Derivative thiazolidinedione, obtaining them and pharmaceutical composition

 

(57) Abstract:

Disclosed are the compounds of formula I, where n = 1, 2, 3, And is part of a 5-membered aromatic heterocycle containing at least one nitrogen atom, which is attached via a carbon atom adjacent to the nitrogen atom in the heterocycle, and which may be substituted by lower alkyl, C3-C6-cycloalkyl, phenyl, naphthyl or an aromatic 5-membered heterocycle containing an oxygen atom or a sulfur atom; is a simple or a double bond, or their pharmacologically acceptable salts, methods for their preparation and pharmaceutical composition based on them having hypoglycemic and gipolipidemicescoy activity. The invention can be used in medicine as a drug for the treatment of diabetes. 4 C. and 7 C.p. f-crystals, 10 PL.

The present invention relates to a new derivative thiazolidinedione, which possesses hypoglycemic and gipolipidemicescoy activity, and it contains drug against diabetes; these properties can be used for pharmaceutical purposes.

Traditionally as medicine for diabetes uses derivatives biguanidine, sulfo the Ute acidosis lactic acid, while connection-based sulfonmethane with potential hypoglycemic action, often cause severe hypoglycemia and require special precautions in their use. Known derivative thiazolidinedione, which possess hypoglycemic and gipolipidemicescoy activity and is free from these defects.

For example, in the examined patent publication Japan N 57635/1987 describes a series of derivatives of 5-[(2-alkoxy-5-pyridyl)-methyl]-2,4-thiazolidinedione containing in position 5 (substituted-3 - pyridyl)methyl group.

The authors of the present invention investigated derivatives of 5-[(substituted-3-pyridyl)methyl]-2,4-thiazolidinedione, which have the potential gipoglikemicheskoy and gipolipidemicescoy activity, and found that their activity is greatly increased when introduced as a substituent in the pyridine ring, alkoxy group, including a fragment of the 5-membered aromatic heterocycle containing at least one atom of the nitrogen cycle, which is attached via a carbon atom adjacent to the nitrogen atom in the heterocycle, and which may be substituted.

Thus, the present invention includes

1. pricescope heterocycle, containing at least one nitrogen atom, which is attached via a carbon atom adjacent to the nitrogen atom in the heterocycle, and which may be substituted; is a simple bond or a double bond,

or its pharmacologically acceptable salt,

2. pharmaceutical composition containing as an active ingredient derived thiazolidinedione in the General formula (I) or its pharmacologically acceptable salt,

3. the method of deriving thiazolidinedione General formula (I-1)

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where the meaning of the symbols indicated earlier,

which includes hydrolysis of compounds on the basis of aminothiazoline General formula (II)

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where the meaning of the symbols indicated earlier,

4. the method of obtaining derivatives thiazolidinedione formula (I), which involves the condensation of compounds of General formula (III)

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where the meaning of the symbols indicated earlier,

with 2,4-thiazolidinedione and restore, if necessary, the obtained compound.

In the General formula (I), (I-1), (II), (III) n=1, 2, 3, but the preferred value is 2 or 3.

The compound of General formula (I), which denotes a simple link, separately presents the General formula (I-1), a compound of the General formula the tins stated previously.

From compounds of General formula (I) preferred are those that have a simple link in the fragment, indicated in General formula (I).

With regard to the above General formulas (I), (I-1), (I-2), (II) and (III), the fragment is a 5-membered aromatic heterocycle A is determined as follows: (1) is a 5-membered ring; (2) it is a heterocycle containing at least one nitrogen atom as a component of the ring; (3) it may contain as a component of rings two or more nitrogen atoms and heteroatoms other than nitrogen, such as oxygen atoms or sulfur; (4) the ring is aromatic, containing unsaturated linkages; (5) it is a group attached through a carbon atom adjacent to the nitrogen atom in the ring; (6) it can be substituted on any position in the specified ring. Examples of such a fragment of A 5-membered aromatic heterocycle are pyrrolidine group (2-pyrrolidine group), personilnya group (3-personilnya group), imidazolidine group (2-imidazolidine group, 4-imidazolidinyl group), thiazolidine group (1,2,3-thiazole-4-ilen group, 1,2,4-thiazol-3-ilen group), tetrataenia group, oxazoline group (2-oxazoline group, 4-oxazolidine group) and the thiazole is ment may contain one or more substituents in any position of the specified ring. Examples of these substituents are hydrocarbon radicals and heterocyclic radicals, which may have their own deputies.

These hydrocarbon radicals include fragments of aliphatic hydrocarbons, fragments alicyclic hydrocarbon fragments alicyclics-aliphatic hydrocarbon fragments arylaliphatic hydrocarbons and fragments of aromatic hydrocarbons. These fragments aliphatic hydrocarbons include those which have from 1 to 8 carbon atoms, in particular fragments of saturated aliphatic hydrocarbons containing from 1 to 8 carbon atoms, such as methyl group, ethyl group, through the group, ISO-sawn group, bucilina group, ISO-bucilina group, sec-bucilina group, tert-bucilina group, pencilina group, ISO-pencilina group, neopentylene group, tert-pencilina group, exilda group, ISO-exilda group, heptylene group and anjilina group, and fragments of unsaturated aliphatic hydrocarbons containing from 2 to 8 carbon atoms, such as Attila group, 1-protanilla group, 2-protanilla group, 1-bucinellina group, 2-bucinellina group, 3-bucinellina group, 2-methyl-1-propenyl the-bucinellina group, 1-examilia group, 3-examilia group, 2,4-hexadienyl group, 5-examilia group, 1-leptanillinae group, 1-octenidine group, etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 1-penicilina group, 2-penicilina group, 3-penicilina group, 4-penicilina group, 1-hexylamine group, 3-hexylamine group, 2,4-hexadienyl group, 5-hexylamine group, 1-gattinella group, 1-actinella group. These fragments alicyclic hydrocarbons include those which have from 3 to 7 carbon atoms, in particular fragments of a saturated alicyclic hydrocarbons containing from 3 to 7 carbon atoms, such as cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group and cyclopentenone group, and fragments of unsaturated alicyclic hydrocarbons containing from 5 to 7 carbon atoms, such as 1-cyclopentene group, 2-cyclopentenone group, 3-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 1-cycloheptenyl group, 2-cycloheptenyl group, 3-cycloheptenyl group and 2,4-cycloheptatriene group is of the above fragments alicyclic hydrocarbons and the above fragments of aliphatic hydrocarbons, having from 4 to 9 carbon atoms, such as cyclopropylmethyl group, cyclopropylethyl group, cyclobutylmethyl group, cyclopentylmethyl group, 2-cyclopentylmethyl group, 3-cyclopentylmethyl group, cyclohexylethyl group, cyclohexylpropionate group, cycloheptylmethyl group and cycloheptylamine group. These fragments arylaliphatic hydrocarbons include phenylaline having 7 to 9 carbon atoms, such as benzyl group, penicilina group, 1-phenylethylene group, 3-phenylpropionate group, 2-phenylpropionate group and 1-phenylpropionate group, and nafcillin having from 11 up to 13 carbon atoms, such as alpha-naphthylmethyl group, alpha naphthylethylene group, beta-naphthylmethyl group and beta-naphthylethylene group. Such fragments of aromatic hydrocarbons include phenyl group and naftalina group (alpha-naftalina group, beta-naftalina group).

The above heterocyclic fragment is a 5 - or 6-membered cyclic group containing, as components of rings from 1 to 3 atoms other than carbon atoms and selected from the atoms N, O or S, and linked via a carbon atom. These heterocyclic Fraga is-thienyl group), furilla group (2-furilla group, 3-furilla group), Peregrina group (2-Peregrina group, 3-Peregrina group, 4-Peregrina group), thiazolidine group (2-thiazolidine group, 4-thiazolidine group, 5-thiazolidine group) and oxazolidine group (2-oxazoline group, 4-oxazolidinyl group, 5-oxazolidine group), and fragments of saturated heterocycles, such as piperideine group (2-piperideine group, 3-piperideine group, 4-piperideine group), pyrrolidinyl group (2-pyrrolidinyl group, 3-pyrrolidinyl group), morpholinyl group (2-morpholinyl group, 3-morpholinyl group) and tetrahydropyridine group (2-tetrahydrofuryl group, 3-tetrahydrofuryl group).

The above hydrocarbon fragments or fragments of heterocycles can be substituted on any position. In that case, if the hydrocarbon fragment comprises a fragment of alicycle, or if it is a fragment of saturated heterocycle, it may contain from 1 to 3 lower alkyl groups having from 1 to 3 carbon atoms (e.g. methyl group, ethyl group, through the group) in the ring (including the nitrogen atom). If the hydrocarbon fragment in the 1 to 4 substituents, the same or different. Examples of such substituents are halogen atoms (fluorine, chlorine, iodine), hydroxy group, cyano group, triptorelin group, lower alkoxy group (e.g. having 1 to 4 carbon atoms, such as methoxy group, ethoxypropan, propoxy group, ISO-propoxy group, butoxy group), a lower alkyl group (e.g. having 1 to 4 carbon atoms, such as methyl group, ethyl group, through the group, ISO-sawn group and bucilina group), lower alkoxycarbonyl group (for example, having from 2 to 4 carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group) and lower alkylthio group (for example, having from 1 to 3 carbon atoms, such as methylthio group, ethylthio group, propyl-thio-group and out-propylthio-group).

In the case where a fragment of the 5-membered aromatic heterocycle, provided by the symbol A, contains, as substituents, two or more hydrocarbon fragment, which are located at adjacent atoms of the 5-membered aromatic heterocycle, they can contact each other to form a saturated ring. This means that the two hydrocarbon fragment obadina 5 carbon atoms. Such linear hydrocarbon fragments includes the groups-CH2CH2CH2-, -CH2CH2CH2CH2- -CH2CH2CH2CH2CH2-, -CH= CHCH2-, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH2and-CH=CH-CH2CH2CH.

From the fragments of the 5-membered aromatic heterocycle represented by the symbol A, preference is given thiazolium or oxazolium represented by formulas

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where R1is a hydrogen atom, a hydrocarbon radical or a fragment of the heterocycle, which may contain substituents;

R2is a hydrogen atom or a lower alkyl group which may be substituted by a hydroxy group;

R3and R4independently are a hydrogen atom or a hydrocarbon radical which may contain substituents, R3and R4can contact each other to form a condensed ring;

X is an oxygen atom or a sulfur atom.

A hydrocarbon radical and a fragment of the heterocycle, identified by the group R1and contained in the substituents can be represented by the same hydrocarbon fragments, heterocyclic fragments and Vice in them, which is already indicated by the radical R2can be represented by alkyl groups containing from 1 to 5 carbon atoms, such as methyl group, ethyl group, through the group, ISO-sawn group, bucilina group, ISO-bucilina group, sec-butylene group, tert-bucilina group and pencilina group, preference is given to groups containing from 1 to 3 carbon atoms. Although these alkyl groups may contain a hydroxy group in any position, preference is given to the alpha position.

Hydrocarbon fragments, indicated by the radicals R3or R4and contained in the substituents can be represented by the same hydrocarbon fragments and Vice in them, which previously considered for a fragment of a 5-membered aromatic heterocycle. R3and R4can contact each other to form a condensed ring, which is the same condensed ring, which is formed in the fragment of the 5-membered aromatic ring containing as substituents two hydrocarbon fragment from the neighboring carbon atoms.

Derived thiazolidinedione represented by the General formula (I) is a compound containing acidic atom asknih salts derived thiazolidinedione (I) include metal salts, such as sodium salt, potassium salt, an aluminium salt, salt, magnesium salt and calcium. Examples of acid salts are salts of inorganic acids such as hydrochloride, sulfate, hydrobromide, and organic acids, such as methanesulfonate or tartrate.

The compound (I) and its pharmacologically acceptable salt according to the present invention has a hypoglycemic effect and may be used by itself or in combination with known pharmaceutically acceptable carrier, auxiliary connection, filler or other additives, for the treatment of mammals, including man, as a remedy for diabetes. The compound (I) or its pharmacologically acceptable salt according to the present invention exhibits the best activity in relation to insulin and can also be used as hypotensor.

The compound (I) of the present invention have low toxicity. For example, when the compound of example 1 is administered to mice for 4 days in the amount of 15 mg/kg, not observed any increases in body weight or liver weight compared with the control group. In the case when the compounds obtained in examples 2, 5 and 6, was administered to mice orally at 100 mg/kg or vnutribrjushinnye (I) of the present invention is usually administered orally in the form of tablets, capsules (including soft capsules and microcapsules), powders, granules and other forms, however, they may be appointed and nearline in the form of compositions for injections, suppositories, pills, and other forms. Single dose for adults with oral appointment is from 0.05 to 10 mg/kg, preferably from 1 to 3 times a day.

The method of obtaining the compound (I) of the present invention is given below.

The compound (I-1) can be obtained by hydrolysis of compound (II). Typically, the hydrolysis of compound (II) is carried out in a suitable solvent in the presence of water and mineral acids. Such solvents include alcohols (e.g. methanol, ethanol, propanol, 2-propanol, butanol, ISO-butanol, 2-methoxyethanol), dimethyl sulfoxide, sulfonyl and mixtures of these compounds. Mineral acids include hydrochloric acid, Hydrobromic acid and sulfuric acid, the amount of which is from 0.1 to 20.0 mol, mostly from 0.2 to 10.0 mol per 1 mol of compound (II). Water is added in excess relative to the compound (II). This reaction is usually carried out by heating or boiling, the typical process temperature is from 60 to 150oC. boiling is usually several hours.

Obtained in this JV is clean, such as evaporation at atmospheric pressure, evaporation under reduced pressure, crystallization, recrystallization, pereosazhdeniya and chromatography.

Aminothiazoline (II) used as starting compound in this way, may be, for example, obtained in the following way:

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In the circuit shown, the process V in the formula (VIII) represents a halogen atom such as chlorine, bromine or iodine; Z in formulas (VII) and (VIII) is a hydrogen atom or a lower alkyl group containing from 1 to 4 carbon atoms, such as methyl group, ethyl group, through the group, ISO-sawn group, bucilina group or ISO-bucilina group; the values of the other characters listed previously.

The conversion of the compound (IV) into the compound (V) is carried out by condensation of the compound (IV) with 2-chloro-5-nitropyridine in the presence of, for example, sodium hydride. This reaction can be carried out in a solvent such as N,N-dimethylformamide: dioxane, tetrahydrofuran or dimethylsulfoxide at a temperature from -20 to 60oC. Next, the conversion of compound (V) into the compound (VI) can easily be implemented by catalytic reduction of compound (V) by conventional methods, for example, used is of zinc or iron and acetic acid. The compound (VI) can be isolated as a pure product or subjected to reaction in the next stage without isolation and purification. The conversion of compound (VI) to the compound (VIII) can be carried AllYouNeed on Maiellano, with the compound (VI) diasterous in the presence of halogenated (HV), and then injected into the reaction with acrylic acid or its ester (VII) in the presence of a copper catalyst (for example, cuprous oxide, copper oxide, copper chloride, chlorine, copper, copper bromide, bromine, copper). The compound (VIII) can be purified chromatographically, etc. but can be used in the next stage without isolation and purification.

The compound (VIII) may further interact with thiourea to form compound (II). This reaction is usually conducted in a solvent such as alcohol (e.g. methanol, ethanol, propanol, 2-propanol, butanol, ISO-butanol, 2-methoxyethanol), dimethylsulfoxide, N,N-dimethylformamide or sulfolane. The process temperature is usually from 20 to 180oC, mostly from 50 to 150oC. the Amount of thiourea is from 1 to 2 mol per 1 mol of compound (VIII). During the reaction as a by-product formed halogenation; to bind, as rascalities is 1 to 1.5 mol per 1 mol of compound (VIII). When implementing these transformations can be obtained the compound (II), which can be distinguished if necessary, however, acid hydrolysis according to the present invention can be carried out without isolating the compound (II).

The alcohol (IV) can be synthesized, for example, by the method described in the examined patent publication Japan N 85372/1986, or modification.

The alcohol (IV), having as A fragment represented by formula XIV

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where the meaning of the symbols indicated earlier,

may be, for example, obtained according to the following scheme:

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where Z' is a lower alkyl group,

the values of other symbols defined previously.

The lower alkyl group denoted by the symbol Z', may be represented by alkyl groups containing from 1 to 4 carbon atoms (e.g. methyl group, ethyl group, ISO-sawn group, butilkoi group, ISO-butilkoi group).

Under this method, the compound (IX) interacts with monoamide malonic acid or monotonical malonic acid (X) with the formation of compound (XI), which is then reduced to compound (IV-1).

The interaction of the compounds of the founders include benzene, toluene, xylene, pyridine, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, methanol, ethanol, propanol and ISO-propanol. The process temperature is usually from about 20 to 200oC, mostly from 50 to 150oC, the time of reaction is from about 30 minutes to 10 hours. The amount used of the compound (X) is usually from about 1 to 10 mol, preferably about 1 to 5 mol per 1 mol of compound (IX). Following this reaction is carried out restoration of the compound (XI) in the alcohol (IV-I). This reaction can be performed by known methods. Recovery methods that can be used for these purposes include the repair using metal hydrides, repair using a metal hydride complex compounds, repair using DIBORANE or substituted DIBORANE and catalytic hydrogenation. In other words, this reaction is performed by processing the compound (XI) reducing agent. Recovery agents include borhydride alkali metals (for example, borohydride sodium, lithium borohydride), metal hydride complex courier, triphenylamine), metals and metal salts, such as compounds of Nickel and zinc compounds, catalytic reductive agents based on a combination of transition metals, such as palladium, platinum or rhodium and hydrogen, and DIBORANE. This reaction is carried out in an organic solvent which does not interfere with its flow. Such solvents include aromatic hydrocarbons such as benzene, toluene and xylene, hydrogen halides, 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, ISO-propanol and 2-methoxyethanol, amides such as N,N-dimethylformamide, and mixtures of these solvents selected for the appropriate remedial agent. The reaction temperature is usually -20 to 150oC, mainly from 0 to 100oC, time course of the process is from 1 to 24 hours.

The compound (I-2) can be obtained by the interaction of the compound (III) with 2,4-thiazolidinedione:

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In the above formulas, the symbols have the above meaning.

Condensation of compound (III) and 2,4-thiazolidinedione assests methanol, ethanol, propanol, ISO-propanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, ISO-propyl ether, dioxane and tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide and acetic acid. Examples of these bases are sodium alkoxides (e.g. sodium methoxide, ethoxide sodium), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate and secondary amines such as piperidine, piperazine, pyrrolidine, morpholine, diethylamine and di-ISO-Propylamine, the amount of 2,4-thiazolidinedione is from 1 to 10 mol, mainly from 1 to 5 mol per 1 mol of compound (III). The amount used of the base is from 0.01 to 5 mol, mostly from 0.05 to 2 mol per 1 mol of compound (III). The reaction is usually carried out at temperatures from 0 to 150oC, mainly from 20 to 100oC for from 0.5 to 30 hours.

Obtained by the above method was derived 2,4-thiazolidinedione (I-2) can be isolated and purified by known methods of separation and purification such as evaporation under normal pressure, evaporation under reduced pressure, solvent extraction, crystallization, recrystallization, pereosazhdeniya and fromprivate formulas, the symbols have the above meaning.

The specified response recovery carried out by conventional means in a solvent in the presence of a catalyst in a hydrogen atmosphere under a pressure from 1 to 150 ATM. Examples of the specified solvent are alcohols such as methanol, ethanol, propanol, ISO-propanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as ethyl ether, ISO-propyl ether, dioxane and tetrahydrofuran, halide derivatives of hydrocarbons, such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane, ethyl acetate, acetic acid and mixtures of these solvents. It is preferable to conduct the reaction in the presence of such a metal catalyst like Nickel or a catalyst based on a transition metal, such as palladium, platinum or rhodium. The reaction temperature is from 0 to 100oC, mainly from 10 to 80oC, the reaction time is from 0.5 to 50 hours.

Thus obtained derivative of 2,4-thiazolidinedione (I-1) can be isolated and purified by known methods of separation and purification such as evaporation under normal pressure, evaporation under reduced pressure, solvent extraction, crystallization, recrystallization, presaged who can be, for example obtained according to the following scheme:

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In the formula (XII) Q is a chlorine atom, bromine or iodine, the value of the remaining symbols are defined above.

In this method, first, subjected to the compound (VI) is known transformations by the reaction of Sandmeyer and get halogenated derivatives (VII). During this reaction, the compound (VI) diasterous slow addition of an aqueous solution of sodium nitrite in a suitable solvent in the presence of hydrochloric acid, Hydrobromic acid or idiscovered acid with subsequent interaction with a solution of sodium halide or potassium halide and get the compound (XII).

An example of the specified solvent are alcohols such as methanol, ethanol, propanol, ISO-propanol and 2-methoxyethanol, ketones, such as acetone and 2-butanone; dioxane and tetrahydrofuran, and mixtures of these solvents. The process temperature is usually from -50 to 100oC, mainly from -20 to 60oC, the time of the process is from 0.5 to 50 hours. Then the compound (XII) is treated with butyllithium, second-butyllithium, tert-butyllithium, methyllithium, phenyllithium, phenylmagnesium and so on, after which it interacts with N,N-dimethylformamide (DMF) is as examples of the solvent can be called ethers, such as ethyl ether, ISO-propyl ether, dioxane or tetrahydrofuran. The number of DMF is from 1 to 3 mol, mostly from 1 to 2 mol per 1 mol of compound (XII). The reaction temperature is from -80 to 50oC, mainly from -80 to 20oC, the time of reaction is from 0.5 to 50 hours.

Thus obtained derivative pyridinediamine (III) can be isolated and purified by known methods of separation and purification such as evaporation under normal pressure, evaporation under reduced pressure, solvent extraction, crystallization, recrystallization, pereosazhdeniya and chromatography.

The study of the hypoglycemic and gipolipidemicheskoe actions in mice.

The studied compound at a content of from 0.01% to 0.001% in the powdered food (CE-2, Clea Tapan) allow mice KKAV(ages 10 to 14 weeks) for 4 days. Pets are not restricted in the water. Take blood from the orbital clusters of veins and carry out analysis on the plasma glucose and triglyceride enzymatic methods using reagent kits Iatrochem - GLU (A) and Iotro - MA701 TG (firm "Iatron"). For each connection is determined by reducing its content in percent. what BR> (1) the contents of the test compound in the diet,

(2) reduction of triglycerides.

As mentioned previously, thiazolidinedione compounds (I) of the present invention have excellent hypoglycemic and gipohloremicheskom impact and have useful pharmaceutical properties as a therapeutic agent for diabetes, hyperlipemia and hypertension.

Example 1. A mixture of 2-amino-5-[[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy-5-pyridyl]methyl]-4-thiazolidinone (0,76 g), 1 n HCl solution (10 ml) and ethanol (10 ml) is refluxed for 20 hours and then evaporated under reduced pressure. The resulting crystals are separated by filtration, washed with water and recrystallized from a mixture of ethanol-chloroform, receiving 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] methyl]-2,4 - thiazolidinedione (0.45 g, 59%) as colorless crystals. So pl.: 191-192,0oC.

Elemental analysis (for C21H19N3O4S):

Calculated: C 61,60; H to 4.68; N 10,26

Found: C 61,20; H of 4.66; N 10,08

Example 2. 5-[[2-[2-(5-Methyl-2-(2-thienyl)-4-oxazolyl)ethoxy]-5-pyridyl] methyl]- 2,4-thiazolidinedione get analogously to example 1 (recrystallized from a mixture of ethanol-chloro what-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionic acid (1.40 g), thiourea (0.25 g) and ethanol (20 ml) is refluxed for 4.5 hours, added 2 n hydrochloric acid (20 ml) and again refluxed for 18 hours. Pour the reaction mixture into water and extracted with dichloromethane. The dichloromethane layer is washed with water and dried over magnesium sulfate, then the solvent is distilled off. The obtained crystals are recrystallized from a mixture of ethanol-chloroform and get 5-[[2-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy] -5-pyridyl] methyl] -2,4-thiazolidinedione (0.66 g, 51%) as colorless crystals. So pl. 195,0 - 197,0oC.

Example 4. 5-[[2-[2-[2-(2-Furyl)-5-methyl-4-oxazolyl]ethoxy]-5-pyridyl] methyl]-2,4 - thiazolidinedione get analogously to example 3 (recrystallized from a mixture of ethanol-chloroform) as colorless crystals. So pl. 160,5 - 162oC.

Examples 5-15. Analogously to example 3, the compounds shown in table. 2.

Example 16. 5-[[2-[2-(4-Benzyl-5-methyl-2-oxazolyl)ethoxy]- 5-pyridyl]methyl] -2,4-thiazolidinedione obtained by the method similar to example 1, then recrystallized from a mixture of ethyl acetate - hexane - ISO-propyl ether and obtain colorless crystals. So pl.: 110 - 111oC.

Example 17. A mixture of 5-formyl-2-[[2-(5-methyl-2-under reflux for 9 hours. The reaction mixture was poured into water, the crystals formed, which is separated by filtration, then recrystallized from a mixture of ethanol-chloroform and get 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methylidene]-2,4-thiazolidinedione (0,232 g, 29%) as yellow crystals. So pl.: 195 - 196oC.

Example 18. A mixture of 2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridinecarboxamide (1.20 g), 2,4-thiazolidinedione (720 mg), piperidine (175 mg) and ethanol (30 ml) is refluxed for 10 hours. To the reaction mixture was added water and the precipitated crystals are separated by filtration and washed with ethanol, receiving 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] methylidene]-2,4-thiazolidinedione (1.35 g, 85%). After recrystallization from a mixture of dichloromethane-methanol to obtain colorless needles. So pl.: 225 - 226oC.

Elemental analysis (for C20H15N3O4S):

Calculated: C 61,06; H 3,84; N IS 10.68

Found: C 60,82; H 3,72; N 10,76

Example 19. The mixture 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]methylidene]-2,4-thiazolidinedione (1,00 g), palladium on coal (5%, and 1.00 g) and tetrahydrofuran (80 ml) is subjected to catalytic recovery at room temperature under a pressure of 1 ATM for 6 hours. Catellani at room temperature under a pressure of 1 ATM for 6 hours. The catalyst is filtered off. The filtrate is evaporated under reduced pressure and the residue purified column chromatography on silica gel. From the fractions that elute with a mixture of 2% methanol-chloroform, isolated crystals of 5-[[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] methyl-2,4-thiazolidinedione (520 mg, 52%). After recrystallization from a mixture of dichloromethane - ISO-propyl ether to obtain colorless prisms. So pl.: 151 - 152oC.

Elemental analysis (for C20H17N3O4S):

Calculated: C 60,75; H 4,33; N 10,63

Found: C 60,52; H 4,36; N 10,48

Example 20. By the method similar to that shown in example 3, get 5-[[2-[2-[2-(2-chlorophenyl)-5-methyl-4-oxazolyl] ethoxy] - 5-pyridyl]methyl]-2,4-thiazolidinedione. Recrystallization from methanol-dichlorethylene ether gives colorless crystals. So pl.: 176 - 177oC.

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) was added in portions sodium hydride in oil (60%, 6,92 g) under stirring and cooling in a bath of ice. The reaction mixture was stirred at room temperature for 15 h, after which it added to water and extracted with ethyl acetate. The organic layer was washed with in what trevanian and recrystallized from ethanol, getting 2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-nitropyridine (25.4 g, 49%) as crystals yellow-brown color. So pl.: 110,5 - 111,5oC.

Elemental analysis (for C17H15N3O4):

Calculated: C 62,76; H 4,65; N 12,92

Found: C 62,80; H 4,58; N 12,96

Reference example 2. 2-[2-(5-Methyl-2-(2-thienyl)-4-oxazolyl)ethoxy]-5-nitropyridine get similar to reference example 1 (recrystallized from a mixture of ethyl acetate-hexane) in the form of crystals of light-yellow color. So pl. is 125.5 - 126oC.

Reference example 3. 2-[2-(2-(2-furyl)-5-methyl-4-oxazolyl)ethoxy]-5-nitropyridine get similar to reference example 1 (recrystallized from a mixture of ethyl acetate-hexane) in the form of crystals of light-yellow color. So pl.: 120,0 - 121,5oC.

Reference example 4. 2-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine get similar to reference example 1 (recrystallized from a mixture of ethyl acetate-hexane) in the form of crystals of light-yellow color. So pl.: 131,0 - 132oC.

Reference example 5. A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (13,4 g), palladium on coal (5%, 1.5 g), ethyl acetate (200 ml) and methanol (150 ml) restore catalytically at room temperature under Yes the, obrazovavsheesya the crystals are filtered and recrystallized from a mixture of ethyl acetate-hexane, obtaining 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (116 g, 93%) as brown crystals. So pl.: 107,0 - 108,0oC.

Elemental analysis (for C17H17N3O2):

Calculated: C 69,14; H 5,80; N 14,23

Found: C 69,01; H 5,94; N 13,99

Reference example 6. 5-Amino-2-[2-(5-methyl-2-(2-thienyl)-4-oxazolyl)ethoxy]pyridine get similar to reference example 5 (recrystallized from a mixture of ethyl acetate-hexane) in the form of crystals light brown color. So pl.: 120 - 122oC.

Reference example 7. 5-Amino-2-[2-(5-methyl-2-(2-furyl)-4-oxazolyl)ethoxy]pyridine get similar to reference example 5 (recrystallized from a mixture of ethyl acetate-ether-hexane) in the form of crystals light brown color. So pl.: 88,0 - 90,0oC.

Reference example 8. 5-Amino-2-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy] pyridine get similar to reference example 5 (recrystallized from a mixture of ethyl acetate-ether-hexane) in the form of crystals light brown color. So pl.: 89,0 - 91,0oC.

Reference example 9. To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (4.5 g), an aqueous solution of HBr (the water (5 ml). After stirring at a temperature of 10oC for 30 minutes the temperature was raised to 30oC and added methyl acrylate (8,3 ml). Then with vigorous stirring slowly added to a mixture of copper oxide (0.1 g) and the reaction mixture is stirred at a temperature of 40 - 45oC for 1 hour, and then evaporated under reduced pressure. After alkalizing concentrated aqueous solution of ammonia, the residue is extracted with ethyl acetate. The organic layer was washed with water, dried (over magnesium sulfate) and the solvent evaporated under reduced pressure. The resulting oil is purified column chromatography. From the fractions that elute with a mixture of ethyl acetate-hexane (2: 1, V/V), distinguish the methyl ester of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]propionic acid (4.7 g, 68%).

An NMR spectrum ( M. D. in CDCl3): of 2.34 (3H, singlet), 2,98 (2H, triplet, J = 6,7 Hz), and 3.16 (1H, doublet of doublets, J = 7,0 Hz and 14.5 Hz), 3,37 (1H, doublet of doublets, J = 7,0 Hz and 14.5 Hz), 3,74 (3H, singlet), or 4.31 (1H, doublet of doublets, J = 8.0 Hz and 7.0 Hz), 4,55 (2H, triplet, J = 6,7 Hz), to 6.67 (1H, doublet, J = 8.6 Hz), 7,35 is 7.50 (4H, multiplet), to $ 7.91 - with 8.05 (3H, multiplet).

Reference example 10. Methyl ester of 2-bromo-3-[2-[2-[5-methyl-2-(2-thienyl)-4-oxazolyl] ethoxy] -5-pyridyl]propionic cotriple, J = 6,7 Hz), and 3.16 (1H, doublet of doublets, J = 7,2 Hz and 14.4 Hz), 3,37 (1H, doublet of doublets, J = 8,2 Hz and 14.5 Hz), 3,74 (3H, singlet), 4,32 (1H, doublet of doublets, J = 8.0 Hz and 7.2 Hz), to 4.52 (2H, triplet, J = 6.8 Hz), 6,66 (1H, doublet, J = 8,4 Hz), 7,07 (1H, doublet of doublets, J = 5.0 and 3.6 Hz), of 7.36 (1H, doublet of doublets, J = 5.0 and 1.2 Hz), 7,42 (1H, doublet of doublets, J = 8.4 and 2.6 Hz), 7,58 (1H, doublet of doublets, J = 3.7 and 1.1 Hz), to 7.99 (1H, doublet, J = 2.2 Hz).

Reference example 11. Methyl ester of 2-bromo-3-[2-[2-[2-(2-furyl)-5-methyl-4-oxazolyl] ethoxy] -5-pyridyl] propionic acid get similar to reference example 9.

An NMR spectrum ( M. D. in CDCl3): 2,32 (3H, singlet), 2,96 (2H, triplet, J = 63.7 Hz), and 3.16 (1H, doublet of doublets, J = 7,4 Hz and 14.4 Hz), 3,37 (1H, doublet of doublets, J = 8,1 Hz and 14.6 Hz), 3,74 (3H, singlet), 4,32 (1H, doublet of doublets, J = 8,2 Hz and 7.2 Hz), of 4.54 (2H, triplet, J = 6,7 Hz), 6,51 (1H, doublet of doublets, J = 3.4, 1.8 Hz), 6,66 (1H, doublet, J = 8,4 Hz), 6,92 (1H, doublet, J = 3.6 Hz), the 7.43 (1H, doublet of doublets, J = 8.5 and 2.5 Hz), 7,52 (1H, doublet, J = 1,8 Hz), 8,00 (1H, doublet, J = 2,6 Hz).

Reference example 12. Methyl ester of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-thiazolyl)ethoxy] -5-pyridyl] propionic acid get similar to reference example 9.

An NMR spectrum ( M. D. in CDCl3): 2,43 (3H, singlet), and 3.16 (1H, doublet of doublets, J = 7,1 Hz and 14.5 Hz), 3,37 (1H, doublet of doublets, J = 8,1 Hz and 14.3 Hz), 3,74 (3H, singlet), 42H, multiplet), 8,01 (1H, doublet, J = 2,6 Hz).

Reference example 13. A mixture of methyl ester of 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] propionic acid (1.07 g), thiourea (0.2 g), sodium acetate (0,22 g) and ethanol (25 ml) is refluxed for 2.5 hours. Added to the reaction mixture, saturated aqueous sodium bicarbonate solution and ether and the resulting crystalline substance separated by filtration, obtaining 2-imino-5-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] -4-thiazolidinone (0,86 g, 88%) (recrystallized from a mixture of chloroform-methanol as colorless crystals. So pl. 213 - 214oC.

Elemental analysis (for C21H20N4O3S):

Calculated: C 61,75, H 4,94; N 13,72

Found: C 61,76; H 5,00; N 13,89

Reference example 14. 2-Imino-5-[2-[2-[5-methyl-2-(2-thienyl)-4-oxazolyl] ethoxy] -5 - pyridyl]-4-thiazolidinone get similar to reference example 13 (recrystallized from a mixture of ethanol-chloroform) as colorless crystals. So pl.: 193 - 194,5oC.

Reference example 15. Similar to reference example 13 get 5-[2-2[-(4-benzyl-5-methyl-2-oxazolyl)ethoxy] -5-pyridyl] methyl] -2 - imino-4-thiazolidinone. Recrystallization from methanol-chloroform apirogennoy in reference example 1, the compounds presented in table. 3 and 4, where

1) clear column chromatography on silica gel.

An NMR spectrum ( M. D. in CDCl3): of 2.20 (3H, singlet), 3,20 (2H, triplet, J = 6,7 Hz), of 3.77 (2H, singlet), 4,79 (2H, triplet, J = 6.8 Hz), to 6.80 (1H, doublet, J = 9,2 Hz), 7,10 - 7,37 (5H, multiplet), with 8.33 (1H, doublet of doublets, J = 2.8 and 9.2 Hz), 9,04 (1H, doublet, J = 3.0 Hz).

Reference examples 28 to 39. Similarly to the method described in reference example 5, the compounds presented in table. 5 and 6.

1) NMR Spectrum ( M. D. in CDCl3): 2,50 (3H, singlet), 3,23 (2H, triplet, J = 6.8 Hz), to 4.62 (2H, triplet, J = 6.9 Hz), 6,60 (1H, doublet, J = 8,8 Hz), 7,02 (1H, doublet of doublets, J = 2.8 and 8.6 Hz), 7,22 - 7,46 (3H, multiplet), 7,58 - to 7.68 (3H, multiplet).

2) NMR Spectrum ( M. D. in CDCl3): 2,03 - of 2.23 (2H, multiplet), 2,82 (3H, singlet), to 2.67 (2H, triplet, J = 7.4 Hz), is 4.21 (2H, triplet, J = 6.3 Hz), 6,60 (1H, doublet, J = 8,8 Hz), 7,03 (1H, doublet of doublets, J = 3.0 and 8.6 Hz), 7,37 - 7,49 (3H, multiplet), to 7.64 (1H, doublet, J = 3.0 Hz), 7,92 - 8,03 (2H, multiplet).

3) NMR Spectrum ( M. D. in CDCl3): 1,17 - of 1.93 (8H, multiplet), 1,93 and 2.13 (2H, multiplet), of 2.20 (3H, singlet), 2,59 - 2,77 (1H, multiplet), 2,85 (2H, triplet, J = 6.9 Hz), to 4.38 (2H, triplet, J = 6.9 Hz), to 6.57 (1H, doublet, J = 8.6 Hz), 7,03 (1H, doublet of doublets, J = 3.0 and 8.6 Hz), to 7.64 (1H, doublet, J = 3.0 Hz).

4) NMR Spectrum ( M. D. in CDCl3): of 2.2 Hz), to 7.64 (1H, doublet, J = 2,8 Hz).

5) NMR Spectrum ( M. D. in CDCl3): of 1.29 (3H, triplet, J = 7,6 Hz), measuring 2.20 (3H, singlet), 2,69 (2H, Quartet, J = 7,6 Hz), 2,84 (2H, triplet, J = 6.9 Hz), 4,39 (2H, triplet, J = 6.9 Hz), 6,55 (1H, doublet, J = 8.6 Hz), 7,01 (1H, doublet of doublets, J = 3.0 and 8.6 Hz), 7,63 (1H, doublet, J = 3.0 Hz).

6) NMR Spectrum ( M. D. in CDCl3): to 0.97 (3H, triplet, J = 7,3 Hz), 1,64 - of 1.85 (2H, multiplet), of 2.20 (3H, singlet), of 2.64 (2H, triplet, J = 7.5 Hz), 2,84 (2H, triplet, J = 7.0 Hz), 4,39 (2H, triplet, J = 6.9 Hz), 6,56 (1H, doublet, J = 8,8 Hz), 7,02 (1H, doublet of doublets, J = 3,0 and 8.8 Hz), to 7.64 (1H, doublet, J = 3.0 Hz).

7) NMR Spectrum ( M. D. in CDCl3): to 2.18 (3H, singlet), 3,14 (2H, triplet, J = 6.9 Hz), of 3.77 (2H, singlet), 4,55 (2H, triplet, J = 6.9 Hz), to 6.57 (1H, doublet, J = 8,4 Hz), 7,00 (1H, doublet of doublets, J = 3.0 and 8.6 Hz), 7,14 - 7,33 (5H, multiplet), a 7.62 (1H, doublet, J = 3.0 Hz).

Reference examples 40 - 51. Similarly to the method described in reference example 9 obtained in the form of oily substances compounds are presented in table. 7 - 9.

Reference example 52. To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4 - oxazolyl)ethoxy] pyridine (10.0 g) and concentrated HCl (of 8.47 ml) and acetone (100 ml), added dropwise, ensuring that the temperature did not rise above 10oC, a solution of sodium nitrite (2,46 g) in water (10 ml). The mixture was stirred at 10oC for 30 minutes and Prib - 35oC for one hour, and then another 1 hour at a temperature of 35 - 40oC, after which the mixture is evaporated under reduced pressure. The residue is poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (over magnesium sulfate) and evaporated under reduced pressure. The resulting oily substance is purified chromatographically on silica gel. From the fraction eluted with a mixture of ethyl acetate-hexane (1:3, V/V), get 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (7,22 g, 52%), which is then recrystallized from a mixture of ethyl acetate-hexane and get colorless crystals. So pl. 105 - 106oC.

Reference example 53. To a solution of 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl)etkisi]pyridine (2.5 g) in tetrahydrofuran (40 ml) at -65oC in a stream of nitrogen was added dropwise a solution of n-utility in hexane (1.6 M, 4.61 in ml). Stirred the mixture at the same temperature for 15 minutes and added dropwise N,N-dimethylformamide (0,71 ml). The cooling bath removed and the mixture is stirred for 30 minutes, and then add saturated aqueous solution of ammonium chloride (6 ml). Pour the reaction mixture into water and extracted with ethyl acetate. The organic layer was washed with water, dried (over sulfate mage is which is then recrystallized from a mixture of ethyl acetate-hexane and produce colorless crystals. So pl. 99 - 100oC.

Reference example 54. A mixture of N-carbaminohemoglobin (40 g), acetic anhydride (54,7 g) and 4-(N,N-dimethylamino)pyridine (1.0 g) is stirred for 2 hours while heating to 80oC. Pour the reaction mixture into water, stirred for 2 hours and extracted with ethyl acetate. The organic layer is successively washed 2 N. HCl solution, water, saturated aqueous sodium bicarbonate, again with water and dried (over magnesium sulfate). The solvent is evaporated under reduced pressure and get 3 acetylamino-4-phenyl-2-butanone (13.5 g, 49%) which is recrystallized from a mixture of ethyl acetate-ISO-propyl ether and produce colorless crystals. So pl.: 96 - 97oC.

Reference example 55. A mixture of 3-acetylamino-4-phenyl-2-butanone (12.5 g), 6 n HCl solution (50 ml) and ethanol (50 ml) is boiled under stirring under reflux for 18 hours. The reaction mixture is evaporated under reduced pressure and receive hydrochloride 3-amino-4-phenyl-2-butanone (9,8 g, 91%).

Reference example 56. A mixture of the hydrochloride of 3-amino-4-phenyl-2-butanone (9,56 g), ethylmaleimide (7,72 g) and benzene (40 ml) stirred at the boil under reflux for 4 hours. The reaction mixture is evaporated under reduced. The organic layer is washed with water, obtaining the ethyl ester of N-(1-benzyl-2-oxopropyl)malonamide acid (7,45 g, 56%), which is then recrystallized from a mixture of ethyl acetate and ISO-propyl ether, highlighting colorless crystals. So pl.: 68 - 69oC.

Reference example 57. A mixture of ethyl ester of N-(1-benzyl-2-oxopropyl)malonamide acid (7.0 g), Chloroacetic phosphorus (5.8 g) and toluene (40 ml) stirred at the boil under reflux for 1 hour. The reaction mixture is evaporated under reduced pressure; the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried (over magnesium sulfate), evaporated under reduced pressure and the residue is purified chromatographically on silica gel. From the fraction eluted with hexane-ethyl acetate (1:3, V/V), distinguish the ethyl ester of 2-(4-benzyl-5-methyl-2-oxazolyl)acetic acid (4,76 g, 63%) as oil.

An NMR spectrum ( M. D. in CDCl3): of 1.26 (3H, triplet, J=7,1 Hz), of 2.21 (3H, singlet), of 3.75 (2H, singlet), with 3.79 (2H, singlet), 4,19 (2H, Quartet, J=7,1 Hz), 7,13 - 7,34 (5H, multiplet).

Reference example 58. To a suspension of socialogical (0.7 g) in ether (40 ml) was added dropwise while cooling in a bath with lederimitat for 1 hour. Then added dropwise water (5 ml), any insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The residue is subjected to chromatographic purification on silica gel. From the fraction eluted with a mixture of chloroform-ethyl acetate (2: 1, V/V), in the form of oils extracted 2-(4-benzyl-5-methyl-2-oxazolyl)ethanol (3.0 g, 75%).

An NMR spectrum ( M. D. in CDCl3): are 2.19 (3H, singlet), is 2.88 (2H, triplet, J= 5.7 Hz in), 3.75 (2H, singlet), of 3.94 (2H, triplet, J=5.8 Hz), 7,13 and 7.36 (5H, multiplet).

Reference example 59. To cooling in the bath with ice to a solution of hydrochloride of methylbenzamide [C6H5C(=NH)OCH3HCl] (13,0 g) in methanol (80 ml) is gradually added methylhydrazine (3.5 g) and then stirred under the same conditions for 3 hours. The crystals formed are separated by filtration and receive hydrochloride of 2-methyl-3-phenylimidazole (10,9 g), which is then recrystallized from methanol-ether. So pl.: 197 - 198oC.

Reference example 60. A mixture of the hydrochloride of 2-meteo-3-phenylimidazole (60 g), ethylmaleimide (5,1 g) and benzene (40 ml) is stirred while boiling under reflux for 6 hours. The reaction mixture is evaporated under reduced pressure, to the residue was added acetic acid (30 m the hinnon pressure; the residue is neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, dried (over magnesium sulfate), evaporated under reduced pressure and the residue is purified chromatographically on silica gel. From the fraction eluted with a mixture of chloroform-ethyl acetate (4:1, V/V), allocate ethyl ester 1-methyl-5-phenyl-1H-1,2,4-triazole-3-DRS-acetic acid (6.2 g, 78%), which is then recrystallized from a mixture of ether-ISO-propyl ether, highlighting colorless prisms. So sq: 82 - 83oC.

Reference example 61. To a mixture of beta-methyl ester of aspartic acid (20 g), sodium bicarbonate (24,0 g), ethyl ether (50 ml) and water (200 ml) under cooling in a bath of ice are added dropwise 2-aftercare (25,9 g). The mixture is stirred at room temperature for 3 hours and separated the organic layer. The aqueous layer was acidified with 2 N. hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried (over magnesium sulfate) and evaporated under reduced pressure, obtaining the product in the form of butter.

The obtained oily substance was added to a mixture of acetic anhydride (69,5 g), 4-(N,N-dimethylamino)pyridine (0.5 g) and pyridine (64 ml) and stirred at tempextract with ethyl acetate. The organic layer is separated, washed sequentially with saturated aqueous sodium bicarbonate solution, dilute aqueous solution of phosphoric acid and water, dried (over magnesium sulfate) and evaporated under reduced pressure, obtaining the product in the form of butter.

The oil obtained is dissolved in acetic anhydride (40 ml) and added dropwise at room temperature was added concentrated sulfuric acid (4.0 ml). The mixture is stirred while heating to 90oC for 1 hour, and then evaporated under reduced pressure. The residue is poured into water, neutralized aqueous phase saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with water, dried (over sodium sulfate) and evaporated under reduced pressure, obtaining the methyl ester of 5-pointed-2-(2-naphthyl)-4-oxazolidone acid (31 g, 81%), which is then recrystallized from a mixture of dichloromethane-ISO-propyl ether, highlighting the product as colorless prisms. So pl.: 86 - 87oC.

Reference example 62. Methyl ester 5-methyl-2-(4-were)-4-oxazolidone acid get similar method described in reference example 61, and recrystallized from a mixture of ethyl acetate-hexane, highlighting bestwe luxusni acid get similar methodology, reference example 61.

An NMR spectrum ( M. D. in CDCl3): of 1.33 (6H, doublet, J=7 Hz), to 3.0 - 3.2 (1H, multiplet), 3,61 (2H, singlet), to 3.73 (3H, singlet), 7,35 is 7.50 (3H, multiplet), 7,95 - with 8.05 (2H, multiplet).

Reference examples of 64 - 67. Similarly to the method described in reference example 58, the compounds presented in table. 10.

Reference example 68. Similarly to the method described in reference example 1, get 2-(5-methyl-2-phenyl-4-oxazolidinone)-5-nitropyridine. By recrystallization from a mixture of dichloromethane-ISO-propyl ether to obtain colorless prisms with so Kip. 142 - 143oC.

Reference example 69. Similarly to the method described in reference example 5, get 5-amino-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine. By recrystallization from methanol-ISO-propyl ether to obtain colorless prisms with so Kip. 106 - 107oC.

Reference example 70. To a solution of 5-amino-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (7,10 g) in a mixture of acetone (200 ml) - water (50 ml) was added dropwise while cooling in a bath with ice and concentrated hydrochloric acid (7,46 g), and then dropwise a saturated solution of sodium nitrite (to 1.83 g) in water (10 ml). The mixture is stirred for 10 minutes. To the resulting CME is the temperature 15 - 20oC for 2 hours. Dilute the mixture with water and neutralized with sodium bicarbonate solution. Extracted with ethyl acetate, the organic extracts washed with water and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is purified chromatographically on silica gel. From the fraction eluted with a mixture of ethyl acetate-hexane (1: 9, V/V), isolated crystals of 5-iodine-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (6,65 g, 67%). Recrystallized from a mixture of ethyl acetate-hexane, obtaining colorless prisms with so pl. 129 - 130oC.

Elemental analysis (for C16H13IN2O2):

Calculated: C 49,00; H 3,34; N 7,14

Found: C 48,87; H 3,10; N 7,22

Reference example 71. To a solution of 5-iodine-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (6,53 g) in tetrahydrofuran (60 ml) at -65oC added dropwise a 1.6 M solution of n-utility in hexane (1.6 M, 10.9 ml) and stirred the mixture at the same temperature for 20 minutes. Add N,N-dimethylformamide (2,43 g) and allow the mixture to warm to room temperature. Add saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, the solvent of othona is a mixture of ethyl acetate-hexane (1:3, about/about), isolated crystals of 2-(5-methyl-2-phenyl-4-oxazolidinone)-5 - pyridinecarboxamide (2,80 g, 57%). By recrystallization from a mixture of ethyl acetate-hexane produce colorless prisms with so pl. 116 - 117oC.

Elemental analysis: (for C17H14N2O3):

Calculated: C 69,38; H 4,79; N 9,52

Found: C 69,47; H 4,75; N 9,60

Reference example 72. Similarly to the method described in reference example 1, get 2-[2-[5-methyl-2-(2-chlorophenyl)-4-oxazolyl]ethoxy]-5-nitropyridine. By recrystallization from a mixture of ethyl acetate-diethyl ether to obtain crystals of pale yellow color; so bales. 100 - 101oC.

Reference example 73. A mixture of 2-[2-[5-methyl-2-(2-chlorophenyl)-4 - oxazolyl] ethoxy] -5-nitropyridine (1,69 g), fine powder of iron (787 mg), acetic acid (25 ml) and water (8 ml) is stirred at a temperature of 65-70oWith over 3 hours any insoluble matter is separated by filtration and the filtrate evaporated under reduced pressure. To the residue was added water and extracted with the mixture with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. The solvent is evaporated and the residue is purified chromatographically on silica gel. From the faction that buirette a mixture of methanol-chloroform (1:m D. in CDCl3): a 2.36 (2H, triplet, J=6,7 Hz), 2,99 (2H, triplet, J= 6,7 Hz), 4,48 (2H, triplet, J=6,7 Hz), 6,59 (1H, doublet, J=8.6 Hz), 7,03 (1H, doublet of doublets, J=3.0 and 9.0 Hz), 7,26 - 7,53 (3H, multiplet), 7,66 (1H, doublet, J=3.0 Hz), 7,88 - 8,03 (2H, multiplet).

Reference example 74. Similarly to the method described in reference example 9, to obtain methyl ester of 2-bromo-3-[2-[2-[2-(2- chlorophenyl)-5-methyl-4-oxazolyl)ethoxy]-5-pyridyl]propyl acid.

An NMR spectrum ( M. D. in CDCl3): 2,35 (2H, triplet, J=6,7 Hz), 3,01 (2H, triplet, J= 6,6 Hz), and 3.16 (1H, doublet of doublets, J=7,3 and 14.5 Hz), 3,37 (1H, doublet of doublets, J= 8,1 and 14.5 Hz), 3,74 (3H, singlet), to 4.33 (1H, doublet of doublets, J= 7.3 and 8.1 Hz), 4,56 (2H, triplet, J=6.6 Hz), to 6.67 (1H, doublet, J=8,4 Hz), 7,26 - 7,51 (4H, multiplet), 7,87 - 8,03 (2H, multiplet).

Example of structure 1.

Preparation of tablets, mg:

1) Compound obtained in example 1 - 30

2) Lactose - 133,4

3) Corn starch - 30

4) Oxypropylation - 6

5) Water, ml - 0,03

6) magnesium Stearate - 0,6

Only 200

The above components(1), (2), (3) and (4) are mixed, and then kneaded with water, then dried in vacuum at 40 oC for 16 hours. The resulting product is ground in a mortar and sieved through a sieve of 16 mesh to obtain granules. After addition of compar CLASS="ptx2">

1. Derived thiazolidinedione General formula (I)

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

A is a fragment of a 5-membered aromatic heterocycle containing at least one nitrogen atom, which is attached via a carbon atom adjacent to the nitrogen atom in the heterocycle, and which may be substituted by lower alkyl, C3- C6-cycloalkyl, phenyl, (lower alkyl)-phenyl, phenyl-(lower alkyl), aloevera, naphthyl or an aromatic 5-membered heterocycle containing an oxygen atom or a sulfur atom;

is a simple or a double bond,

or its pharmacologically acceptable salt.

2. Connection on p. 1, where n = 2.

3. Connection on p. 1, which is a simple link.

4. Connection on p. 1, where is a double bond.

5. Connection on p. 1, representing 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-2,4-thiazolidinedione.

6. Connection on p. 1, representing 5-[[2-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl)ethoxy]-5-pyridyl]methyl]-2,4-thiazolidinedione.

7. Connection on p. 1, representing 5-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]methylidene]-2,4-thiazolidinedione.

8. Pharmaceutical composition having gamy carrier or diluent, characterized in that it contains as active ingredient an effective amount of a derivative thiazolidinedione General formula (I) under item 1 or its pharmacologically acceptable salt.

9. The composition according to p. 8, characterized in that it is a therapeutic drug for diabetes and hyperlipemia.

10. The method of deriving thiazolidinedione General formula (I-1)

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

A is a fragment of a 5-membered aromatic heterocycle containing at least one nitrogen atom attached via a carbon atom adjacent to the nitrogen atom in the heterocycle, and which may be substituted by lower alkyl, C3-C6-cycloalkyl, phenyl, (lower alkyl)-phenyl, phenyl-(lower alkyl), aloevera, naphthyl or an aromatic 5-membered heterocycle containing an oxygen atom or a sulfur atom;

characterized in that conduct the hydrolysis of compounds of aminothiazoline General formula (II)

< / BR>
where the meaning of the symbols listed above.

11. The method of deriving thiazolidinedione General formula (I)

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

A is a fragment of a 5-membered aromatic heterocycle containing at least one nitrogen atom, which Priscila, C3-C6-cycloalkyl, phenyl, (lower alkyl)-phenyl, phenyl-(lower alkyl), aloevera, naphthyl or an aromatic 5-membered heterocycle containing an oxygen atom or a sulfur atom;

is a simple or a double bond,

characterized in that carry out the condensation of the compounds of formula (III)

< / BR>
where the meaning of the symbols indicated earlier,

with 2,4-thiazolidinedione and if necessary the compound obtained restore.

Priority points and features:

28.12.92 on PP. 1 and 8 for the compounds of formula I, where a represents a simple bond, and p. 10;

22.07.93 on PP. 1 and 8 for the compounds of formula I, where is a simple and a double bond, and PP.10 and 11.

 

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The invention relates to new derivatives aminoquinolone

The invention relates to the derivatives of indole, methods and intermediates for their receipt containing their pharmaceutical compositions and to their medical use

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to new derivatives of 2-amino-4-phenylthiazole and their salts, and method of production thereof and to pharmaceutical compositions based on them

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

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