SK391691A3 - Thiazolidinedione derivatives, pharmaceutical compositions containing them and their use - Google Patents

Abstract

Thiazolidinedione derivatives of the general formula (I) are described, wherein A2 represents a group of formula (e), R1 represents a hydrogen atom, C1-6alkyl, C1-6acyl or benzyl, R2 and R3 represent hydrogen atoms or together form a single chemical bond, n is an integer from 2 to 6 and A1 represents any of the groups mentioned in the description. Furthermore, a pharmaceutical composition containing them and their use for the treatment and/or prevention of hyperglycemia or hyperlipidemia are described.

Description

Thiazolidinedione derivatives, pharmaceutical composition containing them and their use

Technical field

The invention relates to novel substituted thiazolidinedione derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the manufacture of pharmaceutical compositions. The novel compounds are suitable for reducing blood glucose concentration.

BACKGROUND OF THE INVENTION

New European patent applications 8 203, 139 421, 155 845, 177 353, 193 256, 207 581 and 208 420 disclose certain thiazolidinedione derivatives as having hypoglycemic and hypolipidemic activity. Chem. Pharm. Bull., 30, 10, 2580-3600 also relates to certain thiazolidinedione derivatives which also have a hypoglycemic and hypolipidemic effect.

SUMMARY OF THE INVENTION

It has now unexpectedly been found that some of the novel substituted thiazolidinedione derivatives have even more advantageous efficacy for lowering blood glucose concentration and are therefore suitable for use in the treatment and / or prevention of hyperglycemia, in particular for the treatment of type II diabetes.

They are also suitable for use in the treatment and / or prevention of other diseases such as hyperlipidemia, elevated blood pressure, cardiovascular diseases and certain eating and nutrition disorders.

Accordingly, the present invention provides thiazolidinedione derivatives of formula (I)

where ô

A ¹ is one of the groups of formulas a, b or c

R ⁴ and R ⁵ independently represent a hydrogen atom, an alkyl of 1 to 6 carbon atoms or together form a group of the formula d wherein:

(D)

R ⁶ and R ⁷ are each independently hydrogen, halogen or C 1 -C 6 alkyl or alkoxy,

X is an oxygen or sulfur atom,

R ¹ is H, alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms or benzyl,

R ² and R ³ are hydrogen or together form a single chemical bond,

A ² is a group of formula e

n is an integer from 2 to 6.

A preferred value for R ⁶ is a hydrogen atom and for R ⁷ a hydrogen atom.

It is preferably both R ⁶ and R ⁷ hydrogen atoms.

A preferred value for n is an integer of 2, 3 or 4, preferably 2 or 3, and especially 2.

It prefers that R ¹ is methyl.

As noted above, the compounds of Formula I may exist in one or more tautomeric forms, all of which are included in the invention. It is to be understood that the invention encompasses all isomeric forms of the compounds of formula I and their pharmaceutically acceptable salts, including any stereoisomeric forms, whether in the form of individual isomers or in the form of a mixture of isomers.

Preferred pharmaceutically acceptable salts are those formed on the thiazolidinedione group and optionally on the carboxyl group.

Suitable pharmaceutically acceptable salts formed on the thiazolidinedione group include metal salts, especially alkali metal salts such as lithium, sodium and potassium salts.

Suitable pharmaceutically acceptable salts on the carboxyl group are metal salts such as aluminum salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts as well as ammonium and substituted ammonium salts, for example salts with lower alkylamines such as triethylamine, hydroxyalkylamines such as 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, and salts with cycloalkylamines such as bicyclohexylamine or procaine, dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabietylamine, N, N-bis-dehydroabietylamine, glucamine, N-methylglucamine or pyridine-type bases such as pyridine, collidine or quinoline.

Suitable pharmaceutically acceptable derivatives are, for example, hydrates.

Compounds of formula I, their tautomeric forms and / or their pharmaceutically acceptable salts, and / or their pharmaceutically acceptable hydrates, can be obtained by reacting a compound of the general formula IIIa.

-4kde

R ² , R ³ and A ² are as defined for formula I, a

R ^a represents a group which can be converted to a group of formula f

R ¹

A ¹ - N - (CH ₂ ) _n - O (f) wherein R ¹ , A ¹ and n are as defined in formula I, with an agent capable of converting the group R ^a into a group of formula f, optionally optionally any of the following degrees:

i) converting a compound of formula I into another compound of formula I, ii) preparing a pharmaceutically acceptable salt of a compound of formula I and / or a pharmaceutically acceptable solvate thereof.

In a preferred embodiment, R ^and R ^{1 are} HN- (CH 2) n O-, wherein R ¹ and n are as defined in formula I.

In the case where R ^a is a given group, the agent capable of converting this group into a group of formula (f) is a compound of formula (IV)

A ¹ - R ^x (IV) where

A ¹ has the meaning given in formula I a

R ^x represents an easily cleavable group.

The preferred group for R ^x is halogen, preferably chlorine or bromine, or thioalkyl, for example thiomethyl.

The reaction between the compound of formula III and the reagent may be carried out under conditions appropriate to the starting material used.

And of the selected reagent. For example, in the above reaction between a compound of formula III wherein R ^a is a group of formula R ¹ HN- (CH 2) n - and a compound of formula IV, the process may be carried out in any suitable solvent, e.g. tetrahydrofuran at room temperature. 0 to 60 ° C.

A compound of formula III can be prepared from a compound of formula V

CHO (V) where

A ² is as defined for formula Ia

R ^b represents a group R ^a or a group which can be converted into this group by proceeding by reacting a compound of the formula V with

2,4-thiazolidinedione and then optionally carrying out one or more of the following steps:

i) the compound of formula III in which R ² and R ³ together form a chemical bond is reduced to give a compound of formula III in which R ² and R ³ are hydrogen atoms, ii) the group R ^b is converted to a group R ^a .

The reaction between the compound of formula V and 2,4-thiazolidinedione will be carried out under conditions appropriate to the nature of the compound of formula V. Typically, the reaction is carried out in a solvent such as toluene, preferably also at elevated temperature, e.g. and preferably in the presence of a suitable catalyst, for example piperidinium acetate or piperidinium benzoate. Preferably, the water resulting from the reaction of the compound of formula V with 2,4-thiazolidinedione is removed from the reaction mixture, for example using a Dean-Stark apparatus.

When R ^a is R ¹ HN- (CH ₂ ) _n -O-, a suitable value for R ^{b is a} hydroxyl group.

The group R ^b can be converted to the group R ^{a by} any suitable method. For example, in the case of R ^b = OH, and R ^a is

The abovementioned group can be converted appropriately by coupling a compound of formula VA

where

R ² , R ³ and A ² are as defined for formula (I) and R ² represents a hydrogen atom or a protecting group on a nitrogen atom, to a compound of formula (VI)

R ¹ NR ^x (CH ₂ ) n -OH (VI) wherein

R ¹ and n are as defined for formula Ia

R ^x represents a hydrogen atom or a protecting group on a nitrogen atom, in the presence of a suitable bonding agent, and then optionally carrying out one or more of the following steps:

i) the compound of formula III in which R ² and R ³ together form a chemical bond is reduced to give a compound of formula III in which R ² and R ³ are hydrogen atoms, ii) any protecting group on the nitrogen atom is removed.

A suitable coupling aid between the compounds of formula (VA) and (VI) is, for example, diethyl azodicarboxylate and triphenylphosphine. The coupling reaction may be carried out in any suitable solvent at low to medium temperature, for example, in tetrahydrofuran at a temperature range of 0 to 60 ° C.

An example of the preparation of a compound of formula VA is a reaction in which a compound of formula VII belonging to a group of compounds of formula V is reacted.

CHO

A ² is as defined for formula I a

R ¹¹ represents a hydroxyl group or a protected hydroxyl group, with 2,4-thiazolidinedione, then optionally removing the protecting group.

It prefers that R ¹¹ is benzyloxy.

Preferred conditions for the reaction between compounds of formula VII and 2,4-thiazolidinedione are those described above for the reaction between compounds of formula V and 2,4-thiazolidinedione.

Compounds of formula (IV), (VI) and (VI) are either known compounds or can be prepared using procedures analogous to those known for the preparation of known compounds.

Preferred protecting groups for the above-mentioned types of reactions are those commonly used in the art. For example, a preferred protecting group on a nitrogen atom is a benzyl group or a benzyloxycarbonyl group, and a preferred protecting group on a hydroxyl group is a benzyl group.

Methods for forming and removing said protecting groups are known and used with respect to the molecule that has been protected. For example, when R ¹¹ is a benzyloxy group, it may be introduced by treating the corresponding compound of formula VII, wherein R ¹¹ is a hydroxyl group, with a benzyl halide such as benzyl bromide, and then optionally removing the benzyl group again using a reagent suitable for cleaving the ether bond under mild conditions, for example by treatment with trimethylsilyl iodide.

A compound of formula I or one of its tautomeric forms and / or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable solvate thereof may also be prepared by reacting a compound of formula VIII

-8R ·

(VIII) wherein R, A ¹ , A ² and n have the meaning given for formula I with 2,4-thiazolidinone, then optionally carrying out one or more of the following steps:

i) converting a compound of formula I into another compound of formula I, ii) preparing a pharmaceutically acceptable salt of a compound of formula I or a pharmaceutically acceptable solvate thereof.

The reaction between compounds of formula VII and 2,4-thiazolidinedione can be carried out under conditions similar to those described for the reaction between compounds of formula V and 2,4-thiazolidinedione.

A compound of formula VIII can be prepared by reacting a compound of formula IX

A ² has the meaning given for formula I a

^And R is as defined for formula III, with a reagent capable of converting R @ ^a to the above group of formula f.

A preferred value for R ^a is, for example, those given for the compound of formula III. ^Thus R may be a group of the formula R ¹ HN- (CH _{2) n} -O-, as was mentioned above. That is, the corresponding compound of formula IX can be reacted

-9 with the above compound of formula IV to give the desired compound of formula VIII.

Preferred reaction conditions for the reaction of a compound of Formula IX with an appropriate reagent are those described above for the preparation of a compound of Formula III using a suitable reagent.

Preferably, a compound of formula IX is used in which R ^a is a readily cleavable group, in particular a fluorine atom. In the case where R ^a is a leaving group, preferably a fluorine atom, a particularly preferred particular reagent of the above type is a compound of formula X

R ¹

I (X)

A ¹ - N - (CH ₂ ) n - OH where R ¹ , A ¹ and n have the meaning given above for formula I.

The reaction between compounds of formula IX and formula X can be carried out under any suitable conditions, for example in a solvent such as dimethylformamide or dimethylsulfoxide at elevated temperature, for example between 100 and 150 ° C, preferably in the presence of a base such as sodium hydride or carbonate potassium.

In the compound of formula (IX), R ^a can also be a hydroxyl group.

When R is ^a hydroxyl group in a compound of formula IX, a particularly preferred agent is a compound of the above formula X or a compound of formula XA

R ¹

I

A ¹ - N - (CH ₂ ) _n - OR ^y (XA) where

A ¹ , R ¹ and n have the meanings given for formula X and R ^y is the radical of tosilate or mesilate.

The reaction between the compounds of formula IX in which R ^a is a hydroxyl group and the reagent of the above formula X can be carried out in an aprotic solvent, for example tetrahydrofuran at a low to medium temperature, for example room temperature, preferably in the presence of a reagent. a coupling aid, for example in the presence of triphenylphosphine and diethyl azodicarboxylate.

The reaction between the compounds of formula IX wherein R ^a is a hydroxyl group and the reagent of the above formula XA can be carried out in an aprotic solvent such as dimethylformamide at a low to medium temperature, for example in the range 50 to 120 ° C, preferably in the presence of a base. for example sodium hydride.

The compound of formula XA may be prepared from the corresponding compound of formula X by reaction with a tosyl halide or mesyl halide in a solvent such as pyridine.

The compounds of formula (IX) are known compounds or can be prepared by methods known for the preparation of known compounds, for example 4-fluorobenzaldehyde or 4-hydroxybenzaldehyde, which are known and commercially available compounds.

The reagent of formula (X) may be prepared by reacting a compound of formula (IV) with a compound of formula (VI), and then removing any nitrogen protecting group, if necessary, using conventional measures.

The reaction between the compounds of formulas IV and VI can be carried out under any suitable conditions, for example in a solvent, for example an aprotic solvent such as tetrahydrofuran at a low to medium temperature, for example at a temperature between 0 and 60 ° C.

In the case where R ¹ is a hydrogen atom, the reaction is preferably carried out using compounds of formula VI as solvent at low to medium temperature, preferably at elevated temperature, for example at a temperature between 100 and 170 ° C.

The above conversion of compounds of formula I to other compounds of formula I may include the following transformations:

-11 a) reducing a compound of formula I wherein R ² and R ³ together form a bond to form a compound of formula I wherein R ² and R ³ are hydrogen atoms, and

b) R ¹ is converted into another radical R ^first

Conversion of compounds of Formula I to another compound of Formula I may be accomplished using any conventional procedures.

In particular, a preferred reduction process for the above-mentioned conversion in a) is catalytic reduction or the use of a reduction system which comprises the simultaneous use of a metal and a solvent.

A preferred catalyst for use in the catalytic reduction is palladium on charcoal, preferably 10% palladium on charcoal. The reduction is usually carried out in a solvent, for example dioxane, usually at room temperature.

A preferred metal-solvent reduction system is a system containing magnesium in methanol.

The abovementioned reduction of compounds of formula III in which R ² and R ³ together form a chemical bond to a compound of formula III in which R ² and R ³ are hydrogen atoms can be carried out under analogous conditions to the above transformation a) in the case of a compound of the formula

I.

In the above conversion of (b), conversion of one R ¹ group to another R ¹ group involves a reaction in which the hydrogen atom is converted to an acyl group.

Conversion of compounds of formula I wherein R ¹ is hydrogen to a compound of formula I wherein R ¹ is acyl may be accomplished using any conventional acylation process, for example by treating an appropriately protected compound of formula I with an acylation agent. For example, acetic anhydride can be used to produce compounds of formula I wherein R 1 is acetyl.

It will be appreciated that in carrying out the above-mentioned transformations according to a) or b), any reactive group in the compound of formula I may be protected, if necessary, using conventional procedures.

If desired, isomeric forms of the compounds of formula (I) as well as their pharmaceutically acceptable salts may be prepared as salts with the individual isomers using conventional chemical procedures.

As mentioned above, the compounds of the invention are described as having valuable pharmacological properties.

It is thus possible to use the compounds of the formula I, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their pharmaceutically acceptable solvates for use as active ingredients in the manufacture of pharmaceutical compositions.

In one embodiment of the invention, the compounds of formula I, their tautomeric forms with / or their pharmaceutically acceptable salts and / or their solvates, pharmaceutically acceptable, are used for the treatment and / or prevention of elevated blood sugar, hyperglycemia.

In another embodiment of the invention, the compounds of formula I, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their solvates, pharmaceutically acceptable, are used for the treatment and / or prevention of elevated blood lipid levels, i.e. hyperlipidemia.

In another embodiment of the invention, the compounds of formula I, their tautomeric forms and / or their pharmaceutically acceptable salts, and / or their solvates, pharmaceutically acceptable, are used for the treatment of elevated blood pressure, cardiovascular diseases and certain eating disorders.

The compounds of the formula I, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their pharmaceutically acceptable solvates can be administered per se, in particular orally, preferably in the form of a pharmaceutical composition which also contains a carrier in addition to the active ingredient. pharmaceutically acceptable.

The term "pharmaceutically acceptable" refers to a compound, composition or ingredient for use in humans or veterinary medicine.

The pharmaceutical composition will usually be provided in the form of a package that is accompanied by written or printed instructions for use.

The pharmaceutical compositions containing the active compounds according to the invention will usually be intended for oral administration, although the active compounds can also be administered by another route, for example by injection or by means of skin absorption.

Particularly preferred compositions for oral administration are dosage forms such as tablets or capsules. However, other forms may also be used, for example powders in sachets.

In accordance with conventional pharmaceutical practice, the carrier may comprise a diluent, a filler, a disintegrant, a wetting agent, a glidant, a colorant, a flavoring, and the like.

Typical carriers are, for example, microcrystalline cellulose, starch, sodium starch glycolate, polyvinylpyrrolidone, polyvinylpyrrolidone, magnesium stearate, sodium lauryl sulfate or sucrose.

Preferably, the pharmaceutical composition is in unit dosage form. Such a single dose will contain an amount of active ingredient in the range of 0.1 to 1000, preferably 0.1 to 500, and especially 0.1 to 250 mg.

The pharmaceutical compositions of the invention may be used to treat and / or prevent hyperglycemia in humans and other animals by administering an effective, non-toxic amount of a compound of formula I, a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate.

The pharmaceutical composition of the invention may also be used to treat hyperlipidemia in a human or other mammal by administering a non-toxic effective amount of a compound of formula I, a tautomeric form thereof, and / or a pharmaceutically acceptable salt thereof, and / or a solvate thereof. from a pharmaceutical point of view.

Thus, the active ingredient may conveniently be administered in the form of the aforementioned pharmaceutical composition of the invention, which preferably constitutes an embodiment of the invention.

In the treatment and / or prevention of hyperglycemia in humans and / or in the treatment and / or prevention of hyperlipidemia in humans, a compound of formula I or a tautomeric form and / or a salt thereof, which is pharmaceutically acceptable and / or is administered.

A pharmaceutically acceptable salt at the above dosage of 1 to 6 times a day such that the total daily dose for an adult human weighing 70 kg is in the range of 0.1 to 6000, preferably 1 to 1500 mg.

For the treatment and / or prevention of hyperglycemia in non-human mammals, particularly dogs, the active ingredient may be administered orally, usually once or twice daily, at a rate of 0.025 to 25 mg / kg, for example 0.1 to 20 mg / kg. Similar dosages may be used to treat and / or prevent hyperglycemia in non-human mammals.

In the case of elevated blood pressure, heart and vascular disease and eating disorders, the dosage range is usually used as described above for the treatment of hyperglycemia.

Furthermore, the invention also relates to the use of the compounds of the formula I, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their pharmaceutically acceptable solvates for the manufacture of a pharmaceutical composition for the treatment and / or prevention of hyperglycemia.

Furthermore, the invention also relates to the use of the compounds of formula I, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their pharmaceutically acceptable solvates for the manufacture of a pharmaceutical composition for the treatment and / or prevention of hyperlipidemia, elevated blood pressure , cardiovascular diseases, and some eating disorders.

The invention is illustrated by the following examples, which are not to be construed as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Preparation 1

4- (2 - (/ V-methyl- / V- (2-benzothiazolyl) amino) ethoxy) benzaldehyde

A mixture of 1.5 g, 4-fluorobenzaldehyde and 2.4 g of (N-methyl- N - (2-benzothiazolyl) amino) ethanol in 50 ml of dimethylsulfoxide containing 2 g of anhydrous potassium carbonate is stirred for 24 hours at a temperature of Mp 100 ° C. The mixture was cooled to room temperature and water (300 ml) was added. The aqueous solution was extracted with 2 x 300 mL diethyl ether. The organic extracts were washed once with 300 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness. The title compound is obtained as a waxy solid after chromatography on silica gel, eluting with 1% methanol in dichloromethane.

¹ H NMR (CDCl ₃ ): 3.2 (3H, s), 3.8 (2H, t), 4.2 (2H, t), 6.8-7.8 (8H, complex), 9, Δ (1H, s).

Preparation 2

2 - (/ V-methyl- / V- (2-benzothiazolyl) amino) ethanol

A mixture of 8.5 g of 2-chlorobenzothiazole and 20 ml of 2-methylaminoethanol is heated to 120 ° C under pressure in a sealed, glass-lined, stainless steel reaction vessel for 18 hours. After cooling, the oily material was poured into 100 ml of water and extracted with 2 x 100 ml of dichloromethane. The organic extracts were dried (MgSO 4), filtered and evaporated to dryness. The oil obtained is chromatographed on silica gel using 2.5% methanol in dichloromethane to give the title product, which is used in Preparation 1 without further purification.

¹ H NMR (CDCl ₃ ): 3.15 (3H, s), 3.4-4.0 (4H, m), 4.7 (1H, broad s, exchange with D ₂ O),

6.8 - 7.6 (4H, complex).

-16Preparation 3

4- (2- (E / methyl / V- (2-benzoxazolyl) amino) ethoxy) benzaldehyde

CHO

To a solution of 9.6 g of 2 - (N-methyl- N - (2-benzoxazolyl) amino) ethanol 13.1 g of triphenylphosphine and 6.1 g of 4-hydroxybenzaldehyde in 150 ml of anhydrous tetrahydrofuran is added dropwise a solution of 9. 1.0 g of diethyl azodicarboxylate in 30 ml of anhydrous tetrahydrofuran under nitrogen atmosphere with stirring at room temperature. The solution was stirred overnight at room temperature and then the solvent was evaporated under reduced pressure. The residue is dissolved in 300 ml of diethyl ether, the solution is filtered and then the ether solution is washed with 200 ml of dilute sodium hydroxide solution, 200 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the solvent is evaporated. Chromatography on silica gel eluting with dichloromethane gave the title product, m.p. 97-98 ° C.

¹ H NMR (CDCl ₃ ): 3.3 (3H, s), 3.85 (2H, t), 4.3 (2H, t), 6.8-7.85 (8H, complex), 9, 85 (1 H, s).

Preparation 4

2 - (/ V-methyl- / V- (2-benzoxazolyl) amino) ethanol

A solution of 15.4 g of 2-chlorobenzoxazole in 50 ml of anhydrous tetrahydrofuran is added dropwise with stirring to a solution of 15.0 g of 2-methylaminoethanol in 100 ml of anhydrous tetrahydrofuran which is cooled with ice while protecting the reaction mixture from atmospheric humidity. The mixture was stirred for 1 hour at 0 ° C, then allowed to warm to room temperature and stirred for a further 2 hours. then

After evaporating the solvent under reduced pressure, the product was dissolved in 200 ml of ethyl acetate and the solution was washed with 2 x 150 ml of saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue is chromatographed on silica gel eluting with dichloromethane to give the title product, m.p. 62-63 ° C, which is used in Preparation 3 without further purification.

¹ H NMR (CDCl ₃ ): 3.12 (3H, s), 3.4-4.0 (4H, m), 4.7 (1H, s, exchange with D ₂ O), 6.87, 4 (4H, complex).

Preparation

4- (2 - (/ V-methyl- / V- (2-pyrimidinyl) amino) ethoxy) benzaldehyde

A mixture of 12 ml of 4-fluorobenzaldehyde and 10.05 g of 2- (N-methyl- N - (2-pyrimidinyl) amino) ethanol in 50 ml of anhydrous dimethylsulfoxide containing 15 g of anhydrous potassium carbonate is stirred at 120 ° C for 6 hours. The mixture was then cooled to room temperature and poured into 2001 water. The aqueous solution was extracted with ethyl acetate (2.times.300 ml), the organic extracts washed with water, dried (MgSO4) and evaporated. Chromatography on silica gel using 2% methanol in dichloromethane as eluent gave the title product as an oil.

¹ H NMR (CDCl 3): 3.3 (3H, s), 3.8-4.4 (4H, complex), 6.5 (1H, t), 7.0 (2H, d), 7.8 (2H, d), 8.3 (2H, d), 9.9 (1H, s).

Preparation 6

2- (N-methyl- / V- (2-pyrimidinyl) amino) ethanol

OH

A mixture of 10 g of 2-chloropyrimidine and 2-methylaminoethanol in 100 ml of anhydrous tetrahydrofuran is heated at reflux for 3 hours. The solution was cooled, water (200 ml) was added and the mixture was extracted with dichloromethane. The organic extracts were dried (MgSO 4), filtered and evaporated to dryness. The remaining oil was used in Preparation 5 without further purification.

¹ H NMR (CDCl ₃ ): 3.2 (3H, s), 3.5-3.9 (4H, m), 4.6 (1H, s, exchange with D ₂ O), 6.4 (1H , dt), 8.2 (2H, d).

Preparation 7

2 - (/ V-methyl- / V- (2- (4,5-dimethylthiazolyl)) amino) ethanol

A solution of 2-chloro-4,5-dimethyl-thiazole (13.2 g) and 2-methylaminoethanol (40 ml) in pyridine (100 ml) was refluxed for 20 hours. After cooling, the oily material was added to 300 ml of water and the mixture was extracted with 3 x 200 ml of ethyl acetate. The organic extracts were washed with 2 x 200 mL aqueous saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness to give the title product which was used in Preparation 14 without further purification.

¹ H NMR (CDCl ₃ ): 2.15 (3H, s), 2.2 (3H, s), 3.1 (3H, s), 3.4-3.9 (4H, m), 5, 25 (1H, broad s, exchange with D ₂ O).

Preparation

2 - (/ V-methyl- / V- (2-thiazolyl) amino) ethanol

The resulting product was prepared as an oil from 15 g of 2-bromothiazole and 45 ml

2-methylaminoethanol as described in Preparation 7.

¹ H NMR (CDCl 3): 3.1 (3H, s), 3.4-3.9 (4H, m), 4.8 (1H, broad s, exchange with D ₂ O),

6.4 (1H, d); 7.0 (1H, d).

Preparation 9

2- (N-methyl-A / - (2- (4-fenyltiazolyl)) amino) ethanol

The resulting oil product can be obtained from 13.5 g of 2-chloro-4-phenylthiazole and 40 ml of 2-methylaminoethanol as described in Preparation 7.

¹ H NMR (CDCl 3): 3.15 (3H, s), 3.6-4.0 (4H, m), 4.6 (1H, broad s, exchange with D ₂ O),

6.7 (1H, s), 7.2-7.9 (5H, complex).

Preparation 10

2 (A / N-methyl-A / - (2- (4-phenyl-5-methyl-thiazolyl)) amino) ethanol

The resulting product was prepared from 13.9 g of 2-chloro-4-phenyl-5-methylthiazole and 50 ml of 2-methylaminoethanol as an oily substance as described in Preparation 7.

¹ H NMR (CDCl 3): 2.38 (3H, s), 3.0 (3H, s), 3.45-3.85 (4H, m), 5.1 (1H, broad s, exchange with D ₂ O), 7.1 - 7.7 (5H, complex).

-20Preparation 11

2 - (/ V-methyl- / V- (2- (4-methyl-5-fenyltiazolyl)) amino) ethanol

OH

The resulting oil product was prepared from 14.8 g of 2-chloro-4-methyl-5-phenylthiazole and 40 ml of 2-methylaminoethanol as described in Preparation 7.

¹ H NMR (CDCl ₃ ): 2.35 (3H, s), 3.1 (3H, s), 3.5-4.0 (4H, m), 5.1 (1H, broad s, exchange with D2O), 7.1 - 7.5 (5H, complex).

Preparation 12

2 (A / methyl / V- (2- (4-methyl-thiazolyl)) amino) ethanol

The resulting compound can be obtained in an analogous manner to Preparation 7 and can be used in the next step without further purification.

¹ H NMR (CDCl 3): 2.25 (3H, s), 3.1 (3H, s), 3.55-3.95 (4H, m), 4.9 (1H, broad s, exchange with D _{20 (} O), 6.1 (1H, s).

Preparation 13

2 - (/ V-methyl- (2- (5-phenyloxazolyl)) amino) ethanol

A solution of 8.3 g of 2-chloro-5-phenyloxazole and 2-methylaminoethanol (30 ml) was stirred at 50 ° C for 10 minutes. After cooling, the oily mixture was poured into 250 ml of water and extracted with 2 x 150 ml of ethyl acetate. The organic extracts were washed with saturated aqueous sodium chloride (2 x 100 mL), dried (MgSO 4) and evaporated to dryness to give the title product, m.p. 73-75 ° C.

¹ H NMR (CDCl ₃ ): 3.2 (3H, s), 3.6 (2H, t), 3.85 (2H, t), 3.9 (1H, broad s, exchange with D ₂ O) 7.0 (1H, s), 7.2-7.55 (5H, complex).

Preparation 14

4- (2 - (/ V-methyl- / V- (2- (4,5-dimethylthiazolyl) amino) ethoxy)) benzaldehyde

CH0

The title compound can be prepared from 13.2 g of 2 - (N-methyl- N - (2- (4,5-dimethylthiazolyl)) amino) ethanol and 23.1 g of 4-fluorobenzaldehyde as described in the preparation 7th

¹ H NMR (CDCl ₃ ): 2.15 (3H, s), 2.2 (3H, s), 3.18 (3H, s), 3.8 (2H, t), 4.3 (2H, s), t), 7.0 (2H, d), 7.8 (2H, d), 10.0 (1H, s).

Preparation 15

4- (2 - (/ V-methyl-A / - (2-thiazolyl) amino) ethoxy)) benzaldehyde

The title compound can be prepared from 10.7 g of 2 - (N-methyl-N- (2-thiazolyl) amino) ethanol and 15.9 g of 4-fluorobenzaldehyde as described in the preparation

5th

¹ H NMR (CDCl ₃ ): 3.15 (3H, s), 3.9 (2H, t), 4.4 (2H, t), 6.5 (1H, d), 7.0 (2H, t, d), 7.15 (1H, d), 7.8 (2H, d), 9.9 (1H, s).

Preparation 16

4- (2- (E / methyl / V- (2- (4-fenyltiazolyl) amino) ethoxy)) benzaldehyde

The resulting compound can be prepared from 16.1 g of 2 - (N -methyl- N - (2- (4-phenylthiazolyl) amino) ethanol) and 17.4 g of 4-fluorobenzaldehyde as described in Preparation 5.

¹ H NMR (CDCl ₃ ): 3.2 (3H, s), 3.95 (2H, t), 4.3 (2H, t), 6.7 (1H, s), 6.95-7, 9 (9H, complex), 9.9 (1H, s).

Preparation 17

4- (2- (N-methyl-N- (2- (4-phenyl-5-methyl-thiazolyl) amino) ethoxy)) benzaldehyde

The resulting compound can be prepared from 13 g of 2- (N-methyl- N - (2- (4-phenyl-5-methylthiazolyl) amino) ethanol) and 9.8 g of 4-fluorobenzaldehyde as described in Preparation 5.

-23 ¹ H NMR (CDCl ₃ ): 2.35 (3Η, s), 3.1 (3H, s), 3.8 (2H, t), 4.2 (2H, t), 6.85- 7.8 (9H, complex), 9.85 (1H, s).

Preparation 18

4- (2 - (/ V-methyl - / \ / - (2- (4-methyl-5rfenyltiazolyl) amino) ethoxy)) benzaldehyde

The resulting product can be prepared from 13 g of 2- (N-methyl- N - (2- (4-methyl-5-phenylthiazolyl) amino) ethanol) and 13 g of 4-fluorobenzaldehyde as described in Preparation 5.

¹ H NMR (CDCl 3): 2.36 (3H, s), 3.2 (3H, s), 3.9 (2H, t), 4.35 (2H, t), 7.05 (2H, d) 7.2, 7.5 (5H, complex), 7.85 (2H, d), 9.95 (1H, s).

Preparation 19

4- (2- (E / methyl / V- (2- (4-methyl-thiazolyl)) amino) ethoxy) benzaldehyde

The title compound can be prepared from 12 g of 2- (N-methyl-N- (2- (4-methylthiazolyl)) amino) ethanol and 14.3 g of 4-fluorobenzaldehyde as described in the preparation

5th

¹ H NMR (CDCl 3): 2.25 (3H, s), 3.2 (3H, s), 3.9 (2H, t), 4.3 (2H, t), 6.1 (1H, s) 7.05 (2H, d), 7.85 (2H, d), 9.95 (1H, s).

-24Preparation 20

4- (2 - (/ V-methyl- / V- (2- (5-phenyloxazolyl)) amino) ethoxy) benzaldehyde

The title compound can be prepared from 9.3 g of 2 - (N-methyl-N- (2- (5-phenyloxazolyl)) amino) ethanol and 7.9 g of 4-fluorobenzaldehyde in a manner analogous to that described in Preparation 5th

¹ H NMR (CDCl ₃ ): 3.25 (3H, s), 3.85 (2H, t), 4.3 (2H, t), 6.95-7.6 (8H, complex), 7, Δ (2H, d), 9.9 (1H, s).

Preparation 21

2 - (/ V-methyl- / V- (2- (4,5-dimethyloxazolyl)) amino) ethanol

A solution of 5 g of 2-chloro-4,5-dimethyloxazole and 15 ml of 2-methylaminoethanol is stirred for 40 minutes at 120 ° C. After cooling, the oily material was poured into 200 ml of water and extracted with 3 x 200 ml of dichloromethane. The organic extracts were washed with saturated aqueous sodium chloride (2 x 100 mL), dried (MgSO 4), filtered and evaporated to dryness to give the title product as a waxy solid which was used in Preparation 22 without further purification.

¹ H NMR (CDCl 3): 1.95 (3H, s), 2.1 (3H, s), 3.05 (3H, s), 3.5 (2H, t), 3.8 (2H, t) 4.4 (1H, broad s, exchange with D2O).

-25Preparation 22

4- (2 - (/ V-methyl- / V- (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzaldehyde

To a stirred solution of 2.7 g of 2- (N-methyl- N - (2- (4,5-dimethyloxazolyl)) amino) ethanol in 60 ml of dimethylformamide was added portionwise, under a nitrogen atmosphere, 0.7 g of sodium hydride in 60% dispersion in oil. When the vigorous reaction ceased, 2.9 g of 4-fluorobenzaldehyde was added and the reaction mixture was heated at 80 ° C for 16 hours. After cooling, 400 ml of water are added to the mixture. The aqueous solution was extracted with diethyl ether (3 x 250 mL). The organic extracts were washed with saturated aqueous sodium chloride (2 x 100 mL), dried (MgSO 4) and evaporated to dryness. The resulting product is obtained as an oil after chromatography of the residue on silica gel, eluting with 1% methanol in dichloromethane.

¹ H NMR (CDCl ₃ ): 1.95 (3H, s), 2.15 (3H, s), 3.15 (3H, s), 3.8 (2H, t), 4.25 (2H, s), t), 7.0 (2H, d), 7.9 (2H, d), 10.0 (1H, s).

Preparation 23

2 - (/ V- (2-benzoxazolyl) -N / methylamino) ethanol 4-toluene sulfonyl

19.0 g of 4-toluenesulfonyl chloride is added portionwise to a solution of 19.2 g of N (benzoxazolyl) -N-methylaminoethanol in 100 ml of anhydrous pyridine at room temperature. The mixture was stirred at room temperature for 3 hours, poured into 500 ml of water and extracted with 3 x 250 ml of dichloromethane. The extracts are combined,

Wash with 3 x 250 ml of 2M hydrochloric acid, 250 ml of aqueous sodium bicarbonate solution and 250 ml of saturated aqueous sodium chloride solution, then dry over magnesium sulphate, filter and evaporate. After recrystallization, the pure product is obtained from ethanol, m.p.

121 ° C.

¹ H NMR (DMSO-d 6): 2.25 (3H, s), 3.05 (3H, s), 3.75 (2H, t), 4.35 (2H, t), 7.0-7 4 (6H, complex), 7.7 (2H, d).

Preparation 24

2 - (N - (2-Benzoxazolyl) - N -methylamino) ethanol methanesulfonyl ester

The resulting product, m.p. 97-98 ° C, was prepared using 19.2 g of N - (2-benzoxazolyl) - N -methylaminoethanol and 11.5 g of methanesulfonyl chloride in a similar manner to the product of Preparation 23.

¹ H NMR (CDCl ₃ ): 2.9 (3H, s), 3.25 (3H, s), 3.7 (2H, t), 4.5 (2H, t), 6.9-7, 4 (4H, complex).

Preparation 25

4- (2 - (/ V-methyl- / V- (2-benzoxazolyl) amino) ethoxy) benzaldehyde

7.32 g of 4-hydroxybenzaldehyde are dissolved in 100 ml of anhydrous dimethylformamide and 2.4 g of sodium hydride as a 60% dispersion in oil are added in portions with stirring under nitrogen at room temperature. When

The gas is stopped to evolve, a solution of 17.3 g of 2 (N-methyl-N- (2-benzoxazolyl) amino) ethanol in anhydrous dimethylformamide is added dropwise. The mixture was heated to 80 ° C and stirred at this temperature overnight. After cooling, the solution is poured into 1 l of a mixture of water and crushed ice, extracted with 3 x 500 ml of ethyl acetate, the extracts are combined, washed with 500 ml of 2M aqueous sodium hydroxide solution and 500 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Recrystallization from ethanol gave the pure product, m.p. 96-98 ° C.

¹ H NMR (DMSO-d 6): 3.25 (3H, s), 3.95 (2H, t), 4.4 (2H, t), 6.9-7.4 (6H, complex),

7.85 (2 H, d), 9.9 (1 H, s).

Preparation 26

4- (2 - (/ V-methyl- / V- (2-benzoxazolyl) amino) ethoxy) benzaldehyde

The title compound can be prepared using 1.22 g of 4-hydroxybenzaldehyde and 2.7 g of 2- (N-methyl-N- (2-benzoxazolyl) amino) ethanol as the methanesulfonyl ester in a similar manner to the product of Preparation 25.

Preparation 27

2- (2-pyrimidinyl) ethanol

2-Chloropyrimidine (g) and ethanolamine (15 ml) were stirred at 140 ° C for 2 hours. After cooling, the mixture is poured into 200 ml of water and extracted continuously with 500 ml of ethyl acetate for 16 hours. Dry the organic extract with magnesium sulfate, filter and filter

-28 Evaporates to dryness. The resulting product is obtained after chromatography on silica gel using 3% methanol in dichloromethane as a solid, mp 66 ° C.

¹ H NMR (CDCl 3): 3.55 (2H, complex), 3.8 (2H, t), 4.3 (1H, broad s, exchange with D ₂ O),

6.1 (1H, broad s, exchange with D ₂ O), 6.55 (1H, t), 8.3 (2H, d).

Preparation 28

4- (2- (2-pyrimidinyl) ethoxy) benzaldehyde

CHO

1.2 g of sodium hydride as a 60% dispersion in oil are added portionwise to a stirred solution of 4 g of 2- (2-pyrimidinylamino) ethanol in 140 ml of dimethylformamide under a nitrogen atmosphere. When a violent reaction resolved, 5.35 g of 4-fluorobenzaldehyde was added and the solution was heated to 80 ° C for 20 hours. After cooling, the mixture is poured into 500 ml of water and extracted with 3 x 300 ml of diethyl ether. The organic extracts were washed with saturated aqueous sodium chloride (2 x 200 mL), dried (MgSO 4), filtered and evaporated to dryness. The residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent to give the title product, which was used in the next step without further purification.

¹ H NMR (CDCl 3): 2.8 (2H, complex), 4.2 (2H, t), 5.7 (1H, broad s, exchange with D ₂ O),

6.5 (1H, t), 7.0 (2H, d), 7.8 (2H, d), 8.3 (2H, d), 9.9 (1H, s).

Preparation

2 - (/ V- (2-benzothiazolyl) - / V-benzylamino) -ethanol

-2913 g of 2-chlorobenzothiazole and 29 g of 2- (benzylamino) ethanol are heated together at 120 ° C in a sealed vessel for 20 hours. After cooling, the reaction mixture is dissolved in 200 ml of ethyl acetate and the solution is washed with 3 x 100 ml of aqueous sodium bicarbonate solution, 3 x 100 ml of water and 100 ml of saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. Recrystallization from dichloromethane / hexane gave the title compound, m.p. 95-96 ° C.

¹ H NMR (CDCl ₃ ): 3.8 (3H, m), 4.5 (1H, broad s, exchange with D ₂ O), 4.7 (2H, s), 6.9 7.7 (9H) , complex).

Preparation 30

4- (2 - (/ \ / - (2-benzothiazolyl) -N / benzylamino) ethoxy) benzaldehyde

The resulting product was prepared using 8.25 g of 2- (N- (2-benzothiazolyl) -N-benzylamino) ethanol and 3.6 g of 4-fluorobenzaldehyde in an analogous manner to the product of Preparation 22.

¹ H NMR (CDCl 3): 4.0 (2H, t), 4.4 (2H, t), 4.9 (2H, s), 6.9-8.0 (13H, complex), 10.0 (1 H, s).

Preparation 31

4- (3 - (/ V-methyl- / V- (2-benzoxazolyl) amino) propoxy) -benzaldehyde

The resulting product was prepared using 7.5 g of 3 - ((N- (2-benzoxazolyl) - N -methyl) amino) propan-1-ol and 6.78 g of 4-fluorobenzaldehyde in a similar manner to the product of Preparation 22.

¹ H NMR (CDCl ₃ ): 2.0-2.4 (2H, complex), 3.2 (3H, s), 3.75 (2H, t), 4.2 (2H, t), 6, Δ 7.5 (6H, complex), 7.8 (2H, d), 9.9 (1H, s).

Preparation

3 - ((A / - (2-benzoxazolyl) -N-methyl) amino) propan-1-ol

15.36 g of 2-chlorobenzoxazole in 50 ml of anhydrous tetrahydrofuran is added dropwise to a mixture of 9.8 g of 3- N -methylaminopropan-1-ol and 20.2 g of triethylamine in 130 ml of anhydrous tetrahydrofuran with stirring at room temperature. . The mixture was stirred overnight at room temperature and the solvent was evaporated. The residue was dissolved in dichloromethane (150 ml), washed with water (3.times.100 ml) and brine (150 ml), dried (MgSO4) and evaporated. The resulting product is obtained after chromatography on silica gel using 2.5 to 3% methanol in dichloromethane as an oil.

¹ H NMR (CDCl 3): 1.8-2.1 (2H, complex), 3.2 (3H, s), 3.5-3.85 (4H, complex), 4.3 (1H, broad) s, exchange with D ₂ O), 6.8 - 7.5 (4H, complex).

Preparation 33

4- (2 - (/ V-methyl- / V- (2-pyridyl) amino) ethoxy) benzaldehyde

The resulting product can be prepared using 8.9 g of 2- (N-methyl- N - (2-pyridyl) amino) ethanol and 4-fluorobenzaldehyde in a similar manner to the product of Preparation 22.

¹ H NMR (CDCl ₃ ): 3.2 (3H, s), 3.8 (2H, t), 4.2 (2H, t), 6.4 (2H, t), 6.9 (2H, t, d), 7.3 (1H, complex), 7.75 (2H, d), 8.15 (1H, d), 9.9 (1H, s).

Example 1

5- (4- (2 - (/ V-methyl- / V- (2-benzothiazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione

g of 5- (4- (2- (N-methyl- N - (2-benzothiazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione in 70 ml of anhydrous 1,4-dioxane is reduced in the presence of 3 g 10% palladium on activated carbon at room temperature and at atmospheric pressure until no more hydrogen is consumed. Then the mixture is filtered through diatomaceous earth, the filter cake is washed thoroughly in dioxane, the filtrates are combined and evaporated to dryness in vacuo. Crystallization from methanol gave the title compound as a solid, m.p. 167-168 ° C.

¹ H NMR (DMSO-d 6): 2.9-3.4 (2H, complex), 3.25 (3H, s), 3.9 (2H, complex), 4.25 (2H, complex), 6 8 - 7.75 (8H, complex), 12.0 (1H, s, exchange with D ₂ O).

Example 2

5- (4- (2 - (/ V-methyl-A / - (2-benzothiazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

CH

-32Solution 1.9 g of 4- (2- (N-methyl-N- (2-benzothiazolyl) amino) ethoxy) benzaldehyde and

0.8 g of 2,4-thiazolidinedione in 100 ml of toluene containing a catalytic amount of piperidinium acetate is heated to reflux using a Dean-Stark apparatus. The mixture was cooled and filtered, and the filtered solid was dried to give the title compound, m.p. 219 ° C.

¹ H NMR (DMSO-d 6): 3.2 (3H, s), 3.9 (2H, t), 4.35 (2H, t), 6.8-7.7 (10H, complex).

Example 3

5- (4- (2 - (/ V-methyl- / V- (2-benzoxazolyl) amino) ethoxy) benzyl) -2,4-tiazolidíndiónhemihydrát

1.5 g of 5- (4- (2 - (N-methyl- N - (2-benzoxazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione in 80 ml of anhydrous 1,4-dioxane is reduced with hydrogen in the presence of 2 g of 10% palladium on charcoal at room temperature and at atmospheric pressure until no more hydrogen was consumed. The solution is filtered through a pad of diatomaceous earth, the filter cake is washed thoroughly with dioxane, the filtrates are combined and evaporated to dryness in vacuo. Crystallization from methanol gave the title compound, m.p. 147-149 ° C.

¹ H NMR (DMSO-d ₆ + D ₂ O): 3.1-3.5 (2H, complex), 3.3 (3H, s), 3.95 (2H, complex),

4.25 (2H, complex), 4.4 (1H, complex), 6.8-7.3 (8H, complex).

Example 4

5- (4- (2 - (/ V-methyl-A / - (2-benzoxazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

-33Solution 1.6 g of 4- (2- (N-methyl- N - (2-benzoxazolyl) amino) ethoxy) benzaldehyde and

0.63 g of 2,4-thiazolidinedione in 100 ml of toluene containing a catalytic amount of piperidinium acetate is heated under reflux for 2 hours using a Dean-Stark apparatus. The mixture was cooled and filtered to give the title product, m.p. 227-229 ° C.

¹ H NMR (DMSO-d 6): 3.2 (3H, s), 3.9 (2H, t), 4.3 (2H, t), 6.9-7.75 (10H, complex).

Example 5

5- (4- (2- (N-methyl- / V- (2-pyrimidinyl) ethoxy) benzyl) -2,4-thiazolidinedione

2.4 g of 5- (4- (2 - (N-methyl-N- (2-pyrimidinyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione in 150 ml of anhydrous 1,4-dioxane are reduced with hydrogen in the presence of 3 g of 10% palladium on activated carbon until the consumption of hydrogen ceased. Then the solution is filtered through a pad of diatomaceous earth, the filter cake is washed thoroughly with dioxane, the filtrates are combined and evaporated to dryness in vacuo. Crystallization of the residue from methanol yields the title compound, m.p. 150-151 ° C.

¹ H NMR (DMSO-d 6): 2.9-3.4 (2H, complex), 3.2 (3H, s), 3.9 (2H, complex), 4.2 (2H, complex), 4 9 (1H, complex), 6.6 (1H, t), 6.9 (2H, d), 7.2 (2H, d), 8.4 (2H, d), 12.0 (1H, wide s, exchange with D ₂ O).

Example 6

5- (4- (2 - (/ V-methyl-A / - (2-pyrimidinyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

1.7 g of 4- (2- (N-methyl-N- (2-pyrimidinyl) amino) ethoxy) benzaldehyde and 0.7 g of 2,4-thiazolidinedione are dissolved in 100 ml of toluene containing a catalytic amount of pyridinium acetate and the mixture is boiled 2 hours under reflux using a Dean-Stark apparatus. The mixture was cooled and filtered to give the title product, m.p. 189-190 ° C.

¹ H NMR (DMSO-d ₆ + D ₂ O): 3.2 (3H, s), 3.7-4.4 (4H, complex), 6.6 (1H, t), 7.1 (2H) d), 7.5 (2H, d), 7.7 (1H, s), 8.4 (2H, d).

Example 7

5- (4- (2 - (/ V-methyl- / V- (2- (4,5-dimethylthiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

Dissolve 1.6 g of 5- (4- (2 - (N-methyl- N - (2- (4,5-dimethylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione in a mixture of 50 ml of methanol and 50 ml dioxane. Then add

1.5 g of magnesium sawdust and the solution was stirred until gas evolution ceased. The mixture was poured into 300 ml of water, acidified by the addition of 2M hydrochloric acid to give a solution which was neutralized with a saturated aqueous sodium bicarbonate solution, filtered and dried. The solid is then dissolved in 100 ml of dioxane, absorbed onto 20 g of silica and the resulting material is then obtained by chromatography on silica gel using 5% dioxane.

-35 in dichloromethane as eluent. After crystallization, the title compound is obtained with a melting point of 177 ° C.

¹ H NMR (DMSO-d 6): 2.05 (3H, s), 2.15 (3H, s), 3.0 (3H, s), 3.0-3.4 (2H, complex),

3.8 (2H, t), 4.2 (2H, t), 4.85 (1H, complex), 6.9 (2H, d), 7.1 (2H, d), 12.0 (1H , wide s, exchange with D ₂ O).

Example 8

5- (4- (2- (N-methyl- N - (2- (4,5-dimethylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidine dione

The resulting product, m.p. 175 DEG C., was prepared in a similar manner to the product of Example 4.

¹ H NMR (DMSO-d 6): 2.0 (3H, s), 2.1 (3H, s), 3.0 (3H, s), 3.7 (2H, t), 4.25 (2H t, 7.1 (2H, d), 7.55 (2H, d), 7.75 (1H, s), 12.0 (1H, broad s, exchange with D ₂ O).

Example 9

5- (4- (2 - (/ V-methyl- / V- (2-thiazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product, m.p. 186 DEG C. after recrystallization from methanol, can be obtained in a similar manner to the product of Example 7.

-36 ¹ H NMR (DMSO-d ₆ ): 3.0-3.4 (2H, complex), 3.1 (3H, s), 3.8 (2H, t), 4.2 (2H, t ), 4.85 (1H, complex), 6.7-7.3 (6H, complex), 12.0 (1H, broad s, exchange with D ₂ O).

Example 10

5- (4- (2 - (/ V-methyl - / \ / - (2-thiazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product having a melting point of 212 ° C can be prepared in a similar manner to the product of Example 4.

¹ H NMR (DMSO-d ₆ ): 3.1 (3H, s), 3.85 (2H, t), 4.3 (2H, t), 6.75 (1H, d), 7.1- 7.3 (3H, complex), 7.6 (2H, d), 7.75 (1H, s), 12.0 (1H, broad s, exchange with D ₂ O).

Example 11

5- (4- (2 - (/ V-methyl- / V- (2- (4-fenyltiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product, m.p. 62-65 ° C, is obtained as a foam in the form of 1.6 g of 5- (4- (2- (N-methyl- N - (2- (4-phenylthiazolyl)) amino)) (ethoxy) -benzylidene) -2,4-thiazolidinedione in a similar manner to Example 7.

¹ H NMR (DMSO-d 6): 3.15 (3H, s), 3.0-3.4 (2H, complex), 3.9 (2H, t), 4.25 (2H, t),

4.85 (1H, complex), 6.9 (2H, d), 7.1-7.45 (6H, complex), 7.85 (2H, d), 12.0 (1H, broad s, exchange) with D ₂ O).

Example 37

5- (4- (2 - (/ V-methyl- / V- (2- (4-fenyltiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product, m.p. 134 ° C, was prepared using 4- (2- (2- (N-methyl- N - (2- (4-phenylthiazolyl)) amino) ethoxy) benzaldehyde as in Example 4. ¹ H NMR ( DMSO-d6): 3.2 (3H, s), 3.9 (2H, t), 4.32 (2H, t), 7.1-7.95 (11H, complex), 12.0 ( 1H, broad s, exchange with D ₂ O).

Example 13

5- (4- (2 - (/ V-methyl-A / - (2- (4-phenyl-5-methyl-thiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product is obtained in the form of a foam with a melting point of 60-62 ° C in an analogous manner to the resulting product of Example 7.

¹ H NMR (DMSO-d 6): 2.35 (3H, s), 3.1 (3H, s), 3.0-3.4 (2H, complex), 3.8 (2H, t),

4.2 (2H, t), 4.85 (1H, complex), 6.9 (2H, d), 7.2 (2H, d), 7.25 - 7.5 (3H, complex), 7 65 (2H, d), 12.0 (1H, broad s, exchange with D ₂ O).

Example 14

5- (4- (2 - (/ V-methyl- / V- (2- (4-phenyl-5-methyl-thiazolyl)) amino) ethoxy) benzylidene) -2,4-tiazoiidíndión

The resulting product can be prepared from 4- (2- (N-methyl-N- (2- (4-phenyl-5-methylthiazolyl)) amino) ethoxy) benzaldehyde in a similar manner to the product of Example 4. This material is used. in Example 13 without further purification.

¹ H NMR (DMSO-d 6): 2.4 (3H, s), 3.1 (3H, s), 3.8 (2H, t), 4.35 (2H, t), 7.1-7 75 (10H, complex), 12.0 (1H, broad s, exchange with D ₂ O).

Example 15

5- (4- (2 - (/ V-methyl-A / - (2- (4-methyl-5-fenyltiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The title compound, m.p. 174 DEG C. after recrystallization from methanol, can be obtained using 5- (4- (2- (N-methyl- N - (2- (4-methyl-5-phenylthiazolyl)) amino) ethoxy). benzylidene) -2,4-thiazolidinedione in an analogous manner to the product of Example 7.

¹ H NMR (DMSO-d ₆ ): 2.3 (3H, s), 3.0-3.4 (2H, complex), 3.15 (3H, s), 3.85 (2H, t),

4.25 (2H, t), 4.85 (1H, complex), 6.95 (2H, d), 7.2 (2H, d), 7.45 (5H, complex), 12.0 (1 H, broad s, exchange with D ₂ O).

Example 16

-395- (4- (2 - (N -methyl- N - (2- (4-methyl-5-phenylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione O

CH,

The resulting product can be prepared using (4- (2- (N-methyl- N - (2- (4-methyl-5-phenylthiazolyl)) amino) ethoxy) benzaldehyde in a similar manner to Example 4. This product is used in Example 15 without further purification.

¹ H NMR (DMSO-d 6): 2.3 (3H, s), 3.1 (3H, s), 3.85 (2H, t), 4.35 (2H, t), 7.15-7 75 (10H, complex), 12.0 (1H, broad s, exchange with D2O).

Example 17

5- (4- (2 - (/ V-methyl- / V- (2- (4-methyl-thiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product is prepared using 5- (4- (2- (N-methyl-N- (2- (4-methylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione as a foam, m.p. 121 ° C in a similar manner to Example 7.

¹ H NMR (DMSO-d 6): 2.1 (3H, s), 3.0-3.4 (2H, complex), 3.1 (3H, s), 3.75 (2H, t),

4.15 (2H, t), 4.85 (1H, complex), 6.3 (1H, s), 6.9 (2H, d), 7.2 (2H, d), 12.0 (1H , wide s, exchange with D ₂ O).

Example 18

-405- (4- (2 - (/ \ / - methyl- / V- (2- (4-methyl-thiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product was prepared and 5- (4- (2- (N-methyl-N- (2- (4-methylthiazolyl)) amino) ethoxy) benzaldehyde) in a similar manner to Example 4. The resulting product was used in Example 17 without further purification. cleaning.

¹ H NMR (DMSO-d ₆ ): 2.1 (3H, s), 3.1 (3H, s), 3.85 (2H, d), 4.3 (2H, d), 6.3 ( 1H, s),

7.15 (2H, d), 7.6 (2H, d), 7.75 (1H, s), 12.0 (1H, broad s, D ₂ O exchange).

Example 19

5- (4- (2- (N-methyl- / V- (2- (5-phenyloxazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product, m.p. 200 ° C after recrystallization from methanol, was prepared using 5- (4- (2- (N-methyl-N - (2- (5-phenyloxazolyl)) amino) ethoxy) benzylidene) -2. 4-thiazolidinedione in a similar manner to the product of Example 7.

¹ H NMR (DMSO-d 6): 3.0-3.4 (2H, complex), 3.15 (3H, s), 3.8 (2H, t), 4.2 (2H, t),

4.85 (1H, complex), 6.9 (2H, d), 7.1-7.4 (6H, complex), 7.5 (2H, d), 12.0 (1H, broad s, exchange) with D ₂ O).

Example 20

-41 5- (4- (2- (N-methyl-N- (2- (5-phenyloxazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product, m.p. 191 DEG C., was prepared from 4- (2- (N-methyl- N - (2- (5-phenyloxazolyl)) amino) ethoxy) benzaldehyde in an analogous manner to the product of Example 4.

¹ H NMR (DMSO-d ₆ ): 3.2 (3H, s), 3.8 (2H, t), 4.35 (2H, t), 7.1-7.7 (10H, complex),

7.8 (1H, s), 12.0 (1H, broad s), exchange with D ₂ O).

Example 21

5- (4- (2 - (/ V-methyl - / \ / - (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione

1.2 g of 5- (4- (2- (N-methyl- N - (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzylidene) 2,4-thiazolidinedione in 100 ml of anhydrous 1 The 4-dioxane is reduced with hydrogen in the presence of 2.5 g of 10% palladium on charcoal until hydrogen uptake ceases, the solution is filtered through diatomaceous earth, the filter cake is thoroughly washed with dioxane and the filtrates are combined, evaporated to dryness. In vacuo, after chromatography on silica gel using 1% methanol as eluent, the title compound is obtained as a foam, m.p. 53-54 ° C.

¹ H NMR (DMSO-d 6): 1.85 (3H, s), 2.05 (3H, s), 3.0 (3H, s), 3.0-3.4 (2H, complex), 3 65 (2H, t), 4.1 (2H, t), 4.85 (1H, complex), 6.85 (2H, d), 7.15 (2H, d), 12.0 (1H, wide s, exchange with D ₂ O).

-42Example 22

5- (4- (2 - (/ V-methyl- / V- (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

n

U

The resulting material having a softening point of 149 ° C was prepared in a similar manner to the product of Example 4.

¹ H NMR (DMSO-d ₆ ): 1.85 (3H, s), 2.05 (3H, s), 3.0 (3H, s), 3.7 (2H, t), 4.35 ( 2H, t)

7.1 (2H, d), 7.5 (2H, d), 7.5 (2H, d), 7.75 (1H, s), 12.0 (1H, broad s, exchange with D ₂ O) ).

Example 23

5- (4- (2- (2-pyrimidinyl) ethoxy) benzyl) -2,4-thiazolidinedione

A mixture of 3 g of 5- (4- (2- (2-pyrimidinylamino) ethoxy) benzylidene) -2,4-thiazolidinedione with 8 g of 10% palladium on charcoal in 70 ml of dimethylformamide is stirred at 1.4 MPa of hydrogen for so long. until hydrogen uptake ceases. The mixture was filtered through diatomaceous earth and the filter cake was washed thoroughly with dimethylformamide. The filtrates were combined, evaporated to dryness and recrystallized from methanol to give the title product, m.p. 173 ° C.

¹ H NMR (DMSO-d 6): 3.0 - 3.4 (2H, complex), 3.65 (2H, complex), 4.1 (2H, t), 4.85 (1H, complex), 6 6 (1H, t), 6.85 (2H, d), 7.15 (2H, d), 7.25 (1H, t, exchange with D ₂ O),

8.5 (2H, d), 12.0 (1H, broad s, exchange with D ₂ O).

-43Example 24

5- (4- (2- (2-pyrimidinylamino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product, m.p. 234 DEG C., was obtained using 4- (2- (2-pyrimidinylamino) ethoxy) benzaldehyde and 2,4-thiazolidinediol in an analogous manner to the product of Example 6.

¹ H NMR (DMSO-d 6): 3.65 (2H, complex), 4.2 (2H, t), 6.6 (1H, t), 7.0-7.6 (5H, complex, single exchange) Proton with D ₂ O), 7.7 (1 H, s), 8.3 (2H, d), 12.0 (1 H, broad s, exchange with D ₂ O).

Example 25

4- (4- (2- (N-acetyl-N- (2-pyrimidinyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione

A solution of 800 mg of 5- (4- (2- (2-pyrimidinylamino) ethoxy) benzyl) -2,4-thiazolidinedione in a mixture of 15 ml of acetic anhydride and 5 ml of 1,4-dioxane is stirred and refluxed for 3 hours. condenser. After cooling, the mixture is poured into 300 ml of water, neutralized with sodium bicarbonate and then extracted with 3 x 200 ml of dichloromethane. The organic extracts were combined, washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness. Chromatography of the obtained oil on silica gel using

-44 dichloromethane as eluent gave the title product, m.p. 137 ° C.

¹ H NMR (DMSO-d 6): 2.3 (3H, s), 2.93 (2H, complex), 4.15 (2H, t), 4.35 (2H, t), 4.85 (1H) , complex), 6.7 (2H, d), 7.1 (2H, d), 7.35 (1H, t), 8.8 (2H, d), 12.0 (1H, broad s, exchange) with D2O).

Example 26

5- (4- (2 - (/ V- (2-benzothiazolyl) - / \ / - benzylamino) ethoxy) benzylidene) -2,4-thiazolidinedione

g of 4- (2- (N - (2-benzothiazolyl) - N -benzylamino) ethoxy) benzaldehyde and 1 g of 2,4-thiazolidinedione are dissolved in 200 ml of toluene containing 0.2 ml of piperidine and 0.2 g of acid of benzoic acid and the mixture was refluxed for 4 hours using a Dean-Stark apparatus. After cooling, the solution was evaporated in vacuo to 50% of its volume. The resultant material, which crystallizes, is collected by filtration and then dried under vacuum. This product, m.p. 185-188 ° C, was used in Example 27 without further purification.

¹ H NMR (DMSO-d 6): 4.0 (2H, t), 4.4 (2H, t), 4.9 (2H, s), 7.1-7.9 (14H, complex), 12 -13 (1 H, br s, exchanges with D ₂ O).

Example 27

5- (4- (2- (N- (2-benzothiazolyl) - / V-benzylamino) ethoxy) benzyl) -2,4-thiazolidinedione

2.4 g of 5- (4- (2 - (N - (2-benzothiazolyl) - N -benzylamino) ethoxy) benzylidene) -2,4-thiazolidinedione in 150 ml dioxane are hydrogenated in the presence of 4.8 g 10 % palladium on activated carbon for 3 hours at room temperature and atmospheric pressure. An additional 2.4 g of catalyst was then added and the hydrogenation was continued for a total of 20 hours. The mixture was filtered through diatomaceous earth and the solvent was evaporated. The residue was chromatographed on silica gel using 3% methanol in dichloromethane as eluent to give the title product as a foam, melting at 78 ° C.

¹ H NMR (CDCl ₃ ): 3.1 (1H, dd), 3.4 (1H, dd), 4.0 (2H, t), 4.25 (2H, t), 4.5 (1H, dd)

4.9 (2H, s), 6.8-7.6 (13H, m), 8.3 (1H, broad s, exchange with D ₂ O).

Example 28

5- (4- (3 - (/ V-methyl- / V- (2-benzoxazolyl) amino) propoxy) benzyl) -2,4-thiazolidinedione

about

The resulting product, m.p. 171-173 ° C after recrystallization from ethanol, can be obtained using 5- (4- (3- (N-methyl-N - (2-benzoxazolyl) amino) propoxy) benzylidene) -2, 4-thiazolidinedione according to the method of Example 1.

¹ H NMR (DMSO-d 6): 2.0-2.35 (2H, complex), 2.9-3.6 (2H, complex), 3.2 (3H, s),

3.7 (2H, t), 4.2 (2H, t), 4.9 (1H, complex), 6.8-7.4 (8H, complex), 12, 12.5 (1H, broad s) , exchange with D ₂ O).

-46Example 29

5- (4- (3 - (/ V-methyl- / V- (2-benzoxazolyl) amino) propoxy) benzylidene) -2,4-thiazolidinedione

The resulting product, m.p. 202-204 ° C, was prepared using 4- (3 - (N-methyl- N - (2-benzoxazolyl) amino) propoxy) benzaldehyde and 2.2 g of 2,4-thiazolidinedione in a similar manner to the product from Example 4.

¹ H NMR (DMSO-d 6): 2.0-2.35 (2H, complex), 3.15 (3H, s), 3.7 (2H, t), 4.2 (2H, t), 7 0 - 7.7 (8H, complex), 7.8 (1H, s), 12.0 (1H, broad s, exchange with D ₂ O).

Example 30

5- (4- (2 - (/ V-methyl- / V- (2-pyridyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione

The resulting product, m.p. 153-155 ° C after recrystallization from methanol, affords 5- (4- (2- (N-methyl- N - (2-pyridyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione according to the method of of Example 4.

¹ H NMR (DMSO-d 6): 2.9-3.4 (2H, complex), 3.1 (3H, s), 3.9 (2H, t), 4.15 (2H, t), 4 Δ (1H, complex), 6.5 - 6.85 (2H, complex), 6.8 (2H, d), 7.2 (2H, d), 7.5 (1H, complex),

8.1 (1H, d), 12.05 (1H, broad s, exchange with D ₂ O).

Example 31

5- (4- (2 - (/ V-methyl - / \ / - (2-pyridyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione

The resulting product, m.p. 177-179 ° C, was obtained using 3.2 g of 4- (2 - (N-methyl- N - (2-pyridyl) amino) ethoxy) benzaldehyde with 1.1 g of 2,4- thiazolidinedione in a similar manner to the product of Example 4 ¹ H NMR (DMSO-D ₂ O): 3.1 (3H, s), 3.9 (2H, t), 4.2 (2H, t), 6.4- 7.5 (7H, complex),

7.7 (1 H, s), 8.1 (1 H, d).

Efficacy of the compounds of the invention

Experiment in obese mice, oral glucose test

Obese (ob / ob) 257p1 / 6 mice were fed a powdered oxoid feed. After at least one week of administration of this feed, the mice were either fed the same feed or were fed the same feed with the compound of interest. After eight days of the experiment, the mice were left without food for five hours, after which they were orally administered 3 g / kg of glucose. Following glucose administration, blood samples were taken to determine the glucose concentration at 0.45, 90, and 135 minutes after glucose administration, and the results were expressed as a reduction in area under the blood glucose concentration percentage as a percentage of the control group. Seven mice were used for each assay. The results are shown in the table.

Example compound no. Amount in feed in pmol / kg feed Reduce area below glucose concentration curve in blood in% 1 100 51 2 300 30 3 10 39 4 300 30 5 100 40 7 50 47 9 100 58 11 100 34 13 100 37 15 100 39 17 100 34 19 30 22 21 30 33 24 30 15 25 30 19 27 300 56 29 300 32

toxicology

No toxic effects could be detected for the desired compound.

Claims (15)

PATENT CLAIMS Claims 1. Thiazolidinedione derivatives of the general formula I A ¹ is one of the groups of formulas a, b or c R '(a) (b) (c) where R ⁴ and R ⁵ independently represent a hydrogen atom, an alkyl of 1 to 6 carbon atoms or together form a group of the formula d R ⁶ and R ⁷ are each independently hydrogen, halogen or C 1 -C 6 alkyl or alkoxy, X is an oxygen or sulfur atom, R ¹ is H, alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms or benzyl, R ² and R ³ are hydrogen or together form a single chemical bond, A ² is a group of formula and en is an integer from 2 to 6. The thiazolidinedione derivatives of claim 1, wherein R ⁶ and R ⁷ are hydrogen atoms. The thiazolidinedione derivatives of claims 1 and 2, wherein n is an integer of 2 or 3. The thiazolidinedione derivatives of claims 1 to 3, wherein R ¹ is methyl. The thiazolidinedione derivatives of claim 1 which are 5- (4- (2- (N-methyl- N - (2-benzothiazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- ( 2-N-methyl-N- (2-benzothiazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, or tautomeric forms and / or salts thereof, pharmaceutically acceptable and / or solvates, pharmaceutically acceptable . The thiazolidinedione derivatives of claim 1 which are 5- (4- (2- (N-methyl-N- (2-benzoxazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- ( 2- (N-methyl- N - (2-benzoxazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, or a tautomeric form and / or a salt thereof, pharmaceutically acceptable and / or solvates, pharmaceutically acceptable . The thiazolidinedione derivatives of claim 1 which are 5- (4- (2- (N-methyl- N - (2-pyrimidinyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2-N-methyl- N - (2-pyrimidinyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, or pharmaceutically acceptable tautomeric forms and / or salts thereof, and / or solvates, pharmaceutically acceptable perspective. -51 The thiazolidinedione derivatives of claim 1 which are 5- (4- (2- (N-methyl- N - (2- (4,5-dimethylthiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione ₁ 5- (4- (2 - (/ V-methyl- / V- (2- (4,5-dimethylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2- (N-methyl- N - (2-thiazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, • 5- (4- (2 - (N-methyl- A / - (2-thiazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ \ / - methyl- / V- (2- (4-fenyltiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, IN 5- (4- (2- (E / methyl - / \ / - (2- (4-fenyltiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl- / V- (2- (4-phenyl-5-methyl-thiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2- (N-methyl- / V- (2- (4-phenyl-5-methyl-thiazolyl)) amino) ethoxy) benzylidene) -2,4tiazolidíndión. 5- (4- (2- (N-methyl-N- (2- (4-methyl-5-fenyitiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2- (N-methyl-N- (2- (4-methyl-5-phenylthiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl- / V- (2- (4-methyl-thiazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl-A / - (2- (4-methyl-thiazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl- / V- (2- (5-phenyloxazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl- / V- (2- (5-phenyloxazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-methyl- / V- (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2- (N-methyl-N- (2- (4,5-dimethyloxazolyl)) amino) ethoxy) benzylidene) -2,4-thiazolidinedione; - (2-pyrimidinylamino) ethoxy) benzyl) -2,4-thiazolidinedione,. 5- (4- (2- (2-pyrimidinylamino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2 - (/ V-acetyl- / V- (2-pyrimidinyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2 - (/ V- (2-benzothiazolyl) - / V-benzylamino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (2 - (/ V- (2-benzothiazolyl) - / V-benzylamino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (3- (S / N-methyl-A / - (2-benzoxazolyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione, 5- (4- (3- (N-methyl- / V- (2-benzoxazolyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione, 5- (4- (2- (N-methyl- N - (2-pyridyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione and -525- (4- (2- (N-methyl- N - (2-pyridyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione or their tautomeric forms and / or their salts, pharmaceutically acceptable; and and / or solvates thereof, which are pharmaceutically acceptable. The thiazolidinedione derivative according to claim 1 which is 5- (4- (2- (N-methyl- N - (2-pyridyl) amino) ethoxy) benzyl) -2,4-thiazolidinedione or its tautomeric form and / or or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof. The thiazolidinedione derivative according to claim 1 which is 5- (4- (2- (N-methyl-N- (2-pyridyl) amino) ethoxy) benzylidene) -2,4-thiazolidinedione or its tautomeric form and / or its a pharmaceutically acceptable salt and / or a pharmaceutically acceptable solvate thereof. Pharmaceutical composition for reducing glucose concentration and / or reducing hyperlipidemia, characterized in that it comprises as its active ingredient a thiazolidinedione derivative of the formula I according to claim 1, or a tautomeric form thereof and / or a pharmaceutically acceptable salt thereof, and / or or a pharmaceutically acceptable solvate thereof. The thiazolidinedione derivatives of the formula I according to claim 1, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their solvates, pharmaceutically acceptable for use in therapy. The thiazolidinedione derivatives of the general formula I according to claim 1, their tautomeric forms and / or their pharmaceutically acceptable salts and / or their solvates, pharmaceutically acceptable for use in the treatment and / or prevention of hyperglycemia. Use of thiazolidinedione derivatives of the general formula I according to claim 1, or their tautomeric forms and / or their salts, acceptable from a pharmaceutical 53 aspects and / or solvates thereof, pharmaceutically acceptable for the manufacture of a medicament for the treatment and / or prevention of hyperglycemia. Use of thiazolidinedione derivatives of the general formula I according to claim 1, or their tautomeric forms and / or their pharmaceutically acceptable salts and / or their solvates, pharmaceutically acceptable for the manufacture of a medicament for the treatment and / or prevention of hyperlipidemia.