MXPA01000979A - Antidiabetic piperazine derivatives, processes for their preparation and compositions containing them - Google Patents

Abstract

The invention relates to novel piperazine derivatives of formula (I) wherein (Z)i, X, N and Ar have the meanings as given in claim 1, and which are of use in the treatment of pathologies associated with insulin-resistance syndrome.

Description

DERIVATIVES OF THE PIPERAZINE WITH ANTIDIABETIC EFFECT, PROCEDURES FOR ITS PREPARATION AND COMPOSITIONS THAT THEY CONTAIN THEM DESCRIPTION OF THE INVENTION The present invention relates to the new piperazine derivatives that can be used in the treatment of pathologies associated with the insulin resistance syndrome. The compounds of the invention respond to the formula: where n represents 2, 3, 4, 5 or 6; X represents O or S; Ar represents an aromatic nucleus selected from the group consisting of phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, the aromatic nucleus being optionally substituted with one or more radicals selected from a group of Ref: 125947 halogen atom; an alkoxy group (C? _6); an aryloxy group (C6-? o); a group of aryl (C6 -? _ o) alkoxy (C? _6) in which the part of the aryl is optionally substituted with halogen, alkyl (C! _6) or alkoxy (C? _6); and an alkyl group (Ci-β) substituted with one or more halogen atoms; i represents 0, 1, 2, 3 or 4; and each Z group independently represents a halogen atom; and also the salts of these compounds obtained by the addition of bases or acids acceptable from the pharmaceutical point of view. The invention also relates to the solvates of the compounds of formula I. By "alkyl" is meant, according to the invention, a straight or branched chain hydrocarbon group. As examples of alkyl groups may be mentioned methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, tertbutyl, isoamino, teramyl, sec-amyl, pentyl and hexyl groups. The alkyl portions of the alkoxy and arylalkoxy groups have the same definition as indicated above for the alkyl group. As examples of the alkyl groups substituted with one or more halogen atoms can be cite perfluoroalkyl groups such as trifluoromethyl or pentafluoroethyl. The aryl group is a mono- or polycyclic aromatic group, preferably mono- or bicyclic, such as phenyl or naphthyl. This same definition applies to the aryl portions of the aryloxy and arylalkoxy groups. The halogen atoms are selected from the group consisting of bromine, fluorine, iodine and chlorine. When Ar represents a substituted phenyl, then the phenyl nucleus can carry one, two, three, four or five substituents. However, when Ar represents a substituted phenyl, the latter is preferably mono-, di- or tri-substituted. In this case, the substituents are preferably in the meta or para position. Among the preferred examples of the aryloxy groups are phenoxy and naphthyloxy. As a preferred example of an arylalkoxy group, the benzyloxy group can be named. The group -CH 2 -COOH is located in the compounds of the invention either in ortho position, in meta position or in para position with respect to the chain However, those compounds in which the group -CH 2 -COOH is in the para or other position are preferred, with the para position being particularly preferred. The compounds of formula I have a carboxyl functional group and can be converted into salts. Accordingly, they are presented in the form of their addition salts which are formed with organic and inorganic bases. The salts formed by the addition of bases are, for example, the pharmaceutically acceptable salts such as the sodium salts, the potassium salts or the calcium salts which are obtained by using the corresponding hydroxides of the alkali metal as bases. or alkaline earth. Another type of salts formed by the addition of pharmaceutically acceptable bases are, for example, the salts formed with amines and, in particular, with glucamine, N-methylglucamine, N, N-dimethyl-glucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compounds of formula I can also be converted into salts with inorganic or organic acids, preferably with pharmaceutically acceptable acids, such as hydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalic acid, sulfuric acid, ascorbic acid, tartaric acid, maleic acid, Mandelic acid, methanesulfonic acid, lactobionic acid, gluconic acid, glucaric acid, succinic acid, sulphonic acid or hydroxypropanesulfonic acid. The salts of the compounds of formula I which are formed with acids and bases which are not acceptable from the pharmaceutical point of view constitute another aspect of the invention. These salts are intermediate compounds that can be used in the preparation of the compounds of the invention. This is because the compounds of the invention can be isolated as intermediates in the form of one of their pharmaceutically unacceptable salts, before being converted into a pharmaceutically acceptable compound. A first group of preferred compounds is that which is constituted by compounds of formula I in which X represents an oxygen atom.

Particularly preferred among the compounds of the invention are those in which n represents 2 or 3, and even more those in which n is 2. Another preferred group of compounds is that which consists of compounds in which Ar represents unsubstituted pyridyl, unsubstituted pyrimidinyl or optionally substituted phenyl. When Ar represents substituted phenyl, then the phenyl group preferably bears one or two substituents selected from the group consisting of (C6-6) alkoxy, halogen, phenoxy, trifluoromethyl and benzyloxy. Better still, when Ar represents substituted phenyl, the phenyl group is substituted in the meta position with an alkoxy group (Ci-β), a phenoxy group, a trifluoromethyl group or a halogen atom such as a fluorine or chlorine atom. Another preferred group of compounds is that composed of compounds of formula I in which i is 1 or 0, preferably 0. According to a preferred alternative of the invention, when i is 1, the -CH 2 -COOH group is located in position ortho, with respect to the chain -X- (C and the substituent Z is in para position with respect to this same chain. A last group of preferred compounds is that which is composed of compounds of formula I in which the -CH2-COOH group is located in the para position of the phenyl group with respect to the chain -X- (C The invention also relates to two processes for preparing the compounds of formula I. According to a first process, an aromatic compound of the formula II is reacted: H P? O wherein Z, X and i have the meanings indicated above for formula I and Pi represents a protective group of a carboxyl functional group, with a piperazine of formula III: \\\ where n and Ar have the meanings indicated above for formula I and Grpí is a leaving group. Among the protecting groups that are adapted to protect a carboxyl function are those that are described generally in Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), Green T. and uts P.G.M., published by John Wiley and Sons, 1991, and in Protective Groups (Protective Groups), Kocienski P.J., 1994, Georg Thieme Verlag. The carboxyl group can be protected, for example, in the form of an ester: in this case, Pi represents alkyl (Ci-e). As an example of a Grpi group, a halogen atom (for example, chlorine or bromine), a group of aryl (C6-? O) sulfonyloxy in which the aryl group is optionally substituted with one or more alkyl groups (Ci-e), or an alkyl ((Ci-e) sulfonyloxy group in which the alkyl group is optionally substituted with one or more halogen atoms) The operating conditions for the reaction of compound II with piperazine III they can be easily determined by the person skilled in the art, considering that this reaction is a nucleophilic substitution.

The reaction of the compound II with the piperazine III is conveniently carried out in a polar aprotic solvent and in the presence of a base. Suitable solvents include, for example, acetonitrile, dimethylformamide, acetone, dimethyl sulfoxide and halogenated hydrocarbons such as dichloromethane or dichloromethane. As a base, potassium carbonate is particularly preferred. According to a preferred embodiment, the reaction of II with III is carried out at a temperature of 50 to 120 ° C, for example, at the reflux temperature of acetonitrile, when the latter is chosen as solvent, and in the presence of an alkali metal iodide such as potassium iodide. The amount of potassium iodide to be used is variable and depends mainly on the nature of the reactants, the nature of the solvent and the reaction temperature. It generally suffices to employ a catalytic amount of potassium iodide (less than 1 molar equivalent with respect to compound II). The reaction between the compound II and the compound III is stoichiometric. However, the reaction can be carried out in the presence of a slight excess of piperazine III, such that the molar reaction between III and II is generally between 1 and 1.2. Reaction of compound II with piperazine III yields a compound of formula IV: wherein Pi, X, Z, i, n and Ar have the meaning indicated above, which compound is then transformed into a compound of formula I by deprotection of the carboxyl group. Deprotection methods are those commonly used in the prior art. These methods are described, for example, in Protective Groups in Organic Synthesis (Protective Groups in Organic Chemistry), Green T.W. and Wuts P.G.M., published by John Wiley and Sons, 1991, and in Protective Groups (Protective Groups), Kocienski P.J., 1994, Georg Thieme Verlag. When Pi represents alkyl (Ci-e), the deprotection can encompass the saponification of the ester group, for example, by the action of a dilute solution of sodium hydroxide. In general, the compounds of formula II can be purchased in stores, or they can be prepared easily by known techniques which are indicated below. The compounds of formula III can be prepared by reaction of a piperazine of formula V: wherein Ar has the meaning indicated above, with a compound of formula VIII: Grpí- (CH2) n-T VIII where Grpi has the meaning indicated above and T is a leaving group equal to or different from Grpi and preferably a nucleofuge better than Grpi. The person skilled in the art knows in particular that a leaving group becomes increasingly labile as the corresponding negatively charged species, resulting from heterologous cleavage of the bond, becomes more stable. In this particular case, T must be more stable that Grpí so that T is better nucleofugal than Grpí. According to a preferred embodiment of the invention, Grpi is a chlorine atom and T is a bromine atom. The reaction of V with VIII is preferably carried out in a polar aprotic solvent chosen from the group defined above, at a temperature comprised between 15 and 80 ° C, preferably between 15 and 35 ° C, for example at room temperature (20 to 35 ° C). at 25 ° C). As the solvent, dimethylformamide is preferred. The reaction of the piperazine V with the compound VIII is conveniently carried out in the presence of a base such as potassium carbonate. Another method for preparing the compounds of formula I is to react a piperazine of formula V wherein Ar has the meaning indicated above for formula I, with a carboxyl derivative of formula VI wherein n, X, Z and i have the meanings indicated above for formula I, P2 represents a protecting group of a carboxyl function and Grp2 represents a leaving group. P2 can adopt any of the meanings indicated above for Pi. As in the case of Px, the preferred meaning of P2 is alkyl (Ci-β) • Grp2 is a leaving group and its meaning is not a critical point for the invention. Generally, Grp2 can represent a halogen atom, a group of aryl (C6_? 0) sulfonyloxy in which the aryl part is optionally substituted with one or more alkyl groups (Ci-β), or a group of alkyl ((C6-6) sulfonyloxy in which the alkyl group is optionally substituted with one or more halogen atoms The reaction of the piperazine V with the compound VI can be carried out in one of the aprotic polar solvents defined above, preferably in acetonitrile Both the yield and the kinetics of the reaction improve markedly when the reaction is carried out in presence of a base, in particular, in the presence of potassium carbonate. The reaction can be carried out at a temperature between 50 and 120 ° C, for example, at the reflux temperature of acetonitrile, when the latter acts as a solvent. By way of example it may be mentioned that the piperazine of formula V is reacted with at least one equivalent of the compound of formula VI in acetonitrile and in the presence of 1.5 to 3 equivalents of K2C03, referring to the piperazine of formula V. The molar ratio of the compound of formula VI to the piperazine V is conveniently from 1 to 1.5, preferably from 1 to 1.2. According to a preferred embodiment of the invention, the reaction of V with VI is carried out in the presence of an alkali metal iodide such as potassium iodide. It may be useful to use up to 1 equivalent of the alkali metal iodide, based on the amount of the piperazine V. Thus, the molar ratio between the alkali metal iodide and the piperazine V may vary between 0.1 and 1.5 equivalents. By reaction of the piperazine V with the compound VI a compound of the formula VII is obtained: POOC-CH, X- (CH2) n- N N-Ar VII (Z) i wherein n, X, Z, Ar, i and P2 have the meaning indicated above, which compound is then transformed into a compound of formula I by deprotection of the carboxyl group. The operating conditions for the deprotection reaction can be easily established by the person skilled in the art based on the nature of the P2 group. When P2 represents alkyl (Ci-e), deprotection may encompass the saponification of the ester group, for example, by the action of a dilute solution of sodium hydroxide. In general, the compounds of formula V are commercially available, or can be prepared easily from commercial compounds. The compounds of formula VI can be prepared easily by reaction of a compound of formula IX: P2OOC-CH2- ya »IX where P2, X, Z and i have the meaning indicated above for formula VI, with a derivative of formula X: A- (CH2) "- Grp2 X wherein n and Grp2 have the meaning indicated above for formula VI and A is a leaving group equal to or different from Grp2 and preferably a nucleofuge better than Grp2. According to a preferred embodiment of the invention, A represents bromine and Grp2 represents chlorine. The person skilled in the art can easily determine the operating conditions for this reaction using his general knowledge of organic chemistry. The reaction of IX with X is preferably carried out in a polar aprotic solvent, in the presence of a base and at a temperature comprised between 15 and 120 ° C. By way of example it can be mentioned that compound IX can be reacted with 1 to 4 equivalents, preferably with 1.4 to 3 equivalents, of the X derivative using acetonitrile as solvent, in the presence of 1.5 to 3.5 equivalents of K2C03, referred to the amount of compound IX, and to temperature between 40 and 120 ° C. The molar ratio between K2C03 and compound X is conveniently between 0.8 and 1.2. The compounds of the invention are used for the treatment of pathologies associated with the syndrome of insulin resistance (syndrome X). Insulin resistance is characterized by a reduction in the action of insulin. { cf. Presee Médicale, 1997, 26 (n ° 14), p. 671-677) and is involved in a large number of pathological conditions such as diabetes and, in particular, non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidemia, obesity, hypertension and certain microvascular complications and macrovascular diseases such as atherosclerosis, retinopathies and neuropathies. On this subject it can be consulted in, for example, Diabetes, vol. 37, 1988, p. 1595-1607, Journal of Diabetes and its Complications, 1998, 12, p. 110-119, or in Horm. Res., 1992, 38, pgs. 28-32. The compounds of the invention exhibit, in particular, a high hypoglycemic or hypolipidemic activity.

Therefore, another object of the present invention are the pharmaceutical compositions which, as the active ingredient, contain a compound of the invention. The pharmaceutical compositions of the invention can be brought into the dosage forms which are intended for parenteral, oral, rectal, permucosal or percutaneous administration. Thus, these compositions are presented in the form of injectable solutions or suspensions or of multi-dose vials, in the form of coated or uncoated tablets, of dragees, of capsules, including hard gelatin capsules, of pills, of cachets , powders, suppositories or rectal capsules, solutions or suspensions for percutaneous use, and in a polar solvent for use permucously. Suitable excipients for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches, modified starches or lactose for solid forms. For rectal use, excipients such as cocoa butter or polyethylene glycol stearates are preferred.

For parenteral use it is advisable to use vehicles such as water, aqueous solutions, physiological saline solutions or isotonic solutions. The posology may vary within wide margins depending on the therapeutic indication and the route of administration, and also on the age and weight of the patient. Accordingly, the invention also relates to the use of the compounds of formula I in the preparation of medicaments for the treatment of diabetes. The following examples illustrate the preparation of the compounds of formula I and of the intermediates of formulas III and VI. The following abbreviations are used below: NMR nuclear magnetic resonance chemical shift s singlet d double triplet m muí tiplete IR infrared A - Example on the preparation of a compound of formula III Preparation of 1- (2-chloroethyl) -4-phenylpiperazine (III: Grp! = Cl, n = 2, Ar = C6H5) 358.52 g of l-bromo- 2-chloroethane a 80 ml of anhydrous dimethylformamide at 20 ° C located inside a three-neck balloon equipped with a mechanical stirrer, and then add 138 g of potassium carbonate and 81.12 g of N-phenylpiperazine dissolved in 300 ml of dimethylformamide. The reaction mixture is stirred for 2 h at 30 'at room temperature. The reaction mixture is then returned to 1 liter of saturated aqueous sodium chloride solution and extracted with diethyl ether. The organic phases are combined and evaporated. 67 g of a yellow oil are obtained which is purified on silica gel using ethyl acetate as eluent. NMR (200 MHz), CDC13, ppm: 2.68 (t, 4H), 2.80 (t, 2H), 3.25 (t, 4H), 3.64 (t, 2H), 6.93 (m, 3H), 7.28 (t, 2H) ) IR (cm '1); film: 2677, 1593, 1297.

B - Examples on the preparation of compounds of formula VI 1 - . 1 - Preparation of methyl [4- (2-chloroethoxy) -phenyl] acetate (VI: Grp2 = Cl, n = 2, i = 0, P2 = CH3) With mechanical stirring 100 g of [4-hydroxyphenyl] are added methyl acetate and 248.6 g of potassium carbonate in a three-neck balloon containing 900 ml of acetonitrile. The reaction mixture is brought to 50 ° C and in a lapse of one hour 258.13 g of l-bromo-2-chloroethane dissolved in 250 ml of acetonitrile are added. The reaction mixture is then heated to the reflux temperature of the solvent for 48 hours. After filtering the reaction mixture, the solvent is evaporated. The residual oil is taken with a mixture of water and diethyl ether. The ether phases are combined, washed with a normal sodium hydroxide solution and then washed several times with water. After drying and evaporating the solvent, a grayish oil is obtained which is then purified by distillation (boiling point at 0.1 mm of mercury = 112-116 ° C). NMR (200 MHz), CDC13, ppm: 3.60 (s, 2H), 3.70 (s, 3H), 3.82 (t, 2H), 4.25 (t, 2H), 6.85 (d, 2H), 7.22 (d, 2H) ) IR (cm-1; film: 2953, 1736, 1513, 1243.

The intermediate compounds of formula VI, VI.2 to VI.6, which are indicated in Table 1 below, are prepared and isolated in a similar manner.

TABLE 1 (a) boiling point at 0.1 mm Hg In the table indicated above, o, m and p represent respectively ortho, meta and para. The position of the -CH2-COOH group is indicated with respect to the -0- (CH2) n-Cl chain. The position of the substituent Z is also indicated with respect to the -O- (CH2) n-Cl chain.

C - Examples on the preparation of compounds of formula I 1 - Preparation of (4- {2- [4- (3-methoxyphenyl) -piperazin-1-yl} ethoxy} phenyl) acetic acid (Example 1) [I: Ar = -C6H4-OCH3, n = 2, i = 0] In a three-neck, mechanically agitated balloon containing 400 ml of acetonitrile, 34.6 g of 1- (3-methoxy) phenylpiperazine are added, 74.52 g of potassium carbonate and 29.88 g of potassium iodide. Then, in a period of 15 minutes, 41.16 g of methyl [4- (2-chloroethoxy) phenyl] acetate dissolved in 250 ml of acetonitrile are added. The reaction mixture is maintained at the reflux temperature of the solvent for 72 hours. The reaction mixture is then allowed to cool to room temperature, filter and evaporate the solvent. The residue is taken up in a mixture of water and ethyl acetate. The organic phases are combined, then dried and evaporated. In this way, 48.79 g of an orange oil are isolated. To the latter compound is added 400 ml of methanol and 189.2 ml of 1N sodium hydroxide solution and the mixture is kept for 2 hours at the reflux temperature of the solvent. After evaporating the solvent to dryness, the residue is triturated several times with diethyl ether. After Remove the ethereal phases, add 1 liter of water to the residue. Stir for 10 minutes and add 189.2 ml of IN hydrochloric acid. A beige precipitate forms. This precipitate is removed by filtration, the reaction mixture is washed with water, dried and 42 g of a solid are obtained. Recrystallization of ethanol at 95 ° C gives 38 g of the title compound, the melting point of which is between 156 and 158 ° C. NMR (200 MHz), d6-DMSO, ppm: 2.48 (t, 4H), 2.60 (t, 2H), 2.95 (t, 4H), 3.35 (s, 2H), 3.60 (s, 3H), 3.95 (t , 2H), 6.30 (, 3H), 6.70 (d, 2H), 7.0 (m, 3H) IR (crn-1); KBr: 2957, 1716, 1597, 1604, 1242. The compounds of examples 2 to 19, which are indicated in table 2 and in which X represents 0 in the following formula: they are prepared using one of the procedures described above. t n o cp or cp í Ul t cp or p Cp rO rO cp O cp O n Also, the compound 20 indicated below is prepared using a procedure analogous to those described above: This compound has a melting point of 142 ° C and is characterized by the following spectral data: D6-DM.SO: 2.43 (t, 6H), 2.99 (t, 6H), 3.42 (s, 2H), 3.59 (s) , 3H), 6.32 (m, 3H), 7.11 (m, 5H). The results of the pharmacological tests are indicated below.

Testing the antidiabetic activity in the rat The antidiabetic activity of the compounds of formula I administered orally was determined on an experimental model of non-insulin-dependent diabetes that was induced in the rat by s treptozotocin. The non-insulin-dependent diabetes model is obtained in the rat by a neonatal injection (on the day of birth) of s treptozotocin. The diabetic rats that were used were 8 weeks old. The animals were kept, from the day of its birth until the day of the trial, in a cage at a regulated temperature of 21 to 22 ° C, and were subjected to fixed cycles of light (from 7 am to 7 pm) and darkness (from 7 pm to 7 pm ). His diet consisted of a maintenance diet; they were provided with water and food at will, except for the 2 hours of fasting before the test in which the food was withdrawn (postabsorption state). During the day the rats were treated orally with the test compound. Two hours after anesthetizing the animals with sodium pentobarbital (Nembutal®), a blood sample of 300 ul was taken from the end of the collaborators in order to determine the glycemia. The results obtained are shown in Table 3. These results are expressed in percentage of evolution of the glycemia: - to the Dl (after 1 day of treatment) with respect to the DO (before the treatment); and - to D4 (after 4 days of treatment) with respect to OD (before treatment) for 2 different administration doses (20 mg / kg / day and 200 mg / kg / day) of the active ingredient.

TABLE 3 These results show the effectiveness of the compounds of formula I to induce a decrease in glycemia in diabetic animals.

Assay of the hypolipidemic activity in the rat The hypolipidemic activity of the compounds of formula I administered orally was determined on an experimental model of non-insulin-dependent diabetes that was induced in the rat by streptozotocin. The model of non-insulin-dependent diabetes is obtained in the rat by a neonatal injection (5 days after birth) of streptozotocin.

The diabetic rats that were used were 6 months old. The animals were maintained, from the day of their birth until the day of the test, in a cage at a regulated temperature of 21 to 22 ° C, and were subjected to fixed cycles of light (from 7 to 19 h) and darkness ( from 7pm to 7am). His diet consisted of a maintenance diet; they were provided with water and food, except for the 18 hours of fasting before taking the blood samples on which the lipid balances were carried out. The rats were treated orally with the compound of Example 1 for 7 days. A sample of 300 ul was taken 18 hours after the last administration of this compound. Total cholesterol was determined quantitatively using the Trinder CHOE / CHOD / POD method as the end point (reagent for laboratory instruments) in a Monarch plus analyzer (laboratory instruments). The total of the triglycerides was determined using the Trinder / GPO method as the final point (Sigma diagnostic reagent) in a Monarch analyzer (laboratory instruments).

Conditions for taking ajcolesterol tottalTriglycerides out the test (mg / dl) total (mg / dl) In the absence of treatment 90 167 When dealing with compound 102 of example 1 The latter clearly demonstrate the hypolipidemic activity of the compounds of the invention. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compound of formula I characterized in that n represents 2, 3, 4, 5 or 6; X represents O or S; Ar represents phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, optionally substituted with one or more radicals chosen from an alkoxy group (Ci-β); halogen; an aryloxy group (Cβ-io); a group of aryl (Cβ-io) alkoxy (C? _) in which the aryl part is optionally substituted by halogen, alkyl (Ci-β) or alkoxy (Ci-e); and an alkyl group (C6-6) substituted with one or more halogen atoms; i represents 0, 1, 2, 3 or 4; Y each Z group independently represents a halogen atom; and also their solvates and their salts obtained by the addition of bases or acids acceptable from the pharmaceutical point of view.

2. Compounds of formula I, according to claim 1, characterized in that X represents an oxygen atom.

3. Compound according to any of the preceding claims, characterized in that n is 2 or 3, preferably 2.

4. Compound according to any of the preceding claims, characterized in that Ar represents pyridyl; pyridinyl; benzoxazolyl; benzothiazolyl; benzimidazolyl; phenyl; or phenyl substituted with one or more radicals chosen from alkoxy (Ci-β); halogen; phenoxy; trifluoromethyl and benzyloxy.

5. Compound according to any of the preceding claims, characterized in that Ar represents phenyl substituted in the metal position with alkoxy (C'i-e), a halogen atom, phenoxy or trifluoromethyl.

; 6. Compound according to any of the preceding claims, characterized in that i is 0.

7. Compound according to any of the preceding claims, characterized in that the -CH 2 -COOH group is located in the para position of the phenyl group with respect to the chain:

8. Process for preparing the compounds of formula I, according to claim 1, characterized in that it consists of reacting an aromatic compound of formula II: (Z), wherein Z, X and i have the meanings indicated in claim 1 for formula I and Pi represents a protective group of a carboxyl functional group, with a piperazine of formula III: wherein n and Ar have the meanings indicated in claim 1 for formula I and Grp i is a leaving group, to obtain a compound of formula IV: wherein Pi, X, Z, i, n and Ar have the meanings indicated above, which compound is transformed into a compound of formula I by deprotection of the carboxyl functional group.

9. Process for preparing a compound of formula I, according to claim 1, characterized in that it consists in reacting a piperazine of formula V wherein Ar has the meaning indicated in claim 1 for formula I, with a carboxylic derivative of formula VI wherein n, Z, X and i have the meanings indicated in claim 1 for formula I, P2 represents a protecting group of a carboxyl function and Grp2 represents a leaving group, to obtain a compound of formula VII: wherein n, X, Z, Ar, i and P2 have the meanings indicated above, which compound is transformed into a compound of formula I by deprotection of the carboxyl functional group.

10. Pharmaceutical composition, characterized in that, as the active ingredient, it contains one or more compounds according to any of claims 1 to 7, together with at least one pharmaceutically acceptable excipient.

11. Use of a compound according to any of claims 1 to 7, in the preparation of a medicament that can be used for the treatment of pathologies associated with the syndrome of insulin resistance.

12. Use according to claim 11 in the preparation of a medicament that can be used for the treatment of diabetes, dyslipidemia, obesity, arterial hypertension, neuropathies, retinopathies and atherosclerosis.