FR2670489A1 - 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 (IA): in which: R represents an alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1A, R2A, R3A and R5A are such that: either R1A, R2A, R3A and R5A 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 an 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 -OR6, -CO2R7 and -R11 radicals, in which radicals R6 and R7 represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms and R11 is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms and which are optionally substituted, b) alkenyl radicals 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 carboxyl radical or a tetrazolyl radical. These products have advantageous pharmacological properties which justify their use as medicaments.

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, R1A, R2A, R3A et R5A sont tels que soit R1A, R2A, R3A 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 -CHZ-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 hydroxy 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 salifié, ou un radical tétrazolyle, 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 et organiques desdits produits de formule
La présente invention a ainsi pour objet les produits de formule (IA), telle que définie ci-dessus et répondant à la formule (I)

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 représente un radical carboxy libre, estérifié 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 et organiques desdits produits de formule (I).The subject of the present invention is the products of 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, R3A and R5A are identical and represent a hydrogen atom, that is one of R2A and R5A represents a hydrogen atom or a radical -CHZ-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 the other 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, - the optionally acylated hydroxy radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 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 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, or a tetrazolyl radical, said products of formula (IA) being in all the possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said formula products
The subject of the present invention is thus the products of formula (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 forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I ).

qui représente un radical amino éventuellement substitué par un ou deux radicaux désigne de préférence 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 éventuellement substitués comme par exemple dans hydroxyméthyle, hydroxyéthyle, méthoxyméthyle, méthoxyéthyle ou encore éthoxyéthyle ; 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.In the products of formula (IA) and (I) and in the following, the term "linear or branched alkyl radical" preferably denotes methyl, ethyl, propyl or isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals, but can 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 radicals; can represent -O-R10 and -O-R6 are formed for example with the alkyl and alkenyl radicals as defined above, we can mention for the alkyloxy radicals, preferably the methoxy or ethoxy radicals, but also the radicals pro poxy isopropoxy, butoxy, sec-butoxy, tert-butoxy or pentoxy, - for alkenyloxy radicals, vinyloxy or propenyloxy radicals may be mentioned, for the esterified carboxy radicals, there may be mentioned: preferably an alkyloxy or alkenyloxy 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 an atom of oxygen such as for example acetoxy or benzoyloxy, - the group

which represents an amino radical optionally substituted with one or two radicals preferably denotes monoalkyl and dialkylamino radicals in which the alkyl radicals can take the meanings indicated above such as, for example, methyl, ethyl, isopropyl, butyl, isobutyl, these radicals. being optionally substituted, for example in hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl or ethoxyethyl; the amino radical may also be substituted by one or two alkenyl radicals as defined above and, for example, the vinyl, allyl, 1-propenyl and 1-butenyl radicals.

 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 the inorganic or organic acids of the products of formula (IA) and (I) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic or acetic acids, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulphonic acids such as by methanedisulfonic acid, 1,2-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.

 Particularly preferred are the salts formed with hydrochloric acid.

The subject of the invention is particularly the products of formula (IA) as defined above, in which R represents a butyl or 1-butenyl radical and RA 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 the addition salts with the mineral and organic acids of said products of formula
Among these 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 RSA represents a hydrogen atom, a hydrogen atom or a hydrogen atom. hydroxy radical or an alkyloxy 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 1 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 these products in which R 1A 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 invention also particularly relates to the products of formula (IA) as defined above, in which R represents a butyl radical and RIA, 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 and organic acids of said products of formula
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, 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 et organiques desdits produits de formule
L'invention a notamment pour objet les produits de formule (IA) telle que définie ci-dessus, dans laquelle R représente un radical butyle et R, R2A et R5A représentent un atome d'hydrogène, et R3A représente un radical carboxy libre ou estérifié par un radical alkyle renfermant au plus 4 atomes de carbone ; formyle ; alkyle ou alkényle renfermant au plus 4 atomes de carbone ; alkyle substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxy, acyloxy, amino éventuellement substitué par un ou deux radicaux alkyle renfermant au plus 4 atomes de carbone carboxy libre, salifié ou estérifié, 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 et organiques desdits produits de formule
Parmi les produits objet de l'invention, peuvent être cités tout particulièrement : le 4'-((2-butyl lH-benzimidazoll-yl) méthyl] biphényle-2-carboxylate de méthyle et ses sels avec les acides minéraux ou organiques, l'acide 4' - E (2-butyl lH-benzimidazol-l-yl) méthyl] biphényle2-carboxylique et ses sels avec les acides minéraux ou organiques, l'acide 2-butyl l-((2'-carboxy biphényl-4-yl) méthyl] 1Hbenzimidazole-7-carboxylique et ses sels avec les acides minéraux ou organiques, l'acide 4' - E [2-butyl 7-(2-hydroxy éthyl) lH-benzimidazol-l-yl] méthyl] biphényle-2-carboxylique et ses sels avec les acides minéraux ou organiques, l'acide 4' - E (2-butyl 7-formyl lH-benzimidazol-l-yl) méthyl] biphényle-2-carboxylique et ses sels avec les acides minéraux ou organiques.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 chain 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, said products of formula (IA) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, and that the addition salts with the mineral and organic acids of said products of formula
The subject of the invention is in particular the products of formula (IA) as defined above, in which R represents a butyl radical and R, 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; alkyl substituted with one or more radicals chosen from halogen atoms, hydroxy, acyloxy and amino radicals optionally substituted by one or two alkyl radicals containing at most 4 free carboxy, salified or esterified carboxy atoms, said products of formula (IA ) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula
Among the products which are the subject of the invention, methyl 4 '- ((2-butyl-1H-benzimidazol-yl) methyl] biphenyl-2-carboxylate and its salts with mineral or organic acids can be mentioned in particular. 4 '- E (2-butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and its salts with inorganic or organic acids, 2-butyl 1 - ((2'-carboxybiphenyl) -4 -yl) methyl] 1H-benzimidazole-7-carboxylic acid and its salts with inorganic or organic acids, 4 '- E [2-butyl 7- (2-hydroxyethyl) -1H-benzimidazol-1-yl] methyl] biphenyl acid -2-carboxylic acid and its salts with mineral or organic acids, 4 '- E (2-butyl-7-formyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and its salts with mineral acids or organic.

 Among the salts, the hydrochloride is preferred.

dans laquelle RIA', R2A', R3A' et R5A' ont les significations indiquées ci-dessus respectivement pour RlA, R2A, R3A et R5A dans lesquelles les éventuelles fonctions réactives sont si désiré protégées par des groupements protecteurs, avec un composé de formule (VA)

dans laquelle Hal représente un atome d'halogène et R4A' a la signification indiquée ci-dessus pour R4A dans lequel les éventuelles fonctions réactives sont si désiré, protégées par des groupements protecteurs, pour obtenir des produits de formule (IXA)

dans laquelle R, R1A', R2A', R3A', R5A' et R4A' ont les significations indiquées ci-dessus, soit a) l'on fait réagir un composé de formule (VIA)

dans laquelle R1A', R2A', R3A' et R5A' ont les significations précédentes, ou bien avec le composé de formule (II)::

dans laquelle R et R9 ont les significations indiquées cidessus, pour obtenir le produit de formule (XA)

dans laquelle R, R1A', R2A', R3A' et R5A' ont les significations précédentes, l'on fait réagir un composé de formule (VIA')

dans laquelle R1A', R2A', R3A' et R5A' ont les significations précédentes, avec le composé de formule (II) tel que défini ci-dessus pour obtenir le produit de formule (XA')

dans laquelle R1A', R2A', R3A', RSA' et R ont les significations indiquées précédemment, que l'on soumet à une réaction de nitration pour obtenir le composé de formule (XA) tel que défini ci-dessus, produit de formule (XA) que l'on fait réagir avec le composé de formule (VA) telle que définie ci-dessus, pour obtenir un produit de formule (XIA)

dans laquelle R, R1A', R2A', R3A', R5A' et R4A' ont les significations précédentes, que l'on soumet à une réaction de réduction sélective de la fonction nitro, pour obtenir le produit de formule (XIIA)

dans laquelle R, R1A', R2A', R3A', R5A' et R4A' ont les significations précédentes, que l'on soumet à une réaction de cyclisation pour obtenir des produits de formule (IXA) telle que définie ci-dessus, ou bien l'on fait réagir le composé de formule (VIA) avec le composé de formule (VA) telle que définie ci-dessus, pour obtenir des produits de formule (VIIA) ::

dans laquelle R1A', R2A', R3A', R5A' et R4A' ont les significations indiquées ci-dessus, que l'on soumet à une réaction de réduction sélective du radical nitro en radical amino pour obtenir des produits de formule (VIIIA)

dans laquelle R1A', R2A', R3A', R5A' et R4A' 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, R9 représente un radical hydroxy, alkyloxy ou un atome d'halogène et R a la signification indiquée ci-dessus, pour obtenir un produit de formule (IXA) telle que définie cidessus, produit de formule (IXA) que l'on traite, si désiré et si nécessaire, à l'une ou plusieurs des réactions suivantes, dans un ordre quelconque - une réaction d'élimination des groupements protecteurs que peuvent porter les fonctions réactives protégées, - une réaction de salification par un acide minéral ou organique pour obtenir le sel correspondant, - une réaction d'estérification ou salification de fonction acide, - une réaction d'hydrolyse acide ou alcaline de fonction ester en fonction acide, - une réaction de transformation de fonction alkyloxy en fonction hydroxy, - une réaction de transformation d'un radical haloalkyle en radical alkylène, - une réaction de substitution d'un atome d'halogène par un radical amino, - une réaction de substitution d'un radical hydroxy par un atome d'halogène, - une réaction de réduction d'un radical carboxy estérifié en radical hydroxyalkyle, - une réaction 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 1A \ ainsi obtenus étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères.The subject of the invention is also a process for preparing products of formula (IA) as defined above, characterized in that either a product of formula (IVA) is reacted

in which RIA ', R2A', R3A 'and R5A' have the meanings given above for RlA, R2A, R3A and R5A, respectively, in which the optional reactive functional groups are, if desired, protected by protective groups, with a compound of formula ( GO)

in which Hal represents a halogen atom and R4A 'has the meaning indicated above for R4A in which the optional reactive functions are, if desired, protected by protecting groups, to obtain products of formula (IXA)

wherein R, R1A ', R2A', R3A ', R5A' and R4A 'have the meanings indicated above, or a) reacting a compound of formula (VIA)

in which R 1A ', R 2A', R 3A 'and R 5A' have the above meanings, or with the compound of formula (II) ::

in which R and R9 have the meanings indicated above, to obtain the product of formula (XA)

wherein R, R1A ', R2A', R3A 'and R5A' have the above meanings, reacting a compound of formula (VIA ')

in which R1A ', R2A', R3A 'and R5A' have the above meanings, with the compound of formula (II) as defined above to obtain the product of formula (XA ')

wherein R1A ', R2A', R3A ', RSA' and R have the meanings indicated above, which is subjected to a nitration reaction to obtain the compound of formula (XA) as defined above, product of formula (XA) which is reacted with the compound of formula (VA) as defined above, to obtain a product of formula (XIA)

in which R, R 1A ', R 2A', R 3A ', R 5A' and R 4A 'have the above meanings, which are subjected to a selective reduction reaction of the nitro function, to obtain the product of formula (XIIA)

wherein R, R1A ', R2A', R3A ', R5A' and R4A 'have the above meanings, which are subjected to a cyclization reaction to obtain products of formula (IXA) as defined above, or the compound of formula (VIA) is reacted with the compound of formula (VA) as defined above to obtain products of formula (VIIA):

wherein R1A ', R2A', R3A ', R5A' and R4A 'have the meanings indicated above, which is subjected to a selective reduction reaction of the nitro radical to amino radical to obtain products of formula (VIIIA)

wherein R1A ', R2A', R3A ', R5A' and R4A '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, R9 represents a hydroxy, alkyloxy or a halogen atom and R has the meaning indicated above, to obtain a product of formula (IXA) as defined above, a product of formula (IXA) which is treated, if desired and if necessary, with one or more of the following reactions, in any order - an elimination reaction of the protective groups which can be carried by the protected reactive functions - a salification reaction with an inorganic or organic acid to obtain the corresponding salt, - an esterification reaction or salification of an acid function, - an acidic or alkaline hydrolysis reaction of ester function in acid function, - a reaction of conversion of alkyloxy function to hydroxy function, a conversion reaction of a haloalkyl radical to an 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 hydroxyalkyl radical; an oxidation reaction of a hydroxyalkyl radical with an esterified carboxy radical; oxidation of a hydroxymethyl radical to the formyl radical; - a reaction of resolution of the racemic forms to split products; - a conversion reaction of a free, salified or esterified carboxy function to the tetrazolyl radical, said products of formula 1A \ and obtained being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms.

Under preferred conditions of implementation of the invention, the above process is carried out as follows
The products of formula (IVA) can be condensed with a compound of formula (VA) to obtain products of formula (IXA)
The condensation reaction of the products of formula (IVA) with a compound of formula (VA) in which the halogen atom is preferably a bromine atom can be carried out, for example, in an organic solvent such as dimethylformamide or tetrahydrofuran: thus the halogenated derivative can be condensed on the anion of the imidazole of formula (IVA) prepared for example by the action of a strong base such as sodium or potassium hydride or an alcoholate of sodium or potassium such as, for example, sodium methoxide.

 The addition reaction of the compounds of formula (II) on the free amine function of the compounds of formula (VIA) to obtain the products of formula (XA) can be carried out by simply heating at a temperature of about 1200C to 1700C a compound of formula (II) may be for example valeric acid, then used, preferably in excess relative to the compound of formula (VIA).

 The addition reaction of the compounds of formula (II) on the free amine function of the compounds of formula (VIA ') to give the products of formula (XA') can be carried out under the same conditions as those of the addition reaction compounds of formula (II) on the free amine function of the compounds of formula (VIA) to give the products of formula (XA).

The nitration reaction of the products of formula (XA ') to give the products of formula (XA) 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 temperature of about 0 to 10 5 C h
The addition reaction of the compounds of formula (VA) to the amide function of the compounds of formula (XA) to obtain the products of formula (XIA) can be carried out at room temperature or by heating at a temperature of about 200C to 1500C, preferably in the presence of a base such as, for example, triethylamine, sodium hydroxide, sodium methoxide or ethoxide or sodium hydride in a solvent such as, for example, tetrahydrofuran or dimethylformamide.

 The reduction of the nitro radical of the products of formula (XIA) to amino radical to obtain the products of formula (XIIA) can be carried out according to the usual methods known to those skilled in the art including a 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 (XIIA) to obtain the products of formula (IXA) 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 (VA) to the free amine function of the compounds of formula (VIA) to obtain the products of formula (VIIA) can be carried out under the same conditions as those described above for the addition compounds of formula (VA) on the products of formula (IVA).

 The reduction of the nitro radical of the products of formula (VIIA) to amino radical to obtain the products of formula (VIIIA) 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 (XIA) to amino radical to obtain the products of formula (XIIA).

 The addition reaction of the compounds of formula (III) to the free amine radical of the products of formula (VIIIA) followed by the cyclization of the products thus obtained can be carried out under various reaction conditions; in particular, a compound of formula (III) may be condensed on a compound of formula (VIIIA), preferably in an organic solvent such as, for example, tetrahydrofuran or dimethylformamide at a temperature of between 20 ° C. and 2000 ° C.

The compound of formula (III) can be, for example, when
X represents = NH, ethyl pentanimidoate and when X represents = 0, for example, valeric acid.

 As indicated above, the products of formula (IXA) can thus be obtained - either by reaction of the products of formula (IVA) with a compound of formula (VA) - or by a cyclization reaction of the products of formula (XIIA) - or by reaction of product of formula (VIIIA) with the compound of formula (III).

According to the values of R1A ', R2A', R3A and RSA ', the products of formula (IXA) are or not products of formula
The various reactive functions which certain compounds of the reactions 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 can be mentioned - the hydroxy radicals can be protected for example by the trimethylsilyl, methoxymethyl or tetrahydropyranyl radicals, the carboxy groups can 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 protecting groups can be carried out under the usual conditions known to those skilled in the art, in particular acid hydrolysis carried out with an acid such as hydrochloric, benzenesulphonic, para-toluenesulphonic, formic or trifluoroacetic acids.

 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 subjected to salification reactions with an inorganic or organic acid carried out according to the usual methods known to those skilled in the art.

 Any ester functional changes in the acid function 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 acid or alkaline hydrolysis, for example with sodium hydroxide or potassium hydroxide. alcoholic medium such as, for example, in methanol or by hydrochloric or sulfuric acid.

 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 possible 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 treatment of 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 thienyl chloride. The chlorinated derivative may in turn be substituted with an amino 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 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 (IA) may be prepared by resolution of the racemates 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 (IA) 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 therapeutic application and the subject of the invention is also, as medicaments, the products as defined by the formula (IA) above, said products of formula (IA) being in all isomeric forms possible racemic or optically as well as addition salts with pharmaceutically acceptable inorganic or organic acids of said products of formula
The subject of the invention is, as medicaments, the products of formula (IA) as defined above in which R represents a butyl or 1-butenyl radical and RA represents a hydrogen atom, and especially the products of formula (IA) as defined above in which R represents a butyl radical and R, R2A, R3A and R5A are identical and each represents a hydrogen atom, as well as the addition salts with the mineral or organic acids pharmaceutically acceptable salts of said products of formula
The subject of the invention is more particularly, as medicaments, the products of formula (IA) following methyl 4'-t (2-butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate, the acid 4 '- [(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'-t (2-butyl-7-formyl) -L benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid, as well as their addition salts with pharmaceutically acceptable inorganic or organic acids.

 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 principle 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), (IVA), (VA), (VIA) and (VIA ') 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 (IVA) is described in: J. Amer. Chem. Soc. (1937) 59, 178.

dans laquelle RI ', R2A', R3A' et RSA' ont la signification indiquée ci-dessus.The other products of formula (IVA) may be prepared by the action of a compound of formula (III) as defined above with a product of formula (IIIA '):

wherein R1 ', R2A', R3A 'and RSA' 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 (VIllA).

 Certain compounds of formula (IIIA ') can be found on the market, for example methyl 3,4-diamino benzoate, for example commercialized by LANCASTER or else valeric acid marketed for example by JANSSEN.

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

 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 valeronitrile, for example commercialized by LONZA. .

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

soit le iodobenzoate de méthyle, commercialisé par exemple, par JANSSEN, à l'action d'un composé de formule (V2)

soit du iodotoluène, commercialisé par exemple, par FLUKA, la réaction est réalisée par exemple en présence de cuivre en poudre à une température d'environ 100"C à 300"C, pour obtenir un produit de formule (V3)

dont le radical carboxy estérifié peut, si désiré, être libéré du radical alkyle par les méthodes classiques connues de l'homme de 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 de métier par exemple par action du
N-bromosuccinimide dans le tétrachlorure de carbone.A process for preparing the products of formula (VA) as defined above may consist in subjecting the compound of formula (V1)

either methyl iodobenzoate, sold for example by JANSSEN, to the action of a compound of formula (V2)

either iodotoluene, marketed for example, by FLUKA, the reaction is carried out for example in the presence of powdered copper at a temperature of about 100 "C to 300" C, to obtain a product of formula (V3)

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 compound of formula (VIA) may be, for example, ortho-nitroaniline, in the form of a product sold, for example, by UCB.

The products of formula (VIA) 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 (VIA ') which are derivatives of aniline can be found on the market such as, for example, para-nitroaniline or 2,4-dimethoxyaniline in
ALDRICH or can be prepared as indicated for example in the following references - 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 intermediates necessary for the preparation of the products of formula (IA), the compounds of formulas (IVA), (VIIA), (VIIIA), (XA ) and (XA ').

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> R1A <SEP> R2A <SEP> R5A <SEP> R3A
<tb> H <SEP> H <SEP> H <SEP> OH
<tb><SEP> 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><SEP> H <SEP> OCH3 <SEP> H <SEP> COOMe
<tb> H <SEP> OCH3 <SEP> H <SEP> COOH
<tb><SEP> H <SEP> OCH3 <SEP> H <SEP> CH3
<tb><SEP> H <SE> OCH3 <SEP> H <SEP> Cl
<tb><SEP> H <SEP> OCH3 <SEP> H <SEP> CH2OH
<tb><SEP> 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>

<tb> R1A <SEP> R2A <SEP> R5A <SEP> R3A
<tb> I <SEP> i <SEP> I <SEP> I
<tb> H <SEP> Cl <SEP> H <SEP> OH
<tb> H <SEP> Cl <SEP> H <SEP> COOMe
<tb> H <SEP> Cl <SEP> H <SEP> CH3
<tb> H <SEP> Cl <SEP> H <SEP> Cl
<tb> H <SEP> Cl <SEP> H <SEP> OH
<tb><SEP> 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> OH <SEP> H <SEP> H <SEP> OH
<tb><SEP> OH <SEP> H <SEP> H <SEP> COOMe
<tb><SEP> OH <SEP> H <SEP> H <SEP> CH3
<tb> OH <SEP> H <SEP> H <SEP> Cl
<tb> OH <SEP> H <SEP> H <SEP> CH2OH
<tb><SEP> OH <SEP> H <SEP> H <SEP> CH2Cl
<tb><SEP> OH <SEP> H <SEP> H <SEP> CH2-CH2-OH
<tb><SEP> 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 methoxide 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 cm3 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 sodium bicarbonate solution 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.

2000 cm-1 (du type

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 (CHCl)
Absorption complex 2800

2000 cm-1 (of the type

1723 cm1 1438 cm-1 c=C
C=N
Aromatique

1620 cm-1 1599 cm-1 1558 cm-1 1510 cm-1 1488 cm-1
EXEMPLE 2 : Acide 4'-E(2-butyl lX-benzimidazol-1-yl) méthyl] biphényle-carboxylique
A une solution de 500 mg de l'ester obtenu à l'exemple 1 sous forme de base, dans 8 cm3 de méthanol, on ajoute 0,8 cm3 de soude 2N. On agite 4 heures 30 au reflux.On évapore le méthanol, refroidit à +10 C et acidifie jusqu'à pH 5-6 avec de l'acide chlorhydrique 2N, on agite 30 minutes à +10 C essore, lave à l'eau, sèche à 80 C sous pression réduite. On obtient 400 mg de produit F = 1900C que l'on recristallise deux fois dans l'isopropanol pour obtenir 125 mg du produit recherché.<tb> o
<tb>'t
<tb> -C-OCH3
<Tb>

1723 cm1 1438 cm-1 c = C
C = N
Aromatic

1620 cm-1 1599 cm -1 1558 cm -1 1510 cm -1 1488 cm -1
EXAMPLE 2: 4'-E (2-butyl-1-benzimidazol-1-yl) methyl] biphenyl-carboxylic acid
To a solution of 500 mg of the ester obtained in Example 1 in base form, in 8 cm3 of methanol is added 0.8 cm3 of 2N sodium hydroxide. The mixture is stirred for 4 hours at reflux. The methanol is evaporated off, cooled to +10 ° C. and acidified to pH 5-6 with 2N hydrochloric acid, stirred for 30 minutes at +10 ° C. and washed with water. dried at 80 ° C. under reduced pressure. 400 mg of F = 1900C product is obtained which is recrystallized twice in isopropanol to obtain 125 mg of the desired product.

Mp 2340 ° C.

1615 cm 1597 cm 1518 cm
PREPARATION 1 : 4'-[N-[2-(méthoxycarbonyl) 6-nitro phényl] N (pentanoyl) aminométhyl] biphényle-2-carboxylate de méthyle
STADE A : Acide 2-amino 3-nitro benzoïque a) acétylation :
A une suspension refroidie à + 10 C de 12 g de 2-amino 3-nitro toluène et 14,4 cm3 d'anhydride acétique, on ajoute 0,65 cm3 d'acide sulfurique concentré, on agite pendant 1 heure à température ambiante, ajoute 50 cm3 d'eau, agite 15 minutes, essore, lave à l'eau puis à l'éther, sèche à 100 C sous pression réduite.On obtient 13,6 g de produit recherché.Analysis for C25H24N2O2 = 384.48
CCHN% calculated 78.10 6.29 7.28% found 78.00 6.3 7.2
IR spectrum (Nujol)
C = O 1682 cal
Aromatic + heteroaromatic

1615 cm 1597 cm 1518 cm
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, 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. 13.6 g of desired product are obtained.

PF = 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. It is stirred for 3 hours at 100 ° C., allowed to return to ambient temperature, cooled to 0 ° C. + 5 ° C., the insoluble filter filtered, the filtrate cooled to 0 ° C. + 5 ° C., 10 cm 3 of concentrated hydrochloric acid (pH 2 are added). -3). Extracted with 4 times 500 cm3 of ethyl acetate, washed with water, dried, filtered and evaporated under reduced pressure. 16.1 g of product are obtained which is crystallized from ethyl ether to give 12.1 g of the desired product. F = 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 1000C 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. PF = 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 = 58OC.

 An analytical sample was prepared by dissolving in 20 cm3 of isopropyl ether under reflux, filtering and concentration to 5 cm. It is left standing for 18 hours at ambient temperature, filtered off and 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, concentrated to 10 cm. Allowed to stand at room temperature for 1 hour, filtered, washed with isopropyl ether. 380 mg of the desired product is obtained. F = 600C.

1608 - 1588 - 1499 -1
NO2 1540 - 1360 cml
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'-(bromomêthyl) 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 vide. 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-1 (max)
C = O complex 1730 cm-1 (ep)
1708 cm-1 (max)
Aromatic
+
Amide II

1608 - 1588 - 1499 -1
NO2 1540 - 1360 cml
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 1.09 g of methyl 4 '- (bromomethyl) biphenyl-2-carboxylate (preparation EP 00253310) are added and the mixture 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 vacuum. 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 (CHCl3)
C = O complex 1726 and 1670 cm-1
NO2 1538 and 1352 cm-1
Aromatic 1600 and 1576 cm 1
EXAMPLE 3: Methyl 2-butyl 1- (2 '- (methoxycarbonyl) biphenyl-4-yl methyl] -1H-benzimidazole-7-carboxylate hydrochloride 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 ambient temperature, the solvents are evaporated and the residue is taken up with 3 times 3 cm 3 of ethyl acetate. We drain, wash with ether. 640 mg of the desired product is obtained. Mp = 1600 C.

 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 Cl N% calculated 68.21 5.93 7.19 5.68% found 67.8 5.8 7.3 5.5
IR spectrum

2380 cm'l
C=O 1727 et 1721 cal
EXEMPLE 4 : Acide 2-butyl l-t(2'-carbowy biphényl-4-yl) méthyl] lH-benzimidazole-7-carboxylique
On agite 1 heure au reflux une solution de 440 mg du produit obtenu à l'exemple 3, avec 10 cm3 d'éthanol, 1 cm3 d'eau, 1 cm3 de lessive de soude. On évapore méthanol, dissout le résidu dans l'eau (10 cm3) et acidifie à pH 3-4 avec de l'acide acétique. Après essorage, on obtient 360 mg de produit F = 1600C, puis 250 C, on recristallise 450 mg de produit obtenu comme ci-dessus, dans 15 cm3 de méthanol, 5 gouttes d'acide acétique et 5 cm3 d'eau.On obtient 370 mg de produit F = 255 C, que l'on dissout dans 20 cm3 de méthanol et 10 cm3 de chlorure de méthylène au reflux, on filtre, évapore le chlorure de méthylène et ajoute 1 goutte d'acide acétique et 5 cm3 d'eau. Après une nuit à température ambiante, on essore et obtient 330 mg de produit. F = 255 C.Typical complex absorption

2380 cm'l
C = O 1727 and 1721 cal
EXAMPLE 4: 2-Butyl-1 (2'-carbowyl-biphenyl-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. Evaporate methanol, dissolve the residue in water (10 cm3) and acidify to pH 3-4 with acetic acid. After wringing, 360 mg of product F = 1600 ° C is obtained, then 250 ° C., 450 mg of product obtained as above, in 15 cm 3 of methanol, 5 drops of acetic acid and 5 cm 3 of water are recrystallized. 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, filtered, the methylene chloride evaporated and 1 drop of acetic acid and 5 cm 3 of 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)
N-CH2 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-[(pentanoxyloxy) méthyle phényl] N-pentanoyl] aminométhyl] biphényle-2-carbo:ylate de méthyle
STADE A :Alcool 2-amino 4-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 cristallisé 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-1
NMR spectrum (DMSO)

0.88 (t) 1.39 (m) 1.76 (m) 2.87 (m)
N-CH2 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 - [(pentanoxyloxy) methyl phenyl] N-pentanoyl] aminomethyl] biphenyl-2-carbo: ylate
STAGE A: 2-amino-4-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 (CHCl3)
OH 3604 cm-1 = C-NH 2 3498-3390 cm -1
NH2 def 1624 cm-1 (F)
NO2 1520-1345 cm-1 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 (Eb 40-700 ° C.) are added, the mixture is filtered off and 2.55 g of the desired product is obtained. Mp = 82 ° C. After recrystallization of 118 mg of the above product in isopropyl ether, 72 g of the product are collected. mg of product F = 84 ° C.

1610 - 1588 - 1538 - 1480 cm-1
STADE C :: 4'-(N-[(2-nitro 6-[(pentanoyloxy) méthyl] phényl] Npentanoyl] aminométhyl] biphényle-2-carboxylate de méthyle
A une solution de 1,35 g du produit obtenu au stade B cidessus, dans 13,5 cm3 de diméthylformamide, 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% calculated 60.70 7.19 8.33% found 60.7 7.3 8.4
IR spectrum (CHCl3) = C-NH 3426 cm 1
C = O 1734 and 1702 cm1
Aromatic N02 +
Amide II

1610 - 1588 - 1538 - 1480 cm-1
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 cm 3 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'-tert-butyl 7-t (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 - 1450C 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 cal
EXEMPLE 6 : Acide 4'-[[2-butyl 7-(hydroxyméthyl) 1H-benzimi dazol-l-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 1'éthanol aqueux en milieu légèrement acétique, puis dans l'méthanol seul pour recueillir 207 mg du produit attendu F = 250 C. Analysis for C69H36N2O4, HCl = 549.124
CH Cl 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 callus
EXAMPLE 6 4 '- [[2-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 methanol alone to collect 207 mg of the expected product F = 250 C.

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

0,87 ppm (t) 1,36 ppm (m) 1,73 ppm (m) 1,81 ppm (m) 4,52 (s)
C6H4 les autres aromatiques

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 : [[2-butyl 7-(hydroxyméthyl) 1H-benzimidazol-1yl] méthyl] biphényle-2-carbo:ylate de méthyle
On agite pendant 30 minutes une solution de 823 mg du produit obtenu à l'exemple 5, dans 8,2 cm3 d'éthanol et 1,6 cm3 de soude 2N.On ajoute ensuite 10 cm3 d'eau, essore et sèche, on obtient 600 mg du produit attendu (F = 138C) 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 -1 C # O 1688 cm -1
Aromatic
+
heterocyclic

1598 - 1518 callus
NMR Spectrum (DMSO) 300 Mhz

0.87 ppm (t) 1.36 ppm (m) 1.73 ppm (m) 1.81 ppm (m) 4.52 (s)
C6H4 other aromatics

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 [[2-butyl 7- (hydroxymethyl) 1H-benzimidazol-1-yl] methyl] biphenyl-2-carbo-ylate
A solution of 823 mg of the product obtained in Example 5 in 8.2 cm 3 of ethanol and 1.6 cm 3 of 2N sodium hydroxide is stirred for 30 minutes. 10 cm 3 of water are then added, the mixture is drained and dried. 600 mg of the expected product (mp = 138 ° C.) are obtained, which is recrystallized from ethyl acetate and then isopropanol (mp = 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-1 C # O 1722 cm-1
EXAMPLE 8 Methyl 4 '- [[2-butyl 7- (chloromethyl) 1H-bemzimidazol-1-yl] methyl] biphenyl-2-carbo-ylate
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-1
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 ml of thionyl chloride for 2 hours at room temperature. Evaporate, add about 5 g of ice then 20 ml of water and stir overnight at room temperature. The water is decanted, taken up in 30 ml 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- [2-nitro 6 - [(2-pentanoxyloxy) 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 = 59C. 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
CCHN% calculated 70.79 8.91 4.59% found 70.9 9.2 4.6
IR spectrum (CHCl3)

Amide II

3360 cm- 3430 cm1 1684 cm-i 1530 cm-1 1720 cm-1
STADE B : Pentanoate de 2-(3-nitro 2-pentanamido phényl) éthyle
A une solution de 9,1 g du produit obtenu au stade A, cidessus, dans 50 cm3 d'anhydride acétique, on ajoute à une température comprise entre 0 et +10 C, un mélange de 7,1 cm3 d'acide acétique. On agite pendant 2 heures entre 0 et 10 C.

3360 cm- 3430 cm1 1684 cm-i 1530 cm-1 1720 cm-1
STAGE B: 2- (3-nitro-2-pentanamido-phenyl) ethyl pentanoate
To 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 between 0 and +10 C, a mixture of 7.1 cm3 of acetic acid. It is stirred for 2 hours between 0 and 10 C.

150 cm3 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 are recrystallized twice 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

3330 cm1 3420 cm1 1725 cm1 1700 cm1 1605 cm-1 1583 cm-1 1535 cal 1478 cal (complexe) 2éme bamds NO2 1348 cm-1
STADE C: 4'-[N-[[2-nitro 6-[(2-pentanoyloxy) éthyl] phényl
N-pentanoyl] aminométhyl] biphényle-2-carboxylate de méthyle
On opère comme au stade C de la préparation 2 à partir de 3,5 g du produit obtenu au stade B ci-dessus, en utilisant 480 mg d'hydrure de sodium à 50 % dans l'huile et 3,05 g de '-(bromométhyl) biphényle-2-carboxylate de méthyle (préparation EP 0253310). Après chromatographie sur silice (éluant acétate d'éthyle - cyclohexane 3-7) on obtient 5,19 g du produit recherché.C = O
aromatic
+ Amide II
+ 1st band NO2

3330 cm1 3420 cm1 1725 cm1 1700 cm1 1605 cm-1 1583 cm-1 1535 cal 1478 cal (complex) 2nd bamd NO2 1348 cm-1
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 from 3.5 g of the product obtained in Step B above, using 480 mg of 50% sodium hydride in oil and 3.05 g of 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.

1728 cm-1 1666 cm1

1438 cal
NO2 1534 cm-1
EXEMPLE 10 : 4'-[[2-butyl 7-[2-butyl 7-[2-(pentanoyloxy) éthyl] 1H-benzimidazol-1-yl] méthyl] hipényle-2-carboxylate de méthyle
On opère comme à l'exemple 3 à partir de 3,38 g du produit obtenu au stade C de la préparation 3, en utilisant 1,03 g de catalyseur. Après chromatographie sur silice (éluant : acétate d'éthyle - cyclohexane (3-7)), on obtient 2,42 g du produit recherché.IR spectrum (CHCl3) (PE 580) # C = O
CH3 of

1728 cm-1 1666 cm1

1438 callus
NO2 1534 cm-1
EXAMPLE 10 Methyl 4 '- [[2-butyl 7- [2-butyl 7- [2- (pentanoyloxy) ethyl] 1H-benzimidazol-1-yl] methyl] hexenyl-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.

1724 cm-1 (F) 1599 cm-1 1520 cal
EXEMPLE 11 : 4'-[[2-butyl 7-(2-hydroxy éthyl) lH-benzimidazoll-yl] méthyl] biphényle-2-carbo:ylate de méthyle
On agite 30 minutes à température ambiante 2,42 g du produit obtenu à l'exemple 10, avec 20 cm3 de méthanol et 5,5 cm3 de soude 1N. On évapore le méthanol extrait avec du chlorure de méthylène, lave à l'eau et évapore à sec sous pression réduite. Le résidu est cristallisé dans l'acétate d'éthyle, on obtient 1,59 g de produit recherché. F = 139 C.IR spectrum (CHCl3) # C = O
Conjugate System + Aromatic

1724 cm-1 (F) 1599 cm-1 1520 cal
EXAMPLE 11 Methyl 4 '- [[2-butyl 7- (2-hydroxyethyl) 1H-benzimidazoll-yl] methyl] biphenyl-2-carbo-ylate
2.42 g of the product obtained in Example 10, with 20 cm3 of methanol and 5.5 cm3 of 1N sodium hydroxide are stirred for 30 minutes at room temperature. 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.

3615 cml 3550 cm1 #C=O 1720 cm-1
EXEMPLE 12 : Acide 4'-t[2-butyl 7-(2-hydroxy éthyl) 1H-benzimidazol-1-yl] méthyl] hiphényle-2-carboxylique
On opère comme à l'exemple 4 à partir de 400 mg du produit obtenu à l'exemple 11. On obtient 371 mg du produit attendu F = 174 C. Le produit est recristallisé deux fois dans l'éthanol, on recueille 96 mg du produit recherché. F = 175 C.Analysis for C23H30N2O3 = 442.56
CHN% calculated 75.99 6.83 6.33% found 75.8 6.8 6.2
IR spectrum (CHCl3)
OH + Associates

3615 cml 3550 cm1 # C = O 1720 cm-1
EXAMPLE 12 4'-t [2-butyl 7- (2-hydroxyethyl) 1H-benzimidazol-1-yl] methyl] hexhenyl-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

1592 cm-1 1512 cml
Spectre de RMN (DMSO) 250 Mhz
Présence d'environ 0,4 mole d'éthanol

Absorption region OH / NH # C = O 1680 cm-1
Conjugate System + Aromatic

1592 cm-1 1512 cml
NMR Spectrum (DMSO) 250 Mhz
Presence of about 0.4 moles of ethanol

2,88 (t) 3,62 (t)
N-CH2-C6H5 5,71 (s)
C6H4 les autres H aromatiques

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 éthyl) îH-benzinidazol-1-yl] méthyl] biphényle-2carboxylate 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> CH3
<tb> CH2
<tb> CH2
<tb><SEP>
<tb> CH2
<tb> 0.87 (t) 1.37 (m) 1.73 (m) 2.80 (t)

2.88 (t) 3.62 (t)
N-CH2-C6H5 5.71 (s)
C6H4 other aromatic H

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-benzinidazol-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

<tb> Spectrum <SEP> IR <SEP> CHCl3
<tb> Absorption <SEP> type <SEP> / <SEP> N &commat; -H
<tb><SEP> O <SEP> f <SEP> 1725 <SEP>cm'l
<tb> ~ 1 ~ OCH3 <SEP> t <SEP> 1434 <SEP> cm <SEP> 1
<tb> Aromatic <SEP> f <SEP> 1624 <SEP> - <SEP> 1600 <SEP> - <SEP> 1565 <SEP> cm <SEP> 1
<tb> Hetero <SEP> aromatic <SEP> 1512 <SEP> - <SEP> 1496 <SEP> cm1
<Tb>
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.

IR spectrum in NUJOL 1698 cm-1
Aromatic 1597 cm 1
Heteroaromatic 1518 cm-1
NMR Spectrum (DMSO) 250 Mhz

0,90 (t) 1,39 (m) 1,77 (m) 2,85 (t) 3,18 (t) 3,64 (t) 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 îK-benzimi- dazol-1-yl] methyl] 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.Cl-CH2 N-CH2 -C6H5
C6H4 other aromatics

0.90 (t) 1.39 (m) 1.77 (m) 2.85 (t) 3.18 (t) 3.64 (t) 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 Methyl 4 '- [[2-butyl 7-formyl] -benzimidazol-1-yl] methyl] biphenyl-2-carboxylate hydrochloride
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. The mixture is stirred for 24 hours at room temperature, filtered and evaporated to dryness under reduced pressure to give 600 mg of the expected product.

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 cm1
Aromatic 1618 - 1599 - 1563 - 1520 cm-1
Heterocycles 1498 cm-1
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 9 ° C. under reduced pressure. 470 mg of product are obtained. F = 2250C.

 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
Protons mobiles

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 10,08 et 12,75
EXEMPLE 17 :: Dichlorhydrate de l'acide 4'-EE2-butyl 7-l(dimé- thylamino) méthyl] lH-bensimidazol-l-yl] méthyl] biphényle-2carboxylique
On dissout 360 mg du produit obtenu à l'exemple 9, dans 10 cm de diméthylamine à 33% dans l'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
Protons mobile

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 10.08 and 12.75
EXAMPLE 17 4'-EE2-butyl 7-1 (dimethylamino) methyl] -1H-bensimidazol-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 for 19 hours at room temperature. Evaporated, extracted with 3 times 20 cm3 of methylene chloride, washed with 2 times 15 cm3 of saline, dried, filtered and evaporated under reduced pressure.

300 mg of the expected product are obtained.

Preparation of the dihydrochloride
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

7,20 (d) 7,34 (d) les autres aromatiques

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 t Chlorhydrate de t2-butys 1-[2'-(méthoxycarbonyl) biphényl-4-yl] méthyl] lK-benzimidazol-7-acétate de méthyle a) Préparation de l'acide [2-butyl 1-(2'-(méthoxycarbonyl) biphényl-4-yl] methyl] lH-benzimidazol-7-acetique
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, evapore 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 t found 65.3 6.5 13.8 8.0
IR spectrum in Nujol
C = O 1770 - 1680 cm -1
Aromatic 1623 - 1597 cm-1
Heterocycles 1514 - 1495 cm-1
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

7.20 (d) 7.34 (d) other aromatics

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 t2-Butyl 1- [2 '- (methoxycarbonyl) biphenyl-4-yl] methyl] -1H-benzimidazol-7-acetate methylhydrochloride a) Preparation of [2-butyl 1- (2') - (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 methyl [2-butyl 1- [2- (methoxycarbonyl) biphenyl-4yl] methyl] 1H-benzimidazol-7-acetate
The product obtained above is dissolved in 10 cm3 of methylene chloride, then esterified with approximately 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.

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-1 (F)
Aromatiques
Hétéroaromatiques

1623 - 1599 cm-1 1565 - 1512 - 1500 cm-1
EXEMPLE 19 : Acide 2-butyl 1-[(2'-carboxy biphényl-4-yl) méthyl] Ig-benoimidasol-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 t 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
N-type absorption -H - 2500 cm-1 1725 - 1714 cm-i

1438 cm-1 (F)
aromatic
heteroaromatic

1623 - 1599 cm-1 1565 - 1512 - 1500 cm-1
EXAMPLE 19: 2-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] Ig-benzimidazol-7-acetic acid
745 mg of the product obtained in Example 18, in 8 cm 3 of ethanol and 1.6 cm 3 of sodium hydroxide at 32 t 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) 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 lH-benzimidazol- l-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 = 0 1712 cm -1
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) 7.29 (d) others aromatic

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, 5 cm3 of water are added, neutralized to pH = 5-6 with acetic acid, filtered off 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 are recrystallized in methyl ethyl ketone and then in isopropane. 278 mg of product is collected. Mp = 2380C.

0,87 (t) 1,37 (m) 1,72 (m) 2,81 (t) 5,27 (dd, J = 1,5 et 11) 5,62 (dd, J = 1,5 et 17)
CH2-CH-C6H5 7.08 (dd, J = 11 et 17)
N-CH2-C6H5- 5,64
C6H4 6,94 (d)
7,31 (d) les autres H aromatiques

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) ethyl] biphényle2-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'ethanol.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-1
System conjugates 1599 cm-1
+ 1589 cm1
Aromatic 1514 cm-1
NMR Spectrum (DMSO) 300 Mhz

0.87 (t) 1.37 (m) 1.72 (m) 2.81 (t) 5.27 (dd, J = 1.5 and 11) 5.62 (dd, J = 1.5 and 17)
CH2-CH-C6H5 7.08 (dd, J = 11 and 17)
N-CH2-C6H5- 5.64
C6H4 6.94 (d)
7.31 (d) other aromatic H

7.10 to 7.25 (m) 2H - 7.31 (m) 1H 7.42 (td) 1H - 7.57 (m) 2H 7.63 (dd) 1H
H mobile 12.77 (<1H)
EXAMPLE 21 Methyl 4 '- [2-butyl 7- (2-dimethylamino) ethyl] 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.

 We maintain 16 hours at 800C. Evaporated under reduced pressure at 60C, extracted with 3 times 60 cm3 of methylene chloride, washed with 3 times 20 cm3 of water, dried and evaporated to dryness.

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

EXAMPLE 22 4 '- [[2-Butyl 7-t 2- (dimethylamino) ethyl] -1H-benzimisazol-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. Extracted with 3 times 60 cm3 of methylene chloride, washed with 2 times 10 cm3 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 600C under reduced pressure. Recrystallized from acetonitrile to give 429 mg of the expected product. M.p. 218 C.

1708 cm-1 1690 cm1 1625 cm1 1598 cm-1 1569 cm-1 1510 cm-1
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 # = 0
Aromatic
+
heteroaromatic

1708 cm-1 1690 cm1 1625 cm1 1598 cm -1 1569 cm -1 1510 cm -1
NMR Spectrum (DMSO) 250 Mhz

0,91 (t) 1,42 (m) 1,82 (m) 3,09 (m) 2H 3,26 (m) 4H 6,04 (sl)
C6H4 les autres H aromatiques

7,23 (d) 2H 7,34 (d) 2H 7,80 (d) 1H - 7,74 (d) 1H 7,56 (m) 2H - 7,44 (m) 2H 7,30 (masqué) 1H les N-CH3 2,65 (sl)
H mobiles 11,38
EXEMPLE 23 t composition pharmaceutique
On a prépare des comprimés répondant à la formule suivante
Produit de l'exemple 2 .................. 10 mg
Excipient pour un comprimé terminé à .... 100 mg (détail de l'excipient : lactose, talc, amidon, stéarate de magnésium).

0.91 (t) 1.42 (m) 1.82 (m) 3.09 (m) 2H 3.26 (m) 4H 6.04 (sl)
C6H4 other aromatic H

7.23 (d) 2H 7.34 (d) 2H 7.80 (d) 1H - 7.74 (d) 1H 7.56 (m) 2H - 7.44 (m) 2H 7.30 (masked) 1H N-CH3 2.65 (sl)
H mobile 11.38
EXAMPLE 23 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).

PHARMACOLOGICAL 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 250.degree. C. for 150 minutes, put back on a water bath at 0.degree. C., 5 minutes, filtered under vacuum, rinsed with Tris buffer pH 7.4 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 concentration of product studied, expressed in nM, necessary to displace 50 t of the specific radioactivity fixed on the studied receptor.

Results

<tb> Product <SEP> of <SEP> Example <SEP> IC50 <SEP> in <SEP> nanomoles
<tb> 2 <SEP> 911
<tb><SEP> 4 <SEP> 52
<tb><SEP> 12 <SEP> 105
<tb> 16 <SEP> 99
<tb> 19 <SEP> 207
<tb> 6 <SEP> 270
<tb> 2 - Demonstration of the angiotensin II antagonistic activity on the 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 370C and oxygen with a 95% O2 mixture, 5% CO 2. 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> the example <SEP> IC50 <SEP> in <SEP> nanomales
<tb><SEP> 4 <SEP> 1 <SEP> 9.5 <SEP> I <SEP>
<tb><SEP> 16 <SEP> 45
<tb><SEP> 2 <SEP> 1000
<tb> 3 - Angiotensin II Antagonist Activity Test in Demenched 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 heparinized (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
inhibitor at 50% of the studied effect is thus determined (Dl50).

 Each animal is considered his own witness.

Results

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

Claims (14)

RIA, R2A, R3A and R5A are such that either R1A, R2A, R3A and R5A are identical and represent a hydrogen atom, one of R2A and R5A 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 RIA and R3A are such that one represents one hydrogen atom and the other is chosen from the radicals -OR6, R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms,  in which

 CLAIMS 1) Products of formula (IA): R4 represents a free, esterified or salified carboxy radical, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I ). 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 represents 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 R1o, 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, R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms,  in which

R4A represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, said products of formula (IA) being in all the possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said formula products 2) Products of formula (IA), as defined in claim 1 and corresponding to formula (I)  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,

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, - the optionally acylated hydroxy radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - the free, esterified or salified carboxy radical, - The radical  -C02R7 and -R11, radicals in which 3) Products of formula (IA) as defined in claim 1 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 and organic acids of said products of formula 4) Products of formula (IA) as defined in claims 1 to 3 wherein R represents a butyl radical and R1A, R2A, R3A and R5A represent a hydrogen atom, said products of formula (IA) being in any form racemic isomers, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula 5) Products of formula (IA) as defined in claim 1, in which R represents a butyl radical, R1A, R2A, and R5A represent a hydrogen atom, and R3A 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 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 hydroxy radical, - alkyloxy radicals or linear or branched alkenyloxy 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 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 that the addition salts with the mineral and organic acids of said products of formula 6) Products of formula (IA) as defined in claims 1 and 4 wherein R represents a butyl radical and R1A, R2A and R5A represent a hydrogen atom, and R3A represents a free carboxy radical or esterified by. an alkyl radical containing at most 4 carbon atoms; alkyl or alkenyl formyl having at most 4 alkyl carbon atoms substituted by one or more radicals selected from halogen atoms, hydroxy, acyloxy, amino optionally substituted by one or two alkyl radicals containing at most 4 carbon atoms; free, salified or esterified carboxy, said products of formula (IA) being in all the possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (7) Methyl 4 '- [(2-butyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylate and its salts with mineral or organic acids, 4'-t (2-butyl) -1H-benzimidazole 1-yl) methyl] biphenyl-2-carboxylic acid and its salts with mineral or organic acids, 2-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] 1H-benzimidazole-7-carboxylic acid and its salts with inorganic or organic acids, 4 '- E [2-butyl 7- (2-hydroxyethyl) -1H-benzimidazol-1-yl] methyl] biphenyl-2-carboxylic acid and its salts with mineral or organic acids , 4 '- [(2-butyl-7-formyl-1H-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid and its salts with inorganic or organic acids. 8) Process for the preparation of products of formula (IA) as defined in claim 1, characterized in that a product of formula (IVA) is reacted

 wherein R1A ', R2A', R3A 'and R5A' have the meanings given in claim 1 respectively for R1A, R2A, R3A and R5A in which the optional reactive functions are optionally protected by protective groups, and R has the meaning indicated in claim 1 with a compound of formula (VA)

 in which Hal represents a halogen atom and R4A 'has the meaning indicated in claim 1 for R4A in which the optional reactive functional groups are optionally protected by protective groups, to obtain products of formula (IXA)

 wherein R, R1A ', R2A', R3A ', R5A' and R4A 'have the meanings indicated above, a product of formula (IXA) which is treated, if desired and if necessary, with one or more the following reactions, in any order - an elimination reaction of the protective groups which can carry the protected reactive functions, - a salification reaction with a mineral or organic acid to obtain the corresponding salt, - an esterification reaction or salification of an acid function, - an acid or alkaline hydrolysis reaction of an ester function in acid function, - a conversion reaction of an alkyloxy function in the hydroxyl function, - a conversion reaction of a radical haloalkyl radical alkylene, - a substitution reaction of a halogen atom with an amino radical, - a substitution reaction of a hydroxyl radical with a halogen atom, - a reduction reaction of an esterified carboxy radical in a hydroxyalkyl, - an oxidation reaction of a hydroxyalkyl radical to an esterified carboxy radical, - an oxidation reaction of a hydroxymethyl radical to a formyl radical, - a doubling reaction of the racemic forms to double products, - a reaction of conversion of a free, salified or esterified carboxy function to a tetrazolyl radical, said products of formula (IA) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereoisomers. 9) Process according to claim 8 characterized in that the products of formula IXA are prepared by reaction or a compound of formula (VIA)

 in which R1A ', R2A', R3Al and R5A 'have the meanings indicated in claim 8, with the compound of formula (II)

 wherein R is as defined in claim 1 and Rg is hydroxy, alkyloxy or halogen to give the product of formula (XA)

  wherein R, R1A ', R2A', R3A 'and R5A' have the above meanings, or by reaction of a compound of formula (VIA ')

 in which R1A ', R2A, R3A' and R5A 'have the above meanings, with the compound of formula (II) as defined above to obtain the product of formula (XA')

 wherein RiA ', R2A', R3A ', R5A' and R have the meanings indicated above, which is subjected to a nitration reaction to obtain the compound of formula (XA) as defined above, and produced from formula (XA) which is reacted with the compound of formula (VA)

 in which Hal represents a halogen atom and R4A 'has the meaning indicated in claim 1 for R4A in which the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (XIA)

 in which R, R 1A ', R 2A', R 3A ', R 5A' and R 4A 'have the above meanings, which are subjected to a selective reduction reaction of the nitro function, to obtain the product of formula (XIIA)

 wherein R ', R1A', R2A ', R3A', R5 'and R4A' have the above meanings, which are subjected to a cyclization reaction to obtain products of formula (IXA). 10) Process according to claim 8 characterized in that the products of formula IXA are prepared by reaction of a compound of formula VIA

 wherein R1 ', R2A', R3A 'and R5A' have the meanings given in claim 1, with the compound of formula (VA)

 in which Hal represents a halogen atom and R4A 'has the meaning indicated in claim 1 for R4A in which the optional reactive functions are optionally protected by protective groups, to obtain products of formula (VIIA)

 wherein R1A ', R2A', R3A ', R5A' and R4A 'have the meanings indicated above, which are subjected to a reduction reaction of the nitro radical to the amino radical to obtain products of formula (VIIIA):

 wherein R1A ', R2A', R3Al R5A 'and R4A' have the meanings indicated above, which is reacted with the product of formula (III)

 in which X represents an oxygen atom or a radical = NH, Rg represents a hydroxy, alkyloxy or a halogen atom and R has the meaning indicated in claim 1, to obtain a product of formula (IXA). 11) As medicaments, the products as defined by the formula (IA) of claim 1, said products of formula (IA) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the pharmaceutically acceptable inorganic and organic acids of said formula products 12) As medicaments, the products of formula (IA) as defined in claims 2 to 7, as well as addition salts with pharmaceutically acceptable inorganic and organic acids of said products of formula 13) Pharmaceutical compositions containing as active principle, at least one of the medicaments as defined in any one of claims 11 and 12. 14) As new industrial products, the compounds of formula (IVA), (VIIA), (VIIIA), (XA) and (XA ').