Derivatives of oxazolidinedione receiving them (options) and pharmaceutical composition

 

(57) Abstract:

Derived 2,4-oxazolidinedione represented by the formula

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where R represents an optionally substituted hydrocarbon residue or heterocyclic group; Y represents a group represented by-CO-, -CH(OH) -, or-NR3- (where R3represents optionally substituted alkyl group); m = 0 or 1; n = 0, 1, or 2; a represents C1-C7the divalent aliphatic hydrocarbon group; R1represents hydrogen or alkyl group; ring E represents a benzene ring having 1 or 2 substituent; L and M respectively represent hydrogen or L and M may be combined with each other with regard education; provided that the group is not a group where R2represents an alkyl group, or its salt, which perfectly reduce the levels of blood sugar and lipid. 6 C. and 19 C.p. f-crystals, 8 PL.

The present invention relates to intended for use in the pharmaceutical industry a new derivative of oxazolidinedione that action, consisting in the reduction of glucose and lipid in blood, the method of its production and to its containing means for the treatment of diabetes.

For example, in JPA H3 (1991)-170478 and WO9202520-A1 described as derivatives of 2,4-oxazolidinedione having substituents in position 5, a number of derivatives of 5- (substituted benzyl)-2,4-oxazolidinedione, JPB S62 (1987)-30933 described derivatives of 2,4-oxazolidinedione, substituted alicyclic hydrocarbon group in position 5, and JPB S63 (1988) -35632 described derivative, substituted, inter alia, substituted aromatic ring in position 5.

These inventors have conducted extensive studies of derivatives of 2,4-oxazolidinedione and found that the new derivatives having as substituents in the 5-position of 2,4-oxazolidinedione ring divalent unbranched or branched carbon chain having at the end of samase phenyl) boutelou group, 5-(substituted phenyl) pentelow group and so on, have the effect that reduce levels of blood sugar and lipid, in which appeared the present invention.

More specifically the present invention concerns:

1. derived 2,4-oxazolidinedione represented by the formula

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where R represents an optionally substituted hydrocarbon residue or heterocyclic group; Y represents a group represented by-CO-, -CH(OH) -, or-NR3- (where R3represents optionally substituted alkyl group); m = 0 or 1; n = 0, 1, or 2; A represents C1-7the divalent aliphatic hydrocarbon residue, R1represents hydrogen or alkyl group; ring E represents a benzene ring having one or two substituent; L and M respectively represent hydrogen or L and M may not necessarily be combined with each other with regard education; provided that the partial formula

< / BR>
where R' represents an alkyl group; or its salts;

2. pharmaceutical compositions containing as an active component derived 2,4-oxazolidinedione formula (I) or its pharmaceutically acceptable salt, and

3. the method include receiving a connection represented by the following formula:

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< / BR>
< / BR>
where each symbol has the same meaning as specified above.

Of the compounds represented by formula (I-A1), (I-A2) and (I-A3), preferred compounds are represented by formula (I-A1) and (I-A2), the most preferred compounds represented by formula (I-A1), if you keep in mind the pharmacological activity and toxicity.

The compounds of formula (I), where L and M are combined with each other to bond formation, are compounds represented by the following formula:

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where each symbol has the same meaning as above. A compound of formula (I), where L and M respectively the hydrogen are compounds represented by the following formula:

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where each symbol has the same meaning as specified above.

The compounds represented by the above formula (I - B1), there are (E)- and (Z)-isomers relative to the double bond in position 5 oxazolidinediones rings.

The compounds represented by the above formula (I-B2), there are (R) - and (S) -optical isomers due to the asymmetric carbon atom at the 5-position oxazolidinediones rings. Compounds represented useprivatekey formula (I-B1) and (I-B2) are preferred compounds, represented by formula (I-B2).

As the hydrocarbon moiety in the optionally substituted hydrocarbon radical represented by the symbol R are aliphatic, alicyclic, alicyclic-aliphatic, aromatic - aliphatic and aromatic hydrocarbon radicals. As aliphatic hydrocarbon radicals are radicals with 1 to 8 carbon atoms, including C1-8saturated aliphatic hydrocarbon radicals (e.g., alkyl group), examples of which include methyl, ethyl, Protel, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl, and C2-8unsaturated aliphatic hydrocarbon radicals (e.g., alkenylphenol and alkylamino group), examples of which include ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3 - pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 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 and 1-octenyl. As alicic the cyclic hydrocarbon radicals (e.g., cycloalkyl group), examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, C5-7unsaturated alicyclic hydrocarbon radicals (e.g., cycloalkenyl and cycloalkenyl group), examples of which include 1 - cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1 - cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1 - cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4 - cycloheptadiene. As the alicyclic-aliphatic hydrocarbon radicals are those radicals formed by combining the above-mentioned alicyclic hydrocarbon radicals with aliphatic hydrocarbon radicals (e.g., cycloalkyl-alkyl group, cycloalkenyl-alkyl group, cycloalkenyl is an alkyl group), which have from 4 to 9 carbon atoms, and examples of which are cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3 - cyclohexenylmethyl, cyclohexylethyl, cyclohexylmethyl, cycloheptylmethyl and cycloheptylmethyl. As the aromatic - aliphatic hydrocarbon radicals serve WITH7-9phenylalkyl, for example benzyl, phenethyl, 1-phenylethyl, 3-phenyl is l-naphtalate. As aromatic hydrocarbon radicals are those that have 6-14 carbon atoms, such as phenyl, naphthyl (-naphthyl, naphthyl).

In the above formula (I) as the heterocyclic group in the optionally substituted heterocyclic group represented by the symbol R are, for example, a 5-7-membered heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, 5-6-membered heterocyclic group containing 2-4 nitrogen atom, and 5-6-membered heterocyclic group containing 1-2 nitrogen atom and one sulfur atom or oxygen. These heterocyclic group optionally condensed with a 6-membered ring containing one or two nitrogen atom, benzene ring or 5-membered ring containing one sulfur atom. Examples of these heterocyclic groups include 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-oxadiazol-5-yl, 1,2, 4-triazole-3-yl, 1,2,3-triazole-4-yl, tetrazol-5-yl, benzimidazole-2-yl, indol-3-yl, 1H-in the h-2-yl and 1H - imidazo[4,5-b]pyrazin-2-yl. Which one is preferable oxazolyl, thiazolyl and triazolyl.

In the above formula (I) R is preferably optionally substituted heterocyclic group, and more preferred optionally substituted oxazolidine group.

In the above formula (I) hydrocarbon moiety and heterocyclic group represented by the symbol R may, although not necessarily, having 1-3 substituent capable of substituting provisions. Examples of such substituents include aliphatic hydrocarbon group, alicyclic hydrocarbon group, aryl group, aromatic heterocyclic group, non-aromatic heterocyclic group, a halogen atom, a nitro-group, optionally substituted by an amino group, an optionally substituted acyl group, optionally substituted hydroxyl group, optionally substituted thiol group, and optionally esterified carboxyl group. Examples of these aliphatic hydrocarbon groups include C1-15unbranched or branched aliphatic hydrocarbon group such as alkyl group, preferably C1-10alkyl group, alkenylphenol group, preferably C2-10alkanine examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl. Preferred examples alkenylphenol groups include vinyl, allyl, Isopropenyl, 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, 4-hexenyl and 5-hexenyl. Preferred examples alkenylphenol 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 and 5-hexenyl. As the alicyclic hydrocarbon group are C3-12saturated or unsaturated alicyclic hydrocarbon group, examples of which are cycloalkyl, cycloalkenyl and cycloalkenyl group. Preferred examples cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1] heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2] nonyl, bicyclo[4.2.1]nonyl and BIC is l, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. Preferred examples cycloalkenyl groups include 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl and 2,5 - cyclohexadiene-1-yl. Mentioned aryl group is a monocyclic or condensed polycyclic aromatic hydrocarbon group. Preferred examples of aryl groups include C6-14aryl groups such as phenyl, naphthyl, antril, tenantry and acenaphthylene. Of them, 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, isoxazolyl, 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 and triazinyl; and aromatic condensed heterocyclic group such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H - indazole, benzimidazole, benzoxazolyl, 1,2-benzisoxazole, benzothiazolyl, 1,2-benzothiazolyl, 1H-benzotriazolyl, -carboline-carboline-carbolines, acridines, phenoxazines, phenothiazines, phenazines, phenoxathiin, thianthrene, phenanthridines, fantrainer, 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-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, and 1, 2,4-triazolo[4,3-b]pyridazinyl.

Preferred examples of non-aromatic heterocyclic group include oxiranyl, azetidine, oxetane, titanyl, pyrrolidinyl, tetrahydrofuryl,tylenol, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil, pyrrolidino, piperidino, morpholino. Examples of the halogen include fluorine, chlorine, bromine and iodine. Of them especially preferred fluorine and chlorine. As the optionally substituted amino group is, in addition to unsubstituted amino group, the amino group (-NH2), substituted by one or two C1-10alkilani, C1-10alkenyl, C1-10the acyl or aromatic group (for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamine, cyclohexylamino, acetylamino, propionamido, benzoylamine, phenylamino and N-methyl-N-phenylamino). Optionally substituted acyl group includes nezame the acyl group, formed by condensation of C1-10of alkyl, C1-10alkenyl or C6-12aromatic group with a carbonyl group (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl. the pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexylcarbonyl, crotonyl, 2-cyclohexanecarbonyl, benzoyl and nicotinoyl). As substituted acyl groups are those formed by providing the possibility of introducing in the above-mentioned unsubstituted acyl substituents, such as C1-3alkyl, C1-3alkoxy, halogen (e.g. chlorine, fluorine, bromine and so on), nitro, hydroxy or amino.

Optionally substituted hydroxyl group includes unsubstituted hydroxyl group and a substituted hydroxyl groups, i.e. hydroxyl groups with a suitable Deputy. As the substituted hydroxyl group are such as protected hydroxyl-protecting group, for example, aryloxy except alkoxy, alkenylacyl, aralkylated, acyloxy. Preferred examples of alkoxy include C1-10alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopen is as alkenylacyl are C2-10alkenylacyl, such as allyloxy, krotylov, 2-pentyloxy, 3 hexenoate, 2 - cyclopentyloxy and 2 cyclohexylmethoxy, and as aralkylated is, for example, phenyl-C1-4alkyloxy (for example, benzyloxy, penetrate). Preferred examples of aryloxy include C2-4alkanoyloxy (for example, atomic charges, propionyloxy, butyryloxy, isobutyryloxy). As aryloxy are C6-14aryloxy, such as phenoxy and 4 chlorphenoxy.

As the optionally substituted thiol group are, in addition to the thiol group, the thiol group, which are suitable Deputy, in particular the Deputy used as thiol-protective group. Practical examples include alkylthio, Uralkali, atillio. Preferred examples of alkylthio include C1-10alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, nonillion, cyclobutyl, cyclopentyl, cyclohexylthio). As Uralkali is, for example, phenyl - C1-4alkylthio (for example, benzylthio, penetito). Preferred examples of achilty include C2-4alcantarillados carboxyl group are used, for example, in addition to the unsubstituted carboxyl group, alkoxycarbonyl, for example, C2-5alkoxycarbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl and butoxycarbonyl), Uralelectromed (for example, C8-10aralkylketones, such as benzyloxycarbonyl), aryloxyalkyl (for example, C7-15aryloxyalkyl, such as phenoxycarbonyl and para-tolylacetylene).

Among the substituents on the hydrocarbon moiety and the heterocyclic group represented by the symbol R, is particularly preferred phenyl, naphthyl, furyl, thienyl and C1-3alkyl.

In the above formula (I), the substituents on is represented by the symbol R is a hydrocarbon radical and a heterocyclic group, when they are alicyclic hydrocarbon group, aryl group, aromatic heterocyclic group or non-aromatic heterocyclic group, have one or more (preferably 1-3) suitable substituents, respectively. Examples of these substituents include lower alkyl groups (C1-6), lower alkeneamine group (C2-6), lower alkyline group (C2-6), cycloalkyl group (C3-7), aryl groups (e.g. phenyl and naftalin heterocyclic group (for example, tetrahydrofuryl, morpholino, piperidino, pyrrolidino and piperazine derivatives), kalkilya group (C7-9), amino, N-mono(C1-4)alkylamino, N,N-di(C1-4) alkylamino, alluminare (for example, acetylamino, propionamido and benzoylamine), amidinopropane, C2-8acyl group, karbamoilnuyu group, N - mono(C1-4) alkylcarboxylic group, N,N-di(C1-4) alkylcarboxylic group, sulfamoyl group, N-mono(C1-4) alkylsulfonyl group, N, N-di(C1-4) alkylsulfonyl group, carboxyl group, lower alkoxycarbonyl group (C2-8), hydroxyl group, lower alkoxygroup (C1-4), low alkenylacyl (C2-5), cycloalkylcarbonyl (C3-7), aralkylated (C7-9), alloctype (for example, phenyloxy, naphthyloxy), mercaptopropyl, low allylthiourea (C1-4), arkitip (C7-9), aristocraty (for example, phenylthio, naphthylthio), alphagroup, cyano, asiagraph, a nitrogroup, nitrosolobus and halogen (e.g. fluorine, chlorine, bromine and iodine).

In the formula (I) R is more preferably oxazolidine, thiazolidine or triazolyl group, which optionally is substituted by 1-3 substituents,can be found above formula (I) as the alkyl groups, represented by the symbol R1serve, for example, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Preferred as the radical R1the hydrogen. The symbol m denotes 0 or 1, preferably 0. The symbol n means 0, 1 or 2, preferably 0 or 1, and most preferably 0.

And when m and n is 0, carbon, substituted by the radical R1directly associated with R; when m= 0 and n=1 or 2, R is directly connected with -(CH2)n; and when m=1 and n= 0, R is directly linked to the carbon substituted by the radical R1.

Y represents-CO-, -CH(OH)- or-NH3-, preferably-CH(OH) -, or-N(R3)-. As alkyl groups and optionally substituted alkyl groups represented by R3serve, for example, C1-4alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples of the substituents include halogen (fluorine, chlorine, bromine and iodine), C1-4alkoxygroup (for example, methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy), a hydroxyl group, a nitrogroup, and C1-4acyl groups (e.g. formyl, acetyl and propionyl).

C1-7divalent Alif saturated or unsaturated. Specific examples include saturated [for example, -CH2-, -CH(CH3)-, -(CH2)2, -CH(CH2H5)-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6- and -(CH2)7-] and mentioned unsaturated radicals [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=CH-CH=CH-CH2-. Of them, preferable C1-4saturated hydrocarbon radicals-CH2- or-CH2CH2- and preferable-CH2CH2-.

In the formula (I), the ring E has 1 or 2 substituent at any substitutable positions. Examples of such substituents include alkyl group, optionally substituted hydroxyl group, halogen atom, optionally substituted acyl group and optionally substituted by an amino group. These deputies essentially mean the same as those described as the substituents of the hydrocarbon radical and a heterocyclic group, represented by the radical R.

Ring of E, i.e. the partial formula

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preferably represents a formula

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where R2is optionally substituted hydroxine the amino group. As the optionally substituted hydroxyl group, halogen atom, optionally substituted acyl group and optionally substituted amino groups represented by the radical R2serve as those described as the substituents of the hydrocarbon radical and a heterocyclic group, represented by the symbol R. the Preferred examples of R2include optionally substituted hydroxyl group or halogen atom, more preferably a lower (C1-4) alkoxygroup.

The compound, which partial formula

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in the General formula (I) is the formula

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where R' represents an alkyl group, is not a connection in accordance with the present invention. As the alkyl groups represented by the symbol R', are those groups which are described as the substituents of the hydrocarbon radical and a heterocyclic group, represented by the symbol R.

Preferred examples of the compounds represented by formula (I) include the compounds of formula (I) in which R is oxazolyl, thiazolyl or triazolyl, optionally substituted by 1-3 substituents selected from phenyl, naphthyl, furil, tanila and C1-3of alkyl; m=0; n=0; or 1; R1is hydrogen; ring E, estCH2-; and L and M are both hydrogen.

Preferred specific examples of the compounds represented by formula (I), include

(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxyphenyl] propyl]-2,4-oxazolidinedione;

(S)-(-)-5-[3-[4-[2-(furyl)-5-methyl-4-oxazolidinone] -3-methoxyphenyl] propyl]-2,4-oxazolidinedione;

5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] propyl]-2, 4-oxazolidinedione;

5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)phenyl]-pentyl]-2,4-oxazolidinedione and

5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl]-4-oxazolidinone]- phenyl]propyl] -2,4-oxazolidinedione.

Of these compounds, especially preferred (R)-(+) -5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone] -3 - methoxyphenyl] propyl]-2,4-oxazolidinedione.

As the salts of compound (I) in accordance with the present invention, the preferred pharmaceutically acceptable salts, examples of which include salts formed with inorganic base, salts formed with organic base, salts formed with inorganic acid, salts formed with an organic acid, and salts formed with basic and acidic amino acids. Preferred examples of salts formed with inorganic framework is such as calcium salts and magnesium salts; as well as aluminum salts and ammonium salts. Preferred examples of salts formed with organic base include salts formed, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N,N'-dibenziletilendiaminom. Preferred examples of salts formed with inorganic acid include salts formed, for example, hydrochloric, Hydrobromic, nitric, sulfuric and phosphoric acids. Preferred examples of salts formed with organic acid include salts formed, for example, formic, acetic, triperoxonane, fumaric, oxalic, tartaric, maleic, citric, succinic, malic, metasolv, baselslt - and para-toluensulfonate. Preferred examples of salts formed with basic amino acid include salts formed, for example, arginine, lysine and ornithine, and preferred examples of salts formed with an acidic amino acid include salts formed, for example, aspartic and glutamic acids. Among these salts, preferred salts are sodium and potassium salt.

The compound (I) or its pharmaceutically the reducing sugar and lipid in the blood and increase insulin sensitivity, and can be used as such or in combination, for example, with a known pharmacologically acceptable carrier, excipient and filler as a medicine against diabetes and antihypertensive drugs for mammals (e.g. humans, mice, rats, rabbits, dogs, cats, bulls, horses, pigs, monkeys).

The compound (I) or its pharmaceutically acceptable salt in accordance with the present invention have the effect of providing suppression of the proliferation of tumor cells, and can be used as antitumor agents.

The compound (I) in accordance with the present invention shows low toxicity. For example, oral administration of the compound of working example 22 at the dose of 10 mg/kg/day for 14 days in mice did not cause changes in body mass and mass of the liver compared with the control group (no animals were killed). And yet, oral administration to rats of the compounds of working examples 13 and 14, respectively, at a dose of 30 mg/kg/day for 4 weeks did not lead to death.

Introduction usually applied orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders and granules and, in dependence and pills. Doses for adults in the case of oral administration are in the range from 0.05 to 10 mg/kg/day, preferably with an introduction from one of the others three times a day.

The compound (I) in accordance with the present invention, mixed with pharmaceutically acceptable carriers, may be administered orally or neironalna in the form of solid dosage forms such as tablets, capsules, granules and powders, or in liquid dosage forms such as syrups and dosage forms for injection.

As pharmaceutically acceptable carriers using conventional organic or inorganic carriers for pharmaceuticals, in particular, for example, excipients, lubricants, binders and disintegrating agents for solid dosage forms, and solvents, soljubilizatory, suspendresume substances, the isotonic agents, buffering agents and the local anestesiologia anaesthetics for liquid dosage forms. And if necessary use more additives such as antiseptics, antioxidants, coloring and sweetening agents. Preferred examples of the excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose and light is LC and colloidal silicon dioxide. Preferred examples of bonding agents include crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone. Preferred examples of disintegrating agents include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose and sodium carboxymethylate starch. Preferred examples of solvents include distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferred examples of solubilization include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, Tris-aminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferred prmery suspendida substances include surfactants, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl, lecithin, benzylaniline, benzathine, glycerylmonostearate, and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Preferred examples of isotonicity buffer solutions of phosphate, acetates, carbonates and citrates. Preferred examples of local anesthetics include benzyl alcohol. Preferred examples of the antiseptics include esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, dehydroacetic acid and sorbic acid. Preferred examples of the antioxidants include sulfites and ascorbic acid.

Below describes the method of obtaining the compound (I) in accordance with the present invention.

HOW A

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where each symbol has the same meaning as specified above.

The compound (I-B1) can be obtained by condensation of compound (II) with 2,4-oxazolidinedione. This reaction is carried out in a solvent in the presence of a base. As the solvent are alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran: N,N-dimethylformamide, dimethylsulfoxide and acetic acid. As the base used, the sodium alkoxide (e.g. sodium methoxide and ethoxide sodium), potassium carbonate, sodium carbonate, g is min and Diisopropylamine. The amount of 2,4-oxazolidinedione is in the range from 1 to 10 molar equivalents, preferably 1-5 molar equivalents, relative to compound (II). This reaction is carried out at a temperature in the range from 0 to 150oC, preferably from 20 to 100oC for period time in the range from 0.5 to 30 hours.

The compound (I-B1) obtained in accordance with the above method, in some cases, are in the form of a mixture of (E -) connection and Z-connection with respect to the double bond in the 5-position of 2,4-oxazolidinedione.

Collected in this way the derivative (I-B1) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

METHOD B

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where Z is hydrogen, a lower alkyl group or aracelio group, and other symbols represent the same as above.

In the above formula (III) as the lower alkyl groups represented by the symbol Z, is C1-4alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-the th group as substituent (arylalkyl group). Examples of aryl groups include phenyl and naphthyl which may be optionally substituted by the above lower alkyl groups, (C1-4), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), a hydroxyl group and a nitro-group. Examples of alkyl groups include C1-4alkyl groups such as methyl, ethyl and propyl. Preferred examples aranceles groups include benzyl, phenethyl, 3-phenylpropyl, (1-naphthyl) methyl and (2-naphthyl)-methyl. Of them preferred benzyl and phenethyl.

The alkali metal salt of compound (I-B2) can be obtained by providing the possibility of chemical interaction between the 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 obtain the compound (I-B2). The reaction of the compound (III) with an alkali metal cyanate is carried out in a suitable solvent. The solvent is usually used alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol and butanol; N,N-dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile or appropriate their mixture. The amount used of the alkali metal cyanate is in the range from 1 to 10 molar equivalents, pre whom I ranging from 0 to 180oC, preferably from 30 to 150oC, and the reaction time is in the range from 0.5 to 100 hours. Collected in this way, the alkali metal salt of compound (I-B2) is treated with acid in a traditional way, to obtain the compound (I-B2) This acid treatment is carried out in the presence or absence of a suitable solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol and butanol; aromatic hydrocarbons, such as benzene, toluene and xylene; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane; ethyl acetate, acetonitrile, or a suitable mixture of these solvents. The acid is preferably used an excessive amount of an inorganic acid, such as hydrochloric, sulphuric, nitric and Hydrobromic acid, but can also be used, and an organic acid, such as acetic, citric or tartaric.

Collected in this way the derivative (I-B2) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration protography.

THE METHOD C

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where A1represents C1-7unbranched or branched divalent saturated aliphatic hydrocarbon radical and the other symbols represent the same as above.

C1-7unbranched or branched divalent saturated aliphatic hydrocarbon radical represented by the symbol A1means saturated one divalent aliphatic hydrocarbon radicals represented by the symbol A.

Subjecting the compound (I-B1) restoration, it is possible to obtain the compound (I-B2a). This recovery is carried out in accordance with the traditional way in a solvent in the presence of a catalyst in an environment of hydrogen under a pressure of 1-150 bar. As the solvent are alcohols such as methanol, ethanol, propanol, isopropanol and 2 - methoxyethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl 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. Examples of preferred catalysts vkluchay reaction are in the range from 0 to 150oC, preferably from 10 to 120oC. the reaction Time ranges from 0.5 to 100 hours.

Collected in this way the derivative (I-B2a) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

METHOD D

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where B represents lower alkoxy, lower alkylthio or lower acyloxy, and other symbols have the same meaning as specified above.

As the lower alkoxy represented by the symbol B are, for example, C1-4lower alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy; as the lower ancilliary serve, for example, C1-4low allylthiourea, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio; and as the lower acyloxy serve, for example, C1-4lower acyloxy, such as atomic charges, propionyloxy. Depending on the circumstances of the two radical B can be combined with each other to form, for example, Ethylenedioxy, Propylenediamine or decimation. In other words, -CH(B)2formula (IV) poluchit (I-B1). This condensation reaction is conducted essentially the same as the reaction between the compound (II) and 2,4 - oxazolidinedione in method A.

The compound (I-B1), obtained as described above, in some cases, are in the form of (E)-compound and (Z)-connection with respect to the double bond in the 5-position of 2,4 - oxazolidinedione.

Collected in this way the derivative (I - B1) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

METHOD E

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where Q represents a leaving group, and other symbols have the same meanings as above.

As the leaving group represented by the symbol Q, can be used a halogen atom (chlorine, bromine, iodine), methansulfonate, benzosulfimide and pair-toluensulfonate. The compound (V) is condensed with compound (VI) to obtain the compound (I-C1) This reaction is carried out in accordance with the traditional way in a suitable solvent in the presence of a base. As the solvent are, for example, aromatic hydrocarbons such as acetone and 2-butanone; N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2, 2-tetrachlorethane and suitable mixtures of these solvents. As the base can serve salt of an alkali metal such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine and N,N-dimethylaniline; a metal hydride such as sodium hydride and potassium hydride; ethoxide sodium, sodium methoxide and tert-piperonyl potassium. The number of these used grounds is preferably in the range of about 1-5 molar equivalents relative to compound (V). This reaction is usually carried out at temperatures ranging from -50 to 150oC, preferably about 10-100oC. the reaction Time ranges from 0.5 to 50 hours.

Obtained in the manner described above derivative (I-C1) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

Of the compounds (I-C1) obtained by method E, the compounds in which R contains unsaturated linkages (C-C double bond C-C tro is z) in R is reduced by carrying essentially the same reaction recovery, as in method C.

Among the compounds obtained by method E, compound (I-C2) can give compound (I-C3), if the first is additionally subjected to recovery.

METHOD F

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where each symbol has the same meaning as specified above.

In this method, compound (I-C2) obtained by method E, restores to obtain the compound (I-C3). This reaction may also be conducted by a known per se manner, such as restoring the metal hydride, the restoration of a complex compound of a metal hydride, the restoration of the DIBORANE and substituted borane and catalytic hydrogenation. In other words, this reaction is carried out by treatment of the compound (I-C2) a reducing agent. As the reducing agent can be borohydride alkali metal (for example, borohydride sodium and borohydride lithium); the complex compound of the metal hydride, such as sociallyengaged; a metal hydride such as sodium hydride; ORGANOTIN compound (for example, triphenylphosphite); metals and metal salts, comprising compounds of Nickel, zinc compounds, or etc.; agent for catalytic restore the.p., together with hydrogen, and DIBORANE, etc. is most advantageous to use borohydride alkali metal (for example, borohydride sodium, borohydride lithium). This reaction is carried out in an organic solvent which has no adverse effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2 - tetrachlorethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, isopropanol, 2-methoxyethanol; amides such as N,N - dimethylformamide, or a suitable mixture of these solvents. Of them the suitable solvent is selected depending on the types of reducing agents. The reaction temperature ranges from -20 to 150oC, in particular from 0 to 100oC. the reaction Time is in the range of about 1 to 24 hours.

Obtained in the manner described above, the compound (I-C3) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, and chromium is/BR>< / BR>
where R5and R6independently represent a lower alkyl group; R4represents hydrogen or a lower alkyl group; q is 0, 1 or 2; and other symbols have the same meanings as above.

Examples of the lower alkyl groups represented by the symbols R4, R5and R6include C1-4alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl.

In this method, first, provide the possibility of chemical interaction between the carbonyl derivative (VII-1) with derivative (VII-1) phosphonocarboxylates acid to produce an unsaturated ester derivative (IX-1). The reaction between compound (VI-1) and compound (VIII-1) is carried out in accordance with the traditional way in a suitable solvent in the presence of a base. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2.2-tetrachlorethane, as well as a suitable mixture of these solvents. Examples of the base include alkali metal salts, such as hydroxide NAT is lean; metal hydrides such as sodium hydride and potassium hydride; ethoxide sodium, sodium methoxide and tert-piperonyl potassium. The number of these used grounds is preferably in the range of about 1 to 5 molar equivalents relative to the compound (VIII-1). The amount used of the compound (VIII-1) is in the range from 1 to 5 molar equivalents, preferably about 1-3 molar equivalents, relative to compound (VII-1). This reaction is carried out usually at temperatures ranging from -50 to 150oC, preferably from about -10 to 100oC reaction Time ranges from 0.5 to 30 hours.

Then the compound (IX-1) is subjected to restore, to obtain an alcohol derivative (X-1). This reaction may also be conducted by a known per se manner, for example by restoring the metal hydride, the restoration of a complex compound of the metal hydride and the restoration of the DIBORANE and substituted borane. In other words, this reaction can be carried out by treating the compound (IX - 1) a reducing agent. Examples of reducing agents include alkali metal borohydride (e.g. sodium borohydride and lithium borohydride); complex metal hydride, such as lithium which the reaction is carried out in an organic solvent, not having a harmful effect on 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, among them the suitable solvent is selected depending on the type of reducing agent. The reaction temperature ranges from -20 to 150oC, particularly preferably from 0 to 100oC, and the reaction time is in the range of about 1 to 24 hours.

Then, the compound (X-1) is subjected to oxidation reaction to obtain unsaturated alleging derivative (II-1). This oxidation reaction can be carried out is known in itself by means such as oxidation by manganese dioxide oxidation of chromic acid oxidation of the sulfoxide or so on, in Other words, this reaction is carried out by treatment of the compound (X-1) oxidizing agent. As the oxidizing agent used dioxide Mar is the initial test. This reaction is carried out in an organic solvent which has no adverse effect on the reaction. As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2 - tetrachlorethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; dimethyl sulfoxide or a suitable mixture of these solvents, among them the suitable solvent is selected depending on the type of oxidizing agent. The reaction temperature range from -20 to 150oC, preferably, in particular in the range from 0 to 100oC, and the reaction time ranges from about 1 to 24 hours.

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

Obtained in the manner described above aldehyde derivative (II-1), (II-2) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase is definerowana in the compound (II-4) and (II-5), with extended carbon chain, for example, by the method of H.

METHOD H

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where l=0 or 1, and other symbols represent the same as above.

This process is carried out essentially the same as the method of G. in Other words, the chemical interaction of the compound (II-3) with compound (VIII-2) carry out essentially the same as the reaction between the compound (VII-1) and compound (VIII - 1) in method G, and the recovery of the compound (IX-2) are essentially the same as the reduction of compound (IX-1) in method G. in Addition, oxidation of the compound (X-2) exercise, essentially, as well as oxidation of the compound (X-1) in method G, and the result is the compound (II-4), which is subjected to restore essentially the same way as the reduction of compound (II-1) in method C, to obtain the compound (II-5).

Collected in this way aldehyde derivative (II-4) and (II-5) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

Used in the way In the compound (III) can be obtained, for example, spocky hydrocarbon radical; A3represents a bond or C1-6divalent saturated aliphatic hydrocarbon radical; and the other symbols represent the same as above.

C1-6the divalent aliphatic hydrocarbon radicals represented by the symbol A2are C1-6radicals of divalent aliphatic hydrocarbon radicals represented by the symbol A, and C1-6divalent saturated aliphatic hydrocarbon radicals represented by the symbol A3are saturated uglevodorodnye radicals from those represented by the symbol A2.

In this method, first, the compound (VII-2) condense with pyruvic acid, resulting in receiving the compound (XI). The condensation reaction of compound (VII-2) with pyruvic acid is performed in essentially the same manner as the reaction between the compound (II) and 2,4 - oxazolidinedione in method A. Then the compound (XI) is subjected to esterification to obtain the compound (XII). This esterification reaction can be carried out is known per se manner, for example by a method that includes providing the possibility of interaction of the compound (XI) directly from the alcohol (R6indosposeable derived compounds (XI), for example, acid anhydride, acid halide (acid chloride, bromohydrin), imidazoline or mixed acid anhydride (e.g., anhydride with methylcarbonate, anhydride with ethylcarbonate, anhydride with isobutylketone or so on), the ability to properly interact with alcohol (R6IT). Then the compound (XII) is subjected to catalytic reduction to obtain compound (XIII). This catalytic reduction is carried out, essentially, in the same way as in method C. Then, the compound (XIII) is subjected to reduction to obtain compound (III-1). This reaction may also be carried out essentially in the same way as in method F.

Obtained in the manner described above the compound (III-1) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

The compound (IV) used in method D, can be obtained, for example, by the method of J.

METHOD J

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where W represents a halogen atom; t denotes an integer from 1 to 6, and the other symbols mean the same as indicated to enter the ode.

In this method, first, allow the compound (VII-1) chemically interact with the compound (XIV) to obtain the compound (IV-1). This reaction is carried out essentially in the same way as the reaction between the compound (VII-1) and compound (VII-1) in method C. Then, the compound (IV-1) is subjected to restore, to obtain the compound (IV-2). This restoration is carried out essentially in the same way as in method C.

Obtained in the manner described above, the compound (IV-1 and IV-2) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography. And yet, the compounds (IV-1 and IV-2) as a result of the removal of the protective group, respectively, by means of acid in an aqueous solvent can give the aldehyde derivative (II-6) and (II-7), respectively. Examples of the solvent include mixtures of water with alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran and dioxane, acetonitrile, acetone, 2-butanone or acetic acid. As acid addition of inorganic acids such as hydrochloric, sulphuric, nitric and Hydrobromic acid, shall be obtained in accordance with method K.

THE WAY TO

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where each symbol means the same as above.

In this method, first, the compound (IX-3), obtained by catalytic reduction of compound (IX-1) or (IX-2), is subjected to restore, to obtain the compound (X-3). This recovery is carried out, essentially as well as the recovery of the compound (IX-1) in method G. Then the compound (X-3) is subjected to oxidation to obtain a compound (II-8). Oxidation of compound (X-3) in the compound (II-8) is carried out according to known per se by way of oxidation, for example by oxidation with chromic acid, such as oxidation by the method of Jones using a mixture of chromium oxide - sulfuric acid - pyridine, oxidation by the method of Collins with the use of a complex of a chromium oxide - pyridine, oxidation using pyridinediamine (PCC) and oxidation using pyridinediamine (PDC); oxidation with activated DMSO or oxidation using salts of examone. Preferred is the oxidation with activated DMSO. Oxidation using activated dimethyl sulfoxide (DMSO) is carried out in a solvent in the joint presence of DMSO and electrophilic re hydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and xylene; N, N-dimethylformamide (DMF); halogenated hydrocarbons such as chloroform and dichloromethane; pyridine and dimethyl sulfoxide. Of these solvents appropriate solvent is selected depending on the type of electrophilic reagent.

Obtained in the manner described above, the compound (II-8) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography. Incidentally, the compound (II-8) can be used for method D, after aldehyde group subjected to azetilirovaniu or dithioacetals the traditional way.

Part of the intermediate product (IX-1) in method G or starting compound (IX-3) in method K can be obtained in accordance with the method L.

METHOD L

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where each symbol means the same as above.

In this way first is the reaction of interaction of the compound (XV) with the compound (XVI) to obtain the compound (XVII). This reaction is carried out, on sushestvitelnoe can be made known as such a method, but it is more profitable to spend it in accordance with method C.

Then the compound (XVIII) is subjected to well-known reaction of arilirovaniya method of Meerwein to obtain the compound (XIX). In accordance with the reaction of the first compound (XVIII) diazotised by adding thereto dropwise an aqueous solution of sodium nitrite (NaNO2) in a solvent in the presence of halogen acids (for example, HCl, HBr and HI), and then give him the opportunity to react with a complex ester of acrylic acid (CH2=CHCOOR6in the presence of a copper catalyst (e.g. copper oxide (1), oxide of copper (2) chloride copper (1) chloride copper (2), copper bromide (1) and copper bromide (2)) to obtain compound (XIX). The solvent can be used alcohols such as methanol, ethanol, propanol and isopropanol; ethers such as dioxane and tetrahydrofuran; acetone, 2-butanone, or a suitable mixture of these solvents. The reaction temperature is in the range from -50 to 100oC, preferably from -20 to 60oC. the reaction Time ranges from 0.5 to 20 hours. Then the compound (XIX) is subjected to dehydrohalogenation to obtain the compound (IX-4). This reaction is carried out in a suitable solvent in the presence of a base. P is 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 a suitable mixture of these solvents. As the base used inorganic bases, including, for example, alkali metal hydroxide (e.g. sodium hydroxide and potassium hydroxide), alkali earth metal hydroxide (e.g. magnesium hydroxide and calcium hydroxide), a carbonate of an alkali metal (e.g. sodium carbonate and potassium carbonate), carbonate of alkaline earth metal (e.g. magnesium carbonate and calcium carbonate, a bicarbonate of an alkali metal (e.g. sodium bicarbonate and potassium bicarbonate) and an alkali metal acetate (e.g. sodium acetate and potassium acetate; and organic bases, including trialkylamine (for example, trimethylamine and triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5 - diazabicyclo[4.3.0] non-5-ene, 1,4-diazabicyclo[2.2.2]non-5 - ene and 1,8-diazabicyclo[5.4.0] -7-undecene. The number of these used bases preferably is in the range from about 1 to 5 molar equivalents relative to compound (XIX). This react is. EDINENIE (IX-4) can give compound (IX-5) according to method C.

Obtained in the manner described above, the compound (IX-4 and IX-5) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

The original compound (VII-1) in method G can be obtained, for example, by the method of M.

METHOD M

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where each symbol means the same as above.

In this way allow interaction of the compound (XX) with the compound (XXI) to obtain compound (VII-1). This reaction is carried out essentially in the same way as in method E.

Collected in this way the compound (VII-1) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phasic transfer and chromatography.

The compound (I-B2) can be obtained also by the way N, described below. This method is advantageous, in particular, to obtain optically active compounds OTP

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where R7in the formula (XXIII) is a lower alkyl group or a substituted phenyl group, and other symbols represent the same as above.

Compounds represented by the above formulae (XXII), (III), (XXIII) and (XXIV) include optically active compounds, due to the presence of asymmetric atom in the-position of the ester moiety, and the compound represented by formula (I-B2) include optically active compounds, due to the presence of asymmetric carbon atom at the 5-position of 2,4-oxazolidinone rings.

As the lower alkyl groups represented by the symbol R7in the formula (XXIII) is C1-4alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl and isobutyl). Examples of the substituent in the substituted phenyl group represented by the symbol R7include the above-mentioned lower alkyl group (group C1-4), halogen atoms (fluorine, chlorine, bromine and iodine), hydroxyl group and nitro-group,

This method is a way of obtaining derivative (I-B2) 2,4-oxazolidinedione of complex-acetoxyethyl represented by the formula (XXII). In this method, first get derivative (III) of ester-hydroxycarbonate kiln) in the presence of acid. The number of alcohol (Z-HE) and the acid is usually taken in large excess. This reaction is usually carried out at temperatures ranging from -80 to 100oC, preferably from about -50 to 30oC reaction Time ranges from 0.5 to 100 hours. Then the compound (III) provide an opportunity to react with chlorogonium ether (ClCOOR7), after which the reaction mixture provides the opportunity to interact with ammonia to obtain the compound (XXIV) the Reaction of the compound (III) with chlorogonium ether (ClCOOR7) is carried out in accordance with the traditional way in a suitable solvent in the presence of a base. As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane and a suitable mixture of these solvents. As the Foundation of the use of salts of alkaline metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium hydrogen carbonate, and amines, such as pyridine, triethylamine and N,N-dimethylaniline. The number of these used bases preferably is in the range from at the ut can also be used as solvents. The number gloryhole ether (ClCOOR7) is in the range from about 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, relative to compound (III). This reaction is carried out usually at temperatures ranging from -80 to 100oC, preferably from about -50 to 50oC reaction Time ranges from 0.5 to 30 hours.

Then the product (XXIII) is subjected to interaction with ammonia to obtain the compound (XXIV). This reaction is usually carried out in a suitable solvent in the presence of ammonia. As the solvent used aromatic hydrocarbons, such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, ethyl acetate, and a suitable mixture of these solvents. As ammonium using gaseous or aqueous ammonia, and the reaction is carried out at temperatures in the range from -100 to 50oC, preferably from approximately -80 to 30oC. the reaction Time ranges from 0.5 to 30 hours Obtained in the manner described compound (XXIV) is subjected to cyclization to obtain the derivative (I-B2) 2,4-oxazolidinedione. The cyclization reaction is carried is oritel. As the solvent used, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachlorethane, acetonitrile or a suitable mixture of these solvents as the Foundation of the use of salts of alkaline metals such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate; amines such as pyridine, triethylamine, N, N - dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5 - diazabicyclo[4.3.0]non-5-ene (DBN); ethoxide sodium, sodium methoxide, tert-piperonyl potassium or so on the Used amount of these bases is in the range from 1 to 5 molar equivalents relative to the compound (XXIV) This reaction is usually carried out at temperatures ranging from -80 to 50oC, preferably from about -50 to 30oC. the reaction Time ranges from 0.5 to 30 hours.

Obtained in the manner described above derivative (I-B2) 2,4-oxazolidinedione can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, precrystallization in method II, can be obtained, for example, by way o

METHOD O

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where each symbol means the same as above.

In this method, the compound (IX-6) is subjected to interaction with diethyl ether (COOR6)2oxalic acid in the presence of a base. The reaction between the compound (IX-6) and diethyl ether (COOR6)2oxalic acid is carried out in accordance with the traditional way in a suitable solvent in the presence of a base. As the solvent used, for example, alcohols such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane; N,N-dimethylformamide and a suitable mixture of these solvents. As the base used ethoxide sodium, sodium methoxide and tert-piperonyl potassium or so on the Used amount of these bases is in the range of about 1 to 5 molar equivalents relative to the compound (IX-6) and the amount used (COOR6)2preferably is within Torah in the range from -50 to 150oC, preferably from about -10 to 100oC. the reaction Time ranges from 0.5 to 50 hours.

Obtained in the manner described above, the condensate is subjected to decarboxylation reaction to produce complex ether-keto-acid (XIII-1). This decarboxylation reaction is carried out with heating in an aqueous solution of dimethyl sulfoxide in the presence of sodium chloride or lithium chloride. The amount of sodium chloride or lithium chloride is in the range from 1 to 5 molar equivalents. The reaction temperature is from 50 to 150oC, preferably from about 80 to 120oC. the reaction Time ranges from 0.5 to 50 hours. Then obtained in the manner described above ester-ketoacids (XIII-1) is subjected to reduction to obtain compound (III-2). This recovery can be made known in itself by the way, such as the recovery of the metal hydride, the restoration of a complex compound with a metal hydride, the restoration of the DIBORANE and substituted DIBORANE, catalytic hydrogenation or so on, in Other words, this reaction is carried out by treatment of the compound (XIII-1) regenerating agent. Examples of the reducing agent uklocation metals, such as sociallyengaged; metal hydrides such as sodium hydride; ORGANOTIN compounds (e.g., triphenylamine), metals, such as connection of Nickel or a compound of zinc, and their salts; catalytic agents for recovery using a transition metal such as palladium, platinum or rhodium, and hydrogen; and DIBORANE, and the use of these alkali metal borohydride (e.g. sodium borohydride or lithium borohydride) is to provide opportunities advantageous to perform the reaction. This reaction is carried out in an organic solvent which has no adverse effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2 - tetrachlorethane; ethers, such as diethyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, isopropanol and 2-methoxyethanol; amides such as N,N - dimethylformamide, or a suitable mixture of these solvents, among them the suitable solvent is selected depending on the type of reducing agent. The reaction temperature range from -20 to 150o<

Optically active compound of the compound (III-2) can be obtained from compound (XIII-1) according to known per se asymmetric recovery, such as asymmetric recovery of the ketone to the alcohol using baking yeast; asymmetric recovery of the ketone to the alcohol using optically active DIOP/[Rh(COD)Cl2] 2Ph2SiH2; asymmetric recovery of the ketone to the alcohol by asymmetric hydrogenation using chiral catalyst [(Cinchonidine, Pt-Al2O3), (Quinidine, Pt - Al2O3), (Cinchonidine, Pt-Al2O3), (optically active BINAP, RuCl2and so on]. Optically active compound of the compound (XXII) can be obtained by optical separation based on theory of kinetic process known in itself enzymatic reaction. For example, enable the racemate compound (III-2) to react in toluene in the presence of vinyl acetate and lipase to obtain optically active compounds (XXII).

Of the compounds represented by the General formula (IX-6) from the way O, the compound (IX-9) can be obtained from the carbonyl derivative (VII-3) in accordance with method D first enable carbonyl derivative (VII-3) to interact with derivative (VIII-2) phosphonooxy acid to produce an unsaturated ester derivative (IX-7). The reaction of the compound (VII-3) with compound (VIII-2) are essentially the same manner as the reaction of the compound (VII-1) with compound (VIII-1) in method G. Then the compound (IX-7) is treated essentially the same as at the catalytic reduction of compound (II-1) in method G, to obtain the compound (IX-8) Next, the compound (IX-8) should be treated essentially the same way as with the recovery of the compound (IX-1) in method G, to obtain an alcohol derivative (X-4). The alcohol derivative (X-4) were known in itself reactions such as chlorination with thionyl chloride, bromirovanii tribromide phosphorus or methylsulfonylamino methanesulfonamido, to obtain the compounds of formula (XXV), where Q is Cl, Br and OSO2CH3respectively. The compound (XXV) gives compound represented by the formula (XXVI), while providing him the opportunity to interact with potassium cyanide or sodium cyanide in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; alcohols such as methanol, ethanol and propanol; N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethylene is in the range from 1 to 5 molar equivalents relative to the compound (XXV). This reaction is usually carried out at temperatures in the range from 0 to 150oC, preferably from about 20 to 100oC. the reaction Time ranges from 0.5 to 30 hours. Then the compound (XXVI) is subjected to hydrolysis to obtain the derivative (XXVII) carboxylic acid. This hydrolysis is carried out preferably in an aqueous solvent in the presence of potassium hydroxide or sodium hydroxide. Derivative (XXVII) carboxylic acid is treated essentially the same as in the esterification of the compound (XI) in method I, to obtain the compound (IX-9).

Ester derivative (IX-9) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

The original compound (II) in method A, the original compound (IV) in method D, the original compound (VII-1) in method G, method J, the original compound (VII-2) and compound (XIII) in method I, the original compound (IX-3) in method K, the original compound (IX-6) in the way O the original compound (VII-3) in the method P, etc. can be obtained also by a method Q.

METHOD Q

< / BR>
where F predstavlen2COOR5and the other symbols represent the same as above.

In this method, compound (XXVIII) interacts with the compound (XXIX) to obtain the compound (XXX). This method is carried out according to known per se by reaction of Mitsunobu.

This reaction is preferably carried out in a solvent in the presence of triphenylphosphine and diethylazodicarboxylate. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane and a suitable mixture of these solvents. The number of triphenylphosphine and diethylazodicarboxylate preferably is in the range from 1 to 5 molar equivalents relative to the compound (XXVIII), respectively, and the amount of compound (XXIX) is preferably in the range from 1 to 2 molar equivalents relative to compound (XXVIII). This reaction is carried out usually at temperatures ranging from -50 to 100oC, preferably from about -30 to 80oC. the reaction Time ranges from 0.5 to 50 hours.

Received above ncentrate, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

The original compound (V) in method E can be obtained, for example, as described below R way S way t

HOW R

< / BR>
where each symbol means the same as above.

In this way benzyl compound (I-C4), obtained in accordance with method A, B, D, or N, is subjected to reaction removal of the benzyl group to obtain the compound (V-1). This process is carried out essentially the same as method C.

Obtained in the manner described above, the compound (V-1) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

WAY S

< / BR>
where each symbol means the same as above.

In this way isopropyl compound (I-C5) obtained in accordance with methods A, B, C, D, or N, is subjected to the reaction of cleavage of the isopropyl group to obtain the compound (V).

This reaction soorim silicon or etc. Examples of the solvent include halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichloromethane, 1,1,2,2-tetrachlorethane; acetonitrile and a suitable mixture of these solvents. The amount of titanium tetrachloride, trichloride titanium, trichloride boron, silicon tetrachloride, or etc., is preferably in the range from 1 to 6 molar equivalents relative to one of the isopropyl group of the compound (I-C5). This reaction is usually carried out at temperatures ranging from 80 to 100oC, preferably from about -50 to 80oC. the reaction Time ranges from 0.5 to 50 hours. The reaction is carried out essentially in the same manner as in method C.

Obtained in the manner described above, the compound (V) can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

WAY T

In this method, the compound obtained in accordance with methods A, B, C, D, E, F, or N and having a methoxy group as a substituent in the ring E, is subjected to the reaction of cleavage of a methyl group to obtain the phenolic proizvod and dodecylmercaptan, in the presence of aluminium chloride. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and 1,1,2,2-tetrachlorethane, and a suitable mixture of these solvents. The amount of aluminum chloride is preferably in the range from 5 to 20 molar equivalents relative to methoxypropanol and the amount of titanium tetrachloride is preferably in the range from 5 to 20 molar equivalents relative to methoxypropanol. This reaction is carried out usually at temperatures ranging from -80 to 100oC, preferably from about -50 to 50oC. the reaction Time ranges from 0.5 to 50 hours.

Obtained in the manner described above phenol derivative can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography or etc.

The compound (I) in accordance with the present invention or its salts exhibit high ISU below.

EXPERIMENTAL EXAMPLE

Gipoglikemicheskoe and hypolipidemic effect in mice

The test compound mixed in powdered food (CE-2, Clea Japan Inc. ) at the rate of 0.005%, was given to mice KKAy(ages 9-14 weeks) freely within 4 days. During this period the animals were allowed free access to water. Blood was taken from the orbital venous plexus. Using the plasma enzyme was determined by the amount of glucose and triglycerides using the kit Iatrochem-GLU (A) and Iatro-MA TG (Iatron Laboratories Inc. ). The respective values indicating a decrease in the percent (%) detected in the groups of mice that received the drug, relative to a control group of mice that did not receive the test compound shown in table 1.

As shown above, the derivatives (I) in accordance with the present invention exhibit high hypoglycemic and hypolipidemic activity when tested on mice suffering from non-insulin dependent diabetes mellitus, and pharmaceutically usable as medicines for the treatment of, inter alia, diabetes, hyperlipemia and hypertension.

The following working examples, examples in which I, presented in greater detail and in no way should be considered as defining the scope of invention.

WORKING EXAMPLE 1

A mixture of 3-methoxy-4-(2-phenyl-4-oxazolidinone)cinnamaldehyde (5.5 g), 2,4-oxazolidinedione (6.7 g), piperidine (1.4 g) and acetic acid (120 ml) was stirred for three days while heating under reflux. The reaction mixture was cooled and the resulting crystalline precipitate was filtered and then washed with water, ethanol and diisopropyl ether, resulting in 5-[3-methoxy-4-(2-phenyl-4-oxazolidinone) cinnamamide] -2,4-oxazolidinedione (2.9 g, 43%) which was recrystallized from a mixture of chloroform-methanol gave yellow needle crystals, so pl. 227 - 228oC.

WORKING EXAMPLES 2-4

Were obtained essentially the same manner as in working example 1, and the compounds shown in table 2.

WORKING EXAMPLE 5

A mixture of 5-[3-methoxy-4-(2-phenyl-4-oxazolidinone) cinnamamide] -2,4-oxazolidinedione (1.0 g), platinum oxide (PtO2) (0.2 g) and a mixture of tetrahydrofuran (THF), acetic acid (4:1, 190 ml) was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate kontsentrirovanii, saturated aqueous sodium hydrogen carbonate solution and water followed by drying (MgSO4). The chloroform layer was concentrated under reduced pressure and the concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of chloroform-ethyl acetate (4:1), was obtained 5-[3-[3-methoxy-4-(2-phenyl-4-oxazolidinone) phenyl] propyl] -2,4-oxazolidinedione (0,19 g, 19%). Recrystallization of the product from a mixture of ethyl acetate-hexane gave colorless prism crystals, so pl. 134 - 135oC.

WORKING EXAMPLE 6

A mixture of 5-[3-methoxy-4-(2-phenyl-4 - thiazoleacetate) cinnamamide] -2,4 - oxazolidinedione (0,76 g), palladium on coal (5%, 1.0 g) and tetrahydrofuran (THF) (100 ml) was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of chloroform - ethyl acetate (4: 1), was obtained 5-[3-[3-methoxy-4-(2-phenyl-4 - thiazoleacetate)phenyl] propyl]-2,4-oxazolidinedione (0.25 g, 32%). Recrystallization of the product from a mixture of ethyl acetate-hexane gave colorless prism crystals, so pl. 96 - 97oC.

WORK Predin] - 2,4-oxazolidinedione was subjected to catalytic hydrogenation, resulting in 5-[3-[3-ethoxy-4- (5-methyl-2 - phenyl-4-oxazolidinone) phenyl]propyl]-2,4 - oxazolidinedione. The product was recrystallized from a mixture of dichloromethane-diethyl ether gave colorless prism crystals, so pl. 129 - 130oC.

WORKING EXAMPLE 8

A mixture of 5-(4-isopropoxy-3-methoxycinnamyl) -2,4-oxazolidinedione (7,1 g), palladium on coal (5% and 7.1 g) and tetrahydrofuran (THF) (150 ml) was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya from a mixture of chloroform-ethyl acetate (4:1), was obtained 5-[3-(4-isopropoxy-3-methoxyphenyl)propyl]- 2,4-oxazolidinedione (4.3 g, 60%) as an oily product. NMR (, memorial plaques in CDCl3): of 1.35 (6H, d, J=6 Hz), 1,79-of 2.05 (4H, m), 2,62 (2H, t, J=7 Hz), of 3.84 (3H, s), 4,47 (1H, m), 4,84 (1H, DD, J=7 and 5 Hz), to 6.67 (1H, DD, J=8 and 2 Hz), 6,69 (1H, s), PC 6.82 (1H, d, J=8 Hz), with 8.33 (1H, C).

WORKING EXAMPLE 9

To a solution of 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione (1.0 g) in N,N-dimethylformamide (DMF) (20 ml) was added at 0oC sodium hydride (60% in oil, 0.32 chlormethyl-2-[(E)-styryl] -oxazol (0.87 g) and the resulting mixture was stirred 3.5 hours at 90oC. Pour the reaction mixture into water and podkolis 2 N. HCl, extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure, resulting in 5-[3-[3-methoxy-4-[2-[(E)-styryl] -4 - oxazolidinone]phenyl]propyl]-2,4-oxazolidinedione (1.1 g, 66%). The product was recrystallized from a mixture of ethylacetate that gave colorless prism crystals, so pl. 178 - 179oC.

WORKING EXAMPLE 10

Essentially, the same as in working example 9, gave 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]- 2,4-oxazolidinedione the opportunity to interact with 4 - chloromethyl-2-[(E)-styryl] -thiazole, resulting received 5-[3-[3-methoxy-4-[2-[(E)-styryl] -4 - thiazoleacetate] phenyl] propyl]-2,4-oxazolidinedione. The product was recrystallized from a mixture of chloroform-methanol, which resulted in colorless prismatic crystals, so pl. 202 - 203oC.

WORKING EXAMPLE 11

A mixture of 3-ethoxy-4-(2-phenyl-4-oxazolidinone)cinnamaldehyde (3.0 g), 2,4-oxazolidinedione (1.7 g), piperidine (0.73 g) and acetic acid (50 ml) was stirred for 24 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure and was then filtered polucen the aqueous solution of sodium bicarbonate, water, 1 N. HCl and water,

then was dried (MgSO4). The ethyl acetate layer was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (50:1), was obtained 5-[3-[3-ethoxy-4- (2-phenyl-4-oxazolidinone) phenyl]propyl]-2,4 - oxazolidinedione, which was recrystallized from a mixture of chloroform-diethyl ether, which resulted in colorless prismatic crystals, so pl. 119 - 120oC.

WORKING EXAMPLE 12

Essentially, the same as in working example 11, 4-[5-methyl-2- (2-naphthyl)-4-oxazolidinone] -3-methoxycinnamaldehyde are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation, resulting in 5-[3-[4- [5-methyl-2-(2-naphthyl)-4-oxazolidinone]-3-methoxyphenyl] - propyl]-2,4-oxazolidinedione. The product was recrystallized from a mixture of chloroform-methanol-diethyl ether gave colorless prism crystals, so pl. 173 - 174oC.

WORKING EXAMPLE 13

Essentially, the same as in the working example 11, 4-[2-(2-furyl)- 5-methyl-4-oxazolidinone]-3-methoxycinnamaldehyde are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation, receiving financial p is allisonville from a mixture of dichloromethane-diethyl ether, that gave colorless prism crystals, so pl. 127 - 129oC.

WORKING EXAMPLE 14

Essentially, the same as in working example 11, 3-isopropoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)cinnamaldehyde are condensed with 2,4 - oxazolidinedione. The condensate was subjected to catalytic hydrogenation, resulting in 5-[3-[3-isopropoxy-4-(5 - methyl-2-phenyl-4-oxazolidinone)phenyl] propyl]-2,4 - oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 120 - 121oC.

WORKING EXAMPLE 15

Essentially, the same as in example 11, (E,E)-5-[3-methoxy-4-(5-methoxy-2-phenyl-4 - oxazolidinone)phenyl] -2,4-pentadien-1-al are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation, resulting in 5-[5-[3-methoxy-4- (5-methoxy-2-phenyl - 4 - oxazolidinone) phenyl] pentyl]-2,4 - oxazolidinedione.

The product was recrystallized from a mixture of dichloromethane-diethyl ether gave colorless prism crystals, so pl. 114 - 115oC.

WORKING EXAMPLE 16

Essentially, the same as in working example 11, 4- (5-methyl-2-phenyl-4-oxazolidinone)-3-propositionally are condensed with 2,4-oxazolidinedione)- 3 - propoxyphenyl] propyl]-2,4 - oxazolidinedione, which is recrystallized from a mixture of ethyl acetate-diethyl ether gave colorless needle crystals, so pl. 119 - 120oC.

WORKING EXAMPLE 17

Essentially, the same as in working example 11, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone) cinnamaldehyde are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation, resulting in 5- [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone) phenyl]propyl] -2,4-oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 161-162oC.

WORKING EXAMPLE 18

A mixture of 2-[5-[3-methoxy-4- (5-methyl-2-phenyl-4 - oxazolidinone)phenyl]pentenyl] -1,3-dioxolane (3.6 g), 2,4 - oxazolidinedione (1.7 g), piperidine (0,72 g) and acetic acid (50 ml) was stirred for 16 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure and the concentrate was dissolved in ethyl acetate. The solution was sequentially washed with saturated aqueous sodium hydrogen carbonate solution, water, 1 N. HCl and water and then was dried (MgSO4). The ethyl acetate layer was concentrated under reduced pressure. The concentrate was subjected to column chromatography on when polymethoxy)-phenyl]hexylidene]-2,4-oxazolidinedione in the form of an oily product. The oily product was dissolved in tetrahydrofuran (THF) (80 ml) and the resulting solution was added palladium on coal (5%, 1.0 g). The mixture was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya mixture of chloroform-methanol (50: 1), was obtained 5-[6-[3 - methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] hexyl]- 2,4-oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-diisopropyl ether gave colorless prism crystals, so pl. 113 - 117oC.

WORKING EXAMPLE 19

Essentially, the same as in the working example 18, 2-[6-[3- methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]hexyl]- 1,3-dioxolane are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation, resulting in 5-[7-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)-phenyl] heptyl]-2,4-oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 109 - 111oC.

WORKING EXAMPLE 20

Essentially, the same as in relocalization. The condensate was subjected to catalytic hydrogenation, resulting in 5-[4-[3-methoxy-4-(5 - methyl-2-phenyl-4-oxazolidinone)-phenyl] butyl] - 2,4-oxazolidinedione, which was recrystallized from a mixture of dichloromethane-diisopropyl ether gave colorless prism crystals, so pl. 135 - 136oC.

WORKING EXAMPLE 21

To a solution of 5-[3-[3 - isopropoxy-4- (5-methyl-2-phenyl-4-oxazolidinone) phenyl] propyl]-2,4-oxazolidinedione (0.7 g) in dichloromethane (25 ml) was added dropwise at 0oC solution of titanium tetrachloride (TiCl4) (1.1 g) in dichloromethane (5 ml). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into 2 N. HCl and stirred for 15 minutes at room temperature. Separated the organic layer and the aqueous layer was extracted with chloroform. The organic layers were combined and washed successively with water, 2 N. HCl and water, then dried (MgSO4) and concentrated. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (50:1), was obtained 5-[3-[3 - hydroxy-4-(5-methyl-2-phenyl-4-oxazolidinone) phenyl] propyl]-2,4-oxazolidinedione (0,22 g, 34%) which was recrystallized from a mixture of chloroform-methanol, which gave b is, the AK in working example 11, 3-fluoro-4-(5-methyl - 2-phenyl-4 - oxazolidinone) cinnamaldehyde are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic recovery, resulting in 5-[3-[3 - fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]propyl]-2,4 - oxazolidinedione, which was recrystallized from a mixture of dichloro-methanol gave colorless prism crystals, so pl. 180 - 181oC.

WORKING EXAMPLE 23

Essentially, the same as in working example 11, 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone) cinnamaldehyde are condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic restoration, receiving the resultant 5-[3-[3-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone) phenyl]propyl] -2,4-oxazolidinedione, which was recrystallized from a mixture of chloroform-methanol gave colorless prism crystals, so pl. 185 - 187oC.

WORKING EXAMPLE 24

To a solution of methyl-(R)-(+)-2-carbamoylated-5-[4- [2-(2-furyl)-5-methyl-4-oxazolidinone] -3 - methoxyphenyl]pentanoate (2,92 g) in chloroform (100 ml) was added dropwise at a temperature in the range from -5 to 0oC 1,8 - diazabicyclo[5.4.0] -7-undecene (DBU) (1.54 g). The mixture was stirred for one hour at temperatures in the same ol result (R)-(+)-5-[3-[4-(2-furyl)-5-methyl-4-oxazolidinone] - 3-methoxyphenyl] propyl] -2,4-oxazolidinedione (2,46 g, 91%) which was recrystallized from a mixture of acetone-diisopropyl ether gave colorless needle crystals, so pl. 122 - 123oC. []D+ 39,4o(c = 0,495, CHCl3).

WORKING EXAMPLE 25

Essentially, the same as in working example 24 was obtained (S)-(-)-5-[3-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl] propyl]-2,4 - oxazolidinedione of methyl-(S)-(-)-2-carbamoylated-5- [4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl] pentanoate. The product was recrystallized from a mixture of acetone-diisopropyl ether gave colorless needle crystals, so pl. 122 - 123oC. []D- 39,8o(c = 0,500, CHCl3).

WORKING EXAMPLE 26

Essentially, the same as in the working example 9, 5-[2-(4- hydroxy-3-methoxyphenyl)ethyl] -2,4-oxazolidinedione was introduced in cooperation with 4-chloromethyl-5-methyl-phenyloxazole, resulting in received 5-[2-[4-(5-methyl-2-phenyl-4 - oxazolidinone)-3-methoxyphenyl]ethyl]-2,4-oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-chloroform gave colorless prism crystals, so pl. 194 - 195oC.

WORKING EXAMPLE 27

Essentially, the same as in the working example 9, 5-[3-(4-hydroxy-3-methoxyphenyl received 5-[3-[3-methoxy-4- [2-(5-methyl-2-phenyl-4-oxazolyl)-2-oksidoksi]phenyl]propyl]- 2,4-oxazolidinedione in the form of an oily product.

NMR ( M. D., CDCl3): 1,7-of 2.15 (4H, m), 2.63 in (2H, t, J=7 Hz), 2,73 (3H, s), 3,91 (3H, s), is 4.85 (1H, DD, J=6.5 and 5 Hz), 5,43 (2H, s), of 6.65 (1H, DD, J=8 and 2 Hz), was 6.73 (1H, d, J= 2 Hz), 6,79 (1H, d, J=8 Hz), 7,45-of 7.55 (3H, m), 7,95 (1H, Shir. C) of 8.0 to 8.1 (2H, m).

WORKING EXAMPLE 28

To a solution of 5-[3-[3-methoxy-4-[2-(5-methyl-2-phenyl - 4-oxazolyl)-2-oksidoksi] phenyl]propyl]-2,4-oxazolidinedione (0,37 g) in a mixture of tetrahydrofuran (THF) (5 ml) and ethanol (5 ml) was added by portions at room temperature borohydride sodium (0,045 g). The mixture was stirred 2 hours at room temperature. The reaction mixture was poured into water, which was acidified using 2 N. HCl, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4and then drove the solvent. The residual oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of chloroform-methanol (100:1, o/o), received 5-[3-[4-[2-hydroxy-2- (5-methyl-2-phenyl-4-oxazolyl)ethoxy] -3-methoxyphenyl)propyl] - 2,4-oxazolidinedione (0.31 g, 83%) which was recrystallized from a mixture of acetone-diisopropyl ether gave colorless prism crystals, so pl. 151 - 152oC.

WORKING EXAMPLE 29

Essentially, the same as in working example 11, 3-methoxy-4-[1- (5-methyl-2-phenyl-4-oxazolyl)ethoxy] cinnamaldehyde received 5-[3- [3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl]-propyl]-2,4-oxazolidinedione.

NMR ( M. D. in CDCl3): of 1.73 (3H, d, J= 6.5 Hz), a 1.7-2.1 (4H, m), of 2.28 (3H, s) at 2.59 (2H, t, J=7 Hz), 3,85 (3H, s), 4,82 (1H, DD, J=7 and 4 Hz), 5,32 (1H, q, J= 6.5 Hz), 6,59 (1H, DD, J=8 and 2 Hz), of 6.68 (1H, d, J=2 Hz)that is 6.78 (1H, d, J=8 Hz), 7,35 is 7.5 (3H, m), 7.95 is to 8.1 (2H, m), 8,66 (1H, Shir. C).

WORKING EXAMPLE 30

A mixture of 5-[3-[3-methoxy-4-[2-[(E)-styryl] - 4-oxazolidinone]phenyl]propyl]-2,4-oxazolidinedione (0.64 g), palladium on coal (5%, 1.3 g) and tetrahydrofuran (THF) (35 ml) was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure, resulting in received 5-[3-[3-methoxy-4- [2- (2-phenylethyl)-4 - oxazolidinone] phenyl]-propyl]- 2,4 - oxazolidinedione (0,43 g, 67%). The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 122 - 123oC.

WORKING EXAMPLE 31

Essentially, the same as in the working example 30, 5-[3-[3- methoxy-4-[2-[(E)-styryl] -4-thiazoleacetate]phenyl]propyl]-2,4-oxazolidinedione was subjected to catalytic hydrogenation under a pressure of 1 atmosphere at room temperature and the obtained 5- [3-[3-methoxy-4-[2-(2-phenylethyl)-4 - thiazoleacetate] phenyl]propyl]-2,4-oxazolidinedione. The product was recrystallized from a mixture of ethyl acetate-gestu, in the same way as in working example 9, 5-[3-4-hydroxy-3-methoxyphenyl)propyl] -2,4-oxazolidinedione was introduced in cooperation with 4-chloromethyl-5-methyl-2-phenylthiazole and as a result received 5-[3-[3-methoxy - 4- (5-methyl-2-phenyl-4 - thiazoleacetate]phenyl]propyl]-2,4 - oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-chloroform gave colorless prism crystals, so pl. 128 - 129oC.

WORKING EXAMPLE 33

Essentially, in the same way as in working example 9, 5-[3-[4- hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was introduced into a chemical reaction with 5-chloromethyl-3-phenyl-1,2,4 - oxadiazole, resulting received 5-[3-[3-methoxy-4-(3 - phenyl-1,2,4-oxadiazol-5-ylethoxy)phenyl] propyl]-2,4 - oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 110 - 111oC.

WORKING EXAMPLE 34

A mixture of 6-(4-benzyloxy-3 - methoxyphenyl)-2-hydroxyhexanoate (15,22 g), potassium cyanate (KCNO) (13,26 g) and butanol (180 ml) was stirred for 72 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, acidified with 2 N. HCl, then was extracted with ethyl acetate. The ethyl acetate layer was washed adjustment chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1: 1, o/o), received 5-[4-(4-benzyloxy-3-methoxyphenyl)butyl] -2,4 - oxazolidinedione (11,22 g, 74%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 92 - 93oC.

WORKING EXAMPLE 35

Essentially, the same as in the working example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4 - oxazolidinedione was introduced in cooperation with 4-chloromethyl-5-methyl - 2-[(E) -styryl]oxazolam and as a result received 5-[4-[3 - methoxy-4-[2-[(E)-styryl] -4-oxazolidinone]phenyl]butyl]- 2,4-oxazolidinedione, which is recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 171 - 172oC.

WORKING EXAMPLE 36

Essentially, the same as in the working example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4 - oxazolidinedione was introduced in cooperation with 4-chloromethyl-5-methyl - 2-[(E)-styryl] thiazole, resulting received 5-[4-[3 - methoxy-4-[2-[(E)-styryl] -4-thiazoleacetate] phenyl]butyl]- 2,4-oxazolidinedione, which is recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 167 - 168oC.

WORKING EXAMPLE 37

Essentially, the same as in working example 34, the result is 5-[2-(4-benzyloxy-3-ethoxyphenyl) ethyl]-2,4-oxazolidinedione, which is recrystallized from a mixture of ethyl acetate-hexane, which resulted in colorless prismatic crystals, so pl. 143 - 144oC.

WORKING EXAMPLE 38

Essentially, the same as in working example 34 ethyl-4-(3 - benzyloxy-4-methoxyphenyl)-2-hydroxybutanoic entered into interaction with potassium cyanate (KCNO) and the result obtained 5-[2-benzyloxy-4-methoxyphenyl)ethyl]-2,4 - oxazolidinedione in the form of an oily product.

NMR ( M. D., CDCl3): 1.95-of 2.25 (2H, m), 2,59 - 2,84 (2H, m), a 3.87 (3H, s), 4,58 (1H, DD, J=8,2 and 4.8 Hz), further 5.15 (2H, s), 6,72-6,86 (3H, m), 7,26 was 7.45 (5H, m), charged 8.52 (1H, Shir. C.).

WORKING EXAMPLE 39

Essentially, the same as in the working example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl] -2,4-oxazolidinedione was introduced in cooperation with 4-chloromethyl-2-[(E) -2- (2-naphthyl) ethyl]oxazole, resulting received 5-[4-[3-methoxy-4- [2-[(E)-2-(2-naphthyl)ethynyl] -4 - oxazolidinone]phenyl]butyl] -2,4-oxazolidinedione, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 169 - 170oC.

WORKING EXAMPLE 40

Essentially, the same as in working example 1, 4 - benzyloxy-3,5-dimethoxybenzaldehyde are condensed with 2,4 - oxazolidinedione, receiving 5-[3-(4-benzyloxy-3,5 - dio yellow prismatic crystals so pl. 181 - 182oC.

WORKING EXAMPLE 41

Essentially, the same as in the working example 9, 5-[3-(4- hydroxy-3,5-acid)propyl] -2,4-oxazolidinedione was introduced in cooperation with 4-chloromethyl-5-methyl-2-[(E)- styryl]-oxazole and as a result received 5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl] -4 - oxazolidinone]phenyl]propyl]-2,4-oxazolidinedione, which is recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 94 - 95oC.

WORKING EXAMPLE 42

To a suspension of aluminium chloride (1.56 g) in dichloromethane (30 ml) was added at 0oC 1-dodecanthiol and the resulting mixture was stirred for 10 minutes. To the mixture was added dropwise at the same temperature, the solution 5-[3-[4-(2-furyl)-5-methyl-4 - oxazolidinone]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (0.5 g) in dichloromethane (10 ml). The reaction mixture was stirred 2 hours at room temperature, poured into ice-cold water and then was extracted with dichloromethane. The dichloromethane layer was washed with water, dried (MgSO4), and then drove the solvent. The residual oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-chloroform (1: 3, o/o), received 5-[3-[4-[2-(2-furyl)- 5-IU is whether from a mixture of dichloromethane-methanol, that resulted in colorless prismatic crystals, so pl. 152 - 153oC.

WORKING EXAMPLE 43

Essentially, the same as in working example 11, 3-fluoro-4-[2-[N-methyl - N-(2-pyridyl) amino]ethoxy] cinnamaldehyde are condensed with 2,4 - oxazolidinedione. The condensate was subjected to catalytic hydrogenation, which resulted in 5-[3-[3-fluoro-4-[2- [N - methyl-N-(2-pyridyl) amino]ethoxy]phenyl] propyl-2,4 - oxazolidinedione, which was recrystallized from a mixture of ethyl acetate - hexane, and the obtained colorless prismatic crystals, so pl. 124 - 125oC.

EXAMPLE 1.

The manufacture of dosage forms (manufacture of tablets)

(1) 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolyl-methoxy) phenyl]propyl] -2,4-oxazolidinedione (compound obtained in working example 17) - 10 g

(2) lactose 50 g

(3) corn starch 15 g

(4) calcium carboxymethylcellulose - 44 g

(5) magnesium stearate 1 g

1000 tablets - 120 g

Full amount (1), (2) and (3) and 30 g (4) was mixed with water, the resulting mixture was subjected to vacuum drying, and then was granulated. Granulated in this way the powder was mixed with 14 g (4) and 1 g (5) and then alloy preformed using a tablet machine, as a result, castendyk forms (manufacture of tablets)

(1) 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone) phenyl]propyl]-2,4-oxazolidinedione (compound obtained in working example 22) 30 grams

(2) lactose 50 g

(3) corn starch 15 g

(4) calcium carboxymethylcellulose - 44 g

(5) magnesium stearate 1 g

1000 tablets - 140 g

Full amount (1), (2) and (3) and 30 g (4) was mixed with water, the resulting mixture was subjected to vacuum drying, and then was granulated. The obtained granulated powder was mixed with 14 g (4) and 1 g (5) and using a tablet machine, alloy preformed, resulting in 1000 tablets containing 30 mg (1) per pill.

REFERENCE EXAMPLE 1

The mixture cinnamamide (25,3 g) and 1,3-dichloroacetone (20,9 g) was heated for one hour at 130oC. the Reaction mixture was poured into water, neutralized with potassium carbonate, and then was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The concentrate was purified by column chromatography on silica gel. From the faction, elyuirovaniya a mixture of diethyl ether-hexane (1: 5: o/o), received 4-chloromethyl-2-[(E)-styryl]oxazol (16,9 g, 47%) which was recrystallized from a mixture of diethyl ether-hexane, resulting in colorless needle crystals,anola (145 ml) was stirred for one hour while heating under reflux. The reaction mixture was poured into ice water, neutralized with potassium carbonate, and then was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The concentrate was purified by column chromatography on silica gel. From the faction, elyuirovaniya a mixture of diethyl ether - hexane (1:6, o/o), received 4-chloromethyl-2-[(E)-styryl]thiazole (9.4 g, 56%) which was recrystallized from a mixture of diethyl ether-hexane, which resulted in colourless plates, so pl. 88 - 89oC.

REFERENCE EXAMPLE 3

A mixture of 4-chloromethyl-2-phenyloxazole (10.0 g), vanillin (7.9 g), potassium carbonate (8.6 g) and N,N - dimethylformamide (DMF) (90 ml) was stirred 2 hours at 100oC. the Reaction mixture was poured into ice water. The resulting crystalline precipitate was filtered and dissolved in chloroform (400 ml). The chloroform layer was washed with water, dried (MgSO4) and concentrated. The remaining crystalline product was filtered, resulting in 3-methoxy-4-(2-phenyl-4 - oxazolidinone)benzaldehyde (15,4 g, 97%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 119 - 120oC.

REFERENCE EXAMPLES 4-12

Essentially, the same as in the SS is the solution triethylphosphate (10,81 g) and 3-methoxy-4-(2-phenyl-4-oxazolidinone) benzaldehyde (14,62 g) in N,N-dimethylformamide (DMF) (230 ml) was added by portions at 0oC sodium hydride (60% in oil, of 1.93 g). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated, resulting in ethyl-3-methoxy-4-(2-phenyl-4 - oxazolidinone)cinnamate (17,24 g, 96%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 128 - 129oC.

REFERENCE EXAMPLES 14-15

Essentially, the same as in the reference example 13, were obtained the compounds shown in table 4.

REFERENCE EXAMPLE 16

It chilled with ice to a solution of trimethylphosphate (3.2 g) and 3-ethoxy-4-(2-phenyl-4 - oxazolidinone)benzaldehyde (5,1 g) in N,N-dimethylformamide (DMF) (30 ml) was added dropwise methanol solution of sodium methoxide (28%, 3.4 g). The mixture was stirred for 5 minutes under ice cooling and then for 4 hours at room temperature. The reaction mixture was poured into ice water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated, resulting in methyl-3-ethoxy-4- (2-phenyl-4-oxazolidinone) tsinn the ical crystals, so pl. 125 - 126oC.

REFERENCE EXAMPLES 17-22.

Essentially, the same as in the reference example 16, were obtained the compounds shown in table 5.

REFERENCE EXAMPLE 23

Essentially, the same as in the reference example 16 gave 3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)cinnamaldehyde the opportunity to interact with trimethylphosphate, the result obtained methyl (E, E)-5-[3-methoxy-4- [5-methyl-2-phenyl - 4-oxazolidinone) phenyl]-2,4 - pentadienoic, which was recrystallized from ethyl acetate gave colorless prism crystals, so pl. 166 - 167oC.

REFERENCE EXAMPLE 24

To a solution of ethyl-3-methoxy-4- (2-phenyl-4-oxazolidinone)cinnamate (16.4 g) in tetrahydrofuran (THF) (240 ml) was added dropwise at 0oC toluene solution diisobutylaluminium (1.5 M, 72,2 ml). The mixture was stirred 2 hours at room temperature and was added thereto under ice cooling, methanol (7 ml). The reaction mixture was poured into 2 N. HCl (600 ml) and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated, resulting in (E)- 3-[3-methoxy-4-(2-phenyl-4-oxazolidinone)phenyl] -2-propen-1 - ol (14.4 g, 98%), which/SUP>C.

REFERENCE EXAMPLES 25-32

Essentially, the same as in reference example 24, were obtained the compounds shown in table 6.

REFERENCE EXAMPLE 33

Essentially, the same as in the reference example 24 methyl(E,E)-5-[3-methoxy - 4-(5-methyl - 2-phenyl-4-oxazolidinone)- phenyl]-2,4-pentadienoic subjected to restore diisobutylaluminium and as a result received (E, E)-5-[3-methoxy - 4-(5-methyl-2-phenyl-4 - oxazolidinone) phenyl] -2,4 - pentadien-1-ol, which was recrystallized from ethyl acetate, that gave colorless needle crystals, so pl. 149 - 151oC.

REFERENCE EXAMPLE 34

To a suspension of sociallyengaged (LiAlH4) (6.4 g) in diethyl ether (270 ml) was added dropwise at 0oC a solution of aluminium chloride (AlCl3) (6,1 g) in diethyl ether (70 ml).

The mixture was stirred 10 minutes at room temperature and was added thereto dropwise at room temperature a solution of ethyl-4 - isopropoxy-3-methoxycinnamate (35.4 g) in a mixture of diethyl ether - tetrahydrofuran (THF) (3:1, 220 ml). The mixture was stirred 2 hours at room temperature and was added thereto dropwise while cooling with ice water (170 ml) and 6 N. H2SO4(230 ml). Separated the organic layer and the aqueous layer was subjected to what was tarawali. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:2, o/o), received (E)- 3-(4-isopropoxy-3-methoxyphenyl)-2-propen-1-ol (27,0 g, 91%).

NMR ( M. D. in CDCl3): of 1.37 (6H, d, J=6 Hz), of 1.52 (1H, a 3.87 (3H, s), 4,30 (2H, DD, J=6 and 1 Hz) to 4.52 (1H, m), 6,24 (1H, dt, J=16 and 6 Hz), 6,55 (1H, d, J= 16 Hz), 6,83 (1H, d, J=8 Hz), 6.90 to (1H, DD, J=8 and 2 Hz), 6,94 (1H, d, J=2 Hz).

REFERENCE EXAMPLE 35

To a solution of (E)-3-[3-methoxy-4- (2-phenyl-4-oxazolidinone)phenyl]-2-propen-1-ol (13,6 g) in chloroform (250 ml) was added activated manganese dioxide (28,0 g). The mixture was stirred for 8 hours at room temperature, then was filtered through a layer of celite. The filtrate was concentrated and received as a result of 3-methoxy-4- (2-phenyl - 4-oxazolidinone)-cinnamaldehyde (11.8 g, 88%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 144 - 145oC.

REFERENCE EXAMPLES 36-44

Essentially, the same as in reference example 35, were obtained the compounds shown in table 7.

REFERENCE EXAMPLE 45

Essentially, the same as in reference example 35, (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)phenyl] -2,4-pentadien-1-ol was subjected to oxidation activated dial, which is recrystallized from ethyl acetate gave colorless needle crystals, so pl. 133 - 134oC.

REFERENCE EXAMPLE 46

To a solution of 5-[3-(4-isopropoxy-3 - methoxyphenyl) propyl]-2,4-oxazolidinedione (4.3 g) in dichloromethane (130 ml) was added dropwise at 0oC solution of titanium tetrachloride (TiCl4) (10.6 g) in dichloromethane (10 ml). The mixture was stirred for one hour at 0oC, after which it was poured into 2 N. HCl and stirred for a further 15 minutes at room temperature. Separated the organic layer and the aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed successively with water, 2 N. HCl and water, dried (MgSO4) and then concentrated, resulting in 5-[3-(4-hydroxy-3-methoxyphenyl)-propyl] -2,4-oxazolidinedione (2, 8 g, 76%). Recrystallization of the product from a mixture of ethanol-hexane gave colorless prism crystals, so pl. 147 - 148oC.

REFERENCE EXAMPLE 47

A mixture of 3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)-cinnamaldehyde (5.6 g), palladium on coal (5%, 0.5 g) and tetrahydrofuran (THF) (160 ml) was subjected to catalytic hydrogenation at room temperature under a pressure of 1 atmosphere. The catalyst was filtered and the filtrate was concentrated Ponoi a mixture of ethyl acetate-hexane (1:1), received 3-[3 - methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone) phenyl]Propionaldehyde, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 80 - 81oC.

REFERENCE EXAMPLE 48

To a suspension of [2-(1,3 - dioxolane-2-yl)ethyl]triphenylphosphonium bromide (6.7 g) in tetrahydrofuran (THF) (60 ml) was added dropwise at -30oC in the streams of the nitrogen hexane solution of n-utility (1.6 M, and 9.4 ml). The mixture was stirred for one hour at the same temperature and then added to it dropwise at -30oC solution of 3-[3 - methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone) phenyl] Propionaldehyde (4.1 g) in tetrahydrofuran (THF) (10 ml). The cooling bath was removed and the reaction mixture was stirred one hour at room temperature. The reaction mixture was poured into ice water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove away the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1: 2), was obtained 2-[5-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)phenyl]-3-pentenyl]-1,3-dioxolane in the form of an oily product (4,5 palladium on coal (5%, 0.5 g) and subjected to the solution to catalytic hydrogenation at room temperature under a pressure of 1 atmosphere. The catalyst was filtered and the filtrate was concentrated under reduced pressure, resulting in a received 2-[5-[3-methoxy-4- (5 - methyl-2-phenyl-4-oxazolidinone)phenyl]pentyl] -1,3-dioxolane (3.8 g, 75%) which was recrystallized from a mixture of ethyl acetate - hexane, which gave colorless needle crystals, so pl. 81 - 82oC.

REFERENCE EXAMPLE 49

Essentially, the same as in reference example 48, the reaction product obtained in the result of the interaction [2-(1,3-dioxolane-2-yl)ethyl]triphenylphosphonium bromide with 3-methoxy-4-(5-methyl-2-phenyl-4-oxaliletoh) benzaldehyde, was subjected to catalytic hydrogenation, resulting in a received 2-[3-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)propyl-1,3-dioxolane, which is recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 74 - 75oC.

REFERENCE EXAMPLE 50

To a suspension of (5-ethoxycarbonylphenyl) triphenylphosphorane (3.0 g) in tetrahydrofuran (THF) (70 ml) was added dropwise in the jets of nitrogen at -30oC hexane solution of n-utility (1.6 M, 3.9 ml). The mixture was stirred for 30 minutes is polymethoxy)benzaldehyde (1.0 g) in tetrahydrofuran (THF) (10 ml). The resulting mixture was stirred 4 hours at a temperature in the range from 50 to 60oC. Then the reaction mixture was poured into water and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove away the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (2:4), received ethyl-7-[3 - methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] heptanoate (9.7 g, 85%) as an oily product

NMR ( M. D. in CDCl3): 1,25-1,75 (11H, m) to 2.29 (2H, t, J=7.5 Hz), 2.40 a (3H, s) to 2.55 (2H, t, J=7.5 Hz), 3,86 (3H, s), of 4.12 (2H, q, J=7,1 Hz), to 5.03 (2H, c), 6,65 to 6.75 (2H, m), to 6.95 (1H, d, J=8 Hz), 7,38-7,51 (3H, m), 7,95-of 8.00 (2H, m).

REFERENCE EXAMPLE 51

A solution of ethyl-7-[3-methoxy-4-(5-methyl-2 - phenyl-4-oxazolidinone)phenyl] heptanoate (9.6 g) in tetrahydrofuran (THF) (50 ml) was added dropwise at room temperature to a suspension of sociallyengaged (0.96 g) in tetrahydrofuran (THF) (50 ml). The mixture was stirred for 30 minutes at room temperature, then added to it water (6 ml) under cooling with ice. Was filtered, the insoluble materials and the filtrate was concentrated. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya mixture establishfemale from a mixture of chloroform-diethyl ether, that gave colorless needle crystals, so pl. 78 - 79oC.

REFERENCE EXAMPLE 52

A solution of dimethyl sulfoxide (DMSO) (4 g) in dichloromethane (10 ml) was added dropwise at a temperature in the range from -60 to -50oC to a solution of oxalicacid (CDCl2) (2.9 g) in dichloromethane (100 ml). The mixture was stirred 10 minutes at the same temperature, and then thereto was added dropwise a solution of 7-[3-methoxy-4-(5-methyl-2-phenyl-4 - oxazolidinone)-phenyl]heptanol (4.3 g) in dichloromethane (15 ml). The mixture was stirred for 30 minutes at 0oC and added to it dropwise at -20oC triethylamine (10.6 g). Stirred the mixture for another 30 minutes at the same temperature. Poured the reaction mixture into water and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove away the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:3), obtained 7-[3-methoxy-4-(5-methyl-2 - phenyl-4-oxazolidinone)phenyl] heptanal, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 64 - 65oC.

REFERENCE EXAMPLE 53

A mixture of 7-[3-methoxy-4-(5-and toluene (50 ml) was stirred for 4 hours while heating under reflux. The reaction mixture was cooled, then washed with water and dried (MgSO4), and then drove away the solvent under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1: 3), was obtained 2-[6-[3-methoxy-4-(5-methyl - 2-phenyl-4-oxazolidinone)-phenyl] hexyl] -1,3-dioxolane (3,9 g, 94%) as an oily product.

NMR ( M. D. in CDCl3): 1,20-of 1.74 (10H, m), is 2.40 (3H, s) to 2.54 (2H, t, J= 7,6 Hz), 3.72 points-to 4.01 (4H, m), 3,86 (3H, s), 4,84 (1H, t, J=4,7 Hz), 5,02 (2H, s), 6,62-6,76 (2H, m), to 6.95 (1H, d, J=7.8 Hz), of 7.36-7,52 (3H, m), 7,95-8,08 (2H, m).

REFERENCE EXAMPLE 54

To a solution of 3,4-deformirovannoe (8.8 g) and 5-methyl-2-phenyl-4-oxazolidinone (10.0 g) in N,N - dimethylformamide (DMF) (100 ml) was added by portions at 0oC sodium hydride (60% in oil, 2.2 g). The mixture was stirred 3 hours at room temperature. Poured the reaction mixture into ice water and acidified with 2 N. HCl. Then was filtered, the resulting crystalline precipitate, which was recrystallized from a mixture of dichloromethane-methanol, resulting in 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone) nitrobenzene (14.0 g, 81%) as colorless prismatic crystals, so pl. 155 - 156oC.

REFERENCE EXAMPLE 55

A mixture of 3-fluoro-4-(5-methyl-2-phenyl-4-ox the economic hydrogenation under a pressure of 1 atmosphere at room temperature. The catalyst was filtered and the filtrate was concentrated under reduced pressure, resulting in 3-fluoro-4-(5-methyl-2-phenyl-4 - oxazolidinone)aniline in the form of an oily product.

NMR ( M. D. in CDCl3): of 2.38 (3H, s), 3,53 (2H, Shir. C) 4,96 (2H, s), 6.35mm (1H, DDD, J=8,5, 3 and 3.1 Hz), 6,46 (1H, DD, J=12.5 and 3 Hz), 6,91 (1H, t, J=9 Hz), 7,35 is 7.5 (3H, m), 7.95 is to 8.1 (2H, m).

REFERENCE EXAMPLE 56

To a mixture of 3-fluoro-4-(5-methyl-2-phenyl-4 - oxazolidinone)-aniline (12.3 g), an aqueous solution of HBr (47%, 28.4 g) and a mixture of acetone (150 ml) and methanol (50 ml) was added dropwise at a temperature in the range from 0 to 5oC a solution of sodium nitrite (NaNO2) (3.1 g) in water (5 ml). The mixture was stirred for 25 minutes in the same temperature range and added to it the methyl acrylate (21,3 g). The mixture was heated at temperatures ranging from 30 to 35oC, then added to it the copper oxide (Cu2O) (0.05 g) in the same temperature range. The whole mixture was intensively stirred. The reaction mixture was stirred for another 30 minutes and then concentrated under reduced pressure. To the concentrate was added aqueous ammonia, and then was extracted with him ethyl acetate. The ethyl acetate layer was washed with water and then dried (MgSO4), and then drove away the solvent under reduced pressure. the n (1: 4), got 2-bromo-3-[3-fluoro-4-(5-methyl - 2-phenyl-4-oxazolidinone)phenyl]propionate (14.2 g) as an oily product.

NMR ( M. D. in CDCl3): to 2.42 (3H, s), and 3.16 (1H, DD, J=14 and 7 Hz), 3,39 (1H, DD, J= 14 and 8.5 Hz), to 3.73 (3H, s), 4,34 (1H, DD, J=8.5 and 7 Hz), of 5.05 (2H, s), 6,85-7,00 (2H, m), 7,07 (1H, t, J=8.5 Hz), 7,35 is 7.5 (3H, m), of 7.95-with 8.05 (2H, m).

REFERENCE EXAMPLE 57

A mixture of methyl 2-bromo-3-[3-fluoro-4-(5-methoxy-2-phenyl-4 - oxazolidinone)phenyl] propionate (14.1 g), 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU) (4.8 g) and toluene (150 ml) was stirred 2 hours at temperatures ranging from 80 to 90oC. the Reaction mixture was poured into 2 N. HCl and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove away the solvent under reduced pressure, resulting in methyl-3-fluoro-4-(5-methyl-2-phenyl - 4-oxazolidinone)cinnamate (10.0 g). The product was recrystallized from a mixture of dichloromethane-methanol gave colorless prism crystals, so pl. 167 - 168oC.

REFERENCE EXAMPLE 58

To a solution of methyl 3-fluoro-4-(5-methyl-2-phenyl - 4-oxazolidinone)cinnamate (9.3 g) in dichloromethane (200 ml) was added dropwise at 0oC toluene solution diisobutylaluminium (1.5 M, with 37.2 ml). The mixture was stirred 2 hours at room temperature, and then to the th dichloromethane was washed with water, was dried (MgSO4) and concentrated. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-chloroform (1:5), was obtained (E)-3- [3-fluoro-4-(2-phenyl-4-oxazolidinone)phenyl] -2-propen-1-ol (6.9 g, 80%) which was recrystallized from a mixture of dichloromethane-diisopropyl ether, resulting in colorless needle-like crystals, so pl. 134 - 135oC.

REFERENCE EXAMPLE 59

Essentially, the same as in reference example 35, (E)-3-[3-fluoro-4- (2-phenyl-4-oxazolidinone)phenyl]-2-propen-1-ol was subjected to oxidation with activated manganese dioxide and the result was 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone) cinnamaldehyde, which was recrystallized from a mixture of dichloromethane-methanol gave pale-yellow prism crystals, so pl. 133 - 134oC.

REFERENCE EXAMPLE 60

Essentially, the same as in the reference example 3 4-chloro-methyl-5-methyl-2-phenyloxazole allowed to interact with isovanillin and the result obtained 4-methoxy-3-(5-methyl - 2-phenyl-4-oxazolidinone)benzaldehyde, which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 121 - 122oC.

REFERENCE EXAMPLE 61
o
C.

REFERENCE EXAMPLE 62

Essentially, the same as in reference example 24, 4-methoxy-3- (5-methyl-2-phenyl-4-oxazolidinone)cinnamate subjected to restore diisobutylaluminium, resulting in an (E) -3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone) phenyl] -2-propen-1-ol, which was recrystallized from a mixture of ethyl acetate-diethyl ether gave pale-yellow prism crystals, so pl. 137 - 138oC.

REFERENCE EXAMPLE 63

Essentially, the same as in the reference example 35 (E)-3-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] -2-propen-1-ol was subjected to oxidation with activated manganese dioxide and the result obtained 4-methoxy-3- (5 - methyl-2-phenyl-4 - oxazolidinone) cinnamaldehyde, which was recrystallized from a mixture of ethyl acetate-diethyl ether gave pale-yellow needle crystals, so pl. 136 - 137oC.

REFERENCE EXAMPLE 64

Essentially, the same as in the reference example 13, 4-[2- (2-furyl)-5-methyl-4-oxazolidinone] -3-methoxybenzoyl-4-oxazolidinone] -3-methoxycinnamate, which is recrystallized from ethyl acetate, so pl. 142 - 143oC.

REFERENCE EXAMPLE 65

Essentially, the same as in reference example 47, ethyl - 4-[2-(2-furyl)-5-methyl-4-oxazolidinone] -3-methoxycinnamate was subjected to catalytic hydrogenation, resulting in an ethyl-3-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone]-3-methoxyphenyl]propionate, which was recrystallized from a mixture of ethyl acetate-hexane, so pl. 88 - 89oC.

REFERENCE EXAMPLE 66

To a mixture of ethyl-3-[4-[2-(2-furyl)-5 - methyl-4 - oxazolidinone]- 3-methoxyphenyl] propionate (20 g), sodium borohydride (9,8 g) and tetrahydrofuran (THF) (200 ml) was added dropwise methanol (50 ml) for 2 hours while heating under reflux. The reaction mixture was poured into water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated, resulting in 3-[4-[2-(2-furyl)-5 - methyl-4-oxazolidinone] -3-methoxyphenyl]propyl alcohol (15.5 g, 87%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 99 - 100oC.

REFERENCE EXAMPLE 67

To the mixture 3-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone]-3-methoxyphenyl] propanol (14.5 g), treati is) in ethyl acetate (10 ml). The reaction mixture was stirred for 30 minutes at the same temperature, then washed with water, dried (MgSO4) and concentrated, resulting in[3-[4-[2-(2- furyl)-5-methyl-4-oxazolidinone]-3 - methoxyphenyl] propyl] methansulfonate (16.6 g, 94%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 100 - 101oC.

REFERENCE EXAMPLE 68

The mixture[3-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl] propyl] methansulfonate (16.3 g), sodium cyanide (3.9 g) and N,N-dimethylformamide (DMF) (100 ml) was stirred for 2 hours at 80oC, then poured into water. Filtering the resulting crystalline precipitate was obtained 4-[4-[2-[2-furyl)-5-methyl-4-oxazolidinone] -3 - methoxyphenyl]butyronitrile (12.5 g, 91%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 94 - 95oC.

REFERENCE EXAMPLE 69

The mixture 4-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl] butyronitrile (30.0 g), 4 n KOH (150 ml) and 2-methoxyethanol (150 ml) was stirred for 2 hours while heating under reflux. The reaction mixture was poured into ice water and acidified with concentrated HCl. Was filtered, obrazovalis is 98%), which is recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 129 - 130oC.

REFERENCE EXAMPLE 70

The mixture 4-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone] - 3-methoxyphenyl] butane acid (106 g), isopropylidene with (58.2 g), potassium carbonate (47,3 g) and N,N - dimethylformamide (DMF) (100 ml) was stirred 4 hours at temperatures ranging from 65 to 70oC. the Reaction mixture was poured into ice water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1: 2), received isopropyl-4-[4-[2-(2-furyl)-5-methoxy-4-oxazolidinone] -3-methoxyphenyl] butanoate (107 g, 91%) which was recrystallized from a mixture of acetone-hexane, which gave colorless needle crystals, so pl. 45 - 46oC.

REFERENCE EXAMPLE 71

A solution of isopropyl-4-[4-[2-(2-furyl) -5-methyl-4-oxazolidinone] -3 - methoxyphenyl] butanoate (100 g) in a mixture of toluene (30 ml) and N,N-dimethylformamide (DMF) (30 ml) was added dropwise at 100oC to the mixture of diisopropylaniline (84,3 g), sodium hydride (60% in oil, 11.6 g) and a mixture of toluene (300 ml) and N, N-demodu - 2 N. HCl and ethyl acetate. The separated ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was dissolved in a mixture of dimethyl sulfoxide (DMSO) (400 ml), water (40 ml) and the resulting solution was added sodium chloride (14.1 g). The mixture was stirred for 10 hours at 120oC. the Reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was dissolved in a mixture of tetrahydrofuran (100 ml) and isopropanol (200 ml) and the resulting solution was added to portions of borohydride sodium (NaBH4) (1,83 g) under cooling with ice. The reaction mixture was stirred for 90 minutes at 0oC, after which it was poured into ice water and acidified 2 N. HCl and then was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:2), received isopropyl-()-5-[4-[2-(2-furyl)-5-methyl - 4-oxazolidinone] -3-methoxyphenyl] -2-hydroxypentanal (35.1 g, 33%) which was recrystallized from a mixture of ethyl acetate - hexane, which gave colorless prism crystals, so pl. 75 - 76oC.

is alimetari] -3-methoxyphenyl] -2-hydroxypentanal (33,0 g), LIP-301 [fixed lipase derived from Pseudomonas sp., TOYOBO CO. , LTD] (16.5 g), molecular sieve 4A (33 g), toluene (1650 ml) and vinyl acetate (158 ml). The mixture was stirred 4 hours at 23oC. the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the faction, elyuirovaniya diisopropyl ether, received isopropyl-(R)- (+)-2-acetoxy-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl]pentanoate (15.9 g). Chiral analysis of this compound by HPLC showed 96% EE.

NMR ( M. D. in CDCl3): to 1.22 (3H, d, J=6 Hz), of 1.26 (3H, d, 7=6 Hz), 1,6-of 1.95 (4H, m) to 2.13 (3H, s), is 2.40 (3H, s) at 2.59 (2H, t, J=8 Hz), 3,86 (3H, s), of 4.95 (1H, T. J=6 Hz), 4.95 points - of 5.15 (2H, m), of 5.03 (2H, s), of 6.52 (1H, DD, J= 3.5 and 2 Hz), 6,65 to 6.75 (2H, m), the 6.9 to 7.0 (2H, m), 7,53 (1H, DD, J=2 and 1 Hz). []D+12,4o(c=2,0, 2-propanol).

From the faction, elyuirovaniya in the future, got isopropyl-(S)-(-)- 5-[4-[2-(2-furyl)-5 - methyl-4-oxazolidinone]- 3-methoxyphenyl]- 2-hydroxypentanal (19.7 g). Chiral analysis of this compound by HPLC showed 89% EE.

REFERENCE EXAMPLE 73

A 3-liter flask was sequentially loaded isopropyl-(S)-(-)-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl]-2-hydroxypentanal (19,7 g) obtained in reference example 72, LIP-30 is setat (158 ml). The mixture was stirred 4 hours at 23oC. the Reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel Of the fractions, elyuirovaniya diisopropyl ether, received isopropyl-(S)-(-)-5-[4-[2-(2- furyl)-5-methyl-4-oxazolidinone]-3-methoxyphenyl]-2 - hydroxypentanal (13,9 g). Chiral analysis of this compound by HPLC showed 98% EE. Recrystallization of this product from 2-propanol gave colorless prism crystals, so pl. 90 - 91oC.

[]D-2,35o(c=2,0, 2-propanol)

REFERENCE EXAMPLE 74

Isopropyl-(R)-(+)- 2-acetoxy-5- [4-[2-(2-furyl)-5-methyl - 4-oxazolidinone] - 3-methoxyphenyl] pentanoate (4.87 g) was dissolved in methanol HCl solution (5%, 100 ml) and the resulting solution was stirred 12 hours at room temperature. The solution was poured into water and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:1), was obtained methyl(R)-(-)-5- [4-[2-(2-furyl)-5 - methyl-4 - oxazolidinone]- 3-methoxyphenyl]- 2-hydroxypentanal (3.2 g, 77%), which is precrystallization.

[]D-3,08o(c=1,0, CHCl3).

REFERENCE EXAMPLE 75

Isopropyl-(S)- (-)-5-[4-[2-(2- furyl)-5-methyl - 4-oxazolidinone]- 3-methoxyphenyl] -2 - hydroxypentanal (3.55 g) was dissolved in methanol HCl solution (5%, 100 ml). The resulting solution was stirred for 10 hours at room temperature, then was poured into water and was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:1), was obtained methyl(S)-(+)-5- [4-[2-(2-furyl)-5-methyl-4-oxazolidinone] -3-methoxyphenyl] - 2-hydroxypentanal (3.03 g, 91%). Recrystallization from a mixture of ethyl acetate-hexane gave colorless prism crystals, so pl. 80 - 81oC.

[]D3,03o(c=1,0, CHCl3).

REFERENCE EXAMPLE 76

To a solution of methyl-(R)-(-)-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl] -2-hydroxydecanoate (3.15 g) in pyridine (50 ml) was added 4-nitrophenylphosphate (2.3 g) in limited quantities at room temperature. The mixture was stirred for one hour. The reaction mixture was poured into water, acidified 2 N. HCl and then was extracted with ethyl acetate. The ethyl acetate layer about the Le. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:2), was obtained methyl(R)-(+) -5-[4-[2-(2-furyl)-5-methyl - 4-oxazolidinone] -3-methoxyphenyl] -2-(4-nitrophenoxy - carbonyloxy)pentanoate (4.3 g, 98%).

NMR ( M. D. in CDCl3: 1,7-of 2.05 (4H, m), is 2.41 (3H, s), 2.63 in (2H, t, J=7 Hz), 3,81 (3H, s), a 3.87 (3H, s), of 5.03 (2H, s); of 5.06 (1H, t, J=6 Hz), 6,53 (1H, DD, J=3.5 and 2 Hz), 6,65 to 6.75 (2H, m), the 6.9 to 7.0 (2H, m), 7,41 (2H, d, J= 9 Hz), 7,54 (1H, DD, J=2 and 1 Hz), 8,29 (2H, d, J=9 Hz).

[]D+8,06o(C=1,0, CHCl3).

REFERENCE EXAMPLE 77

Essentially, the same as in the reference example 76, of methyl-(S)-(+)-5-[4- [2-(2-furyl)-5-methyl - 4 - oxazolidinone]-3 - methoxyphenyl]- 2-hydroxydecanoate received methyl-(S)-(-)-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl]-2-(4-nitrobenzeneboronic) pentanoate.

[]D8,09o(c=1.0 in CHCl3)

REFERENCE EXAMPLE 78

In tetrahydrofuran (THF) (80 ml) solution of methyl-(R)-(+)-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3-methoxyphenyl]-2-(4 - nitrobenzeneboronic)pentanoate was injected ammonia (gas) for 10 minutes at a temperature ranging from -65oto -70oC. the Reaction mixture was poured into a mixture of water - 6 N. HCl and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The remainder of the paragraph is taught methyl-(R)-(+)-2 - carbamoylated-5-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone] - 3-methoxyphenyl]pentanoate (3.0 g, 89%) which was recrystallized from a mixture of acetone-diisopropyl ether gave colorless needle crystals, so pl. 110 - 111oC []D5,30o(c=1,0, CH3OH).

REFERENCE EXAMPLE 79

Essentially, the same as in the reference example 78, of methyl-(S)- (-)-5-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone] -3 - methoxyphenyl]- 2-(4-nitrobenzeneboronic) pentanoate received methyl-(S)-2-carbamoylated-5-[4-[2-(2-furyl)-5 - methyl-4 - oxazolidinone]-3-methoxyphenyl]pentanoate, which is recrystallized from a mixture of acetone-diisopropyl ether gave colorless needle crystals, so pl. 110 - 111oCo. []D-5,41o(C=1,0, CH3OH)

REFERENCE EXAMPLE 80

To a mixture of (1,3-dioxolane-2-ylmethyl)triphenylphosphonium bromide (a 10.74 g) and tetrahydrofuran (110 ml) was added dropwise at -15oC a solution of n-utility in hexane (1.6 M, the 15.6 ml). The mixture was stirred for 1 hour at the same temperature was added 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde (6,74 g). After stirring for 4 hours at 50oC the reaction mixture was poured into ice water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed successively HCl 0.1 N.,lenity product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1: 2, o/o), received 2-[2-[3-methoxy - 4- (5-methyl-2-phenyl-4-oxazolidinone)phenyl] vinyl] -1,3-dioxolane (4,84 g) as an oily product. This oily product (4,84 g) was dissolved in tetrahydrofuran (90 ml). To the solution was added palladium on coal (5%, 50% RH., 1.8 g) and the resulting mixture was subjected to catalytic hydrogenation at room temperature under a pressure of 1 atmosphere. The catalyst was filtered and the filtrate was concentrated. The remaining oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:3, o/o), received 2-[2-[3-methoxy-4-(5 - methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl]-1,3-dioxolane (3.03 g, 37%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 90 - 91oC.

REFERENCE EXAMPLE 81

A mixture of 2-[2-[3-methoxy-4-(5 - methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl] -1,3-dioxolane (2,73 g) and an aqueous solution of acetic acid (50%, 75 ml) was stirred 3 hours at 80oC. the Reaction mixture was concentrated under reduced pressure. The residue was poured into water and podslushivaet potassium carbonate, and then was extracted with ethyl acetate. Layer etelaat-4- (5-methyl-2-phenyl-4-oxazolidinone)phenyl] Propionaldehyde (2,09 g, 86%) the Product was recrystallized from a mixture of ethyl acetate - hexane, which gave colorless needle crystals, so pl. 85 - 86oC.

REFERENCE EXAMPLE 82

A mixture of 3-[3-methoxy-4-(5-methyl-2 - phenyl-4-oxazolidinone)phenyl]Propionaldehyde (1,79 g), sodium cyanide (0.3 g), acetic anhydride (0,062 g), benzyltrimethylammonium (0,79 g), water (12 ml) and dichloromethane (35 ml) was stirred 15 hours at room temperature. Separated the organic layer and washed with water, dried (MgSO4), and then drove the solvent. The remaining oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:3, o/o), received 2-acetoxy-4-[3 - methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl] butyronitrile (2.0 g, 94%).

NMR ( M. D. in CDCl3): and 2.14 (3H, s), 2,12-2,31 (2H, m), is 2.41 (3H, s), 2,78 (2H, t, J=8 Hz), a 3.87 (3H, s), 5,04 (2H, s), 5,27 (1H, t, J=7 Hz), 6,70 (1H, DD, J=8 and 2 Hz), of 6.71 (1H, d, J=2 Hz), 7,0 (1H, d, J=9 Hz), 7,42-7,47 (3H, m), 7,99-of 8.04 (2H, m).

REFERENCE EXAMPLE 83

A mixture of 2-acetoxy-4-[3-methoxy-4-(5 - methyl-2-phenyl-4-oxazolidinone)phenyl] butoxyethyl (2.0 g), 6 N. HCl (24 ml) and dioxane (12 ml) was stirred for 4 hours while heating under reflux. The reaction mixture was poured into water and the resulting mixture was subjected ACL. In the remaining oily product was added an ethanol solution of hydrochloric acid (10%, 24 ml), after which the mixture was stirred for 1.5 hours while heating under reflux. The reaction mixture was poured into water and the resulting mixture was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and then drove the solvent. The remaining oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:2, o/o), received ethyl-2-hydroxy - 4-(4-hydroxy-3-methoxyphenyl)butanoate (0.73 g, 60%).

NMR ( M. D. in CDCl3): of 1.29 (3H, t, J=7 Hz), 1,81-2,17 (2H, m), 2,70 (2H, t, J=8 Hz), 2,84 (1H, d, J=5 Hz), 3688 (3H, s), 4,13-4,19 (1H, m), 4,22 (2H, q, J=7 Hz), of 5.50 (1H, s) 6,70 (1H, DD, J=7 and 2 Hz), at 6.84 (1H, d, J=9 Hz).

REFERENCE EXAMPLE 84

A mixture of ethyl-2-hydroxy-4-(4-hydroxy-3 - methoxyphenyl)butanoate (0.73 g), potassium cyanate (KCNO) (0.7 g) and butanol (25 ml) was stirred for 18 hours while heating under reflux. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and acidified 2 N. HCl, then was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove the solvent. The remaining oily product podewil 5-[2-(4-hydroxy-3 - methoxyphenyl)ethyl]-2,4-oxazolidinedione (0.2 g, 28%).

NMR ( M. D. in CDCl3): 2,12-of 2.16 (2H, m), 2,73-and 2.83 (2H, m) to 3.89 (3H, s), 4,80 (1H, DD, J=8 and 5 Hz), of 5.53 (1H, s) 6,70 (1H, d, J=2 Hz), 6,72 (1H, DD, J=7 and 2 Hz), 6,86 (1H, d, J=9 Hz), 8,21 (1H, Shir. C).

REFERENCE EXAMPLE 85

To a solution of 4-acetyl-4 - methyl-2-phenyloxazole (15.0 g) in ethanol (100 ml) was added by portions at 0oC borohydride sodium (1,41 g). The mixture was stirred for 1 hour at the same temperature and then for 1 hour at room temperature. The reaction mixture was poured into water and neutralized 2 N. HCl and the obtained 1-(5 - methyl - 2-phenyl-4-oxazolyl)ethanol (13,0 g, 86%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 101 - 102oC

REFERENCE EXAMPLE 86

To a mixture of 1-(5-methyl-2-phenyl-4 - oxazolyl)ethanol (5.0 g), vanillin (3.75 g), triphenylphosphine (Ph3P) (7,1 g) and tetrahydrofuran (THF) (80 ml) was added dropwise while cooling with ice diethylazodicarboxylate (DEAD) (4.71 g). The reaction mixture was stirred 8 hours at room temperature and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:4, o/o), received 3 - methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (4,48 g, is. 104 - 105oC.

REFERENCE EXAMPLE 87

Essentially, the same as in the reference example 13, 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzaldehyde was administered in cooperation with triethylphosphate and as a result received ethyl-3-methoxy - 4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy] cinnamate, which was recrystallized from a mixture of acetone-diisopropyl ether gave colorless needle crystals, so pl. 121 - 122oC.

REFERENCE EXAMPLE 88

Essentially, the same as in the reference example 24 ethyl-3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]cinnamate was subjected to reaction recovery diisobutylaluminium, resulting in an (E)-3-[3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]phenyl]-2-propenyl-1-ol.

NMR ( M. D. in CDCl3): the 1.44 (1H, Shir., t, J=6.5 Hz), a 1.75 (3H, d, J=6.5 Hz), 2,28 (3H, s), 3,88 (3H, s), 4,24 is 4.35 (2H, m), lower than the 5.37 (1H, q, J=6.5 Hz), 6,23 (1H, dt, J=16 and 6 Hz), of 6.52 (1H, dt, J=16 and 1.5 Hz), 6,8-to 6.95 (3H, m), 7,35 is 7.5 (3H, m), 7,95-with 8.05 (2H, m).

REFERENCE EXAMPLE 89

Essentially, the same as in reference example 35, (E)-3-[3-methoxy-4-[1-(5-methyl-2 - phenyl-4-oxazolyl)ethoxy] phenyl] -2-propen-1-ol was subjected to oxidation with activated manganese dioxide, resulting in 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl) atkgalleria crystals, so pl. 152 - 153oC.

REFERENCE EXAMPLE 90

To a solution of 4-benzyloxy-3-methoxybenzaldehyde (46.4 g) and triethylphosphite (50,3 g) in N,N-dimethylformamide (DMF) (190 ml) was added by portions at 0oC sodium hydride (60% in oil, 8,43 g). The mixture was stirred 15 hours at room temperature and then was poured into 1 N. HCl (1 l) and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then drove the solvent. The obtained oily product was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:3, o/o), received ethyl-(E,E) -5- (-4-benzyl-hydroxy-3 - methoxyphenyl)-2,4-pentadienoic (38,3 g, 59%) which was recrystallized from a mixture of ethyl acetate-hexane, which gave pale-yellow needle crystals, so pl. 85 - 86oC

REFERENCE EXAMPLE 91

Essentially, the same as in reference example 47, ethyl-(E,E)-5-(4-benzyloxy-3-methoxyphenyl)-2,4 - pentadienoic was subjected to catalytic restoration, receiving ethyl-5-(4-hydroxy-3-methoxyphenyl)pentanoate.

NMR ( M. D. in CDCl3): a 1.25 (3H,t, J=7 Hz), 1,61-of 1.66 (4H,m), 2,32 (2H, t, J=7 Hz), of 2.56 (2H, t, J=7 Hz), 3,88 (3H, s), of 4.12 (2H, q, J=7 Hz), 5,46 (1H, s), of 6.66 (1H, DD, J= 8 and 2 Hz), 6,83 (1H, d, J= 9 Hz).

SSY is potassium (22.9 g) and N,N - dimethylformamide (DMF) (140 ml) was stirred for 15 hours at 90oC. the Reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the faction, elyuirovaniya a mixture of ethyl acetate-hexane (1:6, o/o), received ethyl-5-(4-benzyloxy-3-methoxyphenyl)pentanoate (31,64 g, 84%).

NMR ( M. D. in CDCl3): a 1.25 (3H, t, J=7 Hz), 1,61-of 1.66 (4H, m), 2,32 (2H, t, J=7 Hz), of 2.56 (2H, t, J=7 Hz), 3,88 (3H, s), of 4.12 (2H, q, J=7 Hz), 5,12 (2H, s), only 6.64 (1H, DD, J=8 and 2 Hz), 6,72 (1H, d, J=2 Hz), to 6.80 (1H, d, J=8 Hz), 7,28 - 7,47 (5H, m).

REFERENCE EXAMPLE 93

Essentially, the same as in the reference example 71 ethyl-5-(4-benzyloxy-3-methoxyphenyl) pentanoate are condensed with diethyloxalate. The product was subjected to decarboxylation reaction and then was reduced by sodium borohydride, receiving ethyl-6-(4-benzyloxy-3-methoxyphenyl)-2 - hydroxyhexanoate.

NMR ( M. D. in CDCl3): of 1.27 (3H, t, J=7 Hz), 1.43-to 1.79 (6H, m) to 2.55 (2H, t, J=8 Hz), 2,73 (1H, d, J=6 Hz), 3,88 (3H, s), 4,12-4,17 (1H, m) to 4.23 (2H, q, J=7 Hz), 5,12 (2H, s), 6,63 (1H, DD, J=8 and 2 Hz), 6,72 (1H, d, J=2 Hz), 6,79 (IH, d, J=8 Hz), 7,26-7,46 (5H, m).

REFERENCE EXAMPLE 94

Essentially, the same as in reference example 47, 5-4-(4 - benzyloxy-3-methoxyphenyl)butyl-2,4-oxazolidinedione was subjected to catalytic recovery, resulting in 5- [4- (4-hydroxy-3-methoxyphenyl)butyl]-2,4-oxazolidinedione. L. 115 - 116oC.

REFERENCE EXAMPLE 95

Essentially, the same as in the reference example 13, 4-benzyloxy-3 - ethoxybenzaldehyde was introduced in cooperation with triethylphosphate and as a result received ethyl-4-benzyloxy-3-methoxycinnamate. The product was recrystallized from a mixture of diisopropyl ether-hexane, which gave colorless needle crystals, so pl. of 74.5 - 75oC.

REFERENCE EXAMPLE 96

Essentially, the same as in reference example 47, ethyl-4-benzyloxy-3-methoxycinnamate was subjected to catalytic hydrogenation in the received ethyl-3-(3-ethoxy-4 - hydroxyphenyl) propionate.

NMR ( M. D. in CDCl3): of 1.24 (3H, t, J=7 Hz), of 1.44 (3H, t, J=7 Hz), to 2.57 (2H, t, J=7,7 Hz), 2,87 (2H, t, J=7,7 Hz), 4.09 to (2H, q, J=7 Hz), of 4.13 (2H, q, J=7 Hz), 5,54 (1H, s), 6,69 (1H, d, J=8,4 Hz), 70 (1H, s), at 6.84 (1H, d, J=8,4 Hz).

REFERENCE EXAMPLE 97

Essentially, the same as in the reference example 92, 3- (3-ethoxy-4-hydroxyphenyl) propionate was administered in cooperation with benzylbromide, resulting in the received 3-(4-benzyloxy - 3-ethoxyphenyl)propionate.

NMR ( M. D. in CDCl3): of 1.23 (3H, t, J=7 Ha) of 1.45 (3H, t, J= 7 Hz), 2,58 (2H, t, J=7,6 Hz), 2,87 (2H, t, J=7,6 Hz), 4.09 to (2H, q, J=7 Hz), of 4.12 (2H, q, J=7 Hz), 5,11 (2H, s), of 6.66 (1H, DD, J=8.3 and 1.9 Hz), 6,76 (1H, d, J=1.9 Hz), PC 6.82 (1H, d, J=8,3 Hz), 7.23 percent-to 7.61 (5H, m)

SILOC is peanut, receiving 4- (4-benzyloxy-3-ethoxyphenyl)-2-hydroxybutanoic. The product was recrystallized from a mixture of ethyl acetate-diisopropyl ether - hexane, which gave colorless needle crystals, so pl. 62 - 63oC.

REFERENCE EXAMPLE 99

Essentially, the same as in the reference example 47, 5-[2-(4-benzyloxy-3-ethoxyphenyl)ethyl]-2,4 - oxazolidinedione was subjected to catalytic hydrogenation in the received 5-[2-(4-hydroxy-3-ethoxyphenyl)ethyl]-2,4 - oxazolidinedione. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 154,5 - 155oC.

REFERENCE EXAMPLE 100

Essentially, the same as in the reference example 13, 3-benzyloxy-4-methoxybenzaldehyde was introduced in cooperation with triethylphosphate and the result obtained 4-benzyloxy-3-methoxycinnamate. The product was recrystallized from a mixture of diethyl ether-hexane, which gave colorless needle crystals, so pl. 95 - 96oC.

REFERENCE EXAMPLE 101

Essentially, the same as in reference example 47, ethyl-4-benzyloxy-3-methoxycinnamate was subjected to catalytic hydrogenation, resulting in an ethyl-3-(3-hydroxy - 4 - methoxyphenyl) propionate.

NMR ( M. D. in CDCl<, =8,2 Hz), 6,78 (1H, d, J=2 Hz).

REFERENCE EXAMPLE 102

Essentially, the same as in the reference example 92 ethyl-3-(3-hydroxy-4-methoxyphenyl) propionate was administered in cooperation with benzylbromide, resulting in an ethyl-3-(3-benzyloxy-4-methoxyphenyl)propionate. The product was recrystallized from hexane gave colorless needle crystals, so pl. 49,5 - 50,5oC.

REFERENCE EXAMPLE 103

Essentially, the same as in the reference example 93, was treated with ethyl-3-(3-benzyloxy-4 - methoxyphenyl) propionate and as a result received ethyl-4-(3 - benzyloxy-4-methoxyphenyl)-2-hydroxybutanoic. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 93 - 94oC.

REFERENCE EXAMPLE 104

Essentially, the same as in the reference example 47, 5- [2-(3-benzyloxy-4-methoxyphenyl)ethyl]-2,4-oxazolidinedione was subjected to catalytic hydrogenation, resulting in 5- [2-(3-hydroxy-4-methoxyphenyl)ethyl]-2,4-oxazolidinedione. The product was recrystallized from a mixture of diisopropyl ether - hexane, which gave colorless prism crystals, so pl. 121 - 122oC.

REFERENCE EXAMPLE 105

Essentially, the same as in the reference example 92, syringaldazine-3,5-dimethoxybenzaldehyde. The product was recrystallized from a mixture of etelaat-hexane, which gave colorless prism crystals, so pl. 65 - 66oC.

REFERENCE EXAMPLE 106

Essentially, the same as in the reference example 13, 4-benzyloxy-3,5-dimethoxybenzaldehyde was introduced in cooperation with triethylphosphate and as a result received ethyl-4-benzyloxy-3,5-dimethoxycinnamic. The product was recrystallized from a mixture of diethyl ether-hexane, which gave colorless plates, so pl. 68 - 69oC.

REFERENCE EXAMPLE 107

Essentially, the same as in the reference example 34 ethyl-4-benzyloxy-3,5-dimethoxycinnamic was subjected to catalytic hydrogenation, resulting in (E)-3-(4 - benzyloxy-3,5-acid)-2-propen-1-ol. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 72 - 73oC.

REFERENCE EXAMPLE 108

Essentially, the same as in the reference example 35 (E)- 3-(4-benzyloxy-3,5-acid)-2-propen-1-ol was subjected to oxidation with activated manganese dioxide, resulting in 4-benzyloxy-3,5-dimethoxybenzaldehyde. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless plates, so pl. 114 - 115oC.

the Eden] -2,4-oxazolidinedione was subjected to catalytic hydrogenation in the received 5-[3-(4-hydroxy-3,5-acid)propyl] -2,4 - oxazolidinedione. The product was recrystallized from a mixture of ethanol - hexane, which gave colorless prism crystals, so pl. 155 - 156oC.

REFERENCE EXAMPLE 110

Essentially, the same as in the reference example 54, 3,4-diplomarbeit was introduced in the interaction with the 2-[N-methyl-9-(2-pyridyl)amino]ethanol and the obtained 3 - fluoro-4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]nitrobenzene. The product was recrystallized from a mixture of ethyl acetate-hexane, gave the yellow prismatic crystals, so pl. 95 - 96oC.

REFERENCE EXAMPLE 111

Essentially, the same as in the reference example 55, 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl) amino] ethoxy]nitrobenzene was subjected to catalytic hydrogenation in the received 3-fluoro-4-[2-[N-methyl-N- (2-pyridyl)amino]ethoxy]aniline in the form of an oily product.

NMR ( M. D., CDCl3): 3.15 in (3H, s), 3,40-3,55 (2H, Shir.C) of 3.96 (2H, t, J= 5.4 Hz), of 4.16 (2H, t, J=5.4 Hz), 6.30-in-6,37 (1H, m), 6,41-to 6.58 (3H, m), 6.73 x-6,83 (1H, ml), 7,40-7,50 (1H, m), 8,12-8,17 (1H, m).

REFERENCE EXAMPLE 112

Essentially, the same as in reference example 56, was treated with 3-fluoro-4-[2-[N-methyl-N- (2-pyridyl) amino]ethoxy]aniline, resulting in methyl-2 - bromo-3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl) amino] ethoxy]phenyl]propionate in the form of an oily product.

NMR (who DD, J=7.0 and 8.2 Hz), of 6.49 return of 6.58 (2H, m), 6,86-of 6.96 (3H, m), 7,45 (1H, DDD, J=1,8, to 6.8 and 8.8 Hz), 8,12-8,16 (1H, m).

REFERENCE EXAMPLE 113

Essentially, the same as in the reference example 57, was treated with methyl 2-bromo-3-[3-fluoro-4-[2-[N-methyl-N-(2 - pyridyl)-amino] ethoxy] phenyl]propionate, resulting in 3-fluoro-4[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]cinnamate. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless prism crystals, so pl. 110 - 111oC.

REFERENCE EXAMPLE 114

Essentially, the same as in reference example 58, methyl-3-fluoro-4-[2-[N-methyl-N-(2 - pyridyl)amino]ethoxy]cinnamate were subjected to reduction reaction of diisobutylaluminium, resulting in an (E)-3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl) amino] ethoxy] phenyl] -2-propen-1-ol. The product was recrystallized from a mixture of ethyl acetate-hexane, which gave colorless needle crystals, so pl. 80 - 81oC.

REFERENCE EXAMPLE 115

Essentially, the same as in the reference example 35 (E)- 3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino] ethoxy]phenyl]-2 - propen-1-ol was subjected to oxidation reaction of activated manganese dioxide and the result was 3-fluoro - 4-[2-[N - methyl-N- (2-pyridyl)amino] ethoxy] cinnamaldehyde, which was recrystallized from a mixture of ethyl acetate-GLYCEMIC ACTIVITY.

The EXPERIMENTS.

1) compound.

< / BR>
Compound a: 5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone] - 3-methoxyphenyl]propyl]-2,4-oxazolidinedione

< / BR>
Compound B: 5-[3-[4-[2-(2-furyl)-5-methyl-4 - oxazolidinone]phenyl] propyl]-2,4-oxazolidinedione

2) Method (hypoglycemic activity of the tested compounds on rats)

Fattened up the male Wistar rats aged 13-15 weeks was administered orally compound at a dose of 0.1 or 0.03 mg/kg of body weight per day during the week. The blood was collected from the tail vein and separated plasma. Then the level of plasma glucose was determined enzymatically using the system latrochem-GLU(A) (latron Laboratories Inc.). Next, calculate the percentage reduction (%) level of plasma glucose in rats treated with compound compared with the level in rats that had not received them. The results are presented in table 8.

1. Derived 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkalinit group-CO-, -CH(OH) -, or-NR3- (where R3- C1-4alkyl group);

m = 0 or 1;

n = 0, 1, or 2;

A represents A C1-7the divalent aliphatic hydrocarbon residue;

R1represents hydrogen or alkyl group;

ring E represents a benzene ring having 1 or 2 substituent selected from a hydroxy-group, possibly substituted C1-4the alkyl, or halogen atom;

L and M respectively represent hydrogen or L and M may optionally be combined with each other with education connection,

or its salt.

2. Connection on p. 1, where the formula

< / BR>
is the formula

< / BR>
where R2represents optionally substituted C1-4the alkyl of the hydroxy-group or halogen atom.

3. Connection on p. 1, where the formula

< / BR>
is the formula

< / BR>
4. Connection on p. 3, where n = 0 or 1; A - C1-4divalent saturated hydrocarbon residue; L and M respectively the hydrogen and R2is a halogen atom or C1-4alkoxygroup.

5. Connection on p. 4, where A is-CH2CH2-.

6. Connection on p. 4, where R represents a pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 atom AZ is 10 alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine.

7. Connection on p. 4, where R is oxazolidinyl group, possibly substituted by phenyl, naphthyl, C1-10the alkyl, stillam, ventilation, C1-4alkoxygroup, fullam, tanila or afteraction.

8. Connection on p. 4, where R is oxazolidinyl group, optionally substituted by phenyl, naphthyl, fullam, tanila or C1-3alkyl group.

9. Connection on p. 2, where Y represents-CO-, n = 0, A - C1-4divalent saturated aliphatic hydrocarbon residue; L and M respectively the hydrogen.

10. Connection on p. 9, where A represents A-CH2- or-CH2CH2-.

11. Connection on p. 2, where R2represents a hydroxyl group, possibly substituted C1-4the alkyl.

12. Connection on p. 11, where R2represents C1-4alkoxygroup.

13. Connection on p. 1, which is (R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione.

14. Connection on p. 1, which is 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]propyl]-2,4-oxazolidinedione.

16. Connection on p. 1, which is 5-[3-[3,5-dimethoxy-4-[2-[(E)-styryl] -4-oxazolidinone]phenyl]propyl]-2,4-oxazolidinedione.

17. Pharmaceutical composition, characterized in that it contains as an active ingredient derived 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine;

Y represents a group-CO-, -CH(OH) -, or-NR3- (where R3- C1-4alkyl group);

m = 0 or 1;

n = 0, 1, or 2;

A represents A C1-7the divalent aliphatic hydrocarbon residue;

R1represents hydrogen or alkyl group;

ring E represents a benzene ring having 1 or 2 substituent selected from a hydroxy-group, possibly substituted C1-4the alkyl, or halogen atom;

L and M respectively represent hydrogen or L and M may optionally be combined with each other with the way the .17, characterized in that the composition is to reduce the level of blood sugar.

19. The pharmaceutical composition under item 17, characterized in that the composition is to reduce the content of lipid in the blood.

20. The pharmaceutical composition under item 17, characterized in that it is a therapeutic remedy for diabetes.

21. The pharmaceutical composition under item 17, characterized in that it is a therapeutic remedy for hyperlipidemia.

22. The method of obtaining the derivative of 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine;

Y represents a group-CO-, -CH(OH) -, or-NR3- (where R3- C1-4alkyl group);

m = 0 or 1;

n = 0, 1, or 2;

A represents A C1-7the divalent aliphatic hydrocarbon residue;

R1represents hydrogen or alkylen PPI, possibly substituted C1-4the alkyl, or halogen atom,

characterized in that interact compounds represented by the General formula

< / BR>
where Z is hydrogen, a lower alkyl group or Uralkaliy, and other symbols represent the same as above,

with an alkali metal cyanate, followed by acidification.

23. The method of obtaining the derivative of 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine;

Y represents a group-CO-, -CH(OH) -, or-NR3- (where R3- C1-4alkyl group);

m = 0 or 1;

n = 0, 1, or 2;

A1represents C1-7divalent saturated aliphatic hydrocarbon residue;

R1represents hydrogen or alkyl group;

ring E represents a benzene ring having 1 or 2 substituent selected from hydrox zestawienie formula

< / BR>
where A represents A C1-7the divalent aliphatic hydrocarbon residue, and other symbols represent the same as above,

subjected to recovery.

24. The method of obtaining the derivative of 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine;

m = 0 or 1;

A represents A C1-7the divalent aliphatic hydrocarbon residue;

ring E represents a benzene ring having 1 or 2 substituent selected from a hydroxy-group, possibly substituted C1-4the alkyl, or halogen atom;

L and M respectively represent hydrogen or L and M may optionally be combined with each other with education connection,

characterized in that interact compounds represented by formula

< / BR>
where the symbols mean the same as above,

with soetenga symbols mean the same, what is listed above.

25. The method of obtaining the derivative of 2,4-oxazolidinedione represented by the formula

< / BR>
where R is C1-8saturated aliphatic hydrocarbon radical, phenyl, pyridyl or 5 - to 6-membered heterocyclic group containing 1 to 2 nitrogen atom and one sulfur atom or oxygen, possibly substituted by 1 to 3 substituents selected from phenyl, naphthyl, C1-10alkyl group, sterile, phenylethyl, C1-4alkoxygroup, furil, tanila or naphthylamine;

Y represents a group-CO-, -CH(OH) -, or-NR3- (where R3- C1-4alkyl group);

m = 0 or 1;

n = 0, 1, or 2;

A represents A C1-7the divalent aliphatic hydrocarbon residue;

R1represents hydrogen or alkyl group;

ring E represents a benzene ring having 1 or 2 substituent selected from a hydroxy-group, possibly substituted C1-4the alkyl, or halogen atom,

characterized in that the compound represented by formula

< / BR>
where Z is hydrogen, a lower alkyl group or aracelio group, and other symbols represent the same as above,

subjected to cyclization.

Priorities on items and features:

02.11.94-C4-the alkyl hydroxy-group or halogen atom;

07.07.95 on PP.11 to 13, 25, where E is the specified value;

29.08.95 on PP.1 - 25, except, where E is the specified values.

 

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