FR2827862A1 - New imidazolyl alkyl aryl alkanoic acid derivatives useful for the treatment of hyperglycemia and related disorders, especially type II diabetes - Google Patents

Abstract

Imidazolyl alkyl aryl alkanoic acid derivatives (I), their tautomers, enantiomers, diastereoisomers, and epimers, and their salts. Imidazolyl alkyl aryl alkanoic acid derivatives (I), their tautomers, enantiomers, diastereoisomers, and epimers, and their salts. X = CH, N, O or S, and each is independent of the others; R1, R2, R3, R4 and R5 = 1-20C alkyl, (optionally substituted by halogen, 1-5C alkyl, 3-8C cycloalkyl, 1-5C alkoxy, amino, substituted amino, carbonyl, ester, amide, O, S, or P), 2-20C alkylene or alkyne (both optionally substituted by halogen, 1-5C alkyl or alkoxy, or 3-8C cycloalkyl), 3-8C cycloalkyl (optionally substituted by 1-5C alkyl or alkoxy), 3-8c heterocycloalkyl (having 1-3 hetero atoms (O, N, S)and optionally substituted by 1-5C alkyl or alkoxy), 6-14C aryl 3-8C alkyl (optionally substituted by amino, OH, SH, halogen, 1-5C alkyl, alkoxy, alkylthio or alkylamino, 6-14C aryl, aryl 1-5C sulfonylalkyl, aryloxy, aryl 1-5C alkoxy, CN, CF3, carboxy as the free acid or ester, carboxymethyl or carboxyethyl), 6-14C aryl (optionally substituted by amino, OH, SH, halogen, 1-5C alkyl, alkoxy, alkylthio or alkylamino, 6-14C aryl, aryl 1-5C sulfonylalkyl, aryloxy, aryl 1-5C alkoxy, CN, CF3, carboxy, carboxymethyl or carboxyethyl), or 1-13C heteroaryl (containing one or more heteroatoms (O, N, S) and optionally substituted by amino, OH, SH, halogen, 1-5C alkyl, alkoxy, alkylthio or alkylamino, 6-14C aryl, aryl 1-5C sulfonylalkyl, aryloxy, aryl 1-5C alkoxy, CN, CF3, carboxy, carboxymethyl or carboxyethyl); A = 1-6C alkyl (optionally substituted by halogen, 3-8C cycloalkyl, 1-5C alkoxy, amino, substituted amino, ester, amide, O, S, or P); B' = a bond or 1-6C alkyl (optionally substituted by halogen, 3-8C cycloalkyl, 1-5C alkoxy, amino, substituted amino, ester, amide, O, S, or P) except for those compounds of formula (I) in which R1 = R2 = H, R3 = H or CH3, R4 = H or -NH-CH2-C6H5, R5 = H, A = CH2, and B is a bond.

Description

:::

R246N34B

  The present invention relates to imidazolylalkylarylalkanoic derivatives useful in the treatment of pathologies associated with insulin resistance syndrome. The compounds of the invention have the following general formula (I): 3, (1) in which: o X represents, independently of one another, CH, a nitrogen, oxygen or sulfur atom, R1, R2, R3, R4 and R5, identical or different, are chosen indifferently from the groups: - Alkyl (Cj-C20) substituted or not by one or more of the following groups: halogen, alkyl (C1-C5), cycloalkyl (C3- C3), alkoxy (Ci-C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, an oxygen, sulfur or phosphorus atom, - Alkylene (C2-C20) substituted or not by halogen, alkyl ( C4-C5), alkoxy (C4-C5), cycloalkyl (C3-Ce) - Alkyne (C2-C20) substituted or not by halogen, alkyl (C4-C5), alkoxy (C4-C5), cycloalkyl (C3-Ce ) - Cycloalkyle (C3-C, 3) substituted or not by alkyl (Ci-C5), alkoxy (C4-C5) - Heterocycloalkyle (C3-Ce) carrying one or more heteroatoms chosen from N.O and S and substituted or not by alkyl (C4-C5), aikoxy (Ci-C5), - Aryl (C 6-C, 4) (C-C20) alkyl substituted or not by amino, hydroxy, thio,

  halogen, (C4-C5) alkyl, alkoxy (C4-C5), alkylthio (C4-C5), alkylamino (C-

  C5), aryl (C6-C'4), aryl (C6-C, 4) sulfonylalkyl (C4-C5), aryl (C6-C, 4) oxy, aryl (C6-C4) alkoxy (C, -C5) , cyano, trifluoromethyl, carboxy optionally in the form of an acid or ester, carboxymethyl or carboxyethyl, - Aryl (C6-C4) substituted or not by amino, hydroxy, thio, halogen, alkyl (C4-C5), alkoxy (C4 -C5), alkylthio (C4-C5), alkylamino (Ci-C5), aryl s (C6-C4), aryl (C6-C4) oxy, aryl (C6-C4) alkoxy (Ci-C5), cyano, trifluoromethyl , carboxy, carboxymethyl or carboxyethyl, Heteroaryl (C4-C43) carrying one or more heterontomes chosen from N.O and S and substituted or not by amino, hydroxy, thio, halogen, alkyl (C4-C5), alkoxy (Ci-C5 ), alkylthio (Ci-C5), alkylamino (C4-C5), aryl (C6 C44), aryl (C6-C4) oxy, aryl (C6-C'4) alkoxy (C4-C5), cyano, trifluoromethyl, carboxy , carboxymethyl or carboxyethyl, A represents an alkyl group (C′-C6) optionally substituted by one or more of the following groups: halogen, cycloalkyl (C3-C, 3), alkoxy ( C'-C5), s substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, B represents a single bond or an alkyl group (C-C6) optionally substituted by one or more of the groups following: halogen, cycloalkyl (C3 Ce), alkoxy (C'-C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, excluding the compounds of 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 a single bond; as well as the tautomeric, enantiomeric, diastereoisomeric forms and

  epimers and pharmaceutically acceptable salts.

  A particular group of compounds of formula (I) is that in which the compounds have the following general formula (II): R4

R2A, BCOOR5

(11) in which:

  R, R2, R3, R4, R5, A, B and X are as defined above.

  According to a preferred aspect of the invention, the compounds of formula (II) are those for which X represents CH eVou R and R2 represent a hydrogen atom. A particular group of compounds of formulas (1) or (II) defined as above is that in which A is a methylene group

o possibly substituted.

  A particular group of compounds of formulas (1) or (II) defined such that

  previously is that in which B a single bond.

  Another particular group of compounds of formula (1) or (II) defined as above is that in which B is an optionally substituted methylene group. Another particular group of compounds of formula (1) or (II) is that in which R4 is an alkoxy radical (C-C20), preferably (C-C6), such as

especially methoxy or ethoxy.

  Another particular group of compounds of formula (1) or (II) is that in which the function -B-COOR5 is found in the para position on the ring by

compared to -A-.

  Another particular group of compounds of formula (1) or (II) is that

  in which R4 is in the meta position on the cycle with respect to -A-.

  According to the present invention, the alkyl radicals have from 1 to 20

  carbon atoms, preferably from 1 to 6 carbon atoms.

  Mention may in particular be made, when they are linear, of the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl radicals,

hexadecyl, and octadecyl.

  Mention may in particular be made, when they are branched or substituted with one or more

  several alkyl radicals, isopropyl, tert-butyl, 2ethylhexyl, 2-

  methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl.

  The alkoxy radicals according to the present invention are radicals of

  s formula -O-alkyl, the alkyl being as defined above.

  Among the halogen atoms, mention is made more particularly of the atoms of

  fluorine, chlorine, bromine and iodine.

  The alkylene radicals include one or more ethylenic unsaturations. Among the alkylene radicals, mention may in particular be made of the radicals

o allyl or vinyl.

  Alkyne radicals include one or more unsaturations

  acetylene. Among the alkyne radicals, mention may especially be made of acetylene.

  The cycloalkyl radical (C3-C, 3) is a cyclic hydrocarbon radical, such as

  in particular cyclopropyl, cyclopentyl or cyclohexyl.

  The heterocycloalkyl radical is a cycloaikyl radical as defined above containing, in place of one or more carbon atoms of the ring, one or more heteroatoms chosen from N.O and S. Among the heterocycloalkyl radicals, we can therefore especially mention the

  piperidyl, pyrazolidinyl, piperazinyl and morpholinyl radical.

  o The aryl radical corresponds more particularly to an aromatic ring of 6 carbon atoms, such as the phenyl radical, optionally condensed by one or two other aromatic rings to 6 carbon atoms, such as the naphthyl radical. Among the aryl radicals, there may therefore be mentioned in particular the phenyl radical,

  piUS particularly substituted by at least one halogen atom.

  Among the aryl (C6-C4) alkyl (C, -C20) radicals, mention may in particular be made of:

benzyl or phenetyl radical.

  The heteroaryl radical corresponds more particularly to an aromatic heterocycle with 5 or 6 atoms containing one or two heterostomes chosen from N. o S and O. condensed or not by one or two aromatic rings with 6 atoms

  carbon or heteroaromatic rings with 5 or 6 atoms.

  Among the heteroaryl radicals, mention may be made of the furyl, pyridyl, quinolinyl, indolyl, isoindolyl, quinolyl, imidazolyl, pyrimidinyl or carbazolyl radical. Among the heterocycles, mention may in particular be made of piperidine rings,

  morpholine, pyrrolidine, imidazolidine, pyrazolidine and piperazine.

  Preferably, R1 and R2, identical or different, represent

  an alkyl chain (C1-C6) or a hydrogen atom.

  The invention also relates to tautomeric forms, enantiomers, diasterooisomers, epimers and organic or mineral salts

  compounds of general formula (I).

  The compounds of the invention of formula (I) defined as above having a sufficiently acidic function or a sufficiently basic o function or both, can include the corresponding salts of organic acid

  or mineral or pharmaceutically acceptable organic or mineral base.

  It may for example be salts such as the hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulfonate, maleate, parachlorophenoxyisobutyrate, {5 formate, lactate, succinate, sulfete, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanonte, hexadecanost, octodecanoate, benzenesulfonate, tri methoxybenzoate, pa ratol u ènesu lfonate, ad a manta neca rboxylate, g lycoxylate, glutamate, pyrrolidonecarboxylate, niththalenesulfate, naphthalenesulfate, naphthalenesulfate , dobesilate, thioctate, hippurate, 3

  o benzamidopropanoate, glucuronate, L-pyrrolidone-5-carboxylate, cholate, u-

  glucose-1-phosphate, aiginate, 4-amino-benzoate, chondroitin sulfete and salts

  of alkali metals, such as sodium.

  The compounds of general formula (I) as described above for which can be prepared according to method (I) a)

- 'NH2 CI A R4

(X1NH2 0 COORs N COORs

(2) () (4) R5 H

b): BCOO + R3-Hal -X B

(4) (5) (6)

c) -XR3} COORs N A: ó>

(6) () R5 = H

  Method (I) Step a) can be carried out in an apolar solvent, such as for example dichloromethane, in the presence or not of an organic or mineral base such as for example triethylamine, at the amblant temperature or by heating the solvent.

  The intermediate amide thus obtained can be cyclized in an acid medium.

  Preferably, the cyclization can be carried out by reflux heating in

  a concentrated hydrochloric acid ethanol mixture.

  Step b) is an N-alkylation reaction well known in the literature.

  It can be carried out in particular in the DMF in the presence of a base such as

sodium hydride.

  Step c) is a conventional 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 general formula (II) as described above, for which R = R2 = H, used in J. Med.Chem. 1998, 41, 2709-2719, can be diagrammed by the following method (II) NHz '2HC A R4 A R4 ó> NH N Bs BCOOR

(2) () (4) R5 H

  0 Method (I l) This cyclization can be carried out in an alcoholic solvent catalyzed by a metal alcoholate. Preferably, the reagents (2) and (8) are stirred at

  amblant temperature in methanol in the presence of sodium methylate.

  Another method for preparing the compounds of general formula (II) as described above, for which R = R2 = H can be diagrammed by

the following method (111).

óNHz HCl, HNA COORs B

(2) (9) (4) R5 H

  Method 111 This cyclization can be carried out in a solvent, preferably the

  s DMF at room temperature or with heating.

  Compound (9) can preferably be synthesized by the well-known method of Pinner (Organic Functional Group Preparation Vol.3, 1972) at

from nitrile (8).

  o Another method of preparing the compounds of general formula (II) as described above, for which R = R2 = H can be schematized by

the following method (IV).

ó: N H2 O: A COORs B

(2) (7) (4) R5 H

2 Method IV

  This cyclization can be carried out by heating (2) and (7) at reflux in 2N HCl.

  o When the groups R eVou R2 are different from H. the compounds of 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 cycle, in particular on the cycle benzimidazole, and to avoid the formation of a

mixture of isomeric regions.

at)

R3, NO2 R2, <NO2

R1 l + R3-Hal R1 l X NH2 X Nl H

(10) (11)

b)

R2, << NO2 R2, KNH2

R1 l + H2 - R1 l

(12) (13) R3

vs)

R 1 N H 2 R 2 A B. \ C O C

(13) R3 (1)

  Method V Step a) can be carried out in the solvents usually used for this well-known Williamson reaction, preferably the compound o (10) can be heated in acetonitrile in the presence of an organic or inorganic base, preferably K2CO3 Alternatively, the compound of formula (11) can be obtained by the well-known reaction of an aldehyde on the aniline (10) followed by a hydrogenation catalyzed by Pd / C: Method Vl R2,, wNO2 R2 NO2 H. R2NO

R1 - 1 + R'3 -O R1, R1, 1

  \ X'NH X Pd / C X NH (10) (16) O Rr3 (11) Method Vl The compound of formula (11) can also be obtained according to Method Vl1

R2 R2

,, NO2 rNO2 R1 l + R3-NH2 X INH

(15) (16) (11)

  s Method V! l This reaction can be carried out in a solvent, preferably ethanol in

  heating or not, preferably in an autoclave if the amine is volatile.

  Step b) consists of a reduction under the usual conditions of

  o reductions in aromatic nitro compounds.

  Preferably, the compound (11) can be reduced by hydrogen in

  ethanol in the presence of a catalyst such as Pd / C.

  Alternatively, the compound (11) can be reduced by hydrazine hydrate in a solvent such as ethanol in the presence of a catalyst such as nickel

s Raney.

  Step c) of benzimidezole cyclization can be carried out in a manner analogous to Method I (step a), Method II, or Method III described above. These methods are also applicable to compounds of formula (I)

  o different from the compounds of formula (II).

  Thus, the present invention also relates to a process for the preparation of compounds of formula (1) in which R = R2 = H, characterized in that the following steps are carried out: a) step of cyclization on the amine functions d '' a compound of the following formula (2):

X, NH2

  Ixl 1 X '': (2) by bringing it into contact with a compound chosen from the compounds of the following formulas: R4 Cl: n, A: BCOOR5 (3) R4

N / / \: HBCOOR5

(8) B OEt COOR5 (9)

OH BCOOR5

  (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 obtain the corresponding acid,

  formulas in which R4, R5, A, B and X are as defined above.

  The present invention also relates to a process for the preparation of compounds of formula (I), in which the groups R eVou R2 are different from H. characterized in that the following steps are implemented, prior to the steps mentioned above : i) bringing a compound of the following formula R2 X: 2 R1 j into contact:

X '' NH

  (10) o with a compound chosen from the compounds of the following formulas: R3-Hal, 3, followed in this case by a hydrogenation step, R'3 having the same definition as R3, and R3NH2, Hal representing an atom halogen, ii) a step of reducing the nitro-aromatic compound obtained in i),

  formulas in which R, R2, R3, and X are as defined above.

  Insulin resistance is characterized by a reduction in the action of insulin (cf. Presse Médicale, 1997, 26 (n 14), 671-677) and is involved in a large number of pathological conditions, such as diabetes. and more particularly non-insulin-dependent diabetes (type 11 diabetes or NIDDM), dyslipidemia, obesity, high blood pressure, as well as certain microvascular and macrovascular complications such as atherosclerosis,

retinopathies and neuropathies.

  On this subject, one will refer 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 humans, hyperglycemia is the result of two major defects: an alteration of insulin secretion and a decrease in insulin efficiency at three sites (liver, muscles

and fatty tissue).

  The compounds of the present invention increase insulin secretion by pancreatic beta cells. They are therefore likely to improve the

  blood glucose of non-insulin dependent diabetic patients.

  The compounds of formula (1) are therefore useful in the treatment of pathologies associated with hyperglycemia. In this case, the compounds of formula (1) are those previously described, including those previously

excluded by (i).

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

specifically diabetes.

  The present invention therefore also relates to the use of at least one compound according to the invention, including those previously excluded by (i) for the preparation of a pharmaceutical composition intended for treating

  pathologies associated with hyperglycemia and more specifically diabetes.

  The pharmaceutical compositions according to the invention can be presented in forms intended for parenteral administration,

  o oral, rectal, mucous or percutaneous.

  They will therefore be presented in the form of solutions or injectable suspensions or multi-dose vials, in the form of bare or coated tablets, dragees, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules , solutions or suspensions, for

  Percutaneous use in a polar solvent, for the use of skin.

  The excipients which are suitable for such administrations are

  derived from cellulose or microcrystalline cellulose, alkaline carbonates

  earthy, magnesium phosphate, starches, modified starches,

lactose for solid forms.

  o For rectal use, cocoa butter or stearates

  polyethylene glycol are the preferred excipients.

  For parenteral use, water, aqueous solutions, physiological saline,

  isotonic solutions are the most conveniently used vehicles.

  The dosage may vary within wide limits (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as

of the subject’s rage and weight.

  The following examples illustrate the invention without, however, limiting it.

INSULIN SECRETION TEST

  Solon the method described dens Endocrinolouv, 1992 vol.130 (1! Pp.167-178 No C SeclNS -3 TO 5 M 90o / o r

N CH3 2 10-5M 58%

  O CH3 (; 3N "me, 3 10-s M 51% 4 105M 86o / 0

O CH3

F 5 10-5 M 61%

O CH3

'CH IO s N1 1' / 'Nit 10 5 M 909;

> OH 105M 69%

jar H3 105M 68%

  10 5 M 56%

  11 10 5 M 529 / o [a 51 CHIN 105 M,:, jÈ 10 5 M 81% - OH 14 10sM t, - CH3 10 5 M 39 ó, ô 105M 163 / o

î CH3 10 M 54%

= 10 5 M a;% H3C

-5 M 54%

'C VoH3 20 10 M 5 5i

9 21 10 5 M 103%

[I N Y

  Br3 OH 22 10-5 M 69% N O "OH 23 105M 560 / o

  Sec INS corresponds to the% of insulin secretion.

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

  The starting products used are known products or prepared according to

known operating mods.

  Example 1: Acid 4- [1 - (2-methylphenyl) methyl-benzim idezol-2yl] methyl-2-

  ethoxybenzoque - 3-ethoxy-4-ethoxycarbonyl-benzenescetyl chloride 300 ml of dichloromethane are charged into a one-liter flask, followed by 15g (0.06M) of 3-ethoxy-4-ethoxycarbonylbenzene acetic acid with stirring. After dissolution, 5.25 g (0.06M) of oxalyl chloride are added dropwise. The solution obtained is stirred for 2 hours at room temperature, then concentrated to dryness under vacuum. A clear yellow oil is obtained which is used in the stage

next without purification.

  - 4- (2-aminophenylamino-2-oxoethvl) -2-ethoxvbenz Ethylate In a 250 ml flask containing 100 ml of THF, 6.54 g (0.06 M) of ophenylenediamine is dissolved and 5.25 ml of triethylamine are added . The acid chloride prepared above and dissolved in 50 ml of dichloromethane is added

  drop by drop in a quarter of an hour.

  The slightly exothermic reaction is maintained at temperature below C during the casting, then is vigorously stirred for 18 h at

room.

  To the solution obtained, add 20ml of demineralized water carefully. The resectional medium is concentrated under reduced pressure. The residue is taken up with 400ml of demineralized water and then extracted 3 times with ethyl acetate. The combined organic phases are washed with demineralized water then with brine and then dried over magnesium sulfete. After filtration, the solvent is removed under reduced pressure: the residue is taken up in diisopropyl ether, filtered, dried under

reduced pressure.

14.2 g of white solid are obtained.

  Yield = 70% s pf: 105-110 C 1 H NMR (DMSO-d6): 9.46 (1 H, d); 7.62-6.60 t7H, m); 4.90 (1 H, s); 4.26 (2H, q); 4.12 (2H, q); 3.71 (2H, m); 1.35 (6H, t); s 4.17 g of the preceding amide are dissolved in a mixture of ethanol (250 ml) and concentrated hydrochloric acid (25 ml) and then heated for 2 h at 80 C. The medium is concentrated to dryness under vacuum. The residue is taken up in water, neutralized 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 sulphate, filtered and concentrated to dryness under vacuum. The oil obtained crystallizes from diisopropyl ether. 8g of

solid are obtained.

  Overall yield = 60% Pf: 185-190 C 1 H NMR (DMSO-d6): 6.78-7.57 (8H, m); 4. 49 (2H, s); 4.10 (4H, q); 1.16 (6H, t);

  4- [1- (2-methylphenyl) methyl-benzimidazol-2vl] methil-2- hydrochloride

  ethyl ethoxybenzoste In a three-necked flask containing 250 ml of anhydrous dimethylformamide are dissolved o 32.92g (0.101M) of ethyl 4- (2benzimidezolyl) methyl-2-ethoxybenzoate then slowly adds 4.06g (0.101M) of hydride of sodium at 60%. The reaction medium is stirred for 12 hours at room temperature, then added dropwise with 14.2 ml (0.12M) of 2-methyl benzyl bromide at 96%. The reaction medium is stirred for 12 h at room temperature then poured into 11 of ice / water mixture and extracted 3 times with ethyl acetate. The combined organic phases are washed with demineralized water and then with brine, dried over magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The oil obtained is dissolved in 100ml of dichloromethane and then added with a solution of hydrochloric acid in dioxane until acid pH. After one hour of stirring, the solvents are evaporated under reduced pressure. The oil obtained crystallizes from diisopropyl ether. The solid is filtered, dried: xxg of whitish product are obtained. Yield: 27% Pf: 100 C

1 H NMR (CDCI3):

  7.93 (1H, d); 7.56-6.93 (8H, m); 6.67 (1H, d); 6.14 (1H, 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); Acid 4-, 1 -2methyl phenil) methvl-benzimidazol-2yl] methvl-2-ethoxvbenzoic In a flask containing 60ml of ethanol and 20ml of demineralized water, 0.57g (O7O14M) of sodium hydroxide is dissolved in 97% 7 then 6g (0.014M) of

previous hydrochloride.

  o The reaction medium is heated for 4 hours at reflux of the solvent. After cooling, it is poured into 150 ml of demineralized 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, washed with demineralized water, dried.

5 g of white solid are obtained.

  - Yield: 89% Pf: 205 C 1 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 Acid 4- (1-phenylmethyl-benzimidazol-2yl) methyl-2-

  ethoxybenzo.'que Sodium derivative of ethyl 4- (2-benzimidazolylmethyl-2ethoxybenzoate) In a flask containing 100ml of tetrahydrofuran and 0.7g (0.017M) of hydride

  of sodium, are added drop by drop 5.7g (0.017M) of 4- (2-

  benzimidazolyl) ethyl 2-methyl-ethoxybenzoate (obtained according to the method o described in Example 1) dissolved in 150 ml of tetrahydrofuran. By stirring for 2 hours at the ambient temperature, a gray solid precipitates. It is filtered, washed with tétrehydrofurane and dried under reduced pressure. 6g of solid are obtained 4- [1 - (4-Methyl) phenyl methyl-benzimidazol-2yl] methyl-2-ethoxybenzoate of ethvia A 1 70mg (0.49mM) of the preceding product dissolved in 2ml of dimethylformemide, 1 09mg (0.59mM) of benzyl bromide and stirred

  room temperature for 20 hours.

  The reaction medium is then poured into 15 ml of demineralized 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 silica column: eluent cyclohexane

(50) / ethyl acetate (50).

  o Acid 4- [1- (4-Methvl) phenylmethyl-benzimidezol-2vl] methvl -2ethoxvbenzoque The previous ester dissolved in 3ml of ethanol is treated with an equivalent of 1N sodium hydroxide solution at 40 C for 1 hour. Then added 15 ml of demineralized water, extracted twice with ethyl acetate. The aqueous phase is acidified with acetic acid and then extracted with 2 times 10 ml of ethyl acetate. The combined organic phases are concentrated under reduced pressure to give

the product.

  Found mass: 400.2 Theoretical mass: 400.48 By way of example, the following compounds are prepared according to the procedures o procedures described in Example 2: Products Structure Mass Found theoretical mass i / (I- l ^) I

26 LOCH

27 F /: 455.2 454.45

28;, 1 È 412.2 411.46

Nit OH 29 W

POOH 523.2 522.44

F (/ F N O:

31 OH 431.2 430.46

32 H 473.2 472.44

33 =; H 471 470.45

Q4: OH d.2 43

36: r, -

37 CIOH 421 420.90

38 art; - 0 437.2 436.51

455.2 454.45

_ 463.3 462.55

  41 cot 417.2 416.48 42:> oH3 401.2 400.46

43; :: 405.2 404.44

4.

H3C OH 401.2 400.48

CH3

46: OH 456.5 455.34

-7,405.2 404.44

48 O OH 421, 2 420, 90

43 _ fg'iÉ K j

OH 401.2 400.48

  The above-mentioned compounds were characterized by the following analytical techniques: The NMR spectra were carried out using a RON Brucker Advanced DPX 200mHz spectrometer The Masses were determined by H.P.L.C. coupled to an Arglient 1100 Series mass detector The melting points (Pf) were measured on a Kofler Leica type bench

o VMHB.

Claims (10)

  1- Compounds of general formula (I) R4 R3 BCOOR5 R1 X-X   (1) in which: o X represents, independently of one another, CH, a nitrogen, oxygen or sulfur atom, R1, R2, R3, R4 and R5, identical or different, are chosen indifferently from the groups: - H - (C, -C20) alkyl substituted or not substituted by one or more of the following groups: halogen, (C1-C5) alkyl, cycloalkyl (C3-C8), alkoxy (C4-C5), amino substituted or not , optionally substituted carbonyl, ester, amide, an oxygen, sulfur or phosphorus atom, - Alkylene (C2-C20) substituted or not by halogen, alkyl (C4-C5), alkoxy (C4-C5), cycloalkyl ( C3-C8) Alkyne (C2-C20) substituted or not substituted by halogen, alkyl (Ci-C5), alkoxy (C4-C5), cycloalkyle (C3-C8) - Cycloalkyle (C3-C8) substituted or not by alkyl (C4 -C5), alkoxy (C4-C5) - Heterocycloalkyl (C3-C8) carrying one or more heteroatoms chosen from N.O and S and substituted or not by alkyl (Ci-C5), alkoxy (C4-C5), - Aryl (C6-C, 4) (C-C20) alkyl substituted or not by amino, hydroxy, thio,   halogen, (C4-C5) alkyl, alkoxy (C'-C5), alkylthio (C4-C5), alkylamino (C-   C5), aryl (C6-C4), aryl (C6-C, 4) sulfonylalkyl (C4-C5), aryl (C6-C4) oxy, aryl (C6-C4) alkoxy (C4-C5), cyanO7 trifluoromethyl, carboxy optionally in the form of an acid or an ester, carboxymethyl or carboxyethyl, - Aryl (C6-C4) substituted or not by amino, hydroxy, thio, halogen, alkyl (C4-C5), alkoxy (C4-C5), alkylthio ( C4-C5), alkylamino (C4-C5), aryl (C6-C44), aryl (C6-C4) oxy, aryl (C6-C4) alkoxy (C4-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, Heteroaryl (CC, 3) carrying one or more heteroatoms chosen from N.O and S and substituted or not by amino, hydroxy, thio, halogen, alkyl (C4C5), alkoxy (C4-C5), alkylthIo (C4-C5), alkylamino (C4-C5), aryl (C6 C44), aryl (C6-C'4) oxy, aryl (C6-C'4) alkoxy (C4-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, A represents an alkyl group (C-C6) optionally substituted by one or more of the following groups: halogen, cycloalkyl (C3-C), alkoxy (C4-C5) , s substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, B represents a single bond or an (C 1 -C 6) alkyl group optionally substituted by one or more of the following groups: halogen, cycloalkyl (C3 o C), alkoxy (C4-C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, excluding the compounds of 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 a single bond; as well as the tautomeric, enantiomeric, diastereoisomeric forms and   epimers and pharmaceutically acceptable salts.   2- Compounds according to claim 1, characterized in that they have the following general formula (II): R4 R2 R3RBCOOR5   (11) in which R., R2, Ra, R4, R5, A, B and X are as defined in claim 1.   s 3- Compounds according to the preceding claim, characterized in that X   represents CH and / or R. and R2 represent a hydrogen atom.   4- Compounds according to one of the preceding claims, characterized in that   o A is an optionally substituted methylene group.   - Compounds according to any one of the preceding claims,   characterized in that B is an optionally substituted methylene group.   s 6- Compounds according to one of claims 1 to 4, characterized in that B is a simple bond.   7- Compounds according to any one of the preceding claims,   characterized in that R4 is an alkoxy radical (C'-C20), preferably (C-C6).   8- Compounds according to any one of the preceding claims,   characterized in that the -B-COOR5 function is in the para position on the cycle with respect to -A-.   s 9- Compounds according to any one of the preceding claims,   characterized in that R4 is in the meta position on the cycle with respect to -A-.   - Compounds according to any one of the preceding claims,   characterized in that R1 and R2, identical or different, represent a   o alkyl chain (C1-C6) or a hydrogen atom.   11- PcAdA of pparatn of Warmup compounds 0) dens lacquerMe R1 = R = H, tea qua dAchts in lane des revenUlcadons pcAdentes, carac16hsA in that ran puts in Louvre the following steps: a) CycHsaton step on the mentions amine of a compound from Rome (2) as follows: NH, NH (2) by bringing it into contact with a compound choler prmi tea composed of sulphurous Morals: Cl ABCOOR5 (3) 1Q R4 NO 1 BE COOR (8) HCI, HNA OR SCOOT (9) OH COOT   (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 obtain the corresponding acid, formulas in which R4, R5, A, B and X are as defined in one of previous claims.   12. Process for the preparation of compounds of formula (I), in which the groups R eVou R2 are different from H. as described in one of the   Claims 1 to 10, characterized in that the steps are carried out   o following, prior to the steps of the process according to claim 11: i) bringing into contact of a compound of the following formula R2 X: 2 R1 XX '' NH2   (10) with a compound chosen from the following formulas: R'O R3-Hal, 3, followed in the latter case by a hydrogenation step, R'3 having the same definition as R3, and R3NH2, Hal representing a halogen atom, ii) a step of reducing the nitro-aromatic compound obtained in i), formulas in which R, R2, R3, and X are as defined in one of claims 1 to 10.   13- Pharmaceutical composition comprising, as active principle, a compound of general formula (I) below: R4 R24; RA3BCOOR5   (1) in which: X represents, independently of each other, CH, a nitrogen, oxygen or sulfur atom, R1, R2, R3, R4 and R5, identical or different, are chosen indifferently from the groups : - Alkyl (C'-C20) substituted or not substituted by one or more of the following groups: halogen, alkyl (C1-C5), cycloalkyl (C3-C3), alkoxy (C4-C5), amino substituted or not, carbonyl optionally substituted, ester, amide, o an oxygen, sulfur or phosphorus atom, - Alkylene (C2-C20) substituted or not by halogen, alkyl (C4-C5), alkoxy (C4-C5), cycloalkyl (C3- C8) Alkyne (C2-C20) substituted or not by halogen, alkyl (C4-C5), alkoxy (C4-C5), cycloalkyle (C3-C73) - Cycloalkyle (C3- Cr3) substituted or not by alkyl (C4-C5 ), alkoxy (C4-C5) - Heterocycloalkyle (C3-Ce) carrying one or more heteroatoms chosen from N.O and S and substituted or not by alkyl (C4-C5), alkoxy (Ci-C5), - Aryl (C6 -C4) alkyl (C'-C20) substituted or not by amino, hydroxy, thio,   halogen, alkyl (C4-C5), alkoxy (Ci-C5), alkylthio (C4-C5), alkylamino (C-   C5), aryl (C6-C4), aryl (C6-C4) sulfonylalkyl (C4-C5), aryl (C6-C, 4) oxy, aryl (C6-C, 4) alkoxy (C4-C5), cyano, trifluoromethyl, carboxy optionally in the form of acid or ester, carboxymethyl or carboxyethyl, - Aryl (C6-C'4) substituted or not by amino, hydroxy, thio, halogen, alkyl (C4-C5), alkoxy (C4- C5), alkylthio (C4-C5), alkylamino (C4-C5), aryl (C6-C'4), aryl (C6-C4) oxy, aryl (C6-C'4) alkoxy (C4-C5), cyano , trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, Heteroaryl (C4-C43) carrying one or more heteroatoms chosen from N.O and S and substituted or not by amino, hydroxy, thio, halogen, (C4-C5) alkyl, (C4-C5) alkyl '-C5), alkylthio (C4-C5), aikylamino (C4-C5), aryl (C6 C44), aryl (C6-C4) oxy, aryl (C6-C4) alkoxy (C4-C5), cyano, trifluoromethyl, carboxy, carboxymethyl or carboxyethyl, A represents an alkyl group (C-C6) optionally substituted by one or more of the following groups: halogen, cycloalkyl (C3-Ce), alkoxy (C4- C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, B represents a single bond or an alkyl group (C-C6) optionally   substituted by one or more of the following groups: halogen, cycloalkyl (C3-   C, 3), alkoxy (C4-C5), substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom, as well as its tautomeric, enantiomeric, diastereoisomeric and epimeric forms   and its pharmaceutically acceptable salts.   14- Composition according to claim 13 intended to increase the secretion of insulin. - Composition according to claim 13 intended to treat pathologies,. associated with hyperglyceme.   16- Composition according to claim 13 intended to treat diabetes.   17- Use of at least one compound as defined in claim 13 for the preparation of a pharmaceutical composition intended to treat pathologies