Thiazolidinone compounds, methods for their preparation, method of lowering blood glucose in mammals

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds exhibiting hypoglycemic activity. The inventive thiazolidinone compounds of General formula I:

,

where

R1-C1-C5-alkyl, R2and R3-same or different and are C1-C5-alkyl, C1-C5-alkoxy, or R2and R3together form a benzene ring, R1represents a hydrogen atom, halogen or C1-C5-alkyl, R4and R5is a hydrogen atom, Y1and Y2-same or different and represent a hydrogen atom, a C1-C5-alkyl, aliphatic carboxylic acyl group having 1-7 carbon atoms, or pyridylcarbonyl group, W is a single bond or C1-C5-alkylene, Z is an atom or 1/X equivalent of a cation, where X is the charge of the cation. Proposed 2 methods of preparing compounds of formula I and a method of reducing blood sugar in mammals using these compounds. 4 C. and 17 C.p. f-crystals, 7 ill.,7 table.

The invention relates to a number of derivatives of thiazolidine, characterized by the presence along with other hydroxynonenal group or naphthohydroquinone, including antidiabetic activity, and, therefore, the invention also provides methods and compositions using these compounds for the treatment and prevention of diabetes and diabetic complications, as described in more detail. The invention also provides methods of obtaining these new compounds.

The number of known compounds in which the 5-position of thiazolidin-2,4-dinoboy group substituted attached alkoxybenzyl group. These compounds in General can be represented by the formula (A):

< / BR>
For example, in European patent publication N 8203 revealed a number of compounds of the type shown by formula (A), in which Racan be alkyl or cycloalkyl group. In European patent publication N 139421 such compounds are disclosed, in which the group, equivalent to Rain the formula (A), above, is Romanovo or similar group, and Y. Kawamatsu and other Chem. Pharm. Bull. 30, 3580-3600 (1962)) reveal a broad range of compounds of the formula (A), in which Racan present in a variety of phenyl, substituted phenyl, alkylamino, cycloalkyl, terpinolene and heterocyclic group.

They say that all of the known proizvoda, it is achieved by reducing the resistance to insulin in the peripheral system.

Currently, however, believe that the compounds of the prior art, which are closest to the compounds of the present invention are disclosed in European patent publication N 441605, because they, like the compounds according to the invention can contain hydroxynonenal group or naphthohydroquinone group, though otherwise attached in alkalinous group of the formula -(CH2)n.

Currently, discovered a number of new compounds, which in addition to the ability to reduce insulin resistance in peripheral tissues (which is the only basis protivodiabeticescoy activity of most of the compounds of the prior art), also show other types of activity, for example, as compounds of European patent publication N 441605, these compounds possess the ability to inhibit the hepatic gluconeogenesis in the liver, which is one of the causes of diabetes. These additional activities in combination with low toxicity means that the compounds according to the invention are more efficient than known compounds, and are able Leche is ucsay activity than known compounds of European patent publication N 441605.

Brief description of the invention.

Thus, the object of the invention is the provision of a range of new thiazolidinone compounds having benzohydroquinone or naphthohydroquinone group.

Another aim of the invention is to provide such compounds which have useful therapeutic activity, such as antidiabetic activity.

Other objectives and advantages will become apparent upon further description of the invention.

Accordingly, the compounds according to the invention are compounds of formula (I):

< / BR>
where:

R1represents an alkyl group having from 1 to 5 carbon atoms;

R2and R3are the same or different and each represents alkyl group having 1 to 5 carbon atoms, or alkoxy group having from 1 to 5 carbon atoms, or

R2and R3together form a benzene ring which is unsubstituted or which is substituted by at least one Deputy, selected from the group consisting of substituents A, defined below, and, when R2and Rilen group, having from 1 to 5 carbon atoms;

R4and R5both represent hydrogen atoms, or R4and R5together represent a single carbon-carbon bond (forming a double bond between two carbon atoms to which they are attached, as shown);

Y1and Y2are the same with each other or different and each represents:

a hydrogen atom,

alkyl group having from 1 to 5 carbon atoms,

Aliphatic carbocyclic acyl group having from 1 to 7 carbon atoms, or

benzoyloxy, naftolin, pyridylcarbonyl or chinainternational group, which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents A defined below;

W represents a single bond or alkilinity group having from 1 to 5 carbon atoms; and

Z represents a hydrogen atom or 1/x equivalent of a cation, where X is the charge of the cation; and

the substituents A are selected from the group consisting of alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms, and halogen atoms.

The invention is also the pharmaceutical is active compounds in a mixture with a pharmaceutically acceptable carrier or diluent, a given active compound selected from the group consisting of compounds of the formula (I) defined above.

Further, the invention provides a method of treatment or prevention of diabetes or hyperlipemia in mammals, which may be people, which includes the appointment to receive the specified mammal an effective amount of an active compound, and wherein the active compound is selected from the group consisting of compounds of the formula (I) defined above.

The invention also provides methods of making compounds according to the invention, which are described in more detail below.

In the compounds according to the invention, when R1, R2, R3, Y1, Y2or A Deputy represents an alkyl group, it may be an alkyl group with straight or branched chain, having from 1 to 5 carbon atoms, and examples include methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, petillo, neopentylene and isopentyl group. One of them we preferred alkyl groups having from 1 to 4 carbon atoms, most preferably methyl group.

When R2and R3VM is tohydrogen group), it may be unsubstituted or may have on the ring part, represented by the symbols R2and R3one or more substituents selected from the group consisting of substituents A, examples of which are given below. In addition, in this case, R1can represent a hydrogen atom, halogen or one of the alkyl groups, examples of which are outlined above. In this case, the substituents A can be selected from the group consisting of alkyl groups having from 1 to 5 carbon atoms, such as groups, examples of which are outlined above, alkoxy groups having from 1 to 5 carbon atoms.

When the resulting condensed benzene ring is substituted in the ratio of the number of deputies there are no special restrictions, except those that may be imposed by the number capable of substitution provisions or possible spatial (physical) constraints. Usually you can have from 1 to 4 substituents, although the preferred fewer, typically more preferably the presence of from 1 to 3, and still more preferably 1 or 2 substituent. We most prefer this condensed benzene ring without deputies.

When R1or Deputy And represents a halogen atom, it may be, for example, chlorine atom, fluorine or bromine, preferably chlorine atom or fluorine, and most preferably a chlorine atom.

When Y1and/or Y2represents an aliphatic carboxylic acyl group having from 1 to 7 carbon atoms, it may be a group with a straight or branched chain, and examples of such acyl groups include formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, valerino isovaleryl, pivaloyl, pentanoyl and geanology group. One of them we preferred aliphatic carboxylic acyl group, straight or branched chain, having from 2 to 4 carbon atoms, and most preferred acetyl group.

When Y1and/or Y2is necessarily substituted benzoyloxy, naftolin, pyridylcarbonyl or healingherbs is, nicotinoyl, isonicotinoyl, quinoline-2-carbonyl, quinoline-3-carbonyl and quinoline-4-carbonyl group. One of them we preferred optionally substituted benzoyloxy group or optionally substituted pyridylcarbonyl group, and most preferred nicotinell group.

W can represent a single bond or alkilinity group. When W represents alkylenes group, it may be Allenova group with a straight or branched chain, having from 1 to 5 carbon atoms. Communication alkalinous group, to which it is attached from one side to hydroxynonenal or naphthohydroquinone group, and on the other side to the oxygen atom can have the same carbon atom or from different carbon atoms. When relations are the same carbon atoms, these groups are sometimes called "alkylidene groups". However, the common or usual is to use the General term "Allenova group" to include both those groups, whose relations are one and the same carbon atom and those in which they are at different carbon atoms. Examples of such groups include methylene, ethylene, trimethylene, tetramethylene pentamethylenetetrazol and 3-methyltetrahydrofuran group, of which we prefer those alkylene group (which may be groups with straight or branched chain), having from 1 to 4 carbon atoms, and most preferred alkylene group with a straight chain having 2 or 3 carbon atoms.

Z can represent a hydrogen atom or a cation. When the cation has multiple charge, for example, 2+, then Z represents the number of equivalents of the cation, which is the appropriate charge. For example, when Z represents an alkali metal, examples of alkali metals include lithium, sodium, or potassium, and the charge carried by these metals is 1+, Z represents for each equivalent of the compound of formula (1) one equivalent of a metal. When Z represents an alkaline-earth metal, examples of such metals include calcium or barium, and the charge carried by these metals is 2+, Z represents for each equivalent of the compound of formula (1) half of the equivalent metal. When Z represents a basic amino acid, examples of such amino acids include leasing or arginine, and the charge carried by these acids is 1+, Z represents for each equivalent of the compound of formula (1), one equivalent of acid.

Preferably Z pre the tx2">

Compounds according to the invention contain at least one asymmetric carbon at the 5-position thiazolidinones rings, and depending on the nature of the groups and atoms represented by the symbols R1, R2, R3, Y1, Y2and W may contain several asymmetric carbon atoms in their molecules. They can also form optical isomers. They can also form the tautomers due to interconversion kidney group formed by the oxo groups in 2 - and 4 - positions thiazolidinone ring, a group of the formula N= C/OH/-. Although these optical isomers and tautomers are all represented here one molecular formula, the invention includes, as selected individual isomers and mixtures, including the racemates. When applied stereospecific methods of synthesis or as a source of materials used optically active compounds can be directly obtained individual isomers; on the other hand, if the result is a mixture of isomers, an individual isomers can be obtained by using conventional separation techniques.

A preferred class of compounds according to the invention are those compounds of formula (1) in which:

R1Preli different (particularly preferably, the same), and each represents alkyl group having 1 to 5 carbon atoms, or alkoxy group having from 1 to 5 carbon atoms, or R2and R3together form a benzene ring which is unsubstituted or substituted by at least one Deputy, selected from the group consisting of substituents A, defined above, and, when R2and R3together form the indicated benzene ring, R1represents a hydrogen atom, halogen atom or alkyl group having from 1 to 65 carbon atoms.

R4and R5each represents a hydrogen atom;

Y1and Y2is the same or different and each represents a hydrogen atom, methyl group, acetyl group, benzoyloxy group or nicotinoyl group;

W represents alkylenes group having from 1 to 5 carbon atoms; and

Z represents a hydrogen atom or a sodium atom.

A more preferred class of compounds of this invention are those compounds of formula (1) in which:

R1represents an alkyl group with 1-5 carbon atoms;

R2and R3are identical and each represents alkyl group having from 1 to 5 ATO is SUP> together form the indicated benzene ring, R1represents a hydrogen atom, methyl group or chlorine atom, more preferably a hydrogen atom;

R4and R5each represents a hydrogen atom;

Y1and Y2are the same or different and each represents a hydrogen atom, methyl group or acetyl group, more preferably a methyl or acetyl group;

W represents alkylenes group having from 2 to 4 carbon atoms; and

Z represents a hydrogen atom or a sodium atom.

The most preferred class of compounds of this invention are compounds of formula (1) in which:

R1, R2and R3each represents a methyl group;

Y1and Y2are the same and each represents methyl or acetyl group;

W represents ethylene or trimethylene group; and

Z represents a hydrogen atom or a sodium atom.

Specific examples of the compounds of the invention are compounds having the formulas (1-1) to (1-3), see Fig. 1, in which the substituents have the meanings given in one table.1-3, i.e., PL. 1 relates to formula (1-1), PL. 2 to the formula (1-2) and the table is achene atoms are standard internationally recognized symbols:

Ac acetyl Et ethyl

Boz benzoyl Me methyl

Bu butyl Nic nicotinoyl

Byr butyryl Ipr isopropyl

Of the compounds listed above, preferred are compounds N:

1-7. 5- 4-[3-(2,5-Dihydroxy-3,4,6-trimetilfenil)propoxy]benzyl} thiazolidine-2,4-dione;

1-14. 5-[4-(2,5-dimethoxy-3,4,6-trimethylbenzene)(benzyl] thiazolidin-2,4-dione sodium salt,

1-17. 5-{4-[3-(2,5-dimethoxy-3,4,6-trimetilfenil)propoxy]benzyl} thiazolidine-2,4-dione.

1-18. 5-{4-[3-(2,5-dimethoxy-3,4,6-trimetilfenil)propoxy]benzyl} thiazolidine-2,4-dione sodium salt;

1-20. 5-{4-[4-(2,5-dimethoxy-3,4,6-trimetilfenil)butoxy]benzyl} thiazolidine-2,4-dione sodium salt,

1-23. 5-[4-(2,5-diacetoxy-3,4,6-trimethylpentane)benzyl] thiazolidin-2,4-dione.

1-27. 5-{4-[2-(2,5 diacetoxy-3,4,6-trimetilfenil)ethoxy]benzyl} thiazolidine-2,4-dione.

1-30. Sodium salt of 5-{4-[2,5-diacetoxy-3,4,6-trimetilfenil) propoxy] benzyl}thiazolidine-2,4-dione.

1-47. 5-{4-[2-(2,3,4,5-tetrametoksi-6-were)-ethoxy]benzyl} thiazolidine-2,4-dione sodium salt.

1-49. Sodium salt 5-{4-[3-(2,3,4,5-tetrametoksi-6-were) propoxy]benzyl}thiazolidine-2,4-dione,

1-50. 5-{4-[4-(2,3,4,5-tetrametoksi-6 - were)butoxy]benzyl} thiazolidine-2,4-dione,

1-51. Sodium toxi)benzyl]thiazolidin-2,4-dione,

2-5. Sodium salt of 5 [4-(2,7-dimethoxyphenoxy)benzyl]-thiazolidine-2,4-dione,

2-12. 5-[4(2,7-dimethoxy-8-methylnaphthalene)benzyl] thiazolidin-2,4-dione,

2-14. 5-{4-[2-(2,7-dimethoxymethyl)ethoxy]benzyl} thiazolidine-2,4-dione, and

2-15. Sodium salt 5-{4- [2-(2,7-dimethoxymethyl)ethoxy]benzyl} thiazolidine-2,4-dione.

Of these preferred compounds NN 1-18, 1-27, 2-4, 2-14, and the most preferred compounds NN 1-18 m 2-14.

Compounds according to the invention can be obtained using a wide variety of processes known for this type of compounds. For example, they can be illustrated by the following methods A-H.

Method A:

Method A involves the implementation of procedures described in European patent publication N 139421 (Japanese patent application Kokai N Sh 060-51189) Japanese patent publication N He i 2-31079), details of which are included in the description for the link. The desired compound of formula (I) can be obtained by the interaction of the compounds of General formula (II):

< / BR>
(in which R1, R2, R3, Y1, Y2and W have the meanings defined above, A represents A carboxyl, alkoxycarbonyl or karbamoilnuyu group, or a group of the formula-COOM; and-haloalkaliphilic acids, used as source materials and/or in the "Reference examples" with thiourea to obtain the intermediate compounds of formula (III):

< / BR>
(in which R1, R2, R3, Y1, Y2and W have the meanings given above), and then hydrolysis of the compounds of formula (III), for example, as described in the cited patent.

Examples alkoxycarbonyl groups, which can be represented by the symbol A, include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl group. In the group of the formula-COOM M represents a metal atom such as sodium, potassium, calcium or aluminum, or equivalent cation such as ammonium ion. X represents halogen atom such as chlorine atom, bromine or iodine.

The reaction of the compound of formula (II) with thiourea is normally and preferably carried out in the presence of a solvent. On the nature of the employed solvent has no particular restrictions, provided that it does not adversely affect the reaction or on the reagents involved in the reaction and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol, atakan; ketones, such as acetone; sulfoxidov, such as dimethylsulfoxide or sulfolan; and amides, especially amides of fatty acids, such as dimethylformamide and dimethylacetamide. There are no special restrictions in terms molar ratio of the compounds of formula (II) to the thiourea, but preferably the reaction is carried out using at least a small molar excess of thiourea per mole of the compounds of formula (II). It is more preferable to use from 1 to 2 moles of thiourea per mole of the compounds of formula (II).

The reaction can be carried out in a wide range of temperatures and the precise reaction temperature is not critical for the invention and the preferred temperature may vary depending on the nature of the source material and solvent used. Usually we find it convenient to carry out the reaction at the boiling temperature of the solvent or at a temperature of from 80 to 150oC. the Time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the applied reagent and solvent. However, provided that the reaction is carried out in the preferred conditions described above, is usually sufficient period of heating it in a suitable solvent and in the presence of water and an organic acid, such as acetic acid, or mineral acids such as sulfuric or hydrochloric acid, or mineral acids such as sulfuric or hydrochloric acid. The reaction is normally and preferably carried out in the presence of a solvent. There are no special restrictions regarding the nature of the employed solvent, provided that it does not adversely affect the reaction and the reagents involved in the reaction and provided that he may at least to some extent dissolve the reagents. Examples of suitable solvents include: sulfoxidov, such as sulfolane; and alcohols, such as methanol, ethanol and etilenglikolevye ether. The amount of acid used is typically and preferably ranges from 0.1 to 10 moles, more preferably from 0.2 to 3 moles, per mole of the compounds of formula (III). Water or an aqueous solvent is added usually in large excess relative to the molar amount of the compounds of formula (III).

The reaction can occur in a wide range of temperatures, and the precise reaction temperature is not essential for the invention. Usually we find it convenient to carry out the reaction at a temperature of about 50-100oC. the Time required for the reaction may also widely fastwrites. However, provided that the reaction is carried out in the preferred conditions described above, is usually sufficient period of from several hours to several tens hours.

After hydrolysis, Y1and Y2in the compound of formula (I), each typically represents a hydrogen atom or a corresponding alkyl group. When Y1and Y2each represents an acyl group, they can remain unaffected, depending on the choice of reaction conditions.

Method B:

Method B provides for compounds of formula (I) using the procedures described in J. Med. Chem. 1538 (1991)), information about which is included in the description for details. Cm. Fig. 2.

In the above formulas, R1, R2, R3, Y1, Y2and W have the meanings defined above, and R6represents a hydrogen atom or a protective group.

In method B, the alcohol compound of the formula (IV), which is used as starting material may be obtained using procedures described, for example, in J. Am. Chem. Soc. 64, 440 (1942), J. Am. chem. soc. 94, 227 (1972)f, J. Chem. soc. Perkin Jrans. 1. 1591 (1 83), Japanese patent application Kokai N Sho 58-83698)= Japanese patent publication N Hei 1-33114), Japanese patent application Kokai N 58-17434 the stop. The desired compound of formula (VI) can then be obtained through reaction of dehydration condensation, for example, reaction, known as reaction Mitsunobu Fiesen Fieser, "Reagents for Grganic Synthesis," vol. 6, page 645, duplication Wheelie-Intersience, edition, John Wiley and sons), between the compound of formula (IV) and do not necessarily protected thiazolidinone compound of formula (V).

The reaction is normally and preferably carried out in the presence of a solvent. Regarding the nature of the employed solvent there are no particular restrictions, the only condition is that it is not detrimental to the reaction and the reagents and can dissolve the reagents, at least to some extent. Examples of suitable solvents include: aromatic hydrocarbons, such as benzene or toluene; aliphatic hydrocarbons such as hexane or hapten; ethers, such as tetrahydrofuran or dioxane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride; and sulfoxidov, such as dimethylsulfoxide. The molar ratio of compounds of formula (Iv) to the compound of formula (V) has no special meaning, but is preferred to use from 1 to 3 moles of temperature, but the precise reaction temperature is not critical for the reaction. Usually we find it convenient to carry out the reaction at a temperature of from -20 to 150oC. the Time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions described above, is usually sufficient period of from 10 minutes to several tens hours.

When the compound of the formula (VI) thus obtained has a protective group, for example trityloxy group, if necessary can be achieved by removing protection by processing the compounds of formula (VI) an organic acid, such as triperoxonane acid, giving the compound of formula (I).

The reaction is normally and preferably carried out in the presence of a solvent. There are no restrictions on the nature of the employed solvent, provided that it does not adversely affect the course of the reaction or on the reagents involved in the reaction and can dissolve at least to some extent reagents. Examples of suitable solvents include ethers, such as t the cities, such as methylenchlorid. The molar ratio triperoxonane acid to the compound of formula (VI) is preferably from 0.5:1 to a large excess.

The reaction can be carried out in a wide temperature range, but the precise reaction temperature is not critical for the invention and the preferred temperature may vary depending on the nature of the source material and solvent used. Usually we consider convenient to carry out the reaction at a temperature of from -20 to 40oC. the Time required for the reaction may also vary widely, depending on many reactors, namely the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions outlined above, is usually sufficient period of from several minutes to several tens hours.

Method C:

According to the method C, the desired compound of formula (I) can be obtained by turning the compounds of formula (IV) described in method B, the active hard-ether derivative or halogenated connection and interaction of the product with the compound of the formula (V).

In the first stage, the compounds of formula (II) prevraschaemsya conventional means or halogenated compound, such as chloride, bromide or iodide, using known means. The desired compound of formula (I) can then be obtained by the reaction of active hard-ether compound or halogenated compounds, thus obtained, with a compound of formula (V).

The reaction of the active hard-ether compound or halogenated compounds with the compound of the formula (V) is usually preferably carried out in the presence of a base, for example an inorganic base such as a carbonate of an alkali metal (e.g. sodium carbonate or potassium carbonate), or hydrooxide alkali metal (e.g. sodium hydroxide or potassium hydroxide); an alcoholate of an alkali metal, such as metalat sodium, ethylate or tert-butyl potassium, or a metal hydride such as sodium hydride, potassium hydride or lithium hydride. The reaction is usually preferably carried out in the presence of a solvent. With respect to the applicable solvent there are no particular restrictions, provided that it does not affect adversely on the reaction or on the involved reagents and can dissolve the reagents, at least to some extent. The preferred solvent used varies depending on the nature of ispolzuemuyu or xylene; ethers, such as diethyl ether, tetrahydrofuran or dimethylformamide or dimethylacetamide; organic sulfur compounds such as dimethylsulfoxide or sulfolane.

Of them preferred amides. The molar ratio of compounds of formula (V) to the base is usually from 0.5:1 to 5:1, more preferably from 1:1 to 3:1. The molar ratio of compounds of formula (V) to the active hard-efiemu or halogenated compound is usually from 0.5:1 to 4.1, more preferably from 1:1 to 3:1.

The reaction may proceed in a wide range of temperatures, and the precise reaction temperature is not critical for the invention, preferred used temperature varies depending on the nature of the source material, the base and the solvent used in the reaction. Usually we find it convenient to carry out the reaction at a temperature of 0-50oC, more preferably 5-20oC. the Time required for the reaction may also vary widely, depending on many factors, namely, the reaction temperature and the nature of the reagents and solvent. However, provided that the reaction is carried out in the preferred conditions described above, usually Dostatok, if necessary, be removed using the procedure described in Method B.

Method D:

In this method a compound of formula (1) can be obtained using the procedures described, for example, in European patent publication N 306228 (Japanese patent publication Kokan N Hei-1-131169), see Fig. 3.

In the above formulas, R1, R2, R3, Y1, Y2and W have the meanings given above.

According to this reaction scheme, the compound of formula (I) can be obtained through the condensation reaction between the aldehyde compound of the formula (VII), obtained using the procedure described in the above patent, with thiazolidin-2,4-donovin compound of formula (VIII), giving the compound of formula (Ia), which is then restored.

The alternate connection of the formula (Ia) can also be obtained from compounds of formula (X) with the appropriate choice of reaction conditions in Method E described below. Thus, the compound of formula (X) is oxidized using cerium ammonium nitrate (CAN) as described in Method E, giving benzylidene compound of formula (XI), and the product is recovered using sodium borohydride using the procedure described in Method E, giving benzile and alkylation benzylidene the compounds of formula (XII), obtained above, using conventional means, for example, using the procedure described in Method F.

This reaction sequence is illustrated in reaction scheme D, shown in Fig. 4.

In this scheme, R1, R2, R3and W have the meanings defined above, and Y3and Y4that may be the same or different from each other, each represents an alkyl group, preferably having from 1 to 5 carbon atoms, for example, also as defined above in relation to R1preferably, a methyl group.

Method E:

According to this compound of formula (I) in which Y1and Y2both represent hydrogen atoms, can be obtained by using the reaction scheme E below (see Fig. 5).

In the above formulas, R1, R2, R3, Y3, Y4and W have the meanings given above.

At the stage of EI this scheme of reactions of the compound of formula (X), where Y3and Y4each represents a lower alkyl group, preferably methyl group, is converted by oxidation using cerium ammonium nitrate in the compound of formula (XIII) with the help of the C, the details of which are included in this description for details. The oxidation reaction using cerium ammonium nitrate is normally and preferably carried out in the presence of a solvent. In regard to the nature of the employed solvent has no particular restrictions, provided that it does not adversely affect the reaction and the participating agents, and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include water; NITRILES, such as acetonitrile; ketones, such as acetone; and mixtures of any two or more of the above solvents. The amount of cerium ammonium nitrate is not particularly critical, but preferably 1-10 moles of cerium ammonium nitrate per mole of the compounds of formula (X). The reaction may proceed in a wide temperature range, not a precise reaction temperature is not critical, although the preferred temperature may vary depending on the nature of the used starting material and solvent. Usually convenient to carry out the reaction at a temperature of from -10 to 40oC. the Time required for the reaction may also vary widely, depending on many factors, and they who are conducted in preferred conditions, described above is usually sufficient period of reaction from several minutes to several tens hours.

Subsequently, the compound of formula (XIV) can be obtained from compounds of formula (XIII) with the help of recovery, for example by catalytic reduction or by using a reducing agent such as a hydride (e.g. sodium borohydride) or metal (such as zinc or iron).

If necessary, the original connection may be first oxidation using cerium ammonium nitrate, for example, as shown in reaction scheme E:

< / BR>
(in which

R1, R2, R3, Y3, Y4and W have the meanings given above, and Br represents benzyl or zameshannuu benzyl group). As an example, this method is applied to the compound of formula (XV), i.e. the compound of formula (IV), in which the hydroxyl group is protected with benzyl group, giving the compound of formula (XVI).

Method F:

This method consists in obtaining the compounds of formula (i) in which Y1and Y2each is alalou group.

In this way quinone or nattokinese connection, for example a compound of formula (XIV), which can Bergueda the acylation using conventional means, giving the connection is equivalent to the compound of formula (X), but in which the alkyl groups represented by the symbols Y3and Y4, substituted acyl groups.

This reaction can optionally be carried out at the stage of obtaining raw materials. For example, as shown in reaction scheme F, shown in Fig.6.

In the above formulas, R1, R2, R3, Y3, Y4and W have the meanings defined above; X represents a halogen atom such as chlorine atom, bromine or iodine; and Y5and Y6are the same or different and each represents an acyl group as defined for Y1and Y2.

In this reaction scheme, the compound of formula (XVII) in which Y3and Y4each represents a lower alkyl group (particularly, as described in Method E, giving the compound of formula (XVIII). Subsequently dianiline compound of formula (XX) can be obtained for use as source material by restoring the compounds of formula (XVIII) using the procedure described in method E, giving the compound of formula (XIX), and then acylation product, giving the compounds of formula (XX).

The acylation can be performed after which rmula (XIX), the compound of formula (XX) Can be obtained by restoring the compounds of formula (XVIII) using a metal, such as zinc or iron, in the presence of Alliluyeva agent such as an acid anhydride (e.g. acetic anhydride), or halogenated acyl compound (for example, acetylchloride). The reaction is normally and preferably carried out in the presence of a solvent. With respect to the applicable solvent has no particular restrictions, provided that it has no adverse effect on the reaction and the involved reagents and can dissolve the reagents, at least to some extent. Examples of suitable solvents include organic acids such as acetic acid or propionic acid; and organic bases such as pyridine.

Method G:

According to reaction scheme G of the desired compound of formula (I) for example, where Z represents a sodium atom, can be obtained in salt form, i.e., by substitution of a hydrogen atom kidney group metal atom with the cooperation of the compounds of formula (I) in which Z represents a hydrogen atom, with a suitable base using conventional means. In regard to the nature of the used grounds there are no special restrictions. Pretrieve salts of organic acids, such as 2-ethylhexanoate, sodium. The reaction is normally and preferably carried out in the presence of a solvent. On the nature of the used solvent is not restricted provided that it has no adverse effect on the reaction and the involved reagents, and can dissolve the reagents, at least to some extent. Used preferred solvents may vary depending on the nature of the used grounds and examples of solvents that can be used include lower alcohols, such as methanol or ethanol: esters such as ethyl acetate or propyl; ethers, such as tetrahydrofuran or dioxane; water; and mixtures of any two or more of the above solvents.

Salts of other metals, such as potassium or calcium, or the corresponding salts of basic amino acids or other organic bases can be prepared by the method analogous to obtain sodium salts described above.

Method H:

This method can be used to obtain compounds of formula (T) in which R2and R3together form a benzene ring, having from 1 to 4 substituents selected from the group consisting of the Deputy the Birmingham reactions H; shown in Fig.7. (in which R1, R2, R3and X have the meanings defined above).

The reaction is normally and preferably effected in the presence of a base or salt of an alkali metal (e.g. sodium salt) 5-/4-hydroxybenzyl/thiazolidin-2,4-dione of the formula (XXII). Used the base, the solvent, reaction temperature and time required for the reaction are similar to those of the method of G.

The alternate connection of the formula (XXI) may be subjected to interaction with 4-hydroxymidazolam or salt it, giving 3-halogen-2-/4-nitrophenoxy/-1,4-nattokinese) is derived, and then the product is converted to the compound of formula (II) using the procedure described in the literature for Method A. Subsequently, after the procedure of Method A compound of formula (I) can be obtained from compounds of formula (II). The reaction is carried out under the same conditions as for Method A.

After completing any of the above reactions, the desired compound can be released from the reaction mixture and, if necessary, be purified conventional techniques, for example, using a variety of chromatography techniques, such as chromatography on a column or pomosty to the reaction mixture and then the Stripping of the solvent from the extract. The residue, thus obtained, can be purified using chromatography on a column of silica gel or similar, giving the desired compound in a pure state.

In addition, when the compound obtained comprises a mixture of different isomers, these isomers may be separated using conventional separation techniques at an appropriate stage.

Biological activity

Thiazolidinone the compounds of this invention showed excellent hypoglycemic activity and a remarkable inhibitory effect against hepatic gluconeogenesis in the system tests using genetically diabetic animals. Accordingly, it is expected that the compounds of the invention are useful for the treatment and/or prevention of diabetes, diabetic complications, hyperlipidemia, hyperlipoproteinemia related to the accuracy or completeness of hypertension, osteoporosis and similar.

Compounds according to the invention can be administered in a variety of forms depending on the disorder to be treated, and the condition of the patient, as is well known in this field. For example, when connections are assumed for oral purposes, they can be transformed into f is an injection (intravenous, intramuscular or subcutaneous), drugs for drip infusion or suppositories. To accept the way through the ophthalmic mucous membrane they can be formed in the form of eye drops or ointment for the eyes. These formulation may be prepared by conventional means and, if necessary, the active ingredient can be mixed with any conventional additive, such as a carrier, a binder, disintegrator, lubricant agent, corrigent, solubilizers agent, suspension auxiliary agent, emulsifying agent or covering agent. Although the dosage varies depending on symptoms, age and body weight of the patient, nature and severity of the disease under treatment or prevention, the method of appointment and form of medicines, for the treatment of diabetes, diabetic complications and/or hyperlipemia. The adult recommended daily dose of 1 to 1000 mg of the compound, and this dose may be administered in a single dose or in separate doses.

The activity of the compounds of the present invention is illustrated by the following experiment.

Experiment.

Hypoglycemic activity.

Used experimental animals were Sino 50 mg/kg of the test compound, and then they were given the opportunity to eat freely for 18 hours At the end of this time from the tail vein without anesthesia the blood was collected. We determined the level of glucose in blood using glucose analyzer (GL 101, manufactured by Mitsubishi Cassis To.

The degree of reduction in blood glucose was calculated using the following equation:

The degree of reduction in blood glucose (5)=

[(BGLs-BGLt)/BGLs]100

where:

BGLsthe decrease in blood glucose (BGL) in the group receiving the solvent; and

BGLt-BGL group, which was appointed for receiving the test compound.

The results are shown below, where each connection according to the invention is identified by the number of connections the following examples, in which is illustrated obtaining them.

As a control, we also used the following test compounds:

5-{4-[2-methyl-2-hydroxy-4-(3,5,6-trimethyl-1,4-benzoquinone-2-yl) butoxy] benzyl}thiazolidine-2,4-dione, which is a combination of example 1, described in European patent publication N 441605). This connection is referred to as "Control 1"; and

5-{ 4-[-(2,5-dihydroxy-3,4,6-trimetilfenil)-2-hydroxy-2-methylbutoxy] benzyl} thiazolide connection is identified as "Control 2".

Connection Degree of reduction BGL (%)

The compound of example 7 24,0

The compound of example 9 28,8

The compound of example 10 46,0

The compound of example 12 24,0

The compound of example 16 20,2

The compound of example 18 22,0

The compound of example 19 26,6

The compound of example 21 33,4

The compound of example 23 24,4

The compound of example 31 32,9

The compound of example 33 28,4

The compound of example 34 40,0

Control 1 and-0.6

Control 2 10,4

As you can see from the above results, the compounds according to the invention showed much higher activity than the compound of the prior art.

Obtaining the compounds according to the invention is further illustrated by the following non-limiting examples, and various intermediate products used in these examples is illustrated in the following receipts.

Example 1. 5-[4-(2,4,5-Trimethyl-3,6-dimethoxyphenoxy)benzyl]thiazolidin-2, 4-dione (compound N 1-11).

A mixture of 5.7 g of butyl 2-bromo-3-[4-(2,4,5-trimethyl-3,6-dimethoxy-phenoxy) phenyl]propionate (obtained as described in obtaining 1); 1.2 g of thiourea and 10 ml of sulfolane was heated at 120oC for 5 h under nitrogen atmosphere, and then to the resulting mixture were added 10 ml of 2 N. water with the water, and then was extracted with benzene. The extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent was removed from the extract by distillation under reduced pressure and the residue thus obtained was purified using chromatography on a column by passing through silica gel using 9:1 by volume mixture of benzene and ethyl acetate as eluent, giving 4.7 g named the title compound as a white glazed powder, razmyagchayuschiesya at 47-50oC.

Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide) million dollars.

of 1.97 (3H, singlet)

2,11 (3H, singlet), of 2.15 (3H, singlet),

totaling 3.04 (1H, doublet of doublets, J=9 & 14 Hz),

of 3.32 (1H, doublet of doublets, J=4 and 14 Hz),

of 3.54 (3H, singlet, 3,61 (3H, singlet),

is 4.85 (1H, doublet of doublets, J=4 and 9 Hz),

6,70 (2H, doublet, J=8 Hz),

7.15m (2M, doublet, J=8 Hz).

Example 2. 5-{4-[2(2,4,5-Trimethyl-3,6-acid), ethoxy]benzyl} thiazolidine-2,4-dione (compound 1-15 N).

3.2 g of diethylazodicarboxylate was added dropwise under ice cooling and under nitrogen atmosphere to a solution of 3.5 g of 2-/2,4,5-trimethyl-3,6-acid/ethanol, 7,3 g 5-/4-hydroxybenzyl/ -3-triphenyltetrazolium-2,4-dione (obtained as described is based temperature for 5 hours At the end of this period the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent then was removed from the extract by distillation under reduced pressure and the resulting residue was purified using chromatography on a column of silica gel using a mixture of 4:1 by volume of hexane and atelocerata as eluent, giving 5-{4-[2-(2,4,5-trimethyl-3,6-acid), ethoxy] benzyl}-3-triphenyltetrazolium-2,4-dione as an oily intermediate substance. Was added 50 ml triperoxonane acid under ice cooling to 7.9 g of the intermediate product and the resulting mixture was stirred for 1 h At the end of this time the reaction mixture was diluted with water, after which it was ekstragirovanie with ethyl acetate. The extract was washed twice, each time with water saturated sodium bicarbonate solution, then removed by distillation under reduced pressure and the residue thus obtained was purified using chromatography on a column by passing through silica gel using 3:1 by volume mixture of hexane and ethyl acetate as eluent iletiler)propoxy]benzyl}thiazolidine-2,4-dione (compound 1-17 N).

8,01 g of 5-(4-hydroxybenzyl)thiazolidine-2,4-dione was added in small quantities under ice cooling to a suspension prepared by adding 80 ml of dimethylformamide to of 3.45 g of sodium hydride (as a 55 wt.) dispersion in mineral oil, which previously were washed twice with dry hexane). The resulting mixture was stirred at the same temperature for 30 min, after which the solution was added dropwise a solution of 13,73 g 3-/2,5-dimethoxy-3,4,5-trimetilfenil/propyliodide /received, as described in obtaining 15/ 20 ml of dimethylformamide. The mixture was then stirred at room temperature for 1.5 hours At the end of this period the reaction mixture was poured into 300 ml of ice and water, after which it was extracted with ethyl acetate. The extract was washed twice, each time with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent then was removed from the extract by distillation under reduced pressure, and the residue, thus obtained, was purified using chromatography on a column by passing through silica gel using the method of gradient elution using mixtures of hexane and ethyl acetate with the change from 3: 1 to 2:1 by volume in kacki-3,4,5-trimethylphenol)benzyl] thiazolidin-2,4-dione (compound N 1-1).

50 mg of sodium borohydride was added under ice cooling to a mixture of 480 mg of 5-[4 - 3,5,6-trimethyl-1,4-banthine-2-yloxy)benzyl] -thiazolidine-2,4-dione (obtained as described in obtaining 2) in 8 ml of ethanol, and the resulting mixture stirred at room temperature for 30 minutes At the end of this period the reaction mixture was poured and cooled dilute aqueous hydrochloric acid to precipitate crystals, which were collected by filtration, thus giving 470 mg of the target compound, melting at 124-130oC.

Example 5. 5-[4-(2,4,5-Trimethyl-3,6-acid)benzyl]thiazolidin-2,4-dione sodium salt (compound N 1-12).

35 mg of sodium methylate was added to a solution of 250 mg of 5-[4-(2,4,5-trimethyl-3,6-dimethoxyphenoxy)benzyl] thiazolidin-2,4-dione (obtained as described in example 1) in 2 ml of methanol. At the end of this time the solvent was removed sreaction mixture by distillation under reduced pressure, yielding 240 mg of the target compound as colorless glazed powder, melting at 120-125oC (softening point).

Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide) d million dollars.

to 1.98 (3H, singlet), 2,11 '3H, singlet), 3,61 (3H, singlet),

to 4.14 (1H, doublet of doublets, J 3 and 10 Hz),

only 6.64 (2H, doublet, J 8 Hz), 7,10 (2H, doublet, J 8 Hz).

Example 6. 5-{ 4-[2-(2,4,5-Trimethyl-3,6-acid), ethoxy] benzyl} thiazolidine-2,4-dione sodium salt (compound 1-16 N).

0.12 g of 2-ethylhexanoate sodium was added to a solution of 0.3 g 5-{ 4-[2-(2,4,5-trimethyl-3,6-acid), ethoxy] benzyl} thiazolidine-2,4-dione (obtained as described in example 2) in 10 ml of ethyl acetate, and the resulting mixture stirred at room temperature for 17 hours At the end of this period the solvent was removed from the reaction mixture by distillation under reduced pressure. The resulting crystalline residue was then washed with 10 ml mi hexane, 252 mg of the target compound, melting at 165-170oC.

Example 7. 5-[4-(2,5-Diacetoxy-3,4,6-trimethylpentane)benzyl] thiazolidin-2,4-dione (compound 1-23 N).

0.4 g of acetic anhydride and 0.3 g of pyridine was added to a solution of 340 mg of 5-[4-(2,5-dihydroxy-3,4,6-trimethylpentane)benzyl] -thiazolidine-2,4-dione (obtained as described in example 4) and 6 ml of toluene, and the resulting mixture stirred at room temperature for 3 days. At the end of this time the reaction mixture was diluted with benzene, and rubbable what I'm using distillation under reduced pressure. The resulting residue was purified using column chromatography by passing through silica gel using 4:1 by volume mixture of benzene and ethyl acetate as eluent, yielding 340 mg of the target compound, melting at 174-176oC.

Examples 8-25.Following the procedures similar to the procedures described in examples 1-7 above, we have also obtained the compounds of formula (1-4):

< / BR>
in which R2, R3, W and Z have the meanings given in table. 4. In table.4 column, "As in ex. N indicates the number of the example, the procedure is performed.

In table. 4 and 5 the following abbreviations are used:

Ac acetyl, Me is methyl,

MeO methoxy, Nic nicotinoyl,

Cpd N Connection N (from table. 1-3)

(d) the point of decomposition; and

(S) softening point

Example 26-29. Following the procedures similar to those described in examples 4, 6, and 7 above, we have also obtained the compounds of formula (1-5):

< / BR>
in which

Y1, Y2n and Z have the meanings defined for the table. 5. In this table, the column "As in the example N" indicates the number of the example, the procedure which was followed, and abbreviations shall be decoded as defined in relation to the table. 4.

Examples 30-39. Following the procedure in which

R1, Y1, Y2, n and Z have the meanings given in table.6. In table.6 column, "As in ex. N indicates the number of the example, the procedure which was followed, and abbreviations shall be decoded as specified in the relation table. 4.

Below is given the note to the table.6.

xAn NMR spectrum of the compound of example 30 (Delta mln. hexadeuterated dimethyl sulfoxide): of 2.21 (3H, singlet), to 2.55 (3H, singlet), 3,10 (1H, doublet of doublets, J 9 and 14 Hz), 3,3-3,4 (1H, not specified), 4,89 (1H, doublet of doublets, J 4 and 9 Hz), at 6.84 (2H, doublet, J 8gts), 7,21 (2H, doublet, J 8 Hz), 7,21 (2H, doublet, J 8 Hz), to 7.67 to 7.75 (2H, multiplet), of 7.95 and 8.1 (2H, multiplet), a 12.03 (1H, broad singlet).

xSpectrum of nuclear magnetic resonance compound of example 31 (Delta mln. SDS3): of 3.12 (1H, doublet of doublets, J 9 and 14 Hz), of 3.46 (1H, doublet of doublets, J 4 and 14 Hz), of 3.94 (3H, singlet), 3,98 (3H, singlet), 4,51 (1H, doublet of doublets, J 4 and 9 Hz), of 5.26 (2H, singlet), 6,87 (1H, singlet), 7,00 (2H, doublet, J 9 Hz), 7,16 (2H, doublet, J 9 Hz),7,45-7,60 (2H, multiplet), 8,08 (1H, doublet, J 8 Hz), 8,16 (1H, broad singlet), 8,24 (1H, doublet, J 9 Hz).

xRange nuclear magnetic separation of the compound of example 32 ( Delta mln. hexadeuterated dimethyl sulfoxide): a 2.71 (1H, doublet of doublets, J 10 and 14 Hz), to 3.33 (1H, doublet of doublets, J is blet, J 8 Hz), to 7.15 (2H, doublet, J 8 Hz), 7,55 (1H, doublet, J 8 Hz), to 7.61 (1H, triplet, J 8 Hz), of 8.04 (1H, doublet, J 8 Hz), 8,16 (1H, doublet, J 8 Hz).

xAn NMR spectrum of the compound of example 33 (Delta mln. SDS3: to 2.46 (3H, singlet), of 3.13 (1H,doublet of doublets, J 9 and 14 Hz), of 3.48 (1H, doublet of doublets, J 4 and 14 Hz), 3,88 (3H, singlet), of 3.95 (3H, singlet), to 4.52 (1H, doublet of doublets, J 4 and 9 Hz), 5,24 (2H, singlet), 7,03 (2H, doublet, J 9 Hz), 7,20 (2H, doublet, J 9 Hz), 7,45-7,53 (2H, multiplet), 8.07-a is 8.16 (2H, multiplet), 8,42 (1H, broad singlet).

xAn NMR spectrum of the compound of example 34 (Delta mln. SDS3): 3,10 (1H, doublet of doublets, J 14 and 9 Hz)), or 3.28 (2H, triplet, J 7 Hz), 3,44 (1H, doublet of doublets, J 14 and 4 Hz), 3,93 (3H, singlet), 3,98 (3H, singlet), 4,25 (2H, triplet, J 7 Hz), 4,49 (1H, doublet of doublets, J 9 and 4 Hz), of 6.71 (1H, singlet), to 6.88 (2H, doublet, J 9 Hz), 7,13 (2H, doublet, J 9 Hz), 7,42-7,58 (2H, multiplet), 7,99-to 8.12 (1H, broad singlet), 8,08 (1H, doublet, J 8 Hz).

xSpectrum of nuclear magnetic resonance compound of example 35 (Delta mln. hexadecacarbonyl dimethylsulfoxid): 2,63 (1H, doublet of doublets, J 10 and 14 Hz),3,20 (2H, triplet, J 7 Hz) and 3.31 (1H, doublet of doublets, J 4 and 14 Hz), 3,85 (3H, singlet), of 3.94 (3H, singlet), of 4.12 (1H, bullet of doublets, J 4 and 14 Hz), 4,25 (2H, triplet, J 7 Hz), to 6.88 (2H, doublet, J 9 Hz), to 6.95 (1H, singlet), 7,10 (2H, doublet, J 9 Hz), of 7.48 (1H triplet, J 8 Hz), EUR 7.57 (NTA million dollars.SDS3): 2,12 was 2.25 (2H, multiplet), 2,99 (2H, triplet, J 8 Hz), 3,10 (1H, doublet of doublets, J 14 and GC), of 3.45 (1H, doublet of doublets, J 14 and 4 Hz), 3,88 (3H, singlet), 3,90 (3H, singlet), to 4.01 (2H, triplet, J 6 Hz), 4,50 (1H, doublet of doublets, J 9 and 4 Hz), is 6.61 (1H singlet), 8,86 (2H, doublet, J 9 Hz), 7,14 (2H, doublet, J 9 Hz), 7,40-EUR 7.57 (2H, multiplet), 7,98-to 8.12 (1H, broad singlet), 8,02 (1H, doublet, J Hz), to 8.20 (1H, doublet, J 9 Hz).

xSpectrum of nuclear magnetic resonance compound of example 37 (Delta mln. hexadeuterated dimethyl sulfoxide): 2,05-2,14 (2H, multiplet), 2,63 (1H, doublet of doublets, J 11 and 14 Hz), only 2.91 (2H, triplet, J 8gts), and 3.31 (1H, doublet of doublets, J 4 and 14 Hz), 3,30 (3H, singlet), a 3.87 (3H, singlet), of 4.00 (2H, triplet, J 6 Hz), 4,11 (1H, doublet of doublets, J 4 and 11 Hz), to 6.80 (1H, singlet, at 6.84 (2H, doublet, J 9 Hz), 7,10 (2H, doublet, J 9 Hz), 7,46 (1H, triplet, J 8 Hz), 7,55 (1H, triplet, J 8 Hz), of 7.96 (1H, doublet, J 8 Hz), 8,10 (1H, doublet, J 8 Hz).

xAn NMR spectrum of the compound of example 38 (Delta mln. SDS3): 1,84-of 1.93 (4H, multiplet), 2,82 of 2.92 (2H, multiplet), 3,10 (1H, doublet of doublets, J 9 and 14 Hz), 3,44 (1H, doublet of doublets, J 4 and 14 Hz), 3,57 (3H, singlet), of 3.97 (3H, singlet), 3.95 to Android 4.04 (2H, multiplet), 4,50 (1H, doublet of doublets, J 4 and 9 Hz), 6,63 (1H, singlet), at 6.84 (2H,doublet, J 9 Hz), 7,12 (2H, doublet, J 9 Hz), 7,41-of 7.55 (2H, multiplet), 7,88 (1H,broad singlet), 8,02 (1H,doublet, J 9 Hz), to 8.20 (1H, doublet, J 9 G2">

1(a) 2,5-Dimethoxy-3,4,6-trimethylphenol

A solution of 9.4 g m-chlormadinone acid (70% purity) in 100 ml of methylene chloride is added dropwise under ice cooling to a solution of 4.6 g of 1,4-dimethoxy-2,3,5-trimethylbenzene in 20 ml of methylene chloride, and the resulting mixture was stirred at the same temperature for 30 min and then at room temperature for 5 hours At the end of this period the reaction mixture was filtered to 5 wt./about. aqueous solution of sodium bisulfite, 5 wt. /about. aqueous sodium bicarbonate solution and water in that order, after which it was dried over anhydrous sodium sulfate. The solvent then was removed from the reaction mixture by distillation under reduced pressure, and the resulting residue was purified using chromatography on silica gel using benzene and 50:1 by volume mixture of benzene and ethyl acetate as eluents, giving 1.3 g of the target compound.

Spectrum of nuclear magnetic resonance (CDCl3) million dollars.

a 2.12 (3H, singlet), 2,17 (6H, singlet), the 3.65 (3H, singlet), to 3.73 (3H, singlet), 5,59 (1H, singlet, disappeared when adding deuterium oxide).

1(b) 2,5-dimethoxy-3,4,6-trimethyl-1-(4-nitrophenoxy/benzene.

5.8 g of 2,5-Dimethoxy-3,4,6-trimethylphenol (obtained as op is Persii in mineral oil) in 50 ml of dimethylformamide under ice cooling, and the mixture is stirred at room temperature for 2 hours At the end of this time to the mixture was added a solution of 4.6 g of p-peritrabecular in 10 ml of dimethylformamide under ice cooling. The mixture was then stirred at room temperature for 1 h and then at 80oC for 7 hours At the end of this period the mixture was poured into water, and the resulting crude oil was extracted with benzene. The benzene extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure and the resulting oil was purified using chromatography on a column by passing through silica gel, using 4:1 by volume mixture of benzene and hexane, and then one benzene as eluent, giving 3,9 g specified in the connection header.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

of 2.08 (3H, singlet), are 2.19 (3H, singlet), of 2.23 (3H, singlet), the 3.65 (3H, singlet), 3,70 (3H, singlet), 6,89 (2H, doublet, J 9 Hz), 8,17 (2H, doublet, J 9 Hz).

1(c) 4-(2,5-Dimethoxy-3,4,6-trimethylpentane/aniline.

A mixture of 4.8 g of 2,5-dimethoxy-3,4,6-trimethyl-1-/4-nitrobenzoxazole (obtained as described in stage (b) above), 1.0 g of 10 wt./wt. palladium on coal and 100 ml of thisand the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, giving 3.9 g of the target compound.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

of 2.09 (3H, singlet), 2,17 (3H, singlet), of 2.20 (3H, singlet), 3,4 (2H, broad singlet), disappeared when adding deuterium oxide), RUB 3.674 (3H, singlet), 6,59 (2H, doublet, J 9 Hz), of 6.65 (2H, doublet, J 9 Hz).

1(D) Butyl 2-bromo-3-[2,4,6-trimethyl-3,6-dimethoxyphenoxy)-phenyl]propionate.

7,7 g 47 wt./about. aqueous solution of Hydrobromic acid and a solution of 1.3 g of sodium nitrite in 3 ml of water were added dropwise in that order to a solution of 4.3 g of 4-/2,5-dimethoxy-3,4,6-trimethylpentane/aniline/ obtained as described in stage (c) above) in 10 ml of acetone, and then to the mixture was added 21 ml of butyl acrylate. Then gradually added 0.3 g of copper bromide (2), and the resulting mixture stirred at room temperature for 4 h In the end of this period the reaction mixture was poured into water, after which it was extracted with benzene. The extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure from the extract, and the resulting residue was purified using chromatogra is TBE eluent, giving 5.7 g of the target compound.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

of 0.87 (3H, singlet), of 0.91 (3H, singlet), of 0.93 (3H, singlet), 1,2-1,4 (2H, multiplet), 1,5-of 1.65 (2H, multiplet), 2,07 (3H, singlet), 2,17 (3H, singlet), of 2.21 (3H, singlet), and 3.16 (1H, doublet of doublets, J=7 and 10 Hz), 3,39 (1H, doublet of doublets, J=9 & 14 Hz)

the 3.65 (3 H, singlet), 3,68 (3H, singlet),

of 4.11 (2H, triplet, J=7 ),

4,33 /1H, doublet of doublets, J=7 and 9 Hz),

of 6.73 (2H, doublet, J=9 Hz),

Getting 2 (J A 2 a).

5-[4-(3,5,6-trimethyl-1,4-benzoline-2-yloxy)benzyl]thiazolidin-2,4-dione.

A solution of 2.1 g of cerium ammonium nitrite in a mixture of 2 ml water and 2 ml of acetonitrile was added dropwise at 0oC to a solution of 0.4 g of 5-[4-(2,4,5-trimethyl-3,6-dimethoxyphenoxy)benzyl] thiazolidin-2,4-dione (obtained as described in example 1) in 3 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 1 h In the end of this period the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent then was removed from the extract by distillation under reduced pressure, and the residue thus obtained Ob ethyl acetate as eluent, giving 260 mg of the target compound, melting at 153-156oC (decomposition).

Getting 3 (JA 2-b).

5-{ 4-[2-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)ethoxy]benzyl} thiazolidine-2,4-dione.

Following the procedure similar to that described in the getting 2, but when using 5-{ 4-[2-(2,4,5-trimethyl-3,6-acid)-ethoxy] benzyl} thiazolidine-2,4-dione (obtained as described in example 2), was obtained target compound, melting at 157-158oC.

Getting 4 (JA 2-c).

5-{ 4-[3-(3,5,6-Trimethyl-1,4-benzophenone-2-yl)propoxy] benzyl} thiazolidine-2,4-dione.

Following a procedure similar to that described in the getting 2, but using 5-{4-[3-(2,4,5-trimethyl-3,6-acid)-propoxy]-benzyl} thiazolidine-2,4-dione (obtained as described in example 10), was obtained target compound, melting at 118-120oC (decomposition).

Getting 5 (JA 2-d).

5-{ 4-[4-(3,5,6-Trimethyl-1,4-benzoquinone-2-yl)butoxy]benzyl}thiazolidine-2,4-dione.

Following a procedure similar to that described in the getting 2, but using 5-{4-[4-(2,4,5-trimethyl-3,6-acid)-butoxy]benzyl} thiazolidine-2,4-dione (obtained as described in example II) was received by the target compound as a yellow foamy powder.


to 2.55 (2H, triplet, J=7 Hz),

3,10 (1H, doublet of doublets, J=9 & 14 Hz),

of 3.45 (1H, doublet of doublets, J=4 and 14 Hz),

of 3.96 (2H, triplet, J=6 Hz),

4,50 (1H, doublet of doublets, J=4 and 9 Hz),

6,83 (2H, doublet, J=9 Hz), 7,13 (2H, doublet, J=9 Hz),

8,24 (1H, broad signet).

Obtaining 6 (J 3).

3-Chloro-2-(4-nitrophenoxy)-1,4-naphthoquinone.

10 g of 2,3-dichloro-1,4-naphthoquinone was added to a solution of 7 g of sodium salt of p-NITROPHENOL in 100 ml of dimethylformamide, and the resulting mixture stirred at room temperature for 5 hours At the end of this period the reaction mixture was poured into water, after it was extracted with benzene. The extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent then was removed from the extract by distillation under reduced pressure, and the residue, thus obtained, was purified using chromatography on a column of silica gel using 1:4 by volume mixture of hexane and benzene as eluent, giving 10 g of target compound, melting at 179-182oC.

Getting 7 (J A 4).

Butyl 2-bromo-3-[4-(1,4-diacetoxy-3-chloro-2-naphthyloxy)phenyl]-propionate.

7(a) 3-Chloro-1,4-dihydro-2-(4-nitrophenoxy)naphthalene.

1 is obtained as described in obtaining 6) in 150 ml of methanol, and the mixture is stirred under ice cooling for 30 minutes the Mixture was then poured into a mixture of ice and 15 ml of 2 N. aqueous hydrochloric acid, giving a precipitate which was collected by filtration, rinsed with water and dried under reduced pressure in the presence of phosphorus pentoxide, yielding 9 g of 3-chloro-1,4-dihydroxy-2-/4-nitrophenoxy/naphthalene.

7 (b) 1,4-diacetoxy-3-chloro-2-/4-nitrophenoxy/naphthalene.

A mixture of 9 g of the given 3-chloro-1,4-dihydroxy-2-/4-nitrophenoxy/naphthalene (obtained as described in stage (a) (6.6 g of acetic anhydride, 7 g of pyridine and 150 ml of benzene is then stirred at room temperature for 20 h At the end of this period the reaction mixture was poured into a mixture of ice and 15 ml of 2 N. aqueous hydrochloric acid and was extracted with benzene. The extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, yielding 7.8 g of 1,4-diacetoxy-3-chloro-2-/4-nitrophenoxy/naphthalene.

Thin layer chromatography:

The Rf value of 0.40

Adsorbent: silikagelya plate N 5715 (Merck),

Manifested solvent: benzene.

7 (c) 1,4-Diacetoxy-2-/4-aminophenoxy/-3-chloro-naphthalene.

Following the procedure, the anal is higher on stage [(b)] gerasoulis in the atmosphere of hydrogen and in the presence of 1.7 g of 10% palladium on coal in 200 ml of tetrahydrofuran at room temperature for 5 h, the giving of 8.3 g of 1,4-diacetoxy-2-/4-aminophenoxy-3-chloronaphthalene in the form of an oily substance.

Thin layer chromatography:

The magnitude of the Rf 0,10

Adsorbent: silikagelya plate N 5715 (Merck);

Showing solvent: 10:0,3 by volume mixture of benzene and ethyl acetate.

7 (d) Butyl 2-bromo-3-[4-(1,4-diacetoxy-3-chloro-2-naphthyloxy)phenyl]propionate.

Following a procedure similar to that described in obtaining 1(d), 8,3 g 1,41-diacetoxy-2-/4-aminophenoxy/-3-chloro-naphthalene (obtained as described above, at the stage (c) allyoulike using 15 g of 47 wt./about. an aqueous solution of hydrochloric acid, 1.9 grams of sodium nitrate, 27 g of butyl acrylate and 0.5 g of copper bromide, yielding 5.8 g of the target compound as pale yellow oil.

Spectrum of nuclear magnetic resonance (CDCl3partial) d million dollars.

of 0.91 (3H, triplet, J=7 Hz),

3,19 (1H, doublet of doublets, J=14 and 7 Hz),

to 3.41 (1H, doublet of doublets, J=14 and 8 Hz),

4,34 (1H, doublet of doublets, J=8 and 7 Hz).

Getting 8 (JA 5).

5-[4-(3-Chloro-1,4-naphthoquinone-2-yloxy)benzyl]thiazolidin-2,4-dione.

oC for 5 h under nitrogen atmosphere. At the end of this time period, 20 ml nanometrology ether of ethylene glycol and 10 ml of 2 N. aqueous hydrochloric acid was added to the mixture in the presence of atmospheric oxygen, and the resulting mixture was heated at 100oC for 6 hours, the Reaction mixture was then poured into water, after which it was extracted with benzene. The extract was rinsed with water and dried over anhydrous magnesium sulfate. The solvent then was removed from the extract by distillation under reduced pressure and the resulting residue was purified using chromatography on a column of silica gel using 4:1 by volume mixture of benzene and ethyl acetate as eluent. Using recrystallization from a mixture of tetrahydrofuran and benzene was about 2.4 g of target compound as crystals, melting at 250-252oC.

Spectrum of nuclear magnetic resonance hexadeuterated dimethyl sulfoxide) d million dollars.

to 3.09 (1H, doublet of doublets, J=14 and 9 Hz),

3,37 (1H, doublet of doublets, J=14 and 4 Hz),

4,91 (1H, doublet of doublets, J=9 and 4 Hz),

7,13 (2H, doublet, J=8 Hz), 7,22 (2H, doublet, J=8 Hz),

the 7.85-of 7.96 (2H, multiplet), 7,98 shed 8.01 (1H, multiplet),

8,11 (1H, take the 5-(4-[3-(3,5,6-Trimethyl-1,4-benzoquinone-2 - yl)propoxy] benzyliden/thiazolidin-2,4-dione.

Following a procedure similar to that described in the getting 2, but using 15,8 g 5-{4-[3-(2,5-dimethoxy-3,4,5 - trimetilfenil)propoxy]benzyl}thiazolidine-2,4-dione (obtained as described in example 3), 78,1 g of cerium ammonium nitrate and 350 ml of acetonitrile was obtained 1.7 g of target compound, melting at 230-232oC.

Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide d million dollars.

1,80-to 1.87 (2H, multiplet), with 1.92 (3H, singlet),

of 1.94 (6H, singlet), 2,60 (2H, triplet, J=7 Hz),

Android 4.04 (2H, triplet, J=6 Hz),? 7.04 baby mortality (2H, doublet, J=9 Hz),

7,53 (2H, doublet, J=9 Hz, to 7.77 (1H, singlet),

12,49 (1H, broad singlet).

10 (JA 7).

2-/2,3,4,5-Tetrametoksi-6-were/ethanol.

10(a) 1-Allyl-2,3,4,5-tetrametoksi-6-methylbenzo.

A catalytic amount of iodine was added to a suspension of 975 mg of magnesium in 20 ml of tetrahydrofuran, and the resulting mixture was heated to approximately 45oC, giving impetus to the formation of a white turbidity. Then to the mixture was added a solution of 10,61 g 2,3,4-tetrametoksi-6-methyl-bromine benzol in 30 ml of tetrahydrofuran, after which the mixture was heated at about 45oC for several minutes. The mixture was then stirred at room temperature for 30 min, pure within 2 hours At the end of this period the reaction mixture was mixed with saturated aqueous ammonium chloride and then extracted with ethyl acetate. The solvent was removed from the extract by distillation under reduced pressure, and the residue thus obtained was purified using column chromatography on silica gel using 10: 1 by volume mixture of hexane and ethyl acetate as eluent, giving 7.98 g of target compound in the form of butter.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars. reported only the signals due to the allyl group), an estimated 3.4 (2H, multiplet), 4,85-of 5.05 (2H, multiplet), of 5.8-6.0 (1H, multiplet).

10 (b) 2-/2,3,4,5-tetrametoksi-6-were/acetaldehyde.

109 mg of camerahouse OS was added to a solution of 7.98 g of 1-allyl-2,3,4,5-thermatake-6-methylbenzo [obtained as described in stage (a) above] in a mixture of 300 ml of dioxane and 100 ml of water, and the resulting mixture stirred at room temperature for 10 minutes and Then was added dropwise an aqueous solution of 35.6 g of periodate sodium, and the mixture is stirred at room temperature for 2 hours At the end of this period the reaction mixture was freed from dioxane using vapor sodium chloride, after which it was extracted diisopropyl ether. The solvent then was removed from the extract by distillation under reduced pressure, and the resulting residue was purified using chromatography on a column over silica gel using the method of gradient elution with mixtures of hexane and ethyl acetate ranging from 8: 1 to 5:1 by volume as the eluent, giving with 4.64 g of the target compound.

Spectrum of nuclear magnetic resonance (CDCl3) (partial) d million dollars.

3,71 (2H, doublet, J=2 Hz); 9,68 (1H, triplet, J=2 Hz),

10 (c) 2-/2,3,4,5-Tetrametoksi-6-were/ethanol.

5,38 g 2-/2,3,4,5-Tetrametoksi-6-were/acetaldehyde [obtained as described in stage (b)] above was dissolved in 60 ml of ethanol and recovered using 400 mg of sodium borohydride at 0oC. Then the reaction mixture was added 150 ml of a saturated aqueous solution of sodium chloride, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and was concentrated to dryness and by evaporation under reduced pressure giving the crude product. This crude product was then purified using chromatography on a column over silica gel using meth the NTA, giving at 5.27 g of the target compound as a colourless oil.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

are 2.19 (3H, singlet); 2,90 (2H, triplet, J=7 Hz); of 3.75 (2H, triplet, J=7 Hz), of 3.78 (3H, singlet), 3,85 (3H, singlet), 3,90 (3H, singlet), 3,81 (3H, singlet).

Receipt 11 (JA 8).

1,4-Dimethoxy-2-naphthylmethyl.

11(a) Methyl 1,4-dimethoxy-2-nightout.

20.7 g of anhydrous potassium carbonate were added to a solution of 5.1 g of 1,4-dihydroxy-2-naphthoic acid in 50 ml of dimethylformamide and the resulting mixture was dropwise added 28.4 g methyl iodide, and then they were mixed for 19 hours At the end of this period the reaction mixture is poured into water and the aqueous mixture was 3h kind of balanced out. aqueous hydrochloric acid and was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified using chromatography on a column over silica gel using 10:1 by volume mixture of hexane and ethyl acetate as eluent, giving the 5.45 g of the target compound as a yellow oil.

Thin layer chromatography:

The Rf value of 0.24;

Also the Tata.

11(b) 1,4-Dimethoxy-2-naphthylmethyl.

The solution 5,32 methyl 1,4-dimethoxy-2-naphthoate (obtained as described in stage (A) above) in 15 ml of tetrahydrofuran is added dropwise to a suspension of 0.98 g of lithium aluminum hydride in 15 ml of tetrahydrofuran while cooling with ice. The resulting mixture was then stirred at room temperature for 1 h, after which was added 20 ml of a saturated aqueous solution of ammonium chloride. The formed precipitate was filtered off, and then the product was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure, giving of 3.97 g of target compound in the form of a yellow solid, melting at 63-66oC.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

to 3.92 (3H, singlet), 4,0 (3H, singlet), 4,89 (2H, singlet), PC 6.82 (1H, singlet), 7,45 to 7.6 (2H, multiplet) of 8.04 (1H, doublet, J=8 Hz); 8,23 (1H, doublet, J=9 Hz).

Receive 12 (JA 9).

2-(1,4-Dimethoxy-2-naphthyl)ethanol.

12 (a) 1,4-Dimethoxy-2-naphthylethylenediamine chloride.

The solution to 4.73 g of 1,4-dimethoxy-2-naphthylmethyl chloride (obtained as described in obtaining 20) and of 6.29 g tryptohan the and time the reaction mixture was freed from solvent by distillation under reduced pressure, and the resulting crystalline residue was washed with diethyl ether, and air dried, giving of 7.36 g of target compound in the form of a white powder, melting at 244-246oC (decomposition).

12 (b) of 1,4-Dimethoxy-2-vinylnaphthalene.

50 ml of 10% aqueous solution of sodium hydroxide was added dropwise with stirring to a mixture of 7.36 g of 1,4-dimethoxy-2-naphthylethylenediamine chloride (obtained as described in stage (a) above) and 75 ml of 30 vol./about. an aqueous solution of formaldehyde, and the resulting mixture was mixed for 1 h At the end of this period the reaction mixture was kind of balanced out 3 N. aqueous hydrochloric acid, then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified using chromatography on a column over silica gel using 24:1 by volume mixture of hexane and ethyl acetate as eluent, giving of 2.45 g of the target compound as pale yellow oil.

Thin layer chromatography:

The value of Rf0,53;

Adsorbent: silikagelya plate N 5715 (Merck);

Showing Rast g of titanium tetrachloride was added to a mixture of 0.65 g of sodium borohydride and 20 ml of dry dimethyl ether of ethylene glycol, and the resulting mixture stirred at room temperature for 1 h Then the resulting mixture was added a solution of 1.63 g of 1,4-dimethoxy-2-vinylnaphthalene (obtained as described in stage (b) above) in 40 ml of dry dimethyl ether of ethylene glycol, and the mixture is stirred for 21 hours At the end of this period the reaction mixture is poured into water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified using chromatography on a column over silica gel using 1:2 by volume mixture of hexane and ethyl acetate as eluent, giving 0.40 g of the target compound as a colourless oil.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

of 3.07 (2H, triplet, J=7 Hz), 3,91 (H, singlet),

3,93 (2H, triplet, J=7 Hz), 3,98 (H, singlet),

6,63 (1H, singlet), 7,4 7,6 (2H, multiplet),

8,02 (1H, doublet, J=8 Hz), by 8.22 (1H, doublet, J=8 Hz).

13 (JA 10).

3-(1,4-Dimethoxy-2-naphthyl)propanol.

13(a) of 1,4-Dimethoxy-2-formylation.

4,18 g dioxide magnesium was added to a solution of 0.87 is the result of a mixture stirred at room temperature for 6.5 hours At the end of this period the reaction mixture was filtered to remove inorganic substances, and the filtrate was dried over anhydrous sodium sulfate, then the solvent was removed by distillation under reduced pressure. The resulting crystalline residue was washed with hexane and dried in air, giving 0,57 g of the target compound as pale yellow needle-like crystals, melting at 120-123oC.

Thin layer chromatography:

The value of Rf: 0,44;

Adsorbent: silikagelya plate N 5715 (Merck),

Showing solvent: 4:1 by volume mixture of hexane and ethyl acetate.

13(b) Methyl TRANS-3-(1,4-dimethoxy-2-naphthyl)acrylate.

0.40 g of trimethyl phosphorazidate was added to a suspension of 0.10 g of sodium hydride (as a 55% wt./wt. dispersion in mineral oil, which was previously washed with dry hexane) in 6 ml of dimethylsulfoxide, and the resulting mixture was mixed for 20 minutes Then to the mixture was added 0,43 g 1,4-dimethoxy-2-formylation (obtained as described in stage (a) above), while cooling with ice, and the mixture is stirred for 1 h At the end of this period the reaction mixture was levelstotal was removed by distillation under reduced pressure. The residue was purified using chromatography on a column through silica gel, using 4:1 by volume mixture of hexane and ethyl acetate as eluent, giving of 0.47 g of the target compound as pale yellow oil.

Thin layer chromatography:

The value of Rf:0,42;

Adsorbent: silikagelya plate N 5715 (Merck);

Showing solvent: 4:1 by volume mixture of hexane and ethyl acetate.

13(c) Methyl 3-(1,4-dimethoxy-2-naphthyl/propionate.

of 0.47 g of methyl TRANS-3-/1,4-dimethoxy-2-naphthyl/acrylate (obtained as described in stage (b) above) was dissolved in 20 ml of methanol and gerasoulis in the atmosphere of hydrogen and in the presence of 0.20 g of 10 wt./wt. palladium on coal, giving 0,41 g of target compound as a colourless oil.

Thin layer chromatography:

The value of Rf:0,66,

Adsorbent: silikagelya plate N 5715 (Merck).

Showing solvent: 3 2 by volume mixture of hexane and ethyl acetate.

13(d) 3-/1,4-Dimethoxy-2-naphthyl/propanol

Following a similar procedure to that described in 11(b), but with the use of 0.41 g of methyl 3-/1,4-dimethoxy-2-naphthyl)propionate [obtained as described in stage (c) above] 68 mg of lithium aluminum hydride and 6 ml of tetrahydrofurans (CDCl3d million dollars.

of 1.85 to 2.0 (2H, multiplet), only 2.91 (2H, triplet, J 7 Hz),

to 3.58 (2H, triplet, J 6 Hz), 3,91 (3H, singlet),

3,98 (3H, singlet), 6,60 (1H, singlet),

of 7.4 to 7.6 (2H, multiplet), 8,01 (1H, doublet, J 8 Hz),

8,21 (1H, doublet, J 8 Hz).

Getting 14 (JA 11).

4-(1,4-dimethoxy-2-naphthyl/butanol.

14(a) 4-/1,4-Dimethoxy-2-naphthyl/butyronitrile.

The solution to 5.08 g 3-/1,4-dimethoxy-2-naphthyl/propyliodide (obtained as described in obtaining 21) and 0.70 g of sodium cyanide in 60 ml of dry dimethyl sulfoxide was mixed at 60oC (external temperature) for 80 minutes At the end of this period the reaction mixture was cooled and poured into water, then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified using chromatography on a column through silica gel, using 4:1 by volume mixture of hexane and ethyl acetate as eluent, giving 3,36 g of target compound as a colourless oil.

Thin layer chromatography:

The value of Rf:0,19,

The adsorbent, silikagelya plate N 5715 (Merck).

Showing solvent: 7 1.0 M hexane solution of diisobutylaluminium was added at -70oC to the solution to 3.36 g of 4-/1,4-dimethoxy-2-naphthyl/-butyronitrile [obtained as described in stage (a) above] in 100 ml of dry methylene chloride, and the resulting mixture was mixed for 2 hours At the end of this time water was added to the reaction mixture and the insoluble matter was filtered off using Celite (trade mark) filter. Methylenchloride layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, giving 2,96 g of target compound as a colourless oil.

Thin layer chromatography:

Value

Rf:0,19.

Adsorbent: silikagelya plate N 5715 (Merck).

Showing solvent: 7:1 by volume mixture of hexane and ethyl acetate.

14 (c) 4-(1,4-Dimethoxy-2-naphthyl)butanol.

Following the procedure similar to that described in 13(c), but using 2,96 g 4-/1,4-dimethoxy-2-naphthyl/ Butyraldehyde (obtained as described in stage (b) above), 0.87 g of sodium borohydride and 80 ml of ethanol, was obtained 2,84 g of target compound as a colourless oil.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

1,6-of 1.95 (4H, multiplet), 2,83 (blet, J=8 Hz), to 8.20 (1H, doublet, J=8 Hz).

Get 15 (JA 12).

3-(2,5-dimethoxy-3,4,6-trimetilfenil)propyl iodide 2,13 ml methanesulfonamide was added dropwise at 0oC to the mixture vs. 5.47 g of 3-(2,5-dimethoxy-3,4,6-trimetilfenil/propanol, 4.8 ml of triethylamine and 50 ml of methylene chloride, and the resulting mixture was mixed for 30 minutes At the end of this period the reaction mixture was mixed with a mixture of 50 ml of ice water and 50 ml of 10 wt. /about. aqueous hydrochloric acid. The organic layer that separated was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, the residue was dissolved in 100 ml of acetone, and the resulting mixture was added to 6.88 g of iodine sodium. The reaction mixture was then stirred at 50oC for 2 h, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of saturated aqueous sodium thiosulfate solution, after which it was extracted with ethyl acetate. The extract was freed from the solvent by column chromatography through silica compound is placed in the form of butter.

Spectrum of nuclear magnetic resonance (CDCl3d million dollars.

a 2.00 (2H, quintet, J=7 Hz), 2,17 (6H, singlet),

of 2.23 (3H, singlet) a 2.71 (2H, doublet of doublets, J=7 Hz),

of 3.27 (2H, triplet, J=7 Hz), to 3.64 (3H, singlet),

to 3.67 (3H, singlet).

Getting 16-22.

Following the procedure similar to that described in getting 15 above, the following compounds of formula (1-7):

< / BR>
(in which R1, R2, R3N and HaI have the meanings given in table.7) were obtained from the corresponding hydroxy compound by replacement of the hydroxy group of the hydroxy compound with the halogen atom shown in the table.7. Reduction decrypted, as defined in the relation table. 4. In the receive 20, 21, and 22, R2and R3together represent a group shown in their columns.

Spectrum of nuclear magnetic resonance connection of 16 million dollars. CDCl3(partly due W): of 4.66 (2H, singlet).

Spectrum of nuclear magnetic resonance receive connectors 17 d mol. the Dol. CDCl3(partly due W):

1,50-1,70 (2H, multiplet), 1,85 2,00 (2H, multiplet),

2,63 (2H, doublet of doublets, J=8 Hz),

3,24 (2H, triplet, J=7 Hz).

Spectrum of nuclear magnetic resonance receive connectors 18, d million dollars. CDCl3(partially . DCl3(partly due W)):

1,90-2,10 (2H, multiplet),

to 2.67 (2H, doublet of doublets, J=8 Hz),

3,26 (2H, triplet, J=7 Hz).

Spectrum of nuclear magnetic resonance receive connectors 20, d, million dollars. CDCl3(partly due W): 4,85 (2H, multiplet).

Spectrum of nuclear magnetic resonance receive connectors 21, d million dollars. CDCl3(partly due W):

2,22 (2H, quintet, J=7 Hz), 2,90 (2H, triplet, J=7 Hz),

3,26 (2H, triplet, J=7 Hz).

Spectrum of nuclear magnetic resonance receive connectors 22, d million dollars. CDCl3(partly due W):

to 4.92 (2H, singlet).

23.

5-/4-Hydroxybenzyl/-3-triphenylmethyl-thiazolidin-2,4-dione 23(a) -5-/4-acetoxypiperidine/thiazolidin-2,4-dione.

A mixture comprising 200 g of p-hydroxybenzaldehyde, 229 g thiazolidin-2,4-dione, 280 mg of sodium acetate and 660 m dimethylacetamide were mixed at 150oC for 1 h and Then it was cooled and the reaction mixture was added to 370 ml of acetic anhydride and 540 ml of dimethylacetamide. The resulting mixture was then stirred at 50oC for 1.5 h, after which it was poured into water. The solid which was deposited was collected by filtration, rinsed with water and dried CLASS="ptx2">

2.0 g 5-/4-acetoacetanilide (thiazolidin-2,4-dione [obtained as described above, at the stage (a)] was dissolved in 80 ml of acetic acid and gerasoulis in an atmosphere of hydrogen at atmospheric pressure at 90oC for 5 h in the presence of 2.0 g of 10 wt./wt. palladium on coal. At the end of this time the catalyst was filtered, and the filtrate was diluted with toluene. The solvent is acetic acid was then removed by distillation in the form of an azeotrope with toluene. The crystals, which were separated by adding to the concentrate of toluene and hexane, collected by filtration and dried, yielding 1.8 g named in the connection header.

23 (c) 5-/4-Acetoxybenzoic/-3-triphenylmethyl-thiazolidin-2,4-dione of 3.43 g of triethylamine was added to a solution of 9.0 g of 5-/4-acetoxybenzoic /thiazolidin-2,4-dione [obtained in stage (b) as described above] in 70 ml of methylene chloride and the resulting mixture was added dropwise a solution of 9.45 g of triphenylmethylchloride in 30 ml of methylene chloride. The mixture was then stirred at room temperature for 1 h, after which it was left to stand overnight at the same temperature. At the end of this period the reaction mixture was mixed with water and ethyl acetate, and the organic layer was separated, p is, is the quiet was separated during the distillation of the solvent under reduced pressure was washed with a mixture of hexane and ethyl acetate and dried, giving 7,86 g of target compound.

23 (d) 5-(4-Gidroksimetil/-3-triphenylmethyl-thiazolidin-2,4-dione.

The solution to 2.99 g of 28 wt./about. methanolic solution of sodium methylate in 10 ml of methanol was added dropwise with ice cooling to a solution 7,86 g 5-/4-acetoxymethyl-3-triphenylmethyl-thiazolidin-2,4-dione (obtained in stage (c), as described above) in 70 ml of toluene, and the resulting mixture stirred at room temperature for 1 h, after which it was left to stand overnight at the same temperature. The pH of the reaction mixture is then brought to 4 by adding 1N. aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was rinsed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystals which have appeared in the residue was collected, washed with hexane and dried, giving 6.0 g of the target compound.

1. Thiazolidinone compounds of General formula I

< / BR>
in which

R1an alkyl group having 1 to 5 carbon atoms;

R2and R is the STI group, having 1 to 5 carbon atoms, or R2and R3together form a benzene ring and when R2and R3together form the indicated benzene ring, R1represents a hydrogen atom, halogen, or alkyl group having 1 to 5 carbon atoms;

R4and R5hydrogen atoms;

Y1and Y2the same or different and each represents a hydrogen atom, alkyl group having 1 to 5 carbon atoms, an aliphatic carboxylic acyl group having 1 to 7 carbon atoms, or pyridylcarbonyl group;

W single bond or Allenova group having 1 to 5 carbon atoms;

Z is a hydrogen atom or 1/x equivalent of a cation, where x is the charge of the cation.

2. Connection on p. 1, in which Z represents an alkali metal.

3. Connection under item 1 or 2, in which R2and R3the same.

4. The compound according to any one of paragraphs.1 3 in which R4and R5each represents a hydrogen atom.

5. The compound according to any one of paragraphs.1 to 4, in which Y1and Y2the same and each represents a hydrogen atom, methyl group, acetyl group, or nicotinoyl group.

6. The compound according to any one of paragraphs.1 5, in which W alkylenes the atom of sodium.

8. Connection on p. 1, in which R1an alkyl group having 1 to 5 carbon atoms; R2and R3the same or different and each represents alkyl group having 1 to 5 carbon atoms, or alkoxygroup having 1 to 5 carbon atoms, or R2and R3together form a benzene ring and when R2and R3form specified benzene ring; R1a hydrogen atom, halogen atom, or an alkyl group having 1 to 5 carbon atoms; R4and R5each represents a hydrogen atom; Y1and Y2the same and each represents a hydrogen atom, methyl group, acetyl group or nicotinoyl group; W Allenova group having 1 to 5 carbon atoms; Z is a hydrogen atom or a sodium atom.

9. Connection under item 1 or 2, in which R2and R3identical and each represents alkyl group having 1 to 5 carbon atoms, or R2and R3together form a benzene ring and when R2and R3together form the indicated benzene ring, R1represents a hydrogen atom, methyl group or chlorine atom.

10. Connection on p. 9, in which R1the hydrogen atom.

11. The compound according to any one of paragraphs.1, 2, 9 and 10, in which Y1the>12. Connection on p. 11, in which Y1and Y2the same and each represents methyl or acetyl group.

13. The compound according to any one of paragraphs. 1, 2, 9 12, in which W Allenova group having 2 to 4 carbon atoms.

14. Connection on p. 1, in which R1an alkyl group having 1 to 5 carbon atoms, R2and R3identical and each represents alkyl group having 1 to 5 carbon atoms, or R2and R3together form a benzene ring and when R2and R3together form the indicated benzene ring, R1a hydrogen atom, a methyl group or a chlorine atom, R4and R5each represents a hydrogen atom, Y1and Y2the same and each represents a hydrogen atom, methyl group or acetyl group, W Allenova group having 2 to 4 carbon atoms, Z is a hydrogen atom or sodium.

15. Connection under item 1 or 2, in which R1, R2and R3each represents a methyl group.

16. Compounds according to any one of paragraphs.1, 2 and 15, in which W is ethylene or trimethylene group.

17. Connection on p. 1, in which R1, R2and R3each represents a methyl group, Y1and Y2the same and each p is sodium.

18. Connection on p. 1, representing 5-{4-[3-(2,5- dihydroxy-3,4,6-trimetilfenil)propoxy] -benzyl} -thiazolidine-2,4-dione; sodium salt of 5-{ 4-(2,5-dimethoxy-3,4,6-trimethylbenzene)benzyl} thiazolidine-2,4-dione; 5-{ 4-[3- (2,6-dimethoxy-3,4,6-trimetilfenil)propoxy]benzyl}thiazolidine-2,4 - dione; sodium salt of 5-{4-3-(2,6-dimethoxy-3,4,6-trimetilfenil)propoxy]benzyl} thiazolidine-2,4-dione; sodium salt 5-{4-[4-(2,5-dimethoxy-3,4,6-trimetilfenil)butoxy] benzyl} thiazolidine-2,4-dione; 5-[4-(2,5-diacetoxy-3,4,6-trimethylpentane)benzyl] thiazolidin-2,4-dione; 5-{4-[2-(2,5- diacetoxy-3,4,6-trimetilfenil)ethoxy]benzyl}thiazolidin-2,4-dione; sodium salt 5-{ 4-[3-(2,5-diacetoxy-3,4,6-trimetilfenil)propoxy]benzyl}thiazolidine-2,4-dione; sodium salt 5-{4-[2-(2,3,4,5-tetrametoksi-6-were)ethoxy]benzyl} thiazolidine-2,4-dione; sodium salt 5-{4-[3-(2,3,4,5-tetrametoksi-6-were)propoxy] benzyl}thiazolidine-2,4-dione; 5-{4-[4-(2,3,4,6-tetrametoksi-6-were)butoxy] benzyl} thiazolidine-2,4-dione; sodium salt 5-{4-[4-(2,3,4,5-tetrametoksi-6-were)butoxy] benzyl} thiazolidine-2,4-dione; 5-[4-(2,7-dimethoxyphenoxy)benzyl] thiazolidin-2,4-dione; sodium salt of 5-[4-(2,7-dimethoxyphenoxy)benzyl] thiazolidin-2,4-dione; 5-[4-(2,7-dimethoxy-8-methylnaphthalene) benzyl] thiazolidin-2,4-dione; 5-{the}thiazolidin-2,4-dione.

19. The way to reduce blood sugar in a mammal, comprising an introduction to the specified mammal an effective amount of an active compound, characterized in that active compound used is at least one compound of formula I according to any one of paragraphs.1 18.

20. The method of obtaining thiazolidinone compounds of General formula I on p. 1, characterized in that carry out the reaction of the compound of formula II

< / BR>
in which R1, R2, R3, Y1, Y2and W have the meanings given in paragraph 1, And carboxyl, alkoxycarbonyl or carnemolla group, or a group of the formula-SOOMA, where M is a metal atom, X is a halogen atom, with thiourea to obtain the intermediate compounds of formula III

< / BR>
in which R1, R2, R3, Y1, Y2and W have the meanings given above, and then the hydrolysis of the compounds of formula III, optionally acelerou received the product, where Y1and/or Y2is a hydrogen atom, to obtain the compounds of formula I in which Y1and/or Y2acyl group, and/or not necessarily make the product obtained in salt.

21. The method of obtaining thiazolidinone compounds of General formula I according to any one of items 1 to 18, on the1, Y2and W have the meanings given in paragraph 1, or its active complex ether or halogenated derivative with the compound of the formula V

< / BR>
in which R6a hydrogen atom or a protective group,

obtaining the compounds of formula VI

< / BR>
in which R1, R2, R3, R6, Y1, Y2and W have the meanings given above,

and, if necessary, removing the protective group; optional acelerou received the product, where Y1and/or Y2a hydrogen atom, to obtain the compounds of formula I in which Y1and/or Y2represents an acyl group; and/or not necessarily make the product obtained in the Sol.

 

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FIELD: organic chemistry, biochemistry.

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

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

FIELD: medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a solid composition eliciting with an anti-ulcer activity and to a method for its preparing. Pharmaceutical composition consists of a core containing famotidine as an active component and starch, aerosil, stearic acid salt as accessory inert substances wherein a core is covered by polymeric envelope. Core comprises glucose and stearic acid as an accessory inert substance and magnesium stearate as a stearic acid salt. Polymeric envelope comprises oxypropylmethylcellulose, propylene glycol, castor oil, talc and titanium dioxide taken in the definite ratio of all components in the composition. Method for preparing pharmaceutical composition involves preparing raw, mixing therapeutically effective amount of famotidine with glucose and starch, moistening the mixture with starch paste, granulation, drying wetted granulate, repeated granulation, powdering dry granules, tableting and applying polymeric envelope containing oxypropylmethylcellulose on prepared cores with addition of titanium dioxide, propylene glycol, castor oil and talc. Invention provides enhancement of degradability, solubility and stability in storing.

EFFECT: improved method for preparing, valuable pharmaceutical properties of composition.

3 cl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: medicine, therapy, gastroenterology.

SUBSTANCE: method involves preliminary assay of the disorder type in gallbladder motor contraction and bile-excretion ways followed by prescribing thermal low-mineralized hydrocarbonate-sodium-sulfate-calcium-magnesium mineral water in the dose by 200-300 ml, 3 times per a day, 1 h before eating, tubages № 3 with mineral water, bathes and shower with mineral water every day for 10-14 days. In the hypotonic type of motor activity method involves mineral water at temperature 25-30°C, and in the hypertonic type - at temperature 38-40°C. Method provides accelerating in scars formation of ulcers and epithelization of erosions in gastroduodenal system, to prevent frequent exacerbations and to reduce activity of Chelicobacter-induced inflammation.

EFFECT: improved therapy method.

4 tbl, 2 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention relates to treatment of diabetes mellitus in mammals. Invention proposes applying inhibitors of enzyme dipeptidyl peptidase IV as an active component in manufacturing a medicinal agent, and in a method for treatment of diabetes mellitus. Invention provides enhancing the functional activity of insulin-producing cells in animal and differentiation of epithelial cells of the pancreas.

EFFECT: improved method for insulin producing and diabetes treatment.

20 cl, 5 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmacy.

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EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: medicine.

SUBSTANCE: method involves using dipeptidyl peptidase IV (DP IV or CD 26) or DP IV-like enzyme for producing drug for treating stress or anxiety cases. Inhibitors are usable in combination with neuropeptides Y. The inhibitors are transported in physiologically compatible carriers. The inhibitors are also produced as prodrugs.

EFFECT: enhanced effectiveness of treatment.

6 cl, 11 dwg, 2 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to new polymorphous crystalline forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)-amino]-ethoxy]-benzyl]-thiazolidine-2,4-dione maleate of formula and stereomers thereof.

EFFECT: polymorphous crystalline forms of high stability.

12 cl, 1 tbl, 13 dwg, 5 ex

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