WO2003011835A1

WO2003011835A1 - Benzimidazolylalkyl-aryl(alkan) oic acid derivatives and their use as antihyperglycaemics

Info

Publication number: WO2003011835A1
Application number: PCT/EP2002/007220
Authority: WO
Inventors: Gérard Moinet; Eric Metais; Jean-Claude Correc
Original assignee: Merck Patent Gmbh
Priority date: 2001-07-27
Filing date: 2002-07-01
Publication date: 2003-02-13
Also published as: FR2827862A1

Abstract

The invention relates to compounds of the general formula (I): in which R1, R2, R3, R4, R5, A and B are as defined in Claim 1. These compounds may be used in the treatment of pathologies associated with hyperglycaemia.

Description

BENZIMIDAZOLYLALKYL-ARYL (ALKAN) OIC ACID DERIVATIVES AND THEIR USE AS

ANTIHYPERG YCAEMICS

The present invention relates to imidazolylalkylarylalkanoic derivatives that are useful in the treatment of pathologies associated with insulin resistance syndrome.

The compounds of the invention are of the general formula (I) below:

(I) in which:

X represents, independently of each other, CH or a nitrogen, oxygen or sulfur atom, R1 , R2, R3, R4 and R5, which may be identical or different, are chosen without preference from the following groups:

- H

- (CrC₂o) alkyl optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C₃-C₈) cycloalkyl, (C^Cs) alkoxy, substitu- ted or unsubstituted amino, optionally substituted carbonyl, ester, amide, an oxygen, sulfur or phosphorus atom,

- (C₂-C₂o) alkylene optionally substituted by halogen, (C₁-C₅) alkyl, (C₁-C₅) alkoxy or (C₃-C₈) cycloalkyl

- (C₂-C₂₀) alkyne optionally substituted by halogen, (CrC₅) alkyl, (C₁-C₅) alkoxy or (C₃-C₈) cycloalkyl

- (C₃-C₈) cycloalkyl optionally substituted by (C₁-C₅) alkyl or (C₁-C₅) alkoxy

- (C₃-C₈) heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by (C₁-C₅) alkyl or (C₁-C₅) alkoxy,

- (C₆-C₁₄)aryl(Cι-C₂o)alkyl optionally substituted by amino, hydroxyl, thio, halogen, (C₁-C₅) alkyl, (C₁-C5) alkoxy, (C₁-C₅) alkylthio, (C1-C₅) alkylamino,

(C₆-C₁₄) aryl, (C₆-C₁₄)arylsulfonyl(Cι-C₅)alkyl, (C₆-C₁₄) aryloxy, (C₆-C₁₄)- aryl(CrC₅)alkoxy, cyano, trifluoromethyl, carboxyl optionally in acid or ester form, carboxymethyl or carboxyethyl,

- (C₆-Cι₄) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (CrC₅) alkylthio, (C1-C5) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι₄) aryloxy, (C₆-Cι )aryl(Cι-C₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (C1-C1₃) heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C C₅) alkylthio, (C1-C5) alkylamino, (C₆-Cι₄) aryl, (Cβ-C-u) aryloxy, (Cβ-CuJary Ci-CsJalkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

A represents a (Ci-Cβ) alkyl group optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (C₁-C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,

B represents a single bond or a (Ci-Cβ) alkyl group optionally substituted by one or more of the following groups halogen, (C₃-C₈) cycloalkyl, (C₁-C5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, with the exclusion of the compounds of the formula (I) in which: (i) R1 = H, R2 = H, R3 = H or CH3, R4 = H or -NH-CH2-C6H5, R5 = H, when A is -CH2- and B is a single bond; and also the tautomeric forms, enantiomers, diastereoisomers and epi- mers thereof, and the pharmaceutically acceptable salts thereof.

One particular group of compounds of the formula (I) is that in which the compounds are of the general formula (II) below:

(II) in which: Rι, R2, R3, R4. Re, A, B and X are as defined above. According to one preferred aspect of the invention, the compounds of the formula (II) are those for which X represents CH and/or Ri and R₂ represent a hydrogen atom.

Another particular group of compounds of the formula (I) or (II) as defined above is that in which A is an optionally substituted methylene group.

One particular group of compounds of the formula (I) or (II) as defined above is that in which B is a single bond.

Another particular group of compounds of the formula (I) or (II) as defined above is that in which B is an optionally substituted methylene group. Another particular group of compounds of the formula (I) or (II) is that in which R4 is a (C1-C2₀) and preferably (CrC₆) alkoxy radical, especially such as methoxy or ethoxy.

Another particular group of compounds of the formula (I) or (II) is that in which the function -B-COOR5 is in the para position on the ring relative to -A-. Another particular group of compounds of the formula (I) or (II) is that in which the R4 is in the meta position on the ring relative to -A-.

According to the present invention, the alkyl radicals contain from 1 to 20 carbon atoms and preferably from 1 to 6 carbon atoms.

When they are linear, mention may be made especially of the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals.

When they are branched or substituted by one or more alkyl radicals, mention may be made especially of the isopropyl, tert-butyl, 2-ethylhexyl, 2- methylbutyl, 2-methylpentyI, 1 -methylpentyl and 3-methylheptyl radicals. The alkoxy radicals according to the present invention are radicals of the formula -O-alkyl, the alkyl being as defined above.

Among the halogen atoms, mention is made more particularly of the fluorine, chlorine, bromine and iodine atoms.

The alkylene radicals contain one or more ethylenic unsaturations. Among the alkylene radicals that may be mentioned especially are the allyl and vinyl radicals.

The alkyne radicals comprise one or more acetylenic unsaturations. Among the alkyne radicals that may especially be mentioned is acetylene. The (C₃-C₈) cycloalkyl radical is a cyclic hydrocarbon-based radical such as, especially, cyclopropyl, cyclopentyl or cyclohexyl.

The heterocycloalkyl radical is a cycloalkyl radical as defined above containing, instead of one or more ring carbon atoms, one or more hetero atoms chosen from N, O and S.

Among the heterocycloalkyl radicals that may thus especially be mentioned are the piperidyl, pyrazolidinyl, piperazinyl and morpholinyl radicals.

The aryl radical corresponds more particularly to an aromatic ring of 6 carbon atoms, such as the phenyl radical, optionally fused with one or two other aromatic rings containing 6 carbon atoms, such as the naphthyl radical.

Among the aryl radicals that may thus especially be mentioned is the phenyl radical, more particularly substituted by at least one halogen atom.

Among the (C₆-Cι₄)aryl(Cι-C₂o)alkyl radicals that may be mentioned especially are the benzyl and phenethyl radicals. The heteroaryl radical corresponds more particularly to a 5- or 6-atom aromatic heterocycle containing one or two hetero atoms chosen from N, S and O, optionally fused with one or two aromatic rings containing six carbon atoms or 5- or 6-atom heteroaromatic rings.

Among the heteroaryl radicals that may be mentioned are the furyl, pyridyl, quinolinyl, indolyl, isoindolyl, quinolyl, imidazolyl, pyrimidinyl and carbazolyl radicals.

Among the heterocycles that may especially be mentioned are the piperi- dine, morpholine, pyrrolidine, imidazolidine, pyrazolidine and piperazine rings.

Preferentially, R1 and R2, which may be identical or different, represent a (C1-C6) alkyl chain or a hydrogen atom.

The invention also relates to the tautomeric forms, to the enantiomers, dia- stereoisomers and epimers and to the organic or mineral salts of the compounds of the general formula (I).

The compounds of the invention of the formula (I) as defined above con- taining a sufficiently acidic function or a sufficiently basic function, or both, may include the pharmaceutically acceptable corresponding salts of an organic or mineral acid or of an organic or mineral base.

They may be, for example, salts such as the hydrochloride, acetate, ben- zoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulfonate, maleate, para-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesulfonate, tri- methoxybenzoate, para-toluenesulfonate, adamantanecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 -phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate, thioctate, hippurate, 3- benzamidopropanoate, glucuronate, L-pyrrolidone-5-carboxylate, cholate, α- glucose-1 -phosphate, alginate, 4-aminobenzoate or chondroitin sulfate, and alkali metal salts, such as the sodium salt. The compounds of the general formula (I) as described above for which

[lacuna] may be prepared by method (I)

a)

Method (I) Step a) may be carried out in an apolar solvent such as, for example, dichloromethane, in the presence or absence of an organic or mineral base such as, for example, triethyiamine, at room temperature or by heating the solvent.

The intermediate amide thus obtained may be cyclised in acidic medium. Preferentially, the cyclisation may be carried out by heating at reflux in an ethanol/concentrated hydrochloric acid mixture.

Step b) is an N-alkylation reaction that is well known in the literature. It may be carried out especially in DMF in the presence of a base such as sodium hydride. Step c) is a standard hydrolysis of the ester (6) to the corresponding acid.

It is generally carried out by heating the ester in an aqueous solvent, preferably a methanol/water mixture in the presence of sodium hydroxide.

Another method for preparing the compounds of the general formula (II) as described above, for which R^ = R₂ = H, used in J. Med. Chem. 1998, 41, 2709- 2719, may be represented schematically by method (II) below:

Method (II)

This cyclisation may be carried out in an alcoholic solvent catalysed with a metal alkoxide. Preferably, the reagents (2) and (8) are stirred at room temperature in methanol in the presence of sodium methoxide.

Another method for preparing the compounds of the general formula (II) as described above, for which Ri = R₂ = H, may be represented schematically by method (III) below.

This cyclisation may be carried out in a solvent, preferably DMF, at room temperature or with heating.

Compound (9) may be preferentially synthesised by the well-known Pinner method (Organic Functional Group Preparation Vol. 3, 1972) starting with the nitrile (8).

Another method for preparing the compounds of the general formula (II) as described above, for which Ri = R₂ = H, may be represented schematically by method (IV) below.

(7)

(2)

Method IV This cyclisation may be carried out by heating (2) and (7) at reflux in 2N

HCI.

When the groups Ri and/or R₂ are other than H, the compounds of the general formula (I) described above may be prepared by Method V. This strategy makes it possible to unambiguously fix the position of the substituents on the ring, in particular the benzimidazole ring, and to avoid the formation of a mixture of regioisomers.

b)

Method V

Step a) may be carried out in the solvents usually used for this well-known Williamson reaction; preferably, compound (10) may be heated in acetonitrile in the presence of an organic or mineral base, preferably K₂CO₃.

Alternatively, the compound of the formula (11) may be obtained by the well-known reaction of an aldehyde with the aniline (10) followed by a hydrogenation catalysed with Pd/C: Method VI

Method VI The compound of the formula (11) may also be obtained by Method VII

Method VII This reaction may be carried out in a solvent, preferably ethanol with or without heating, preferably in an autoclave if the amine is volatile. Step b) consists of a reduction under the usual conditions for reducing aromatic nitro compounds.

Preferentially, compound (11) may be reduced with hydrogen in ethanol in the presence of a catalyst such as Pd/C.

Alternatively, compound (11) may be reduced with hydrazine hydrate in a solvent such as ethanol in the presence of a catalyst such as Raney nickel. Step c) of cyclisation of the benzimidazole may be performed in a manner similar to Method I (step a), to Method II or to Method III described above. These methods are also applicable to compounds of the formula (I) that are different from the compounds of the formula (II).

Thus, the present invention also relates to a process for preparing compounds of the formula (I) in which Ri = R₂ = H, characterised in that the following steps are carried out: a) cyclisation step on the amine functions of a compound of the formula (2) below:

(2) by placing it in contact with a compound chosen from the compounds of the following formulae:

(3)

(8)

(9)

(7)

b) optionally, an N-alkylation reaction of the product obtained in a), c) optionally, a step of hydrolysis of the ester obtained in a) or b) to give the corresponding acid, in which formulae R₄, R5, A, B and X are as defined above.

The present invention also relates to a process for preparing compounds of the formula (I), in which the groups Ri and/or R₂ are other than H, characterised in that the following steps are carried out, prior to the steps mentioned above: i) placing a compound of the following formula

(10) in contact with a compound chosen from the compounds of the following formulae:

R' — ~O R3-Hal, ³ , followed, in this case, by a hydrogenation step, R'3 having the same definition as R3, and R3NH2, Hal representing a halogen atom, ii) a step of reduction of the aromatic nitro compound obtained in i), in which formulae R-i, R₂, R₃ and X are as defined above.

The insulin resistance is characterised by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes and more particularly non- insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity and arterial hypertension, and also certain microvascular and macrovascular complications, for instance atherosclerosis, retinopathies and neuropathies. In this respect, reference will be made, for example, to Diabetes, vol. 37,

1988, 1595-1607 ; Journal of Diabetes and its complications, 1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32.

In non-insulin-dependent diabetes, in man, the hyperglycaemia is the results of two major defects: an impairment in insulin secretion and a reduction in the efficacy of insulin at three sites (liver, muscles and adipose tissues).

The compounds of the present invention increase the secretion of insulin by the pancreatic beta cells. They are thus capable of improving glycaemia in non-insulin-dependent diabetic patients.

The compounds of the formula (I) are thus useful in the treatment of pathologies associated with hyperglycaemia. In this case, the compounds of the formula (I) are those described above, including therein those previously excluded by (i).

The present invention thus also relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention, including therein those previously excluded by (i). More particularly, these compositions are intended to increase the secretion of insulin or to treat pathologies associated with hyperglycaemia and more specifically diabetes.

The present invention thus also relates to the use of at least one compound according to the invention, including therein those previously excluded by (i), for the preparation of a pharmaceutical composition intended for treating pathologies associated with hyperglycaemia and more specifically diabetes.

The pharmaceutical compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration.

They will thus be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of plain or coated tablets, sugar- coated tablets, wafer capsules, gel capsules, pills, cachets, powders, suppositories or rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent, or for permucous use.

The excipients that are suitable for such administrations are cellulose derivatives or microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms. The preferred excipients for rectal use are cocoa butter or polyethylene glycol stearates.

The vehicles that are most convenient for parenteral use are water, aqueous solutions, physiological saline and isotonic solutions.

The dosage may vary within a wide range (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, and also the age and weight of the individual.

The examples that follow illustrate the invention without, however, limiting it.

INSULIN SECRETION TEST

According to the method described in Endocrinology, 1992 vol. 130 (1) pp. 167-178

Sec INS corresponds to the percentage of insulin secretion.

C corresponds to the concentration of test compound according to the invention.

The starting materials used are known products or products prepared by known procedures.

Example 1 : 4-ri-(2-Methylphenyl)methylbenzimidazol-2-yl1methyl-2-ethoxy- benzoic acid

- 3-Ethoxy-4-ethoxycarbonylbenzeneacetyl chloride 300 ml of dichloromethane are placed in a one litre round-bottomed flask, foilowed by addition of 15 g (0.06 M) of 3-ethoxy-4-ethoxycarbonylbenzeneacetic acid with stirring. After dissolution, 5.25 g (0.06 M) of oxalyl chloride are added dropwise. The solution obtained is stirred for two hours at room temperature and then concentrated to dryness under vacuum. A pale yellow oil is obtained, which is used in the following step without purification. - Ethyl 4-(2-aminophenylamino-2-oxoethyl')-2-ethoxγbenzoate 6.54g (0.06 M) of o-phenylenediamine are dissolved in a 250 ml round bottomed flask containing 100 ml of THF, and 5.25 ml of triethylamine are added. The acid chloride prepared above and dissolved in 50 ml of dichloromethane is added dropwise over a quarter of an hour.

The slightly exothermic reaction is maintained at a temperature below 30°C during the addition, and the mixture is then stirred vigorously at room temperature for 18 hours.

20 ml of demineralised water are added cautiously to the solution obtained. The reaction medium is concentrated under reduced pressure. The residue is taken up in 400 ml of demineralised water and then extracted three times with ethyl acetate. The combined organic phases are washed with demineralised water and brine and then dried over magnesium sulfate. After filtration, the solvent is stripped off under reduced pressure: the residue is taken up in diisopropyl ether, filtered and dried under reduced pressure. 14.2 g of a white solid are obtained. Yield = 70% m.p.: 105-110°C ¹H NMR (DMSO-d₆) : 9.46 (1 H, d) ; 7.62-6.60 (7H, m) ; 4.90 (1H, s) ; 4.26 (2H, q) ;

4.12 (2H, q) ; 3.71 (2H, m) ; 1.35 (6H, t) 4.17 g of the above amide are dissolved in a mixture of ethanol (250 ml) and concentrated hydrochloric acid (25 ml), and the mixture is then heated at 80°C for 2 hours. The medium is concentrated to dryness under vacuum. The residue is taken up in water and neutralised with 250 ml of normal sodium hydroxide. After extraction with ethyl ether, the organic phase is washed with water and then with brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The oil obtained crystallises from diisopropyl ether. 8 g of solid are obtained. Overall yield = 60% m.p.: 185-190°C ¹H NMR (DMSO-d₆) :

6.78-7.57 (8H, m) ; 4.49 (2H, s) ; 4.10 (4H, q) ; 1.16 (6H, t) Ethyl 4-M-(2-methylphenyl)methylbenzimidazol-2-yllmethyl-2-ethoxybenzoate hvdrochloride

32.92 g (0.101 M) of ethyl 4-(2-benzimidazolyl)methyl-2-ethoxybenzoate are dissolved in a three-necked flask containing 250 ml of anhydrous dimethyl- formamide, followed by slow addition of 4.06 g (0.101 M) of 60% sodium hydride.

The reaction medium is stirred for 12 hours at room temperature, followed by dropwise addition of 14.2 ml (0.102 M) of 96% of 2-methylbenzyl bromide. The reaction mixture is stirred for 12 hours at room temperature and then poured into

1 I of an ice/water mixture and extracted 3 times with ethyl acetate. The com- bined organic phases are washed with demineralised water and then with brine, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The oil obtained is dissolved in 100 ml of dichloromethane, followed by addition of a solution of hydrochloric acid in dioxane to acidic pH.

After stirring for one hour, the solvents are evaporated off under reduced pressure. The oil obtained crystallises from diisopropyl ether. The solid is filtered off and dried: xx g of a whitish product are obtained.

Yield: 27% m.p.: 100°C

¹H NMR (CDCI₃) : 7.93 (1 H, d) ; 7.56-6.93 (8H, m) ; 6.67 (1 H, d) ; 6.14 (1 H, d) ;

5.30 (2H, s) ; 4.56 (2H, s) ; 4.25 (2H, q) ; 3.96 (2H, q) ; 2.26 (3H, s) ; 1.28 (6H, t)

4-f1-(2-Methylphenyl)methylbenzimidazol-2-vnmethyl-2-ethoxybenzoic acid 0.57 g (0.014 M) of 97% sodium hydroxide is dissolved in a round-bottomed flask containing 60 ml of ethanol and 20 ml of demineralised water, followed by addition of 6 g (0.014 M) of the above hydrochloride.

The reaction medium is heated for 4 hours at the reflux point of the solvent. After cooling, it is poured into 150 ml of demineralised water and then extracted with diethyl ether, and then with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid: a white solid precipitates with stirring. It is filtered off, washed with demineralised water and dried.

5 g of white solid are obtained. Yield : 89% m.p.: 205°C H NMR (DMSO-d₆) :

12.55 (1 H, s) ; 7.80-6.95 (11 H, m) ; 5.58 (2H, s) ; 4.35 (2H, s) ; 4.03 (2H, q) ; 2.47 (3H, s) ; 1.35 (3H, t)

Example 2 : 4-(1-Phenylmethylbenzimidazol-2-yl)methyl-2-ethoxybenzoic acid

Sodium derivative of ethyl 4-(2-benzimidazolyl)methyl-2-ethoxybenzoate

5.7 g (0.017 M) of ethyl 4-(2-benzimidazolyl)methyl-2-ethoxybenzoate (obtained by the method described in Example 1) dissolved in 150 ml of tetrahydrofuran are added dropwise to a round-bottomed flask containing 100 ml of tetrahydrofuran and 0.7 g (0.017 M) of sodium hydride. On stirring for 2 hours at room tempera- ture, a grey solid precipitates. It is filtered off, washed with tetrahydrofuran and dried under reduced pressure. 6 g of solid are obtained.

Ethyl 4-n-(4-methyl)phenylmethylbenzimidazol-2-vnmethyl-2-ethoxybenzoate 109 mg (0.59 mM) of benzyl bromide are added to 170 mg (0.49 mM) of the above product dissolved in 2 ml of dimethylformamide, and the mixture is stirred at room temperature for 20 hours.

The reaction medium is then poured into 15 ml of demineralised water and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. The residue is taken up in diisopropyl ether: the medium is filtered. The filtrate is purified by elution on a column of silica: eluent cyclohexane (50)/ethyl acetate (50).

4-[1-(4-Methyl)phenylmethylbenzimidazol-2-vnmethyl-2-ethoxybenzoic acid The above ester dissolved in 3 ml of ethanol is treated with one equivalent of 1N caustic soda at 40°C for 1 hour. 15 ml of demineralised water are then added and the mixture is extracted twice with ethyl acetate. The aqueous phase is acidified with acetic acid and then extracted with twice 10 ml of ethyl acetate. The combined organic phases are concentrated under reduced pressure to give the product. Mass found : 400.2; Theoretical mass : 400.48

By way of example, the following compounds are prepared by the procedures described in Example 2:

The compounds mentioned above were characterised by the following analytical techniques: The NMR spectra were recorded using a Brϋker Advanced DPX 200 MHz NMR spectrometer.

The masses were determined by HPLC coupled to an Argilent 1100 Series mass detector. The melting points (m.p.) were measured on a block of Kόfler Leica VMHB type.

Claims

1- Compounds of the general formula (I)

(I)

in which: X represents, independently of each other, CH or a nitrogen, oxygen or sulfur atom,

R1 , R2, R3, R4 and R5, which may be identical or different, are chosen without preference from the following groups: - H - (C₁-C20) alkyl optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C₃-C₈) cycloalkyl, (C₁-C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, an oxygen, sulfur or phosphorus atom,

- (C₂-C o) alkylene optionally substituted by halogen, (C₁-C5) alkyl, (C1-C5) alkoxy or (C₃-C₈) cycloalkyl

- (C₂-C₂o) alkyne optionally substituted by halogen, (C₁-C5) alkyl, (C₁-C5) alkoxy or (C₃-C₈) cycloalkyl

- (C -Cβ) cycloalkyl optionally substituted by (C1-C5) alkyl or (C1-C5) alkoxy

- (C₃-C₈) heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by (C₁-C₅) alkyl or (C1-C5) alkoxy,

- (C₆-Cι₄)aryl(Cι-C₂₀)alkyl optionally substituted by amino, hydroxyl, thio, halogen, (C₁-C₅) alkyl, (C₁-C₅) alkoxy, (C₁-C₅) alkylthio, (C C₅) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι )arylsulfonyl(C₁-C₅)alkyl, (C₆-Cι ) aryloxy, (C₆-C₁₄)- aryl(Cι-C₅)alkoxy, cyano, trifluoromethyl, carboxyl optionally in acid or ester form, carboxymethyl or carboxyethyl,

- (C₆-C₁₄) aryl optionally substituted by amino, hydroxyl, thio, halogen, (Cr C₅) alkyl, (C-1-C5) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (C₆-C₁₄) aryl, (C₆-Cι₄) aryloxy, (C₆-C₁₄)aryl(C₁-C₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (C₁-C₁₃) heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C^Cs) alkoxy, (C C₅) alkylthio, (C_rC₅) alkylamino, (C₆-C₁₄) aryl, (C₆-C-i₄) aryloxy, (C₆-C₁₄)aryl(Cι-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

A represents a (Cι-C₆) alkyl group optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (C-ι-C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,

B represents a single bond or a

alkyl group optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (Cι-C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, with the exclusion of the compounds of the formula (I) in which:

(i) R1 = H, R2 = H, R3 = H or CH3, R4 = H or -NH-CH2-C6H5, R5 = H, when A is -CH2- and B is a single bond; and also the tautomeric forms, enantiomers, diastereoisomers and epimers thereof, and the pharmaceutically acceptable salts thereof.

2- Compounds according to Claim 1 , characterised in that they are of the general formula (II) below:

(II) in which R-i, R₂, R₃, R₄, R_5, A, B and X are as defined in Claim 1.

3- Compounds according to the preceding claim, characterised in that X represents CH and/or Ri and R₂ represent a hydrogen atom.

4- Compounds according to one of the preceding claims, characterised in that A is an optionally substituted methylene group.

5- Compounds according to any one of the preceding claims, characterised in that B is an optionally substituted methylene group.

6- Compounds according to one of Claims 1 to 4, characterised in that B is a single bond.

7- Compounds according to any one of the preceding claims, characterised in that R4 is a (C₁-C20) and preferably (Cι-C₆) alkoxy radical.

8- Compounds according to any one of the preceding claims, characterised in that the function -B-COOR5 is in the para position on the ring relative to -A-.

9- Compounds according to any one of the preceding claims, characterised in that R4 is in the meta position on the ring relative to -A-.

10- Compounds according to any one of the preceding claims, characterised in that R1 and R2, which may be identical or different, represent a (C1-C6) alkyl chain or a hydrogen atom.

11- Process for preparing compounds of the formula (I) in which Ri = R₂ = H, as described in one of the preceding claims, characterised in that the following steps are carried out: d) cyclisation step on the amine functions of a compound of the formula (2) below:

(3)

(8)

(9)

(7)

e) optionally, an N-alkylation reaction of the product obtained in a), f) optionally, a step of hydrolysis of the ester obtained in a) or b) to give the corresponding acid, in which formulae R₄, R_5] A, B and X are as defined in one of the preceding claims.

12. Process for preparing compounds of the formula (I), in which the groups R-i and/or R₂ are other than H, as described in one of Claims 1 to 10, characterised in that the following steps are carried out, prior to the steps of the process according to Claim 11 : i) placing a compound of the following formula

□' ⁼⁼O

R3-Hal, ³ , followed, in this case, by a hydrogenation step, R'3 having the same definition as R3, and R3NH2, Hal representing a halogen atom, ii) a step of reduction of the aromatic nitro compound obtained in i), in which formulae Ri, R₂, R₃ and X are as defined in one of Claims 1 to 10.

13- Pharmaceutical composition comprising, as active principle, a compound of the general formula (I) below:

in which:

X represents, independently of each other, CH or a nitrogen, oxygen or sulfur atom,

R1 , R2, R3, R4 and R5, which may be identical or different, are chosen without preference from the following groups: - H - (C1-C₂₀) alkyl optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C₃-C₈) cycloalkyl, (CrC₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, an oxygen, sulfur or phosphorus atom, - (C₂-C₂₀) alkylene optionally substituted by halogen, (Cι-C₅) alkyl, (C1-C₅) alkoxy or (C₃-C₈) cycloalkyl

- (C₂-C₂₀) alkyne optionally substituted by halogen, (C₁-C₅) alkyl, (C₁-C₅) alkoxy or (C₃-C₈) cycloalkyl

- (C₃-C₈) cycloalkyl optionally substituted by (C₁-C₅) alkyl or (Cι-C₅) alkoxy - (C₃-C₈) heterocycloalkyl bearing one or more hetero atoms chosen from

N, O and S and optionally substituted by (C1-C₅) alkyl or (C Cs) alkoxy,

- (C₆-C ₄)aryl(CrC₂o)alkyl optionally substituted by amino, hydroxyl, thio, halogen, (C Cs) alkyl, (C₁-C5) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι₄)arylsulfonyl(Cι-C₅)alkyl, (C₆-C₁₄) aryloxy, (C₆-C ₄)- aryl(Cι-C₅)alkoxy, cyano, trifluoromethyl, carboxyl optionally in acid or ester form, carboxymethyl or carboxyethyl,

- (C₆-Cι₄) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C C₅) alkylthio, (C₁-C5) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι ) aryloxy, (C₆-C₁₄)aryl(CrC₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (C₁-C-₁3) heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C-₁-C₅) alkyl, (C₁-C5) alkoxy, (C C₅) alkylthio, (C₁-C₅) alkylamino, (C₆-C ) aryl, (C6-C1₄) aryloxy, (C6-C ₄)aryl(CrC5)alkoxy, cyano, trifluoromethyl, car- boxyl, carboxymethyl or carboxyethyl,

A represents a (Ci-Cβ) alkyl group optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (CrC₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,

B represents a single bond or a (Ci-C_δ) alkyl group optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (C1-C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester amide, a sulfur or phosphorus atom, and also the tautomeric forms, enantiomers, diastereoisomers and epimers thereof, and the pharmaceutically acceptable salts thereof.

14- Composition according to Claim 13, intended for increasing the secretion of insulin.

15- Composition according to Claim 13, intended for treating pathologies associated with hyperglycaemia.

16- Composition according to Claim 13, intended for treating diabetes.

17- Use of at least one compound as defined in Claim 13, for the preparation of a pharmaceutical composition intended for treating pathologies associated with hyperglycaemia and more specifically diabetes.