obtain 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] propionitrile (6.11 g, 48%) which is recrystallized from a mixture of ethyl acetate-hexane and get colorless crystals, so pl. 93-94oC.

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) is subjected to catalytic recovery at a pressure of 1 ATM at room temperature. The catalyst is filtered off, then the filtrate concentrated under reduced pressure. The concentrate is subjected to column chromatography on silica gel. Faction buervenich a mixture of ethyl acetate-hexane (2:3, V/V), obtained 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. 105-106oC.

Reference example 28.

A mixture of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxa and N, N-dimethylformamide (50 ml) is stirred for 2.5 h at 120oC. the Reaction mixture was poured into water, which make the extraction with ethyl acetate. An ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled under reduced pressure; remains (E) -3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]Acrylonitrile (3,2, 89%) which is recrystallized from a mixture of ethyl acetate-hexane and obtain pale yellow crystals, so pl. 116-117oC.

Reference example 29.

The mixture 4-[2-[2-(2-chlorophenyl-5-methyl-4-oxazolyl)ethoxy] -benzaldehyde (2.0 g), ethylcyanoacrylate (0,795 g), pyridine (0.15 g) and pyridine (30 ml) is stirred for 2 h at 100-110oC. the Reaction mixture was poured into water. The resulting crystalline precipitate is collected by filtration and recrystallized from a mixture of dichloromethane-ethanol; ethyl-4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl] -ethoxy] --cyanocinnamate (2,45 g, 96%) as colourless needles, so pl. 120-121oC.

Reference example 30.

To a mixture of ethyl-4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl] -ethoxy] --cyanocinnamate (2.25 g) and dioxane (30 ml)-ethanol (30 ml) under cooling with ice add sodium borohydride (0.06 g). The mixture is stirred for one hour at the same temperature. The reaction mixture by water and dried (MgSO4), after which the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on silica gel. Faction buervenich a mixture of chloroform-methanol (50: 1, V/V), obtained ethyl-3-[4-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl] -ethoxy] phenyl] -2-cyanopropionic (2.25 g, Quant.) in the form of an oily product.

NMR ( M. D. in CDCl3) : of 1.27 (3H, t, J = 7 Hz), 2,39 (3H, s) of 3.00 (2H, t, J = 6.5 Hz), of 3.12 (1H, DD, J = 14 and 8 Hz), up 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), of 7.25 and 7.5 (3H, m), a 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-cyanopropionic (2.24 g), 1 n NaOH (15 ml) and ethanol (50 ml) is stirred for one hour at room temperature. The reaction mixture was poured into water and acidified, the extraction is carried out with ethyl acetate. An ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled under reduced pressure; remains crystalline product, which is added to a 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 column chromatography on silica gel. Of fractions, e is which is recrystallized from a mixture of dichloroindophenol ether and obtain pale yellow crystals, so pl. 88 - 89oC.

Reference example 32.

Ethyl-4-(5-methyl-2-phenyl-4-oxazolidinone)cinnamate get in much the same way as described in example 22, recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless prisms, so pl. 145 - 146oC.

Reference example 33.

(E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-2-propen-1-ol obtained in much the same way as described in example for reference 23, recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless prisms, so pl. 134 - 135oC.

Reference example 34.

To a solution of (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-2-propen-1-ol (3.7 g) in dichloromethane (80 ml) was added activated manganese dioxide (MnO2) (9.0 g); the mixture is stirred for one hour at room temperature. The reaction mixture was filtered through a layer of celite. The filtrate is concentrated under reduced pressure and receive 4-(5-methyl-2-phenyl-4-oxazolidinone)-cinnamaldehyde (2.6 g, 70%) which is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless prisms, so pl. 114 - 115oC.

Reference example 35.

To a solution of citizen.metropolitan (1.3 g) in tetrahydrofuran (50 ml) at 0oC in small portions (5-methyl-2-phenyl-4-oxazolidinone)cinnamic aldehyde (2.0 g), then the mixture is stirred for 30 minutes under ice cooling. The reaction mixture was poured into water, from which the extraction is carried out with ethyl acetate. An ethyl acetate layer is washed with water and dried (MgSO4), then concentrate and get (E,E)-5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2,4-pentadienyl (1.5 g, 68%). Recrystallization of the product from a mixture of ethyl acetate-hexane resulted in colourless needles, so pl. 120 - 121oC.

Reference example 36.

In much the same way as described in example 24, the obtained 3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -propene-1-ol, which is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless prisms, so pl. 72 - 73oC.

Reference example 37.

In much the same way as described in example 25, the obtained 3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] propyl bromide, which is recrystallized from a mixture of diethyl ether-hexane and obtain colorless prisms, so pl. 80 - 81oC.

Reference example 38.

A mixture of 3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-propyl bromide (1.5 g), powdered potassium cyanide (1.52 g) and N,N-dimethylformamide (30 ml) is stirred for 3 h at 80oC. the Reaction mixture was poured into water, from which they conduct extrac is 4-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] butyronitrile (1.2 g, 92%). Recrystallization of the product from a mixture of ethyl acetate-hexane resulted in colourless needles, so pl. 73 - 74oC.

Reference example 39.

In much the same way as described in example 38, received 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl]ethoxy]phenyl]butyronitrile, which is recrystallized from a mixture of diethyl ether-hexane with the formation of colorless needles, so pl. 69 - 70oC.

Reference example 40.

In accordance with the method described in example 22, 4-(5-methyl-2-phenyl-4-oxazolidinone)cinnamic aldehyde is introduced into the reaction triethylphosphate and get ethyl-(E, E)-5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2,4-pentadienoic; followed by recrystallization from a mixture of ethyl acetate-hexane obtained colorless prisms, so pl. 137 - 138oC.

Reference example 41.

In accordance with the method described in example 16, ethyl-(E,E)-5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2,4-pentadienoic subjected to catalytic hydrogenation with the formation of ethyl-5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]valerate. Recrystallization from hexane gives colorless plochodrazni crystals, so pl. 57 - 58oC.

Reference example 42.

To a suspension of sociallyengaged (Li)phenyl] -valerate (2.55 g) in ether (20 ml). The mixture is stirred for 15 minutes under ice cooling, and then to it was added water (2 ml). The insoluble solid is filtered off and the filtrate is concentrated; the resulting 5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -1-pentanol (2.15 g, 94%) which is recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless Blockoban crystals, so pl. 78 - 79oC.

Reference example 43.

In accordance with the method described in example 25, conduct the reaction of 5-[4-(5-methyl-2-phenyl-4-oxazolidinone)-phenyl] -1-pentanol with tribromide phosphorus and get 5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]interbreed. Recrystallization from a mixture of ether-hexane gives colorless needles, so pl. 58 - 59oC.

Reference example 44.

In accordance with the method described for example for reference 38, carried out the reaction of 5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]interbreed with potassium cyanide with the formation of 5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] hexanenitrile. Recrystallization from a mixture of ether-hexane gives colorless prisms, so pl. 76 - 77oC.

Reference example 45.

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 grams), para-hydroxyacetophenone (of 7.95 g), potassium carbonate (NUU mixture was poured into water and the extraction is carried out with ethyl acetate. An ethyl acetate layer washed with water and dried (MgSO4), after which the solvent is distilled off; the resulting 4'-(5-methyl-2-phenyl-4-oxazolidinone)acetophenone (11.6 g, 85%). Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 126 - 127oC.

Reference example 46.

In accordance with the method described for example 22, 4-'(5-methyl-2-phenyl-4-oxazolidinone)acetophenone enter into reaction with trimethylphosphate with the formation of methyl-(E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-2-butenoate. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 125 - 126oC.

Reference example 47.

In accordance with the method described for example 23, methyl-(E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butenoate restore diisobutylaluminium education (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-2-butene-1-ol. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 126 - 127oC.

Reference example 48.

In accordance with the method described for example 34, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butene-1-ol oxidized with activated manganese dioxide with the formation of igodit to colorless prisms, so pl. 94 - 95oC.

Reference example 49.

In accordance with the method described for example 35, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butene-1-al is introduced into the reaction citizen.metropolitan with the formation of (E,E)-5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2,4-hexadienal. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 134 - 136oC.

Reference example 50.

In accordance with the method described for example 45, 4-chloromethyl-5-methyl-2-phenyloxazol enter into reaction with methylrosanilinium with the formation of 3-(5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde. Recrystallization from a mixture of ethanol leads to colorless prisms, so pl. 67 - 68oC.

Reference example 51.

In accordance with the method described for example 22, 3-(5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde enter into reaction with triethylphosphite with the formation of ethyl-3-(5-methyl-2-phenyl-4-oxazolidinone)cinnamate.

Reference example 53.

In accordance with the method described for example 34, (E)-3-[3-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-propen-1-ol oxidized with activated manganese dioxide with the formation of (E)-3 is the CIO to colorless prisms, so pl. 103 - 104oC.

Reference example 54.

In accordance with the method described for example 35, (E)-3-[3-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-propen-1-al is introduced into the reaction citizen.metropolitan with the formation of (E,E)-5-[3-(5-methyl-2-phenyl-4-oxazolidinone)-phenyl] -2,4-pentadienyl in the form of an oily product.

Reference example 55.

In accordance with the method described for example 45, 2-chloromethyl-5-methyl-4-phenylthiazol enter into reaction with para-hydroxybenzaldehyde with the formation of 4-(5-methyl-4-phenyl-2-triazolylmethyl)-benzaldehyde. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 81 - 82oC.

Reference example 56.

In accordance with the method described for example 22, 4-(5-methyl-4-phenyl-2-thiazoleacetate)benzaldehyde enter into reaction with trimethylphosphate with the formation of methyl-4-(5-methyl-4-phenyl-2-thiazoleacetate)cinnamate. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 142 - 143oC.

Reference example 57.

In accordance with the method described for example 23, methyl-4-(5-methyl-4-phenyl-2-thiazoleacetate)cinnamate vosstanavlivat the crystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 125 - 126oC.

Reference example 58.

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

Reference example 59.

In accordance with the method described for example to help 35, (E)-3-[4-(5-methyl-4-phenyl-2-thiazoleacetate)phenyl] -2-propen-1-al is introduced into the reaction citizen.metropolitan with the formation of (E,E)-5-[4-(5-methyl-4-phenyl-2-thiazoleacetate)phenyl] -2,4-pentadienyl. Recrystallization from a mixture of ethyl acetate, ether leads to colorless prisms, so pl. 108 - 109oC.

Reference example 60.

In accordance with the method described for example for reference 45, 2-chloromethyl-5-methyl-4-phenyloxazol enter into reaction with para-hydroxybenzaldehyde with the formation of 4-(5-methyl-4-phenyl-2-oxazolidinone)benzaldehyde. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 90 - 91oC.

Reference example 61.

Reference example 62.

In accordance with the method described for example 23, methyl-4-(5-methyl-4-phenyl-2-oxazolidinone)cinnamate restore diisobutylaluminium education (E)-3- [4-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-ol. Recrystallization from a mixture of chloroform-isopropyl ether leads to colorless prisms, so pl. 154 - 155oC.

Reference example 63.

In accordance with the method described for example 34, (E)-3-[4-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-ol oxidized with activated manganese dioxide with the formation of (E)-3-[4-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-al. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 144 - 146oC.

Reference example 64.

In accordance with the method described for example 35, (E)-3-[4-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-al is introduced into the reaction citizen.metropolitan with the formation of (E,E)-5-[4-(5-methyl-4-phenyl-2-oxazolidinone)-phenyl]-2,4-pentadienyl. After that, in accordance with the method described for pringlei with the formation of 5-[4-(5-methyl-4-phenyl-2-oxazolidinone)phenyl]valeronitrile. Recrystallization from a mixture of ethyl acetate-ether-hexane leads to colorless prisms, so pl. 65 - 66oC.

Reference example 65.

In accordance with the method described for example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazol enter into reaction with para-hydroxybenzaldehyde with the formation of 4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone]benzaldehyde. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 163 - 164oC.

Reference example 66.

In accordance with the method described for example 22, 4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] benzaldehyde enter into reaction with trimethylphosphate with the formation of methyl-4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] cinnamate. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 185 - 186oC.

Reference example 67.

In accordance with the method described for example 23, methyl-4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] cinnamate restore diisobutylaluminium education (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] -2-propen-1-ol. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 159 - 160oC.

Reference when the si] phenyl] -2-propen-1-ol oxidized with activated manganese dioxide with the formation of (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] -2-propen-1-al. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 179 - 180oC.

Reference example 69.

In accordance with the method described for example 35, (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone]phenyl]-2-propen-1-al is introduced into the reaction citizen.metropolitan with the formation of (E, E)-5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolyl-methoxy] phenyl]-2,4-pentadienyl. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 159 - 160oC.

Reference example 70.

In accordance with the method described for example 45, 4-chloromethyl-5-methyl-2-(2-naphthyl)oxazol enter into reaction with 4-(4-hydroxyphenyl)butyronitrile with the formation of 4-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] butyronitrile. Recrystallization from a mixture of chloroform-ether leads to colorless prisms, so pl. 149 - 151oC.

Reference example 71.

In accordance with the method described for example 45, 4-chloromethyl-5-methyl-3-(2-naphthyl)oxazol enter into reaction with methyl-5-(4-hydroxyphenyl)valerate with formation of methyl-5-[4-[5-methyl-2-[2-naphthyl-4-oxazolidinone] phenyl] valerate. After that, in accordance with the method described for example 42, methyl-5-[4-[5-methyl-2-(2-naphthyl)-4-oxaz is polymethoxy} phenyl]-pentane-1-ol. Recrystallization from a mixture of ethyl acetate-ether leads to colorless needles, so pl. 128 - 129oC.

Reference example 72.

To a mixture of 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone]-phenyl]-pentane-1-ol (1.1 g), triethylamine (of 0.333 g) and dichloromethane (40 ml) under ice cooling are added dropwise methanesulfonanilide (0,345 g). The mixture is stirred for two hours at room temperature, washed with water and dried (MgSO4). The solvent is distilled off, and remains 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl]pendimethalin (1,21 g, 92%). Recrystallization from a mixture of dichloromethane-ether leads to colorless needles, so pl. 132 - 133oC.

Reference example 73.

In accordance with the method described for example 38, 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl]pendimethalin enter into reaction with potassium cyanide with the formation of 6-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] -hexanenitrile. Recrystallization from a mixture of ethyl acetate-isopropyl ether leads to colorless prisms, so pl. 116 - 117oC.

Reference example 74.

In accordance with the method described for example 35, 4-[3-[5-methyl-2-4-oxazolyl)propoxy] benzaldehyde enter into reaction with citizen.metropolitan with di who isace from a mixture of ethyl acetate-isopropyl ether-hexane leads to colorless prisms, so pl. 97 - 98oC.

Reference example 75.

In accordance with the method described for example 45, 2-chloromethyl-5-methyl-4-phenyloxazol enter into reaction with ortohydroxibenzaldehydes with the formation of 2-(5-methyl-4-phenyl-2-oxazolidinone)benzaldehyde. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 95 - 96oC.

Reference example 76.

In accordance with the method described for example 22, 2-(5-methyl-4-phenyl-2-oxazolidinone)benzaldehyde enter into reaction with trimethylphosphate with the formation of methyl-2-(5-methyl-4-phenyl-2-oxazolidinone)cinnamate. Recrystallization from a mixture of ethyl acetate-chloroform-ether leads to colorless prisms, so pl. 128 - 129oC.

Reference example 77.

In accordance with the method described for example 23, methyl-2-(5-methyl-4-phenyl-2-oxazolidinone)cinnamate restore diisobutylaluminium education (E)-3-[2-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-ol. Recrystallization from a mixture of ethyl acetate-ether leads to colorless prisms, so pl. 128 - 129oC.

Reference example 78.

In accordance with the method described for example 34, (E)-3-[2-(5-methyl-4-phenyl-2-OK is enyl-2-oxazolidinone)phenyl] -2-propen-1-al. Recrystallization from a mixture of chloroform-isopropyl ether leads to colorless prisms, so pl. 112 - 113oC.

Reference example 79.

In accordance with the method described for example 35, (E)-3-[2-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2-propen-1-al is introduced into the reaction citizen.metropolitan with the formation of (E,E)-5-[2-(5-methyl-4-phenyl-2-oxazolidinone)phenyl] -2,4-pentadienyl. Recrystallization from a mixture of ethanol-chloroform leads to colorless prisms, so pl. 128 - 129oC.

Reference example 80.

In accordance with the method described for example 45, 2-(benzo[b]furan-2-yl)-4-chloromethyl-5-methoxazole was introduced in the reaction with 4-(4-hydroxyphenyl)butyronitrile with the formation of 4-[4-[2-(benzo[b]furan-2-yl)-5-methyl-4-oxazolidinone] phenyl] butyronitrile. Recrystallization from a mixture of dichloromethane-isopropyl ether results in colorless prisms, so pl. 118 - 119oC.

Reference example 81.

In accordance with the method described for example 45, 4-chloromethyl-2-(furan-2-yl)-5-methoxazole enter into reaction with 4-(4-hydroxyphenyl)butyronitrile with the formation of 4-[4-[2-(furan-2-yl)-5-methyl-4-oxazolidinone]phenyl]butyronitrile in the form of an oily product.

NMR ( M. D. 1H, d, J = 9 Hz), 7,53 (1H, DD, J = 2 and 1 Hz).

Reference example 82.

In accordance with the method described for example 45, 3-chloromethyl-1-methyl-5-phenyl-1,2,4-triazole is administered in the reaction with 4-(4-hydroxyphenyl)butyronitrile with the formation of 4-[4-(1-methyl-5-phenyl-1,2,4-triazole-3-ylethoxy)phenyl]butyronitrile. Recrystallization from a mixture of dichloromethane-isopropyl ether leads to colorless prisms, so pl. 106 - 107oC.

Reference example 83.

In much the same way as in example 1, by reaction of 2-chloro-5-nitropyridine 5-methyl-2-phenyl-4-oxazolidinone obtained 2-(5-methyl-2-phenyl-4-oxazolidinone-5-nitropyridine. The yield is 84%. Recrystallization from a mixture of dichloromethane-isopropyl ether lead to pale yellow prisms, so pl. 142 - 143oC.

Reference example 84.

In much the same way as in example 2, by catalytic hydrogenation of 2-(5-methyl-2-phenyl-4-oxazolidinone)-5-nitropyridine obtained 5-amino-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine. The yield is 81%. Recrystallization from methanol-isopropyl ether leads to colorless prisms, so pl. 106 - 107oC.

Reference example 85.

To a mixture of 5-amino-2-(5-methyl-2-phenyl-4-oxazolidinone)-pyridinio2) (1.08 g) in water (2 ml). After stirring for 30 min to the mixture of the methyl acrylate (6,12 g), and then the copper oxide (I) (0.20 g) at 10-20oC. the Mixture is stirred for another hour at room temperature, followed by concentration under reduced pressure. The concentrate is diluted with concentrated ammonia solution and the extraction is carried out with ethyl acetate. An ethyl acetate layer is washed with water and dried (MgSO4), after which the solvent is distilled off under reduced pressure. The remaining oily product is subjected to chromatography on silica gel. Faction buervenich a mixture of ethyl acetate-hexane (1:5, V/V), obtained 2-bromo-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] propionate (2,27 g, 37%) as an oily substance.

NMR ( M. D. in CDCl3): 2,48 (3H, c), 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), is 6.78 (1H, d, J = 8.5 Hz), 7,35 and 7.5 (4H, m), 7.95 is to 8.1 (3H, m).

Reference example 86.

A mixture of 2-bromo-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] propionate (4,00 g), 1,8-diazabicyclo [5,4,0]-7-undecene (1,41 g) and toluene (80 ml) is stirred for 2 h at 90-100oC. the Reaction mixture was poured into water and the extraction is carried out with ethyl acetate. An ethyl acetate layer is washed with water and dried (M is Laut chromatography on silica gel. Faction buervenich a mixture of ethyl acetate-hexane (1:3, V/V), obtained methyl(E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]acrylate (2,71 g, 83%). Recrystallization from a mixture of diethyl ether-isopropyl ether leads to colorless prisms, so pl. 116 - 117oC.

Reference example 87.

In much the same way as in example 23, by restoring methyl-(E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] -acrylate-diisobutylaluminium obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-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 - 117oC.

Reference example 88.

In much the same way as in example 34, by oxidation of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]-2-propen-1-ol, manganese dioxide obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-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 - 148oC.

Reference example 89.

In much the same way as in example 24, by catalytic hydrogenation of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyrid stylizacja from a mixture of diethyl ether-isopropyl ether leads to colorless needles, so pl. 89 - 90oC.

Reference example 90.

In much the same way as in example 72, methanesulfonamide 3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]propanol obtained 3-/2-(5-methyl-2-phenyl-4-oxazolidinone)pyridyl/propylaminosulfonyl. The output is 89%.

NMR ( M. D. in CDCl3): 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), is 6.78 (1H, d, J = 8.5 Hz), 7,35 and 7.5 (4H, m), 7.95 is to 8.1 (3H, m).

Referential example 91.

In much the same way as in example 38, by reaction of 3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] propylaminosulfonyl with potassium cyanide obtained 4-[2-(5-methyl-2-phenyl-4-oxazolidinone)pyridyl]butyronitrile in the form of an oily product. The yield is 95%.

NMR ( M. D. in CDCl3): 1,85 - of 2.05 (2H, m) to 2.35 (2H, t, J = 7 Hz), 2,48 (3H, s), by 2.73 (2H, t, J = 7.5 Hz), 5,28 (2H, s), to 6.80 (1H, d, J = 8.5 Hz), 7,35 and 7.5 (4H, m), 7.95 is to 8.1 (3H, m).

Reference example 92.

In much the same way as in example 64, through the reaction of (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] -2-propen-1-al with citizen.metropolitan with subsequent catalytic hydrogenation of the obtained 5-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]valeronitrile. The yield is 96%.

NMR ( M. D. in CDCl3): 1.5 Example 1.

The mixture 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] propionitrile (0.7 g), sodium azide (0,411 g), ammonium chloride (of 0.337 g) and N,N-dimethylformamide (15 ml) is stirred for 24 h at 120oC. the Reaction mixture was poured into water and the extraction is carried out with ethyl acetate. An ethyl acetate layer washed with water and dried, then the solvent is distilled; remains 5-[2-[4-[2-(5-methyl-2-phenyl-oxazolyl)ethoxy] -phenyl] ethyl] tetrazol (0,38 g, 48%) which is recrystallized from a mixture of ethyl acetate-hexane with the formation of colorless prisms, so pl. 143 - 144oC.

Examples 2-14.

The compounds listed in table 4 and table 5 are obtained in much the same way as in example 1.

Note 1 (PL. 5).

Elemental analysis for C16H18N5O2Na M. D. in CDCl3): to 1.15 (3H, d, J = 7 Hz), 1,35 - of 1.85 (4H, m), 2,47 (3H, s), 2,47 of 2.68 (1H, m), 2,68 - 2,95 (2H, m), 4,91 (2H, s), 6.73 x (2H, d, J = 8,8 Hz), 6,92 (2H, d, J = 8,8 Hz), 7,35 - 7,52 (3H, m), of 7.90 - with 8.05 (2H, m).

Example 36.

In much the same way as in example 1, 5-[3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] propyl] -1H-tetrazol obtained by the reaction of 4-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] butyronitrile with sodium azide and ammonium chloride. The yield is 45%. Recrystallization from methanol-etiracetam example 1 5-[4-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] butyl]-1H-tetrazol obtained by the reaction of 5-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] valeronitrile with sodium azide and ammonium chloride. The output is 46%. Recrystallization from a mixture of ethyl acetate-hexane leads to colorless prisms, so pl. 104 - 105oC.

Example compositions 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, d - 15

(4) Calcium carboxymethyl cellulose, g - 44

(5) magnesium Stearate, g - 1 - 1000 tablets 120 g

All quantities above components (1), (2) and (3) and 30 g of the component (4) is ground with water, dried in vacuum, after which granularit. Granulated thus the powder is mixed with 14 g of the component (4) and 1 g of the component (5), and then produce the formation of tablets using the device to obtain tablets; received 1000 tablets each containing 10 mg of the component (1).

Example composition 2 (preparation of tablets)

(1) 5-[3-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)-ethoxy]phenylpropyl]tetrazole (compound obtained in example 7), g - 30

(2) Lactose, g - 50

All quantities above components (1), (2) and (3) and 30 g of the component (4) is ground with water, dried in vacuum, after which produce granulation. Granulated thus the powder is mixed with 14 g of the component (4) and 1 g of the component (5), and then produce the formation of tablets using the device to obtain tablets; received 1000 tablets each containing 30 mg of the component (1).

1. Derivatives tetrazole formula I

< / BR>
where n = 1, 2, 3;

A - aromatic 5-membered cyclic residue formula

< / BR>
where B1Is S, O or NR, where R is a lower alkyl group;

B2- N or C-R2where R2is hydrogen or lower alkyl;

R1- C1- C8alkyl, phenyl, unsubstituted or substituted with halogen or C1- C4the alkyl, naphthyl, C3- C7cyclic alkyl, thienyl, furyl, benzo(b)furanyl, amino group, substituted C1- C4the alkyl and phenyl;

Y - alkylen or albaniles containing 1 to 5 carbon atoms;

X is CH or N,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, where A is the group

< / BR>
where R1- C1- C8alkyl, phenyl, which is optionally substituted GANIL, amino group, substituted C1- C4the alkyl and phenyl;

R2is hydrogen or a lower alkyl group;

B is O or S,

or its pharmaceutically acceptable salt.

3. Connection on p. 1, where A is a group of the formula

< / BR>
where B Is O or S;

R3is phenyl;

R4- C1- C8alkyl;

or its pharmaceutically acceptable salt.

4. Connection on p. 1, where B1Is O, S or NR, where R is a lower alkyl group;

B2- N, or its pharmaceutically acceptable salt.

5. Connection on p. 1, where n = 1 or 2, or its pharmaceutically acceptable salt.

6. Connection on p. 1, where X is CH, or its pharmaceutically acceptable salt.

7. Connection on p. 1, where Y is alkylene with 1 to 5 carbon atoms, or its pharmaceutically acceptable salt.

8. Connection on p. 1, where Y is-CH2CH2CH2- or-CH2CH2CH2CH2or its pharmaceutically acceptable salt.

9. Connection on p. 1, representing 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] ethyl]tetrazol, or its pharmaceutically acceptable salt.

10. Connection on p. 1, representing 5-[2-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] ethyl] Ter the Il-2-phenyl-4-oxazolidinone)phenyl]propyl]tetrazole, or its pharmaceutically acceptable salt.

12. Connection on p. 1, representing 5-[4-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] butyl]tetrazole, or its pharmaceutically acceptable salt.

13. Connection on p. 1, representing 5-[5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]pentyl]tetrazole, or its pharmaceutically acceptable salt.

14. Connection on p. 1, representing 5-[3-[4-(5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] propyl] tetrazole, or its pharmaceutically acceptable salt.

15. Connection on p. 1. representing 5-[5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] pentyl] tetrazole, or its pharmaceutically acceptable salt.

16. Connection on p. 1, representing 5-[3-[4-[5-methyl-2-(2-furyl)-4-oxazolidinone] phenyl] propyl]tetrazole or its pharmaceutically acceptable salt.

17. Connection on p. 1, representing 5-[3-[4-(1-methyl-5-phenyl-1,2,4-triazole-3-ylethoxy)phenyl] propyl] tetrazole, or its pharmaceutically acceptable salt.

18. Connection on p. 1, representing 5-[3-[4-[5-methyl-2-(benzo(b)furan-2-yl)-4-oxazolidinone] phenyl] propyl] tetrazole, or its pharmaceutically acceptable salt.

19. Pharmaceutical whom ecaudata fact, as the active ingredient contains a compound of the formula I

< / BR>
where A, X, Y and n have the meanings specified in paragraph 1,

or its pharmaceutically acceptable salt in an effective amount.

20. Pharmaceutical composition having gipolipidemiceski action, including an active ingredient and an inert filler, characterized in that as the active ingredient contain the compound of the formula I

< / BR>
where A, X, Y and n have the meanings specified in paragraph 1, or its pharmaceutically acceptable salt in an effective amount.

21. The method of obtaining the compounds of formula I

< / BR>
where A, X, Y and n have the meanings specified in paragraph 1,

characterized in that conduct the reaction of the compound of the formula

< / BR>
where each character has a certain higher the value,

with a metal azide.

 

Same patents:

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives aminoquinolone

The invention relates to a new derivative of bisexuality and its pharmaceutically acceptable salts, are useful as pharmaceuticals, in particular as a hypoglycemic drugs (drugs that increase insulin sensitivity), and containing pharmaceutical compositions

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a new derivative of naphthalene, having Antiasthmatic activity, and the method of its production
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