Derivatives of 2,4-oxazolidinedione or their pharmaceutically acceptable salts, methods for their preparation, pharmaceutical composition, providing hypoglycemic and hypolipidemic effect, the method of reducing blood sugar and blood lipids in the treatment of mammals suffering from diabetes or hyperlipidemia

 

(57) Abstract:

Derivatives of 2,4-oxazolidinedione General formula I

where R1-8-alkyl, pyridyl, possibly condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one sulfur atom, one nitrogen atom, and these groups may be substituted WITH1-15-alkyl, possibly substituted by halogen; C2-10-alkenyl substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl; naphthyl, fullam, teinila, benzofuranyl, benzo[b]tanila; Y represents-CO-, -CH(OH) -, or-NR3- where R3- C1-4-alkyl; m is 0 or 1; n is 0,1 or 2; X is CH or N; And divalent straight or branched residue of hydrocarbon chain containing 1-7 carbon atoms; R1and R2is hydrogen or C1-4-alkyl, or R1and R2form a 5-6 membered heterocyclic system optionally containing nitrogen; L and M are hydrogen, or L and M are connected to each other with the formation of the communication; or their pharmaceutically acceptable salt. The connection I have the effect of reducing the sugar content in the blood, have low toxicity and can be used in the compositions as medicaments>The invention concerns new derivatives oxazolidinediones, reducing sugar and blood lipids, method of their production and use as pharmaceutical preparations for the treatment of diabetes.

As drugs for the treatment of diabetes are still used connections on the basis of biguanides and sulfonylureas. However, connection-based biguanide hardly used nowadays, as they cause lactic acidosis, sulfonylureas, with a strong reducing blood sugar levels effect, often cause severe hypoglycemia and therefore require special attention in the application.

On the other hand, derivative thiazolidinedione and oxazolidinedione, reducing blood sugar and blood lipids, not have these disadvantages.

For example, JPA H3 (1991)-170478 and W09202520-A1 describe derivatives of 2,4-oxazolidinedione containing substituents in the 5-position, a series of derivatives of 5-(substituted benzyl)-2,4-oxazolidinedione, JPb S62(1987)-30993 describes derivatives of 2,4-oxazolidinedione, substituted in the 5-position of the alicyclic group, and JPB S63(1988)-35632 describes derivatives of 2,4-oxazolidinedione substituted in 5-position is substituted by an aromatic ring.

The authors present isenia 2,4-oxazolidinedione ring straight or branched hydrocarbon residue, substituted by phenyl or pyridium, for example 2-(substituted phenyl or substituted pyridyl)ethyl group, 3-(substituted phenyl or substituted pyridyl)propyl group, 4-(substituted phenyl or substituted predil)butyl group, 5-(substituted phenyl or substituted pyridyl)pentyl group and so on, have the effect of reducing blood sugar and blood lipids, thus the present invention is filled.

The present invention concerns:

1. Derivatives of 2,4-oxazolidinedione General formula:

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where R is a hydrocarbon residue or heterocyclic group, each of which may be substituted;

Y is-CO-CH(OH) or-NR3- (where R3- alkyl which may be substituted);

m is 0 or 1;

n is 0, 1 or 2;

X is CH or N;

A is a divalent straight or branched hydrocarbon residue having from 1 to 7 carbon atoms;

R1and R2each is hydrogen or alkyl, or R1and R2can be combined with each other to form a 5 - to 6-membered heterocyclic residue may contain nitrogen; L and M each is hydrogen, or L and M together form a bond, or their pharmaceutically acceptable salts.

2. Drugs, containing in the quality of the Cesky acceptable salt.

3. Method of treatment of mammals suffering from diabetes and hyperlipidemia, consisting in the introduction of effective amounts of compounds of formula (I) or its pharmaceutically suitable salts.

4. The use of the compounds of formula (I) or its pharmaceutically suitable salts for the production of a medicinal product for the treatment of mammals suffering from diabetes or hyperlipidemia.

5. Methods of obtaining derivatives of 2,4-oxazolidinedione General formula (I).

Compounds expressed by the General formula (I) include compounds shown by the following formulas (1-A1) (1-A2) (1-A3).

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< / BR>
< / BR>
where each symbol has the meaning given above. Among the compounds (1-A1) (1-A2) (1-A3), compounds (1-A1) and (1-A2) is preferred, and compounds (1-A1) is preferable from the viewpoint of pharmacological activity, toxicity and side effects. The compounds of formula (I), where L and M together form a relationship expressed by the following formula:

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where each symbol has the meaning given above. The compounds of formula (I), where L and M each is hydrogen, can be expressed by the following formula:

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where each symbol has the meaning given above.

The substituents R

The above General formula (1-B1) represents both (E) and (Z)-isomers relative to the double bond in the 5-position of 2,4-oxazolidinedione rings.

In accordance with the above General formula (I) for the case when R1and R2together form a 5-or 6-membered heterocyclic ring may contain N, such compounds are expressed by the following General formula.

(I) R1and R2together form a 5-membered heterocyclic ring.

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< / BR>
(2) R1and R2together form a 6-membered heterocyclic ring.

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< / BR>
< / BR>
(3) R1and R2together form a 5-membered heterocyclic ring containing nitrogen.

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(4) R1and R2together form a 6-membered ring containing nitrogen.

< / BR>
< / BR>
where D is hydrogen or lower alkyl, and other symbols have the meanings given above.

Among the above compounds (1-C1) to (1-C8), the most preferable compounds expressed by the formulas (1-C1), (1-C2), (1-Sz) and (1-C6).

In the above General formula (I) as the hydrocarbon substituent in the hydrocarbon residue, to the " hydrocarbon residue, alicyclic-aliphatic hydrocarbon residue, an aromatic aliphatic residue, an aromatic hydrocarbon residue of aliphatic and aromatic hydrocarbons.

As the aliphatic hydrocarbon residues applied residues having from 1 to 8 carbon atoms, including saturated aliphatic hydrocarbon residues having 1 to 8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl and unsaturated aliphatic hydrocarbon residues having 2 to 8 carbon atoms, such as ethynyl, 1-propenyl, 2-propenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 3,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2 butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4 - pentenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl.

As the alicyclic hydrocarbon residues applied residues having from 3 to 7 carbon atoms, including saturated alicyclic hydrocarbon residues containing from 3 to 7 carbon atoms, e.g. the s residues, containing from 5 to 7 carbon atoms, for example 1-cyclopentyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadiene.

As the alicyclic-aliphatic hydrocarbon residues applied residues, which are formed by combination of the above alicyclic hydrocarbon groups, aliphatic hydrocarbon residues, such residues include from 4 to 9 carbon atoms, examples include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, 3-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylmethyl, cyclohexylprop, cycloheptylmethyl and cycloheptylmethyl.

As the aromatic aliphatic residues used phenylalkyl having 7 to 9 carbon atoms, for example benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl, and nafcillin containing from 7 to 9 carbon atoms, for example - naphthylmethyl - naphtalate - naphthylmethyl - naphtalate. As the aromatic hydrocarbon residues are used, for example phenyl, naphthyl (-naphthyl, naphthyl), and Dr. Dre are formed by combination heterocyclic group, below, with the above-mentioned aliphatic hydrocarbon residues, apply remnants specified as follows.

In the above General formula (I) as the heterocyclic residue substituted heterocyclic group which may be substituted, expressed by the symbol R, is, for example, 5 - to 7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, 5 - to 6-membered heterocyclic group containing 2-4 nitrogen atoms, 5 - to 6-membered heterocyclic group containing 1-2 nitrogen atoms and a sulfur atom or an oxygen atom.

These heterocyclic groups may be condensed with a 6-membered ring containing one or two nitrogen atoms, benzene ring or 5-membered ring containing one sulfur atom.

Examples of such heterocyclic groups are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, isothiazolin, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4 - triazole-3-yl, 1,3,4-triazole-2-yl, 1,2,4-triazole-4-yl, those whom imidazo[4,5-c]pyridine-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl, etc.

In the above General formula (I), the hydrocarbon residue and heterocyclic residue, expressed by the symbol R may have 1-3 substituent in positions that can be substituted.

As such substituents mentioned aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, halogen atom, the nitro-group, possibly substituted amino group, possibly substituted allgroups, possibly substituted hydroxylgroups, possibly substituted toolgroup and possibly esterified carboxyl group.

As the aliphatic hydrocarbon group mentioned straight chain or branched aliphatic hydrocarbon group containing 1-15 carbon atoms, such as accelgroup, preferably altergroup having 1 to 20 carbon atoms, altergroup, preferably altergroup having 2-10 carbon atoms, and Alchemilla, preferably Alchemilla having 2-10 carbon atoms.

Preferred examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-buletinul, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, octyl, nonyl, decyl.

Preferred examples of alkenyl groups include vinyl, allyl, isopentyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3 - hexenyl, 5-hexenyl.

Preferred examples quinil group include ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3 - butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl.

As the alicyclic hydrocarbon group are referred to saturated and unsaturated alicyclic hydrocarbon groups containing 3 to 12 carbon atoms, such as cycloalkyl, cycloalkenyl, cycloalkenyl.

Preferred examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.1] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, etc.

Preferred examples cycloalkenyl groups include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclog nadian-1-yl, 2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl. The above-mentioned aryl group means a monocyclic or condensed polycyclic aromatic hydrocarbon group.

Preferred examples of aryl groups are groups containing 6-14 carbon atoms, such as phenyl, naphthyl, tenantry, antril, acenaphthylene. Among them the most preferred phenyl, 1-naphthyl and 2-naphthyl.

Preferred examples of the aromatic heterocyclic group include aromatic monocyclic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl; aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, IH-indazole, benzoimidazole, benzoxazolyl, 1,2-benzoxazolyl, benzothiazolyl, 1,2-benzisothiazolin, IH-benzotriazolyl, hinely, ethanolic, cinnoline, hintline, honokalani, phthalazine, naphthylidine the Nile, phenazines, phenoxathiin, thianthrene, phenanthridines, phenanthrolines, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-b] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl and 1,2,4-triazolo [4,3-b] pyridazinyl etc.

Preferred examples of non-aromatic heterocyclic groups are oxiranyl, azetidine, oxetane, titanyl, pyrrolidinyl, tetrahydrofuranyl, tylenol, piperidyl, tetrahydropyranyl, morpholinyl, timepanel, pyrrolidino, piperidino, morpholino and piperazinil.

Examples of the halogen include fluorine, chlorine, bromine and iodine. Among them, fluorine and chlorine are particularly preferred. The notion of possibly substituted group include an unsubstituted amino group and substituted an amino group.

As the substituted amino group mentioned amino group (-NH2), in which one or two alkyl having 1-10 carbon atoms, alkenyl having 1-10 carbon atoms, one or two aromatic groups or accelgroup having 2-10 carbon atoms (for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamine, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionamido is Gruppo and replaced allgraph.

As unsubstituted amino group mentioned formyl and groups formed from (C1-C10) alkyl, (C6-C12) alkenyl or (C6-C12aromatic group with carbohidratos (for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanol, Cyclopentanol, cyclohexanol, cycloheptanol, crotonyl, 2-cyclohexanecarbonyl, benzoyl, nicotinoyl).

Substituted allgraph includes accelgroup mentioned in the description of unsubstituted amino groups, which have a substituent(s), such as alkyl containing 1-3 carbon atoms, alkoxy containing 1-3 carbon atoms, halogen (e.g. chlorine, bromine and so on) nitro, hydroxy, amino, etc. the Notion of possibly substituted by a hydroxyl group includes unsubstituted hydroxyl group and substituted hydroxypropyl.

As the substituted hydroxyl group referred to such groups, which have a hydroxyl Deputy, is especially appropriate protective hydroxyl groups, such as alkoxy, alkenylacyl, aralkylated, acyloxy, aryloxy.

Preferred examples of alkoxyl include groups having 1-10 carbon atoms (such as methoxy, ethoxy, xiaxi, heptyloxy, nonyloxy, CYCLOBUTANE, cyclopentane, cyclohexyloxy).

As alkenylacyl mentioned group having 1-10 carbon atoms, including for example allyloxy, krotylov, 2-pentyloxy, 3 hexenoate, 2-cyclopentyloxy and 2 cyclohexylmethoxy, and as aralkylated mentioned, for example, phenyl-(C1-C4)alkyloxy (for example benzyloxy, penetrate).

Preferred examples of aryloxy include alkanoyloxy having 2-4 carbon atoms (for example, atomic charges, propionyloxy, butyryloxy, isobutyryloxy). As aryloxy among other mentioned 4 lovenox.

The concept of possibly substituted toolgroup included, except toolgroup, thiol, substituted acceptable substitute, especially preferred protective group of a thiol, such as alkylthio, Uralkali, atillio.

Preferred examples of alkylthio include alkylthio group having 1-10 carbon atoms (such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, verbality, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, nonillion, cyclobutyl, cyclopentyl, cyclohexylthio.

As kalkilya examples of achilty include alkanity, having 2-4 carbon atoms(for example, acetylthio, propositio, n-butylthio and out-butylthio).

As possible esterified carboxyl group are mentioned, for example, alkoxycarbonyl (for example groups having 2-5 carbon atoms, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and butoxycarbonyl), Uralelectromed (such as benzyloxycarbonyl) and aryloxyalkyl (such as phenoxycarbonyl and p-tolylacetylene).

In the above General formula (I), the substituents on the hydrocarbon residue and heterocyclic group denoted by the symbol R, where they are alicyclic hydrocarbon group, aryl group, aromatic heterocyclic group or non-aromatic heterocyclic group may have preferably 1-3 suitable substitute.

Examples of such substituents are lower alkyl containing 1-4 carbon atoms, lower alkenyl having 2-5 carbon atoms, lower quinil having 2-5 carbon atoms, cycloalkyl containing 3-5 carbon atoms, arrgroups (for example, phenyl, naphthyl and so on), aromatic heterocyclic group (e.g thienyl, furyl, pyridyl, oxazolyl, thiazolyl and so on ), neuronetics so on), kalkilya having 7-9 carbon atoms, n-mono(C1-C4-alkylamino, N,N-di(C1-C4)-alkyl amino group, amidinopropane, allgraph having 2-5 carbon atoms, carbonarra, N-mono-(C1-C4)-alkyl, carbonarra, N,N-di(C1-C4)-alkyl, carbonarra, sulfamoyl, N-mono(C1-C4)-alkyl, sulfamoyl, N,N-di(C1-C4)alkylsulfonyl group, carboxypropyl, low alkoxycarbonyl having 2-5 carbon atoms, hydroxylgroups lowest alkoxygroup having 1-4 carbon atoms, lower alkenylacyl having 2-5 carbon atoms, cycloalkylcarbonyl having 3-7 carbon atoms, aralkylated having 7-9 carbon atoms, alloctype (for example, phenyloxy, naphthyloxy and so on), mercaptopropyl, low ancilliary having 1-4 carbon atoms, arkitip having 7-9 carbon atoms, abilityhub (for example, phenylthio, naphthylthio, and so on), alphagraph, cyano, asiagraph, nitrogroup, nitrosopropane and halogen (for example fluorine, chlorine, bromine, iodine).

In the above formula (I), wherein each m and n = 0, then the carbon with a substituent R1directly associated with R; when m is 0 and n is 1 or 2, R is directly linked to (CH2)n3)-. Altergroup denoted by R3has 1-4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.

As the substituent of the alkyl specifies halogen atom (for example fluorine, chlorine, bromine, iodine), alkoxygroup having 1-4 carbon atoms, for example methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy and so on), hydroxyl, nitro, allgraph having 1-4 carbon atoms (e.g. formyl, acetyl, propionyl and so on).

Divalent straight or branched linear hydrocarbon residue, indicated by the character a, includes a saturated residue (for example,- CH2-, -(CH2)2-, -CH(CH3)-, (CH2)3, -CH(C2H5)-, (CH2)4-, (CH2)5-, (CH2)6and (CH2)7-) and unsaturated residue (e.g.- CH=CH-, -C(CH3)=CH-, -CH=CH-CH2-, -C(C2H5)= CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-CH2-, -CH=CH-CH=CH=-CH2-, -CH=CH-CH=CHCH=CH-CH2-.

In the formula (1-C8)accelgroup, denoted by the symbol D has 1-4 carbon atoms, for example methyl, ethyl, n-propyl, ISO-propyl, n-butyl.

As the salts of compound (I) of this invention, the preferred pharmaceutically acceptable salts, for example salts with the organic acids and salts with basic acidic amino acids.

Preferred examples of salts with inorganic bases include alkali metal salts, such as salts of sodium and potassium salts; salts of alkaline earth metals such as calcium salts and magnesium salts; aluminum salts, ammonium salts and the like.

Preferred examples of salts with organic bases include salts with triethylamine, trimethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N-dibenziletilendiaminom.

Preferred examples of salts with inorganic acids include salts, for example with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.

Preferred examples of salts with organic acids are salts, for example with formic acid, acetic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid and p-toluensulfonate acid.

Preferred examples of salts with basic amino acids are salts OIC acid. Among them the most preferred salts are sodium and potassium.

The compound (I) or its pharmaceutically suitable salts of the present invention have the effect of reducing the sugar content in the blood, have low toxicity and can be used in compositions with, for example, known pharmaceutically acceptable carrier, excipient and filling in as a medicine for treatment of diabetes in mammals, including humans.

The compound (I) or its pharmaceutically acceptable salt of the present invention also exhibit superior activity of insulin resistance and can be used as a means of reducing pressure.

The compound (I) of the present invention has low toxicity. For example, oral administration to mice of compounds of example 18 at a dose of 15 mg/kg/day for 4 days) did not cause changes in body weight and liver weight in comparison with the control group.

Oral introduction of the compound obtained in example 18 in a dose of 100 mg/kg) or intraperitoneally at a dose of 50 mg/kg did not cause death in test animals.

Introduction typically be administered orally in the form, for example tablets, capsules (including soft capsules and micro is for adults with oral introduction amount from 0.05 to 10 mg/kg / day, it is advisable to take three times a day.

The compound (I) of this invention, mixed with pharmaceutically acceptable carriers, may be given orally and nearline in the form of a solid preparative forms, such as tablets, capsules, granules, powders; or in the form of preparative liquid forms such as syrups and injections.

As pharmaceutically acceptable carriers using conventional organic or inorganic carriers for pharmaceuticals, accurate, such as excipients, lubricants, binders and disintegrators for solid preparative forms; solvents, thinners, suspendresume agents, isotonic agents, buffering agents, and local anesthetic agents. And if necessary, additives such as antiseptics, antioxidants, dyes and bleaching agents are used.

Preferred excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicon dioxide. Preferred examples of lubricants are magnesium stearate, calcium stearate, talc and colloidal silica.

Preferred examples of binders include crystalline cellulose, Saha is

Preferred examples of the disintegrator include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium and carboximetilkrahmal sodium.

As the preferred solvent used distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil.

As preferred examples of the diluents used polyethylene glycol, propylene glycol, D-mannitol, benzyl ester benzoic acid, ethanol, Tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.

Preferred examples suspendida agents include surfactants such as stearylamine, sodium lauryl sulfate, lauramidopropyl, lecithin, benzalconi chloride, benzethonium chloride, glycerol monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose.

Preferred examples of isotonic agents are sodium chloride, glycerin, D-mannitol. Preferred examples of the buffer Rasta use benzyl alcohol. As antiseptics - esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid, sorbic acid. Preferred examples of the antioxidants include sulfites and ascorbic acid.

Further description of methods for obtaining the compound (I) of this invention.

Method A

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where each symbol has the values given above.

The compound (1-B1) can be obtained by condensation of compound (II) with 2,4-oxazolidinedione. This reaction is performed in a solvent in the presence of a base.

The solvent includes alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, isopropyl ether, dioxane and tetrahydrofuran; N,N-dimethylformamide, dimethylsulfoxide and acetic acid.

As bases are sodium alkoxides (e.g. sodium methylate, ethoxylate sodium and so on), potassium carbonate, sodium carbonate, sodium hydride, sodium acetate or secondary amines such as piperidine, piperazine, pyrrolidine, morpholine, diethylamine, Diisopropylamine and others.

The quantity is the quantity of base is from 0.01 to 5 mol, preferably from 0.05 to 2 moles relative to the compound (II).

This reaction is performed at temperatures from 0 to 150oC, mainly from 20 to 100oC for a period of from 0.5 to 30 hours

The compound (1-B1) obtained by the above method, in some cases formed a mixture of (E)-compound and (Z)- connection relative double bond in the 5-position of 2,4-oxazolidinedione rings.

Method B

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where Z is hydrogen, lower alkyl or aralkyl group, and other symbols described above.

In the above General formula (III) as lower alkyl, denoted by the symbol Z, is mentioned alkyl having 1-4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl). Kalkilya group denoted by the symbol Z represents altergroup containing as a substituent airgroup.

Examples of airgroup include phenyl, naphthyl, which may be substituted by the above altergroup having 1-4 carbon atoms, halogen atoms (e.g. fluorine, chlorine, bromine, iodine), hydroxylgroups and nitrogroup.

As the alkyl part aranceles using alkali containing 1-4 carbon atoms, such as saws, (1 - naphthyl)methyl and (2-naphthyl)methyl, etc. Among the most preferred benzyl and phenetyl group.

Salt of the alkali metal compound (1-B2) can be obtained by reaction of compound (III) with an alkali metal cyanate, such as potassium cyanate or sodium cyanate. Then salt of an alkali metal is treated with acid to form compound (1-B2). The reaction of the compound (III) with an alkali metal cyanate carried out in a suitable solvent.

The solvent used is usually alcohols, such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol and butanol, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or a suitable mixture of them. The alkali metal cyanate is used in a molar ratio of from 1 to 10, preferably from 1 to 5. The reaction temperature ranges from 0 to 150oC, preferably 10 to 120oC, and the reaction proceeds from 0.5 to 50 hours

Thus obtained salt of an alkali metal compound (1-B2), treated with acid using conventional methods to form a compound (1-B2). The acid treatment is performed in the presence or in the absence of a suitable solvent.

Examples of the solvent include alcohols such as meta is luol and xylene; esters, such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane; ethyl acetate, acetonitrile or a mixture thereof.

As the acid used is preferably an excessive amount of inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and Hydrobromic acid, may also be used organic acids such as acetic acid, citric acid, tartaric acid and the like.

Thus obtained 2,4-oxazolidinedione derivative (1-B2) may be produced and purified using conventional methods of separation and purification such as concentration, concentration under vacuum, solvent extraction, recrystallization, phase transfer, chromatography and others.

Method C

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where A1- saturated, divalent straight or branched hydrocarbon residue having from 1 to 7 carbon atoms, and other symbols have the meanings given above.

Saturated divalent straight or branched residue of a hydrocarbon chain, having from 1 to 7 atoms, and is denoted by afleet obtained compound (1-B2a). This recovery is performed in accordance with conventional methods, in the presence of a catalyst in an atmosphere of hydrogen at 1-150 atmospheres.

As the solvent used alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, halogenated hydrocarbons such as chloroform, dichloromethane, 1,1,2,2-tetrachlorethane, ethyl acetate, N,N-dimethylformamide, or a suitable mixture.

Examples of preferred catalysts include metals such as compounds of Nickel and transition metals, such as palladium, platinum and rhodium. The reaction temperature ranges from 0 to 100oC, preferably from 10 to 80oC. the reaction Time varies from 0.5 to 50 hours

Thus obtained derivative 2,4-oxazolidinedione (1-B2a) can stand out and be purified by conventional methods of separation and purification such as concentration, concentration in vacuo, extraction with solvent, crystallization, recrystallization, phasic transfer and chromatography.

Method D

< / BR>
where B represents the lowest alkoxyl, nissyo alkylthio and lower acyloxy, corresponding to the symbol B, are mentioned, for example, alkoxy groups having 1-4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy; alkylthio having 1-4 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio; atillio group having from 1 to 4 carbon atoms, such as atomic charges, propionyloxy.

In addition, two B substituent can be combined with each other to form, for example, Ethylenedioxy, Propylenediamine or dithiothreitol. In other words, -CH(B)2in the formula (IV) means aldehyde protective group.

The compound (IV) is condensed with 2,4-oxazolidinedione with the formation of compound (1-B1). This condensation reaction is performed in essentially the same manner as the reaction of compound (II) with 2,4-oxazolidinedione method A.

Method E

< / BR>
where Q is a leaving group and other symbols above.

As the leaving group denoted by the symbol Q is halogen (e.g. chlorine, bromine, iodine), methansulfonate, benzosulfimide, p-toluensulfonate.

The compound (V) is condensed with compound (VI) with the formation of compound (1-D1). This reaction is conducted in a conventional way in podhoditi, such as benzene, toluene, xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; ketones, such as acetone and 2-butanone; N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane; suitable mixture of these solvents.

As the base used alkali metal salts, such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium bicarbonate, amines, such as pyridine, triethylamine, N,N-dimethylformamide; a metal hydroxide such as sodium hydroxide, potassium hydroxide; sodium ethylate, sodium methylate and tert-butyl potassium, and others.

The number of base changes predominantly in the range from 1 to 5 moles relative to the compound (V). This reaction is conducted usually at a temperature of from -50oC to 150oC, preferably from -10oC to 100oC. the reaction Time varies from 0.5 to 30 hours.

The original connection method for A can be obtained by the method of F.

Method F

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R4and R5independently of one another represent lower alkyl; R6is hydrogen or lower alkyl; q is 0, 1 or 2; other characters listed above.

Examples of the lower Akilov, obameter, ethyl, propyl, isopropyl and butyl.

According to this method, first, formyl or acyl derivative (VII) to react with a derivative phosphonooxy acid or/ phosphonocarboxylate acids with the formation of derivatives of unsaturated esters (IX). The reaction of (VII) (VIII) is the usual method 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, dimethoxyethane; alcohols such as methanol, ethanol, propanol; N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, as well as the appropriate mixtures thereof.

Examples of bases are alkali metal salts, such as sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate; amines such as pyridine, triethylamine and N,N-dimethylaniline; metal hydrides such as sodium hydride, potassium hydride; sodium ethylate, sodium methylate and tert-butyl potassium. The amount of base is preferably from 1 to 5 mol relative to compound (VIII).

The amount used of the compound (VIII) is from 1 to 5 mol, mostly from 1 to 3 esistono -10oC to 100oC. the reaction Time varies from 0.5 to 30 hours.

Then the compound (IX) is subjected to a recovery for the formation of an alcohol derivative (X). This reaction can be performed with known methods, for example by restoring the hydrides of metals, recovering the complex metal hydride, restoring DIBORANE and substituted borane.

In other words, this reaction can be carried out by treating compound (IX) with a reducing agent. Examples of reducing agents are borhydride metal (such as borohydride sodium and borohydride lithium); complex metal hydrides, such as alumalite lithium; DIBORANE, and use diisobutylaluminium hydride is favorable for the reaction.

This reaction is carried out in an organic solvent inert to the reaction. Examples of such solvents are 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-dimethylformamid the nature of the reducing agent.

The reaction temperature varies from -20oC to 150oC, particularly preferably 0oC to 100oC, reaction time varies from about 1 to 24 hours.

Then, the compound (X) is subjected to oxidation with the formation of unsaturated aldehyde derivative (II-I). This oxidation reaction is carried out with known methods, such as oxidation with manganese dioxide, the oxidation of chromic acid oxidation of dimethylsulfoxide and others.

In other words, this reaction is performed by interaction of the compound (X) with an oxidant. As oxidizers using manganese dioxide or chromic anhydride.

The use of these compounds preferably favorable for the reaction. This reaction is performed in an organic solvent inert to the reaction.

As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachlorethane, ethers, such as diethyl ether, tetrahydrofuran or dioxane, dimethyl sulfoxide or a stable mixture of these solvents, among the solvents of choice is about 150oC, especially in the range from 0oC to 100oC, and the reaction time varies from 1 to 24 hours.

Then the compound (II-1) is subjected to reduction reaction of, to obtain a compound (II-2). This reduction is performed in the same way as in method C.

Thus, the derived aldehyde (II-1), (II-2) was isolated and purified by conventional means, such as concentration, concentration under vacuum, solvent extraction, recrystallization, phase transfer, chromatography and so on

The compound (VII), which is a starting compound in method F, can be synthesized in accordance with the method described, for example, in Chemical Pharmaceutical Bulletin, Vol. 39, p. 1440(1990), JPA H4 (1992)-225978, HPA S61(1986)-85372, HPA S61 (1986)-271287, HPA S63(1988)-139182, HPA H3(1191)-170478, W09119496-A1, EP-428312-A, H1 HPA(1989)-299289 and HPA S63(1988)-230689.

Aldehyde derivative of pyridine (VII-I) can be obtained, for example, by the method of G.

Method G

< / BR>
< / BR>
< / BR>
< / BR>
where Q' is a halogen, and other symbols above.

As the halogen atom denoted by the symbol Q1mentioned chlorine, bromine and iodine.

In this method the first stage of 2-chloro-5-nitropyridine reacts with the alcohol derivative to obrazovannosti Foundation in accordance with a customary method.

As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as dioxane, tetrahydrofuran or dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, and suitable mixtures of these solvents.

As the base used alkali metal salts, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate; amines such as pyridine, triethylamine or N,N-dimethylaniline; metal hydrides such as gitignore or potassium hydride; sodium ethylate, sodium methylate and tert-butyl potassium.

The amount of such a base is preferably 1-5 mmol relative to compound (XI). This reaction is performed usually at a temperature of from -50 to 150oC, preferably from -10 to 100oC. the reaction Time ranges from 0.5 to 30 hours

Then the compound (XII) is reduced to the amino derivative (XIII). Although the reduction can be carried out by known methods, the most beneficial carrying out catalytic reduction using a metal catalyst. This recovery is carried out from the solvents may include alcohols, such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane; ethyl acetate, acetic acid, N,N-dimethylformamide or a suitable mixture of these solvents.

For enabling carrying out the reaction using as a catalyst metal compounds, such as compounds of Nickel, transitional metals, such as palladium, platinum or rhodium. The reaction temperature ranges from 0 to 100oC, mainly from 10 to 80oC, the reaction time is from 0.5 to 50 hours.

Then the compound (XIII) is subjected to well-known reaction of Sandmeyer with the formation of the halogen derivative (XIV). In this reaction, the compound (XIII), first, diazotized adding thereto dropwise an aqueous solution of sodium nitrite; the reaction is carried out in a solvent in the presence of hydrochloric acid, Hydrobromic acid or itestosterone acid. The mixture is then treated with an aqueous solution of halogenated sodium or halogenated potassium to education sidepanel and 2-methoxyethanol; esters, such as acetone, 2-butanone, dioxane, tetrahydrofuran; or a suitable mixture of these solvents. The reaction temperature range from -50oC to 100oC, mainly from -20o60oC. the reaction Time is from 0.5 to 50 hours.

Then the compound (XIV) interacts with butyllithium, terbutaline, tert-bwilliam, methyllithium, phenyllithium or phenylmagnesium, then treated with N,N-dimethylformamide to form compounds (VII-I).

Part of the intermediate compound (IX) in the method F can also be obtained, for example, by the method of H.

Method H

< / BR>
where each of the symbols described above.

This reaction can be carried out in a solvent in the presence of a base. As the solvent used aromatic hydrocarbons, such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, acetone, 2-butanone, and suitable mixtures thereof.

As grounds mentioned inorganic bases, including, for example hydroxides of delacherois magnesium and calcium hydroxide), carbonates of alkali metals (e.g. sodium carbonate and potassium carbonate), carbonates of alkaline earth metals (such as magnesium carbonate and calcium carbonate), bicarbonates of alkali metals (such as sodium bicarbonate and potassium bicarbonate) and acetates of alkali metals (such as sodium acetate and potassium acetate); organic bases, including trialkylamine (such as triethylamine and trimethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0] non-5-ene, 1,4-diazabicyclo[2,2,2]non-5-ene and 1,8 5-diazabicyclo[5,4,0]-7-undecene.

The amount of this base varies from 1 to 5 moles relative to the compound (XV). This reaction is usually carried out at temperatures from -20 to 150oC, preferably from -10 to 100oC.

Methods for the synthesis of starting compound (XV) in method H is described, for example, in Chemical & Pharmaceutical Bulletin, 30, p. 3563 (1982), Chemical & Pharmaceutical Bulletin, 30, p. 3580 (1982), Chemical Pharmaceutical Bulletin, 30, p. 2267 (1984), Arzneimittel - For-schung/Drug Research, 40, p, 37 (1990), Journal of Medicinal Chemistry, 35, p. 2617 (1992), JPA S61 (1986)-267580, JPA S61(1986)-286376, JPA S61(1986)-85372, JPA H2(1990)-31079 and JPA S62(1987)-5981.

The compound (III) used in the method B, the receive method I.

The method I

< / BR>
where A2represents a bond or a bivalent straight or branched or branched hydrocarbon residue chain 1-5 carbon atoms; other characters similar to the above.

Bivalent straight or branched hydrocarbon residue chain is denoted by A2is a remnant of 1-5 carbon atoms, among the divalent straight or branched hydrocarbon residue chains, denoted by the symbol A, and a divalent saturated straight or branched hydrocarbon residue chain is denoted by A3is rich balance among divalent straight or branched hydrocarbon residue chains expressed by the symbol A2.

In this method, firstly, the compound (II-3) is condensed with pyruvic acid with the formation of compound (XVI). The condensation reaction of compound (II-3) with pyruvic acid is carried out in a mixture of alcohol and water, using the same ground as in the reaction of compound (II) with 2,4-oxazolidinedione method A.

Then the compound (XVI) etherification with the formation of compound (XVII). This esterification reaction can be carried out by a known method, for example, the method which consists in the interaction of the compound (XVII) with alcohol (R4OH) in the presence of acid, or method, cats, gelegenheid acid (the acid chloride acid, bromohydrin acid), imidazoline or mixed acid anhydride (for example the anhydride with methylcarbonate, anhydride with ethylcarbonate, anhydride with isobutylketone and others) with alcohol (R4OH).

Then the compound (XVII) is subjected to catalytic recovery before the formation of the compound (XVIII). This catalytic reduction is carried out basically in the same way as in method C.

Then the compound (XVIII) undergoes reduction to form compound (III-I). This reduction can be carried out using a known method, for example, restore using a metal hydride, recovery using complex compounds of metal hydrides, recovery using DIBORANE or substituted DIBORANE, catalytic hydrogenation, and others. In other words, such a recovery is in the interaction of the compound (XVIII) with a reducing agent.

As the reductant used borhydride alkali metals (e.g. sodium borohydride, lithium borohydride, and so on), complex compounds of metal hydrides, such as alumalite lithium metal hydrides, such as gienia Nickel, zinc compounds and other similar catalysts of transition metals, including palladium, platinum, rhodium and other used together with hydrogen, DIBORANE.

The most favourable for the use of borhydride alkali metals (for example sodium borohydride, lithium borohydride, and so on). This reaction is carried out in an organic solvent which does not affect the reaction.

Examples of the solvents 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; or a suitable mixture of these solvents.

A suitable solvent is selected depending on the type of reducing agent. The reaction temperature ranges from -20oC to 150oC, especially from 0oC to 100oC. the reaction Time varies from 1 to 24 hours.

The original compound (IV) of method D and the source connection (II) of method A can be obtained, for example according to the method of J.

the method employed, first, the compound (VII) is condensed with compound (XIX) to form compound (IV-1). This condensation reaction is carried out in essentially the same manner as the reaction of the compound (VII) with compound (VIII) in method F.

Then the compound (IV-1) is subjected to reduction reaction of education (IV-2). This reduction is carried out in essentially the same way as catalytic reduction of compound (I-BI) method C. the Compound (IV-2) can be transformed into aldehyde derived by removing the protective group under treatment with acid in the same solvent.

As the aqueous solvent is referred to the mixture of alcohol, such as methanol, ethanol and propanol; ether such as tetrahydrofuran and dioxane; acetonitrile, acetone, 2-butanone, acetic acid and other similar water.

As acid using p-toluensulfonate acid, also inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and Hydrobromic acid.

Part of the compounds (II) and (IV) can be obtained according to the method of K.

Method K

< / BR>
where W-CHB2B has values similar to those shown above, and other symbols of the anode E.

Part of the compounds obtained by the method of E. can be restored to the compounds (I-B2a2).

Method L

< / BR>
where each character has values similar to those shown above. This reaction is similar to the method of recovery presented in method I, in which the compound (XVIII) is converted to compound (III-1).

The compound (II-2) and (II-4) can also be obtained by the method of M.

Method M

< / BR>
where each character has values similar to those shown above.

The compound (XXII), which is obtained by the catalytic hydrogenation of compound (XI) can be transformed to compound (XXIII).

The reaction is performed in a manner analogous to the reaction of method F, in which the compound (IX) into the compound (X). The compound (XXIII) can be oxidized to compounds (II-2) and (II-4).

This oxidation reaction is known in the usual way, such as the Jones oxidation using a mixture of sulfuric acid pyridine, oxidation Collina using the complex oxide of hamperian, oxidation using chloramine pyridinium, pyridinium dichromate, oxidation using activated dimethylarsine, oxidation using salts to acoolsoft activated DMSO. Oxidation with activated DMSO is performed in a solvent in the presence of DMSO and electrophilic reagent.

The solvent mentioned esters (for example ethyl ether, isopropyl ether, tetrahydrofuran, dioxane and so on), aromatic hydrocarbons (for example benzene, toluene, xylene and so on), N,N-dimethylformamide, halogenated hydrocarbons (e.g. chloroform, dichloromethane, and so on), pyridine, dimethyl sulfoxide. Of these solvents chosen solvent, corresponding to the nature of the electrophilic reagent.

Dicyclohexylcarbodiimide-method, method with acetic anhydride, a method pjatiokisi phosphorus, chlorine method, with sulfur trioxide-pyridine, ketenimine-enamine-method, method with acetate mercury (II), etc. are used in the oxidation using DMSO.

Among them, the method is mainly used with sulfur trioxide-pyridine. This method is performed using a complex of sulfur trioxide-pyridine in DMSO activator in the presence of triethylamine.

This method is carried out with the use of excessive amounts of DMSO as solvent. The triethylamine and a complex of a sulfur trioxide-pyridine, each used in amounts of about what I (XXIII).

The reaction temperature ranges from -70 to 80oC, mainly from -20 to 40oC. the reaction Time ranges from 0.5 to 10 hours

Derivatives of aldehyde (II-2), (II-4), thus obtained, is isolated and purified using conventional purification methods, for example, concentration, concentration in vacuo, extraction with solvent, crystallization, recrystallization, phase transfer, chromatography or similar.

The compound (II-2) and (II-4) is converted into compound (IV-2) acetylation by diltiazemcream.

Among the compounds (XXII), benzoxazole derivative (XII-1) can be obtained by the method of N.

Method N

< / BR>
where each symbol is similar to the above.

This reaction is carried out in an organic solvent inert to the reaction. Examples of the solvents include aromatic hydrocarbons, such as xylene, toluene, benzene, and so on, ethers such as tetrahydrofuran, dioxane and so on, halogenated hydrocarbons such as dichlorobenzene, chlorobenzene, methylene chloride, etc. May be used a solvent mixture of two or more solvents.

This reaction is usually carried out by heating the mixture connected>.

This reaction can be carried out in the presence of a dehydrating agent. As the dehydrating agent used phosphorus compounds, such as patikis phosphorus and phosphorus oxychloride. Dehydrating agent is used in an amount from 1 to 10 mol. equivalents, mainly from 1 to 4 mol. equivalents, relative to compound (XXIV).

In the case of the use of phosphorus oxychloride, it can be used with a large excess as a solvent. In the case of phosphorus pentoxide positive if the reaction to add hexamethyldisiloxane { [(CH3)3Si]O}.

In this case, hexamethyldisiloxane used in an amount of from 2 to 4 mol. equivalents relative to phosphorus pentoxide. The reaction time is usually from 1 to 30 hours, mainly from 1 to 10 hours.

The compound (I) of this invention have excellent hypoglycemic and hypolipidemic activity.

Description of the experiment

Hypoglycemic and glycolipids effect on mice.

Mouse lines KKAY (ages 9-14 weeks) received the test compound mixed with solid food (CE-2, Japan Clea) at a dose of 0.005%, within 4 days of unlimited colijnsplaat.

With the help of instruments Latrochem-GLU(A) and Latro-MA701 TG (Latron Inc.) quantitative enzyme was defined as plasma glucose and triglyceride.

Values represent the percentage of reduction (%) found the group of animals treated with the drug compared with the control group, the drug is not treated. The data shown in table 1.

As shown above, derivatives of 2,4-oxazolidinedione (1) of the present invention exhibit excellent hypoglycemic and hypolipidemic activity and is pharmaceutically suitable for use as drugs for the treatment of diabetes, hyperlipemia and hypertension.

Example 1

A mixture of (E)-4-[2-[5-methyl-2-(3-were)-4-oxazolyl] ethoxy] cinnamic aldehyde (1.2 g), 2,4-oxazolidinedione (0,525 g), piperidine (0.09 g) and ethanol (20 ml) was boiled for 5 hours, poured into water, acidified using 2N HCl, extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried (MgSO4) and was evaporated. The residue was purified on a column of silica gel. Collected fraction, elyuirovaniya chloroform-methanol (50: 1), and received 5-[4-[2-[5-methyl-2--(3-were)-4-oxazolyl] ethoxy]cinnamamide]-2,4-oxazolidinedione (0.51 g, 34%).

Product paracrystalline

Examples 2-7

Similarly to the method of example 1 was obtained compounds are shown in table 2.

Example 8

According to the method of example 1 was received 5-[3-[2-[2-(-5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] -2 - propenylidene]-2,4-oxazolidinedione, recrystallized from a mixture of ethanol-chloroform-isopropyl ether and was isolated as pale-yellow crystals, so pl. 204-205oC.

Example 9

The mixture 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] propyl] -1,3-dioxane (2.0 g), 2,4-oxazolidinedione (0,99 g), piperidine (0.21 g) and acetic acid (50 ml) was boiled for 24 hours, evaporated under vacuum, was added ethyl acetate.

An ethyl acetate layer is washed with aqueous sodium bicarbonate solution, 2N HCl and water, stosil (MgSO4), was evaporated. The residue was chromatographically on a column of silica gel.

From the faction, elyuirovaniya a mixture of chloroform - ethyl acetate (5:1), was isolated 5-[4-[4-[2-(5-methyl-2-phenyl-4 - oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.55 g, 26%), recrystallized from a mixture of ethyl ether - methanol and received colorless needle-like crystals, so pl. 152-153oC.

Examples 10-13

According to the method of example 1 was obtained compounds are shown in table 3.

Example 14

According to the method of example 1 (E-[2-(5-methyl-2-phenyl-4-oxazolyl)benzofuran-5-yl] -2 - propenylidene] -2,4-oxazolidinedione. The yield was 44%. Upon recrystallization from a mixture of dichloromethane-methanol was obtained a light yellow needle-like crystals, so pl. 237-239oC.

Example 15

According to the method of example 1 (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] -2, 4-pentadien-1-al was reacted with 2,4-oxazolidinedione education 5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] -2,4-pentadienyl] -2,4-oxazolidinedione. The yield was 31%. Upon recrystallization from a mixture of dichloromethane-methanol was obtained a yellow needle-like crystals, so pl. 209-211oC.

Example 16

The mixture 5-[4-[2-[5-methyl-2-(3-were)-4-oxazolyl]ethoxy]cinnamamide] - -2,4-oxazolidinedione (0,29 g), palladium on carbon (10%, 0.1 g) and dioxane (50 ml) was first made at room temperature and atmospheric pressure, was filtered. The filtrate was evaporated under reduced pressure.

The residue was chromatographically on a column of silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (100:3), were isolated 5-[3-[4-[2-[5-methyl-2-(3-were)-4-oxazolyl] ethoxy] phenyl]propyl] -2,4-oxazolidinedione (0.28 g, 96%), recrystallized from a mixture of dichloromethane-methanol was obtained colorless privorotnye crystals, so pl. 149 - 150oC.

Elemental analysis for C25H26

Example 23

According to the method of example 16 by the catalytic hydrogenation 5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl] -2-propenylidene]-2,4-oxazolidinedione received 5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-pyridyl] propyl] - 2,4-oxazolidinedione, which was recrystallized from a mixture of chloroform-methanol-isopropyl ether and was obtained colorless crystals, so pl. 169-171oC.

Elemental analysis for CH23H23N3O51/2H2O:

Calculated,%: C 64,18; H 5,62; N 9,76

Found,%: C 64,31; H 5,70; N 9,48

Example 24

A mixture of ethyl ester of 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] butyric acid (0.45 g), powdered potassium cyanate (0.24 g) and butanol (20 ml) was boiled for 4 days, the solvent was evaporated in vacuo, the residue was acidified using 2N HCl and was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and was evaporated.

The residue was chromatographically on a column of silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (100:3), were isolated 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] ethyl] -2,4-oxazolidinedione (0.28 g, 63%) which was recrystallized from a mixture of dichloromethane-ethanol, and instructed colorless privorotnye Krista is C 67,97; H 5,46; N 6,89

Found,%: C 67,92; H 5,61; N 6,64

Example 25

The mixture 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] butylidene] -2,4-oxazolidinedione (0,38 g), palladium on carbon (10%, 0.2 g) and tetrahydrofuran (40 ml) was first made at room temperature and 3 atmospheres. The catalyst was filtered, the filtrate was evaporated in vacuo, the residue was chromatographically on a column of silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (100: 3) was isolated 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] butyl] -2,4-oxazolidinedione (0.25 g, 65%). This product was recrystallized from a mixture of dichloromethane-methanol was obtained colorless crystals in the form of prisms, so pl. 136-137oC.

Examples 26-29

According to the method of example 16 was obtained compounds are shown in table 5.

Example 30

According to the method of example 16 was obtained 5-[3-[2-(5-methyl-2-phenyl-4-oxazolyl)benzofuran-5-yl] propyl] - 2,4-oxazolidinedione, the yield is 80%. This product was recrystallized from a mixture of dichloromethane-methanol in the form of colorless needle-like crystals, so pl. 184-184oC.

Example 31

According to the method of example 16 5-[5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] -2,4-pentadienyl]-2,4-oxazolidinedione catalytically was first made with the formation of 5-[5-[4-[2�oduct from a mixture of dichloromethane-methanol was obtained colorless needle-like crystals, so pl. 157-158oC.

Example 32

According to the method of example 24 was received 5-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] ethyl] -2,4-oxazolidinedione, yield 35%, by recrystallization from a mixture of ethyl acetate-hexane were isolated colorless privorotnye crystals, so pl. 158-159oC.

Example 33

To a solution of 5-[5-(4-hydroxyphenyl)pentyl]-2,4-oxazolidinedione (0.9 g) in N,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 0.28 g), stirred for 15 minutes at room temperature, was added 4-chloromethyl-5-methyl-2-phenyloxazol of 0.85 g), stirred for 2 hours at 70oC, poured into water, acidified using 2N HCl, extracted with ethyl acetate.

The extract was washed with water, dried (MgSO4), the solvent was evaporated, the oily residue was chromatographically on a column of silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-chloroform (1:5, V/V) was allocated 5-[5-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]pentyl]-2, 4-oxazolidinedione (0,86 g, 58%), which precrystallization from a mixture of dichloromethane-isopropyl ether, and obtained colorless crystals in the form of prisms, so pl. 120-121oC.

Example 34

According to the method of example 33 was received 5-[4-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]butyl]-2,4-oxazolidinedione in the form of prisms, so pl. 186-187oC.

Example 35

The mixture 4-[4-[2-(1,3-dioxolane-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole (1.8 g), 2,4-oxazolidinedione (0,925 g), piperidine (0.12 g) and acetic acid (30 ml) was boiled for 15 hours, evaporated under reduced pressure, the residue was treated with saturated aqueous sodium bicarbonate and was extracted with chloroform.

The chloroform layer was washed with water, dried (MgSO4), the solvent was evaporated. The oily residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture metaalgorithm (1:30, V/V), were isolated 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oksidoksi] phenyl] propylidene]-2,4-oxazolidinedione.

The compound was dissolved in tetrahydrofuran (30 ml), was added palladium on carbon (5%, 0.3 g), catalytically was first made, the catalyst was filtered, the filtrate was evaporated in vacuum, the oily residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture ethylacetate (1: 2, V/V), were isolated 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oksidoksi]phenyl]propyl] -2,4-oxazolidinedione (0.32 g, 16%in the form of butter.

NMR (ppm in CDCl3): a 1.7-2.1 (4H, m), 2.63 in (2H, t, J = 7 Hz), is 2.74 (3H, s), 4,84 (1H, DD, J = 7 and 4.5 Hz), lower than the 5.37 (2H,. C), 6,92 (2H, d, J = 9 Hz), to 7.09 (2H) - Rev. XI] phenyl] propyl] -2,4-oxazolidinedione (0.2 g) in tetrahydrofuran (5 ml) - ethanol (5 ml) was added sodium borohydride (0.03 g), stirred 1 hour at room temperature, was added 2N HCl and water, was extracted with ethyl acetate.

The extract was washed with water, dried (MgSO4), the solvent was evaporated, the oily residue was chromatographically on a column of silica gel, fractions, elyuirovaniya mixture of chloroform-methanol (50:1, V/V), were isolated 5-[3-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]- 2,4-oxazolidinedione (0.16 g, 80%) which was recrystallized from a mixture of dichloromethane-isopropyl ether and was obtained colorless crystals in the form of needles, so pl. 146-147oC.

Examples 37 - 50

According to the method of example 33 was obtained compounds are shown in table 6.

The footnote to table 6: 1) NMR (ppm in CDCl3): a 1.7-2.1 (4H, m) of 2.50 (3H, s), 2,62 (2H, t, J = 7 Hz), 4,79 (1H, DD, J = 6.5 and 4.5 Hz), of 6.99 (2H, d, J = 8.5 Hz), 7,10 (2H, d, J = 8.5 Hz), 7,45 to 7.7 (3H, m), a 7.85 - 8,0 (2H, m), 8,15 (1H, DD, J = 7 and 1 Hz), of 9.21 (1H, d, J = 8,5 Hz). Me: methyl, 2-naph: 2-naphthyl, 1-naph: 1-naphthyl

Example 51

A mixture of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamic aldehyde (4,00 g), 2,4-oxazolidinedione (2.86 g), piperidine (0.50 g), ethanol (50 ml) was boiled for 2 hours, evaporated and the residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture of ethyl acetate-chloroformate on carbon (5%, 1.40 g), was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated under reduced pressure, the residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture of chloroform-methanol (100: 2), were isolated 5-[3-4-[2-[N-methyl-N - (2-pyridyl)amino]ethoxy]phenyl]-2,4 - oxazolidinedione (1,17 g, 21%) which was recrystallized from a mixture of dichloromethane-isopropyl ether and was obtained colorless crystals in the form of prisms, so pl. 126-127oC.

Example 52

According to the method of example 51 was received 5-[3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl]propyl] -2,4-oxazolidinedione in the form of oil, yield 22%.

NMR (ppm in CDCl3): 1,7-of 2.15 (4H, m), 2,48 (3H, s), 2,61 (H, t, J = 7 Hz), 4,84 (1H, DD, J = 6.5 and 4.5 Hz), at 5.27 (2H, s) 6,76 (H, d, J = 8.5 Hz), 7,3-7,5 (4H, m), 7.95 is to 8.1 (3H, m), 8,84 (1H, Shir).

Example 53

According to the method of example 35 was received 5-[4-[4-[5- methyl-2-(2-naphthyl)-4-oxazolidinone] phenyl] butyl] -2,4-oxazolidinedione, yield 22%, which was recrystallized from a mixture of dichloromethane-methanol was obtained colorless crystals in the form of prisms, so pl. 163-164oC.

Example 54

According to the method of example 35 was received 5-[3-[2-(2-naphthylmethyl)benzoxazol-5-yl] propyl] -2,4-oxazolidinedione, exit 13%, which was recrystallized from the>/P>Example 55

According to the method of example 1 was received 5-[3-[3-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-propylidene] -2,4-oxazolidinedione, which was recrystallized from a mixture of chloroform-methanol and allocated colorless needle-like crystals, so pl. 229-230oC.

Example 56

According to the method of example 16 was obtained 5-[3-[3-(5-methyl-phenyl-4-oxazolidinone)phenyl] propyl] -2,4 - oxazolidinedione, which was recrystallized from atlatlahucan, and provided in the form of colorless needle-like crystals, so pl. 134-135oC.

Example 57

According to the method of example 51 was obtained 5-[3-(4-isopropoxyphenyl)propyl]-2,4-oxazolidinedione in the form of butter.

NMR (ppm in CDCl3: to 1.32 (6H, d, J = 6 Hz), 1,65-of 2.15 (4H, m), 2,62 (2H, t, J = 7 Hz), 4,4-4,6 (1H, m), 4,84 (1H, DD, J = 7 and 4.5 Hz), for 6.81 (2H, d, J = 8.5 Hz), 7,06 (2H, d, J = 8.5 Hz), 8,00 (1H, Shir).

Example 58

According to the method of example 51 was obtained 5-[4-(4-isopropoxyphenyl)pentyl]-2,4-oxazolidinedione in the form of butter.

NMR (ppm in CDCl3: to 1.32 (6H, d, J = 6 Hz), 1,3-2,1 (8H, m) to 2.54 (2H, t, J = 7.5 Hz), 4,4-4,6 (1H, m), 4,84 (1H, DD, J = 7.5 and 4.5 Hz), to 6.80 (2H, d, J = 8.5 Hz), 7,05 (2H, d, J = 8.5 Hz), 7,98 (1H, Shir).

Example 59

According to the method of example 35 was obtained 5-[4-(4-isopropoxyphenyl)butyl]-2,4-oxazolidinedione by the reaction of 2-[3-(4-isopropoxyphenyl)propyl]-1,3-dioxolane 2 is I the product was recrystallized from a mixture of dichloromethane-isopropyl and was isolated as a colourless pritvorenih crystals, so pl. 81-82oC.

Example 60

According to the method of example 51 was received 5-[3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] butyl] -2,4-oxazolidinedione in the form of a pale yellow amorphous powder.

NMR (ppm in CDCl3: to 1.25 (3H, d, J = 6.8 Hz), 1.30 and a 2.00 (4H, m), 2,43 (3H, s), 2,55 is 2.80 (1H, m), 4,67 of 4.83 (1H, m), equal to 4.97 (2H, s), to 6.95 (2H, d, J = 8,8 Hz), to 7.09 (2H, d, J = 8,8 Hz), 7,35 - 7,53 (3H, m), 7,92-8,10 (2H, m).

Example 61

According to the method of example 33 was received 5-[3-[4-[2-(2-benzo[in]thienyl)- 5-methyl-4-oxazolidinone] phenyl]propyl]- -2,4-oxazolidinedione, yield 76%, so pl. 154-155oC (recrystallized from dichloromethane-isopropyl alcohol).

Example 62

According to the method of example 33 was received 5-[3-[4-[2-(2-benzo[in]furanyl)-5-methyl-4-oxazolidinone]phenyl]propyl]- 2,4-oxazolidinedione, yield 70%, which was recrystallized from a mixture of dichloromethane-isopropyl alcohol, and allocated colorless needle-like crystals so pl. 165-166oC.

Getting the preparative form. Example 1

(Getting tablets)

(1) 5-[3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -pyridyl]propyl]-2,4-oxazolidinedione 10 grams

(2) lactose 50 g

(3) corn starch 15 g

(4) carboxymethylcellulose calcium 44 g

(5) magnesium stearate 1 g 1000 tablets 120 g

Full amount (1), (2) and (3) IP 14 g (4) and 1 g (5), was shaped tablets using a special machine and got 1000 tablets each containing 10 mg (1).

Getting the preparative form. Example 2

(Getting tablets)

(1) 5-[2-[4-[2-(5--methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl]ethyl]-2,4-oxazolidinedione 30 grams

(2) lactose 50 g

(3) corn starch 15 g

(4) carboxymethylcellulose calcium 44 g

(5) magnesium stearate 1 g 1000 tablets 140 grams

The total number(1), (2), (3) and 30 g (4) was mixed with water, was dried under vacuum, was granulated. Thus granulated powder was mixed with 14 g (4) and 1 g (5) was molded using a special machine in tablet and got 1000 tablets, each containing 30 mg (1).

Source. Example 1

To a solution of triethylphosphate (1,79 g) in N,N-dimethyl-formamide (40 ml) was added gradually at 0oC sodium hydride (60% in oil, 0.32 g), stirred for 15 minutes at this temperature, was added 4-[2-[5-methyl-2-(3-were)- 4-oxazolyl]ethoxy]benzaldehyde (2,44 g), stirred 1 hour at room temperature, poured into ice water, acidified by 2N HCl was filtered and the crystals, which are recrystallized from a mixture of ethyl acetate-hexane, and received ethyl ester (E)-4-[2-[5-methyl-2-)-were)-4-aksar> Source. Examples 2-6

Similarly to the method shown in Example 1, was obtained compounds are shown in table 7.

Source. Example 7

The solution diisobutyrate hydride (1.5 M, with 9.3 ml) in toluene was added dropwise at 0oC to a suspension of ethyl ether (E)-4-[2-[5-methyl-2-(3-were)-4-oxazole] ethoxy] cinnamic acid (2,48 g) in dichloromethane (50 ml), stirred 2 hours at room temperature, then added with ice cooling methanol (3 ml) and water (30 ml), filtered through a layer of celite. The organic layer was washed with water, dried (MgSO4) and was evaporated.

The residue was chromatographically on the column and fractions, elyuirovaniya a mixture of ethyl acetate - hexane (1: 1), was isolated (E)-3--[4-[2-[5-methyl-2-(3-were)-4-oxazolyl] ethoxy] phenyl] -2-propen-1-ol (1.44 g, 65%) which was recrystallized from a mixture of dichloromethane-isopropyl ether, and obtained colorless crystals in the form of prisms, so pl. 116-117oC.

Source. Examples 8-13

Similar to the methodology described in example 7, obtained compounds are shown in table 8.

The footnote to table 8: 1) NMR (ppm in CDCl3: 1,24 (3H, d, J = 7.5 Hz), 2.63 in (2H, d, J = 7.5 Hz), 3,23 (2H, t, J = 7 Hz), 4,25-to 4.4 (4H, m), 6,23 (1H, dt, J = 16 and 6 Hz), 6,55 (1H, d, J = 16 Hz), 6,86 (2H, d, J = 9 Hz), 7,19 (1H, d, J = 8 Hz),the-2-(3-were)-4-oxazolyl] ethoxy] phenyl] -2-propen-1-ol (1.4 g) in dichloromethane (50 ml) was added activated dioxide magnesium (2.8 g), was stirred 2 hours at room temperature, filtered through celite.

The filtrate was evaporated and received (E)-4-[2-[5-methyl-2- (3-were)-4-oxazolyl] ethoxy] cinnamic aldehyde (1.27 g, 91%) which was recrystallized from a mixture of dichloromethane-isopropyl ether, and allocated colorless needle-like crystals, so pl. 110-111oC.

Source. Examples 15-20

According to the technique of the Original. Example 14 was obtained compounds are shown in table 9.

Source. Example 21

To a solution of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (3.0 g) and pyruvic acid (3,44 g) in methanol (80 ml) was added dropwise a solution of sodium carbonate (4,14 g) in water (80 ml) was stirred 24 hours at a temperature of 70-80oC, poured into water, washed with ethyl acetate. The aqueous layer was acidified with concentrated HCl and the precipitate was filtered, which was added to ethanol containing hydrogen chloride (5%, 15 ml), boiled for 30 minutes, evaporated. The residue was dissolved in chloroform, washed with water, dried (MgSO4) and was evaporated.

The residue was chromatographically on a column of silica gel, fractions, elyuirovaniya mixture of etelaat - chloroform (1:9), were isolated ethyl ester (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylidene peelie crystals in the form of needles, so pl. 99-100oC.

Source. Example 22

A mixture of ethyl ether (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] benzylidene pyruvic acid (0.85 grams), palladium on carbon (10%, 0.1 g) and dioxane (80 ml) was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated under reduced pressure.

The residue was dissolved in ethanol (20 ml), to the solution was added with ice cooling borgert sodium (0.08 g), the mixture was stirred for 1 hour at room temperature. The reaction mass was poured into water, neutralized IN HCl, extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried (MgSO4), then was evaporated and the residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture of chloroform-ethyl acetate (9:1), was isolated ethyl ester of 2-hydroxy-4-[4-[2- (5-methyl-2-phenyl-4-oxazolyl]ethoxy]phenyl butyric acid (0.55 g, 64%) which was recrystallized from a mixture of ethyl ether-hexane as colourless needles, so pl. 67 - 68oC.

Source. Example 23

To a solution of 2-chloro-5-nitropyridine (25 g), 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (32.1 g) in THF (250 ml) was added by portions under ice cooling sodium hydride (60% in oil, 6,92 g), perimetry layer was washed with water, dried (MgSO4), the solvent was evaporated under reduced pressure and the remaining crystals were filtered and recrystallized from ethanol - and provided 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-nitropyridine (25.4 g, 49%) as yellow-brown crystals, 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

Source. Example 24

A mixture of 2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] -5-nitropyridine (13,4 g), palladium on carbon (5%, 1.5 g) and ethyl acetate (200 ml), methanol (150 ml) was first made at room temperature at atmospheric pressure, the catalyst was filtered, the filtrate was evaporated in vacuum.

The remaining crystals were filtered off and got 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (11.4 g, 93%) which was recrystallized from a mixture of ethyl acetate-hexane, and received brown crystals, so pl. 107,0-108,0oC.

Elemental analysis for C17H17N3O42:

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

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

Source. Example 25

To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (10.0 g), concentrated HCl (of 8.47 ml) and acetone (100 ml) priba the Ali for 30 minutes at 10oC, was added dropwise a solution of potassium iodide (KI) (2,46 g) in water (10 ml) at 10oC, stirred for 1 hour at a temperature of 30-35oC, 1 hour at a temperature of 35-40oC, was evaporated at reduced pressure.

The concentrate was poured into ice water, extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4), the solvent is kept at reduced pressure. The oily residue was chromatographically on silica gel, fractions, elyuirovaniya a mixture of ethyl acetate-hexane (1:3, V/V), were isolated 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (7,22 g, 52%) which was recrystallized from a mixture of ethyl acetate-hexane, and obtained colorless crystals, so pl. 105-106oC.

Elemental analysis for C17H15N2O2I:

Calculated,%: C 50,26; H 3,72; N 6,90

Found,%: C 50,22; H to 3.89; N IS 6.78

Source. Example 26

To a solution of 5-iodine-2-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]pyridine (2.5 g) in tetrahydrofuran (40 ml) at a temperature of -65oC in an atmosphere of nitrogen was added dropwise a solution of n-butyl lithium (1.6 to M 4.61 in ml), stirred for 15 minutes at temperature, was added dropwise N,N-dimethylformamide (0,71 ml) were removed bath cooled, stirred 30 minutes, and made a saturated aqueous solution of chloride of am is sewed (MgSO4), the solvent was taken at reduced pressure, and provided 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] pyridine (1.5 g, 79%) which was recrystallized from a mixture of ethyl acetate-hexane and was obtained colorless crystals, so pl. 99-100oC.

Elemental analysis for C18H16N2O3:

Calculated,%: C 70,12; H 5,23; N IS 9.09

Found,%: C 69,94; H 5,38; N 8,94

Source. Example 27

According to the technique of the Original. Example 1 was received 3-[2-[2- (5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]acrylate, which was recrystallized from ethyl acetate, and provided colorless crystals, so pl. 138-139oC.

Source. Example 28

According to the technique of the Original. Example 7 was obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl] -2-propen-1-ol, which was recrystallized from a mixture of ethyl acetate-isopropyl ether, and provided colorless crystals, so pl. 115-116oC.

Source. Example 29

According to the technique of the Original. Example 14 was obtained (E)-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-5-pyridyl]acrolein, which was recrystallized from a mixture of ethyl acetate-hexane, and provided colorless crystals, so pl. 138-139oC.

Source. Example 30

A mixture of methyl ester of 2-bromo-3-[4-[2-(5-methyl-2-phenyl-4-oxazol the sa in the 70oC, poured into ethyl acetate (200 ml), washed with 2N HCl, saturated aqueous saline solution, dried (MgSO4), the solvent was evaporated under reduced pressure and obtained the methyl ester 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] cinnamic acid (10.8 g, 88%) which was recrystallized from a mixture of ethyl acetate-hexane, and provided colorless crystals, so pl. 114 - 115oC.

Source. Example 31

To a solution of [2-(1,3-dioxa-2-yl)ethyl]triphenylphosphonium bromide (8,9 g) in N, N-dimethylformamide (100 ml) was added at room temperature in portions sodium hydride (60% in oil, 0,78 g), stirred for 30 minutes at this temperature, made 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g), stirred for 15 minutes at room temperature, followed by 5 hours at 70oC, was poured into ice water, acidified using 2N HCl and was extracted with ethyl-acetate.

An ethyl acetate layer was washed with water, dried (MgSO4), the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1: 3), was isolated (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] -2-propenyl] -1,3-dioxane (5,1 g, 77%) as an oily product.

NMR (ppm in CDCl3): 1,25-1,4 (1H, m), 1,95 was 2.25 (1H, m), is 2.37 (3H, s) to 2.66 (1H, DDD, J = 7 and 5 and 2 Hz), 2,, Is, J = 9 Hz), 7,35 is 7.5 (3H, m), of 7.9 to 8.0 (2H, m).

Source. Example 32

A mixture of (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl] -2-propenyl] -1,3-dioxane (5.0 g), palladium on carbon (5%, 0.1 g), and ethanol (100 ml) was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated under reduced pressure, the residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture of hexane-ethyl acetate (1: 1), was isolated 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl] -1,3-dioxane (4.8 g, 96%).

NMR (ppm in CDCl3): 1,25-1,4 (1H, m), 1,5-1,8 (4H, m), 1,9-2,2 (1H, m), is 2.37 (3H, s) to 2.54 (2H, t, J = 7 Hz), 2,96 (2H, t, J = 6.5 Hz), 3,65-of 3.85 (2H, m), 4,0-to 4.15 (2H, m), is 4.21 (2H, t, J = 6.5 Hz), 4,50 (1H, t, J = 5 Hz), to 6.80 (2H, d, J = 9 Hz), 7,06 (2H, d, J = 9 Hz), 7,35 is 7.5 (3H, m), 7,92 to 8.0 (2H, m).

Source. Examples 33-36

According to the technique of the Original. Example 1 was obtained compounds are given in table 10.

The footnote to table 10: 1) NMR (ppm in CDCl3): of 1.30 (3H, t, J = 7.5 Hz), of 1.33 (3H, t, J = 7 Hz), of 2.25 (3H, s), 2,70 (2H, q, J = 7.5 Hz), is 2.88 (1H, t, J = 7 Hz), 4,20 (2H, t, J = 7 Hz), 4,25 (2H, q, J = 7.5 Hz), of 6.29 (1H, d, J = 16 Hz), to 6.88 (2H, d, J = 9 Hz), was 7.45 (2H, d, J = 9 Hz), 7,63 (1H, d, J = 16 Hz).

Source. Example 37

According to the technique of the Original. Example 1 reaction of 5-formyl-2-(5-methyl-2-phenyl-4-oxazolyl)benzofuran with triethylphosphate 74%. The product was recrystallized from a mixture of ether-hexane and taught colorless privorotnye crystals, so pl. 150-151oC.

Source. Example 38

According to the technique of the Original. Example 1 reaction (E)-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] cinnamic aldehyde with triethylphosphate was obtained ethyl (E)-5-[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2,4-pentadiene. Yield 56%. The product was recrystallized from a mixture of ether-hexane and was obtained colorless needle-like crystals, so pl. 102-103oC.

Source. Example 39

A mixture of 4-(5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde (2.9 g), sodium pyruvate (3.3 grams), sodium carbonate (3.2 g), water (80 ml) and methanol (80 ml) was boiled for 6 hours, concentrated at boiling up to 1/3 of the initial volume and the residue was extracted with ethyl acetate.

The aqueous layer was acidified with concentrated HCl, the precipitated crystalline precipitate was filtered and was obtained (E)-4-(5-methyl-2-phenyl-4-oxazolidinone)benzylideneamino acid (1.6 g, 44%) which was recrystallized from a mixture of chloroform-methanol, and provided colorless crystals in the form of needles, so pl. 197-198oC.

Source. Example 40

To a mixture of (E)-4-(5-methyl-2-phenyl-4-oxazolidinone)benzylidenemalononitrile acids which have strayaway with ethyl acetate.

An ethyl acetate layer was washed with water, dried (MgSO4), the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1: 3, V/V), were isolated ethyl ester (E)-4-(5-methyl-2-phenyl-4-oxazolidinone)benzylidenemalononitrile acid (1.2 g, 86%) which was recrystallized from a mixture of ethyl acetate-hexane, and received light yellow privorotnye crystals, so pl. 110-111oC.

Source. Example 41

According to the technique of the Original. Example 22 ethyl ester (E)-4-(5-methyl-2 - phenyl-4-oxazolidinone)benzylidenemalononitrile acid was obtained ethyl ester of 2-hydroxy-4-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] butyric acid. Yield 89%.

NMR (ppm in CDCl3): of 1.28 (3H, t, J = 7 Hz), 1.8-to 2.2 (2H, m), 2,43 (3H, s), a 2.71 (2H, t, J = 7 Hz), 2,84 (1H, d, J = 5,2 Hz), 4,1-4,3 (1H, m), is 4.21 (2H, q, J == 7 Hz), equal to 4.97 (2H, s) 6,94 (2H, d, J = 9 Hz), between 7.4 to 7.5 (3H, m), 7.95 is to 8.1(2H, m).

Source. Examples 42-45

According to the technique of the Original. Example 7 was obtained compounds are shown in table 11.

The footnote to table 11: (1) NMR (ppm in CDCl3): of 1.30 (3H, t, J = 7.5 Hz), of 1.3-1.5 (1H, m), of 2.45 (3H, s), 2,70 (2H, q, J = 7.5 Hz), 2,87 (2H, t, J = 7 Hz), 4,17 (2H, t, J = 7 Hz), 4,25 is 4.35 (2H, m), 6,23 (1H, dt, J = 16 and 6 Hz), 6,55 (1H, d, J = 16 Hz), 6,83 (2H, d, J = 9 Hz), 7,30 (2H, d, J = 9 Hz).

Neil-4-oxazolidinyl)benzofuran-5-yl]acrylic acid was obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl) benzofuran-5-yl]-2-propen-1-ol, yield 57%, by recrystallization from a mixture of dichloromethane-hexane was obtained colorless crystals in the form of needles, so pl. 156-157oC.

Source. Example 47

According to the technique of the Original. Example 7 recovery of ethyl (E,E)-5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] phenyl] -2,4 - pentadienoic received (E, E)-5-[4-[2- (5-methyl-2-phenyl-4-oxazol-yl)ethoxy]phenyl]-2,4 - pentadien-1-ol, yield 63%, after recrystallization from a mixture of dichloromethane-hexane was obtained a colorless product in the form of flakes, so pl. 132-133oC.

Source. Examples 48-51

According to the technique of the Original. Example 14 was obtained compounds are shown in table 12.

The footnote to table 12: (1) NMR (ppm in CDCl3): of 1.30 (3H, t, J = 7.5 Hz), 2,2,5 (3H, s), 2,71 (2H, q, J = 7.5 Hz), 2,90 (2H, t, J = 6.5 Hz), to 4.23 (2H, t, J = 6.5 Hz), 6,60 (1H, DD, J = 16 and 7.5 Hz), 6,93 (2H, d, J = 9 Hz), 7,41 (1H, d, J = 16 Hz), to 7.50 (2H, d, J = 9 Hz), to 9.66 (1H, d, J = 7.5 Hz).

Source. Example 52

According to the technique of the Original. Example 14 (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)benzofuran-5-yl] -2 - propen-1-ol was obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolyl)benzofuran-5-yl] acrolein, yield 93%, which was recrystallized from a mixture of dichloromethane-hexane, and provided colorless crystals in the form of needles, so pl. 136-137oC.

Source. Example 53

if (E,E)-5-[4-[2-(5-methyl-2-phenyl-oxazolyl)ethoxy] phenyl] -2,4-pentadien-1-al, yield 82%, which was recrystallized from a mixture of dichlormethane and received a yellow privorotnye crystals, so pl. 133-134oC.

Source. Example 54

A mixture of 4-bromoacetyl-5-methyl-2-phenyloxazole (2,60 g), 4-[2-(1,3-dioxolane-2-yl)ethyl]phenol (1,82 g), potassium carbonate (1.28 g) and 2-butanone (60 ml) was stirred for 20 hours at a temperature of 70-80oC, was poured into the water.

Precipitated crystalline precipitate was filtered, was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of chloroform-methanol (100: 1, V/V), were isolated 4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyl-oxazol (2,08, 57%) which was recrystallized from a mixture of dichloromethane-isopropyl ether and was identified colorless privorotnye crystals, so pl. 119-120oC.

Source. Example 55

According to the technique of the Original. Example 1 was obtained ethyl ester 4-[2-[N-methyl-N-(2-pyridyl)amino]-etxi]cinnamic acid, yield 97%, recrystallized from dichloromethane-isopropyl ether, and provided colorless crystals in the form of prisms, so pl. 80-81oC.

Source. Example 56

Using the method from the Original Example 1 was obtained ethyl ester (E)-3-[2--(5-methyl-2-phenyl-4-oxazolidinone)- 5-pyridyl]acrylic acid, yield 86%, lly, so pl. 109-110oC.

Source. Example 57

According to the technique of the Original. Example 7 was obtained (E)-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl-2-propen-1-ol in the form of oil, yield: 87%.

NMR (ppm in CDCl3): 3,14 (3H, s), 3,98 (2H, t, J = 5.5 Hz), 4,19 (2H, t, J = 5.5 Hz), the 4.29 (2H, Shire d, J = 5.5 Hz), to 6.22 (1H, dt, J = 16 and b Hz), 6,45-6,6 (3H, m), 6,85 (2H, d, J = 9 Hz), 7,30 (2H, d, J = 9 Hz), was 7.45 (1H, DDD, J = 8.5 Hz), of 8.1 to 8.2 (1H, m).

Source. Example 58

According to the technique of the Original. Example 7 was obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl] -2-propen-1-ol, yield: 57%, recrystallized from a mixture of dichloromethane-isopropyl ether, and provided colorless crystals in the form of prisms, so pl. 116-117oC.

Source. Example 59

According to the technique of the Original. The example was obtained 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamic aldehyde in the form of oil, yield: 100%.

NMR (ppm in CDCl3): 3.15 in (3H, s) to 4.01 (2H, t, J = 5.5 Hz), 4,25 (2H, t, J = 5.5 Hz), 6,5-6,7 (3H, m), to 6.95 (2H, d, J = 9 Hz), 7,41 (1H, d, J = 16 Hz), 7,4-of 7.55 (3H, m), 8,16 (1H, DD, J = 5 and 2 and 1 Hz), 9,65 (1H, d, J = 8 Hz).

Source. Example 60

According to the technique of the Original. Example 14 was obtained (E)-3-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridyl acrolein, yield: 92%, recrystallized from a mixture of dichloromethane-isopropyl ether, was isolated colorless crystals in the form of prisms, is romida (18.6 g) in tetrahydrofuran (180 ml) at -20oC was added dropwise a solution of n-utility in hexane (1,62 m, 25,9 ml), stirred 2 hours, was added 4-[2-(2-naphthyl) -5-methyl-4-oxazolidinone] benzaldehyde (12.0 g), was stirred 4 hours at 50-55oC, poured input with ice and was extracted with ethyl acetate.

An ethyl acetate layer was washed O. IN hydrochloric acid and water, dried over magnesium sulfate, drove the solvent, the residue was chromatographically on a column of silica gel, fractions, elyuirovaniya a mixture of chloroform-methanol (100:5), were isolated crystals (14.8 g), which was dissolved in tetrahydrofuran (250 ml).

To the solution was added palladium on carbon (5%, 3.0 g), was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated and received 4-[4-[3-(1,3-dioxolane-2-yl)propyl]phenoxymethyl] -5-methyl-2-(2-naphthyl)oxazol (12.1 g, 81%) which was recrystallized from a mixture of dichloromethane-isopropyl ether, and provided colorless crystals in the form of prisms, so pl. 141-142oC.

Source. Example 62

According to the method from the Source, the example 1 by the reaction of 4-hydroxy-3-nitrobenzaldehyde with triethylphosphate received atilay ether (E)-4-hydroxy-3-nitrocatechol acid, recrystallized from a mixture of dihl the derivative. Example 63

According to the technique of the Original. Example 23 catalytic recovery of the ethyl ester of (E)-4-hydroxy-3-nitrocatechol acid was obtained ethyl ester 3-(3-amino-4-hydroxyphenyl)propionic acid in the form of butter.

NMR (ppm/ CDCl3): of 1.24 (3H, t, J =7 Hz), 2,5-2,9 (4H, m), of 4.12 (2H, d, J = 7 Hz), of 6.49 (1H, DD, J = 8 and 2 Hz), 6,60 (1H, d, J = 2 Hz), only 6.64 (1H, d, J = 8 Hz).

Source. Example 64

A mixture of phosphorus pentoxide (P2O5) (12.9 g), hexamethyldisiloxane (29.5 g) and 1,2-dichlorobenzene were heated 10 minutes, contributed ethyl ester 3-(3-amino-4-hydroxyphenyl)propionic acid and 4.75 g) and 2-naphthylacetic acid (to 4.23 g), boiled for 3 hours, poured into water and was extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried over magnesium sulfate, the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1:4, V/V), were isolated ethyl ester of 3-[2-(2-naphthylmethyl)benzoxazol-5-yl]propionic acid (5,95 g, 73%), recrystallized from a mixture of episomally ether and obtained colorless crystals in the form of needles, so pl. 81-82oC.

Source. Example 65

To a solution of ethyl ester of 3-[2-(2-naphthylmethyl)- benzoxazol-5-yl]propionic acid (5.8 g) in which the temperature value, contributed water (4 ml), was filtered insoluble components, the filtrate was evaporated under reduced pressure.

The residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1:1, V/V), were isolated 3-[2-(2-naphthylmethyl)-benzoxazol-5-yl] propanol (2.1 g, 41%), recrystallized from a mixture of dichloromethane-isopropyl ether and was obtained colorless crystals in the form of prisms, so pl. 102-103oC.

Source. Example 66

To a solution of dimethyl sulfoxide (1.0 g) in dichloromethane (30 ml) at -30oC was added dropwise, oxalyl chloride [(COCl)2] (0.88 g), contributed 3-2-(2-naphthylmethyl)benzoxazol-5-yl-propanol (2.0 g), stirred for 30 minutes at this temperature, was added triethylamine (3,19 g), stirred 30 minutes, heated to 0oC and poured into 2N HCl.

The organic layer was separated, washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1:2, V/V), were isolated 3-[2-(2-naphthylmethyl)-benzoxazol-5-yl]propionic aldehyde (1.54 g, 77%), recrystallized from a mixture of episomally ether and obtained colorless crystals in the form of needles, so pl. 81-824
), the solvent was evaporated, was allocated 5-[2-(1,3-dioxolane-2-yl)ethyl]-2-(2-naphthylmethyl)-benzoxazol (2,95 g, 89%), recrystallized from a mixture of dichloromethane-isopropyl ether and was obtained colorless crystals in the form of prisms, so pl. 85-86oC.

Source. Example 68

A mixture of 2-chloromethyl-5-methyl-2-phenyloxazole (20,8 g), 3-hydroxybenzaldehyde (12.2 g), potassium carbonate (27,6 g) and N,N-dimethylformamide (200 ml) was heated for 2 hours at 90oC, poured into water and was extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, and provided 3- (5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde (26.5 g, 90%), recrystallized from ethanol and obtained colorless crystals in the form of prisms, so pl. 67-68oC.

Source. Example 69

According to the technique of the Original. Example 1 was obtained ethyl ester (E)-3-(5-methyl-2-phenyl-4-oxazolidinone) cinnamic acid, recrystallized from ethanol and obtained colorless crystals in the form of prisms, so pl. 91-92o

The organic layer was separated, washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, was isolated (E)-3-(5-methyl-2-phenyl--4-oxazolidinone)phenyl] -2-propen-1-ol (11.5 g, 92%), recrystallized from ethyl acetate and obtained colorless crystals in the form of prisms, so pl. 120-121oC.

Source. Example 71

According to the technique of the Original. Example 14 was obtained (E)-3- (5-methyl-2-phenyl-4-oxazolidinone)cinnamic aldehyde, recrystallized from a mixture of ethyl acetate-hexane, and provided colorless crystals in the form of rods, so pl. 103-104oC.

Source. Example 72

According to the technique of the Original. Example 23 was obtained 2-(5-methyl-2-phenyl-4-oxazolidinone)-5-nitropyridine, recrystallized from a mixture of dichloromethane-isopropylate ether, and provided light yellow crystals in the form of prisms, so pl. 142-143oC.

Source. Example 73

According to the technique of the Original. Example 24 was obtained 5-amino-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine, recrystallized from methanol-isopropyl ether, and provided colorless crystals in the form of prisms, so pl. 106-107oC.

Source. Example 74

According to the method of ESATA and provided colorless crystals in the form of prisms, so pl. 129-130oC.

Source. Example 75

According to the technique of the Original. Example 26 was obtained 5-formyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine, recrystallized from a mixture of ethyl acetate-hexane, and provided colorless crystals in the form of prisms, so pl. 116-117oC.

Source. Example 76

To a mixture of 4-benzyloxybenzaldehyde (4.5 g), (1,3-dioxolane-2-ylmethyl)triphenylphosphonium bromide and N, N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 0.935 g), stirred 3 hours at 60oC, was poured into ice water, neutralized 2N HCl and was extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya chloroform was allocated 2-vinyl-1,3-dioxolane derivative (5.7 g) as an oily substance.

The oil was dissolved in ethanol (150 ml), was added palladium on carbon (5%, 2.0 g), was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated. The residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture chloroformate (50: 1, V/V), were isolated 2-[2-(4-hidroxi), 4,88 (1H, t, J = 4.5 Hz), to 6.75 (2H, d, J = 8.5 Hz), 7,07 (2H, d, J = 8,5 Hz).

Source. Example 77

According to the technique of the Original. Example 1 was obtained crude ethyl ester of (E)-4-isopropoxybenzoic acid, which was chromatographically on a column of silica gel with elution with a mixture of ether-hexane (1:5, V/V).

NMR (ppm in CDCl3): of 1.33 (3H, t, J = 7 Hz), of 1.35 (6H, d, J = 6 Hz), 4,25 (2H, q, J = 7 Hz), 4,5-4,7 (1H, m), 6,30 (1H, d, J = 16 Hz), 6.87 in (2H, d, J = 9 Hz), 7,46 (2H, d, J = 9 Hz), 7,63 (1H, d, J = 16 Hz).

Source. Example 78

According to the technique of the Original. Example 1 was obtained (E)-3-(4 - isoproterenol)-2-propen-1-ol, which was purified by chromatography on a column of silica gel with elution with a mixture of ethyl acetate-hexane (1:4, V/V).

NMR (ppm in CDCl3): of 1.33 (6H, d, J = 6 Hz), to 1.38 (1H, t, J = 6 Hz), 4,30 (2H, dt, J = 6 and 1.5 Hz), 4,45 with 4.65 (1H, m), 6,23 (1H, dt, J = 16 and 6 Hz), 6,56 (1H, d, J = 16 Hz), at 6.84 (2H, d, J = 8.5 Hz), 7,31 (2H,n, J = 8,5 Hz).

Source. Example 79

According to the technique of the Original. Example 14 was obtained (E)-4 - isopropoxycarbonyl aldehyde in the form of butter.

NMR (ppm in CDCl3): of 1.37 (6H, d, J = 6 Hz), 4,5-4,7 (1H, m), is 6.61 (1H, DD,J = 16 and 8 Hz), 6,92 (2H, d, J = 9 Hz), 7,42 (1H, d, J = 16 Hz), 7,51 (2H, d J = 9 Hz).

Source. Example 80

To a solution of 5-[3-(4-isopropoxyphenyl)propyl]-2,4 - oxazolidinedione (1.5 g) in dichloromethane (70 ml) was added dropwise at 0

An ethyl acetate layer was washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1:4, V/V), were isolated 5-[3-(4-hydroxyphenyl)propyl] -2,4-oxazolidinedione (0,755 g, 59%), recrystallized from a mixture of acetone-hexane and was obtained colorless crystals in the form of prisms, so pl. 132-133oC.

Source. Example 81

To a mixture of 4-isopropoxybenzonitrile (15.0 g), triethyl 4-phosphonocrotonate cases (27.3 g) and N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, of 4.38 g) was stirred 16 hours at room temperature, poured into ice water, neutralized 2N HCl and was extracted with ethyl acetate.

An ethyl acetate layer was washed with water, dried over magnesium sulfate (MgSO4), the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya ether-hexane, was allocated ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienoic (13,7 g, 58%), recrystallized from a mixture of ether-hexane and was obtained colorless crystals in the form of prisms, so pl. 64-65oC.

Source. Example 82

According to the technique of the Original. Example 7 recovery of ethyl (E,E)-5-(4-isopropoxyphenyl)-2,4-libavifile of isopropyl ether and was identified colorless crystals in the form of needles, so pl. 91-92oC.

Source. Example 83

According to the technique of the Original. Example 14 the oxidation of (E,E)- 5-(4-isopropoxyphenyl)-2,4-pentadien-1-ol with manganese dioxide was obtained (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadien-1-al in the form of butter.

NMR (ppm in CDCl3): of 1.36 (6H, d, J = 6 Hz), 4,5-4,7 (1H, m), from 6.22 (1H, DD, J = 15 and 8 Hz), 6,8-7,05 (4H, m), 7,26 (1H, DD, J = 15 and 10 Hz), 7,44 (2H, d, J = 9 Hz), 9,59 (1H, d, J = 8 Hz),

Source. Example 84

According to the technique of the Original. Example 80 was obtained 5-[5-(4-hydroxyphenyl]-2,4-oxazolidinedione, recrystallized from a mixture of episomally ether, and provided colorless crystals in the form of prisms, so pl. 96-97oC.

Source. Example 85

To a solution of 2-(1,3-dioxolane-2-yl)ethyl of triphenyl phosphonium bromide (51,0 g) M M-dimethylformamide (200 ml) was added by portions under ice cooling sodium hydride (60% in oil, 4.6 g), stirred 15 minutes, made 4-isopropoxybenzonitrile (18.0 g), stirred 5 hours at 80-85oC, was poured into ice water, neutralized 2N HCl and was extracted with ether.

The ether layer was washed with water, dried with magnesium sulfate, the solvent was evaporated, the residue was chromatographically on a column of silica gel and the fractions elyuirovaniya a mixture of ethyl acetate-hexane (1:4, V/V), were isolated 1,3-dioxolane p is ulali palladium on carbon (5%, 5.0 g) as a catalyst, was first made at room temperature and atmospheric pressure, the catalyst was filtered, the filtrate was evaporated under reduced pressure.

The residue was chromatographically on a column of silica gel, was isolated from fractions, elyuirovaniya a mixture of ethyl acetate-hexane (1:5, about/about), 2-[3-(4-isopropoxyphenyl)propyl]-1,3 - dioxolane (6.7 g, 24%) as oil.

NMR (ppm in CDCl3): of 1.32 (6H, d, J = 6 Hz), 1,6-1,8 (4H, m), a 2.5 to 2.65 (2H, m), 3,8-4,0 (4H, m), 4,4-4,6 (1H, m), 4,8-43 (1H, m), 6,8 (2H, d, J = 8.5 Hz), 7,07 (2H, d, J = 8,5 Hz).

Source. Example 86

According to the technique of the Original. Example 80 was obtained 5-[4-(4-hydroxyphenyl)butyl] -2,4-oxazolidinedione, recrystallized from a mixture of dichloromethane-methanol and allocated colorless privorotnye crystals, so pl. 151-152oC.

Source. Example 87

According to the technique of the Original. Example 68 by the reaction of 4-chloromethyl-5-methyl-2-phenyloxazole with p-hydroxyacetophenone received 4-(5-methyl-2-phenyl-4-oxazolidinone)acetophenone, recrystallized from ethyl acetate-hexane, and provided colorless crystals, so pl. 126-127oC.

Source. Example 88

According to the technique of the Original. Example 88 by the reaction of 4-(5-methyl-2-phenyl-4-oxazolidinone)of acetophenone with trimethylphosphate been met is Zetta-ether, and provided colorless crystals, so pl. 125-126oC.

Source. Example 89

According to the technique of the Original. Example 7 recovery of methyl ester (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butenova acid diisobutylaluminium hydride was obtained methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-2-butene-1-ol, recrystallized from ethyl acetate-ether, so pl. 126-127oC.

Source. Examples 90

According to the technique of the Original. Example 14 oxidation (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butene-1-ol with manganese dioxide was obtained methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-butene-1-al, recrystallized from ethyl acetate-ether and obtained colorless crystals, so pl. 94-95oC.

1. Derivatives of 2,4-oxazolidinedione General formula I

< / BR>
where R represents a saturated aliphatic hydrocarbon residue having from 1 to 8 carbon atoms; naphthyl; pyridyl which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom; and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, the possibility is tenderly substituted by halogen or lower alkyl, containing 1 to 4 carbon atoms, which is optionally substituted with halogen; naphthyl; fullam; tanila; benzofuranyl; benzo[b]tanila;

Y represents-CO-, -CH(OH)) -, or-NR3- where R3represents an alkyl group having 1 to 4 carbon atoms;

m = 0 or 1;

n = 0, 1, or 2;

X is CH or N;

A - bivalent straight or branched residue of hydrocarbon chain containing 1 to 7 carbon atoms;

R1and R2each is hydrogen or alkyl group having from 1 to 4 carbon atoms, or R1and R2together form a 5 - to 6-membered heterocyclic system optionally containing nitrogen;

L and M each is hydrogen or L and M are connected to each other with the formation of the connection,

or their pharmaceutically acceptable salt.

2. Derivatives under item 1, where the group of the formula

< / BR>
represents a group

< / BR>
3. Derivatives under item 1, where n is 0 or 1, R represents pyridyl, which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom, and these groups may be substituted by straight or eUSA 2 - 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl having 1 to 4 carbon atoms, which is optionally substituted with halogen, naphthyl; fullam; tanila; benzofuranyl; benzo[b]tanila; Rather it represents a saturated divalent straight or branched residue of hydrocarbon chain having 1 to 4 carbon atoms; L and M each is hydrogen; R1and R2each is hydrogen or R1and R2are connected to each other to form a 5-membered heterocyclic group containing nitrogen.

4. Derivatives under item 3, where a represents-CH2CH2-.

5. Derivatives under item 3, where R is pyridium, which may be condensed with a benzene ring; a 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom; and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl having 1 to 4 carbon atoms, which neobyazatel is on p. 3, where R is oxazoline group which may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl having 1 to 4 carbon atoms, which is optionally substituted with halogen, naphthyl; fullam; tanila; benzofuranyl; benzo[b]tanila.

7. Derivatives under item 3, where R is oxazoline group which may be substituted by phenyl, naphthyl, fullam, tanila or (C1-C3)alkyl.

8. Derivatives under item 3, where Y is-CO-, n is 0, a is a saturated divalent straight or branched residue of a hydrocarbon chain containing 1 to 4 carbon atoms, L and M each is hydrogen.

9. Derivatives under item 8, where R1and R2each is hydrogen.

10. Derivatives under item 8, where a is-CH2- or-CH2CH2-.

11. Derivatives under item 8, where X represents CH.

12. Derivatives under item 8, where X represents nitrogen.

13. Derivatives under item 1, where the group of the formula

< / BR>
represents a group

< / BR>
14. Pron or its pharmaceutically acceptable salt.

15. Derived under item 1, representing 5-(3-(4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

16. Derived under item 1, representing 5-(3-(2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-pyridyl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

17. Derived under item 1, representing 5-(3-(2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzofuran-5-yl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

18. Derived under item 1, representing 5-(3-(2-(2-naphthylmethyl)benzoxazol-5-yl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

19. Derived under item 1, representing 5-(3-(4-(5-methyl-4-phenyl-2-thiazolyl-methoxy)phenyl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

20. Derived under item 1, representing 5-(5-(4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl)pentyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

21. Derived under item 1, representing 5-(4-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)phenyl)butylidene)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

22. The derivative of whether its pharmaceutically acceptable salt.

23. Derived under item 1, representing 5-(3-(4-(2-(N-methyl-N-(2-pyridyl)-amino)ethoxy)phenyl)propyl)-2,4-oxazolidinedione or its pharmaceutically acceptable salt.

24. Pharmaceutical composition providing hypoglycemic and hypolipidemic effect, comprising as an active ingredient derived 2,4-oxazolidinedione, characterized in that as a derivative of 2,4-oxazolidinedione it contains a compound of formula I under item 1 or its pharmaceutically acceptable salt.

25. A pharmaceutical composition according to p. 24, characterized in that the group of the formula

< / BR>
represents a group

< / BR>
26. A pharmaceutical composition according to p. 24, characterized in that it is a means of reducing the blood sugar in the treatment of diabetes.

27. A pharmaceutical composition according to p. 24, characterized in that it is a tool that reduces the content of lipids in the blood in the treatment of hyperlipidemia.

28. A method of reducing blood sugar and blood lipids in the treatment of mammals suffering from diabetes or hyperlipidemia, which includes the introduction of mammal an effective amount of a derivative of 2,4-oxazolidinedione, characterized in that as a derivative of 2,4-oxazole obtain derivatives of 2,4-oxazolidinedione General formula

< / BR>
where R represents a saturated aliphatic hydrocarbon residue having from 1 to 8 carbon atoms; naphthyl; pyridyl which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom, and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl, containing 1 to 4 carbon atoms, which is optionally substituted with halogen; naphthyl; fullam; tanila; benzofuranyl; benzo[b]tanila;

Y represents-CO-, -C(OH) -, or-NR3- where R3represents an alkyl group having 1 to 4 carbon atoms;

m = 0 or 1;

n = 0, 1, or 2;

X is CH or N;

A - bivalent straight or branched residue of hydrocarbon chain containing 1 to 7 carbon atoms;

R1and R2each is hydrogen or alkyl group having from 1 to 4 carbon atoms, or R1and R2together form a 5 - to 6-membered heterocyclic BR> where Z is hydrogen, lower alkyl or aralkyl, and the other radicals have the meanings given above,

with an alkali metal cyanate, followed by separation of the reaction product under acidic conditions.

30. The method of obtaining derivatives of 2,4-oxazolidinedione General formula

< / BR>
where R represents a saturated aliphatic hydrocarbon residue having from 1 to 8 carbon atoms; naphthyl; pyridyl which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom, and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl, containing 1 to 4 carbon atoms, which is optionally substituted with halogen; naphthyl; fullam; tanila; benzofuranyl; benzo[b]tanila;

Y represents-CO-, -CH(OH) -, or-NR3- where R3represents an alkyl group having 1 to 4 carbon atoms;

m = 0 or 1;

n = 0, 1, or 2;

X is CH or N;

AND1
R1and R2each is hydrogen or alkyl group having from 1 to 4 carbon atoms, or R1and R2together form a 5 - to 6-membered heterocyclic system optionally containing nitrogen, which includes the recovery of compounds of General formula

< / BR>
where a is a divalent straight or branched residue of a hydrocarbon chain containing 1 to 7 carbon atoms and the other radicals have the meanings given above.

31. The method of obtaining derivatives of 2,4-oxazolidinedione General formula:

< / BR>
where R represents a saturated aliphatic hydrocarbon residue having from 1 to 8 carbon atoms; naphthyl; pyridyl which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom; and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl, containing 1 to 4 carbon atoms, which is optionally substituted by the th straight or branched residue of the hydrocarbon chain, containing 1 to 7 carbon atoms; L and M each is hydrogen, or L and M are connected to each other with the formation of the connection, which includes the interaction of the compounds corresponding to General formula

< / BR>
where the values of the radicals listed above,

with a compound of General formula

R - (CO)m-CH2-Q

where Q is a leaving group and the other radicals have the meanings given above.

32. The method of obtaining derivatives of 2,4-oxazolidinedione General formula

< / BR>
where R represents a saturated aliphatic hydrocarbon residue having from 1 to 8 carbon atoms; naphthyl; pyridyl which may be condensed with benzene ring or 5-membered aromatic heterocyclic group containing one nitrogen atom and one oxygen atom or one sulfur atom, one nitrogen atom; and these groups may be substituted by straight or branched alkyl containing 1 to 15 carbon atoms, possibly substituted by halogen; alkenylphenol group having 2 to 10 carbon atoms substituted by phenyl; phenyl, possibly substituted by halogen or lower alkyl, containing 1 to 4 carbon atoms, which is optionally substituted with halogen; naphthyl; fullam; tanila; benzofuran the ing group, having 1 to 4 carbon atoms;

m = 0 or 1;

n = 0, 1, or 2;

X is CH or N;

A - bivalent straight or branched residue of hydrocarbon chain containing 1 to 7 carbon atoms;

R1and R2each is hydrogen or alkyl group having from 1 to 4 carbon atoms, or R1and R2together form a 5 - to 6-membered heterocyclic system optionally containing nitrogen, which comprises the interaction of the compounds of General formula

< / BR>
where T is the formyl residue, or-CH ()2where is the lowest alkoxyl, lower alkylthio or lower acyloxy or two To connect with the formation of Ethylenedioxy, trimethylenediamine or dithiothreitol ring, and the other radicals have the meanings given above,

with 2,4-exiledonline.

Priority points:

26.02.93 - on the grounds of p. 1: compound where Y is - CO-, n is 0; L and M are hydrogen; And - (CH2), (CH2)2, (CH2)3or (CH2)4; and the position of the substituent And para-position relative to the oxygen atom; p. 29: compounds where Y IS-CO-; n is 0; A - (CH2), (CH2)2, (CH2)3or (CH2)4; and the position of the substituent And para-position relative to the>(CH2)3or (CH2)4; the position of the substituent And para-position relative to the oxygen atom; p. 32: compounds where Y IS-CO-; n is 0; A - (CH2)2, (CH2)3, (CH2)4, (CH2)5; (CH=CH) or (CH=CH)2; the position of the substituent And para-position relative to the oxygen atom and T - formyl; compounds where Y IS-CO-; n is 0; A - (CH2)2, (CH2)3or (CH2)4and the position of the substituent And para-position relative to the oxygen atom and T - CH(B)2;

09.08.93 - on the grounds of p. 31: connections, where L and M are hydrogen atom; Q is halogen; A is - (CH2), (CH2)2, (CH2)3or (CH2)4; the position of the substituent And para-position relative to the oxygen atom.

 

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