WO2003024937A1

WO2003024937A1 - Benzimidazolylalkoxyaryl alkanoic acid derivatives and their use as antihyperglycemics

Info

Publication number: WO2003024937A1
Application number: PCT/EP2002/009832
Authority: WO
Inventors: Gérard Moinet; Jean-Claude Correc; Eric Metais
Original assignee: Merck Patent Gmbh
Priority date: 2001-09-14
Filing date: 2002-09-03
Publication date: 2003-03-27
Also published as: FR2829765A1

Abstract

The invention relates to compounds of the general formula (I): in which x is amongst C or N, R1, R2, R3, R4 and R5 are H or substituents, A is an optionally substituted alkylene, and B is a bond or an optionally substituted alkylene. These compounds can be used in the treatment of pathologies associated with hyperglycaemia.

Description

BENZIMIDAZO YLA KOXYARY A KANOIC ACID DERIVATIVES AND THEIR USE AS ANTIHYPERG YCEMICS

The present invention relates to imidazolylalkylarylaikanoic 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, a carbon, nitrogen, oxygen or sulfur atom,

R1 , R2, R3, R4 and R5, which may be identical or different, are chosen from the following groups: - H

- (C1-C2₀) alkyl which is optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C₃-C₈) cycloalkyl, (C C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,

- (C2-C₂₀) alkylene which is optionally substituted by halogen, (C1-C5) alkyl, (CrC₅) alkoxy or (C-₃-Cs) cycloalkyl

- (C₂-C₂₀) alkyne which is optionally substituted by halogen, (C1-C5) alkyl, (C_rC₅) alkoxy or (C₃-C₈) cycloalkyl

- (C₃-Cs) cycloalkyl which is optionally substituted by (C C₅) alkyl or (C₁-C₅) alkoxy

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

- (C₆-Ci₄)aryl(CrC₂o)alkyl optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (C C₅) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (Cβ-C-u) aryl, (Cβ-Cu) aryloxy, (C₆-Ci₄)aryl(CrC₅)alkoxy, cyano, trifluoro- methyl, carboxyl, carboxymethyl or carboxyethyl,

- (Cβ-Cu) aryl optionally substituted by amino, hydroxyl, thio or halogen, (C C₅) alkyl, (C1-C5) alkoxy, (C C₅) alkylthio, (C1-C5) alkylamino, (C_e-C₁₄) aryl, (C₆-Cι ) aryloxy, (C₆-Ci₄)aryl(Cι-C₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (CrC₁₃) heteroaryl which carries one or more hetero atoms chosen from N, O and S and which is optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (C1-C5) alkoxy, (C C₅) alkylthio, (C₁-C5) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι₄) aryloxy, (C₆-Ci₄)aryl(CrC₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

A represents a (CrC₆) alkyl group which is 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, unsubstituted amide, a sulfur or phosphorus atom,

B represents a single bond or a (CrC₆) alkyl group which is optionally substituted by one or more of the following groups: halogen, (C-3-Cβ) 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 (!) in which:

- R1 is a hydrogen atom, R2 is a hydrogen atom, a halogen atom or a (C₁-C5) alkyl radical, R3 is a hydrogen atom or a methyl or benzyl radical, R4 is a hydrogen atom, A is a methylene radical and B is a single bond,

- R2, R3, R4 and R5 represent a hydrogen atom, R1 is an imidazole group, A is a methylene radical and B is a single bond,

- R4 is an arylmethoxy radical, which is optionally substituted on the methyl and/or aryl radical, A is an optionally substituted methylene radical and B is a single bond, and also the tautomeric forms, enantiomers, diastereoisomers and epimers 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: Ri , R₂, R₃, R_4J R5, 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 a carbon 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 hydrogen atom.

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-0-.

Among the C₁-C₂0 alkyl radicals that may especially be mentioned are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, hexadecyl and octadecyl radicals.

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

When they are branched or substituted by one or more alkyl radicals, mention may especially be made of isopropyl, tert-butyl, 2-ethylhexyl, 2-methyl- butyl, 2-methylpentyl, 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. The amino substituents correspond to groups that contain at least one amine function.

The methylene radical is a divalent radical of the formula -CH₂- and the carbonyl radical is a divalent radical of the formula -CO-. Among the halogen atoms, mention is made more particularly of the fluorine, chlorine, bromine and iodine atoms.

The alkylene radicals comprise one or more ethylenic unsatu rations. Among the alkylene radicals that may be mentioned especially are the allyl and vinyl radicals. The alkyne radicals comprise one or more acetylenic unsatu rations.

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 con- taining, 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 to 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-Cι )aryl(CrC₂o)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 fuiγl, pyridyl, quinolinyl, indolyl, isoindolyl, quinolyl, imidazolyl, pyrimidinyl and carbazolyl radicals. The invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers 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, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palm- oate, aspartate, methanes u If onate, maleate, para-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesu If onate, trimethoxybenzoate, para-toluenesulfonate, adamantanecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 -phosphate, nitrate, sulfite, dithionate, phosphate, dobesilate, thioctate, hippurate, 3-benz- amidopropanoate, 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 Ri = R₂ = H can be prepared by method (I)

(4) (5) (6)

Method

Step a) can be carried out in an nonpolar solvent, such as, for example, dichloromethane, in the presence or absence of an organic or mineral base, such as, for example, triethylamine, at room temperature or by heating the solvent.

The intermediate amide thus obtained may be cyclised in acidic medium. The cyclisation can preferably be carried out by heating under reflux in an ethanol/concentrated hydrochloric acid mixture.

Step b) is an N-alkylation reaction that is well known in the literature. It can preferably be carried out 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 (4) as described above, for which R_T = R₂ = H, used in J. Med. Chem. 1998, 41, 2709- 2719, can be represented schematically by method (II) below:

(2) R5^ H

(9) (4)

Method II This cyclisation can be carried out in an alcoholic solvent, preferably methanol, after having reacted the reagent (9) beforehand, at room temperature, in methanol in the presence of sodium methoxide.

Another method for preparing the compounds of the general formula (I) described above, for which Ri = R₂ = H, can be represented schematically by method III

(2) (10) ^{(4) R5}^^H

Method III

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

Compound (9) can preferably be synthesised by the well-known Pinner method (Organic Functional Group Preparation Vol. 3, 1972) starting from the nitrite (9).

Another method for preparing the compounds of the general formula (4) as described above, for which R_t = R₂ = H, can be represented schematically by method IV

(2)

Method IV

This cyclisation can be carried out by heating (2) and (11) at reflux in 2N HCI.

When X = C, R1 = R2 = H and A = CH₂, the compounds of the general formula (4) can be obtained by method V :

R5^ H

Method V

When the groups

and/or R₂ are other than H, the compounds of the general formula (1 ) described above can be prepared by method V. This strategy makes it possible to unambiguously fix the position of the substituents on the ring, in particular on the benzimidazole ring, and to avoid the formation of a mixture of regioisomers.

Method VI

Step a) can be carried out in the solvents usually used for this well-known Williamson reaction. Compound (12) can preferably be heated in acetonitrile in the presence of an organic or mineral base, preferably K₂C0₃.

Alternatively, the compound of the formula (13) can be obtained by the well-known reaction of an aldehyde with the aniline (12) followed by a hydrogena- tion catalysed by Pd/C: Method VII

Met! ιode VII

The compound of the formula (11) can also be obtained by method VIII

Method VIII

This reactionmbe 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. Compound (13) is preferably reduced with hydrogen in ethanol in the presence of a catalyst, such as Pd/C.

Alternatively, compound (13) can be reduced using 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 can 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) which 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 R-, = 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:

0)

b) optionally, an N-alkylation reaction of the product obtained in a), c) optionally, a hydrolysis step 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

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

R' — ⁼0 R₃-Hal, ³ , followed, in this case, by a hydrogenation step, where R'₃ is as defined for R₃, and R₃NH₂, where Hal represents a halogen atom, ii) a reduction step of the aromatic nitro compound obtained in i), in which formulae Ri, R₂, R₃ and X are as defined above.

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 result 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 patho- logies associated with hyperglycaemia.

The present invention therefore also relates to pharmaceutical compositions comprising, as active principle, at least one compound according to the invention. The pharmaceutical compositions according to the invention can 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 sol- vent, 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, potassium phosphate, starches, modified starches, lactose or glucose 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..

On the basis of his general knowledge, a person skilled in the art can readily determine the adjuvants that are suitable for the desired formulation of the composition according to the invention so as to prepare a pharmacologically acceptable support.

The dosage can vary within a wide range as a function of the therapeutic indication and the route of administration, and also the age and weight of the individual. Thus, on average, for a patient weighing about 75 kg, the daily dose can range from 0.5 mg to 1000 mg/kg, preferably from 0.5 mg to 500 mg/kg, more preferably from 0.05 mg to 100 mg/kg and advantageously from 0.01 mg to 20 mg/kg of body weight. The present invention therefore also relates to the use of compounds of the general formula (I) for the preparation of pharmaceutical compositions intended for treating pathologies associated with hyperglycaemia, more particularly diabetes, the general formula (I) being as follows:

(I) in which:

- (C₁-C-₂0) alkyl which is 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, a sulfur or phosphorus atom,

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

- (C-2-C20) alkyne which is optionally substituted by halogen, (C C₅) alkyl, (C1-C5) alkoxy or (C₃-C₈) cycloalkyl - (C₃-C₈) cycloalkyl which is optionally substituted by (C C ) alkyl or

(C1-C5) alkoxy

- (C₃-C₈) heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by (C_rC₅) alkyl or (C1-C-5) alkoxy,

- (C₆-Ci4)aryl(CrC₂o)alkyl which is optionally substituted by amino, hydroxyl, thio, halogen, (C₁-C5) alkyl, (C C₅) alkoxy, (C C₅) alkylthio,

(C1-C5) alkylamino, (Cβ-Cu) aryl, (C₆-Cι₄) aryloxy, (C_e-C )aryl(Ci-C₅)- alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C-₆-C₁₄) aryl which is optionally substituted by amino, hydroxyl, thio or halogen,

(C C₅) alkyl, (C1-C5) alkoxy, (Cι-C₅) alkylthio, (C C₅) alkylamino, (Cβ-Cu) aryl, (C₆-Cι₄) aryloxy,

cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (CrCi₃) heteroaryl bearing one or more hetero atoms chosen from N, 0 and S and optionally substituted by amino, hydroxyl, thio, halogen, (C₁-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C C₅) alkylamino, (C₆-Cι₄) aryl, (Cβ-Cu) aryloxy, (C₆-C₁₄)aryl(Cι-C₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

A represents a (CrC₆) alkyl group which is optionally substituted by one or more of the following groups: halogen, (C₃-C₈) cycloalkyl, (C C₅) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, unsubstituted amide, a sulfur or phosphorus atom,

B represents a single bond or a (C Cβ) alkyl group which is 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.

The examples that follow illustrate the invention, but without limiting it. The starting materials used are known products or products prepared by known procedures.

Example 1 : 4-(1-ethyl-6-methyl-2-benzimidazolvπmethoxybenzoic acid

- N-ethyl-5-methyl-2-nitroaniline

100 g (0.64 M) of 3-fluoro-4-nitrotoluene, 200 ml of ethanol and 102 ml of aqueous 70% ethylamine (1.27 M) are placed in a one litre round-bottomed flask. The mixture is heated under pressure at 85°C for 6 hours. After cooling, the reaction medium is poured into 11 of demineralised water. The orange precipitate formed is filtered off, washed with demineralised water and then dried at 40°C. 113 g of orange solid are obtained, m.p. : 60°C Yield : 99% by weight - N²-ethyl-4-methylbenzene-1,2-diamine dihydrochloride

113 g (0.63 M) of N²-ethyl-5-methyl-2-nitroaniline, 500 ml of methanol and about 0.1 g of Raney nickel are introduced into a 21 three-necked flask. The mixture is brought to the reflux point of the solvent, with stirring, and 90 ml (0.85 M) of hydrazine hydrate are then added dropwise. Refluxing is continued for 1 hour after the evolution of hydrogen has ceased. After cooling, the catalyst is filtered off over Clarcel. The filtrate is evaporated under vacuum. The oil obtained crystallises from ethyl ether. The solid is dissolved in 300 ml of acetonitrile. The solution is acidified with 5N hydrochloric isopropanol solution to pH 1. A solid precipitates out with stirring at room temperature over 0.5 hour. The solid is filtered off, washed with acetonitrile and then with isopropyl ether and finally dried at 40°C under vacuum.

106.6 g of a pink solid are obtained, m.p. : 164°C Yield : 76% - methyl 4-(1-ethyl-6-methyl-2-benzimidazolyl)methoxybenzoate

26 g (0.14 M) of methyl 4-cyanomethoxybenzoate and 350 ml of anhydrous methanol are introduced into a 21 three-necked flask. 26 ml (0.14 M) of 30% sodium methoxide in methanol are added to the suspension obtained. Dissolution is observed: after stirring for 1 hour at room temperature, a precipitate forms. 30.3 g (0.14 M) of N²-ethyl-4-methylbenzene-1,2-diamine dihydrochloride are added and stirring is continued for 18 hours at room temperature. The reaction medium is then poured into 1.21 of an ice/water mixture. The precipitate formed is filtered off, washed with demineralised water and then with isopropyl ether, and then dried under vacuum. 25.5 g of a grey solid are obtained, m.p. : 148-150°C Yield : 58% ¹H NMR (DMSO-de) :

8.04 (2H, d) ; 7.65 (1 H, d) ; 7.50 (1 H, s) ; 7.36 (2H, m) ; 7.15 (1 H, m) ; 5.56 (2H, s); 4.39 (2H, q); 3.91 (3H, s); 2.55 (3H, s); 1.44 (3H, t); - 4-(1 -ethyl-6-methyl-2-benzimidazolvDmethoxybenzoic acid

100 ml of methanol, 30 ml of demineralised water, 6.5 g (0.16 M) of 97% sodium hydroxide and 25.5 g (0.08 M) of methyl 4-(1-ethyl-6-methyl-2-benzimidazolyl)- methoxybenzoate are introduced into a 11 round-bottomed flask. The mixture is refluxed until dissolved (about 4 hours). The reaction medium is then poured into 11 of an ice/water mixture. The solution is acidified to pH 1 with concentrated hydrochloric acid. A white solid forms: the medium is stirred for 1 hour and the solid is then filtered off, washed with demineralised water and dried under vacuum. It is recrystallised from acetic acid. 18.5 g of a white solid are obtained. m.p. : 259°C

Yield : 76% ¹H NMR (DMSO-de) : 7.33 (7H, m) ; 5.57 (2H, s) ; 4.42 (2H, q); 2.55 (3H, s); 1.45 (3H, t);

By way of example, the following compounds are prepared by the procedures of Example 1 described above.

4-(1 -phenylmethylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 195°C ¹H NMR (DMSO-d₆) :

12.30 (1 H, s) ; 7.20 (11 H, m) ; 6.90 (2H, d); 5.70 (2H, s); 5.55 (2H, s); 3.62 (2H, s) ; 4-(1 -ethylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 182°C ¹H NMR (DMSO-de) :

12.22 (2H, dd) ; 9.55 (6H, m) ; 7.05 (2H, s); 5.30 (2H, d); 3.40 (2H, s); 1.20 (3H, t) ; 4-(1-ethyl-6-methylbenzimidazol-2-yl)methoxybenzenepropanoic acid m.p. : 213°C ¹H NMR (DMSO-de) :

12.22 (1 H, s);7.56 (1 H, d) ; 7.42 (1 H, s) ; 7.09 (5H, m) ; 5.37 (2H, s); 4.33 (2H, q); 2.79 (2H, t); 2.53 (5H, m) ; 1.37 (3H, t) ; 4-(5-chloro-1-phenylmethylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 190°C ¹H NMR (DMSO-d₆) :

12.20 (1 H, s) ; 9.90 (2H, m) ; 7.20 (8H, m) ; 6.80 (2H, d); 5.60 (2H, s); 5.40 (2H, s); 3.45 (2H, s) ; -(5-chloro-1 -ethylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 185°C

¹H NMR (DMSO-d₆) :

12.10 (1 H, s) ; 8.60 (2H, m) ; 7.03 (3H, m) ; 6.85 (2H, d); 5.25 (2H, s); 4.15 (2H, q); 3.35 (2H, s) ; 1.20 (3H, t) ; -(5-methyl1-phenylmethylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 167°C

¹H NMR (DMSO-de) :

12.55 (1 H, s) ; 7.25 (12H, m) ; 5.70 (2H, s) ; 5.50 (2H, s); 3.70 (2H, s); 2.55 (3H, s) ; -(1 -carboxymethylbenzimidazol-2-yl) methoxybenzeneacetic acid m.p. : 223°C

¹H NMR (DMSO-de) :

12.78 (1 H, s) ; 7.69 (2H, dd) ; 7.24 (6H, m) ; 5.40 (2H, s); 5.20 (2H, s); 3.52 (1 H, s); -(1-carboxymethylbenzimidazol-2-yl)methoxybenzenepropanoic acid m.p. : 228°C H NMR (DMSO-d₆) :

7.02- 6.98 (8H, m) ; 5.38 (2H, s); 5.19 (2H, s); 2.82 (2H, t) ; 2.53 (2H, t) ; -(5, 6-dimethyl-1-phenylmethylbenzimidazol-2-yl) methoxybenzeneacetic acid m.p. : 192°C

¹H NMR (DMSO-d₆) :

7.15 (11 H, m) ; 5.43 (2H, s); 5.23 (2H, s); 3.39 (2H, s); 2.20 (6H, d) ; -(1-ethyl-5-methylbenzimidazol-2-yl)methoxybenzenepropanoic acid m.p. : 198°C ¹H NMR (DMSO-de) :

7.49 (2H, d) ; 7.18 (5H, m) ; 5.37 (2H, s); 4.34 (2H, q); 2.79 (2H, t); 2.53 (5H, m) ; 1.37 (3H, t) ; -(1-phenylmethyl-5-methylbenzimidazol-2-yl)methoxybenzeneacetic acid m.p. : 206°C ¹H NMR (DMSO-d₆) :

6.98 (12H, m) ; 5.39 (2H, s) ; 5.20 (2H, s); 3.35 (2H, s); 2.24 (3H, s); -(1-phenylmethyl-5-methylbenzimidazol-2-yl)methoxybenzenepropanoic acid m.p. : 207°C ¹H NMR (DMSO-de) : 12.22 (1 H, s) ; 7.15 (12H, m) ; 5.57 (2H, s); 5.38 (2H, s); 2.79 (2H, t);

2.52 - 2.41 (5H, s+t) ; -(1 -ethyl-5-methylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 242°C ¹H NMR (DMSO-de) : 12.5 (1 H, s); 7.50 (7H, m) ; 5.52 (2H, s) ; 4.33 (2H, d); 2.45 (3H, s);

1.38 (3H, t); -(5-methyl-1-phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 183°C ¹H NMR (DMSO-d₆) : 7.34 (12H, m) ; 5.62 (2H, s) ; 5.49 (2H, s); 2.40 (3H, s); -(1 -ethyl-5-methylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 177°C ¹H NMR (DMSO-de) :

12.5 (1 H, s); 7.38 (7H, m) ; 5.51 (2H, s) ; 4.27 (2H, q); 2.36 (3H, s); 1.29 (3H, t); -(5-methyl-1-phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 258°C ¹H NMR (DMSO-de) :

7.38 (12H, m) ; 5.64 (2H, s) ; 5.54 (2H, s); 2.48(3H, s); -(1-ethyl-5-chlorobenzimidazol-2-yl)methoxybenzoic acid m.p. : 236°C ¹H NMR (DMSO-de) :

12.90 (1 H, s); 7.80 (7H, m) ; 5.72 (2H, s) ; 4.55 (2H, q); 1.50 (3H, t); -(1 -carboxymethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : >265°C

¹H NMR (DMSO-de) :

12.95 (1 H, s); 7.85 (2H, d) ; 7.58 (2H, dd) ; 7.25 (4H, m) ; 5.46 (2H, s); 5.16 (2H, s); -(5, 6-dimethyl-1-ethylbenzimidazol-2-yI)methoxybenzoic acid m.p. : 262°C

¹H NMR (DMSO-de) :

8.10 (2H, d); 7.60 (2H, d) ; 7.35 (2H, d) ; 5.60 (2H, s); 4.40 (2H, q);

2.50 (6H, 2s); 1.50 (3H, t); -(1 -phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 231°C

¹H NMR (DMSO-d₆) :

7.65(13H, m) ; 5.60 (2H, s) ; 5.50 (2H, s); -(1 -ethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : >265 ¹H NMR (DMSO-de) :

12.90 (1 H, s); 8.10 (2H, d) ; 7.90 (2H, m) ; 7.43 (4H, m); 5.70 (2H, s) ; 4.55 (2H, q); 1.60 (3H, t); -(5-methyl-1-phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 228°C ¹H NMR (DMSO-d₆) :

12.75 (1 H, s); 7.92 (2H, d) ; 7.30 (10H, m) ; 5.60 (2H, s) ; 5.55 (2H, s); 2.40 (3H, s); -(1 -ethyl-5-methylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 230°C ¹H NMR (DMSO-de) :

7.51 (7H, m) ; 5.52 (2H, s) ; 4.40 (2H, q); 2.48 (3H, s); 1.41 (3H, t); -(benzothiazol-2-yl)methoxybenzoic acid m.p. : >265°C ¹H NMR (DMSO-d₆) : 12.80 (1 H, s); 8.16 (4H, m) ; 7.66 (2H, m); 7.28 (2H, d); 5.81 (2H, s); -(5-benzoyl-1-phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 250 ¹H NMR (DMSO-de) :

7.62 (17H, m) ; 5.76 (2H, s) ; 5.65 (2H, s); 4-(1 -hepthylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 213°C ¹H NMR (DMSO-d₆) :

7.65 (8H, m) ; 5.60 (2H, s) ; 4.28 (2H, t);1.58 (2H, s); 1.08 (8H, m) ; 0.60 (3H, t);

2-ethoxy-4-(1-ethyl-5-methylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 170°C ¹H NMR (DMSO-de) :

12.20 (1 H, s); 7.30 (6H, m) ; 5.52 (2H, s);4.35 (2H, q); 4.10 (2H, q); 2.40 (3H, s); 1.45 (6H, t);

2-ethoxy-4-(5-methyl-1 -phenylmethylbenzimidazol-2-yl)methoxy benzoic acid m.p. : 197°C ¹H NMR (DMSO-de) :

12.40 (1 H, s); 7.52 (9H, m) ; 6.72 (2H, s); 5.80 (2H, s); 5.65 (2H, s); 4.21 (2H, q); 2.60 (3H, s); 1.52 (3H, t);

2-ethoxy-4-(1 -ethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 222°C ¹H NMR (DMSO-de) :

12.15 (1 H, s); 7.40 (3H, m) ; 7.20 (2H, m); 6.70 (2H, s+d); 5.45 (2H, s); 4.35 (2H, q); 4.07 (2H, q); 1.30 (6H, t);

2-ethoxy-4-(1-phenylmethylbenzimidazol-2-yl)methoxybenzoic acid m.p. : 180°C ¹H NMR (DMSO-de) :

12.20 (1 H, s); 7.30 (12H, m) ; 5.70 (2H, s); 5.50 (2H, s);4.05 (2H, q); 1.35 (3H, t);

Example 2 : 3-π-(2-chloro-4-fluoro henylmethyl-2-benzimidazolvnmethoxy- phenylacetic acid

- Sodium derivative of methyl 3-(2-benzimidazolyl)methoxyphenylacetate

100 ml of methanol and 7.94 g (0.039 M) of methyl 3-cyanomethoxyacetate are placed in a 500 ml three-necked flask. 7.4 ml (0.039 M) of a 5.25N solution of sodium methoxide in methanol are added slowly to this solution at a temperature below 35°C. The medium is stirred for 1.5 hours at room temperature, followed by addition of 7 g (0.039 M) of 1 ,2-diaminobenzene dihydrochloride. After stirring for 3 hours at room temperature, the medium is poured into 800 ml of an ice/water mixture and extracted three times with diethyl ether. After washing the combined organic phases with water and concentrating under reduced pressure, the solid obtained is filtered off and washed with diisopropyl ether. The white solid obtained is dissolved in 70 ml of tetrahydrofuran and 0.96 g (1 equivalent) of 60% sodium hydride is then added cautiously. The precipitate formed is stirred for 1 hour and then filtered off, washed with diisopropyl ether, filtered off and dried under reduced pressure.

8.3 g of a white solid are obtained.

Yield : 66.8% ¹H NMR (DMSO-de) :

7.33-6.75 (8H, m) ; 5.13 (2H, s); 3.68 (5H, 2s);

- methyl 3-[1 -(2-chloro-4-fluoro)phenylmethyl-2-benzimidazolyl]methoxyphenyl- acetate 150 mg (4.7x10^"4 M) of the sodium derivative of methyl 3-(2-benzimidazolyl)- methoxyphenylacetate dissolved in 2 ml of DMF are added to a 50 ml reactor containing 137 mg (6.13x10^"4 M, i.e. 1.3 equivalents) of bromomethylbenzene. The reaction medium is stirred for 18 hours at room temperature. 10 ml of demineralised water^* are then added, the mixture is extracted with twice 10 ml of ethyl acetate and the organic phases are concentrated to dryness under reduced pressure.

- 3-[1 -(2-chloro-4-fluoro)phenylmethyl-2-benzimidazolyl]methoxyphenylacetic acid 1 ml of ethanol is added to the solid obtained above, the mixture is stirred for 5 minutes and 1 ml of 10N sodium hydroxide solution is added. The medium is stirred for 5 minutes at 80°C, followed by addition of 1 ml of demineralised water and stirring for a further 30 minutes at 80°C. 5 ml of demineralised water are then added and stirring is continued for 3 hours at room temperature. The reaction medium is then acidified with 0.6 ml of acetic acid^* and then extracted with twice 10 ml of ethyl acetate. The combined organic phases are concentrated to dry- ness under reduced pressure.

^* at this stage, if the expected product precipitates out, it is filtered off with suction, washed with demineralised water and then dried under reduced pressure.

HPLC/mass analysis of the solid obtained: Theoretical mass: 424.86

Mass found: 423.1

By way of example, the following compounds are prepared by the procedures of Example 2 described above.

33

39

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 Kδfler Leica VMHB block. STUDY OF ANTIDIABETIC ACTIVITY IN NOSTZ RATS

The oral antidiabetic activity of the compounds of the formula (I) was determined on an experimental model of non-insulin-dependent diabetes induced in rats using steptozotocin.

The model of non-insulin-dependent diabetes is obtained in rats by means of a neonatal injection (on the day of birth) of steptozotocin.

The diabetic rats used are eight weeks old. The animals are housed, from the day of birth to the day of the experiment, in an animal house at a regulated temperature of 21 to 22°C and are subjected to a fixed cycle of light (from 7 a.m. to 7 p.m.) and of darkness (from 7 p.m. to 7 a.m.). Their feed consisted of a maintenance diet, and water and feed were supplied "ad libitum", with the exception of fasting for the two hours preceding the tests, during which time the feed was removed (post-absorptive state).

The rats are treated orally for one (D1) or four (D4) days with the test product. Two hours after the final administration of the product and 30 minutes after the animals have been anaesthetised with pentobarbital sodium (Nembutal®), a 300 μl blood sample is taken from the end of the tail. The results obtained are collated in the table below by way of example.

These results show the efficacy of the compounds mentioned for reducing glycaemia in the diabetic animals. These results are expressed as a percentage change in the glycaemia at D4 (number of days of treatment) relative to DO (before the treatment).

Claims

1- Compounds of the general formula (1)

(I) in which:

- (C1-C20) alkyl which is 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, a sulfur or phosphorus atom, - (C2-C20) alkylene which is optionally substituted by halogen, (C₁-C₅) alkyl,

(C1-C5) alkoxy or (C₃-C₈) cycloalkyl

- (C2-C20) alkyne which is optionally substituted by halogen, (C-₁-C₅) alkyl, (C₁-C5) alkoxy or (C₃-C₈) cycloalkyl

- (C₃-C₈) Cycloalkyl which is optionally substituted by (C₁-C₅) alkyl or (C1-C5) alkoxy

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

- (C₆-Ci4)aryl(CrC₂o)alkyl which is optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (C C₅) alkoxy, (C C₅) alkylthio, (C

C₅) alkylamino, (C₆-C₁₄) aryl, (C_β-Cu) aryloxy, (C6-C₁₄)aryl(CrC₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C₆-Cι₄) aryl which is optionally substituted by amino, hydroxyl, thio or halogen,

(C₁-C₅) alkyl, (C C₅) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (C₆-C₁₄) aryl, (C₆-Cι₄) aryloxy, (C₆-Cι₄)aryl(CrC₅)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (C₁-C₁₃) heteroaryl which carries one or more hetero atoms chosen from N, O and S and which is optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (C_rC₅) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (C₆-Cι₄) aryl, (C₆-Cι ) aryloxy, (C₆-Cι₄)aryl(Cι-C₅)alkoxy, cyano, trifluoro- methyl, carboxyl, carboxymethyl or carboxyethyl,

B represents a single bond or a (CrC₆) alkyl group which is 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:

- R1 is a hydrogen atom, R2 is a hydrogen atom, a halogen atom or a (C1-C5) alkyl radical, R3 is a hydrogen atom or a methyl or benzyl radical, R4 is a hydrogen atom, A is a methylene radical and B is a single bond,

- R4 is an arylmethoxy radical, which is optionally substituted on the methyl and/or aryl radical, A is an optionally substituted methylene radical 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:

00 in which R_T , R₂, R₃, R₄, Rs, A, B and X are as defined in Claim 1.

3- Compounds according to the preceding claim, characterised in that X represents a carbon 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 hydrogen atom.

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-0-.

9- Compounds according to any one of the preceding claims, characterised in that R1 and R2, which may be identical or different, represent a (C C₆) alkyl chain or a hydrogen atom. 10- Process for preparing compounds of the formula (I) in which R-, = 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:

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

e) optionally, an N-alkylation reaction of the product obtained in a), f) optionally, a hydrolysis step 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 in one of the preceding claims.

11- 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 9, characterised in that the following steps are carried out, prior to the steps of the process according to Claim 10: i) placing a compound of the following formula

R¹ — ^=:0 R₃-Hal, ³ , followed, in this case, by a hydrogenation step, where R'₃ is as defined for R₃, and R₃NH₂, where Hal represents a halogen atom, ii) a reduction step of the aromatic nitro compound obtained in i), in which formulae Ri, R , R₃ and X are as defined in one of Claims 1 to 9.

12- Pharmaceutical composition comprising, as active principle, a compound according to any one of Claims 1 to 9.

13- Composition according to Claim 12 for treating pathologies associated with insulin resistance syndrome.

14- Composition according to Claim 12 for treating pathologies associated with hyperglycaemia.

15- Composition according to Claim 12 for treating diabetes, dyslipidaemia, obesity, arterial hypertension, neuropathies, nephropathies or atherosclerosis.

16- Composition according to Claim 12 for treating diabetes. 17- Use of at least one compound of the general formula (I) for preparing a pharmaceutical composition for treating pathologies associated with insulin resistance or hyperglycaemia, more particularly diabetes or its complications, the general formula (I) being as follows:

(I) in which:

- (C₁-C₂₀) alkyl which is 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, a sulfur or phosphorus atom,

- (C-₂-C₂₀) alkylene which is optionally substituted by halogen, (C₁-C5) alkyl, (C₁-C₅) alkoxy or (C₃-C₈) cycloalkyl

- (C-₂-C20) alkyne which is optionally substituted by halogen, (C₁-C₅) alkyl, (C1-C5) alkoxy or (C₃-C₈) cycloalkyl - (C₃-C₈) cycloalkyl which is optionally substituted by (C₁-C₅) alkyl or

(CrC₅) alkoxy

- (C₃-C₈) heterocycloalkyl which carries one or more hetero atoms chosen from N, O and S and which is optionally substituted by (C₁-C5) alkyl or (C1-C5) alkoxy, - (C₆-Cι₄)aryl(C C-₂o)alkyl which is optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (C₁-C₅) alkoxy, (C_rC₅) alkylthio, (C1-C5) alkylamino, (C₆-C₁₄) aryl, (C_β-Cι ) aryloxy, (C₆-Cι₄)aryl(Cι-C₅)- alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl, - (C₆-Cι₄) aryl which is optionally substituted by amino, hydroxyl, thio or halogen,

(C1-C5) alkyl, (C C₅) alkoxy, (C1-C5) alkylthio, (C C₅) alkylamino, (C₆-C ) aryl, (C₆-Cι₄) aryloxy, (C₆-Cι )aryl(Cι-C5)alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,

- (C₁-C₁₃) heteroaryl which carries one or more hetero atoms chosen from N, 0 and S and which is optionally substituted by amino, hydroxyl, thio, halogen, (C C₅) alkyl, (CrC₅) alkoxy, (C C₅) alkylthio, (C C₅) alkylamino, (C₆-Cι₄) aryl, (C₆-Cu) aryloxy, (C₆-Ci4)aryl(Cι-C₅)alkoxy, cyano, trifluoro- methyl, carboxyl, carboxymethyl or carboxyethyl,

A represents a (CrC₆) alkyl group which is 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, unsubstituted amide, a sulfur or phosphorus atom,

B represents a single bond or a (C-ι-C₆) alkyl group which is 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,