FR2674523A1 - New benzimidazole derivatives, process for their preparation, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the invention is the products of formula (IB): in which: R represents alkyl or alkenyl, either R1B, R2B, R3B and R5B represent hydrogen, or one of R2B and R5B represents hydrogen or -CH2-O-R10, with R10 representing hydrogen, alkyl, alkenyl or and R1B and R3B such that one represents hydrogen and the other is chosen from -OR6, -CO2R7 and -R11, with R6 and R7 representing hydrogen, alkyl or alkenyl, and R11 representing alkyl, alkenyl, acyl or or at most one of R1B, R2B, R3B and R5B represents hydrogen and the others are chosen from -CH2-O-R10, -OR6, -CO2-R7, -R11 and R4B represents carboxyl, tetrazolyl or -(CH2)m-SO2-X-R12 with m representing an integer from 0 to 4, (-X-R12) representing NH2 or X representing a single bond, -NH-, -NH-CO-NH- or -NH-CO- and R12 representing alkyl, alkenyl or aryl, and the addition salts of the said products of formula (IB). These products have pharmacological properties.

Description

 The present invention relates to novel benzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments and pharmaceutical compositions containing them.

dans laquelle
R représente un radical alkyle ou alkényle linéaire ou ramifié renfermant 3 ou 4 atomes de carbone, RlB, R2B' R3B et R5B sont tels que soit R1B, R2B, R3B et R5B sont identiques et représentent un atome d'hydrogène, soit l'un de R2B et R5B représente un atome d'hydrogène ou un radical -CH2-O-R10, dans lequel R10 représente un atome d'hydrogène ou un radical alkyle ou alkényle linéaire ou ramifié renfermant au plus 5 atomes de carbone, ou le radical

dans lequel R c et Rd, identiques ou différents représentent les valeurs définies ci-après pour Ra et Rb et l'autre représente un atome d'hydrogène et, R1B et R33 sont tels que l'un représente un atome d'hydrogène et l'autre est choisi parmi les radicaux -OR6, -CO2R7 et -R11, radicaux dans lesquels
R6 et R7 identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ou alkényle linéaire ou ramifié renfermant au plus 5 atomes de carbone, R11 est choisi dans le groupe formé par a) les radicaux alkyles ayant au plus 4 atomes de carbone, éventuellement substitués par un ou plusieurs radicaux choisis parmi - les atomes d'halogène, - le radical hydroxyle éventuellement acylé, - les radicaux alkyloxy ou alkényloxy linéaire ou ramifié ayant au plus 5 atomes de carbone, - les radicaux aryle éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, le radical hydroxyle, trifluorométhyle, cyano, nitro, amino, les radicaux alcoxy renfermant au plus 4 atomes de carbone, phényle, benzyle, carboxy libre salifié ou estérifié et tétrazolyle, - le radical carboxy libre, estérifié ou salifié, - le radical

dans lequel R a et Rb identiques ou différents sont choisis parmi les atomes d'hydrogène, les radicaux alkyle ou alkényle ayant de 1 à 4 atomes de carbone et aryle, tous ces radicaux étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, ou le radical hydroxyle, trifluorométhyle, cyano, nitro, amino, les radicaux alcoxy renfermant au plus 4 atomes de carbone, phényle, benzyle, carboxy libre salifié ou estérifié et tétrazolyle, b) les radicaux alkényles linéaires ou ramifiés ayant de 2 à 5 atomes de carbone, c) les radicaux acyles ayant de 2 à 7 atomes de carbone et le radical formyle, d) le radical

dans lequel R a et Rb ont la signification indiquée ci-dessus, soit l'un au plus de R1B, R2B, R3B et R5B représente un atome d'hydrogène, et les autres sont choisis parmi les radicaux -CH2-O-R10, 6' C 2R7' -R11 et le radical

dans lesquels R6, R7, R10, Roll, Rc et Rd ont les valeurs indiquées ci-dessus,
R4B représente un radical carboxy libre, estérifié ou salifié, ou un radical tétrazolyle, ou un radical -(CH2)m-S02-X-R12 dans lequel m représente un entier de 0 à 4 et soit (X-R12) représente NH2 soit X représente une simple liaison, ou les radicaux -NH-, -NH-CO-NH- ou -NH-CO- et R12 représente un radical alkyle, alkényle ou aryle, ces radicaux étant éventuellement substitués, lesdits produits de formule (IB) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux ou organiques et les bases minérales ou organiques desdits produits de formule (IB).The subject of the present invention is the products of formula (Ig)

in which
R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1B, R2B 'R3B and R5B are such that either R1B, R2B, R3B and R5B are identical and represent a hydrogen atom, that is one of R2B and R5B represents a hydrogen atom or a radical -CH2-O-R10, wherein R10 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms, or the radical

in which R c and Rd, which are identical or different, represent the values defined below for Ra and Rb and the other represents a hydrogen atom and R1B and R33 are such that one represents a hydrogen atom and other is selected from the radicals -OR6, -CO2R7 and -R11, radicals in which
R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R11 is chosen from the group formed by a) alkyl radicals having at most 4 carbon atoms, optionally substituted with one or more radicals chosen from - halogen atoms, - optionally acylated hydroxyl radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - optionally substituted aryl radicals with one or more radicals chosen from halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro and amino radicals, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl, free carboxy, salified or esterified, and tetrazolyl, the free carboxy radical, esterified or salified, - the radical

in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms and aryl, all these radicals being optionally substituted with one or more radicals chosen from the atoms of halogen, or the hydroxyl, trifluoromethyl, cyano, nitro, amino radical, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl, free carboxy salt or esterified and tetrazolyl, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, d) the radical

in which R a and Rb have the meaning indicated above, at most one of R 1 B, R 2 B, R 3 B and R 5 B represents a hydrogen atom, and the others are selected from the radicals -CH 2 -O-R 10, 6 'C 2R7' -R11 and the radical

in which R6, R7, R10, Roll, Rc and Rd have the values indicated above,
R4B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, or a - (CH2) m -SO2-X-R12 radical in which m represents an integer of 0 to 4 and either (X-R12) represents NH2 or X represents a single bond, or the radicals -NH-, -NH-CO-NH- or -NH-CO- and R12 represents an alkyl, alkenyl or aryl radical, these radicals being optionally substituted, said products of formula (IB) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with mineral or organic acids and inorganic or organic bases of said products of formula (IB).

dans lequel R c et Rd, identiques ou différents, sont choisis parmi les atomes d'hydrogène, les radicaux alkyle ou alkényle ayant de 1 à 4 atomes de carbone et phényle, tous ces radicaux étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, le radical hydroxyle, trifluorométhyle, cyano, nitro, amino, les radicaux alcoxy renfermant au plus 4 atomes de carbone, phényle, benzyle, carboxy libre salifié ou estérifié et tétrazolyle, et l'autre représente un atome d'hydrogène,
R1B représente un radical alkyle ayant au plus 4 atomes de carbone éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène, le radical hydroxyle, les radicaux méthoxy, éthoxy, carboxy libre, salifié ou estérifié, amino, mono- ou dialkylamino et le radical phényle lui-même éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux méthoxy, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié et tétrazolyle,
R3B est choisi parmi les radicaux OR6 et CO2R7 dans lesquels
R6 et R7 représentent un atome d'hydrogène ou un radical alkyle ou alkényle renfermant au plus 5 atomes de carbone,
R4B représente un radical carboxy libre, estérifié ou salifié, ou un radical tétrazolyle, ou un radical -(CH2)p-SO2-Xd-R12d dans lequel p représente les valeurs 0 et 1 Xd représente les radicaux -NH-, -NH-CO-NH-, -NH-CO- ou une simple liaison et R12d représente un radical méthyle, vinyle, allyle, phényle, benzyle, pyridylméthyle ou pyridyléthyle, lesdits produits de formule (Ig) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux ou organiques et les bases minérales ou organiques desdits produits de formule (in). The subject of the present invention is in particular the products of formula (IB), as defined above, in which
R represents a butyl or buten-1-yl radical, R2B and R5B are such that one of R2B and R5B represents a radical

in which R c and Rd, identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms and phenyl, all these radicals being optionally substituted with one or more radicals chosen from halogen atoms, the hydroxyl radical, trifluoromethyl, cyano, nitro, amino, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl, free carboxy salt or esterified and tetrazolyl, and the other represents a hydrogen atom; ,
R 1 B represents an alkyl radical having at most 4 carbon atoms optionally substituted with one or more radicals chosen from halogen atoms, the hydroxyl radical, the methoxy, ethoxy, free carboxy, salified or esterified, amino, mono- or dialkylamino radicals; and the phenyl radical itself optionally substituted by one or more radicals chosen from halogen atoms, methoxy, trifluoromethyl, cyano, free carboxy, salified or esterified and tetrazolyl radicals,
R3B is chosen from the radicals OR6 and CO2R7 in which
R6 and R7 represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms,
R4B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, or a radical - (CH2) p -SO2-Xd-R12d in which p represents the values 0 and 1 Xd represents the radicals -NH-, -NH- CO-NH-, -NH-CO- or a single bond and R12d represents a methyl, vinyl, allyl, phenyl, benzyl, pyridylmethyl or pyridylethyl radical, said products of formula (Ig) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic or organic acids and mineral or organic bases of said products of formula (in).

dans laquelle
R représente un radical alkyle ou alkényle linéaire ou ramifié renfermant 3 ou 4 atomes de carbone, R1A, R2A' R3A et R5A sont tels que soit R1A, R2A, R32 & et R5A sont identiques et représentent un atome d'hydrogène, soit l'un de R2A et R5A représente un atome d'hydrogène ou un radical -CH2-O-R10, dans lequel R10 représente un atome d'hydrogène ou un radical alkyle ou alkényle linéaire ou ramifié renfermant au plus 5 atomes de carbone, et l'autre représente un atome d'hydrogène et, R1A et R3A sont tels que l'un représente un atome d'hydrogène et l'autre est choisi parmi les radicaux -OR6, -CO2R7 et -R11, radicaux dans lesquels
R6 et R7 identiques ou différents représentent un atome d'hydrogène ou un radical alkyle ou alkényle linéaire ou ramifié renfermant au plus 5 atomes de carbone, R11 est choisi dans le groupe formé par a) les radicaux alkyles ayant au plus 4 atomes de carbone, éventuellement substitués par un ou plusieurs radicaux choisis parmi - les atomes d'halogène, - le radical hydroxyle éventuellement acylé, - les radicaux alkyloxy ou alkényloxy linéaire ou ramifié ayant au plus 5 atomes de carbone, - le radical carboxy libre estérifié ou salifié, - le radical

dans lequel R a et Rb identiques ou différents sont choisis parmi les atomes d'hydrogène, les radicaux alkyle ou alkényle ayant de 1 à 4 atomes de carbone éventuellement substitués par un atome d'halogène ou un radical hydroxy, b) les radicaux alkényles linéaires ou ramifiés ayant de 2 à 5 atomes de carbone, c) les radicaux acyles ayant de 2 à 7 atomes de carbone et le radical formyle,
R4A représente un radical carboxy libre, estérifié ou salifie, cyano, ou un radical tétrazolyle, éventuellement salifié, lesdits produits de formule (IA) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux ou organiques et les bases minérales ou organiques desdits produits de formule (IA). The subject of the present invention is particularly the products of formula (Ig) corresponding to formula (IA)

in which
R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1A, R2A 'R3A and R5A are such that either R1A, R2A, R32 & and R5A are identical and represent a hydrogen atom, or one of R2A and R5A represents a hydrogen atom or a radical -CH2-O-R10, in which R10 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms, and another represents a hydrogen atom and R1A and R3A are such that one represents a hydrogen atom and the other is selected from the radicals -OR6, -CO2R7 and -R11, radicals in which
R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R11 is chosen from the group formed by a) alkyl radicals having at most 4 carbon atoms, optionally substituted with one or more radicals chosen from - halogen atoms, - optionally acylated hydroxyl radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - esterified or salified free carboxy radical, - The radical

in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxyl radical, b) linear alkenyl radicals; or branched having from 2 to 5 carbon atoms, c) acyl radicals having from 2 to 7 carbon atoms and the formyl radical,
R4A represents a free, esterified or salified carboxy radical, cyano, or a tetrazolyl radical, optionally salified, said products of formula (IA) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the inorganic or organic acids and the inorganic or organic bases of said products of formula (IA).

dans laquelle
R représente un radical alkyle ou alkényle linéaire ou ramifié renfermant 3 ou 4 atomes de carbone,
R1, R2, R3 et R5 sont tels que soit R1, R2, R3 et R5 sont identiques et représentent un atome d'hydrogène, soit l'un de R2 et R5 représente un atome d'hydrogène ou un radical -CH2-O-R10 et l'autre représente un atome d'hydrogène, et R1 et R3 sont tels que l'un représente un atome d'hydrogène et l'autre est choisi parmi les radicaux -OR6, -CO2R7 et -CH2-O-R8, lesquels radicaux R10, R6, R7 et R8, identiques ou différents, représentent un atome d'hydrogène ou un radical alkyle ou alkényle linéaire ou ramifié renfermant au plus 5 atomes de carbone,
R4 represente un radical carboxy libre, estérifie ou salifié, lesdits produits de formule (I) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux ou organiques et les bases minerales ou organiques desdits produits de formule (I).The subject of the present invention is thus the products of formulas (Ig) and (IA), as defined above, and corresponding to formula (I)

in which
R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms,
R1, R2, R3 and R5 are such that either R1, R2, R3 and R5 are identical and represent a hydrogen atom, one of R2 and R5 represents a hydrogen atom or a radical -CH2-O- R10 and the other represent a hydrogen atom, and R1 and R3 are such that one represents a hydrogen atom and the other is selected from the radicals -OR6, -CO2R7 and -CH2-O-R8, which radicals R10, R6, R7 and R8, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms,
R4 represents a free, esterified or salified carboxy radical, said products of formula (I) being in all the possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral or organic acids and mineral or organic bases said products of formula (I).

 In the products of formulas (in), (IA) and (I) and in what follows - the term linear or branched alkyl radical designee preferably methyl, ethyl, propyl or isopropyl, butyl, isobutyl, sec-butyl or tert-butyl but may also represent a pentyl radical and in particular tert-pentyl, - the term linear or branched alkenyl radical preferably denotes a vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl radical but may also represent a 1-pentenyl, 2-pentenyl or 3-pentenyl radical, the term halogen atom preferably denotes the bromine atom, but may also represent a fluorine, chlorine or iodine atom, the alkyloxy and alkenyloxy radicals that can represent -O-R10 and -O-R6 are formed, for example, with the alkyl and alkenyl radicals as defined above, mention may be made for the alkyloxy radicals, preferably the methoxy or ethoxy radicals; but also propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy or pentoxy radicals, for the alkenyloxy radicals, vinyloxy or propenyloxy radicals may be mentioned, for the esterified carboxy radicals, preferably a (alkyloxy or alkenyloxy) group may be mentioned; lower carbonyl) such as methoxycarbonyl or ethoxycarbonyl, but also the radicals propoxycarbonyl, butoxycarbonyl, butenyloxycarbonyl, tert-butoxycarbonyl or pentoxycarbonyl, the term acyl radical preferably denotes a radical having at most 7 carbon atoms such as the formyl radical, acetyl propionyl, butyryl or benzoyl, but may also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical, the term "acyloxy radical" preferably denotes groups containing one of the acyl radicals as defined above and bonded to a hydrogen atom. oxygen such as for example acetoxy or benzoylpxy, - the term aryl radical designates the monocyclic or fused carbocyclic or heterocyclic radicals, it being understood that heterocyclic radicals may contain one or more heteroatoms selected from oxygen, nitrogen or heteroatom, the heteroatoms of these heterocyclic radicals may be the same or different.

 The term monocyclic radical preferably denotes the radicals which contain 5 or 6 members, as a carbocyclic monocyclic radical, mention may be made of the phenyl radical among the heterocyclic monocyclic radicals, for example the thienyl, furyl, pyranyl and pyrrolyl radicals, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl such as delta 2-pyrrolinyl, imidazolinyl such as delta 2-imidazolinyl, pyrazolinyl such as delta 3pyrazolinyl and the positional isomers of the heteroatom (s) that these radicals may contain such as, for example, isothiazolyl or isoxazolyl radicals.

 The term radical consisting of condensed rings preferably denotes radicals which contain 8 to 14 members among the radicals consisting of carbocyclic fused rings, for example naphthyl and phenanthryl radicals, among radicals consisting of heterocyclic fused rings, mention may be made, for example, of benzothienyl, naphtho 2,3-b] thienyl, indanyl, indenyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, imidazopyridyl, pyrimidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl , carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl or else condensed polycyclic systems consisting of monocyclic heterocyclic as defined above, such as, for example, furo (2,3-b) pyrrole or thieno [2,3-b] furan.

 Examples of such an aryl radical include phenyl, naphthyl and thienyl radicals such as thien-2-yl and thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3-yl, pyrimidyl and pyrrolyl. thiazolyl, isothiazolyl, diazolyl, triazolyl, tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl; fused heterocyclic groups containing at least one hetero atom selected from sulfur, nitrogen and oxygen, for example benzothienyl such as benzothien-3-yl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

qui représentent un radical amino éventuellement substitué par un ou deux radicaux identiques ou différents, désignent par exemple des radicaux monoalkyl et dialkylamino dans lesquels les radicaux alkyle peuvent prendre les significations indiquées ci-dessus telles que par exemple, méthyle, éthyle, isopropyle, butyle, isobutyle, ces radicaux étant éventuel- lement substitués comme par exemple dans hydroxyméthyle, hydroxyéthyle, méthoxymethyle, méthoxyethyle ou encore ethoxyéthyle, trifluorométhyle, pentafluorométhyle ; le radical amino peut également être substitué par un ou deux radicaux alkényle tel que défini ci-dessus et comme par exemple les radicaux vinyle, allyle, l-propényle, 1-butényle parmi les substituants de ces radicaux amino, on peut également citer les radicaux aryles et aralkyles tels que, par exemple, les radicaux phényle, benzyle, phénéthyle, naphtyle, indolyle, indolinyle, thiényle, furyle, pyrrolyle, pyridyle, pyrrolidinyle, pipéridino, morpholino, pipérazinyle, ces radicaux pouvant être substitués par un ou plusieurs radicaux tels que définis ci-dessus comme par exemple dans méthylpipérazinyle, fluorométhylpipérazinyle, éthylpipérazinyle, propylpipérazinyle, phénylpipérazinyle ou benzylpipérazinyle.Such aryl radicals may optionally be substituted, such as, for example, the N-substituted pyrrolyl radical, for example N-methylpyrrolyl, the substituted 3- or 4-isoxazolyl radical, for example 3-aryl-5-methylisoxazol-4-yl, aryl group being for example a phenyl or halophenyl group - the groups

which represent an amino radical optionally substituted with one or two identical or different radicals, denote, for example, monoalkyl and dialkylamino radicals in which the alkyl radicals may take the meanings indicated above, such as, for example, methyl, ethyl, isopropyl or butyl, isobutyl, these radicals being optionally substituted as for example in hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl or ethoxyethyl, trifluoromethyl, pentafluoromethyl; the amino radical may also be substituted by one or two alkenyl radicals as defined above and, for example, the vinyl, allyl, 1-propenyl or 1-butenyl radicals among the substituents of these amino radicals, radicals may also be mentioned; aryls and aralkyls such as, for example, phenyl, benzyl, phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino, morpholino and piperazinyl radicals which may be substituted by one or more radicals such as as defined above, such as, for example, in methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl.

the radical '(CH 2) -SO, -X-R 12 may for example represent the radicals in which (CH 2) m represents the alkylene values of the alkyl radicals indicated above such as, for example, methylene, ethylene, n-propylene isopropylene, isobutylene or tert-butylene and R12 may represent an alkyl radical chosen from the values defined above or an aryl radical also chosen from the values indicated above for this radical such as, for example, phenyl, biphenyl, naphthyl or tetrazolyl; the alkyl radical that can represent the radical R12 may optionally be substituted by an aryl radical chosen from the values defined above to form an aralkyl radical.

 These alkyl, aryl and aralkyl radicals can themselves be substituted as indicated above for these radicals.

 For example, the radicals -SO2-NH2, -SO2-NH-CH3, -SO2-NH-CF3, -SO2-NH-C6H5, -SO2-NH-CH2-C6H5 may be mentioned, for example, in a non-exhaustive manner.

 The radical R preferably represents a propyl, 1-propenyl, butyl or 1-butenyl radical, but may also represent an isopropyl, sec-butyl, tert-butyl and 2-butenyl radical.

 The addition salts with inorganic or organic acids and the inorganic or organic bases of the products of formulas IB '(IB), (IA) and (I) may be, for example, the salts formed with hydrochloric, hydrobromic acids, iodine, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyl disulfonic acids such as, for example, methanedisulphonic acid, 1,2-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.

 Particularly preferred are the salts formed with hydrochloric acid.

 The carboxyl group (s) of the products of formula (I) may be salified with inorganic bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as that, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, Ndimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

 The subject of the invention is particularly the products of formula (zig) corresponding to formula (IA) as defined above, in which R represents a butyl or l-butenyl radical and R1A represents a hydrogen atom or an alkyloxy radical, said products of formula (IA) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with mineral or organic acids and inorganic or organic bases of said products of formula (IA).

Among the products in which R1A represents a hydrogen atom, the preferred products are thus those in which R2A, R3A and R5A are identical and represent a hydrogen atom and those in which R2A or n represents a hydrogen atom, a hydrogen atom or a hydrogen atom. hydroxy radical or an alkynoxy radical, and R3A represents a hydroxy, alkyloxy radical, or is chosen from the radicals -OR6, -CO2R7 and -R11, radicals in which
R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms.

dans lequel R a et Rb identiques ou différents sont choisis parmi les atomes d'hydrogène, les radicaux alkyle ou alkényle ayant de 1 à 4 atomes de carbone éventuellement substitués par un atome d'halogène ou un radical hydroxy, b) les radicaux alkényles linéaires ou ramifiés ayant de 2 à 5 atomes de carbone, c) les radicaux acyles ayant de 2 à 7 atomes de carbone et le radical formyle, et R4A représente un radical tétrazolyle ou carboxy libre, salifié ou estérifié par un radical alkyle, les radicaux alkyle et alkyloxy tels que définis ci-dessus renferment de,l à 5 atomes de carbone.R11 is selected from the group consisting of a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals selected from - halogen atoms, - optionally acylated hydroxy radical, - alkyloxy or alkenyloxy radicals linear or branched compounds having not more than 5 carbon atoms, - the esterified or salified free carboxy radical, - the radical

in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxyl radical, b) linear alkenyl radicals; or branched having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, and R4A is a free tetrazolyl or carboxy radical, salified or esterified with an alkyl radical, the alkyl radicals and alkyloxy as defined above contain from 1 to 5 carbon atoms.

 Among the products in which R1A represents an alkyloxy radical, there may be mentioned, for example, the products in which R2A, R3A and R5A represent a hydrogen atom.

 In the preferred products indicated above, the alkyl and alkyloxy radicals contain from 1 to 5 carbon atoms and preferably represent, respectively, for the alkyl radicals, the methyl and ethyl radicals, and for the alkyloxy radicals, the methoxy and ethoxy radicals.

The subject of the invention is particularly the products of formula (IA) as defined above, in which R represents a butyl radical and R1A, R2A, R3A and
R5A represent a hydrogen atom, said products of formula (IA) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral or organic acids and the mineral or organic bases of said products of formula (IA).

The subject of the invention is more particularly the products of formula (IA) as defined above, in which R represents a butyl radical, R1A, R2A, and R5A represent a hydrogen atom, and R3A is chosen from radicals. -OR6, -CO2R7 and -R11, radicals in which
R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms.

dans lequel R a et Rb identiques ou différents sont choisis parmi les atomes d'hydrogène, les radicaux alkyles ou alkényles ayant de 1 à 4 atomes de carbone éventuellement substitués par un atome d'halogène ou un radical hydroxy, b) les radicaux alkényles linéaires ou ramifiés ayant de 2 à 5 atomes de carbone, c) les radicaux acyles ayant de 2 à 7 atomes de carbone et le radical formyle, R4A ayant la signification indiquée cidessus, lesdits produits de formule (IA) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux ou organiques et les bases minérales ou organiques desdits produits de formule (lA). R11 is selected from the group consisting of a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals selected from - halogen atoms, - optionally acylated hydroxy radical, - alkyloxy or alkenyloxy radicals linear or branched compounds having not more than 5 carbon atoms, - free, esterified or salified carboxy radicals, - radical

in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxyl radical, b) linear alkenyl radicals; or branched having from 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, R4A having the meaning indicated above, said products of formula (IA) being in all possible isomeric forms racemic, enantiomeric and diastereoisomerically, as well as addition salts with inorganic or organic acids and inorganic or organic bases of said products of formula (IA).

 The subject of the invention is in particular the products of formula (IA) as defined above, in which R represents a butyl radical and R1A, R2A and R5A represent a hydrogen atom, and R3A represents a free or esterified carboxy radical. by an alkyl radical containing at most 4 carbon atoms; formyl; alkyl or alkenyl containing at most 4 carbon atoms; the alkyl radical being optionally substituted by one or more radicals chosen from halogen atoms, hydroxy, acyloxy, amino radicals optionally substituted by one or two alkyl radicals containing at most 4 carbon atoms; said products of formula (IA) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with mineral or organic acids and inorganic or organic bases of said products of formula (IA).

 Among the products which are the subject of the invention, mention may be made especially of methyl 4 '- [(2-butyl-1H-benzimidazol-yl) methyl] biphenyl-2-carboxylate and its salts, 4'-E-acid. (2-Butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and its salts, 2-butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] 1H-benzimidazole-7-carboxylic acid and its salts salts, 4 '- [[2-butyl-7- (2-hydroxyethyl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and its salts, 4' - [(2- butyl 7-formyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and its salts, 2-butyl 1-E 2 '- (1H-tetrazol-5-yl) biphenyl) 4-yl] methyl] 1H-benzimidazole-7-carboxylic acid and its salts.

dans laquelle R a la signification indiquée ci-dessus et R1B',
R2B', R3B' et R5B' ont les significations indiquées ci-dessus respectivement pour R1B, R2B, R3B et R5B dans lesquelles les éventuelles fonctions réactives sont si désiré protégées par des groupements protecteurs, avec un composé de formule (VB)

dans laquelle Hal représente un atome d'halogène et R4B' a la signification indiquée ci-dessus pour R4B dans lequel les éventuelles fonctions réactives sont si désiré, protégées par des groupements protecteurs, pour obtenir un produit de formule (IXB)

dans laquelle R, R1B', R2B', R3B', R5B' et R4B' ont les significations indiquées ci-dessus, soit a) l'on fait réagir un composé de formule (VIB)

dans laquelle R1B', R2B', R3B' et R5B' ont les significations précédentes, avec le composé de formule (II) :

dans laquelle R9 représente un radical hydroxy, alkyloxy ou un atome d'halogène et R a la signification indiquée ci-dessus, pour obtenir le produit de formule (XB) ::

dans laquelle R, R1B', R2B', R3B' et R5B' ont les significations précédentes, b) l'on fait réagir un composé de formule (VIB')

dans laquelle R1B', R2B', R3B' et R5B' ont les significations )précédentes, avec le composé de formule (II) telle que définie ci-dessus pour obtenir le produit de formule (XB')

dans laquelle R1B', R2B', R3B', R5B' et R ont les significations indiquées précédemment, que l'on soumet à une réaction de nitration pour obtenir le composé de formule (XB) telle que définie ci-dessus, produit de formule (XB) que l'on fait réagir avec le composé de formule (VB) telle que définie ci-dessus, pour obtenir un produit de formule (XIB)

dans laquelle R, R1B', R2B', R3B', R5B' et R5B' et R4B' ont les significations précédentes, que l'on soumet à une réaction de réduction sélective de la fonction nitro, pour obtenir le produit de formule (XIIB)

dans laquelle R, R1B', R2B', R3B', R5B' et R4B' ont les significations précédentes, que l'on soumet à une réaction de cyclisation pour obtenir des produits de formule (IXB) telle que définie ci-dessus, soit l'on fait réagir le composé de formule (VIB) avec le composé de formule (VB) telle que définie ci-dessus, pour obtenir un produit de formule (VIIB)

dans laquelle R1B', R2B', R3B', R5B' et R4B' ont les significations indiquées ci-dessus, que l'on soumet à une réaction de réduction sélective du radical nitro pour obtenir un produit de formule (VIIIB)

dans laquelle R1B', R2B', R3B', R5B' et R4B' ont les significations indiquées ci-dessus, que l'on fait réagir avec le produit de formule (III)

dans laquelle X représente un atome d'oxygène ou un radical
NH, Rg et R ont la signification indiquée ci-dessus, pour obtenir un produit de formule (IXB) telle que définie cidessus, produit de formule (IXB) que, si désiré et si nécessaire, l'on-soumet à l'une ou plusieurs des réactions suivantes, dans un ordre quelconque - une réaction d'élimination des éventuels groupements protecteurs, - une réaction de salification par un acide ou une base minéral ou organique pour obtenir le sel correspondant, - une réaction d'estérification ou de salification de fonction acide, - une réaction d'hydrolyse acide ou alcaline de fonction ester en fonction acide, - une réaction de transformation d'un radical alkyloxy en radical hydroxy, - une réaction de transformation d'un radical haloalkyle en radical alkylène, - une reaction de substitution d'un atome d'halogène par un radical amino, - une reaction de substitution d'un radical hydroxy par un atome d'halogène, - une réaction de reduction d'un radical carboxy estérifié en radical hydroxyalkyle, - une reaction d'oxydation d'un radical hydroxyalkyle en radical carboxy estérifié, - une réaction d'oxydation d'un radical hydroxyméthyle en radical formyle, - une réaction de dédoublement des formes racémiques en produits dédoublés, - une réaction de transformation d'une fonction carboxy libre, salifiée ou estérifiée en radical tétrazolyle, lesdits produits de formule (zig) ainsi obtenus étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères.The subject of the invention is also a process for the preparation of products of formula (zig) as defined above, characterized in that either a product of formula (IVB) is reacted

in which R has the meaning indicated above and R1B ',
R2B ', R3B' and R5B 'have the meanings given above for R1B, R2B, R3B and R5B, respectively, in which the optional reactive functional groups are, if desired, protected by protective groups, with a compound of formula (VB)

in which Hal represents a halogen atom and R4B 'has the meaning indicated above for R4B in which the optional reactive functions are, if desired, protected by protecting groups, to obtain a product of formula (IXB)

wherein R, R1B ', R2B', R3B ', R5B' and R4B 'have the meanings given above, or a) reacting a compound of formula (VIB)

in which R1B ', R2B', R3B 'and R5B' have the above meanings, with the compound of formula (II):

in which R 9 represents a hydroxy, alkyloxy or halogen atom and R has the meaning indicated above, to obtain the product of formula (XB) ::

in which R, R1B ', R2B', R3B 'and R5B' have the above meanings, b) reacting a compound of formula (VIB ')

wherein R1B ', R2B', R3B 'and R5B' have the above meanings, with the compound of formula (II) as defined above to obtain the product of formula (XB ')

in which R1B ', R2B', R3B ', R5B' and R have the meanings indicated above, which is subjected to a nitration reaction to obtain the compound of formula (XB) as defined above, product of formula (XB) which is reacted with the compound of formula (VB) as defined above, to obtain a product of formula (XIB)

wherein R, R1B ', R2B', R3B ', R5B' and R5B 'and R4B' have the above meanings, which are subjected to a selective reduction reaction of the nitro function, to obtain the product of formula (XIIB )

wherein R, R1B ', R2B', R3B ', R5B' and R4B 'have the above meanings, which is subjected to a cyclization reaction to obtain products of formula (IXB) as defined above, either the compound of formula (VIB) is reacted with the compound of formula (VB) as defined above to obtain a product of formula (VIIB)

wherein R1B ', R2B', R3B ', R5B' and R4B 'have the meanings indicated above, which is subjected to a selective reduction reaction of the nitro radical to obtain a product of formula (VIIIB)

wherein R1B ', R2B', R3B ', R5B' and R4B 'have the meanings given above, which is reacted with the product of formula (III)

in which X represents an oxygen atom or a radical
NH, Rg and R have the meaning indicated above, to obtain a product of formula (IXB) as defined above, product of formula (IXB) that, if desired and if necessary, subject to one or more of the following reactions, in any order - an elimination reaction of any protective groups, - a salification reaction with an acid or an inorganic or organic base to obtain the corresponding salt, - an esterification or salification reaction acid function, - an acidic or alkaline hydrolysis reaction of ester function in acid function, - a conversion reaction of an alkyloxy radical to hydroxy radical, - a conversion reaction of a haloalkyl radical to alkylene radical, - a substitution reaction of a halogen atom with an amino radical, a substitution reaction of a hydroxy radical with a halogen atom, a reduction reaction of a carboxy radical esterified with a hydroxyl radical alkyl, - an oxidation reaction of a hydroxyalkyl radical to an esterified carboxy radical, - an oxidation reaction of a hydroxymethyl radical to formyl radical, - a reaction of resolution of the racemic forms to split products, - a reaction reaction a free carboxy function, salified or esterified to the tetrazolyl radical, said products of formula (zig) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

Under preferred conditions of implementation of the invention, the above process is carried out as follows
The reaction of the compound of formula (VB) in which the halogen atom is preferably a bromine atom on the anion of imidazole of formula (IVB) prepared for example by the action of an alkaline agent such as Sodium or potassium hydride or a sodium or potassium alkoxide such as, for example, sodium methoxide, may be carried out, for example, in an organic solvent such as dimethylformamide or tetrahydrofuran.

The addition reaction of the compounds of formula (II) to the free amine function of the compounds of formula (VIB) or (VIB ') to obtain respectively the products of formula (XB) or (XB') can be carried out by simple heating at a temperature of about 120 ° C to 170 ° C: a compound of formula (II) may be for example valeric acid, then used, preferably in excess relative to the compound of formula (VIB) or (VIB ')
The nitration reaction of the products of formula (Xg ') to give the products of formula (XB) can be carried out for example in the presence of nitric acid in a solvent such as, for example, acetic anhydride and acetic acid at a concentration of temperature between 0 and 10 C.

 The addition reaction of the compounds of formula (VB) to the amide function of the compounds of formula (XB) to obtain the products of formula (XIB) can be carried out at ambient temperature or by heating at a temperature of between 20 ° C. and 1500C, preferably in the presence of an alkaline agent such as, for example, sodium triethylamine, sodium hydroxide, methoxide or sodium ethylate, or sodium hydride in a solvent such as, for example, tetrahydrofuran or dimethylformamide .

 The reduction of the nitro radical of the products of formula (XIB) to amino radical to obtain the products of formula (XIIB) can be carried out according to the usual methods known to those skilled in the art in particular by catalytic hydrogenation in the presence of palladium hydroxide in a solvent such as, for example, ethanol or with zinc in a solvent such as, for example, acetic acid in the presence of sodium acetate or sodium borohydride.

 The cyclization reaction of the products of formula (XIIB) to obtain the products of formula (IXB) can be carried out by simple heating or in the presence of a catalyst such as, for example, thionyl chloride, phosphorus pentachloride or else phosphoric anhydride in a solvent such as, for example, tetrahydrofuran or dimethylformamide.

The addition reaction of the compounds of formula (VB) on the free amine function of the compounds of formula (VIB) to obtain the products of formula (VIIB) can be carried out under the same conditions as those described above for the addition compounds of formula (VB) on the products of formula (IVB)
The reduction of the nitro radical of the products of formula (VIIB) to amino radical to obtain the products of formula (VIIIB) can be carried out according to the usual methods known to those skilled in the art in particular under the same conditions as those described above for the reduction of the nitro radical of the products of formula (XIB).

 The addition reaction of the compounds of formula (III) on the free amine radical of the products of formula (VIIIB) followed by the cyclization of the products thus obtained can be carried out according to various reaction conditions known to those skilled in the art, preferably in an organic solvent such as, for example, tetrahydrofuran or dimethylformamide at a temperature of between 20 ° C and 200 ° C.

The compound of formula (III) can be, for example, when
X is NH, ethyl pentanimidoate and when X is O, for example, valeric acid.

According to the values of Rob ', Rabi' R3B and Rob ', the products of formula (IXB) constitute or not formula products
The various reactive functions that certain compounds defined above may carry may, if necessary, be protected: for example, they are free hydroxy or carboxy radicals which may be protected by the appropriate easily removable protecting groups.

 The following non-exhaustive list of examples of protection of reactive functions may be mentioned - the hydroxy radicals may be protected for example by the trimethylsilyl, methoxymethyl or tetrahydropyranyl radicals, the carboxy groups may be protected for example in the form of esters formed with readily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.

 The removal of these protective groups can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzenesulphonic acid, para-toluenesulphonic acid, formic acid or trifluoroacetic acid.

 A list of different protecting groups that can be used, for example, in the patent FR 2,499,995.

 The products described above may, if desired, be the subject of salification reactions with a mineral or organic acid made according to the usual methods known to those skilled in the art.

 The possible ester function transformations in acid function of the products described above can be, if desired, carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis with hydrochloric or sulfuric acid, or else by hydrolysis. alkaline for example with sodium hydroxide or potassium hydroxide in an alcoholic medium such as, for example, in methanol.

 The optional alkyloxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into an alcohol function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as, for example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or refluxing acetic acid.

 The optional conversion of a haloalkyl radical to an alkylene radical of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by saponification and dehalogenation, for example in the presence of aqueous sodium hydroxide. an alcohol such as for example methanol.

 The optional substitution reaction of a halogen atom with an amino radical of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by treating the halogenated compound with a derivative amine such as for example dimethylamine at room temperature in a solvent such as an alcohol such as for example ethanol or methanol.

 The substitution reaction of a hydroxy radical with a halogen atom can be carried out under the usual conditions known to those skilled in the art such as in particular by chlorination with thionyl chloride.

 The chlorinated derivative may optionally be substituted in turn with an amine derivative such as, for example, dimethylamine.

 The reduction reaction of an esterified carboxy radical to a hydroxyalkyl radical can be carried out under the usual conditions known to those skilled in the art, such as, in particular, by the action of lithium aluminum hydride, of diisobutylaluminum hydride, or of other reducing agents known to those skilled in the art.

 The oxidation reaction of a hydroxyalkyl radical to an esterified carboxy radical can be carried out under the usual conditions known to those skilled in the art, such as in particular by an oxidizing mixture such as the BOWERS reagent, followed by an esterification, by example by diazomethane.

 The oxymethylation reaction of the hydroxymethyl radical to the formyl radical can be carried out under the usual conditions known to those skilled in the art, such as in particular by the action of activated manganese dioxide in methylene chloride.

 Any optically active forms of the products of formula (zig) may be prepared by resolution of the racemic agents according to the usual methods known to those skilled in the art. For example, salts formed with optically active bases may be used.

 The compounds of formula (zig) as defined above and their addition salts with acids have interesting pharmacological properties.

 The products are endowed with antagonistic properties for the angiotensin II receptor and are thus notably inhibitors of the effects of angiotensin II, in particular the vasoconstrictor effect and also the trophic effect on myocytes.

These properties justify their application in therapeutics and the invention also relates as medicaments, the products as defined by the formula (zig) above, said products of formula (zig) being in all possible isomeric forms racemic or optically as well as the addition salts with inorganic or organic acids and the pharmaceutically acceptable inorganic or organic bases of said products of formula
The invention particularly relates, as medicaments, to the products of formula (Ig) as defined above in which R represents a butyl or 1-butenyl radical and R1B represents a hydrogen atom, and especially the products of formula (Ig) as defined above in which R represents a butyl radical and
R1B, R23 and R53 are identical and each represents a hydrogen atom and R3B represents a hydrogen atom, a carboxy radical which is free or esterified with an alkyl radical containing at most 4 carbon atoms; formyl; alkyl or alkenyl containing at most 4 carbon atoms; alkyl substituted with one or more radicals selected from halogen atoms, hydroxyl, acyloxy, amino radicals optionally substituted with one or two alkyl radicals containing at most 4 carbon atoms and free carboxy, salified or esterified, R4B represents a carboxy radical; free, salified or esterified, optionally salified cyano or tetrazolyl, as well as the addition salts with inorganic or organic acids and the pharmaceutically acceptable inorganic or organic bases of said products of formula (IB).

 The subject of the invention is more particularly, as medicaments, the products of formula (Ig) following methyl 4'-t (2-butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate, the acid 4 '- E (2-butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, 2-butyl 1 - [[2'-carboxybiphenyl-4-yl] methyl] 1H-benzimidazole-7-carboxylic acid, 4'-E [2-butyl 7- (2-hydroxyethyl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid, 4'-E (2-butyl 7-formyl) H benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, 2-butyl 1-E [2 '- (1H-tetrazol-5-yl) (1,1'-biphenyl) 4-yl] methyl ] 1H-benzimidazole-7-carboxylic acid, as well as their addition salts with inorganic or organic acids and pharmaceutically acceptable inorganic or organic bases.

 The medicaments which are the subject of the invention can be used in the treatment of arterial hypertension, heart failure, renal insufficiency and in the prevention of post-angioplasty restenosis.

 They can also be used in the treatment of certain gastrointestinal and gynecological disorders and in particular for their relaxing effect on the uterus.

 The invention extends to pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined above.

 These pharmaceutical compositions can be administered orally, rectally, parenterally or locally by topical application to the skin and mucous membranes.

 These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, single or coated tablets, capsules, granules, suppositories, injectables, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.

 The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 1 to 100 mg per day in adults, orally.

 The starting compounds of formulas (II), (III), (IVB), (VI), (VIB) and (VIB ') may be commercially available or may be prepared according to the usual methods known to those skilled in the art. job.

 The preparation of certain compounds of formula (IVB) is described in: J. Amer. Chem. Soc. (1937) 59, 178.

dans laquelle R1B', R23,1 R3B' et R5B' ont la signification indiquée ci-dessus.The other products of formula (IVB) may be prepared by the action of a compound of formula (III) as defined above with a product of formula (XIII)

wherein R1B ', R23, R3B' and R5B 'have the meaning indicated above.

 The operating conditions are the same as those indicated above for the action of the products of formula (III) on the products of formula (VIIIB).

 Certain compounds of formula (XIII) can be found commercially, such as, for example, methyl 3,4-diamino benzoate, for example commercialized by LANCASTER.

An example of preparation of these compounds of formula (XIII) is given in
Journal of the Chemical Society, Chemical Communications, (1957) 2197-2201.

 Among the compounds of formulas (II) and (III) is, for example, ethyl pentanimidoate which may be prepared, for example, by the action of gaseous hydrochloric acid in ethanol on valetronitrile, for example commercialized by LONZA. .

 An example of preparation of these compounds of formula (III) is given in J. Amer. Chem. Soc. (1942), 64, 1827.

dont le radical carboxy estérifié peut, si désiré, être libéré du radical alkyle par les méthodes classiques connues de l'homme du métier ou indiquées ci-dessus, par exemple l'hydrolyse acide ou alcaline, que l'on peut soumettre à une réaction de bromation sur le radical méthyle par les méthodes classiques connues de l'homme du métier par exemple par action du
N-bromosuccinimide dans le tétrachlorure de carbone.A process for the preparation of the products of formula (Vg) as defined above can consist in subjecting methyl iodobenzoate, marketed for example, by
JANSSEN, the action of iodotoluene, marketed for example by FLUKA, the reaction is carried out for example in the presence of powdered copper at a temperature of 100 "C to 300 C, to obtain a product of formula (Vg ')

wherein the esterified carboxy radical can, if desired, be liberated from the alkyl radical by conventional methods known to those skilled in the art or indicated above, for example acidic or alkaline hydrolysis, which can be subjected to a reaction bromination on the methyl radical by conventional methods known to those skilled in the art, for example by the action of the
N-bromosuccinimide in carbon tetrachloride.

 The preparation of certain compounds of formula (Vg) or (vil) or also certain transformations of the R4B radical of the products of formula (IXB) can be found, for example, in US Pat. No. 4,880,804 or EP 0 253 310.

 The compound of formula (VIB) may be, for example, orthonitroaniline, in the form of a product sold, for example, by UCB.

The products of formula (VIB) can also be prepared, for example, by the process described in
Canadian Journal of Chemistry, (1977), 55 (10), pp 1653-1657.

 The products of formula (VIB ') which are derivatives of aniline can be found commercially such as for example 2,4-dimethoxy aniline in ALDRICH or can be prepared as indicated for example in references following - BEILSTEIN volume XII, 3rd supplement p. 1662 - BEILSTEIN volume XIII, 3rd supplement p. 2128.

 The subject of the present invention is finally, as new industrial products and especially as intermediate products necessary for the preparation of the products of formula (IB), the compounds of formulas (IVB), (VIIB), (VIIIB), (XB ) and (XB ').

In addition to the products described in the examples which illustrate the invention without limiting it, the following products are products that can be obtained in the context of the present invention: these products of formula (IA) are such that R represents a butyl radical R4A represents a carboxy radical and R1A, R2A, R3A and R5A have the meanings indicated in the table below

<tb><SEP> R1A <SEP> R2A <SEP> R5A <SEP> R3A
<tb> H <SEP> H <SEP> H <SEP> OH
<tb> H <SEP> H <SEP> H <SEP> COOMe
<tb> H <SEP> H <SEP> H <SEP> CH3
<tb> H <SEP> H <SEP> H <SEP> Cl
<tb> H <SEP> CH2OH <SEP> H <SEP> OH
<tb> H <SEP> CH2OH <SEP> H <SEP> COOMe
<tb> H <SEP> CH2OH <SEP> H <SEP> COOH
<tb> H <SEP> CH2OH <SEP> H <SEP> CH3
<tb> H <SEP> CH2OH <SEP> H <SEP> Cl
<tb> H <SEP> CH2OH <SEP> H <SEP> CH2OH
<tb> H <SEP> CH2OH <SEP> H <SEP> CH2Cl
<tb> H <SEP> CH2OH <SEP> H <SEP> CH2-CH2-OH
<tb> H <SEP> CH2OH <SEP> H <SEP> CH2-CH2-Cl
<tb> H <SEP> OCH3 <SEP> H <SEP> OH
<tb> H <SEP> OCH3 <SEP> H <SEP> COOMe
<tb> H <SEP> OCH3 <SEP> H <SEP> COOH
<tb> H <SEP> OCH3 <SEP> H <SEP> CH3
<tb> H <SEP> OCH3 <SEP> H <SEP> Cl
<tb> H <SEP> OCH3 <SEP> H <SEP> CH2OH
<tb> H <SEP> OCH3 <SEP> H <SEP> CH2Cl
<tb> H <SEP> OCH3 <SEP> H <SEP> CH2-CH2-OH
<tb> H <SEP> OCH3 <SEP> H <SEP> CH2-CH2-Cl
<tb> H <SEP> Cl <SEP> H <SEP> OH
<tb> H <SEP> Cl <SEP> H <SEP> COOMe
<tb> H <SEP> Cl <SEP> H <SEP> COOH
<tb> H <SEP> Cl <SEP> H <SEP> CH3
<tb> H <SEP> Cl <SEP> H <SEP> Cl
<tb> H <SEP> Cl <SEP> H <SEP> CH2OH
<tb> H <SEP> Cl <SEP> H <SEP> CH2Cl
<tb> H <SEP> Cl <SEP> H <SEP> CH2-CH2-OH
<tb> H <SEP> Cl <SEP> H <SEP> CH2-CH2-Cl
<Tb>

<tb> I <SEP> I <SEP> I <SEP> I
<tb><SEP> R1A <SEP> R2A <SEP> R5A <SEP> R3A
<tb> OH <SEP> H <SEP> H <SEP> OH
<tb> OH <SEP> H <SEP> H <SEP> COOMe
<tb> OH <SEP> H <SEP> H <SEP> CH3
<tb> OH <SEP> H <SEP> H <SEP> Cl
<tb> OH <SEP> H <SEP> H <SEP> CH2OH
<tb> OH <SEP> H <SEP> H <SEP> CH2Cl
<tb> OH <SEP> H <SEP> H <SEP> CH2-CH2-OH
<tb> OH <SEP> H <SEP> H <SEP> CH2-CH2-Cl
<Tb>
The following examples illustrate the invention without limiting it.

EXAMPLE 1 Methyl 4 '- ((2-butyl 1H-benzimidazol-1-yl) methyl) biphenyl-2-carboxylate hydrochloride
To a suspension of 650 mg of sodium methylate in 5 cm3 of dimethylformamide, cooled to 0 ° C., a solution of 2 g of 2-butyl 1H-benzimidazole (prepared according to
WO Pool, HJ HARWOOD and AW RALSTON - J. Amer. Chem. Soc., (1937) 59, 178) in 3 cm of dimethylformamide. Stirred 15 minutes allowing to return to room temperature. A solution of 3.6 g of methyl 4 '- (bromomethyl) biphenyl-2-carboxylate (obtained according to EP 0253310) in 5 cm3 of dimethylformamide is added over 15 minutes.

 It is stirred for 4 hours at 40 ° C., the dimethylformamide is evaporated and 50 cm 3 of an aqueous solution of sodium bicarbonate are added. Extracted with 3 times 100 cm3 of ethyl acetate, washed with water, dried, filtered and evaporated to dryness. The residue (4.6 g) is chromatographed on silica (eluent ethyl acetate-cyclohexane (1-1)). 1.8 g of desired product are obtained in base form.

salification
To a solution of 500 mg of the base obtained above in isopropanol is added a solution of ethyl acetate hydrochloric acid until acidic pH. The ethyl acetate is evaporated, the product is crystallized in isopropanol, filtered off, washed with isopropanol, dried under reduced pressure at 100 ° C. 350 mg of hydrochloride F = 155 ° C. are obtained, which is recrystallized. twice in isopropanol. 230 mg of the desired product is thus obtained in the form of hydrochloride F = 155-160 ° C.

Analysis for C26H27N2O2Cl = 435.01
CH Cl N% calculated 71.79 6.25 8.15 6.44% found 72.00 6.2 8.3 6.3
IR spectrum (CHCl3)

<tb> Absorption <SEP> Complex <SEP> 2800 <SEP>----><SEP> 2000 <SEP> cm- <SEP> (From <SEP> Type <SEP>: <SEP># N # <SEP ><SEP> -H)
<Tb>

<tb> O <SEP> 1723 <SEP> cm1
<tb><SEP> I <SEP> I
<tb> -C-OCH3 <SEP> 1438 <SEP> at
<Tb>

<tb> C = C <SEP> 1620 <SEP> cm-
<tb> C = N <SEP> 1599 <SEP> cm-
<tb> Aromatic <SEP> 1558 <SEP> -1 <SEP>
<tb><SEP> 1510 <SEP> cm-
<tb><SEP> 1488 <SEP> cm-
<Tb>
EXAMPLE 2: 4 '- [(2-Butyl 1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid
To a solution of 500 mg of the ester obtained in Example 1 in the form of base, in 8 cm3 of methanol is added 0.8 cm3 of 2N sodium hydroxide. The mixture is stirred for 4 hours under reflux. The methanol is evaporated, cooled to +10 ° C. and acidified to pH 5-6 with 2N hydrochloric acid, stirred for 30 minutes at +10 ° C., filtered off, washed with water and dried at 80 ° C. under pressure. scaled down. 400 mg of F = 190 C product is obtained which is recrystallized twice in isopropanol to obtain 125 mg of the desired product.

Mp = 234 C.

Analysis for C25H24N2O2 = 384.48
CHN% calculated 78.10 6.29 7.28% found 78.00 6.3 7.2
IR spectrum (Nujol)
C = O 1682 cm-

<tb> Aromatic <SEP> + <SEP> 1615 <SEP> at <SEP>
<tb> heteroaromatic <SEP> 1597 <SEP> cm <SEP>
<tb><SEP> 1518 <SEP> cm1 <SEP>
<Tb>
PREPARATION 1: Methyl 4 '- [N- (2- (methoxycarbonyl) 6-nitro phenyl) N (pentanoyl) aminomethyl] biphenyl-2-carboxylate
STAGE A: 2-amino-3-nitro benzoic acid a) acetylation
To a suspension cooled to +10 ° C. of 12 g of 2-amino-3-nitro-toluene and 14.4 cm 3 of acetic anhydride, 0.65 cm 3 of concentrated sulfuric acid are added and the mixture is stirred for 1 hour at room temperature. 50 cm3 of water are added, the mixture is stirred for 15 minutes, drained, washed with water and then with ether, dried at 100 ° C. under reduced pressure to give 13.6 g of desired product.

 F = 156 C.

b) oxidation
To a suspension of 29.48 g of potassium permanganate, 21.44 g of magnesium sulfate in 1470 cm3 of water, 13.4 g of the compound obtained above is added. Stirred for 3 hours at 100 ° C, allowed to warm to room temperature, cooled to 0 ° C + 5 ° C, filtered insoluble, filtrate cooled to 0 ° C + 5 ° C, 10 cm3 concentrated hydrochloric acid (pH 2-3) Extracted with 4 times 500 cm3 of ethyl acetate, washed with water, dried, filtered and evaporated under reduced pressure to give 16.1 g of product which is crystallized from ethyl ether to collect 12.1 g of the desired product, mp = 192 ° C.

c) hydrolysis
12 g of the product obtained above are stirred for 4 hours at 1200C with 75 cm3 of water at 5% concentrated hydrochloric acid, allowed to warm to room temperature, cooled to 0 C +5 ° C, stirred for 1 hour at this temperature. drained, washed with water and then with ether, dried at 100 ° C. under reduced pressure. 8.8 g of the desired product are obtained. F = 210 C.

STAGE B: Methyl 2-amino-3-nitro benzoate
A suspension of 1 g of the acid obtained in Stage A, 15 cm3 of methanol and 1.4 cm3 of 95-97% sulfuric acid is stirred for 48 hours under reflux. The methanol is evaporated, water (100 cc) is added, basified by addition of sodium bicarbonate, extracted with methylene chloride (3 × 200 cc), washed with water, dried, filtered and evaporated under reduced pressure.

1 g of expected product is obtained. M.p. 96 ° C.

STAGE C: Methyl 3-nitro 2-pentanamido benzoate
850 mg of the product obtained in Stage B above and 5 cm 3 of valeryl chloride are stirred for 1 hour under reflux.

It is evaporated to dryness and the residue is taken up in 80 cm3 of ethyl ether, treated with activated charcoal, filtered and evaporated under reduced pressure. 1.3 g of product is obtained which is crystallized from a mixture of isopropyl ether and pentane, 1 g of desired product is collected. F = 58 C.

 An analytical sample was prepared by dissolving in 20 cm 3 of isopropyl ether under reflux, filtration and concentration at 5 cm 3. Allowed to stand for 18 hours at room temperature, filtered, washed with isopropyl ether. We obtain 710 mg. F = 60 C.

 These 710 mg are dissolved in 25 cm3 of hot isopropyl ether, treated with activated charcoal, filtered and concentrated to 10 cm 3. Allowed to stand at room temperature for 1 hour, filtered, washed with isopropyl ether. 380 mg of the desired product is obtained. F = 60 C.

1608 - 1588 - 1499 cm-1 1540 - 1360 cm 1
STADE D :4'-[N-(2-(méthoxycarbonyl) 6-nitro phényl] N-(pentanoyl) aminométhyl] biphényle-2-carboxylate de méthyle
A une solution de 1 g du produit obtenu au stade B cidessus, dans 5 cm3 de diméthylformamide, on ajoute 170 mg d'hydrure de sodium à 50 % dans l'huile.On agite encore 5 minutes après la fin du dégagement d'hydrogène puis ajoute 1,09 g de 4'-(bromométhyl) biphényle-2-carboxylate de méthyle (préparation EP 00253310) on agite pendant 1 heure à température ambiante. On évapore le solvant et reprend le résidu par 3 fois 250 cm3 d'acétate d'éthyle puis lave avec 3 fois 50 cm3 d'eau, sèche, filtre et évapore sous pression réduite. On obtient 2 g de produit que l'on chromatographie sur silice (éluant : chlorure de méthylène-méthanol 99-1). On recueille 1,6 g du prouduit recherché.Analysis for C13H16N2O5 = 280.27
CHN% calculated 55.71 5.75 10.00% found 55.8 5.38 9.9
IR spectrum (CHCl3)
NH complex 3400 cm'l (ep)
3330 cm'l (max)
C = O complex 1730 cm-1 (ep)
1708 cm'l (max)
Aromatic
+
Amide II
N02

1608 - 1588 - 1499 cm-1 1540 - 1360 cm 1
STAGE D: Methyl 4 '- [N- (2- (methoxycarbonyl) 6-nitro phenyl] N- (pentanoyl) aminomethyl] biphenyl-2-carboxylate
To a solution of 1 g of the product obtained in Stage B above, in 5 cm3 of dimethylformamide, 170 mg of 50% sodium hydride in oil are added. The mixture is stirred for a further 5 minutes after the end of hydrogen evolution. then added 1.09 g of methyl 4 '- (bromomethyl) biphenyl-2-carboxylate (preparation EP 00253310) is stirred for 1 hour at room temperature. The solvent is evaporated and the residue is taken up with ethyl acetate (3 × 250 cc), then washed with water (3 × 50 cc), dried, filtered and evaporated under reduced pressure. 2 g of product are obtained which is chromatographed on silica (eluent: 99-1 methylene chloride-methanol). 1.6 g of the desired product is collected.

IR spectrum (CHC13)
C = O complex 1726 and 1670 cm-
NO2 1538 and 1352 cm-
Aromatic 1600 and 1576 cm-
EXAMPLE 3: Methyl 2-butyl 1- [2 '- (methoxycarbonyl) biphenyl-4-yl) methyl hydrochloride 1H-benzinidazole-7-carboxylate a) Hydrogenation
To a solution of 730 mg of the compound obtained in Step D of Preparation 1, in 15 cm3 of tetrahydrofuran is added 365 mg of 18% palladium on activated charcoal, stirred for 1 hour 30 minutes, under a hydrogen atmosphere. cm.sup.3 of hydrogen are absorbed) the catalyst is filtered off, rinsed with methylene chloride and evaporated to dryness under reduced pressure to give 730 mg of product.

b) cyclization
The above 730 mg of product are dissolved in 5 cm3 of ethyl acetate and 5 cm3 of isopropanol and a large excess of a solution of hydrochloric acid in ethyl acetate is added. The mixture is heated at 50 ° C. for 5 minutes and left for 30 minutes at room temperature, the solvents are evaporated and the residue is taken up with 3 times 3 cm 3 of ethyl acetate, filtered off and washed with ether to give 640 mg. of the desired product, F = 1600C.

 190 mg of the above product are recrystallized from isopropanol to give 163 mg of the expected product.

 F = 1600C.

Analysis for C28H28N2O4, HCl = 492.99
CH C1 N% calculated 68.21 5.93 7.19 5.68% found 67.8 5.8 7.3 5.5
IR spectrum

Complex absorption type # N # -H 2380 cm-
C = O 1727 and 1721 cm -1
EXAMPLE 4: 2-butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] 1H-benzimidazole-7-carboxylic acid
A solution of 440 mg of the product obtained in Example 3, with 10 cm 3 of ethanol, 1 cm 3 of water and 1 cm 3 of sodium hydroxide solution is stirred under reflux for 1 hour. The ethanol is evaporated, the residue dissolved in water (10 cm3) and acidified to pH 3-4 with acetic acid. After wringing, 360 mg of product F = 160 ° C. is obtained, then 250 ° C., 450 mg of product obtained as above is recrystallized in 15 cm 3 of methanol, 5 drops of acetic acid and 5 cm 3 of water. 370 mg of product F = 255 ° C., which is dissolved in 20 cm 3 of methanol and 10 cm 3 of methylene chloride under reflux, is filtered, the methylene chloride is evaporated off and 1 drop of acetic acid and 5 cm 3 of dichloromethane are added. 'water. After one night at room temperature, the product is filtered off and 330 mg of product is obtained. Mp = 255 C.

0,88 (t) 1,39 (m) 1,76 (m) 2,87 (m) 5,90 (s)
C6H4 6,88 (d,l) 7,23 (d,l) 7 autres H aromatiques 7,20 à 7,90 (m)
H mobiles - 12,95 (m)
PREPARATION 2 : 4'-[N-[[2-nitro 6-[(pentanoyloxy) méthyl] phényl) N-pentanoyl) aminométhyl) biphényle-2-carboxylate de méthyle
STADE A :Alcool 2-amino 3-nitrobenzylique
A une solution de 3,54 g du produit obtenu au stade B de la préparation 1, dans 90 cm3 de tétrahydrofuranne, on ajoute, en 1 heure 30 et à une température comprise entre +7 et +8 C, 50 cm3 d'hydrure de diisobutylaluminium (en solution 1,0 M dans l'hexane). On agite 30 minutes puis ajoute en 15 minutes 40 cm3 de tétrahydrofuranne à 10 % d'eau, agite puis ajoute 10 cm3 d'eau et on agite 30 minutes à température ambiante, on ajoute 350 cm3 de chlorure de méthylène à 10 % de méthanol, agite 15 minutes, filtre et évapore à sec sous pression réduite. Le résidu obtenu, 3,3 g est cristallise dans 10 cm3 d'éther isopropylique. On obtient 2,22 g du produit recherché.Analysis for C26H24N2O4 = 428.47
CHN% calculated 72.88 5.65 6.54% found 73.0 5.6 6.5
IR spectrum (nujol)
General absorption OH / NH region
C = O 1704 cm-
NMR spectrum (DMSO)

0.88 (t) 1.39 (m) 1.76 (m) 2.87 (m) 5.90 (s)
C6H4 6.88 (d, 1) 7.23 (d, 1) 7 other aromatic Hs 7.20 to 7.90 (m)
H mobile - 12.95 (m)
PREPARATION 2: Methyl 4 '- [N - [[2-nitro 6 - [(pentanoyloxy) methyl] phenyl) -N-pentanoyl) aminomethyl) biphenyl-2-carboxylate
STAGE A: 2-amino-3-nitrobenzyl alcohol
To a solution of 3.54 g of the product obtained in Stage B of Preparation 1, in 90 cm 3 of tetrahydrofuran, 50 cm 3 of hydride is added over 1 hour and at a temperature of between +7 and + 8 ° C. of diisobutylaluminum (in 1.0 M solution in hexane). Stirred for 30 minutes and then added in 15 minutes 40 cm3 of 10% tetrahydrofuran water, stirred and then 10 cm3 of water and stirred for 30 minutes at room temperature, 350 cm3 of methylene chloride 10% methanol , stirred for 15 minutes, filtered and evaporated to dryness under reduced pressure. The residue obtained, 3.3 g is crystallized in 10 cm3 of isopropyl ether. 2.22 g of the desired product are obtained.

 F = 110 C.

 An analytical sample was obtained by recrystallizing 170 mg of the above product, hot and cold, in isopropyl ether. 80 mg of pure product is collected. F = 112 C.

Analysis for C7H8N2O3 = 168.15
CHN% calculated 50.00 4.80 16.66% found 49.8 4.8 16.5
IR spectrum (CHC13)
OH 3604 cm -1 = C-NH 2 3498-3390 cm -1
NH2 def 1624 cm- (F)
NO2 1520-1345 cm- complex
Aromatic 1580 cml
STAGE B: 3-nitro pentanoate 2-pentanamido benzyl
1.5 g of the product obtained in Stage A and 15 cm3 of valeroyl chloride are stirred for 6 hours at room temperature. 80 cm3 of gasoline G (40-70 ° C.) are added, the mixture is drained and 2.55 g of the desired product, mp = 82 ° C., are obtained. After recrystallization of 118 mg of the above product in isopropyl ether, it is collected 72 mg of product F = 84 C.

1610 - 1588 - 1538 - 1480 cm-
STADE C : 4'-[N-[[2-nitro 6-[(pentanoyloxy) méthyl] phényl] Npentanoyl] aminométhyl] biphenyle-2-carboxylate de méthyle
A une solution de 1,35 g du produit obtenu au stade B cidessus, dans 13,5 cm3 de dimethylformamide, on ajoute 240 mg d'hydrure de sodium à 50 % dans l'huile, on agite 15 minutes puis on ajoute 1,35 g de 4'-(bromométhyl) biphényle-2-carboxylate de méthyle (préparation selon EP 00253310) on agite 30 minutes à température ambiante, extrait avec 3 fois 50 cm3 de chlorure de méthylène, lave avec de l'eau, sèche, filtre et évapore à sec, sous pression réduite. On chromatographie le résidu (2,7 g) sur silice, (éluant : cyclohexane - acétate d'éthyle 8-2). On obtient 2,05 g du produit recherché utilisé tel quel (Rf 0,20 (cyclohexane-acétate d'éthyle 8-2)).Analysis for C17H24N2O3 = 336.38
CHN% clasped 60.70 7.19 8.33% found 60.7 7.3 8.4
IR spectrum (CHCl 3) = C-NH 3426 cm -1
C = O 1734 and 1702 cm -1
aromatic
NO2 +
Amide II

1610 - 1588 - 1538 - 1480 cm-
STAGE C: methyl 4 '- [N - [[2-nitro 6 - [(pentanoyloxy) methyl] phenyl] Npentanoyl] aminomethyl] biphenyl-2-carboxylate
To a solution of 1.35 g of the product obtained in Stage B above, in 13.5 cm3 of dimethylformamide, 240 mg of 50% sodium hydride in oil are added, the mixture is stirred for 15 minutes and then 1 ml. 35 g of methyl 4 '- (bromomethyl) biphenyl-2-carboxylate (preparation according to EP 00253310) are stirred for 30 minutes at room temperature, extracted with 3 times 50 cm 3 of methylene chloride, washed with water, dried, filter and evaporate to dryness, under reduced pressure. The residue (2.7 g) is chromatographed on silica (eluent: cyclohexane-ethyl acetate 8-2). 2.05 g of the desired product used as such (Rf 0.20 (cyclohexane-ethyl acetate 8-2)) are obtained.

EXAMPLE 5 Methyl 4 '- ((2-butyl 7 - [(pentanoyloxy) methyl) 1H-benzimidazol-1-yl] methyl) biphenyl-2-carboxylate hydrochloride
The procedure is as in Example 3 starting from 2.05 g of the product obtained in Step C of Preparation 2, using 1.025 g of palladium on activated carbon and 20 cm3 of ethyl acetate saturated with hydrochloric acid gas. . 1.8 g of the desired product F-145C are obtained.

 300 mg of the above product are recrystallized from isopropanol. 180 mg of product F = 145 ° C. is collected.

1624 - 1599 - 1568 - 1510 et 1498 cm-
EXEMPLE 6 : Acide 4'-EE2-butyl 7-(hydroxyméthyl) lH-benzimi- dazol-1-yl] méthyl] biphényle-2-carboxylique
On opère comme à l'exemple 4, à partir de 400 mg du produit obtenu à l'exemple 5. On obtient 290 mg de produit recherché (F = 250 C) que l'on recristallise dans l'éthanol aqueux en milieu legèrement acétique, puis dans l'éthanol seul pour recueillir 207 mg du produit attendu F = 250 C.Analysis for C 69 H 36 N 2 O 4, HCl = 549.124
CH C1 N% calculated 69.99 6.79 8.33 5.10% found 69.9 6.9 6.5 5.2
IR spectrum (CHCl3)
Absorptions region NH 2000 - 2800 cm 1
C = O 1726 cm 1 (F) complex
Conjugate system
+
Aromatic

1624 - 1599 - 1568 - 1510 and 1498 cm-
EXAMPLE 6 4'-EE2-butyl 7- (hydroxymethyl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid
The procedure is as in Example 4, starting from 400 mg of the product obtained in Example 5. 290 mg of desired product (mp = 250 ° C.) is obtained which is recrystallized from aqueous ethanol in a slightly acetic medium. then in ethanol alone to collect 207 mg of the expected product F = 250 C.

1598 - 1518 cm-
Spectre de RMN (DMSO) 300 Mhz

0,87 ppm (t) 1,36 ppm (m) 1,73 ppm (m) 1,81 ppm (m)
C6H4-CH2-O
C6H4 les autres aromatiques

4,52 (s) 6,91 (d) 7,28 (d) -7,08 (m) 2H - 7,32 1H -7,54 (m) 2H - 7,70 (d) 1H - 5,50
EXEMPLE 7 : 4'-[[2-butyl 7-(hydroxyméthyl) 1H-benzimidazol-1 yl) méthyl] biphényle-2-carboxylate de méthyle
On agite pendant 30 minutes une solution de 823 mg du produit obtenu à l'exemple 5, dans 8,2 cm d'éthanol et 1,6 cm de soude 2N.On ajoute ensuite 10 cm d'eau, essore et sèche, on obtient 600 mg du produit attendu (F = 138 C) que l'on recristallise dans l'acétate d'éthyle puis l'isopropanol
F = 140 C.Analysis for C26H26N2O3 = 414.51
CHN% calculated 75.34 6.32 6.76% found 75.2 6.3 6.8
IR spectrum (CHCl3)
Absorptions OH / NH - 3480 cm
C = O 1688 cm1
Aromatic
+
heterocyclic

1598 - 1518 cm-
NMR Spectrum (DMSO) 300 Mhz

0.87 ppm (t) 1.36 ppm (m) 1.73 ppm (m) 1.81 ppm (m)
C6H4-CH2-O
C6H4 other aromatics

4.52 (s) 6.91 (d) 7.28 (d) -7.08 (m) 2H-7.32 1H-7.54 (m) 2H-7.70 (d) 1H-5, 50
EXAMPLE 7 Methyl 4 '- [[2-butyl 7- (hydroxymethyl) 1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate
A solution of 823 mg of the product obtained in Example 5 is stirred for 30 minutes in 8.2 cm 3 of ethanol and 1.6 cm of 2N sodium hydroxide. 10 cm 3 of water are then added, the mixture is drained and dried. obtains 600 mg of the expected product (mp = 138 ° C.) which is recrystallized from ethyl acetate and then isopropanol
F = 140 C.

Analysis for C27H28N2O3 = 428.51
CHN% calculated 75.67 6.59 6.54% found 75.8 6.5 6.5
IR spectrum (CHCl3)
OH 3600 cm-
C = O 1722 cm-
EXAMPLE 8 Methyl 4 '- [[2-butyl 7- (chloromethyl) 1H-benzimidazol-1-yl] methyl) biphenyl-2-carboxylate hydrochloride
To a solution of 250 mg of the product obtained in Example 7 in 25 cm3 of methylene chloride is added a solution of 1 cm3 of thionyl chloride in 5 cm3 of methylene chloride and stir 15 minutes. It is evaporated to dryness and the residue is crystallized with a mixture of ethyl acetate and ether.

250 mg of desired product is obtained. F = 150C

Analysis for C27H28Cl2N2O2 = 483.43
CH C1 N% calculated 67.08 5.84 14.66 5.80% found 67.0 5.9 14.4 5.9
IR spectrum (CHCl3)
C = O 1724 cm
EXAMPLE 9 4 '- [[2-butyl 7- (chloromethyl) 1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid
350 mg of the product obtained in Example 6 are stirred in 5 cm3 of thionyl chloride for 2 hours at room temperature. Evaporate, add about 5 g of ice then 20 cm3 of water and stir overnight at room temperature. The water is decanted, taken up in 30 cm3 of methylene chloride, dried, filtered and evaporated to dryness under reduced pressure.

 360 mg of the expected product is obtained in the form of an oil.

TLC Rf = 0.40 (methylene chloride-methanol (9-1)).

PREPARATION 3: Methyl 4 '- (N-E2-nitro 6 - [(2-pentanoyloxy) ethyl phenyl) N-pentanoyl) aminomethyl) biphenyl-2-carboxylate
STAGE A: 2- (2-Pentanamido phenyl) ethyl pentanoate
The procedure is as in Stage B of Preparation 2 from 5 cm3 of 2-amino phenethyl alcohol. We obtain 10.06 g of expected product F = 59 C. An analytical sample was prepared by 2 successive recrystallizations in gasoline G on 1.1 g of product, 610 mg of purified product is obtained.

F = 62C.

Analysis for C18H27NO3 = 305.42
CHN% calculated 70.79 8.91 4.59% found 70.9 9.2 4.6
IR spectrum (CHCl @) # -NH

1720 cm-
STADE B : Pentanoate de 2-(3-nitro 2-pentanamido phényl) éthyle
On ajoute à une température comprise entre 0 et +10 C, 7,1 cm3 d'acide acétique, à une solution de 9,1 g du produit obtenu au stade A, ci-dessus, dans 50 cm3 d'anhydride acétique. On agite pendant 2 heures entre 0 et 10 C. On ajoute 150 cm d'eau, essore, lave à l'eau. On obtient 9,90 g de produit que l'on chromatographie sur silice (éluant : acétate d'éthyle - cyclohexane 30-70), on obtient 5,89 g de produit recherché.<tb> 3360 <SEP> cm-
<tb><SEP> 3430 <SEP> cm-
<tb># -O 1684 cm
Amide II 1530 cm-

1720 cm-
STAGE B: 2- (3-nitro-2-pentanamido-phenyl) ethyl pentanoate
A solution of 9.1 g of the product obtained in Step A, above, in 50 cm3 of acetic anhydride is added at a temperature of between 0 and +10 C, 7.1 cm3 of acetic acid. It is stirred for 2 hours between 0 and 10 C. 150 cm 3 of water are added, drained, washed with water. 9.90 g of product are obtained, which is chromatographed on silica (eluent: ethyl acetate-cyclohexane 30-70) to give 5.89 g of the desired product.

 F = 117 C.

 859 mg of the above product is recrystallized from isopropyl ether and then from ether, 494 mg of the expected product are collected. F = 120 C.

Analysis for C18H26N2O5 = 350.42
CHN% calculated 61.7 7.48 7.99% found 61.5 7.5 7.9
IR spectrum

<Tb>

<SEP> - # - NH <SEP> 3330 <SEP><SEP> cm-
<tb> 3420 <SEP> cm-
<tb> C = O <SEP> 1735 <SEP> cm-
<tb><SEP> 1700 <SEP> cm-
<tb> Aromatic <SEP> 1605 <SEP> cm-
<tb><SEP> + <SEP> Amide <SEP> II <SEP> 1583 <SEP> cm-
<tb><SEP> + <SEP><SEP> band <SEP> NO2 <SEP> 1535 <SEP> cm-
<tb><SEP> 1478 <SEP> cm- <SEP> (complex)
<tb> 2nd <SEP> Tape <SEP> NOn <SEP> 1348 <SEP> cm- <SEP>
<Tb>
STAGE C: 4 '- [N - [[2-nitro 6 - [(2-pentanoyloxy) ethyl] phenyl]
Methyl N-pentanoyl] aminomethyl] biphenyl-2-carboxylate
The procedure is as in Stage C of Preparation 2 starting from 3.5 g of the product obtained in Stage B above, using 480 mg of 50% sodium hydride in oil and 3.05 g of 4 g. Methyl - (bromomethyl) biphenyl-2-carboxylate (preparation EP 0253310). After chromatography on silica (eluent ethyl acetate - cyclohexane 3-7), 5.19 g of the desired product is obtained.

IR spectrum (CHCl3) (PE 580) sc = o

<tb> 1728 <SEP> cm-
<tb> 1666 <SEP> cm-
<Tb>

<tb><SEP> vo
<tb> CH3 <SEP> of <SEP> -C
<tb><SEP> ȮCH3
<tb> 1438 cm
NO2 1534 cm- @
EXAMPLE 10 Methyl 4 '- [[2-butyl 7- [2- (pentanoyloxy) ethyl] 1H-benzimidazol-1-ylmethyl) biphenyl-2-carboxylate
The procedure is as in Example 3 from 3.38 g of the product obtained in Step C of Preparation 3, using 1.03 g of catalyst. After chromatography on silica (eluent: ethyl acetate - cyclohexane (3-7)), 2.42 g of the desired product are obtained.

IR spectrum (CHCl3) C = O
Conjugate System + Aromatic

<tb><SEP> 1724 <SEP> cm- <SEP> (F)
<tb> 1599 <SEP> cm-
<tb><SEP> 1520 <SEP> cm-
<Tb>
EXAMPLE 11 Methyl 4 '- ((2-butyl 7- (2-hydroxyethyl) 1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate
2.42 g of the product obtained in Example 10 are stirred for 30 minutes at room temperature, with 20 cm of methanol and 5.5 cm of 1N sodium hydroxide. The methanol extracted is evaporated with methylene chloride, washed with water and evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate to give 1.59 g of the desired product. Mp = 139 C.

 An analytical sample was prepared by recrystallization of 110 mg of the above product, in ethyl acetate 79 mg of product is collected. Mp = 139 C.

Analysis for C23H30N2O3 = 442.56
CHN% calculated 75.99 6.83 6.33 9s found 75.8 6.8 6.2
IR spectrum (CHCl3)

<tb> OH <SEP> - <SEP> 3615 <SEP> cm-
<tb> + <SEP> Associates <SEP> 3550 <SEP> cm-
<Tb>
# = O 1720 cm
EXAMPLE 12: 4'-tert-butyl-7- (2-hydroxyethyl-1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid
The procedure is as in Example 4 starting from 400 mg of the product obtained in Example 11. 371 mg of the expected product F = 174 ° C. is obtained. The product is recrystallized twice in ethanol, 96 mg of the product is recovered. sought product. Mp = 175 C.

Analysis for C27H28N2O3, 1/2 C2H5OH = 451.574
CHN% calculated 74.48 6.92 6.20% found 74.15 6.2 6.2
IR spectrum

Absorption region OH / NH # = O 1680 cm-

0,87 (t) 1,37 (m) 1,73 (m) 2,80 (t) 2,88 (t) 3,62 (t)
N-CH2-C6H5
C6H4 les autres H aromatiques

5,71 (s) 6,92 (d) 7,29 (d) 6,96 (d) 1H - 7,10 (t) 1H 7,34 (d) 1H - 7,40 à 7,60 3H 7,70 (dd) 1H
H mobile 4,2 à 5,0
EXEMPLE 13 : Chlorhydrate de 4'-[[2-butyl 7-(2-chloro éthyle 1H-benzimidazol-1-yl] méthyl) biphényle-2-carboxylate de méthyle
On agite pendant 45 minutes à 80 C un mélange de 714 mg du produit obtenu à l'exemple 11 avec 14 cm3 de chlorure de thionyle.Après évaporation du chlorure de thionyle, le mélange est repris avec 3 fois 20 cm3 de chlorure de méthylène et évaporé à sec à chaque fois. L'extrait sec final est cristallisé dans l'acétate d'éthyle. On obtient 733 mg de produit recherché F = 151 C. Un échantillon microanalytique a été obtenu par deux recristallisations successives dans le mélange éther-acétate d'éthyle (1-1). On obtient le produit purifié.<tb> System <SEP> Conjugate <SEP> 1592 <SEP> cml <SEP>
<tb> + <SEP> Aromatic <SEP> 1512 <SEP> cm <SEP> 1
<Tb>
NMR Spectrum (DMSO) 250 Mhz
Presence of about 0.4 moles of ethanol

0.87 (t) 1.37 (m) 1.73 (m) 2.80 (t) 2.88 (t) 3.62 (t)
N-CH2-C6H5
C6H4 other aromatic H

5.71 (s) 6.92 (d) 7.29 (d) 6.96 (d) 1H - 7.10 (t) 1H 7.34 (d) 1H - 7.40 to 7.60 3H 7 , 70 (dd) 1H
H mobile 4.2 to 5.0
EXAMPLE 13 Hydrochloride of methyl 4 '- [[2-butyl 7- (2-chloroethyl 1H-benzimidazol-1-yl) methyl) biphenyl-2-carboxylate
A mixture of 714 mg of the product obtained in Example 11 with 14 cm3 of thionyl chloride is stirred for 45 minutes at 80 ° C. After evaporation of the thionyl chloride, the mixture is taken up with 3 times 20 cm 3 of methylene chloride and evaporated dry each time. The final dry extract is crystallized in ethyl acetate. 733 mg of desired product F = 151 ° C. is obtained. A microanalytical sample was obtained by two successive recrystallizations in the ether-ethyl acetate mixture (1-1). The purified product is obtained.

 F = 1600C.

Analysis for C28H30N2O2Cl2 = 497.47
CHN C1% calculated 67.60 6.08 5.63 14.25% found 67.5 6.08 5.6 14.2
IR CHCl3 spectrum
Absorption type - NH

1725 cm- 1434 cm-
Aromatique
Hétéro aromatique

1624 - 1600 - 1565 cm- 1512 - 1496 cm'l
EXEMPLE 14 : Acide 4'-((2-butyl 7-(2-chloro éthyl) lH-benzimidazol-1-yl] méthyl] biphényle-2-carboxylique
On introduit sous agitation à la température ambiante 500 mg du produit obtenu à l'exemple 13 dans 35 ml d'acide chlorhydrique à 36 %. On met à reflux pendant 2 heures et demie, puis évapore.

1725 cm - 1434 cm
Aromatic
Aromatic hetero

1624 - 1600 - 1565 cm - 1512 - 1496 cm-1
EXAMPLE 14 4 '- ((2-Butyl 7- (2-chloroethyl) 1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid
500 mg of the product obtained in Example 13 in 35 ml of 36% hydrochloric acid are introduced with stirring at ambient temperature. It is refluxed for 2 hours and then evaporated.

 It is chromatographed on silica (eluent: methylene chloride methylene (1-9)) and obtains 479 mg of product which is dissolved in 60 ml of a 50/50 mixture of water and methanol brought to pH-10 with sodium hydroxide then neutralized to pH - 5 with acetic acid. The methanol is evaporated, drained, washed with ether and dried under reduced pressure at about 100 ° C. 310 mg of desired product is obtained. Mp = 226 C.

 It is recrystallized three times in methanol and 112 mg of expected product is obtained. Mp = 233 C.

0,90 (t) 1,39 (m) 1,77 (m) 2,85 (t) 3,18 (t) 3,64 (t)
N-CH2 -C6H5
C6H4 autres aromatiques

5,64 (s) 6,92 (d) 7,29 (d) 7,05 (d) 1H - 7,13 (t) 1H - 7,33 (d) 1H - 7,40 à 7,60 3H 7,70 (dd) 1H
EXEMPLE 15 : Chlorhydrate de 4'-[[2-butyl 7-formyl lH-benzimi- dazol-1-yl) méthyl) biphényle-2-carboxylate de méthyle
On dissout 600 mg du produit obtenu à l'exemple 7, dans 60 cm3 de chlorure de méthylène et ajoute 1,2 g de dioxyde de manganèse activé. On agite 24 heures à la température ambiante, filtre et évapore à sec sous pression réduite, on obtient 600 mg du produit attendu sous forme de base.IR spectrum in NUJOL
# = O 1698 cm-
Aromatic 1597 cm-
Heteroaromatic 1518 cm-
NMR Spectrum (DMSO) 250 Mhz

0.90 (t) 1.39 (m) 1.77 (m) 2.85 (t) 3.18 (t) 3.64 (t)
N-CH2 -C6H5
C6H4 other aromatics

5.64 (s) 6.92 (d) 7.29 (d) 7.05 (d) 1H - 7.13 (t) 1H - 7.33 (d) 1H - 7.40 to 7.60 3H 7.70 (dd) 1H
EXAMPLE 15 Hydrochloride of methyl 4 '- [[2-butyl-7-formyl-1H-benzimidazol-1-yl) methyl) biphenyl-2-carboxylate
600 mg of the product obtained in Example 7 are dissolved in 60 cm 3 of methylene chloride and 1.2 g of activated manganese dioxide are added. It is stirred for 24 hours at room temperature, filtered and evaporated to dryness under reduced pressure to give 600 mg of the expected product in base form.

Preparation of the hydrochloride
600 mg of the product obtained above is dissolved in ethyl acetate (3 cc) and a mixture of ethyl acetate and hydrochloric acid is added in excess.

 The mixture is filtered off, washed with ether and dried at 80 ° C. under reduced pressure.

 610 mg of the expected hydrochloride are obtained. F = 145C

IR spectrum in CHCl3
C = O 1723-1706 cm-
Aromatic 1618 - 1599 - 1563 - 1520 cm-
Heterocycles 1498 cm-
EXAMPLE 16 4 '- ((2-Butyl-7-formyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid
600 mg of the product obtained in Example 15 are dissolved in 6 cm 3 of ethanol, 0.8 cm 3 of water and 0.8 cm 3 of sodium hydroxide solution and the mixture is stirred for 2 hours at 50 ° C. cm3 of water and acetic acid to pH = 4-5.

 It is stirred for 30 minutes at room temperature, drained, washed with water and dried at 90 ° C. under reduced pressure to give 470 mg of product, mp = 225.degree.

 The product obtained above is dissolved in 30 cm3 of methanol at reflux, filtered, concentrated and allowed to crystallize at room temperature. It is filtered, washed with methanol and dried at 90 ° C. under reduced pressure. 360 mg of the expected product is obtained. F = 230 C.

0,88 (t) 1,38 (m) 1,75 (m) 2,88 (m) 6,05 (sl)
C6H4 les autres aromatiques

6,93 (d) 7,25 (d) 7,31 (d) 1H - 7,42 (m) 2H 7,53 (td) 1H - 7,69 (d) 1H 7,83 (d) 1H - 8,0 (d) 1H
Protons mobiles 10,08 et 12,75
EXEMPLE 17 : Dichlorhydrate de l'acide 4'-((2-butyl 7-t(dimé- thylamino) méthyl] 1H-benzimidazol-1-yl] méthyl] biphényle-2carboxylique
On dissout 360 mg du produit obtenu à l'exemple 9, dans 10 cm3 de diméthylamine à 33 % dans 1'éthanol et agite 19 heures à température ambiante.On évapore, extrait avec 3 fois 20 cm3 de chlorure de méthylène, lave avec 2 fois 15 cm3 d'eau salée, sèche, filtre et évapore sous pression réduite.Analysis for C26H24N2O3 = 412.47
CHN% calculated 75.7 5.87 6.79% found 75.5 5.8 6.7
IR spectrum in Nujol
C = O 1690 cm -1
Aromatic 1600 - 1580 cm 1
Heterocycle 1516 cm 1
NMR Spectrum (DMSO) 300 Mhz

0.88 (t) 1.38 (m) 1.75 (m) 2.88 (m) 6.05 (sl)
C6H4 other aromatics

6.93 (d) 7.25 (d) 7.31 (d) 1H - 7.42 (m) 2H 7.53 (td) 1H - 7.69 (d) 1H 7.83 (d) 1H - 8.0 (d) 1H
Mobile Protons 10.08 and 12.75
EXAMPLE 17: 4 '- ((2-Butyl 7-t (dimethylamino) methyl] 1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid dihydrochloride
360 mg of the product obtained in Example 9 is dissolved in 10 cm 3 of 33% dimethylamine in ethanol and stirred 19 hours at room temperature. Evaporated, extracted with 3 times 20 cm 3 of methylene chloride, washed with 2 ml 15 cm3 of salt water, dry, filter and evaporate under reduced pressure.

300 mg of the expected product is obtained in base form.

Preparation of dichlorhydrate
The procedure is as in Example 15, by dissolving 300 mg of the product obtained above in 5 cm3 of isopropanol in the presence of an excess of ethyl acetate and hydrochloric acid.

 We obtain 110 mg of the expected product. Mp = 260 C.

0,92 ppm (t) 1,44 (m) 1,83 (m) 3,24 (m) 4,38 (m) 5,98 (sl)
C6H4 les autres aromatiques

7,20 (d) 7,34 (d) 7,56 (d) 1H - 7,88 (d) 1H 7,75 (d) 1H - 7,55 (m) 2H 7,47 (t) 1H - - 7,37 masqué 1H
Protons mobiles 11,39 et 12,78
EXEMPLE 18 :Chlorhydrate de (2-butyl 1-[2'-(méthoxycarbonyl) biphényl-4-yl) méthyl) lH-benzimidazol-7-acétate de méthyle a) Préparation de l'acide r2-butvl l-r2'-(méthoxvcarbonvl biphényl-4-yl] méthyl] 1H-benzimidazol-7-acétique
On introduit 1 g du produit obtenu à l'exemple 11, dans 10 cm3 d'acétone et 1,5 cm3 de réactif de BOWERS. On agite 1 heure à température ambiante. On filtre, rince au chlorure de méthylène, évapore et reprend par 50 cm3 d'eau et 50 cm3 de méthanol, amène le pH à 12 avec de la soude 1N, puis acidifie à pH = 4-5 avec de l'acide acétique. On évapore, extrait par 3 fois 100 cm3 de chlorure de méthylène, lave par 2 fois 40 cm3 d'eau, sèche, filtre et évapore à sec.Analysis for C28H31N3O2, 2HCl = 514.47
CH C1 N% calculated 65.36 6.46 13.78 8.17% found 65.3 6.5 13.8 8.0
IR spectrum in Nujol
C = O 1770 - 1680 cm -1
Aromatic 1623 - 1597 cm
Heterocycles 1514 - 1495 cm-
NMR Spectrum (DMSO) 300 Mhz

0.92 ppm (t) 1.44 (m) 1.83 (m) 3.24 (m) 4.38 (m) 5.98 (sl)
C6H4 other aromatics

7.20 (d) 7.34 (d) 7.56 (d) 1H - 7.88 (d) 1H 7.75 (d) 1H - 7.55 (m) 2H 7.47 (t) 1H - - 7.37 masked 1H
Protons mobile 11,39 and 12,78
EXAMPLE 18: Methyl (2-butyl 1- [2 '- (methoxycarbonyl) biphenyl-4-yl) methyl] -1H-benzimidazol-7-acetate hydrochloride a) Preparation of r2-butyl-1-r2'-acid (Methoxycarbonyl biphenyl-4-yl) methyl] 1H-benzimidazol-7-acetic acid
1 g of the product obtained in Example 11, in 10 cm3 of acetone and 1.5 cm3 of BOWERS reagent are introduced. Stir 1 hour at room temperature. It is filtered, rinsed with methylene chloride, evaporated and taken up in 50 cm3 of water and 50 cm3 of methanol, the pH is brought to 12 with 1N sodium hydroxide and then acidified to pH = 4-5 with acetic acid. Evaporated, extracted with 3 times 100 cm3 of methylene chloride, washed with twice 40 cm3 of water, dried, filtered and evaporated to dryness.

 1.07 g of the expected product is obtained.

b) Preparation of [2-butyl 1- [2- (methoxycarbonyl) biphenyl-4-methyl-1H-benzimidazol-7-methyl acetate
The product obtained above is dissolved in 10 cm3 of methylene chloride, then esterified with about 10 cm3 of diazomethane in methylene chloride, evaporated to dryness and 968 mg of product are collected and chromatographed on silica (eluent: ethyl acetate-flugene (7-3)).

745 mg of the expected product is obtained in base form.

c) Preparation of the hydrochloride
The procedure is as in Example 15, starting from 303 mg of the product obtained above, in a mixture of ethyl acetate and hydrochloric acid.

280 mg of the expected hydrochloride are obtained. F = 128 C.

1438 cm- (F)
Aromatiques
Hétéroaromatiques

1623 - 1599 cm- 1565 - 1512 - 1500 cm-
EXEMPLE 19 : Acide 2-butyl l-( < 2'-carboxy biphényl-4-yl) méthyl] 1H-benzimidazol-7-acétique
On introduit à température ambiante 745 mg du produit obtenu à l'exemple 18, dans 8 cm3 d'éthanol et 1,6 cm3 de soude à 32 % et agite 1 heure au reflux de l'éthanol. On évapore, reprend dans 10 cm3 d'eau acidifie à pH = 5 avec de l'acide acétique, essore, lave à l'eau et sèche sous pression réduite à 80 C. On obtient 516 mg de produit attendu.IR spectrum in chloroform
Absorption type # N # -H # 2500 cm- 1725 - 1714 cm-

1438 cm- (F)
aromatic
heteroaromatic

1623 - 1599 cm - 1565 - 1512 - 1500 cm-
EXAMPLE 19 2-Butyl 1- (2'-carboxybiphenyl-4-yl) methyl] 1H-benzimidazol-7-acetic acid
745 mg of the product obtained in Example 18, in 8 cm3 of ethanol and 1.6 cm3 of 32% sodium hydroxide are introduced at ambient temperature and the mixture is stirred for 1 hour under reflux of the ethanol. Evaporated, taken up in 10 cm3 of acidified water at pH = 5 with acetic acid, filtered, washed with water and dried under reduced pressure at 80 C. 516 mg of expected product is obtained.

Mp = 161 ° C. Recrystallize from isopropanol and then methyl ethyl ketone. 184 mg of expected product is obtained.

F = 220 C.

0,88 (t) 1,38 (m) 1,75 (m) 2,33 (t) 3,62 (s) 5,65 (s)
6,90 (d)
C6H4 7,29 (d) les autres aromatiques

6,39 (d) 1H - 7,13 (t) 1H 7,34 (d) 2H - 7,43 (dd) 2H 7,54 (m) 2H - 7,71 (dd) 1H
H mobile 12,75
EXEMPLE 20 : Acide 4'-[[2-butyl 7-éthényl 1H-benzimidazol1-yl] méthyl] biphényle-2-carboxylique
On introduit à température ambiante 300 mg du produit de l'exemple 13, dans 3 cm3 de méthanol, 0,6 cm3 d'eau et 0,6 cm3 de soude à 32 %.Analysis for C27H26N2O4 = 442.52
CHN% calculated 73.29 5.92 6.33% found 73.3 5.9 6.3
Nujol IR Spectrum
OH / NH Very associated general absorption
C = O 1712 cm
NMR Spectrum (DMSO) 300 Mhz

0.88 (t) 1.38 (m) 1.75 (m) 2.33 (t) 3.62 (s) 5.65 (s)
6.90 (d)
C6H4 7.29 (d) other aromatics

6.39 (d) 1H - 7.13 (t) 1H 7.34 (d) 2H - 7.43 (dd) 2H 7.54 (m) 2H - 7.71 (dd) 1H
H mobile 12.75
EXAMPLE 20 4 '- [[2-butyl-7-ethenyl-1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid
300 mg of the product of Example 13, in 3 cm 3 of methanol, 0.6 cm 3 of water and 0.6 cm 3 of 32% sodium hydroxide are introduced at ambient temperature.

 The mixture is stirred for 1 hour under reflux. The methanol is evaporated, water (5 cc) is added, neutralized to pH = 5-6 with acetic acid, drained, washed with water and dried at 100 ° C. under reduced pressure. 228 mg of expected product are obtained. Mp = 228 C.

 474 mg of product obtained as above is recrystallized from methylethylketone and then from isopropanol, 278 mg of desired product is collected. Mp = 238 C.

6,97 (d) 7,31 (d) 7,10 à 7,25 (m) 2H - 7,31 (m) 1H 7,42 (td) 1H - 7,57 (m) 2H 7,63 (dd) 1H
H mobiles 12,77 ( < 1H)
EXEMPLE 21 : 4'-[2-butyl 7-(2-diméthylamino) éthyl] lH-benzi- midazol-l-yl] méthyl] biphényle-2-carboxylate de méthyle
On introduit sous agitation à température ambiante 1,05 g de produit obtenu à l'exemple 13, dans 25 cm3 de diméthylamine à 33 % dans l'éthanol.Analysis for C27H26N2O2 = 410.52
CHN% calculated 79.00 6.38 6.82% found 79.2 6.5 6.9
Nujol IR Spectrum
OH / NH Very associated general absorption 1678 cm-
1599 cm conjugate system
+ 1589 cm'l
Aromatic 1514 cm 1
NMR Spectrum (DMSO) 300 Mhz
CH3 0.87 (t)
CH2 1.37 (m)
CH2 1.72 (m)
CH2-C 2.81 (t) CH2 = C-C6H5 5.27 (dd, J = 1.5 and 11)
H, 5.62 (dd, J = 1.5 and 17)
CH2-CH-C6H5 7.08 (dd, J = 11 and 17) N-CH2-C6H5- 5.64
C6H4 other aromatic H

6.97 (d) 7.31 (d) 7.10 to 7.25 (m) 2H - 7.31 (m) 1H 7.42 (td) 1H - 7.57 (m) 2H 7.63 (m) dd) 1H
H mobile 12.77 (<1H)
EXAMPLE 21 Methyl 4 '- [2-butyl 7- (2-dimethylamino) ethyl] -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylate
1.05 g of product obtained in Example 13 in 25 cm3 of 33% dimethylamine in ethanol are introduced with stirring at ambient temperature.

 It is kept at 80 ° C. for 16 hours. It is evaporated under reduced pressure at 60 ° C., extracted with methylene chloride (3 × 60 cc), washed with water (3 × 20 cc), dried and evaporated to dryness.

 After chromatography on silica (eluent: methylene methanolchloride (1-9)), 789 mg of the expected product are obtained. TLC: Rf 0.37 (eluent: methylene chloride methanol (9-1)).

EXAMPLE 22: 4 '- ((2-Butyl 7- (2- (dimethylamino) ethyl] 1H-benzimidazol-1-yl] methyl biphenyl-2-carboxylic acid dihydrochloride
789 mg of the product obtained in Example 21, in 15 cm3 of ethanol and 1.3 cm3 of 32% sodium hydroxide are introduced at ambient temperature.

 The mixture is stirred for 1 hour at 85 ° C. It is evaporated, taken up with water (10 cc) and acidified to pH = 5 with acetic acid. The mixture is extracted 3 times with 60 cm 3 of methylene chloride, washed twice with 10 cm 3 of water, dried, filtered and evaporated to dryness.

 Is dissolved in 5 cm3 of methyl ethyl ketone, add 5 cm3 of a mixture of ethyl acetate and hydrochloric acid and allowed to crystallize at room temperature, then filtered, washed with methyl ethyl ketone and dried at 60 C under reduced pressure. Recrystallized from acetonitrile to give 429 mg of the expected product. M.p. 218 C.

1708 cm- 1690 cm- 1625 cm-1 1598 cm- 1569 cm- 1510 cm-
Spectre RMN (DMSO) 250 Mhz

Analysis for C29H33N302, 2HCl
CH C1 N% calculated 65.9 6.67 13.42 7.95% found 65.7 6.6 13.1 8.2
Nujol IR Spectrum
OH / NH Very associated general absorption # = O
Aromatic
+
heteroaromatic

1708 cm- 1690 cm- 1625 cm-1 1598 cm- 1569 cm- 1510 cm-
NMR Spectrum (DMSO) 250 Mhz

<tb> C1H3 <SEP> 0.91 <SEP> (t)
<tb> CH2 <SEP> 1.42 <SEP> (m)
<tb> C1H2 <SEP> 1.82 <SEP> (m)
<tb> CH2-C1
<tb> C6H5-CH2 <SEP> CH2 <SEP> f <SEP> 3.09 <SEP> (m) <SEP> 2H
<tb> and <SEP> = C-CH2-CH2 <SEP> 1 <SEP> 3.26 <SEP> (m) <SEP> 4H
<tb> N-CH2-C6H5 6.04 (sl)

<tb> C6H4 <SEP> 7.23 <SEP> (d) <SEP> 2H
<tb><SEP> 7.34 <SEP> (d) <SEP> 2H
<tb><SEP> 7.80 <SEP> (d) <SEP> 1H <SEP> - <SEP> 7.74 <SEP> (d) <SEP> 1H
<tb> the <SEP> other <SEP> H <SEP> aromatic <SEP> 7,56 <SEP> (m) <SEP> 2H <SEP> - <SEP> 7,44 <SEP> (m) <SEP > 2H <SEP>
<tb><SEP> 7.30 <SEP> (hidden) <SEP> 1H
<tb> N-CH3 2.65 (sl)
H mobile 11.38
EXAMPLE 23: Methyl 2-butyl 1- [2'-cyano- (1,1'-biphenyl) -4-yl) methyl] 1H-benzimidazole-7-carboxylate hydrochloride
STAGE A: Methyl 3-amino-2-pentanamido benzoate
560 mg of the product obtained in Stage C of Preparation 1 are dissolved in 12 cm 3 of tetrahydrofuran, 280 mg of 18% palladium on active charcoal are added and the reaction medium is hydrogenated for 30 minutes (absorption of 160 cm 3 of hydrogen). It is stirred for a further 10 minutes, filtered, the solvent is evaporated off under reduced pressure, the residue is taken up in isopropyl ether, filtered and dried at 80 ° C. under reduced pressure.

450 mg of crude product is recovered which is recrystallized from isopropyl ether. F = 90 C.

Analysis for C13H18N2O3, 250.29
CHN% calculated 62.38 7.25 11.19% found 62.4 7.4 11.1
IR spectrum (CHCl 3) = C-NH 3420 cm-3340 cm -1
C = O 1698 cm- Max.

 1680 cm- Epaul.

Aromatic NH2 def.

1620, 1601, 1580, 1514 cm 1
STADE B : 4'-[N-[[2-(méthoxycarbony) 6-aminophényl] n-pentanoyl] aminométhyl biphényl 2-carboxylate de méthyle
A une solution de 250 mg de produit obtenu au stade A cidessus, dans 2 cm3 de diméthylformamide, on ajoute 52 mg d'hydrure de sodium à 50 % dans l'huile, agite 15 minutes puis ajoute 300 mg de 4'-(bromométhyl) biphényle-2-nitrile et agite 15 minutes à température ambiante. On évapore le solvant, ajoute 60 cm3 d'eau, extrait au chlorure de méthylène, lave à l'eau, sèche et évapore à sec sous pression réduite. On recueille 600 mg de produit attendu brut que l'on chromatographie sur silice (éluant flugène-acétate d'éthyle (7-3)) puis cristallise dans l'éther isopropylique puis dans l'éther éthylique.Amide II

1620, 1601, 1580, 1514 cm 1
STAGE B: Methyl 4 '- [N - [[2- (methoxycarbonyl) 6-aminophenyl] n-pentanoyl] aminomethylbiphenyl 2-carboxylate
To a solution of 250 mg of the product obtained in Stage A above, in 2 cm 3 of dimethylformamide, 52 mg of 50% sodium hydride in oil are added, the mixture is stirred for 15 minutes and then 300 mg of 4 '- (bromomethyl) are added. ) biphenyl-2-nitrile and stirred for 15 minutes at room temperature. The solvent is evaporated, 60 cm3 of water are added, the mixture is extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. 600 mg of crude expected product is collected which is chromatographed on silica (eluent flugene-ethyl acetate (7-3)) and crystallizes in isopropyl ether and then in ethyl ether.

 125 mg of expected product is obtained. F = 80 C then 145 C.

Analysis for C27H27N303 441.51
CHN% calculated 73.45 6.16 9.52% found 73.4 6.2 9.2
IR spectrum (CHCl 3) = C-NH 2 3496CM-3395cm-C = N 2226cm-C = O 1722- 1656 cm -1

<tb> Aromatic <SEP> 1613 <SEP> cm- <SEP> 1597 <SEP> cm-
<tb> NH2 <SEP> def. <SEP> 1588 <SEP> cm- <SEP> 1515 <SEP> cm-
<Tb>
STAGE C: Methyl 2-butyl 1- [2'-cyano- (1,1'-biphenyl) -4-yl) methyl] 1H-benzimidazol-7-carboxylate hydrochloride
730 mg of the product obtained, as in Stage B, are dissolved in 10 cm 3 of a solution of hydrochloric acid in ethyl acetate and stirred for 10 minutes at 50 ° C. The solvent is evaporated off, the residue is taken up in a methyl ethyl ketone mixture /ether. It is filtered off and dried at 80 ° C. under reduced pressure. 715 mg of crude product is obtained which is recrystallized from ethyl acetate and then from methyl ethyl ketone / ether. 270 mg of expected product is collected. F = 140 C.

Analysis for C27H25N3O2, HC1 459.96
CHN C1% calculated 70.50 5.70 9.14 7.71% found 70.6 5.8 9.2 7.8
IR (CHCl 3) -CO 2 CH 3 spectrum 1723 cm -1 1436 cm -1 2226 cm -1
Complex absorptions max. around 2450 cm- of type -N &commat; -H

<tb> Aromatic <SEP> 1620 <SEP> cm- <SEP> 1598 <SEP> cm-
<tb> Heteroaromatic <SEP> 1564 <SEP> cm- <SEP> 1496 <SEP> cm-
<Tb>
EXAMPLE 24: Methyl 2-butyl 1- [2 '- (1H-tetrazol-5-yl) (1,1'-biphenyl) -4-yl) methyl) -1H-benzimidazole-7-carboxylate a) 10 cm3 is added from a saturated aqueous solution of sodium bicarbonate to a suspension comprising 650 mg of the hydrochloride prepared in Example 23, in 50 cm3 of water, stirred for 10 minutes, extracted with methylene chloride at 2% methanol, washed with water. water, dries and removes the solvents under reduced pressure. 600 mg of base are collected.

b) 600 mg of the above product is dissolved in 6 cm3 of xylene and 511 mg of trimethyltin azide is added. Stirred 23 hours at 115-120 ° C, added 205 mg of additional azide and continued heating for 24 hours. The xylene is evaporated, 30 cm3 of water are added, the mixture is stirred for 15 minutes, 10 cm3 of methanol are added, the mixture is extracted with methylene chloride, dried and evaporated to dryness under reduced pressure.

 1 g of crude product is obtained which is chromatographed on silica (eluent: methylene chloride-methanol (9-1)) and then crystallizes the residue in ether. 470 mg of expected product is obtained. F = 165 C.

EXAMPLE 25 2-Butyl-1 - ((2 R- (1H-tetrazol-5-yl) (1,1'-biphenyl) -4-yl) methyl) -1H-benzimidazole-7-carboxylic acid
470 mg of product obtained in Example 24, dissolved in 12 cm 3 of ethanol in the presence of 3 cm 3 of N sodium hydroxide, is evaporated for 2 hours under reflux, the ethanol is evaporated, 10 cm 3 of water added and then dropwise. 0.8 cm3 of acetic acid. The mixture is stirred for 2 hours at room temperature, drained, washed with water and dried at 80 ° C. under reduced pressure. 420 mg of crude product is collected which is dissolved in 10 cm 3 of methanol-methyl ethyl ketone mixture (1-1), filtered, concentrated to 5 cm 3, added 1 drop of acetic acid and then 5 cm 3 of water, crystallization starts , left at +4 ° C. for 16 hours, drained, washed with water and dried at 90 ° C. under reduced pressure. After recrystallization from ethyl acetate, 310 mg of expected product is obtained.

F # 210-220 C.

Analysis for C26H24N6O2, 452.50
CHN% calculated 69.01 5.35 18.57% found 68.7 5.3 18.3
IR spectrum

Absorption complex OH / NH region
C = O 1700 cm -1

<tb> Aromatic <SEP> 1609 <SEP> cm- <SEP> 1598 <SEP> cm-
<tb> Heteroaromatic <SEP> 1515 <SEP> cm- <SEP> 1488 <SEP> cm-
<Tb>
EXAMPLE 26 Pharmaceutical Composition
Tablets having the following formula were prepared
Product of Example 2 ........................... 10 mg
Excipient for a tablet finished at ....... 100 mg (detail of the excipient: lactose, talc, starch, magnesium stearate).

EXAMPLE 27 Pharmaceutical Composition
Tablets having the following formula were prepared
Product of Example 25 .......................... 10 mg
Excipient for a tablet finished at ....... 100 mg (detail of the excipient: lactose, talc, starch, magnesium stearate).

PHARMOMACOLOGICAL RESULTS 1 - Angiotensin II receptor assay
A fresh membrane preparation obtained from rat liver is used. The tissue is ground with polytron in 50 mM Tris buffer pH 7.4, followed by 3 centrifugations at 30,000 g with intermediate pellets in Tris buffer pH 7.4.

 The last pellets are resuspended in incubation buffer (20 mM Tris, 135 mM NaCl, 10 mM KCl, 5 mM glucose, 10 mM MgCl 2, 0.3 mM phenyl methyl sulfonyl fluoride, 0.1 mM bacitracin, bis (trimethylsilyl) acetamide 0.2%).

 2 ml aliquots are distributed into hemolysis tubes and 125 I angiotensin II (25,000 DPM / tube) and the product to be studied are added. (The product is first tested at 3 x 10 5M in triplicate). When the test product displaces receptor-specific radioactivity by more than 50%, it is tested again in a range of 7 concentrations to determine the concentration that inhibits receptor-specific radioactivity by 50%. The 50% inhibitory concentration is thus determined.

 Nonspecific binding is determined by the addition of a reference product, ie the product of Example 94 of European Patent 0253310 to 10 5M (in triplicate). It is incubated at 25 ° C. for 150 minutes, put back on a water bath at 0 ° C. for 5 minutes, filtered under vacuum, rinsed with Tris pH 7.4 buffer and counts the radioactivity in the presence of Triton scintillant.

 The result is expressed directly in 50% inhibitory concentration (IC 50), that is to say in the studied product concentration, expressed in nM, necessary to displace 50% of the specific radioactivity fixed on the studied receptor.

Results:

<tb> Product <SEP> of <SEP> Example <SEP> IC50 <SEP> in <SEP> nanomoles
<tb><SEP> 2 <SEP> 1 <SEP> | <SEP> 911
<tb><SEP> 4 <SEP> 1 <SEP> | <SEP> 52
<tb><SEP> 12 <SEP> 1 <SEP> 105
<tb><SEP> 16 <SEP> 1 <SEP> 99
<tb><SEP> 19 <SEP> 1 <SEP> 207
<tb><SEP> 6 <SEP> 1 <SEP> | <SEP> 270
<tb> 2 - Demonstration of Antagonistic Inactivity of Angiotensin II on Isolated Portal Vein.

 The portal vein is removed from male Wistar rats (approximately 350 g) (IFFA Crédo Franc) after cervical dislocation, and rapidly placed in physiological solution (see below) at room temperature. A ring of about 1 mm is mounted in an isolated organ bath containing 20 ml of the following physiological solution (composition in mM: NaCl 118.3 - KCl 4.7 - MgSO4 1.2 - KH2PO4 1.2 - NaHCO3 - glucose 11.1 - CaCl2 2.5) the medium is maintained at 37 ° C. and oxygenated with a 95% O2 / 5% CO2 mixture. The initial tension imposed is 1 g, the rings are left to rest for 60 to 90 minutes. In order to avoid spontaneous contractions, verapamil is added to the incubation bath (1.10 6M).

 At the end of the rest period angiotensin II (Ciba hypertensin) 3.10 8M is added to the incubation bath and left in contact with the preparation for 1 minute. This operation is repeated every 30 minutes, the tissue being washed 3 or 4 times between two stimulations with angiotensin. The compound to be studied is introduced into the bath 15 minutes before a new stimulation by angiotensin. As increasing concentrations of the molecule are applied, an IC50 (concentration which produces a 50% inhibition of the response to angiotensin) can be calculated, this is expressed in nanomoles.

Results:

<tb> Product <SEP> of <SEP> Example <SEP> IC50 <SEP> in <SEP> nanomoles
<tb><SEP> 4 <SEP> 1 <SEP> 9.5 <SEP> I <SEP>
<tb><SEP> 16 <SEP> 1 <SEP> 45
<tb><SEP> 2 <SEP> 1 <SEP> 1 <SEP> 1000
<tb> 3 - Angiotensin II Antagonist Activity Test in Dulled Rat
Male Sprague-Dawley rats (250-350 g) are anesthetized by intraperitoneal injection of pentobarbital sodium (50 mg / kg). Diastolic blood pressure is recorded using a heparinised (PE50) catheter introduced into the left carotid of the animal, and connected to a pressure calculator (Gould, Pressure Processor) via a Gould pressure sensor.

 A catheter is introduced into the right jugular of the animal to allow the injection of the molecules to be studied.

 The animal is placed under assisted breathing. A bilateral section of the vagus nerves is performed. The rat is then demulled.

After a period of sufficient stabilization, the study of the antagonism of the molecules with respect to angiotensin II (Hypertensin, CIBA) is approached as follows
1 - Three consecutive injections of angiotensin II
(0.75 micrograms / kg) spaced 15 minutes apart
to obtain a reproducible and stable press response.

2 - While keeping a period of 15 minutes for
the administration of angiotensin II, the molecules (0.01 to
10 mg / kg) are injected 5 minutes before the angio
tensine II.

The pressure effects of angiotensin II in the presence of
the antagonist are expressed as a percentage of the effects
angiotensin II prescribers administered alone. The dose
Inhibitory at 50% of the studied effect is thus determined
undermined
(ID50).

 Each animal is considered as its own witness.

Results

<tb> Product <SEP> of <SEP> Example <SEP> I <SEP> DI50 <SEP> in <SEP> mg / kg <SEP> I
<tb><SEP> 4 <SEP> 0.3
<tb><SEP> 12 <SEP> 1.77
<tb><SEP> 16 <SEP> l <SEP> 1.97 <SEP> I
<Tb>

Claims (16)

R4B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, or a radical - (CHZ) -SO2-XR1, wherein m represents an integer of 0 to 4 and is (X-R12) represents NH2 is X represents a single bond, or the radicals -NH-, -NH-CO-NH- or -NH-CO- and R12 represents an alkyl, alkenyl or aryl radical, these radicals being optionally substituted, said products of formula (IB) being in any isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic or organic acids and mineral or organic bases of said products of formula (IB).  in which R6, R7, R10, R11, Rc and Rd have the values indicated above,

 in which R a and Rb have the meaning indicated above, at most one of R 1 B, R 2 B, R 3 B and R 5 B represents a hydrogen atom, and the others are selected from the radicals -CH 2 -O-R 10, -OR6, CO2R7 -R11 and the radical

 in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms and aryl, all these radicals being optionally substituted with one or more radicals chosen from the atoms of halogen, or the hydroxyl, trifluoromethyl, cyano, nitro, amino radical, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl, free carboxy salt or esterified and tetrazolyl, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, d) the radical

R11 is selected from the group consisting of a) alkyl radicals having at most 4 carbon atoms, optionally substituted with one or more radicals selected from - halogen atoms, - optionally acylated hydroxyl radical, - alkyloxy or alkenyloxy radicals linear or branched chain having at most 5 carbon atoms, - aryl radicals optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, amino radical, alkoxy radicals containing at most 4 atoms. of carbon, phenyl, benzyl, free carboxy salt or esterified and tetrazolyl, - the free carboxy radical, esterified or salified, - the radical R6 and R7, which are identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms,  in which R c and Rd, which are identical or different, represent the values defined hereinafter for Ra and Rb and the other represents a hydrogen atom and R1B and R3B are such that one represents a hydrogen atom and other is selected from the radicals -OR6, -CO2R7 and -R11, radicals in which

R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1Bt R23, R3B and R5B are such that either R1B, R2B, R3B and R5B are identical and represent a hydrogen atom, ie one of R2B and R53 represents a hydrogen atom or a radical -CH2-O-R10, in which R10 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, or the radical  in which

 CLAIMS 1) Formula (IB) products: 2) Products of formula (IB), as defined in claim 1 in which: R represents a butyl or buten-1-yl radical, R2B and R5B are such that one of R2B and R5B represents a radical

 in which R c and Rd, identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms and phenyl, all these radicals being optionally substituted with one or more radicals chosen from halogen atoms, the hydroxyl radical, trifluoromethyl, cyano, nitro, amino, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl, free carboxy salt or esterified and tetrazolyl, and the other represents a hydrogen atom; , R 1 B represents an alkyl radical having at most 4 carbon atoms optionally substituted with one or more radicals chosen from halogen atoms, the hydroxyl radical, the methoxy, ethoxy, free carboxy, salified or esterified, amino, mono- or dialkylamino radicals; and the phenyl radical itself optionally substituted by one or more radicals chosen from halogen atoms, methoxy, trifluoromethyl, cyano, free carboxy, salified or esterified and tetrazolyl radicals, R3B is chosen from the radicals OR6 and CO2R7 in which R6 and R7 represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms, R4B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, or a radical - (CH2) p -SO2-Xd-R12d in which p represents the values 0 and 1 Xd represents the radicals -NH-, -NH- CO-NH-, -NH-CO- or a single bond and R12d represents a methyl, vinyl, allyl, phenyl, benzyl, pyridylmethyl or pyridylethyl radical, said products of formula (13) being in all possible isomeric racemic forms, enantiomers and diastereoisomers, as well as addition salts with inorganic or organic acids and mineral or organic bases of said products of formula (in). 3) Products of formula (1B) as defined in claim 1 and corresponding to formula (IA)

 in which R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1A 'R22 & R2A' R3A and R5A are such that either R1A, R22 & R2A, R3A and R5A are the same and represent a hydrogen atom, one of R2A and R52 & represents a hydrogen atom or a radical -CH2-O-R10, wherein R10 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, and the other represents a hydrogen atom and, R1A and R3A are such that one represents a hydrogen atom and the other is chosen from the radicals -OR6, -CO2R7 and -R11, radicals in which R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R11 is selected from the group consisting of a) alkyl radicals having at most 4 carbon atoms, optionally substituted with one or more radicals selected from - halogen atoms, - optionally acylated hydroxyl radical, - alkyloxy or alkenyloxy radicals linear or branched having at most 5 carbon atoms, - the free carboxy radical, esterified or salified, - the radical

 in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxyl radical, b) linear alkenyl radicals; or branched having from 2 to 5 carbon atoms, c) acyl radicals having from 2 to 7 carbon atoms and the formyl radical, R4A represents a free, esterified or salified carboxy radical, cyano or a tetrazolyl radical, optionally salified, said products of formula (IA) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic or organic and the inorganic or organic bases of said products of formula (IA). 4) Products of formula (Ig) and (IA), as defined in claims 1 and 3 and corresponding to formula (I):

 in which R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1, R2, R3 and R5 are such that either R1, R2, R3 and R5 are identical and represent a hydrogen atom, one of R2 and R5 represents a hydrogen atom or a radical -CH2-O- R10 and the other represent a hydrogen atom, and R1 and R3 are such that one represents a hydrogen atom and the other is selected from the radicals -OR6, -CO2R7 and -CH2-O-R8, which radicals R10, R6, R7 and R8, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing not more than 5 carbon atoms, R4 represents a free, esterified or salified carboxy radical, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral or organic acids and mineral or organic bases; said products of formula (I). 5) Products of formula (IA) as defined in claim 3 wherein R represents a butyl or 1-butenyl radical and R1A represents a hydrogen atom or an alkyloxy radical, said products of formula (IA) being in all racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral or organic acids and the mineral or organic bases of said products of formula (IA). 6) Products of formula (IA) as defined in claim 3 wherein R represents a butyl radical and R1A, R2A, R3A and R5A represent a hydrogen atom, said products of formula (IA) being in all isomeric forms racemic, enantiomeric and diastereoisomerically, as well as addition salts with inorganic or organic acids and mineral or organic bases of said products of formula (IA). 7) Products of formula (IA) as defined in claim 3, in which R represents a butyl radical, R1A, R2A, and R5A represent a hydrogen atom, and R3A is chosen from the radicals -OR6, -CO2R7 and -R11, radicals in which R6 and R7, which may be identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R11 is chosen from the group formed by a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals chosen from - halogen atoms, - optionally acylated hydroxy radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - free carboxy, esterified or salified radical, - The radical

 in which R a and Rb, which are identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having from 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxyl radical, b) linear alkenyl radicals; or branched having from 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, said products of formula (IA) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, and the addition salts with the mineral or organic acids and the mineral or organic bases of said products of formula (IA). 8) Products of formula (1B) as defined in claims 1, 3 and 4 wherein R represents a butyl radical and R1B, R2B and R5B represent a hydrogen atom, and R3B represents a hydrogen atom, a carboxy radical free or esterified with an alkyl radical containing at most 4 carbon atoms, formyl, alkyl or alkenyl containing at most 4 carbon atoms, alkyl substituted by one or more radicals chosen from halogen atoms, hydroxyl, acyloxy and amino radicals; optionally substituted with one or two alkyl radicals containing at most 4 carbon atoms and free, salified or esterified carboxy, R4B represents a free, salified or esterified carboxy radical, optionally salified cyano or tetrazolyl, said products of formula (zig) being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as addition salts with mineral or organic acids and mineral bases ales or organic of said products of formula 9) Methyl 4 '- [(2-butyl 1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate and its salts, 4' - [(2-butyl 1H-benzimidazol-1-yl) methyl) ] biphenyl-2-carboxylic acid and its salts, 2-butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] 1H-benzimidazole-7-carboxylic acid and its salts, 4 '- [[2-butyl] 7- (2-hydroxyethyl) 1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and its salts, 4 '- [(2-butyl-7-formyl-1H-benzimidazol-1-yl) methyl) ] Biphenyl-2-carboxylic acid and its salts, 2-butyl 1 - [[2 '- (1H-tetrazol-5-yl) (1,1'-biphenyl) 4-yl] methyl] 1H-benzimidazole 7-carboxylic acid and its salts. 10) Process for the preparation of products of formula (IB) as defined in claim 1, characterized in that either a product of formula (IVB) is reacted

 in which R has the meaning indicated in claim 1, R1B ', R2B', R3B 'and R5B' have the meanings given in claim 1 respectively for R1B, R2B, R3B and R5B in which the possible reactive functions are optionally protected by protecting groups, with a compound of formula (VB>

 in which Hal represents a halogen atom and R4B 'has the meaning indicated in claim 1 for R4B in which the optional reactive functional groups are optionally protected by protecting groups to obtain products of formula (IXB)

 wherein R, R1B ', R2B', R3B ', R5B' and R4B 'have the meanings indicated above, a product of formula (IXB) which is treated, if desired and if necessary, with one or more the following reactions, in any order - an elimination reaction of the protecting groups which the protected reactive functions can carry, - a salification reaction with an acid or an inorganic or organic base to obtain the corresponding salt, - a reaction of esterification or salification of an acid function, - an acid or alkaline hydrolysis reaction of an acid-functional ester function, - a conversion reaction of an alkyloxy function to a hydroxy function, - a transformation reaction of a radical haloalkyl to an alkylene radical; - a substitution reaction of a halogen atom by an amino radical; - a substitution reaction of a hydroxy radical with a halogen atom; - a reduction reaction of a carboxy radical; hydroxyalkyl radical; - an oxidation reaction of a hydroxyalkyl radical to an esterified carboxy radical; - an oxymethylation reaction of a hydroxymethyl radical to formyl radical; - a reaction of resolution of racemic forms to split products; conversion reaction of a free, salified or esterified carboxy function to a tetrazolyl radical, said products of formula (zig) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereoisomers. 11) Process according to Claim 10, characterized in that the products of formula (IXB) are prepared either by reaction of a compound of formula (VIB)

 wherein R1B ', R2B', R3B 'and R5B' have the meanings given in claim 1 for R1B, R2B, respectively, R3B and R5B in which the optional reactive functional groups are optionally protected by protective groups, or with the compound of formula (II)

 in which R 9 represents a hydroxy, alkyloxy or halogen radical and R has the meaning indicated in claim 1, to obtain the product of formula (Xg)

  in which R, R1B ', R2B', R3B 'and R5B' have the above meanings, or by reaction of a compound of formula (VIB ')

 in which R1B ', R2B1, R3B' and R5B 'have the above meanings, with the compound of formula (II) as defined above to obtain the product of formula (XB')

 wherein R1B ', R2B', R3B ', R5B' and R have the meanings indicated above, which is subjected to a nitration reaction to obtain the compound of formula (XB) as defined above, product of formula (XB) which is reacted with the compound of formula (VB) as defined above, to obtain a product of formula (XIB) ::

  wherein R, R1B ', R2B', R3B ', R5B' and R4B 'have the above meanings, which are subjected to a selective reduction reaction of the nitro function, to obtain the product of formula (XIIB)

 wherein R, R1B ', R2B', R3B ', R5B' and R4B 'have the above meanings, which are subjected to a cyclization reaction to obtain products of formula (IXB). 12) Process according to claim 10 characterized in that the products of formula (IXB) are prepared by reaction of a compound of formula (VIB)

 in which R1B ', R2B1, R3B and R5B' have the meanings indicated in claim 1, with the compound of formula (VB):

  in which Hal represents a halogen atom and R4B 'has the meaning indicated in claim 1 for R4B in which the optional reactive functional groups are optionally protected by protective groups, to obtain products of formula (VIIB) ::

 wherein R1B ', R2B', R3B ', R5B' and R4B 'have the meanings indicated above, which is subjected to a reduction reaction of the nitro radical to the amino radical to obtain products of formula (VIIIB)

 wherein R1B ', R2B', R3B ', R5B' and R4B1 have the meanings given above, which is reacted with the product of formula (III)

  in which X represents an oxygen atom or a radical NH, Rg and R have the meaning indicated above, to obtain a product of formula (IXB). 13) As medicaments, the products of formula (IB) as defined in claim 1 or 2, said products of formula (zig) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as salts of addition with inorganic or organic acids and pharmaceutically acceptable inorganic or organic bases of said products of formula (IB). 14) As medicaments, the products of formula (IA) and (I) as defined in any one of claims 3 to 9, as well as the addition salts with mineral or organic acids and mineral bases or pharmaceutically acceptable organic compounds of said products of formula (IA) and (I). 15) The pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined in any one of claims 13 and 14. 16) As new industrial products, the compounds of formula (IVB), (VIIB) and (VIIIB).