OA12492A - New salt of thiazolidinedione and its polymorphs as antidiabetic agents and method for obtaining them. - Google Patents

Description

012492

NEW SALT OF THIAZOLIDINEDIONE AND ITS POLYMORPHS AS

ANTIDIABETIC AGENTS AND METHOD FOR OBTAINING THEM 5 Field of the invention

This invention relates to a newthiazolidinedione and its polymorphe whichhypoglycémiant activity and which are sait ofhas hightherefore potentially useful in the treatment and/or prophylaxis of 10 diabètes and/or other inhérent to diabètes, hyperlipidemia. alterationssuch as or complicationshyperglycemia or

This invention also relates to a method for making 15 said new sait of thiazolidinedione, together with itspolymorphs.

Background of the invention 20 Spanish patent application no. 9902533 disclosed compounds of thiazolidinedione which présent highhypoglycémiant activity and which are thereforepotentially useful in the treatment and/or prophylaxis ofdiabètes and/or other alterations or complications 25 inhérent to diabètes, such as hyperglycemia or hyperlipidemia.

Notable among these is the compound 5-(4-{2-[(6-methoxypyrimydin-4-yl)-methyl-amino]-ethoxy}-benzyl)- 30 thiazolidin-2,4-dione (hereinafter referred to as CompoundI) , described in that application in the form of a freebase. Compound I in free base form présents problème ofstability and solubility what do not permit it to bepurified and handled suitably. 35

DUPLICATA 012492 2

The bibliography contains a description (WO9405659) of an improvement in the aqueous stability andsolid-form stability of thiazolidinediones of structuresimilar to that of Compound I, by means of formation of5 the corresponding salts of acids, preferably of maleic acid.

However, Compound I does not form salts with acidssuch as tartaric or citric acid, and its corresponding10 salts with hydrochloric and maleic acid do not possessdésirable aqueous solubility, nor good stability of said solution.

Surprisingly, the authors of this invention hâve15 found a new sait of Compound I which is of high aqueoussolubility (higher than 1 mg/ml) and good stability.Advantageously, the new sait object of this inventionpermits its purification without problème ofhygroscopicity or formation of solvatés, which20 characteristics provide it with significant advantages forits industrial formulation and use. The new sait also shows a better oral absorption profile than the free base.

Description of the invention25

The- object of this invention is the sodium sait of 5- (4-{2-[(6^methoxy-pyrimydin-4-yl)-methyl-amino]-ethoxy}-benzyl)-thiazolidin-2,4-dione (hereinafter referred to asSodium Sait). 30

Also object of this invention are threepolymorphie forms of the Sodium Sait, which are disclosedbelow. a) A polymorphie form of the Sodium Sait35 (hereinafter called Polymorph I) characterised in that it

DUPLICATA 012492 3 présents a X-ray powder diffractogram using Cu Karadiation in accordance with Figure 4. The positions ofseveral significant peaks of said diffractogram arepresented in Table 1. 5 Polymorph I provides an IR, spectrum which présents the following characteristic bands at 3009, 2990, 2915 and2904 nm, and of weak intensity at 1427, 1226, 1026, 553 nm(see Figure 1). 0

Table 1

Angle 20 [°] d value O [A] Hkl indices 3.16 ± 0.10 28.0 ± 0.1 00 1 6.31 ± 0.05 14.01 ± 0.05 002 9.47 ± 0.05 9.33 ± 0.05 003 15.78± 0.05 5.61 ± 0.05 1 1 0 18.19 ± 0.05 4.87 + 0.05 0 1 4 19.39 ± 0.05 4.57 ± 0.05 2 0-3 20.68 ± 0.05 4.29 ± 0.05 1 1 4 22.47 ± 0.05 3.96 ± 0.05 2 1 1 29.92 ± 0.05 2.98 ± 0.05 2 0-8 15 b) A polymorphie form of the Sodium Sait(hereinafter called Polymorph II) characterised in that itprovides a X-ray powder diffractogram using Cu Karadiation in accordance with Figure 5. The positions of 20 several significant peaks of said diffractogram arepresented in Table 2.

DUPLICATA 012492

Table 2

Angle 20 [°] d value [Â] 2.96 ± 0.10 29.9 ± 0.1 5.92 ± 0.05 14.93 ± 0.05 8.87 ± 0.05 9.97 + 0.05 13.58 ± 0.05 6.52 ± 0.05 15.95 ± 0.05 5.55 + 0.05 16.41 ± 0.05 5.40+ 0.05 21.55 ± 0.05 4.12 ± 0.05 26.13 ± 0.05 3.41 + 0.05 5 c) A polymorphie form of the Sodium Sait (hereinafter called Polymorph III) characterised in thatit provides a X-ray powder diffractogram using Cu KSeradiation in accordance with Figure 6. The positions ofseveral significant peaks of said diffractogram are 10 presented in Table 3.

Table 3

Angle 20 [°] d value [A] 3.14+ 0.10 28.1 ± 0.1 6.25 ± 0.05 14.13 ± 0.05 9.40 ± 0.05 9.41 ± 0.05 14.43 ± 0.05 6.13 ± 0.05 15.79+ 0.05 5.61 + 0.05 16.52 ± 0.05 5.36+ 0.05 18.05+ 0.05 4.91 ± 0.05

DUPLICATA 012492 5

The IR spectra of Polymorphe II (see Figure 2) andIII (see Figure 3) clearly show différences between theintensifies of the bands between 1200-1185 nm and 570-550nm (see Figures 10 and 11) . Despi te the fact that small5 différences in the spectra can be discerned, the IRtechnique is not very précisé for distinguishing thePolymorphe II and III from each other, although it doespermit these two polymorphe to be distinguished from

Polymorph I. 10

Polymorph I is monoclinic. The organic anion has achiral centre and both enantiomers are présent inPolymorph I. The sodium cation is surrounded by fouroxygen atoms, two nitrogen atoms and one sulphur atom15 belonging to the 1,3- thiazolidin-2,4-dione fragment offive anions. With two of them it forms four-memberchelates through the nitrogen and one oxygen. Thecoordination polyhedron - of the sodium is a highlydistorted pentagonal bipyramid. The ions are arranged in a20 crystal in the form of layers parallel to the plane (001).The centre of the layers is made up of the sodium cationssurrounded by the 1,3- thiazolidin-2,4-dione fragments.The tails of the anions are removed to either side of this central part (see Figure 8) . 25

Also object of this invention is a method forpreparing the Sodium Sait. The Sodium Sait can be preparedby causing 5-(4-{2-[ (6-methoxy-pyrimydin-4-yl)-methyl-amino]-ethoxy}-benzyl)-thiazolidin-2,4-dione to react with30 a source of sodium ion (Na+) of base character, such assodium hydroxide, sodium alkoxide, sodium hydride, in a suitable solvent.

Also object of this invention is a method for3 5 preparing the Polymorph I. Polymorph I can be prepared by

DUPLICATA 012492 précipitation or by crystallisation. Thus, a method forpreparing Polymorph I according to the inventioncomprises : a) preparing a solution of the Sodium Sait, in anorganic solvent or in a mixture of solvents, under reflux,and cooling to room température, or b) preparing a saturated solution of the SodiumSait at room température in methyl or ethyl alcohol andcooling to a température lower than room température, or c) preparing a solution of the Sodium Sait inwater or methyl alcohol and pouring it into aninsolubilising solution, or d) causing a solution of 5-(4-{2-[(6-methoxy-pyrimydin-4-yl)-methyl-amino]-ethoxy}-benzyl)-thiazolidin-2,4-dione in isopropanol to react under reflux with asource of sodium ion of base character, preferably sodiumhydroxide, and cooling to a température lower than roomtempérature. and then isolating the polymorphie form of the solvent.

Also object of this invention is a method formaking Polymorph II. Polymorph II can be prepared byévaporation. Thus, a method for preparing Polymorph IIaccording to the invention comprises: a) -preparing a solution of the Sodium Sait inwater or in an alcohol and eliminating the solvent byévaporation at atmospheric pressure, at room température,or b) preparing a solution of the Sodium Sait in analcohol and eliminating the solvent by évaporation at lowpressure and within a température range of 30-80°C.

Also object of this invention is a method formaking Polymorph III. Polymorph III can be prepared by

DUPLICATA 012492 7 évaporation of an aqueous solution. Thus, a method forpreparing Polymorph III according to the inventioncomprises preparing a solution of the Sodium Sait in waterand eliminating the solvent at low pressure and within atempérature range of 40-80°C.

The Compound (I) is prepared as described inSpanish patent application no. 9902533, whose content isincorporated herein by way of reference.

The compounds object of this invention présenthyperglemic and hyperlipidic activity.

The invention thus provides the Sodium Sait andits polymorphie forms called Polymorphs I, II and III foruse as a therapeutically active substance, and inparticular for use in the treatment and/or prophylaxie ofhyperglicemia and/or hyperlipidemia and/or for use in thetreatment of complications associated with résistance toinsulin, such as hypertension, hyperuricemia or othercardiovascular, metabolic and endocrine disorders.

The compounds object of this invention can be usedalone or in combination with one or more antidiabeticagents such as the sulfonylureas, biguanides,_ alphaglucosidase inhibitors, beta agonists or insulin.

Thus, under another aspect, this inventionprovides the Sodium Sait and the polymorphie forms thereofcalled Polymorph I, II and III, alone or in combinationwith one or more antidiabetic agents, for the manufactureof a medicine for the treatment and/or prophylaxis ofhyperglycemia and/or hyperlipidemia and/or for thetreatment of complications associated with résistance to

DUPLICATA 012492 insulin, such as hypertension, hyperuricemia or othercardiovascular, metabolic and endocrinal disorders.

The compounds object of this invention can beadministered as they are or, preferably, as apharmaceutical composition which includes at least onepharmaceutically acceptable excipient.

In accordance with this, this invention provides apharmaceutical composition which includes the Sodium Saitand the polymorphie forms thereof named Polymorphs I, IIand III, and a therapeutically active and suitablequantity of at least once excipient.

The compositions provided by this invention can beadministered by any appropriate via, but preferably orallyor parenterally.

The compositions for parentéral or topicaladministration can be injectable solutions, infusions,suppositories or transdermic Systems. The pharmaceuticalcompositions for oral administration can be solid, such astablets or capsules prepared by the conventional meanswith pharmaceutically acceptable excipients, or ïiquidssuch as aqueous or oleous solutions, syrups, élixirs,émulsions or suspensions prepared by the conventionalmeans with pharmaceutically acceptable additives.

Tablets and capsules are the preferred forms ofadministration.

In accordance with conventional pharmaceuticalpractice, the excipients can include diluents,disintegrators, wetting agents, lubricants, colorants,flavourings or other conventional adjuvants.

DUPLICATA 012492

Typical excipients include, for example,microcrystalline cellulose, starch, polyvinyl pyrrolidone,magnésium stéarate or sodium lauryl sulphate.

Description of the figures

Figure 1 shows the IR spectrum of Polymorph I. They-axis shows the percentage of transmittance and the x-axis the frequency expressed in cm'1.

Figure 2 shows the IR spectrum of Polymorph II.

Figure 3 shows the IR spectrum of Polymorph III.

Figure 4 shows the X-ray powder diffractogram ofPolymorph I. The y-axis shows the counts and the x-axisangle 2 Thêta.

Figure 4 shows the X-ray powder diffractogram ofPolymorph II.

Figure

Polymorph II.

FigurePolymorph III.

FigurePolymorphs I, shows the X-ray powder diffractogram of shows the X-ray powder diffractogram of 7 shows the three X-ray diffractograms of II and III, respectively, in order tofacilitate comparison thereof, where PI indicatesPolymorph I, P II Polymorph II and P III Polymorph III.

Figure 8 shows the contents of the elemental cellof Polymorph I. .

Figure 9 shows an enlargement of the IR spectrumof Polymorph I, of>the zone included between 2700 and 3150 cm -1

Figure 10 shows an enlargement of the IR spectrumof Polymorph II, of the zone included between 2 700 and3150 cm'1.

DUPLICAŒA 012492 10

Figure 11 shows an enlargement of the IR spectrumof Polymorph III, of the zone included between 2700 and3150 cm-1.

Experimental Part

Below, by way of non-restrictive explanation ofthe invention, is an outline of the following examples.

EXAMPLES OF SYNTHESIS

Example 1:

Sodium_Sait_of_5-(4-(2- (6-methoxy-pyrimydin-4-yl) amino) ethoxy) benzyl) thiazolidin-2,4-dione

To a suspension of 12.0 g of 5-(4-(2-(6-methoxy-pyrimydin- 4-yl) amino) ethoxy)benzyl) thiazolidin-2,4-dione in 60 mlof 95% EtOH is added drop by drop a solution of 1.4 g ofNaOH in a mixture of 6.0 ml of 95% EtOH and 3.6 ml ofwater. Once addition is completed, the mixture is stirredfor 2 hours at room température.

The mixture is cooled to 0-5°C, stirred for one hour andfiltered. The solid is dried in an oven at 40°C. 11Γ5 g ofthe product of the title is obtained. Yield: 90.8%._

Most of the product obtained corresponds to Polymorph I. XH-NMR spectrum (200 MHz, D2O, δ ppm, TMS) : 8,0 (s, 1H, pirimidine) / 7,0 (d, 2H, bencenic ring) / 6,65 (d, 2H, bencenic ring) / 5,6 (s, 1H, pirimidine) /4,4 (d x d, 1H,thiazolidindione) / 4,0 (sc, 2H, CH2O) / 3,7 (sc, 2H,NCH2) / 3,7 (s, 3H, OCH3) / 3,2 (d x d, 1H, CH2 bridge) / 2,85 (s, 3H, NCH3) / 2,8 (d x d, 1H, CH2 bridge).

DUPLICATA 012492 11

Example 2 :

Sodium Sait_of_5-(4-(2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 11.5 g of the product obtained in example 1 is suspendedin 46 ml of IPA. The mixture is stirred and heated underreflux. Water is then added drop by drop until dissolution(12 ml) . The heating is turned off and the mixture isstirred for a few hours. It is cooled to 0-5°C. It isstirred for one hour and filtered. The solid is dried inan oven at 40°C. 9.7 g of the product of the title is obtained. Recryst. yield: 84.3%.

Melting point: décomposition at approx. 240°C. IR spectrum (KBr) (Polymorph I) : 3000-3050 (t CH ar.) /2900-3000 (t CH al.) / 1670, 1600 (t C=N) / 1560 (t C=O) /1540, 1510 (t C=C ar.) / 1230 (t C-0). X-ray spectrum: coïncides with the diffractogram ofPolymorph I.

Example 3 :

Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydinr4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 0.1 g of the product obtained in Example 1 is dissolved in3 ml of water. The solution is poured ail at once, withagitation and at room température, onto 30 ml of acetone.

It is left to rest. It is filtered and the precipitatedproduct is dried to obtain the product of the title.

DUPLICATA 12 X-ray spectrum: coïncides with the diffractogram ofPolymorph I.

Examples 4-8: 5 Sodium_Sait_of_5-(4-(2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 0.1-0.3 g of the product obtained in Example 1 isdissolved in 10 ml of éthanol. The solution is poured ail 10 at once, with agitation and at room température onto 100ml of the solvents indicated below: EXAMPLE Solvent 4 Tetrahydrofuran 5 Acetone 6 Ethyl acetate 7 Chloroform 8 Toluene

It is left to rest. It is filtered and the precipitated15 product is dried to obtain the product of the title. X-ray spectrum: the dif f ractogram of Polymorph (I) isobtained in ail cases. 20 Examples 9-19:

Sodium_Sait of 5-(4-(2-(6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I)

The product obtained in Example 1 is dissolved in a25 solvent under reflux. The resuiting solution is left tocool slowly with stirring to room température. The solidobtained is filtered and dried to obtain the product of the title.

DUPLICATA 0.12492 13

The table which follows shows the amounts of the productof Example 1 used, together with the volume and thesolvent or mixture of solvents used. EXAMPLE Quant ityExample 1 (g) Solvent (s) Vsolvent (ml) 9 0.52 Methanol 20 10 0.48 Ethanol 124 11 0.32 Isopropyl alcohol 232 12 0.41 Water : Acetone 1.2:10 13 1.51 Water : Isopropyl alcohol 3.5:20 14 0.40 Methanol : Acetone 15:20 15 0.50 Methanol : Ethyl Acetate 20:20 16 0.16 Ethanol : Acetone 15:15 17 0.17 Ethanol : Ethyl Acetate 37:37 18 0.21 Ethanol : THF 31:31 19 0.40 Ethanol : Toluene 73:20 X-ray spectrum: the diffractogram of Polymorph (Γ) isobtained in ail cases. 10

Example 20:

Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 15 A saturated solution of the product obtained in Example 1in éthanol is prepared.

The solution is left to cool to 2°C.

DUPLICATA 14

After 48 hours the crystallised product is filtered anddried to obtain the product of the title. X-ray spectrum: coïncides with the diffractogram of5 Polymorph I.

Example 21:

Sodium_Sait_of_5-(4-(2 - (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 10 A saturated solution of the product obtained in Example 1in methanol is prepared.

The solution is left to cool to 2°C. 15

After 48 hours the crystallised product is filtered anddried to obtain the product of the title. ! X-ray spectrum: coïncides with the diffractogram of20 Polymorph I.

Example 22:

Sodium_Sait_of_5-(4-(2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorplï J) 25 A saturated solution of the product obtained in Example 1in éthanol is prepared.

The solution is left to cool to -3°C. 30

After 48 hours the crystallised product is filtered anddried to obtain the product of the title. X-ray spectrum: coïncides with the diffractogram of35 Polymorph I.

DUPLICATA 012492 15

Example 23:

Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph I) 5 12.0 g of 5-(4-(2-(6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione is suspended in48 ml of isopropanol. The mixture is agitated and heatedunder reflux. A solution of 1.36 g of NaOH in 12 ml of 10 water is added drop by drop. Once the addition iscompleted, 2 ml of water is added drop by drop. Thesuspension then changes to a solution. The heating isturned off. The mixture is agitated until it reaches roomtempérature, during which time it is turned once again 15 into a suspension. It is then cooled to 0-5°C, agitatedfor one hour and filtered. The solid is dried in an ovenat 40°C. 9.9 g of the product is obtained.

Yield: 78.1%. 20 Melting point: décomposition at approx. 240°C. IR spectrum (KBr) (Polymorph I): 3000-3050 (t CH ar.) /2900-3000 (t CH al.) / 1670, 1600 (t C=N) / 1560 (t C=O) /1540, 1510 (t C=C ar.) / 1230 (t C-O). 25 X-ray speetrum: coïncides with the diffractogram ofPolymorph I.

Example 24: 3 0 Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph II) 0.15 g of the product obtained in Example 1 is dissolvedin 5 ml of water. 35

DUPLICATA 012492 16

The solvent is evaporated at room température incrystallisation capsules to obtain the product of thetitle. 5 IR spectrum (KBr): coïncides with Figure 2. X-ray spectrum: coïncides with the diffractogram ofPolymorph II. 10 Example 25:

Sodium_Sait_of_5-(4-(2 - (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph II) 0.15 g of the product obtained in Example 1 is dissolved15 in 20 ml of methanol.

The solvent is evaporated at room température in crystallisation capsules > to obtain the product of the title. 20 X-ray spectrum: coïncides with the diffractogram of Polymorph II. Example 26: 25 Sodium Sait of 5-(4 -(2-(6-methoxypyrimydin-4 ζΣΐλ amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph..11) 0.15 g of the product obtained in Example 1 is dissolvedin 180 ml of éthanol. 30

The solvent is evaporated at room température incrystallisation capsules to obtain the product of thetitle.

DUPLICATA 012492 17 X-ray spectrum: coïncides with the diffractogram ofPolymorph II.

Example 27 : 5 Sodium_Sait_of_5-(4-(2-(6-methoxypyr imydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph II) 0.5 g of the product obtained in Example 1 is dissolved in50 ml of methanol. 10

The solvent is eliminated at low pressure, keeping thetempérature of the bath at 50°C to obtain the product ofthe title. X-ray spectrum: coïncides with the diffractogram of15 Polymorph II.

Example 28:

Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph II) 20 0.5 g of the product obtained in Example 1 is dissolved in500 ml of éthanol.

The solvent is eliminated at low pressure, keepiîig the25 température of the bath at 50°C to obtain the product of the title. - X-ray spectrum: coïncides with the diffractogram ofPolymorph II. 30

Example 29:

Sodium_Sait_of_5- (4- (2- (6-methoxypyrimydin-4-yl) amino)ethoxy)benzyl)thiazolidin-2,4-dione (Polymorph III)

DUPLICATA 012492 18 0.5 g of the product obtained in Example 1 is dissolved in0.5 ml of water.

The solvent is eliminated at low pressure, keeping the5 température of the bath at 70 °C to obtain the product of the title. IR spectrum (KBr): coïncides with Figure 3. 10 X-ray spectrum: coïncides with the diffractogram ofPolymorph III.

DUPLICATA

Claims (11)

012492 19 CLAIMS 1. Sodium salt of 5- (4- {2 - [(6-methoxy-pyrimidin-4-yl) -methylamino] -ethoxy} -benzyl) thiazolidin-2,4-dione. 2. Polymorphism of the compound as claimed in Claim 1, characterized in that it is shown in Figure 4. Its X-ray powder 3. Polymorphic form of the compound as claimed in Claim 1, characterized by its X-ray powder Diffractogram is shown in Figure 5. 4. Polymorphism form of the compound as claimed inClaim 1, characterized in that its X-ray powderdiffractogram is shown in Figure 6. Claim 1, characterized in that it includes 5- (4- {2 - [(6-methoxy-pyrimidin-4-yl) -methyl-amino] -ethoxy} -benzyl) Thiazolidin-2,4-dione to react with a source of sodium ion (Na +) of base character. 6. Sodium hydroxide, sodium alkoxide or sodium hydride. A method for making a compound as claimed in claim 2, characterized in that it comprises: a) preparing a solution of the compound as claimed in Claim 1, in an organic solvent or in a mixture of solvents, under reflux, and cooling to room temperature, or b) preparing a saturated solution of the compoundas claimed in Claim 1, at room temperature in methyl or 30 ethyl alcohol and cooling to a temperature lower than roomtemperature, or c) preparing a solution of the compound as claimedin Claim 1, in and (d) a solution of 5- (4- {2 - [(6-methoxy-pyrimidin-4-yl) -methyl-amino] -ethoxy} - benzyl) -thiazolidin-2,4-dione in isopropanol to react with sodium hydroxide, preferably sodium hydroxide, and cooling slowly to a temperature lower than room temperature, and then recovering the polymorphic form of the solvent. A method for making a compound as claimed inClaim 3, characterized in that it comprises: a) preparing a solution of the compound as claimed in Claim 1, in water or in an alcohol, and eliminating thesolvent by evaporation at atmospheric pressure, temperature, gold b) preparing a solution of the compound as claimed in Claim 1, in an alcohol, and eliminating the solvent by evaporation at low temperature and temperature range of 30-80 ° C. A method of making a compound as claimed in claim 4, characterized in that it comprises a solution of the compound having a temperature of 40-80 ° C. 10. Pharmaceutical composition, which comprises a compound of any one of Claims 1 to 4, which is a pharmaceutically active ingredient and a suitable quantity of at least one excipient. 11. Compound as defined in any of claims 1 to 4 for use as an antihyperglycemic agent and / or anantihyperlipidemic agent and / or an insulin sensitizer. 12. Use of a compound as defined in any of claims 1 to 4, alone or in combination with such or such sulfonylureas, biguanides, alpha glucosidase inhibitors, beta agonists or insulin, for the manufacture of a drug for treating / or 35 prophylaxis of hyperglycemia and / or hyperlipidemia and / or DU, for the treatment of complications with toinsulin resistance, such as hypertension, hyperuricemia or othercardiovascular, metabolic and endocrinal disorders. TOTAL PAGES 24 pages BY PROXY FOR THE ACCOUNT DELABORATORIOS VITA, SA ÿ-O CABINET EKANI ADVICE ι ΰϊίίΰ ΰϊίίΰ ΰϊίίΰ f f f,,,, l l l l l l l l l l l l l l l «« «« « TURRFTEP / ÜNTfct ü »" sa Z FAX 224> .u bUB.K 585g YA »üNOË gold DUPLICATE