CZ2001301A3 - Anti-diabetic derivative of piperazine, process of its preparation, use and pharmaceutical preparation in which it is comprised - Google Patents

Abstract

The piperazine derivative of formula I wherein n is 2, 3, 4, 5 or 6; X is O or S; Ar aromatic group of phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl which are optionally substituted with at least one group ■ γ ‘x halogen, C 1-6 alkoxy, C 1-6 alkoxy, C 6-10 arylC 1-6 alkoxy, wherein the aryl is optionally substituted with halogen, Ct. C 1-6 alkyl or C 1-6 alkoxy and C 1-6 alkyl are substituted at least one halogen; 0,1, 2, 3 or 4 and Z independently of each other halogen, and solvates and addition salts thereof with pharmaceutically acceptable salts a base or an acid, a process for its preparation and its use for use in the manufacture of a medicament for the treatment of pathological conditions associated with insulin resistance syndrome

Description

An idiabetic piperazine derivative, use and pharmaceutical composition, a process for its preparation comprising it

Technical field

The invention relates to a novel antidiabetic piperazine derivative which is suitable for the treatment of pathological conditions associated with the insulin resistance syndrome, to a process for the preparation of the derivative, to its use and to a pharmaceutical composition containing it.

SUMMARY OF THE INVENTION

The invention pipera2inu derivative of formula I (Z)? H ₂ -COOH

X - (CH ₂ ) _n -ΝN-A r where n is 2, 3, 4, 5 or 6

X an oxygen or sulfur atom,

Ar is an aromatic group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, which are optionally substituted by one or more of halogen, C1-C6alkoxy, (C6-C10) aryloxy, (C až-C 10) aryl alkoxy having 1 to 6 carbon atoms in the alkoxy moiety, wherein:

• · • • • • · * • «· • · · · ···· · · · • • 9 • Φ • • • · • 4 • • • * • « • • ·· · • · · • · · • 4 4 4 9

the aryl moiety is optionally substituted with a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms substituted with one or more halogen atoms, i, 1, 1, 2, 3 or 4a

Z, independently of one another, is a halogen atom, and its addition salts with pharmaceutically acceptable bases and acids.

The invention also relates to solvates of the compounds of formula I.

The term "alkyl" refers to a linear or branched hydrocarbon group. Examples of alkyl groups include methyl, ethyl, propyl, n-butyl, isobutyl, sec. -butyl, tert-butyl, isoamyl, sec-amyl, tert-amyl, pentyl and hexyl groups.

The alkyl moieties of alkoxy and arylalkoxy groups are as defined above for the alkyl group.

Examples of alkyl groups substituted by one or more halogen atoms are perfluoroalkyl, for example trifluoromethyl or pentafluoroethyl.

The aryl group is a monocyclic or polycyclic aromatic group, preferably a monocyclic and bicyclic group such as phenyl and naphthyl. The same applies to the aryl moiety of aryloxy and arylalkoxy.

and

Halogen atoms are selected from the group consisting of bromine, fluorine, iodine and chlorine.

When Ar is a substituted phenyl group, the phenyl core may have one, two, three, four or five substituents. However, when Ar is a substituted phenyl group, the phenyl core is preferably monosubstituted, disubstituted or trisubstituted. In such a case, the substituents are preferably in the meta or para position.

Examples of preferred aryloxy groups include phenoxy and naphthyloxy. An example of preferred arylalkoxy groups is benzyloxy.

Cha-COOH group in a compound of the invention either in the ortho or meta or para with respect to the chain of general formula -X (CH _{2) n} '- / ΝΆγ

However, compounds in which the -CH2-COOH group is in the para or ortho position are preferred, and it is particularly preferred that it is in the para position.

The compounds of the formula I have a carboxyl function and can therefore be converted into their salts. They may therefore be in the form of addition salts with orange or inorganic bases.

The base addition salts are, for example, pharmaceutically acceptable salts, such as sodium, potassium and calcium salts, which are obtained using the corresponding alkali metal or alkaline earth metal hydroxides as the base.

Other addition salts with pharmaceutically acceptable bases are also mentioned, such as salts of amines and in particular of glucamine, N-methylglucamine, N, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.

The compounds of formula (I) may also be converted into salts with inorganic or organic acids, preferably with pharmaceutically acceptable acids such as hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric, ascorbic, tartaric, maleic, mandelic, methanesulfonic, 1actobionic acids. , gluconic, amber, sulfonic or hydroxypropanesulfonic acid.

Salts of the compounds of formula I with acids and bases which are pharmaceutically unacceptable are also within the scope of the invention. These salts are intermediates for the preparation of the compounds of the invention. Indeed, the compounds of the invention may be isolated as intermediates in the form of one of their pharmaceutically unacceptable salts and subsequently converted to a pharmaceutically acceptable compound.

A first group of preferred compounds of formula I are those compounds of formula I wherein X is O.

Particularly preferred are compounds of formula I wherein n is 2 or 3, and more preferably 2.

Another group of preferred compounds are those compounds of formula (I) wherein Ar is unsubstituted pyridyl, unsubstituted pyrimidinyl or optionally substituted phenyl. When Ar is a substituted phenyl group, the phenyl group preferably has one or two substituents selected from the group consisting of C 1 -C 6 alkoxy, halogen, phenoxy, trifluoromethyl, and benzyloxy. However, it is always more preferred if Ar

means a substituted phenyl group to be substituted in the meta position by meta alkoxy of 1 to 6 carbon atoms, a phenoxy group, a trifluoromethyl group or a halogen atom such as fluorine or chlorine.

Another group of preferred compounds are those compounds of formula (I) wherein R is 1 or zero, preferably zero.

According to another preferred embodiment of the invention, i is 1, the -CH 3 -COOH group is ortho with respect to the chain

-x— (ch ₂ ) n -

N-Ar and Z are in para position with respect to the same chain.

Finally, a group of compounds of formula I is also preferred, wherein the -CH 2 -COOH group is in the para position on the phenyl group with respect to the (CH ₂ ) _n -N

The invention also relates to two processes for the preparation of compounds of formula I.

According to a first method, an aromatic compound of formula II

Pi

β ·

wherein Z, X and i are as defined in formula I and wherein Pi is a carboxyl protecting group, it is reacted with piperazine of formula III

Grpi- (CH2) rN N-Ar (III)

wherein n and Ar are as defined in formula (I) and wherein Grp 1 is a leaving group.

Carboxyl protecting groups generally described in the literature (Greene T.W. and Wuts P.G.M., Run in Groups in Organic Synthesis, John Wiley & Sons, 1991 and Protect in Groups, Kocienski P.J., Georg Thieroe Verlag, 1994) may be suitable. For example, consideration may be given to protecting the carboxyl function in ester form, in which case P 1 is a C 1 -C 6 alkyl group.

Halogen atom (e.g. chlorine or bromine), arylsulfonyloxy group having 6 to 10 carbon atoms, the aryl group being optionally substituted by one or more alkyl groups having 1 to 6 carbon atoms or alkylsulfonyloxy group having 1 to 6 carbon atoms, the alkyl group being optionally substituted with one or several halogen atoms are exemplified by the Grpi group.

Reaction conditions for the reaction of a compound of formula

II with the piperazine of formula III is readily determined by one skilled in the art, the reaction being a nuclophilic substitution.

The reaction of the compound of formula II with piperazine of formula IIII is preferably carried out in a polar aprotic solvent in the presence of a base. Examples of suitable solvents include acetonitrile, dimethylformamide, acetone, dimethylsulfoxide and halogenated hydrocarbons such as,

4

4 4 ice is dichloromethane and dichloroethane. As a particularly preferred base, potassium carbonate is used.

According to a preferred embodiment, the reaction of the compound of formula II with the piperazine of formula III is carried out at a temperature of 50 to 120 ° C, e.g. at reflux temperature of acetonitrile when used as a solvent, in the presence of an alkali metal iodide such as potassium iodide. The amount of potassium iodide used is controlled essentially by the nature of the reactants, the nature of the solvent used, and the reaction temperature. Generally, a catalytic amount of potassium iodide (less than 1 molar equivalent with respect to the compound of formula II) is sufficient.

The reaction of the compound of formula II with the piperazine of formula IIII is stoichiometric. However, the reaction may be carried out in the presence of a slight excess of the piperazine of formula III at a molar ratio of the piperazine of formula III to the compound of formula II generally from 1 to 1.2.

Reaction of a compound of formula II with a piperazine of formula IIII results in a compound of formula IV

P jOOC-CH

• X- _(CH2) n- Ν N-Ar

(IV) where Pi, transforms the protective

X, Z, i, Ar are as defined above, which is a functional carboxyl group on the compound of formula I by removal of the group.

Methods for removing the protecting group are known in the art. They are described in the literature (for example (Greene T.W. and Wuts P.G.M., Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 and Protective Groups, Kocienski P.J.,

Georg Thieme Verlag, 1994).

When Pi represents an alkyl group having 1 to 6 carbon atoms, the protecting group may be protected. by saponification of the ester function, for example by treatment with a dilute sodium hydroxide solution.

and

The compounds of formula (II) are generally commercially available or can be readily prepared by the following known methods.

Compounds of formula (III) and piperazine of formula (V) may be prepared by reaction

(V) wherein Ar is as defined above, with a compound of Formula VIII

Grpi - (CHa) n - Τ (VIII) wherein Grpi is as defined above and T represents a released group equal to or different from that of Grpi and preferably better nucleofugacity than Grpi.

It is particularly known to those skilled in the art that the liberated moiety becomes increasingly labile when the stability of the corresponding negatively charged moiety resulting from the heterocyclic cleavage of the bond increases. In such a special case, T 'must be more stable than Grpi to make T more nucleofugue than Grpi. According to a preferred embodiment of the invention, Grp 1 is chlorine and T is bromine.

The reaction of a compound of formula V with a compound of formula VIII is preferably carried out in a polar aprotic

a solvent as defined above at a temperature of 15 to 80 ° C, preferably 15 to 35 ° C, for example at room temperature (20 to 25 ° C)

C). Dimethylformamide is the preferred solvent.

The reaction of the piperazine of formula V with a compound of formula VIII is preferably carried out in the presence of a base such as potassium carbonate.

A second method of preparing a compound of formula I is by reacting a piperazine of formula V

(V) wherein Ar is as defined above with a carboxyl derivative of the general Formula VI

(VI) where η, X, Z and χ are as defined above, P3 represents a carboxyl functionality protecting group and Grp2 represents a released group. P2 may have any of the meanings given above for Pi. As in the case of Pi, P2 is preferably an alkyl group having 1 to 6 carbon atoms. The symbol Grp2 represents a liberated group which is not critical according to the invention. Generally, Grp2 is halogen, arylsulfonyloxy of 6 to 10 carbon atoms, wherein the aryl group is optionally substituted by one or more alkyl groups of 1 to 6 carbon atoms or alkylsulfonyloxy group of 1 to 6 carbon atoms, the alkyl group optionally substituted by one or more atoms halogen.

·· · ··· · · · · · · · · · · · · · ·

The reaction of a compound of formula V with a compound of formula VI is preferably carried out in a polar aprotic solvent as defined above, preferably in acetonitrile. The yield and kinetics of the reaction are greatly improved when the reaction is carried out in the presence of a base and in particular in the presence of potassium carbonate. The reaction is carried out at a temperature of 50 to 120 ° C, for example at the reflux temperature of acetonitrile when used as solvent.

For example, piperazine of formula V is reacted with at least one equivalent of compound of formula VI in acetonitrile in the presence of 1.5 to 3 equivalents of potassium carbonate with respect to piperazine of formula V. The molar ratio of compound of formula VI to piperazine of formula V is 0, 1 to 1.5 equivalents, preferably 1 to 1.2.

According to a preferred embodiment of the invention, the reaction of the compound of the formula V with the compound of the formula VI is carried out in the presence of an alkali metal iodide, for example potassium iodide. Up to 1 equivalent of alkali metal iodide may be used with respect to the amount of piperazine of formula (V). Thus, the molar ratio of alkali metal iodide to piperazine of formula (V) may be 0.1 to 1.5 equivalents.

Treatment of the piperazine of formula V with a compound of formula VI gives a compound of formula VII

X- (CH _{2) n} -N

N-Ar (VII) wherein η, X, Z, Ar, i and P3 are as defined above, which is converted to a compound of formula I by removal of the carboxyl protecting group. Reaction conditions for deprotection can be readily determined by those skilled in the art according to the nature of the P2 group.

If P2 is an alkyl group having 1 to 6 carbon atoms, the protecting group is removed by saponification of the ester function, for example by treatment with a dilute sodium hydroxide solution.

Compounds of formula V are commercially available or can be readily prepared from commercially available compounds.

VI is easy to prepare

Compounds of formula ( _II) by reacting a compound of formula (IX) p ₂ ooc-ch ₂ -

(IX) is of the formula wherein P2, X, Z and i have the above VI, with a compound of formula X

A- _(CH2) n-Grp2 <X) where Grp2 are as defined above for formula VI and A represents a leaving group the same or different groups from Grp2 and preferably more nucleofugic group than GRP2. According to a preferred embodiment, A is bromine and Grp2 is chlorine.

The reaction conditions for this reaction are readily determined by one skilled in the art based on general knowledge in the field of organic chemistry.

The reaction of the compound of the formula IX with the compound of the formula X is preferably carried out in a polar aprotic solvent in the presence of a base at a temperature of 15 to 120 ° C.

For example, piperazine IX is reacted with 1-4 equivalents, preferably 1.4-3 equivalents of the compound of formula X in acetonitrile as a solvent in the presence of 1.5 to 3.5 equivalents of potassium carbonate with respect to piperazine IX The molar ratio of potassium carbonate to the compound of formula X is preferably 0.8 to 1.2.

The compounds of formula I according to the invention are used in the treatment of pathological conditions associated with insulin resistance syndrome (syndrome X).

Insulin resistance is characterized by a decrease in insulin action (for example, Presse Medicale, 26, 14, pp. 671-677, 1997) and is the implication of a number of pathological conditions such as diabetes, and in particular non-insulin dependent / type II diabetes or NIDDM) dyslipidemia, obesity, arterial hypertension and certain microvascular and macrovascular complications such as atherosclerosis, retinopathy and neuropathy (e.g., Diabetes, Vol. 37, pp. 1595-1607, 1988: Journal of Diabetes and Its Complications, 12, pp. 110-119); 1998; or Horm. Res. 38: 28-32 (1992).

The compounds of the invention have particularly potent hypoglycemic or hypolidemic activity.

The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of the invention. The pharmaceutical compositions may be for parenteral, oral, rectal, permucosal or percutaneous administration.

Thus, they may be in the form of injectable solutions and suspensions or multidose vials, coated and uncoated tablets, dragees, capsules including hard gelatine capsules, pills, sachets, powders, suppositories or rectal capsules, solutions or suspensions, in the form of percutaneous administration in polar solvent or permucosal administration.

4 ·· 4 44 • · 4 4 '44 4 4 • 44 «4 · 44

4444444 4 44 44 4

4 · · 4 4 4 • 44 · ·· 443 «·

Solid excipients suitable for such administration include cellulose derivatives or microcrystalline cellulose, alkali metal carbonates, sodium phosphate, starches, modified starches or lactose.

For rectal administration, cocoa butter or polyethylene glycol stearates are preferred excipients.

For parenteral administration, the most commonly used carriers are water, aqueous solutions, physiological saline or isotonic solutions.

The dosage varies over a wide range depending on the therapeutic indication, the route of administration, and the age and weight of the subject being treated.

The invention therefore also relates to the use of the compounds of formula I for the preparation of medicaments for the treatment of diabetes.

The invention is illustrated by the following examples. Shortcuts used have the following meaning:

NMR nuclear magnetic resonance <5 chemical shift with singlet d doublet t triplet m uncleaved peak

IR infrared

DETAILED DESCRIPTION OF THE INVENTION

A- Example of preparation of a compound of formula III

Preparation of 1- (2-chloroethyl) -4-phenylpiperazine (III: Grpi =

Cl, η = 2, Ar = ₆ H ₅ CH

To 80 ml of dry dimethylformamide in a three - necked flask of

With stirring at 35 ° C, 358.52 g of 1-bromo-2-chloroethane are added, followed by 138 g of potassium carbonate and 81.12 g of N-phenylpiperazine dissolved in 300 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours 30 minutes. It was then poured into 1 liter of saturated aqueous sodium chloride solution and extracted with diethyl ether. The organic layers were combined and evaporated. 67 g of a yellow oil are obtained, which is purified on a silica cake using ethyl acetate as eluent.

NMR (200 MHz), CDCl ₃ , 2.68 (t, 4H), 2.80 (t, (m, 3H), 7.28 (t, 2H), IR (cm ^-1 )), film: 2677, <5 ppm :

2H), 3.25 (t, 4H), 3.64 (t, 2H), 6.93

1593, 1297.

B - Examples of preparation of compounds of formula VI

- Preparation of methyl [4- (2-chloroethoxy) phenyl] acetate (VI; GrP2 = Cl, n = 2, i = 0, P2 = CH3

Add 100 g of methyl [4-hydroxyphenyl acetate] and 248,6 g of potassium carbonate to a three-necked flask containing 900 ml of

acetonitrile. The reaction mixture was heated to 50 DEG C. and 1-bromo-2-chloroethane (258.13 g) dissolved in acetonitrile (250 ml) was added over 1 hour. The reaction mixture is maintained at the reflux temperature of the solvent for 48 hours.

After filtering the reaction mixture, solvent ^{1 was} evaporated. The residual oil was taken up in a mixture of water and diethyl ether. The ether phases were combined, washed with normal sodium hydroxide solution and washed several times with water. After drying and evaporation of the solvent, a gray oil is obtained, which is purified by distillation (b.p. 112-116 C.).

NMR (200 MHz), CDCl 3, δ ppm:

3.60 (s, 2H), 3.70 (s, 3H), (d, 2H), 7.22 (d, 2H), IR (cm ^-1 ), film: 2953, 1736,

3.82 (t, 2H), 4.25 (b, 2H), 6.85

1513, 1243.

of Formulas VI, VI.2 to VI.6, prepared and isolated by a similar intermediate number in column II

Intermediates of the following table I with bem (in column I of the table the position of the group CH2-COOH)

CH 3 OOC-CH 2

- (CH ₂ ) _n -Cl

Table I

AND II and OF n e Boiling point (C) ^a VI .2 P 0 / 2 112 to 116 VI. 3 m 0 / 2 oil VI. 4 0 0 / 2 oil VI. 5 P 0 / 3 oil VI. 6 P 0 / 4 oil and temperature boiling is indicated for pressure 0.0133 kPa in ' table means 0, Map ortho, metha, para. After- loha groups -CHa-COOH is indicated relative to the chain -O- (CHa) n -Cl.

The position of the substituent Z is also indicated relative to the chain -O- (CH 2) n -Cl.

C- Examples of Preparation of Compounds of Formula I

EXAMPLE 1

- Preparation of (4- [2- [4- (3-methoxyphenyl) píperaziη-1-yl] ethoxy) phenyl) acetic acid [I: Ar = -C6H4-0CH _3, n = 2, i = 03

To a three-necked flask containing 400 ml of acetonitrile was added, with magnetic stirring, 34.6 g of 1- (3-methoxy) phenylpiperazine (sic), 74.52 g of potassium carbonate and 29.88 g of potassium iodide. 41.16 g of methyl [4- (2-chloroethoxy) phenyl acetate] dissolved in 250 ml of acetonitrile are added over 15 minutes. The reaction mixture is maintained at the reflux temperature of the solvent for 72 hours. After cooling to room temperature, the reaction mixture was filtered and the solvent was evaporated. The residue was taken up in a mixture of water and ethyl acetate. The combined organic phases were dried and evaporated. 48.79 g of an orange oil are obtained.

To this oil was added 400 mL of methanol and 189.2 mL of 1 N sodium hydroxide solution. The reaction mixture is maintained at the reflux temperature of the solvent for 2 hours. After evaporation of the solvent to dryness, the residue was triturated several times with diethyl ether. After removal of the ether phase, 1 liter of water was added to the residue. After stirring for 10 minutes, 189.2 ml of 1N hydrochloric acid was added. A beige precipitate formed. The precipitate was filtered off and the reaction mixture was washed with water and dried to give 42 g

solids. Recrystallization from ethanol at 95 DEG C. (sic) yields 38 g of the title compound, m.p.

is 156 to 158 C. NMR (200 MHz), d6-DMSO, < 5 ppm: 2.48 (t, 4H); 2.60 (t, 2 H) , 2.95 (t, 4H) 3.35 (s, 2H) , 3.60 (s, 3H) 3.95 (t, 2H) 6.30 (m, 4H) , 6.70 (d, 2H), 7.0 (m, 4H) IR (cm ^_1), potassium bromide: : 2957, 1716 1597, 1604, 1242.

The compounds of Examples 2 to 19 listed in Table II were prepared as described above, wherein X in the following formula represents an oxygen atom (column number is an example number):

(Z) i _{(CH2) n} --N

N — Ar

- 18 Table II

• ·

Table II (continued)

Table II (continued)

- 21 Table II (continued)

Similarly, compound 20 was prepared as described above

HOOC-CH ₂

och ₃ o

having a melting point of 142 Ca, the following spectral data:

d6-DMSO =

2.43 (t, 6H), 2.99 (t, 6H), 3.42 (s, 2H), 3.59 (s, 3H), 6.32 (m, 3H), 7.11 (m , 5H).

Furthermore, the results of the pharmacological study are conducted.

Study of anti-diabetic effect in rats

The anti-diabetic activity of the compounds of formula I administered via the oral route is investigated in an experimental model of insulin-independent diabetes induced by streptozotocin in rats. An insulin-independent diabetes model is obtained in rats by neonatal injection of streptozotocin on the day of birth.

The diabetic rats used were 8 weeks old. Animals are kept in a controlled cage from the day of birth until the day of the experiment

B at a temperature of 21 to 22 ° C and subjected to a fixed light cycle (light from 7 to 19 hours, dark from 19 to 7 hours). Food is a maintenance diet, water and food at will, with the exception of a two-hour fast in front of the dough when the food is taken (postabsorptive state).

Rats are treated by the oral route during the day with administration of the test compound. Two hours after the final administration of the test compound and 30 minutes after anesthesia of the rat with natriumpentobarbital (Nembutal ^R ), 300 µl of tail blood was collected for blood glucose determination. The results are shown in Table III (column I of the table shows the compound of the example).

···············································

In the table, the test results are expressed as the percentage change in blood glucose:

- at D1 (after treatment for one day) with regard to DO (before treatment)

at D4 (after treatment for four days) with respect to DO (pre-treatment) for two different doses of active ingredient administered (20 mg / kg / day and 200 mg / kg / day).

Table III

AND Dose to be administered % glycemia Dl 20 mg / kg / day % glycemia D4 Dose administered 200 mg / kg / day % glycemia Dl % glycemia D4 1 -8 -10 -24 -34 4 / -2 -16 -20 -24 6 2 - 12 -2 - 19 8 9 -6 19 Dec -18 9 -2 3 1 -25 10 -26 - 13 -30 -27 13 ........ -10 -10 -23 -23

These results demonstrate the efficacy of compounds of Formula I in inducing a decrease in glycemia in diabetic animals.

Hypolipidemic efficacy studies in rats

The hypolipidemic action of the compounds of formula I administered orally is investigated in an experimental model of insulin-independent diabetes induced by streptozotocin in rats. Model

insulin-independent diabetes is obtained in rats by neonatal injection of streptozotocin five days after birth.

The diabetic rats used were 8 weeks old. The animals are kept from the day of birth until the day of the experiment in a cage controlled by

temperature 21 to 22 C and subjected to a fixed light cycle (light from 7 to 19 hours, dark from 19 to 7 hours). The food is a maintenance diet, water and food ad libitum, except for an 18-hour fast before the test, when a blood sample is taken to perform lipid balance.

Rats are treated by the oral route by administering the compound of Example 1 for seven days. A sample of 300 [mu] l is taken 18 hours after the final administration of the test compound.

Total cholesterol was quantitated by the CH0E / CH0D / P0D Trinder method as the endpoint (Instrumentation Laboratory reagent [lacuna] on a Monarch plus analyzer (Instrumentation Laboratory).

Total glycerides are quantitated by GP0 / Trinder as an endpoint (Sigma Diagnostic reagent) on a Monarch Analyzer (Instrumentation Laboratory). The test results are in the following table cholesterol Total triglycerides mg / dl mg / dl

167

102 hypolipidemic activity of the compounds

Performance conditions Total tests without treatment with the compound of Example 1 The results clearly demonstrate the invention.

Industrial applicability

A piperazine derivative for the manufacture of a medicament for the treatment of pathological conditions associated with insulin resistance syndrome.

Claims (12)

PATENT CLAIMS The piperazine derivative of formula I (2) Γ CH ₂ -COOH -X- (CH ₂ ) _n ^--N where n is 2, 3, 4, 5 or 6 X is oxygen or sulfur, Ar is an aromatic group selected from the group consisting of phenyl, pyridyl, pyrimidinyl, benzooxazolyl, benzothiazolyl and benzimidazolyl, which are optionally substituted by one or more halogen, C1-6 alkoxy, C6-10 aryloxy, (C6-C10) arylalkoxy is from about 6 to about 6 carbon atoms in the alkoxy moiety, wherein the aryl moiety is optionally substituted by halogen, (C1-C6) alkyl or (C1-C6) alkoxy; carbon atoms are substituted with one or more halogen atoms, i, 0, 1, 2, 3 or 4a Z independently of one another is a halogen atom, and its solvates and addition salts with pharmaceutically acceptable bases or acids. 2. A compound according to claim 1, wherein X is oxygen and the other symbols are as defined in claim 1. • * ···· ·· The piperazine derivative according to claim 1 or 2, wherein n is 2 or 3, preferably 2 and the other symbols are as defined in claims 1 and 2. 4. A compound according to claim 1, wherein Ar is pyridyl, pyrimidinyl, benzenesulfonyl, benzothiazolyl and benzimidazolyl, phenyl or phenyl substituted by one or more C 1-6 alkoxy, halogen, phenoxy. and trifluoromethyl and benzyloxy, and the other symbols are as defined in claims 1 to 3. A piperazine derivative according to any one of claims 1 to 4 wherein Ar is phenyl substituted at the meta position with C 1 -C 6 alkoxy, halogen, phenoxy or trifluoromethyl, and the other symbols are as defined in claims 1 to 4. A piperazine derivative according to any one of claims 1 to 5 wherein Z is zero and the other symbols are as defined in claims 1 to 5. 7. A piperazine derivative according to claim 1, wherein the -CH2-COOH group is in the para-position on the phenyl ring with respect to the chain &quot; X &quot; (CH2) n ~ &quot; 1 to 6 are given. 8. A process for the preparation of a piperazine derivative according to claim 1, wherein the symbols are as defined in claim 1, wherein Z, X and I are as defined in claim 1 and wherein: The carboxyl-functional protecting group P ₁ is reacted with a piperazine of the formula III ^Gr Pr (CH ₂ ) _n -Nt-Ar (III) wherein Ar is as defined above and where Grp is a leaving group to give the compound of the formula IV Pi ooc-ch ₂ - -Q- X- (CH ₂ ) _n - (Z) i (IV) where Pi, transforms the protecting X, Z, X, n and Ar are as defined above, which is a functional carboxyl group, by removal of the functional group of formula (I). 9. A process for the preparation of a piperazine derivative according to claim 1, wherein each of the symbols is as defined in claim 1, wherein Ar is as defined in formula (VI ₎ . _-CH2-ICH X ^ n-Grp., with a carboxylic derivative (VI) (Z) wherein η i, X, Z and even have the meaning given in claim 1, P 2 represents a protecting group of carboxyl functional group and Grp2 represents a leaving group to give compounds of formula VII P ₂ OOC-CH ₂ (Z) i (VII) wherein η, X, Z, Ar, J and P2 are as defined above, which is converted to a compound of formula I by removal of a functional carboxyl protecting group. 10. A pharmaceutical composition comprising a piperazine derivative of the formula I as claimed in claim 1 and at least one pharmaceutically acceptable excipient. Use of a piperazine derivative according to claims 1 to 7 for the preparation of a medicament for the treatment of pathology conditions associated with insulin resistance syndrome. Use of a piperazine derivative according to claims 1 to 7 for the preparation of a medicament for the treatment of diabetes, dyslipidemia, obesity, arterial hypertension, neuropathy, retinopathy and atherosclerosis.