FR2672597A1 - New N-substituted quinoline 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 (I): in which: R1 represents hydrogen, alkyl, alkenyl, alkynyl, acyl, cyano or carboxyl in the free, salified or esterified form, R2 and R3, which are identical or different, represent: hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, sulpho, formyl, benzoyl, acyl, carboxyl, in the free, salified or esterified form, cycloalkyl, alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, aryl, arylalkyl, arylalkenyl, aryloxy, arylthio, or . The meaning of the other radicals is given in the description. The said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms, and the addition salts of the said products of formula (I). These products have advantageous pharmacological properties.

Description

The present invention relates to novel derivatives
N-substituted quinoline, their process of preparation, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them.

dans laquelle
R1 représente un atome d'hydrogène, un radical alkyle, alkényle ou alkynyle linéaire ou ramifié renfermant au plus 6 atomes de carbone et éventuellement substitué, ou un radical acyle, cyano, carboxy libre, salifié ou estérifié,
R2 et R3, identiques ou différents, représentent a) un atome d'hydrogène, un atome d'halogène, un radical hydroxyle, mercapto, cyano, nitro, sulfo, formyle, benzoyle, acyle ayant au plus 12 atomes de carbone, carboxy libre, salifié ou estérifié, cycloalkyle renfermant de 3 à 7 atomes de carbone, b) un radical alkyle, alkényle, alkynyle, alkyloxy ou alkylthio, ces radicaux étant linéaires ou ramifiés, renfermant au plus 6 atomes de carbone et étant éventuellement substitués, c) un radical aryle, arylalkyle, arylalkényle, aryloxy ou arylthio dans lesquels les radicaux alkyle et alkényle, linéaires ou ramifiés, renferment au plus 6 atomes de carbone, ces radicaux aryle, arylaîkyle, arylalkényle ou arylthio étant tels que le radical aryle représente un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués, d) un radical

dans lesquels ou bien R6 et R7 ou R8 et Rg, identiques ou différents, représentent - un atome d'hydrogène, - un radical alkyle ou alkényle renfermant au plus 6 atomes de carbone et éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle, - un radical alkyle ou alkényle renfermant de 2 à 6 atomes de carbone substitué par un radical alkyloxy renfermant au plus 6 atomes de carbone, - un radical aryle ou arylalkyle dans lequel le radical alkyle linéaire ou ramifié renferme au plus 6 atomes de carbone, ces radicaux aryle et arylalkyle étant tels que le radical aryle représente un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluorométhyle, nitro, les radicaux alkyle, alkényle, alkyloxy, alkylthio et acyle, ces radicaux renfermant au plus 6 atomes de carbone, le radical carboxy libre, salifié ou estérifié, ou bien R6 et R7 ou R8 et Rg forment respectivement ensemble avec l'atome d'azote auxquels ils sont lies un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs héteroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et etant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluorométhyle, nitro, les radicaux alkyle, alkényle, alkyloxy, alkylthio et acyle, ces radicaux renfermant au plus 6 atomes de carbone, le radical carboxy libre, salifié ou estérifié, ou bien R8 et Rg, identiques ou differents ou l'un de R6 ou
R7, représentent un radical acyle dérivé d'acide carboxylique renfermant au plus 6 atomes de carbone,
X represente un atome d'oxygène ou un atome de soufre,
A représente un atome d'azote ou un radical C-R4 dans lequel
R4 peut prendre les mêmes valeurs que le radical R1, etant entendu que lorsque A représente un atome d'azote ou un radical CH, R1 ne représente pas un atome d'hydrogène,
R5 représente un radical divalent alkylène, linéaire ou ramifié, renfermant au plus 4 atomes de carbone,
Y représente le radical -Y1-B-Y2 dans lequel
Y1 représente un radical aryle monocyclique comprenant 5 ou 6 chaînons ou constitué de cycles condenses comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote ou de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les radicaux que peuvent représenter R2 ou R3,
B représente soit une simple liaison entre Y1 et Y2, soit l'un des radicaux divalents suivants : -CO- , -NH-CO-, -CO-NH-, -O-(CH2)n~ ou -S-(CH2), avec n représentant les valeurs 0 à 4, Y2 représente soit, si B représente une simple liaison, un atome d'hydrogène ou d'halogène, un radical hydroxyle, cyano, nitro, trifluorométhyle, carboxy libre, salifié ou estérifié, tetrazole ou isoxazole, soit, quelle que soit la valeur de B et Y2 etant identique ou différent de Y1, les valeurs définies pour Y1, étant entendu que les produits de formule (I) ne peuvent pas représenter les produits dans lesquels X représente un atome d'oxygène et tels que ou bien A représente un radical CH substitue par un radical méthyle lui-même substitue par un radical carboxy libre ou estérifié, R1, R2 et R3 identiques représentent tous trois un atome d'hydrogène et -RS-Y représente un radical benzyle substitue par un atome de fluor, ou bien A représente un radical CH, R1, R2 et R3, identiques représentent tous trois un radical methyle et -R5 -Y représente un radical benzyle, ou bien A représente un atome d'azote, R1 représente un radical éthyle substitué par un radical carboxy libre ou ester fié, cyano ou carbamoyle, l'un de R2 et R3 représente un atome d'hydrogène et l'autre représente un radical alkyle, alkyloxy ou phényle, -R5-Y represente un radical benzyle éventuellement substitué par un radical alkyle, alkyloxy ou phényle, lesdits produits de formule (I) etant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (I).The subject of the present invention is the products of formula (I)

in which
R1 represents a hydrogen atom, an alkyl, alkenyl or alkynyl linear or branched radical containing at most 6 carbon atoms and optionally substituted, or an acyl, cyano, free carboxy, salified or esterified,
R2 and R3, which may be identical or different, represent a) a hydrogen atom, a halogen atom, a hydroxyl, mercapto, cyano, nitro, sulfo, formyl or benzoyl radical, acyl having at most 12 carbon atoms, and free carboxy; , salified or esterified, cycloalkyl containing from 3 to 7 carbon atoms, b) an alkyl, alkenyl, alkynyl, alkyloxy or alkylthio radical, these radicals being linear or branched, containing at most 6 carbon atoms and being optionally substituted, c) an aryl, arylalkyl, arylalkenyl, aryloxy or arylthio radical in which the linear or branched alkyl and alkenyl radicals contain at most 6 carbon atoms, these aryl, arylalkyl, arylalkenyl or arylthio radicals being such that the aryl radical represents a monocyclic radical; comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from among the atomic groups; oxygen, nitrogen and sulfur, and being optionally substituted, d) a radical

in which either R6 and R7 or R8 and Rg, which are identical or different, represent - a hydrogen atom, - an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted with one or more radicals chosen from the atoms of halogen and the hydroxyl radical, - an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms, - an aryl or arylalkyl radical in which the linear or branched alkyl radical contains at least plus 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals selected from among the atoms halogen, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radical, or R6 and R7 radicals; or R8 and Rg respectively form together with the nitrogen atom to which they are attached a monocyclic radical comprising 5 or 6 members or a radical consisting of 8 to 10 membered fused rings, these radicals optionally containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals; these radicals containing at most 6 carbon atoms, the carboxy radical free, salified or esterified, or R8 and Rg, identical or different or one of R6 or
R7 represents an acyl radical derived from a carboxylic acid containing at most 6 carbon atoms,
X represents an oxygen atom or a sulfur atom,
A represents a nitrogen atom or a radical C-R4 in which
R4 can take the same values as the radical R1, it being understood that when A represents a nitrogen atom or a radical CH, R1 does not represent a hydrogen atom,
R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms,
Y represents the radical -Y1-B-Y2 in which
Y1 represents a monocyclic aryl radical comprising 5 or 6 members or consisting of 8 to 10 membered condensed rings, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, and being optionally substituted by one or more radicals chosen from radicals that can represent R2 or R3,
B represents either a single bond between Y1 and Y2, or one of the following divalent radicals: -CO-, -NH-CO-, -CO-NH-, -O- (CH2) n- or -S- (CH2 ), where n represents the values 0 to 4, Y2 represents either, if B represents a single bond, a hydrogen or halogen atom, a hydroxyl, cyano, nitro, trifluoromethyl, free carboxy, salified or esterified, tetrazole radical; or isoxazole, that is, regardless of the value of B and Y2 being identical to or different from Y1, the values defined for Y1, it being understood that the products of formula (I) can not represent the products in which X represents an atom of oxygen and as such or A represents a radical CH substituted by a methyl radical itself substituted by a free or esterified carboxy radical, R1, R2 and R3 are all identical to a hydrogen atom and -RS-Y represents a benzyl radical substituted by a fluorine atom, or A represents a radical CH, R1, R2 and R3, identical to all of them represent a methyl radical and -R5 -Y represents a benzyl radical, or A represents a nitrogen atom, R1 represents an ethyl radical substituted by a free carboxy radical or ester ester, cyano or carbamoyl, one of R2 and R3 represent a hydrogen atom and the other represents an alkyl, alkyloxy or phenyl radical, -R5-Y represents a benzyl radical optionally substituted by an alkyl, alkyloxy or phenyl radical, said products of formula (I) being under all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

In the products of formula (I) and in the following, the term "linear or branched alkyl radical" preferably denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl radicals, but can also represent a pentyl or hexyl radical and particularly isopentyl and isohexyl, - the term linear or branched alkenyl radical preferably denotes a vinyl, allyl, 1-propenyl, butenyl and particularly buten-1-yl, or pentenyl radical - the radical term linear or branched alkynyl preferably denotes an ethynyl, propargyl, butynyl or pentynyl radical, the term "acyl radical" preferably denotes a radical having at most 7 carbon atoms such as the acyl, propionyl, butyryl or benzoyl radical, but may also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical: mention may also be made of the formyl radical - the term esterified carboxy preferably denotes a lower alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or a benzyloxycarbonyl group; the term halogen atom preferably denotes the chlorine atom, but may also represent a fluorine, bromine or iodine atom; the term cycloalkyl preferably denotes a cyclopropyl, cyclopentyl or cyclohexyl radical, but also cyclobutyl; the term linear or branched alkyloxy radical preferably denotes the methoxy or ethoxy radicals, but may also represent a propoxy, isopropoxy or linear butoxy radical, secondary or tertiary, - the term linear or branched alkylthio radical refers to radicals in which the alkyl radical may represent, for example, the values indicated above for the alkyl radical; the alkylthio radical preferably represents the methylthio or ethylthio radicals, but may also represent a propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, isopentylthio or isohexylthio radical, the term aryl radical denotes the monocyclic radicals or consisting of carbocyclic or heterocyclic fused rings, it being understood that the heterocyclic radicals may contain one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms and that when these heterocyclic radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicals heterocyclic radicals may be the same or different, the term monocyclic radical preferably denotes the radicals which contain 5 or 6 members, as monocyclic carbocyclic radical, there may be mentioned the phenyl radical; among the heterocyclic monocyclic radicals, there may be mentioned, for example, the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl radicals such as delta 2 -pyrrolinyl, imidazolinyl radical; such as delta-2-imidazolinyl, pyrazolinyl such as delta-3-pyrazolinyl, as well as the positional isomers of the heteroatom (s) that these radicals may contain, such as, for example, the tetrazolyl, isothiazolyl or isoxazolyl radicals, the radical term constitutes rings. condensed radicals preferably denotes radicals containing 8 to 14 members among the radicals consisting of carbocyclic fused rings, for example naphthyl and phenanthryl radicals, among radicals consisting of heterocyclic condensed rings, for example, benzothienyl, naphtho [2,3-b] thienyl, indanyl, indenyl, thianthrenyl, isobenzyl, obenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl , quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazo pyrimidinyl or condensed polycyclic systems consisting of monocyclic heterocyclic as defined, for example, above such as for example furo [2,3-b] pyrrole or thieno [2,3-b] furan, as examples of such aryl radical include phenyl, naphthyl, thienyl such as thien-2-yl and thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3-yl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl; , diazolyl, triazolyl, tetrazolyl, thiadiazolyl, thiatriazolyl e, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl; condensed heterocyclic groups containing at least one hetero atom selected from sulfur, nitrogen and oxygen, for example benzothienyl such as benzothien-3-yl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl; such aryl radicals may optionally be substituted, for example the N-substituted pyrrolyl radical, for example
N-methylpyrrolyl, the substituted 3- or 4-isoxazolyl radical, for example, 3-aryl-5-methylisoxazol-4-yl, the aryl group being for example a phenyl or halophenyl group - the terms arylalkyl and arylenkenyl denote radicals in which, respectively, the alkyl, alkenyl and aryl radicals can take the values defined above for these radicals; examples of such arylalkyl radicals include benzyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, indenylmethyl, thienylmethyl such as thien-2-ylmethyl, furylmethyl such as furfuryl, pyridylmethyl, pyrimidylmethyl or pyrrolylmethyl, it being understood that in the list non-exhaustive examples of radicals as mentioned above, the alkyl radical can be -représenté just as equally by the ethyl, propyl or butyl such as, for example, in the phenylethyl radical; examples of arylalkyl radicals are the examples given above of arylalkyl radicals in which the alkyl radical is replaced by an alkenyl radical such as, for example, in the phenylvinyl or phenylallyl radicals, it being understood that in these radicals the phenyl radical may it can also be replaced by a naphthyl or pyridyl radical, for example one of the aryl radicals as defined above in the non-exhaustive list of aralkyl radicals, the terms aryloxy and arylthio denote radicals in which the radical aryl may take the values defined above for this radical in a non-exhaustive manner include examples of such aryloxy and arylthio radicals such as, for example, phenoxy, naphthyloxy, pyridyloxy, phenylthio and naphthylthio radicals.

en particulier carbamoyle substitué représente par exemple un groupe N-monoalkyl inférieur carbamoyle, tel que N-méthylcarbamoyle, N-éthylcarbamoyle, un goupe N,N-dialkyl inférieur carbamoyle, tel que N,N-diméthylcarbamoyle, N,N-diéthylcarbamoyle ; un groupe N-(hydroxyalkyl inférieur) carbamoyle, tel que N-(hydroxyméthyl) carbamoyle, N-(hydroxyéthyl) carbamoyle, un groupe carbamoylalkyle inférieur, tel que carbamoylméthyle, carbamoyléthyle.In the products of formula (I) and in what follows - the terms monocyclic radical and radical consisting of condensed rings denote aryl radicals, ie unsaturated carbocyclic or heterocyclic radicals as defined above, but also denote saturated heterocyclic radicals. , it being understood that the heterocyclic radicals as defined above may contain one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms and that when these heterocycle radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicals may be identical or different from saturated heterocyclic monocyclic radicals, for example pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl radicals, among the radicals consisting of saturated heterocyclic condensed rings, it is possible to mention, for example, mention, for example, diaza-l, 10 anthr yle-4, - the term linear or branched alkylene radical preferably denotes the methylene and ethylene radicals but also the n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene and tert-butylene radicals, the term carbamoyl denotes the unsubstituted carbamoyl radical or the substituted carbamoyl radical, for example, as indicated below for

in particular substituted carbamoyl represents, for example, an N-monoalkyl-lower carbamoyl group, such as N-methylcarbamoyl, N-ethylcarbamoyl, an N, N-dialkyl lower carbamoyl group, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl; N- (lower hydroxyalkyl) carbamoyl, such as N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, lower carbamoylalkyl, such as carbamoylmethyl, carbamoylethyl.

désignent des radicaux dans lesquels à l'atome d'azote sont liés deux radicaux, identiques ou différents, choisis parmi l'atome d'hydrogène ; les radicaux alkyle tels que définis cidessus pour donner de préférence les radicaux monoalkyl- ou dialkylamino dans lesquels les radicaux alkyles linéaires ou ramifiés renferment de 1 à 6 atomes de carbone et en particulier des radicaux méthyle, éthyle, isopropyle, trifluorométhyle, pentafluoroéthyle, hydroxymêthyle, hydroxyéthyle, methoxyméthyle, méthoxyéthyle, éthoxyéthyle ; les radicaux alkényle tels que definis ci-dessus et représentés de préférence par les radicaux vinyle et allyle ; les radicaux aryle ou arylalkyle tels que définis ci-dessus, carbocycliques ou hétérocycliques et en particulier phényle, benzyle, phénéthyle, naphtyle, indolyle, indolinyle, thiényle, furyle, pyrrolyle, pyridylef pyrrolidinyle, pipéridino, morpholino, pipérazinyle, ces radicaux pouvant être substitués par un ou plusieurs radicaux tels que définis ci-dessus comme par exemple dans méthylpipérazinyle, fluorométhylpiperazinyle, ethylpiperazinyle, propylpipérazinyle, phénylpipérazinyle ou ben zylpipérazinyle. The amino radicals that can represent one or more of the possible substituents of the radicals defined in the products of formula (I) and in what follows and that can represent in particular the radicals

denote radicals in which at the nitrogen atom are bound two radicals, identical or different, chosen from the hydrogen atom; the alkyl radicals as defined above to give preferably monoalkyl or dialkylamino radicals in which the linear or branched alkyl radicals contain from 1 to 6 carbon atoms and in particular methyl, ethyl, isopropyl, trifluoromethyl, pentafluoroethyl and hydroxymethyl radicals, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxyethyl; alkenyl radicals as defined above and preferably represented by vinyl and allyl radicals; aryl or arylalkyl radicals as defined above, carbocyclic or heterocyclic and in particular phenyl, benzyl, phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino, morpholino, piperazinyl, these radicals being capable of being substituted by one or more radicals as defined above such as, for example, in methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benylpiperazinyl.

 When R 6 and R 7, on the one hand, or R 8 and R 6, on the other hand, together with the nitrogen atom to which they are bonded, form a heterocycle, it is, for example, a pyrrolyl, imidazolyl or pyridyl ring. pyrazinyl, pyrimidyl, indolyl, indolinyl, purinyl, quinolyl, pyrrolidinyl, piperidyl, piperidino, morpholino, piperazinyl; these radicals may be optionally substituted by the substituents already mentioned above and in particular by one or more radicals chosen from chlorine and fluorine atoms, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy and benzoyl radicals, methoxycarbonyl, ethoxycarbonyl, such as, for example, in methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl. In these last two radicals, the phenyl and benzyl radicals may be substituted as indicated previously in the aryl, arylalkyl and arylalkenyl radicals.

 The acyl radicals that may represent R8 and Rg are as defined above and may be chosen for example from acetyl, propionyl, butyryl, valeryl or carbamoyl radicals.

 The radicals Y1 and Y2 may represent the values defined above for the monocyclic or condensed ring aryl radicals, it being understood that in the case where B represents a single bond Y2 may also represent a non-cyclic radical such as, for example, a hydrogen atom, a cyano radical or a carboxy radical, free, salified or esterified, this esterified carboxy radical preferably denotes a lower alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl.

 The radicals Y1 or Y2, which are identical or different, may represent an aryl radical optionally substituted by one or more radicals chosen, preferably, from halogen atoms, hydroxyl, nitro, tetrazole, isoxazole radicals, alkyl radicals, alkenyl radicals, alkyloxy, acyl and free carboxy, salified or esterified, these radicals containing at most 6 carbon atoms and being as defined above.

 The addition salts with the mineral or organic acids of the products of formula (I) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic or benzoic acids, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulphonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.

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

The alkyl, alkenyl and alkynyl radicals as defined above, as well as the alkyl or alkenyl radicals of the alkylthio, arylalkyl and arylalkenyl radicals as defined above, may not be substituted or carry one or more chosen substituents, for example in the group formed by halogen atoms, such as chloro or bromo, as in, for example, the 2-bromoethyl group; hydroxyl radicals; aryl as defined above, either a monocyclic radical or constituted by carbocyclic or heterocyclic fused rings, it being understood that the heterocyclic radicals as defined above may contain one or more heteroatoms chosen from oxygen, nitrogen and or sulfur and that when these heterocyclic radicals comprise more than one heteroatom, the heteroatoms of these heterocyclic radicals may be identical or different, this heterocyclic radical may be bonded by a carbon atom or, where appropriate, by an atom of arylalkyl nitrogen in which the aryl radical is as defined above; cycloalkyl, for example cyclopropyl, cyclopentyl or cyclohexyl; cycloalkenyl such as for example the cyclohexenyl radical may be optionally substituted, among which 1,3-dimethylcyclohexene may be mentioned; alkyloxy, as defined above, for example methoxy, ethoxy, n-propoxy or iso-propoxy, such as, for example, methoxymethyl or 1-ethoxyethyl; substituted alkyloxy such as (trihaloalkyl) oxy such as, for example, trifluoromethoxy; aryloxy, for example phenoxy; (arylalkyl) oxy, for example benzyloxy mercapto; alkylthio, for example methylthio or substituted ethylthio alkylthio such as trihaloalkylthio such as, for example, trifluoromethylthio; arylthio; aralkylthio; amino as in, for example, the 2-aminoethyl group; amino substituted with one or two radicals selected from, for example, alkyl, alkenyl, aryl and arylalkyl as defined above such as, for example, monoalkylamino in, for example, methylamino or ethylamino, such as, for example, dialkylamino in, for example, dimethylamino; nitro; cyano azido; carboxy; esterified carboxy, for example methoxycarbonyl or ethoxycarbonyl; formyl; acyl, for example acetyl, propionyl or benzoyl; acyl substituted, for example, by an amino radical as defined above or by a cyclic radical bonded to the acyl radical by a nitrogen atom, this cyclic radical possibly containing one or more heteroatoms chosen from nitrogen atoms, oxygen or sulfur and as defined above; acyloxy, for example acetoxy or propionyloxy; carbamoyl; carbamoyl substituted, for example, N-lower monoalkyl carbamoyl, such as N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dialkyl-lower carbamoyl, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl; an N- (lower hydroxyalkyl) carbamoyl group, such as N- (hydroxymethyl) carbamoyl,
N- (hydroxyethyl) carbamoyl, a lower carbamoylalkyl group, such as carbamoylmethyl, carbamoylethyl; phthalimido; acylamido, for example acetamide or benzamido; alkoxycarbonylamino, for example methoxycarbonylamino or ethoxycarbonylamino; or (arylalkyl) oxycarbonylamino, for example benzyloxycarbonylamino.

 The aryl and alkyloxy radicals as defined above and the aryl radicals of the arylalkyl and arylalkenyl radicals as defined above, may not be substituted or carry one or more substituents chosen, for example, from the list indicated above. for the possible substituents of the alkyl, alkenyl and alkynyl radicals as defined above, such as, for example, to give the o-chlorophenyl radical but may also be substituted by one or more radicals chosen from the group formed by the alkyl radicals, such as lower alkyl for example methyl, ethyl, or also isopropyl or tert-butyl; alkenyl; substituted alkyl such as for example trihaloalkyl as in trifluoromethyl; alkenyl such as, for example, vinyl or allyl; alkynyl such as, for example, propargyl.

dans lesquels ou bien R10 et R11 ou R12 et R13, identiques ou differents, représentent - un atome d'hydrogène, - un radical alkyle ou alkényle renfermant au plus 6 atomes de carbone et éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle, - un radical alkyle ou alkényle renfermant de 2 à 6 atomes de carbone substitué par un radical alkyloxy renfermant au plus 6 atomes de carbone, - un radical aryle ou arylalkyle dans lequel le radical alkyle linéaire ou ramifié renferme au plus 6 atomes de carbone, ces radicaux aryle et arylalkyle étant tels que le radical aryle représente un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluorométhyle, nitro, les radicaux alkyle, alkényle, alkyloxy et acyle, ces radicaux renfermant au plus 6 atomes de carbone, les radicaux carboxy libre, salifié ou estérifié, ou bien R10 et R11 ou R12 et R13 forment respectivement avec l'atome d'azote auxquels ils sont liés un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluo méthyle, nitro, les radicaux alkyle, alkényle, alkyloxy et acyle, ces radicaux renfermant au plus 6 atomes de carbone, les radicaux carboxy libre, salifié ou estérifié, ou bien R12 et R13, identiques ou différents, ou l'un de R10 et Roll, représentent un radical acyle dérivé d'acide carboxylique renfermant au plus 6 atomes de carbone, lesdits produits de formule (I) étant sous toutes les formes isomères possibles racémiques, énantiomères et diastéréo isomères, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (I).The subject of the invention is in particular the products of formula (I) as defined above, characterized in that the substituent or substituents, which may be identical or different, may carry a) the alkyl, alkenyl and alkynyl radicals that R 1 may represent, b) the alkyl, alkenyl, alkynyl, alkyloxy and alkylthio radicals which R 2 and R 3 can represent, c) the aryl, arylalkyl, arylalkenyl, aryloxy and arylthio radicals that R 2 and R 3 can represent, are chosen from the group formed by - the atoms of halogen, hydroxyl, cyano, nitro, formyl, acyl or acyloxy radicals having at most 6 carbon atoms, benzoyl, carboxy free, salified or esterified with an alkyl radical containing at most 6 carbon atoms, and alkyl and alkenyl containing at most 6 carbon atoms and optionally substituted by one or more substituents chosen from halogen atoms, the hydroxyl radical and alkyloxy radicals containing at most 6 carbon atoms carbamoyl, free or esterified carboxy, tetrazole, - linear and branched alkyloxy and alkylthio radicals containing at most 6 carbon atoms, - aryl and arylalkyl radicals in which the linear or branched alkyl radical contains not more than 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen atoms, nitrogen and sulfur, and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms. carbon, free, salified or esterified carboxy radicals, radicals

in which R10 and R11 or R12 and R13, identical or different, represent - a hydrogen atom, - an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted by one or more radicals chosen from the atoms of halogen and the hydroxyl radical, - an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms, - an aryl or arylalkyl radical in which the linear or branched alkyl radical contains at least plus 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted with one or more radicals chosen from ato halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms, free, salified or esterified carboxy radicals, or R10 and R11 or R12 and R13 respectively form, with the nitrogen atom to which they are bonded, a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from the atoms of oxygen, nitrogen and sulfur, and being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radicals, or R12 and R13, which are identical or different, or one of R10 and Roll, represent a radical a carboxylic acid derivative acyl radical containing at most 6 carbon atoms, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

tels que définis ci-dessus peuvent prendre respectivement les mêmes valeurs que celles définies pour.Radicals

as defined above can respectively take the same values as those defined for.

the radicals

 Among the substituents which may include the alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, aryl, arylalkyl and arylalkenyl radicals as defined above, may be mentioned more particularly the halogen atoms, such as chloro and bromo; hydroxyl radicals; acyl such as, for example, acetyl, propionyl, butyryl, valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl; benzoyl; esterified carboxy preferably referring to a lower alkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl; alkyl such as methyl or ethyl; amino; substituted amino, such as monoalkyl- and dialkylamino, for example methylamino, ethylamino or dimethylamino; alkyloxy, for example methoxy, ethoxy or isopropoxy; aryl such as phenyl, biphenyl, naphthyl, indenyl, indolyl or indolinyl; aralkyl such as, for example benzyl or phenethyl alkyl, alkyloxy and aryl radicals as defined above may themselves be substituted by one or more radicals, identical or different, chosen, for example, from the group formed by the hydroxyl radicals; alkyl or linear or branched alkyloxy, for example methyl, ethyl, tert-butyl, methoxy, ethoxy, isopropoxy; substituted amino, such as monoalkyl and dialkylamino, for example methylamino, ethylamino or dimethylamino; carbocyclic or heterocyclic monocyclic radicals containing 6 members such as phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidyl, piperazinyl, piperidino and morpholino radicals; carbocyclic or heterocyclic monocyclic radicals containing 5 members, such as, for example, furyl, pyrrolyl, pyrrolinyl, imidazolyl or pyrazolyl, isothiazolyl, isoxazolyl, pyrrolidinyl, imidazolidinyl or pyrazolidinyl radical; radicals consisting of carbocyclic or heterocyclic fused rings, among which for example the naphthyl, indolyl, quinolyl or purinyl radicals, as well as their isomers of position of the heteroatom (s), for example nitrogen, such as, for example, the indazolyl or isoquinolyl radical.

 When such heterocyclic radicals contain one or more nitrogen atoms, this or these nitrogen atoms may not be substituted or one or more of these nitrogen atoms may be substituted, for example, by an alkyl radical or linear or branched alkyloxy containing from 1 to 5 carbon atoms, as defined above, for example methyl, ethyl, isopropyl, tert-butyl, methoxy or ethoxy, a phenyl or benzyl radical, these radicals may themselves be substituted by the substituents already mentioned above for the aryl and arylalkyl radicals: there may be mentioned, as examples, the methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl radicals.

 Among the particularly preferred values of such radicals, mention may be made especially of phenyl, naphthyl, pyridyl, piperazinyl, pyrimidinyl, pyridazinyl and pyrazinyl radicals.

Such products of formula (I) may thus represent quinoline derivatives when A represents a radical
C-R4 as defined above and cinnoline derivatives when A represents a nitrogen atom.

Rla représente un radical n-butyle ou butényle,
R2a et R3at identiques ou différents, sont choisis dans le groupe formé par - l'atome d'hydrogène, - les atomes d'halogène, - le radical hydroxyle, - le radical mercapto, cyano, nitro, formyle, benzoyle, acyle ayant au plus 6 atomes de carbone, sulfo, - les radicaux carboxy libre, salifié ou estérifié par un radical alkyle linéaire ou ramifié renfermant au plus 4 atomes de carbone, tétrazole, - les radicaux alkyle, alkyloxy et alkylthio linéaires ou ramifiés renfermant au plus 6 atomes de carbone, phényle, naphtyle, benzyle et phénylthio, tous ces radicaux étant éventuellement substitués par un ou plusieurs radicaux identiques ou différents choisis parmi les atomes d'halogène, le radical hydroxyle, les radicaux alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, - les radicaux amino, mono- ou dialkylamino, carbamoyle, pyrrolyle, morpholino, pipérazinyle, pyrrolylméthyle, morpholinométhyle, pipérazinylméthyle, pyrrolylcarbonyle, morpholinocarbonyle, pipérazinylcarbonyle, tous les radicaux pipérazinyle étant éventuellement substitués sur le second atome d'azote par un radical alkyle ou-phényle, ces radicaux alkyle et phényle étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes hydroxyle, halogène, nitro, alkyle ou alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, A a représente un atome d'azote ou un radical CR4a dans lequel
R4a représente un atome d'hydrogène, un radical acyle renfermant au plus 6 atomes de carbone, cyano, carboxy libre, salifié ou estérifié par un radical alkyle renfermant au plus 4 atomes de carbone ou alkyle renfermant au plus 6 atomes de carbone éventuellement substitué par un ou plusieurs radicaux choisis parmi le radical hydroxyle et les atomes d'halogène,
X représente un atome d'oxygène ou un atome de soufre,
R5 représente un radical divalent alkylène, linéaire ou ramifié, renfermant au plus 4 atomes de carbone,
Ya représente un radical phényle ou biphenyle éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux hydroxyle, halogène, alkyle et alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, nitro, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, 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 miné-raux et organiques ou avec les bases minérales et organiques desdits produits de formule (I).The subject of the invention is particularly the products of formula (I) as defined above, and corresponding to formula (Ia):

Rla represents an n-butyl or butenyl radical,
R2a and R3at are identical or different, are chosen from the group formed by - the hydrogen atom, - the halogen atoms, - the hydroxyl radical, - the mercapto, cyano, nitro, formyl, benzoyl, acyl radical having at least plus 6 carbon atoms, sulfo, - free carboxy radicals, salified or esterified by a linear or branched alkyl radical containing not more than 4 carbon atoms, tetrazole, - linear or branched alkyl, alkyloxy and alkylthio radicals containing not more than 6 atoms of carbon, phenyl, naphthyl, benzyl and phenylthio, all these radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radical, alkyloxy radicals containing at most 4 carbon atoms, trifluoromethyl, cyano, carboxy free, salified or esterified, tetrazole and isoxazole, - amino, mono- or dialkylamino, carbamoyl, pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morphol radicals inomethyl, piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl, piperazinylcarbonyl, all piperazinyl radicals being optionally substituted on the second nitrogen atom by an alkyl or phenyl radical, these alkyl and phenyl radicals being themselves optionally substituted with one or more radicals chosen from the hydroxyl, halogen, nitro, alkyl or alkyloxy atoms containing at most 4 carbon atoms, trifluoromethyl, cyano, free carboxy, salified or esterified, tetrazole and isoxazole, A a represents a nitrogen atom or a CR4a radical in which
R4a represents a hydrogen atom, an acyl radical containing at most 6 carbon atoms, cyano, free carboxy, salified or esterified with an alkyl radical containing at most 4 carbon atoms or alkyl containing at most 6 carbon atoms optionally substituted by one or more radicals chosen from the hydroxyl radical and the halogen atoms,
X represents an oxygen atom or a sulfur atom,
R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms,
Ya represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from hydroxyl, halogen, alkyl and alkyloxy radicals containing at most 4 carbon atoms, trifluoromethyl, cyano, nitro, free carboxy, salified or esterified, tetrazole and isoxazole, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the invention is particularly the products of formula (I) as defined above, in which
R1 represents an n-butyl radical,
R2 and R3, which are identical or different, are chosen from the group formed by the hydrogen atom, the mercapto and alkylthio radicals, the linear or branched alkyl radicals containing at most 6 carbon atoms and optionally substituted with one or several identical or different substituents chosen from halogen atoms, the hydroxyl radical, the amino, mono- and dialkylamino radical, pyrrolidine, morpholine, piperidine, the free carboxy radical, salified or esterified by a linear or branched alkyl radical containing plus 4 carbon atoms, pyrrolidinylcarbonyl, morpholinylcarbonyl, carbamoyl, dialkylcarbamoyl, piperidynylcarbonyl,
A represents a nitrogen atom or a CH radical,
X represents an oxygen atom or a sulfur atom,
R5 represents a methylene radical,
Y represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from cyano, free carboxy, salified and esterified, tetrazole and isoxazole radicals, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms; as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

 Among the products which are the subject of the invention, the products of formula (I) corresponding to the following definitions may be mentioned in particular: 4 '- F (3-butyl-1,4-dihydro-4-oxo-1-quinolinyl) ) methyl] - (1,1'-biphenyl) -2-carboxylic acid 4 '- ((3-butyl-1,4-dihydro-4-thioxo-1-quinolinyl) methyl] (1,1'-biphenyl) 2-carboxylic acid 3-butyl 1- (2 '-carboxy (1,1'-biphenyl) 4-yl) methyl] -1,4-dihydro-4-oxo-7-quinolinecarboxylic acid 4 '- [(3-Butyl-1,4-dihydro-8-bromo-4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -2-carboxylic acid 4' - ((3-butyl-1,4-) 7- (hydroxymethyl) 4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -carboxylic acid dihydroxy 4 '- [(3-butyl-1,4-dihydro-4-oxo) - ((1-pyrrolidinyl) ) carbonyl] 1-quinolinyl) methyl (1,1'-biphenyl) 2-carboxylic acid.

dans laquelle R2, et R3, ont les significations indiquées ci-dessus, respectivement pour R2 et R3 dans lesquelles les éventuelles fonctions réactives sont éventuellement protégées par des groupements protecteurs, avec un produit de formule (III)

dans laquelle R1' et R4' ont les significations indiquées
ci-dessus, respectivement pour R1 et R4 dans lesquelles les
éventuelles fonctions réactives sont éventuellement protégées
par des groupements protecteurs et alk représente un radical
alkyle renfermant au plus 6 atomes de carbone, pour obtenir
des produits de formule (IV)

dans laquelle R1,, R2', R3', R4, et alk ont les significations indiquées ci-dessus, que l'on cyclise pour obtenir des produits de formule (V)

dans laquelle R1', R2', R3, et R4' ont les significations indiquées ci-dessus, soit l'on fait réagir un produit de formule (VI)

dans laquelle R2, et R3, ont les significations indiquées ci-dessus, avec un produit de formule (VII)
RI1-CCH (VII) dans laquelle R1' a la signification indiquée ci-dessus, pour obtenir des produits de formule (VIII)

dans laquelle R1', R2, et R3' ont les significations indiquées ci-dessus, que l'on soumet à une réaction de cyclisation pour obtenir un produit de formule (IX)

dans laquelle R1', R21 et R3" ont les significations indiquées ci-dessus, produits de formule (V) et (IX) que, si désiré, l'on soumet à une réaction de transformation de la fonction oxo en une fonction thioxo et que l'on fait réagir avec un composé de formule (X)
Hal-R5'-Y' (X) dans laquelle R5' et Y' ont les significations indiquées ci-dessus, respectivement pour R5 et Y dans lesquelles les éventuelles fonctions réactives sont éventuellement protégées par des groupements protecteurs, pour obtenir un produit de formule (I')

dans laquelle R1', R2', R3', R4,, R5' et Y' ont la signification indiquée ci-dessus et dans laquelle A représente le radical C-R4, ou un atome d'azote, et X a la signification indiquée ci-dessus, produit de formule (I') que l'on soumet, si désiré et si nécessaire, à l'une ou plusieurs des réactions suivantes, dans un ordre quelconque - une réaction de transformation de fonction oxo C=O en fonction thioxo C=S, - une réaction d'élimination des groupements protecteurs que peuvent porter les fonctions réactives protégées, - une réaction de salification par un acide minéral ou organique ou par une base minérale ou organique pour obtenir le sel correspondant, - une réaction d'estérification de fonction acide, - une réaction de saponification de fonction ester en fonction acide, - une réaction de transformation de fonction alkyloxy en fonction hydroxyle, - une réaction de transformation de la fonction cyano en fonction acide, - une réaction de réduction de la fonction carboxy en fonction alcool, - une réaction de dédoublement des formes racémiques, lesdits produits de formule (I) 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 (I) as defined above, characterized in that either a product of formula (II) is reacted.

in which R2, and R3, have the meanings indicated above, respectively for R2 and R3 in which the possible reactive functional groups are optionally protected by protective groups, with a product of formula (III)

in which R1 'and R4' have the meanings indicated
above, respectively for R1 and R4 in which the
any reactive functions are eventually protected
by protective groups and alk represents a radical
alkyl having not more than 6 carbon atoms, to obtain
products of formula (IV)

in which R 1, R 2 ', R 3', R 4, and alk have the meanings indicated above, which are cyclized to obtain products of formula (V)

in which R 1 ', R 2', R 3, and R 4 'have the meanings indicated above, or a product of formula (VI) is reacted

in which R2, and R3, have the meanings indicated above, with a product of formula (VII)
RI1-CCH (VII) in which R1 'has the meaning indicated above, to obtain products of formula (VIII)

wherein R1 ', R2, and R3' have the meanings indicated above, which is subjected to a cyclization reaction to obtain a product of formula (IX)

in which R1 ', R21 and R3 "have the meanings indicated above, products of formula (V) and (IX) that, if desired, is subjected to a conversion reaction of the oxo function to a thioxo function and that is reacted with a compound of formula (X)
Hal-R5'-Y '(X) in which R5' and Y 'have the meanings indicated above, respectively for R5 and Y in which the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (I ')

in which R 1 ', R 2', R 3 ', R 4, R 5' and Y 'have the meaning indicated above and wherein A represents the radical C-R 4, or a nitrogen atom, and X has the indicated meaning above, a product of formula (I ') which is subjected, if desired and if necessary, to one or more of the following reactions, in any order - an oxo C = O function conversion reaction depending on the thioxo C = S, - a reaction of elimination of the protective groups that can carry the protected reactive functions, - a salification reaction with a mineral or organic acid or a mineral or organic base to obtain the corresponding salt, - a reaction of esterification of an acid function, - a saponification reaction of an acid functional ester function, - a conversion reaction of alkyloxy function to hydroxyl function, - a conversion reaction of the cyano function to an acid function, - a reaction of reduction of the function of function carboxy in alcohol function, - a resolving reaction of the racemic forms, said products of formula (I) thus obtained being in all isomeric forms possible racemic, enantiomers and diastereoisomers.

 Under preferred conditions of implementation of the invention, the above process is carried out as follows: the product of formula (IV) can be obtained by reaction of the carbonyl derivative of formula (III) with the free amine function of product of formula (II) for example in the presence of a solvent such as for example toluene or an alcohol such as methanol or refluxing acetic acid; the reaction can also be carried out in the absence of solvent by bringing the mixture to the melting point of the compounds, in the presence or absence of a drying agent such as, for example, Siliporite.

 The cyclization reaction of the product of formula (IV) thus formed into a product of formula (V) may be carried out for example by heating the compound to its melting point or in a solvent such as, for example, biphenyl oxide or a mixture of phenyl and biphenyl oxide at a temperature of about 100 to 250OC.

 the product of formula (VIII) can be obtained by reaction of the product of formula (VII) with the halogenated derivative of formula (VI) for example in the presence of a copper salt such as for example copper iodide and a catalyst such as for example a palladium catalyst.

 The cyclization reaction of the product of formula (VIII) thus formed into a product of formula (IX) can be carried out for example by the action of nitrous acid obtained in situ for example in the presence of sodium or potassium nitrite in an acid medium such as as for example in hydrochloric acid.

 The products of formulas (V) and (IX) may be subjected to a conversion reaction of the oxo function to thioxo function which may be carried out according to the usual methods known to those skilled in the art such as for example using the Lawesson reagent or phosphorus pentasulfide reflux in a solvent such as for example toluene or an alcohol such as for example ethanol.

 The addition of the product of formula (X) to the free amine function of the product of formula (V) or (IX) to obtain products of formula (I ') can be carried out for example in the presence of a weak base such that for example sodium carbonate or potassium or in the presence of sodium hydride under reflux in a solvent such as for example acetone, ether or tetrahydrofuran.

 The oxo function of the products of formulas (V) and (IX) can also be protected and the addition reaction then operates on the free amine function defined above, by simple heating with the product of formula (X) .

 The addition of the product of formula (X) to the free amine function of the product of formula (V) gives products of formula (I ') in which A represents the radical = C-R 4, as defined above and addition of the product of formula (X) to the free amine function of the product of formula (IX) gives products of formula (I ') in which A represents a nitrogen atom.

 According to the values of R 1 ', R 2, R 3, R 5', A, Y 'and X, the products of formula (I') thus obtained are or are not products of formula (I).

 The products of formula (I ') thus obtained, in particular to give products of formula (I), may be subjected, if desired and if necessary, to one or more of the reactions indicated above.

 Of these, the conversion reaction of the oxo function to thioxo function can be carried out as indicated above.

 The various reactive functions that certain compounds of the reactions defined above may carry may, if necessary, be protected: for example, they are hydroxyl, acyl, free carboxy or amino and monoalkylamino radicals which may be protected by protective groups. appropriate.

 The following list, not exhaustive, of examples of protection of reactive functions can be mentioned - the hydroxyl groups can be protected for example by alkyl radicals such as tert-butyl, trialkylsilyl, dihydropyran, methoxymethyl or tetrahydropyranyl, - the amino groups can be protected. be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, phthalimido or other radicals known in the peptide chemistry, the acyl groups such as the formyl group may be protected for example in the form of cyclic ketals or non-cyclic such as dimethyl or diethylketal or ethylene dioxyketal, the acid functions of the products described above can be, if desired, amidated by a primary amine or secondary amine for example in methylene chloride in the presence of hydrochloride. ethyl-3- (dimethylaminopropyl) carbodiimide at room temperature, They may be protected, for example, in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.

 The elimination of these protective groups is 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 acid, benzene sulphonic acid or para-toluenesulphonic acid, formic or trifluoroacetic acid.

 The phthalimido group is removed by hydrazine.

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

 The products described above may, if desired, be the subject of salification reactions with a mineral or organic acid or with a mineral or organic base, in particular on the possible carboxy functions, these reactions being able to be carried out according to the usual methods. known to those skilled in the art.

 The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art.

 The optional ester functions of the products described above can be, if desired, saponified in acidic function, these saponification reactions can be carried out under the usual conditions known to those skilled in the art, especially by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid.

 The optional alkyloxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl 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 possible cyano functions of the products described above may, if desired, be converted into an acidic function under the usual conditions known to those skilled in the art, for example by double hydrolysis carried out in acidic medium such as, for example, in a mixture of sulfuric acid of glacial acetic acid and water, these three compounds being preferably in equal proportions, or in a mixture of sodium hydroxide, ethanol and refluxing water.

 The optional carboxy or esterified carboxy functions of the products described above can, if desired, be reduced in alcohol function by the methods known to those skilled in the art and in particular by lithium aluminum hydride in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether.

 The possible optically active forms of the products of formula (I) may be prepared by resolution of the racemates according to the usual methods.

 The subject of the invention is also a process for the preparation of the products of formula (I), characterized in that the products of formulas (V) and (IX) are taken as starting products and in that the operation is carried out as indicated previously.

 The subject of the invention is also a process for the preparation of the products of formulas (V) and (IX), characterized in that the products of formula (II) are taken as starting products and in that the operation is carried out as indicated previously.

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

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

 These properties justify their application in therapy and the subject of the invention is also, as medicaments, the products as defined by formula (I) above, said products of formula (I) being in any isomeric forms possible racemic or optically active, as well as addition salts with pharmaceutically acceptable inorganic or organic acids of said products of formula (I).

Rla représente un radical n-butyle ou butényle,
R2a et R3at identiques ou différents, sont choisis dans le groupe formé par - l'atome d'hydrogène, - les atomes d'halogène, - le radical hydroxyle, - le radical mercapto, cyano, nitro, formyle, benzoyle, acyle ayant au plus 6 atomes de carbone, sulfo, - les radicaux carboxy libre, salifié ou estérifié par un radical alkyle linéaire ou ramifié renfermant au plus 4 atomes de carbone, têtrazole, - les radicaux alkyle, alkyloxy et alkylthio linéaires ou ramifiés renfermant au plus 6 atomes de carbone, phényle, naphtyle, benzyle et phénylthio, tous ces radicaux étant éventuellement substitués par un ou plusieurs radicaux identiques ou différents choisis parmi les atomes d'halogène, le radical hydroxyle, les radicaux alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, - les radicaux amino, mono- ou dialkylamino, carbamoyle, pyrrolyle, morpholino, pipérazinyle, pyrrolylméthyle, morpholinométhyle, pipérazinyleméthyle, pyrrolylcarbonyle, morpholinocarbonyle, pipérazinylcarbonyle, tous les radicaux pipérazinyle étant éventuellement substitués sur le second atome d'azote par un radical alkyle ou phényle, ces radicaux alkyle et phényle étant eux-mêmes éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes hydroxyle, halogène, nitro, alkyle ou alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, A a représente un atome d'azote ou un radical CR4a dans lequel
R4a représente un atome d'hydrogène, un radical acyle renfermant au plus 6 atomes de carbone, cyano, carboxy libre, salifié ou estérifié par un radical alkyle renfermant au plus 4 atomes de carbone ou alkyle renfermant au plus 6 atomes de carbone éventuellement substitué par un ou plusieurs radicaux choisis parmi le radical hydroxyle et les atomes d'halogène,
X représente un atome d'oxygène ou un atome de soufre,
R5 représente un radical divalent alkylène, linéaire ou ramifié, renfermant au plus 4 atomes de carbone, Y a représente un radical phényle ou biphényle éventuellement substitué par un ou plusieurs radicaux choisis parmi les radicaux hydroxyle, halogène, alkyle et alkyloxy renfermant au plus 4 atomes de carbone, trifluorométhyle, cyano, nitro, carboxy libre, salifié ou estérifié, tétrazole et isoxazole, 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 ou avec les bases minérales et organiques desdits produits de formule (I).The invention particularly relates, as medicaments, to the products of formula (I) as defined above and corresponding to formula (Ia)

Rla represents an n-butyl or butenyl radical,
R2a and R3at are identical or different, are chosen from the group formed by - the hydrogen atom, - the halogen atoms, - the hydroxyl radical, - the mercapto, cyano, nitro, formyl, benzoyl, acyl radical having at least plus 6 carbon atoms, sulfo, - free carboxy radicals, salified or esterified by a linear or branched alkyl radical containing not more than 4 carbon atoms, tetrazole, - linear or branched alkyl, alkyloxy and alkylthio radicals containing not more than 6 atoms of carbon, phenyl, naphthyl, benzyl and phenylthio, all these radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radical, alkyloxy radicals containing at most 4 carbon atoms, trifluoromethyl, cyano, carboxy free, salified or esterified, tetrazole and isoxazole, - amino, mono- or dialkylamino, carbamoyl, pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morphol radicals inomethyl, piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl, piperazinylcarbonyl, all piperazinyl radicals being optionally substituted on the second nitrogen atom by an alkyl or phenyl radical, these alkyl and phenyl radicals being themselves optionally substituted with one or more radicals chosen from hydroxyl, halogen, nitro, alkyl or alkyloxy atoms containing at most 4 carbon atoms, trifluoromethyl, cyano, free carboxy, salified or esterified, tetrazole and isoxazole, A a represents a nitrogen atom or a CR4a radical in which
R4a represents a hydrogen atom, an acyl radical containing at most 6 carbon atoms, cyano, free carboxy, salified or esterified with an alkyl radical containing at most 4 carbon atoms or alkyl containing at most 6 carbon atoms optionally substituted by one or more radicals chosen from the hydroxyl radical and the halogen atoms,
X represents an oxygen atom or a sulfur atom,
R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms, Y a represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from hydroxyl, halogen, alkyl and alkyloxy radicals containing at most 4 atoms of carbon, trifluoromethyl, cyano, nitro, free carboxy, salified or esterified, tetrazole and isoxazole, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic or with the inorganic and organic bases of said products of formula (I).

The subject of the invention is, as a medicinal product, the products of formula (I) as defined above, in which
R1 represents an n-butyl radical,
R2 and R3, which are identical or different, are chosen from the group formed by the hydrogen atom, the mercapto and alkylthio radicals, the linear or branched alkyl radicals containing at most 6 carbon atoms and optionally substituted with one or several identical or different substituents chosen from halogen atoms, the hydroxyl radical, the amino, mono- and dialkylamino radical, pyrrolidine, morpholine, piperidine, the free carboxy radical, salified or esterified by a linear or branched alkyl radical containing at most 4 carbon atoms, pyrrolidinylcarbonyl, morpholinylcarbonyl, carbamoyl, dialkylcarbamoyl, piperidynylcarbonyl,
A represents a nitrogen atom or a CH radical,
X represents an oxygen atom or a sulfur atom,
R5 represents a methylene radical,
Y represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from cyano, free carboxy, salified and esterified, tetrazole and isoxazole radicals, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms; as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases, pharmaceutically acceptable of said products of formula (I).

 The subject of the invention is more particularly, as medicaments, the products described hereinafter in the examples and in particular the products of formula (I) following 4 '- [(3-butyl) -1,4-dihydro- 4-oxo-1-quinolinyl) methyl] - (1,1'-biphenyl) -2-carboxylic acid 4 '- F (3-butyl-1,4-dihydro-4-thioxo-1-quinolinyl) methyl] (1,1'-biphenyl) 2-carboxylic acid 3-butyl 1-F <2 '-carboxy (1,1'-biphenyl) 4-yl) methyl] 1,4-dihydro-4-oxo-7 4 '- [(3-butyl-1,4-dihydro-8-bromo-4-oxo-1-quinolinyl) methyl (1,1'-biphenyl) -2-carboxylic acid, 4' - ((3-) -carboxylic acid butyl 1,4-dihydro-7- (hydroxymethyl) -4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -2-carboxylic acid 4'-t (3-butyl-1,4-dihydro-4-oxo) -7- [(1-pyrrolidinyl) carbonyl] 1-quinolinyl) methyl] (1,1'-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 disorders, gynecological and in particular for a relaxing effect in the uterus.

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

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

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

 Among the compounds of formula (II) which can be found commercially include for example certain compounds of formula (II) such that one of R2 'or R3' represents an amino radical such as for example meta-aminobenzoate methyl, which can be found, for example, in the form of a product marketed for example by LANCASTER.

 Other compounds of formula (II) which may be found commercially include, for example, certain compounds of formula (II) such that one of R2, or R3, represents a nitro radical such as, for example, orthonitroaniline which it can be found, for example, in the form of a product marketed by UCB.

 The compounds of formula (III) may constitute esters derived from formylacetic acid.

Among the examples of preparation of such compounds of formula (III) described in the literature, mention may in particular be made of the following references
J. Hel. Chem. 20, p. 623-628 (1983)
Liebigs Ann. Chem. 697, p. 62-68 (1966).

 The compounds of formula (VI) may in particular be derivatives of ortho-halo aniline.

Examples of the preparation of such compounds of formula (VI) described in the literature include the following references:
Ann. Chim. 1962, 52, p. 727.

 The compounds of formula (VII) may in particular be acetylene derivatives.

Among the examples of preparation of such compounds of formula (VII) described in the literature, mention may be made in particular of the following references
J. Am. Chem. Soc. 1937, 59, p. 1490.

 Examples of the preparation of compounds of formula (X) are described in the literature and examples are given in particular in US Patent 4,880,804.

soit le iodobenzoate de méthyle que l'on peut trouver, par exemple, sous forme de produit commercialisé par JANSSEN, à l'action d'un composé de formule (Xb)

soit du iodotoluène que l'on peut trouver, par exemple, sous forme de produit commercialisé par FLUKA, la réaction se réalisant par exemple en présence de cuivre en poudre à une température d'environ 100 C à 300"C, pour obtenir un produit de formule (Xc)

dont le radical carboxy estérifié peut, si désiré, être liberé du radical alkyle par les méthodes classiques connues de l'homme de métier ou indiquées ci-dessus, par exemple d'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 nbromosuccinimide dans le tétrachlorure de carbone.A process for the preparation of certain products of formula (X) as defined above may consist in subjecting the compound of formula (Xa)

either methyl iodobenzoate which can be found, for example, in the form of a product sold by JANSSEN, to the action of a compound of formula (Xb)

iodotoluene, which can be found, for example, in the form of a product marketed by FLUKA, the reaction being carried out for example in the presence of powdered copper at a temperature of about 100 ° C. to 300 ° C., in order to obtain a product of formula (Xc)

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 acid 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 nbromosuccinimide in carbon tetrachloride.

 The subject of the present invention is also, as new industrial products and especially as intermediates necessary for the preparation of the products of formula (I), the compounds of formula (I-V), (V) and (IX).

The subject of the present invention is also the use of the products of formula (F)

dans lesquels ou bien R6 et R7 ou R8 et Rg, identiques ou différents, représentent - un atome d'hydrogène, - un radical alkyle ou alkényle renfermant au plus 6 atomes de carbone et éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et le radical hydroxyle, - un radical alkyle ou alkényle renfermant de 2 à 6 atomes de carbone substitué par un radical alkyloxy renfermant au plus 6 atomes de carbone, - un radical aryle ou arylalkyle dans lequel le radical alkyle linéaire ou ramifié renferme au plus 6 atomes de carbone, ces radicaux aryle et arylalkyle étant tels que le radical aryle représente un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluorométhyle, nitro, les radicaux alkyle, alkényle, alkyloxy, alkylthio et acyle, ces radicaux renfermant au plus 6 atomes de carbone, le radical carboxy libre, salifié ou estérifié, ou bien R6 et R7 ou R8 et Rg forment respectivement ensemble avec l'atome d'azote auxquels ils sont liés un radical monocyclique comprenant 5 ou 6 chaînons ou un radical constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, cyano, trifluorométhyle, nitro, les radicaux alkyle, alkényle, alkyloxy, alkylthio et acyle, ces radicaux renfermant au plus 6 atomes de carbone, le radical carboxy libre, salifié ou estérifié, ou bien R8 et Rg, identiques ou différents, représentent un radical acyle dérivé d'acide carboxylique renfermant au plus 6 atomes de carbone,
X représente un atome d'oxygène ou un atome de soufre,
A représente un atome d'azote ou un radical =C-R4 dans lequel
R4 peut prendre les mêmes valeurs que le radical R1, étant entendu que lorsque A représente un atome d'azote ou un radical =C-H, R1 ne représente pas un atome d'hydrogène,
R5 représente un radical divalent alkylène, linéaire ou ramifié, renfermant au plus 4 atomes de carbone,
Y représente le radical -Y1-B-Y2 dans lequel
Y1 représente un radical aryle monocyclique comprenant 5 ou 6 chaînons ou constitué de cycles condensés comprenant 8 à 10 chaînons, ces radicaux renfermant éventuellement un ou plusieurs hétéroatomes choisis parmi les atomes d'oxygène, d'azote et de soufre, et étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les radicaux que peuvent représenter R2 ou R3,
B représente soit une simple liaison entre Y1 et Y2, soit l'un des radicaux divalents suivants : -CO-, -NH-CO-, -CO-NH-, -O-(CH2)n~ ou -S-(CH2)n~ avec n représentant les valeurs 0 à 4,
Y2 représente soit, si B représente une simple liaison, un atome d'hydrogène ou d'halogène, un radical hydroxyle, cyano, nitro, trifluorométhyle, carboxy libre, salifié ou estérifié, tétrazole ou isoxazole, soit, quelle que soit la valeur de B et Y2 étant identique ou différent de Y1, les valeurs définies pour Y1, lesdits produits de formule (F) étant, sous toutes les formes isomères possibles racémiques, énantiomères et diastéréoisomères, ainsi que les sels d'addition avec les acides minéraux et organiques ou avec les bases minérales et organiques desdits produits de formule (F) pour la préparation de médicaments, destinés soit au traitement de l'hypertension artérielle, des insuffisances cardiaques, des insuffisances rénales et dans la prévention des resténoses post-angioplastie, soit au traitement de certains désordres gastro-intestinaux ou gynécologiques.In which
R1 represents a hydrogen atom, a linear or branched alkyl, alkenyl or alkynyl radical containing at most 6 carbon atoms and optionally substituted, acyl, cyano, free carboxy, salified or esterified,
R2 and R3, which may be identical or different, represent a) a hydrogen atom, a halogen atom, a hydroxyl, mercapto, cyano, nitro, sulfo, formyl or benzoyl radical, acyl having at most 12 carbon atoms, and free carboxy; , salified or esterified, cycloalkyl containing from 3 to 7 carbon atoms, b) an alkyl, alkenyl, alkynyl, alkyloxy or alkylthio radical, these radicals being linear or branched, containing at most 6 carbon atoms and being optionally substituted, c) an aryl, arylalkyl, arylalkenyl, aryloxy or arylthio radical in which the linear or branched alkyl and alkenyl radicals contain at most 6 carbon atoms, these aryl, arylalkyl, arylalkenyl or arylthio radicals being such that the aryl radical represents a monocyclic radical; comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from among the atoms s oxygen, nitrogen and sulfur, and being optionally substituted, d) a radical

in which either R6 and R7 or R8 and Rg, which are identical or different, represent - a hydrogen atom, - an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted with one or more radicals chosen from the atoms of halogen and the hydroxyl radical, - an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms, - an aryl or arylalkyl radical in which the linear or branched alkyl radical contains at least plus 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals selected from among the atoms halogen, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radical, or R6 and R7 radicals; or R8 and Rg respectively form together with the nitrogen atom to which they are bonded a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals; these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radical, or R8 and Rg, which are identical or different, represent a radical a a carboxylic acid derivative compound having not more than 6 carbon atoms,
X represents an oxygen atom or a sulfur atom,
A represents a nitrogen atom or a radical = C-R4 in which
R4 can take the same values as the radical R1, it being understood that when A represents a nitrogen atom or a radical = CH, R1 does not represent a hydrogen atom,
R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms,
Y represents the radical -Y1-B-Y2 in which
Y1 represents a monocyclic aryl radical comprising 5 or 6 members or consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals chosen from radicals that can represent R2 or R3,
B represents either a single bond between Y1 and Y2, or one of the following divalent radicals: -CO-, -NH-CO-, -CO-NH-, -O- (CH2) n- or -S- (CH2 ) n ~ with n representing the values 0 to 4,
Y2 represents either, if B represents a single bond, a hydrogen or halogen atom, a hydroxyl, cyano, nitro, trifluoromethyl, free carboxy, salified or esterified, tetrazole or isoxazole radical, or, whatever the value of B and Y2 being identical to or different from Y1, the values defined for Y1, said products of formula (F) being, in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids; or with the inorganic and organic bases of said products of formula (F) for the preparation of medicaments, intended either for the treatment of arterial hypertension, cardiac insufficiency, renal insufficiency and in the prevention of post-angioplasty restenosis, or at the treatment some gastrointestinal or gynecological disorders.

 The present invention particularly relates to the use as defined above, characterized in that the products of formula (F) are used in the preparation of medicaments for the treatment of arterial hypertension, heart failure, deficiencies renal diseases and in the prevention of post-angioplasty restenosis.

 The present invention more particularly relates to the use as defined above, characterized in that the products of formula (F) correspond to formulas (Ia) and (I) as defined above.

 The following examples illustrate the invention without limiting it.

EXAMPLE 1: 4- <3-Butyl-1,4-dihydro-4-oxoquinolinyl methyl) benzonitrile
To a suspension of 2.3 g of the product obtained in Preparation 1 in 50 cm3 of acetone is added 3.3 g of activated potassium carbonate. After stirring for 10 minutes, 4.7 g of 4-bromobenzonitrile are added and the mixture is heated under reflux for 4 hours. The acetone is evaporated and the residue is taken up with 100 cm3 of water. Extracted with ethyl acetate, washed with saturated ammonium chloride solution, dried and evaporated to dryness. 4.1 g of the expected product are obtained, which is chromatographed on silica (eluent: methylene chloride-methanol (98-2)). 3.3 g of the desired product are collected. F = 168 C.

2235 cm'l 1630 cm'l 1587 cm'l 1558 cm'l 1510 cm'l 1490 cm-1
Préparation de l'exemple 1 : 3-butyl 4-chloro quinoléine
Le produit utilisé au départ de l'exemple 1 a été préparé de la façon suivante.IR spectrum (CHCL3)
Absence of NH C = -N, C = O
C = C
Aromatic

2235 cm -1 1630 cm -1 1587 cm -1 1558 cm -1 1510 cm -1 1490 cm -1
Preparation of Example 1: 3-butyl 4-chloroquinoline
The product used starting from Example 1 was prepared in the following manner.

Stage A: diethyl 2-butyl 3-oxo butanedioate
To a suspension of sodium ethoxide prepared by stirring for 1 hour at 40 ° C. of 2.3 g of sodium and 150 cm 3 of ethanol, and then evaporation of the solvent, in 100 cm 3 of ether, 13.55 cm 3 of diethyl oxalate. It is refluxed for 15 minutes, cooled slightly and 50 cm3 of ethyl caproate are added, the mixture is stirred for 3 hours under reflux and 16 hours at 30-35 C.

50 cm3 of water are added separating the aqueous phase, decantation, washed with ether twice and acidified with 2N hydrochloric acid. Extracted 3 times with ether, the organic phases washed with water and then with saturated sodium chloride solution, dried and evaporated to dryness. The product obtained, 9.5 g is used as such for the next stage.

Stage B: diethyl 2-butyl 3- (phenylamino) 2-butenedioate
It is stirred for 3 days at 75 ° C., a mixture of 1 g of aniline with 2.65 g of the product obtained in Stage A above and 150 mg of siliporite Q NK10, and the reaction medium is cooled and chromatographed on silica (eluent: hexane-ethyl acetate (9-1)) 1.55 g of expected product is obtained.

3260 cm1 1733 - 1656 cm'l 1610 cm1 (épaulement) 1596 cm-1 1584 cm-1 1500 cm-1
Stade C : 3-butyl 4-hydroxy 2-quinoléine carboxylate d'éthyle et 3-butyl 1,4-dihydro 4-oxo 2-quinoleine carboxylate d'éthyle
On chauffe pendant 30 minutes à l'aide d'un bain à 250"C un mélange de 2,5 g du produit obtenu au stade B ci-dessus, avec 30 cm3 de diphényléther. On laisse revenir à température ambiante, essore, lave avec du pentane et recueille 1,82 g de produit recherché.IR spectrum (in CHC1q) = C-NH
C = O
C = C
+
aromatic

3260 cm1 1733 - 1656 cm'l 1610 cm1 (shoulder) 1596 cm-1 1584 cm-1 1500 cm-1
Stage C: ethyl 3-butyl 4-hydroxy-2-quinolinecarboxylate and ethyl 3-butyl-1,4-dihydro-4-oxo-2-quinolinecarboxylate
A mixture of 2.5 g of the product obtained in Stage B above, with 30 cm 3 of diphenyl ether, is heated for 30 minutes using a bath at 250 ° C. The mixture is allowed to come to room temperature, drained, washed with pentane and collect 1.82 g of desired product.

1624 cm'l 1605 cm1 1585 cm'l 1572 cm1 1532 cm'l
Stade D : Acide 3-butyl 1,4-dihydro 4-oxo 2-quinoléine carboxyl ique
On chauffe 1 heure à 60"C, 1,8 g de l'ester obtenu au stade C ci-dessus, avec 25 cm3 de soude en solution N. On refroidit et acidifie avec de l'acide chlorhydrique N, on filtre, lave à l'eau et sèche à 60"C sous pression réduite, on obtient 1,58 g du produit recherché.IR spectrum (in CHCl 3) = C-NH 3425 - 3383 cm -1
C = O 1746 - 1706 cm 1 (F) other C = O
C = C
+
aromatic

1624 cm'l 1605 cm1 1585 cm'l 1572 cm1 1532 cm'l
Stage D: 3-Butyl-1,4-dihydro-4-oxo-2-quinoline carboxylic acid
1 hour at 60 ° C., 1.8 g of the ester obtained in Step C above, are heated with 25 cm 3 of sodium hydroxide solution N. The mixture is cooled and acidified with N hydrochloric acid, filtered, washed with water and dried at 60 ° C under reduced pressure, 1.58 g of the desired product is obtained.

NMR Spectrum 60 MHz (DMSO) ppm CH3-CH2-CH2 CH2 0.89 (t)
CCCC 1.39 (m)
CCCC- 2.78
H6 and H7 7.30 (t) - 7.63 (t)
H5 and H8 7.80 (d) - 8.08 (d)
Proton mobile 11.64
Stage E: 3-butyl 4 (1H) -quinolinone
A mixture of 1.55 g of the product obtained in Stage D above and 10 cm 3 of diphenyl ether is heated for 30 minutes at 250 ° C., cooled, filtered, washed with pentane and dried under reduced pressure. 17 g of product which is dissolved in 80 cm3 of ethanol and treated for 15 minutes under reflux in the presence of activated charcoal, filtered through hyflosupercel, the ethanol is evaporated to dryness and taken up with pentane, filter, lava with pentane and dried at 50 ° C under reduced pressure. 971 mg of desired product is obtained.

1632 cm-1 1590 cm'l 1570 cm'l (épaulement) 1558 cm'l 1524 cm'l 1506 cm-1
Stade F : 3-butyl 4-chloro quinoléine
On chauffe 2 heures à 120 C un mélange de 515 mg du produit obtenu au stade E ci-dessus avec 0,6 cm3 d'oxychlorure de phosphore. On refroidit, ajoute 10 cm3 d'eau et alcalinise à pH 9 avec de l'ammoniaque concentré. On extrait 2 fois avec du chlorure de méthylène, lave avec une solution saturée de chlorure de sodium, sèche et évapore à sec.Le résidu est dissous dans 30 cm3 d'éthanol et traite 15 minutes au reflux en présence de charbon actif, on filtre sur hyflosupercel, on obtient 511 mg du produit recherché
Spectre RMN CDC13 (250 MHz) CH3-CH2-CH2-CH2-C- 0,98 (t)
CH3-CH2-CH2-CH2-C- 1,45 (m) CH3-CH2-CH2 CH2 C 1,68 (m) CH3-CH2-CH2-CH2-C- 2,96 (m)
H aromatiques
H noyau pyridine

7,63 (dt) 7,72 (dt) 8,10 (dd) 8,25 (dd) 8,74 (s)
EXEMPLE 2 : Acide 4-[(3-butyl 1,4-dihydro 4-oxo l-quinoléinyl) méthyle benzoïque
On chauffe au reflux, sous agitation, pendant 4 heures un mélange de 0,5 g du produit obtenu à l'exemple 1 avec 8 cm3 d'éthanol et 1,6 cm3 de soude en solution 5N. On refroidit à 0 C et acidifie avec de l'acide chlorhydrique concentré.On agite 1 nuit à 0 C, essore, lave à l'eau, sèche, évapore à sec. On obtient 0,48 g de produit que l'on recristallise dans 20 cm3 d'éthanol. On recueille 275 mg du produit recherché.IR spectrum (in CHCl 3) (mixture 2 forms: enol and keto) = C-NH 3440 cm -1 + general absorption
C = O
C = C
aromatic

1632 cm -1 1590 cm -1 1570 cm -1 (shoulder) 1558 cm -1 1524 cm -1 1506 cm -1
Stage F: 3-butyl 4-chloroquinoline
A mixture of 515 mg of the product obtained in Stage E above with 0.6 cm3 of phosphorus oxychloride is heated for 2 hours at 120 ° C. Cool, add 10 cm3 of water and basify to pH 9 with concentrated ammonia. Extracted twice with methylene chloride, washed with saturated sodium chloride solution, dried and evaporated to dryness. The residue is dissolved in 30 cm3 of ethanol and treated for 15 minutes under reflux in the presence of activated charcoal. on hyflosupercel, we obtain 511 mg of the desired product
NMR spectrum CDCl3 (250 MHz) CH3-CH2-CH2-CH2-C-0.98 (t)
CH3-CH2-CH2-CH2-C- 1.45 (m) CH3-CH2-CH2 CH2 C 1.68 (m) CH3-CH2-CH2-CH2-C-2.96 (m)
Aromatic H
H pyridine nucleus

7.63 (dt) 7.72 (dt) 8.10 (dd) 8.25 (dd) 8.74 (s)
EXAMPLE 2: 4 - [(3-Butyl-1,4-dihydro-4-oxo-1-quinolinyl) methyl benzoic acid
A mixture of 0.5 g of the product obtained in Example 1 with 8 cm 3 of ethanol and 1.6 cm 3 of 5N sodium hydroxide is refluxed under stirring for 4 hours. It is cooled to 0 ° C. and acidified with concentrated hydrochloric acid. It is stirred overnight at 0 ° C., filtered off, washed with water, dried and evaporated to dryness. 0.48 g of product is obtained which is recrystallized from 20 cm3 of ethanol. 275 mg of the desired product is collected.

Mp = 224 C.

1623 cm-1 1614 cm-1 1562 cm-1 1535 cm-1 1494 cm-1
EXEMPLE 3 : 4'-E < 3-butyl 1,4-dihydro 4-oxo l-quinoléinyl) méthylj (l,l'-biphényl) 2-carboxylate de méthyle
On opère comme à l'exemple 1, à partir de 4,02 g du composé obtenu à la préparation 1 stade C, en utilisant 5,52 g de carbonate de potassium et 6,2 g de bromométhyl-(l,1'-biphé- nyl) 2-carboxylate de méthyle (préparation selon EP 0253310).Analysis for C21H21NO3 = 335.41
CHN% calculated 75.20 6.31 4.17% found 75.3 6.3 4.1
IR spectrum (CHC13)
Absence C = -N
Absorption complex type OH acid # C = O 1699 cm -1 -C = C
Aromatic other C = O

1623 cm-1 1614 cm-1 1562 cm-1 1535 cm-1 1494 cm-1
EXAMPLE 3 Methyl 4'-E-3-butyl-1,4-dihydro-4-oxo-quinolinyl) methyl (1,1'-biphenyl) -carboxylate
The procedure is as in Example 1, starting from 4.02 g of the compound obtained in Preparation 1, Stage C, using 5.52 g of potassium carbonate and 6.2 g of bromomethyl (l, l). biphenyl) 2-methyl carboxylate (preparation according to EP 0253310).

After chromatography on silica (eluent: methylene chloride-methanol (98-2)). 8 g of the desired product are obtained.

1723 cml 1437 cm-1
Autre C=O
C=C +
Aromatique

1628 cm-1 1583 cm1 1556 cm-1 1492 cm-1
EXEMPLE 4 : Acide 4'-E(3-butyî 1,4-dihydro 4-oxo l-quino léinyl) méthyl] (1,1'-biphényl) 2-carboxylique
On opère comme à l'exemple 2 à partir de 0,48 g du produit obtenu à l'exemple 3.IR spectrum (CHCl3)

1723 cml 1437 cm -1
Other C = O
C = C +
Aromatic

1628 cm-1 1583 cm1 1556 cm-1 1492 cm-1
EXAMPLE 4: 4'-E (3-butyl-1,4-dihydro-4-oxo-l-quinolinyl) methyl] (1,1'-biphenyl) -carboxylic acid
The procedure is as in Example 2 starting from 0.48 g of the product obtained in Example 3.

 After recrystallization from ethanol, 0.240 g of desired product is collected. Mp = 214 C.

1602 cm-1 1560 cm-1 1530 cm-1
EXEMPLE 5 : 49-[(3-butyl 1,4-dihydro 4-thioxo l-quinoléinyl) méthyle (1,1'-biphényl) 2-carboxylate de méthyle
A une solution de 400 mg du produit obtenu à l'exemple 3, dans 20 cm3 de toluène, on ajoute 210 mg de réactif de Lawesson et chauffe 1 heure 30 au reflux. On verse dans 100 cm3 d'eau et extrait avec de l'acétate d'éthyle, lave à l'eau, sèche, filtre et évapore à sec, on obtient 0,6 g du produit attendu que l'on chromatographie sur silice (éluant chlorure de méthylène - acétone (98-2)) pour recueillir 0,42 g du produit recherché F = 158 C.Analysis for: C27H25NO3 = 411.51
CHN% calculated 78.8 6.12 3.403% found 78.7 6.1 3.4
IR spectrum (CHC13)
Absorption complex OH / NH region # C = O 1665 - 1615 cm-1 -C = C
aromatic

1602 cm-1 1560 cm-1 1530 cm-1
EXAMPLE 5: Methyl (methyl 1,1'-biphenyl) 2-carboxylate methyl [1- (3-butyl-1,4-dihydro-4-thioxol-1-quinolinyl) methyl)
To a solution of 400 mg of the product obtained in Example 3, in 20 cm3 of toluene, 210 mg of Lawesson's reagent are added and the mixture is refluxed for 1 hour. Poured into 100 cm3 of water and extracted with ethyl acetate, washed with water, dried, filtered and evaporated to dryness, 0.6 g of the expected product is obtained which is chromatographed on silica ( eluent methylene chloride - acetone (98-2)) to collect 0.42 g of the desired product F = 158 C.

IR spectrum: CDCl3, C = O (ester) 1724 cm-1

<tb> System <SEP> Conjugate <SEP> 616 <SEP> cm-1 <SEP>
<tb><SEP> + <SEP> 1602 <SEP>cm'l<SEP>
<tb> Aromatic <SEP> 1548 <SEP> cm-1 <SEP>
<tb><SEP> 1499 <SEP> cm-1 <SEP>
<Tb>
EXAMPLE 6 4-Butyl-1,4-dihydro-4-thioxo-1-quinolinyl) -ethyl) (1,1'-biphenyl) -carboxylic acid
The procedure is as in Example 2 starting from 400 mg of product obtained in Example 5 using 15 cm3 of concentrated sodium hydroxide, 0.35 g of crude product F> 260 ° C. is collected. After recrystallization from ethanol, 270 mg of the desired product is obtained. F> 260 C.

Analysis for C27H25NO2S = 427.57
CHNS% calculated 75.85 5.89 3.27 7.5% found 75.7 5.8 3.2 7.5
IR spectrum (Nujol)
Acid OH region absorption
C = O 1701 - 1675 cm1

<tb><SEP> (l612 <SEP> cm-1 <SEP>
<tb> C = C <SEP> 1602 <SEP> cm-1 <SEP>
<tb><SEP> + <SEP>#<SEP><SEP> 1574 <SEP> cm-1 <SEP>
<tb> Aromatic <SEP> 1545 <SEP> cm-1 <SEP>
<tb><SEP> 1500 <SEP> cm-1 <SEP>
<Tb>
EXAMPLE 7 Methyl 4 '- [[3-butyl-1,4-dihydro-5- (methylthio) -4-oxo-1-quinolinyl] methyl] (1,1'-biphenyl) -carboxylate
The procedure is as in Example 1, starting from 1.1 g of the product obtained in Stage D of Preparation 2, using 1.63 g of methyl 4-bromomethyl (1,1'-biphenyl) 2-carboxylate. (prepared according to EP 0253310) and 1.2 g of potassium carbonate. After chromatography on silica (eluent: ethyl acetate-hexane (5-5)). 270 mg of the expected product are obtained.

NMR Spectrum (CDCl3) 250 MHz
CH3- (CH2) 2-CH2-C-0.91 (t)
CH3-CH2-CH2-CH2-C- 1.36 (m) CH3-CH2-CH2-CH2-C- 1.58 (m)
CH3- (CH2) 2 -CH2-C-2.56 (m)
SCH3 2.37 (s)
N-CH = C 7.47 (s)
N-CH2-C6H4 5.99 (o) CO2-CH3 3.57 (o)
7.04 - 7.21 (dl) aromatics and 7.25 to 7.83 (m) (6H)
8.44 (dd) (1H)
Preparation of Example 7: 3-butyl 5- (methylthio) 4- (1H) quinolinone
Step A: Diethyl 2-butyl 3 - [((3-methylthio) phenyl] amino] 2-butene dioate a) Preparation of diethyl 2-butyl-3-oxo-butenedioate
To a solution of sodium ethoxide, prepared by stirring for 1 hour at 40 ° C. with 2.3 g of sodium and 150 cm 3 of ethanol and then evaporation of the solvent, 100 cm 3 of ether and then 13.55 cm 3 of diethyl oxalate are added. . It is refluxed for 15 minutes, cooled slightly and 50 cm3 of ethyl caproate are added, the mixture is stirred for 3 hours at reflux and 16 hours at 30-35 ° C. 50 cm3 of water are added and the aqueous phase is separated by decantation. washed with ether twice and acidified with 2N hydrochloric acid. Extracted 3 times with ether, the organic phases washed with water and then with saturated sodium chloride solution, dried and evaporated to dryness. The product obtained 9.5 g is used as such for the next stage.

b) To a solution of 4.3 g of the product obtained above with 2 cm3 of 2-methyl mercaptoaniline, in 100 cm3 of toluene, 50 mg of para-toluenesulphonic acid is added. The mixture is stirred under reflux for 4 hours, removing the water formed. After evaporation to dryness and chromatography the residue on silica (eluent: methylene chloride at 30% hexane), 5.1 g of the desired product is obtained. F = 55 C.

IR spectrum (CHCl3) = C-NH complex 3240 cm -1
C = O 1732 - 1658 cm -1

<tb> C = C <SEP> 1598 <SEP> cm-1 <SEP>
<tb><SEP> + <SEP>#<SEP> 1583 <SEP> cm-1 <SEP>
<tb> Aromatic <SEP> l1488 <SEP> at <SEP>
<Tb>
Stage B: Ethyl 3-butyl-1,4-dihydro-5- (methylthio) -4-oxo-2-quinoline carboxylate
45 minutes at 250 ° C., 1 g of the product obtained in Stage A are heated for 45 minutes. The crude reaction product (eluent: methylene chloride) is cooled and chromatographed on silica to give 700 mg of the desired product. F = 80 C.

IR spectrum (CHCl3)
NH complex 3330 cm 1 (F)

<tb><SEP> 1743 <SEP> cm-1
<tb> C = O <SEP>#<SEP> 1707 <SEP><SEP> (f) <SEP>
<tb> C = O <SEP> + <SEP> 1610 <SEP> cm-1 <SEP>
<tb> C = C <SEP> + <SEP>, <SEP> 1596 <SEP> cm-1 <SEP>
<tb><SEP> 1559 <SEP> cm1 <SEP>
<tb> Aromatic <SEP> 1530 <SEP> at <SEP>
<Tb>
Stage C: 3-Butyl-1,4-dihydro-5 (methylthio) 4-oxo-2-quinoline carboxylic acid hydrochloride
0.63 g of the product obtained in Stage B above is stirred for 2 hours in 10 cm 3 of a sodium N solution. Poured into ice water, acidified with concentrated hydrochloric acid, filtered, washed with water, dried and pasted in 100 cm3 of ethyl acetate. 495 mg of the desired product are obtained.

1610 cm'l 1592 cm'l 1560 cm'l 1540 cm1 1516 cm1
Stade D : 3-butyl 5-(méthylthio) 4-(1H) quinoléinone
On chauffe 5 minutes à 260 C, 390 mg du produit obtenu au stade C. On obtient 300 mg de produit recherché. F = 144 C.IR spectrum (Nujol)
Absorption OH / NH 3328 cm-1
C = O 1744 cm-i
C = O
+
C = C
Aromatic

1610 cm'l 1592 cm'l 1560 cm'l 1540 cm1 1516 cm1
Stage D: 3-butyl 5- (methylthio) 4- (1H) quinolinone
The product obtained in Stage C is heated for 5 minutes at 260 ° C. and 390 mg of the product obtained. The desired product is obtained 300 mg. Mp = 144C.

1627 cm'l 1609 cm-1 1585 cm-1 1560 cm-1 1520 cm-1
EXEMPLE 8 : Acide 4'-[(3-butyl 1,4-dihydro 5-(méthylthio) 4-oxo l-quinoléinyl) méthyl) (l,l'-biphényl) 2-carboxylique
On agite pendant 2 heures au reflux un mélange de 270 mg du produit obtenu à l'exemple 7 avec 5 cm3 d'une solution de soude 5N dans 5 cm3 d'éthanol. On coule dans l'eau et acidifie avec de l'hydrogénophosphate de sodium, extrait avec de l'acétate d'éthyle, lave à l'eau, sèche et évapore à sec. On chromatographie le résidu sur silice (éluant : chlorure de méthylène-méthanol (9-1)). On empâte le produit obtenu dans un mélange de 5 cm3 d'acétate d'étyle et 5 cm3 d'éther isopropylique. On recueille ainsi 90 mg du composé recherché.IR spectrum (CHCl3) = C-NH 3365 cm-1
C = O
C = C
Aromatic

1627 cm -1 1609 cm -1 1585 cm -1 1560 cm -1 1520 cm -1
EXAMPLE 8 4 '- [(3-Butyl-1,4-dihydro-5- (methylthio) -4-oxo-1-quinolinyl) methyl) (1,1'-biphenyl) -2-carboxylic acid
A mixture of 270 mg of the product obtained in Example 7 with 5 cm 3 of a 5N sodium hydroxide solution in 5 cm 3 of ethanol is stirred for 2 hours under reflux. It is poured into water and acidified with sodium hydrogenphosphate, extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The residue is chromatographed on silica (eluent: methylene chloride-methanol (9-1)). The product obtained is impasted in a mixture of 5 cm 3 of ethyl acetate and 5 cm 3 of isopropyl ether. 90 mg of the desired compound is thus collected.

 F = 155 -C.

1728 cm-1 (ep) acide 1698 cm'l (max) 1624 cm1 1604 cm-1 1577 cm-1 1542 cm1
EXEMPLE 9 : 3-butyl 1-[[2'-(methoxycarbonyl) (l,l'-biphényl) 4-yl] méthyl) 1,4-dihydro 4-oxo 7-quinoléine carboxylate de méthyle
On opère comme à l'exemple 1 à partir de 220 mg du produit obtenu au stade E de la préparation ci-dessous et en utilisant 285 mg de bromométhyl (1-1'-biphényl) 2-carboxylate de méthyle (préparation selon EP 0253310).Analysis for C28H27NO3S = 457.60
CHNS% calculated 73.5 5.95 3.06 7.00% found 73.5 5.8 3.2 6.8
IR spectrum (CHCl)
C = O
C = O +
C = C +
aromatic

1728 cm-1 (ep) acid 1698 cm -1 (max) 1624 cm -1 1604 cm -1 1577 cm -1 1542 cm -1
EXAMPLE 9 Methyl 3-butyl 1 - [[2 '- (methoxycarbonyl) (1,1'-biphenyl) -4-yl] methyl) 1,4-dihydro-4-oxo-7-quinolinecarboxylate
The procedure is as in Example 1 starting from 220 mg of the product obtained in Step E of the preparation below and using 285 mg of methyl bromomethyl (1-1'-biphenyl) 2-carboxylate (preparation according to EP 0253310 ).

 After chromatography on silica (eluent: methylene chloride - acetonitrile 87-13), 340 mg of the desired product is obtained.

IR spectrum (CHCl3)
C = O 1723 cm-1 (F) ester

<tb> C = O <SEP> 1631 <SEP> cm-1 <SEP>
<tb><SEP> + <SEP> 1590 <SEP> cm-1 <SEP>
<tb> Aromatic <SEP>#<SEP><SEP> 1548 <SEP> cm-1 <SEP>
<tb><SEP> + <SEP> 1514 <SEP> cm-1 <SEP>
<tb> C = C <SEP> 1495 <SEP> cm-1 <SEP>
PREPARATION OF EXAMPLE 9 Methyl 3-butyl-1,4-dihydro-4-oxo-7-quinolinecarboxylate
Stage A: 2-butyl 3-tt3- (methoxycarbonyl) phenyl] amine diethyl 2-butenedioate
A solution of 3.02 g of methyl meta-benzoate and 4.9 g of diethyl 2-butyl-3-oxo-butane dioate is prepared in 100 ml of toluene to which 20 mg of para-toluenesulphonic acid is added. It is stirred under reflux for about 4 hours. The mixture is evaporated to dryness and the residue is chromatographed on silica (eluent: ethyl acetate-hexane (2-8)).

6.5 g of expected product are obtained.

avec Me : 1438 cm 1
C=O 1655 cm'l ester chelaté
C=C +
Aromatique

1596 cm-1 (F) 1493 cm'l
Stade B : 3-butyl 1,4-dihydro 4-oxo 2,7-quinoléine dicarboxylate de 2-éthyle 7-méthyle
On opère comme au stade B de la préparation 2 à partir de 6 g du produit obtenu au stade A ci-dessus.IR spectrum (CHCl 3) = C-NH complex -3250 cm -1
C = O 1725 cm-1 conjugated esters of which

with Me: 1438 cm 1
C = O 1655 cm -1 chelated ester
C = C +
Aromatic

1596 cm-1 (F) 1493 cm -1
Stage B: 2-ethyl 7-methyl 3-butyl 1,4-dihydro 4-oxo 2,7-quinoline dicarboxylate
The procedure is as in Stage B of Preparation 2 from 6 g of the product obtained in Step A above.

 After chromatography on silica (eluent ethyl acetate-hexane (4-6)) 1.8 g of the expected product.

F = 210 C.

3422 cm-1 3377 cm'l
Max : 1724 cm-1 (esters) 1631 cm'l 1605 cm-1 1569 cm'l 1537 cm-1 1439 cm-1
Stade C : Acide 3-butyl 1,4-dihydro 4-oxo 7-quinoléine carboxylique
On opère comme au stade C de la préparation 2 à partir de 1,8 g du produit obtenu ci-dessus au stade B.IR spectrum (CHCl3) = C-NH
C = O complex
Region C = O
C = C +
aromatic
Me CO2CH3

3422 cm-1 3377 cm-1
Max: 1724 cm -1 (esters) 1631 cm -1 1605 cm -1 1569 cm -1 1537 cm -1 1439 cm -1
Stage C: 3-butyl-1,4-dihydro-4-oxo-7-quinoline carboxylic acid
The procedure is as in Stage C of Preparation 2 from 1.8 g of the product obtained above in Stage B.

 1.27 g of the expected product are obtained. F> 260 C.

1631 cm-1 1593 cm-1 1550 cm'l 1520 cm-1
Stade D : Acide 3-butyl 1,4-dihydro 4-oxo 2,7-quinoléine dicarboxyl ique
On opère comme au stade D de la préparation 2 à partir de 1,23 g du produit obtenu au stade C ci-dessus.IR spectrum (Nujol)
Region OH / NH Max 3385 cm-1
3280 cm-1 + general absorption
C = O 1688 cm-1 complex
C = C
+
aromatic

1631 cm -1 1593 cm -1 1550 cm -1 1520 cm -1
Stage D: 3-butyl-1,4-dihydro-4-oxo-2,7-quinoline dicarboxylic acid
The procedure is as in Stage D of Preparation 2 from 1.23 g of the product obtained in Step C above.

 1 g of the expected product is obtained.

1710 cm-1 1692 cm1 1640 cm-1 1619 cm-1 1594 cm1 1570 cm-1 1517 cm-1
Stade E : 3-butyl 1,4-dihydro 4-oxo 7-quinoléine carboxylate de méthyle
A une solution dans le chlorure de méthylène du produit obtenu ci-dessus au stade D, on ajoute du diazométhane jusqu'à coloration jaune persistante. L'excès de diazométhane est détruit à l'acide acétique. On évapore à sec le milieu et on recueille le produit attendu.IR spectrum (Nujol)
Absorption complex OH / NH region
C = O
C = C
aromatic

1710 cm-1 1692 cm1 1640 cm-1 1619 cm-1 1594 cm1 1570 cm-1 1517 cm-1
Stage E: Methyl 3-butyl-1,4-dihydro-4-oxo-7-quinoline carboxylate
To a solution in methylene chloride of the product obtained above in Stage D, diazomethane is added until a persistent yellow coloring. Excess diazomethane is destroyed with acetic acid. The medium is evaporated to dryness and the expected product is collected.

EXAMPLE 10: 3-Butyl-1 - ((2'-carboxy (1,1'-biphenyl) -4-yl] methyl] 1,4-dihydro-4-oxo-7-quinoline carboxylic acid
The procedure is as in Example 2, from 290 mg of the product obtained in Example 9, using 5 cm3 of a 5N sodium hydroxide solution. 210 mg of the desired product is obtained.

F> 260 C.

1706 cm-1 1628 cm-1 1590 cm-1 1576 cm-1 1540 cm-1 1498 cm-1
EXEMPLE il : 4'-(3-butyl 1,4-dihydro 7-(hydroxyméthyl) 4-oxo 1-quinoléimyl) méthyl] (1,1'-biphényl) 2-carboxylate de méthyle
On opère comme à l'exemple 1 à partir de 160 mg du produit obtenu selon la préparation décrite ci-après, en utilisant 260 mg de bromométhyl (1,1'-biphényl) 2-carboxylate de méthyle (préparation selon EP 0253310). Après chromatographie sur silice (éluant : chlorure de méthylène-méthanol (955)). On obtient 280 mg du produit recherché. F = 140 C.Analysis for C28H25NO5 = 455.515
CHN% calculated 73.83 5.53 3.07% found 73.7 5.5 3.0
IR spectrum (Nujol)
General OH / NH absorption
C = O
C = C
aromatic

1706 cm-1 1628 cm -1 1590 cm -1 1576 cm -1 1540 cm -1 1498 cm -1
EXAMPLE 11 Methyl 4 '- (3-butyl-1,4-dihydro-7- (hydroxymethyl) -4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -carboxylate
The procedure is as in Example 1 starting from 160 mg of the product obtained according to the preparation described hereinafter, using 260 mg of methyl bromomethyl (1,1'-biphenyl) 2-carboxylate (preparation according to EP 0253310). After chromatography on silica (eluent: methylene chloride-methanol (955)). 280 mg of the desired product is obtained. F = 140 C.

1719 cm-1 ester 1628 cmi cétone conjuguée 1583 cm'l 1548 cm-1 1518 cm'l 1501 cm-1
Préparation de 1'exemple 11 : 3-butyl 7-hydroxy méthyl 4-(1H)quinoléinone
A une solution de 240 mg du produit obtenu au stade E de la préparation de l'exemple 9, dans 50 cm3 de tétrahydrofuranne, on ajoute 35 mg d'hydrure d'aluminium-lithium, on agite 30 minutes à température ambiante. On ajoute du tétrahydrofuranne à 10 % d'eau puis 50 cm3 d'eau. On extrait avec de l'acétate d'éthyle, lave à l'eau, sèche et évapore à sec.IR spectrum (CHC13)
OH 3610 cm-1 + associate (strong)
C = O
C = C
aromatic

1719 cm-1 ester 1628 conjugated ketone 1583 cm -1 1548 cm -1 1518 cm -1 1501 cm -1
Preparation of Example 11: 3-butyl 7-hydroxy methyl 4- (1H) quinolinone
To a solution of 240 mg of the product obtained in Step E of the preparation of Example 9, in 50 cm3 of tetrahydrofuran, 35 mg of lithium aluminum hydride are added and the mixture is stirred for 30 minutes at room temperature. Tetrahydrofuran is added to 10% water and then 50 cm3 of water. Extracted with ethyl acetate, washed with water, dried and evaporated to dryness.

After chromatography on silica (eluent: methylene chloride-methanol (9-1)), 170 mg of the desired product is obtained. F = 200 C.

1640 cm-1 1616 cm-1 1558 cm-1 1526 cm-1 1503 cm-1
EXEMPLE 12 : Acide 41-EE3-butyl 1,4-dihydro 7-(hydroxyméthyl > 4-oxo 1-quinoléinyl) méthyl) (l,l'-biphényl) 2-carboxylique
On opère comme à l'exemple 2, à partir de 280 mg du produit obtenu à l'exemple 11 en utilisant 5 cm3 d'une solution normale de soude. Après recristallisation dans l'éthanol à 50 % d'eau, on obtient 200 mg du produit recherché.IR spectrum (Nujol)
Absence of C = O ester
Absorptions complex OH / NH regions
Aromatic c = c
C = O

1640 cm -1 1616 cm -1 1558 cm -1 1526 cm -1 1503 cm -1
EXAMPLE 12: 41-EE3-Butyl-1,4-dihydro-7- (hydroxymethyl-4-oxo-1-quinolinyl) methyl) (1,1'-biphenyl) -2-carboxylic acid
The procedure is as in Example 2, from 280 mg of the product obtained in Example 11 using 5 cm3 of a normal solution of sodium hydroxide. After recrystallization from ethanol at 50% water, 200 mg of the desired product is obtained.

F = 212 C.

1727 cm-1 (F) 1714 cm'l 1626 cm'l 1618 cm-1 1527 cm-1 1506 cm-1 1492 cm-1
EXEMPLE 13 : 4-[[3-butyl 1,4-dihydro 4-oxo l-cinnoléinyl méthyl) benzonitrile
On opère comme à l'exemple 1, à partir de 406 mg du produit obtenu à la préparation ci-dessus, en utilisant 430 mg de 4-bromométhyl benzonitrile et 830 mg de carbonate de potassium. Après chromatographie sur silice (éluant : chlorure de méthylène-méthanol (98-2)), on obtient 460 mg du produit recherché. F = 1800C. Analysis for C28H27NO4 = 441.5
CHN% calculated 76.17 6.16 3.17% found 76.4 6.0 3.1
IR spectrum (CHC13)
General uptake OH / NH c = O
C = O conjugated
+
aromatic

1727 cm-1 (F) 1714 cm -1 1626 cm -1 1618 cm -1 1527 cm -1 1506 cm -1 1492 cm -1
EXAMPLE 13 4 - [[3-butyl-1,4-dihydro-4-oxo-1-cinnolinyl methyl] benzonitrile
The procedure is as in Example 1, from 406 mg of the product obtained in the above preparation, using 430 mg of 4-bromomethyl benzonitrile and 830 mg of potassium carbonate. After chromatography on silica (eluent: methylene chloride-methanol (98-2)), 460 mg of the desired product is obtained. F = 1800C.

1622 cm-1 1606 cm-1 1574 cm-1 1526 cm-1 1510 cm-1
Préparation de l'exemple 13 : 3-butyl 4-hydroxy cinnoline
Stade A : 2-(1-hexynyl) benzène amine
A une solution de 4,4 g de 2-iodoaniline dans 100 cm3 de triéthylamine, on ajoute 32 mg d'iodure de cuivre et 140 mg de chlorure de bis < triphénylphosphine) palladium puis 2,3 cm3 de l-hexyne. On agite 15 heures à température ambiante. On évapore à sec, reprend le résidu avec de l'éther, filtre l'insoluble, le lave à l'éther et évapore à sec le filtrat. Le résidu est chromatographié sur silice (éluant : hexane-acétate d'éthyle (9-1)).On obtient 3,27 g de produit recherché.
Spectre IR (CHCl3) -C6H4-NH2 NH2 déf
+
Aromatique

3486 cm'l 3390 cm'l 1613 cm-1 1570 cm-1 1493 cm-1
Stade B : 3-butyl 4-hydroxy cinnoline
A une suspension préparée à 0 C, de 3,2 g du produit obtenu au stade A dans 100 cm3 d'acide chlorhydrique concentré, on ajoute à oec, une solution de 2 g de nitrite de sodium dans 60 cm3 d'eau. On agite pendant 1 heure 30 minutes à 0 C puis 1 heure à 100 C. On verse le milieu réactionnel refroidi, dans 100 cm3 d'eau glacée.On essore et lave à l'eau, le produit brut humide est repris par 100 cm3 d'eau alcalinisé avec de l'ammoniaque concentré, on essore et lave à l'eau, on obtient après séchage à 70 C, 1,47 g du produit recherché.IR spectrum (CHC13)
Absence of OH C = N conjugate 2233 cm-1 c = C
C = N
aromatic
C = O

1622 cm -1 1606 cm -1 1574 cm -1 1526 cm -1 1510 cm -1
Preparation of Example 13: 3-butyl 4-hydroxy cinnoline
Step A: 2- (1-hexynyl) benzene amine
To a solution of 4.4 g of 2-iodoaniline in 100 cm3 of triethylamine was added 32 mg of copper iodide and 140 mg of bis (triphenylphosphine) palladium chloride followed by 2.3 cm3 of 1-hexyne. Stirred 15 hours at room temperature. It is evaporated to dryness, the residue is taken up in ether, the insoluble material is filtered off, the mixture is washed with ether and the filtrate is evaporated to dryness. The residue is chromatographed on silica (eluent: hexane-ethyl acetate (9-1)) to give 3.27 g of the desired product.
IR spectrum (CHCl3) -C6H4-NH2 NH2 def
+
Aromatic

3486 cm -1 3390 cm -1 1613 cm -1 1570 cm -1 1493 cm -1
Stage B: 3-butyl 4-hydroxy cinnoline
To a suspension prepared at 0 ° C., 3.2 g of the product obtained in Stage A in 100 cm 3 of concentrated hydrochloric acid, a solution of 2 g of sodium nitrite in 60 cm 3 of water is added at 0 ° C. The mixture is stirred for 1 hour 30 minutes at 0 ° C. and then for 1 hour at 100 ° C. The cooled reaction medium is poured into ice water (100 cc). The wet crude product is filtered off with suction and washed with water. water alkalized with concentrated ammonia, filtered and washed with water, obtained after drying at 70 C, 1.47 g of the desired product.

 F = 1800C.

1636 cm-1 1604 cm-1 1580 cm-1 1578 cm-1 1498 cm-1
EXEMPLE 14 : Acide 4-((3-butyl 1,4-dihydro 4-oxo 1-cinnolinyl) méthyl) benzoïque
On opère comme à l'exemple 2 à partir de 400 mg du produit obtenu à l'exemple 13 en utilisant 4 cm3 d'une solution de soude 5N. On obtient 400 mg de produit attendu. F = 220 C.IR spectrum (Nujol)
NH / OH region absorption
C = C
+
aromatic

1636 cm -1 1604 cm -1 1580 cm -1 1578 cm -1 1498 cm -1
EXAMPLE 14: 4 - ((3-Butyl-1,4-dihydro-4-oxo-1-cinnolinyl) methyl) benzoic acid
The procedure is as in Example 2 from 400 mg of the product obtained in Example 13 using 4 cm3 of a 5N sodium hydroxide solution. 400 mg of expected product is obtained. F = 220 C.

After recrystallization from acetonitrile (50 cm3), 270 mg of purified product are collected. F = 220 C.

1609 cm'l (ep) 1596 cm-1 1577 cm-1 1523 cm-1 1490 cm-1
EXEMPLE 15 : 4 3-butyl 1,4-dihydro 4-oxo 7-( < 1-pyrroîi- dinyl) carbonyl) 1-guinoléinyll néthyl) (1,1'-biphényl) 2carboxylate de méthyle
Stade A : 3-butyl 1,4-dihydro 4-oxo 7-((l-pyrrolîdinyl) carbonyl quinoléine
On prépare une suspension de 1,52 g du produit obtenu au stade D de la préparation de l'exemple 9 dans 100 cm3 de tétrahydrofuranne à laquelle on ajoute 0,65 cm3 de pyrrolidine, le milieu réactionnel est refroidi à 0 C et on y ajoute successivement 1 cm3 de triéthylamine 100 cm3 de chlorure de méthylène, 1 g d'hydroxybenzotriazole et 1,82 g de 1 (3-diméthylaminopropyl) 3 -éthyl carbodiimide hydrochloride.Analysis for C20H20N2O3 = 336.393
CHN% calculated 71.41 5.99 8.33% found 71.3 6.0 8.3
IR spectrum (Nujol)
Absence of C = -N
Acid with C = O 1700 cm-1
Aromatic
+
hetero

1609 cm -1 (ep) 1596 cm -1 1577 cm -1 1523 cm -1 1490 cm -1
EXAMPLE 15 4-Methyl-3-butyl-1,4-dihydro-4-oxo-7- (β-1-pyridinyl) carbonyl) -guinolinylmethyl) (1,1'-biphenyl) -carboxylate
Step A: 3-butyl-1,4-dihydro-4-oxo 7 - ((1-pyrrolidinyl) carbonyl quinoline
A suspension of 1.52 g of the product obtained in Stage D of the preparation of Example 9 is prepared in 100 cm3 of tetrahydrofuran to which 0.65 cm3 of pyrrolidine is added, the reaction medium is cooled to 0.degree. 1 cm3 of triethylamine (100 cc) of methylene chloride, 1 g of hydroxybenzotriazole and 1.82 g of 1 (3-dimethylaminopropyl) 3-ethyl carbodiimide hydrochloride are added successively.

 It is stirred for 3 hours at room temperature. Ice-cold water, acidified to pH = 5-6, is then added with 0.1N hydrochloric acid. The organic phase is washed with water, dried and evaporated to dryness. The residue is chromatographed on silica (eluent: methylene chloride-methanol (9-1)). 1.8 g of the expected product are obtained.

3430 cm-1 3240 cm-1 3190 cm-1 3130 cm-1 3090 cm-1 1638 cm-1 1605 cm1 (complexe)
Stade B : 4'-[[3-butyl 1,4-dihydro 4-oxo 7-t(1-pyrrolidinyl) carbonyl] 1-quinoléinyl] méthyl] (1,1'-biphényl) 2-carboxylate de méthyle
On opère comme à l'exemple 3 à partir de 500 mg du produit obtenu au stade A ci-dessus. On obtient 0,675 g du produit attendu.F = 191 C après empâtage éther isopropylique.
Spectre IR (CHC13)
C=O (ester) 1723 cm-1
Autre C=O
Aromatique +
Hétérocycle

1618 cm1 (complexe) 1588 cm-1 1543 cm-1 1498 cm-1
EXEMPLE 16 : Acide 4'-t[3-butyl 1,4-dihydro 4-oxo 7-(1-pyrro- lidinyl) carbonyl] 1-quinoléinyl] méthyl] (1,1'-biphényl) 2carboxylique
On opère comme à l'exemple 2 à partir de 1,1 g du produit obtenu à l'exemple 15. On obtient, après recristallisation dans l'éthanol, 0,67 g du produit attendu. PF > 260 C.IR spectrum (CHCl 3)
NH complex absorption
C = O +
Aromatic +
heterocyclic

3430 cm-1 3240 cm-1 3190 cm-1 3130 cm-1 3090 cm-1 1638 cm-1 1605 cm1 (complex)
Step B: methyl 4 '- [[3-butyl-1,4-dihydro-4-oxo-7-t (1-pyrrolidinyl) carbonyl] -1-quinolinyl] methyl] (1,1'-biphenyl) -2-carboxylate
The procedure is as in Example 3 from 500 mg of the product obtained in Step A above. 0.675 g of the expected product is obtained. Mp = 191 ° C. after pasting isopropyl ether.
IR spectrum (CHC13)
C = O (ester) 1723 cm -1
Other C = O
Aromatic +
heterocyclic

1618 cm1 (complex) 1588 cm -1 1543 cm -1 1498 cm -1
EXAMPLE 16 4'-t [3-Butyl-1,4-dihydro-4-oxo-7- (1-pyrrolidinyl) carbonyl] -1-quinolinyl] methyl] (1,1'-biphenyl) -carboxylic acid
The procedure is as in Example 2 starting from 1.1 g of the product obtained in Example 15. After recrystallization from ethanol, 0.67 g of the expected product is obtained. PF> 260 C.

1714 cmi (ep) 1695 cmi (max) 1618 cm (ep) 1607 cmi (max) 1598 cm-1 1563 cm-1 1524 cm-1 1500 cm-1
Microanalyse pour C32H32N2o4 = 508,62
C H N t calculés 75,57 6,34 5,51 % trouvés 75,4 6,2 5,3
EXEMPLE 17 : 4'-tt3-butyl 1,4-dihydro 8-bromo 4-oxo l-quino léinyl) méthyl] (l,l'-biphényl) 2-carboxylate de méthyle
On maintient pendant 15 heures à 130 C, un mélange de 500 mg du produit obtenu à la préparation 17 et 500 mg de bromométhyl (l,1'-biphényl) 2-carboxylate de méthyle.Après chromatographie sur silice (éluant : chlorure de méthylèneméthanol (95-5)), on obtient 490 mg de produit recherché.IR spectrum (Nujol)
Absorption region OH / NH
C = O
Aromatic
heteroaromatic

1714 cmi (ep) 1695 cmi (max) 1618 cm (ep) 1607 cmi (max) 1598 cm -1 1563 cm -1 1524 cm -1 1500 cm -1
Microanalysis for C32H32N2O4 = 508.62
CHN t calculated 75.57 6.34 5.51% found 75.4 6.2 5.3
EXAMPLE 17 Methyl 4'-t3-butyl-1,4-dihydro-8-bromo-4-oxo-1-quinolinyl) methyl] (1,1-biphenyl) -carboxylate
A mixture of 500 mg of the product obtained in Preparation 17 and 500 mg of methyl bromomethyl (1,1'-biphenyl) -carboxylate is maintained for 15 hours at 130 ° C., after chromatography on silica (eluent: methylenemethanol chloride). (95-5)), 490 mg of desired product is obtained.

1625 cm-1 1614 cm-1 1583 cm-1 1540 cm-1
Préparation de l'exemple 17 : 4-E(3-butyl 8-bromo 4-quino- Iéinyl] oxy) benzoyle
Stade A : 2-butyl 3-([2-bromophényl] amino] 2-butènedioate de diéthyle
On agite pendant 4 heures au reflux une solution de 5 g de bromoaniline avec 7,9 g de 2-butyl 3-oxo butanedioate de diéthyle dans 100 cm de toluène et 100 mg d'acide paratoluène sulfonique. On évapore à sec et chromatographie le résidu sur silice (éluant : chlorure de méthylène-hexane (6-4)). On obtient 7,2 g du produit recherché.IR spectrum (CHC13)
C = O 1720 cm-1
Aromatic
+
C = C

1625 cm -1 1614 cm -1 1583 cm -1 1540 cm -1
Preparation of Example 17: 4-E (3-butyl-8-bromo-4-quinolinyl) oxy) benzoyl
Step A: Diethyl 2-butyl 3 - ([2-bromophenyl] amino] 2-butenedioate
A solution of 5 g of bromoaniline is stirred for 4 hours with 7.9 g of diethyl 2-butyl-3-oxo butanedioate in 100 cm 3 of toluene and 100 mg of para-toluenesulphonic acid. The mixture is evaporated to dryness and the residue is chromatographed on silica (eluent: methylene chloride-hexane (6-4)). 7.2 g of the desired product are obtained.

1600 cm'l 1572 cm-1 1490 cm-1
Stade B : 3-butyl 1,4-dihydro 8-bromo 4-oxo 2-quinoléine carboxylate d'éthyle
On opère comme au stade B de la préparation 2 à partir de 7 g du produit obtenu au stade A. Après chromatographie sur silice (éluant : chlorure de méthylène), on obtient 6,3 g du produit attendu (F = 88 C).IR spectrum (CHC13)
NH 3230 cm-1
C = O 1732 - 1658 cm -1
C = C
Aromatic

1600 cm -1 1572 cm -1 1490 cm -1
Stage B: Ethyl 3-butyl-1,4-dihydro-8-bromo-4-oxo-2-quinoline carboxylate
The procedure is as in Stage B of Preparation 2 from 7 g of the product obtained in Stage A. After chromatography on silica (eluent: methylene chloride), 6.3 g of the expected product (mp = 88 ° C.) are obtained.

1620 cm1 1598 cm-1 1558 cm-1 1530 cm1
Stade C : Acide 3-butyl 1,4-dihydro 8-bromo 4-oxo 2-quinoléine carboxylique
On opere comme au stade C de la préparation 2 à partir de 6,3 g du produit obtenu au stade B ci-dessus. On obtient 6 g du produit recherché (F = 220 C).IR spectrum (CHCl 3) = C-NH 3398 - 3350 cm -1
C = O 1744 - 1708 cm -1
C = O +
C = C +
Aromatic

1620 cm1 1598 cm-1 1558 cm-1 1530 cm1
Stage C: 3-Butyl-1,4-dihydro-8-bromo-4-oxo-2-quinoline carboxylic acid
The procedure is as in Stage C of Preparation 2 from 6.3 g of the product obtained in Step B above. 6 g of the desired product are obtained (mp = 220 ° C.).

1618 cm'l 1590 cm-1 1560 cm-1 1542 cm-1 1518 cm-1
Stade D : 3-butyl 8-bromo 4-(1H) quinoléinone
On opère comme au stade D de la préparation 2 à partir de 6 g du produit obtenu au stade C ci-dessus. On obtient 3,4 g du produit recherché (F = 172 C).IR spectrum (Nujol)
Absorption OH / NH 3376 - 3316 cm-1 -C = O 1734 - 1704 cm1
C = O
C = C
+
Aromatic

1618 cm -1 1590 cm -1 1560 cm -1 1542 cm -1 1518 cm -1
Stage D: 3-butyl 8-bromo 4- (1H) quinolinone
The procedure is as in Stage D of Preparation 2 from 6 g of the product obtained in Step C above. 3.4 g of the desired product are obtained (mp = 172 ° C.).

1638 cm-1 1626 cm-1 1610 cm-1 1580 cm-1 1546 cm-1 1520 cm-1
Stade E : 4-( < 3-butyl 8-bromo 4-quinolinyl) oxy] benzyle.IR spectrum (Nujol)
C = O
C = C
Aromatic

1638 cm-1 1626 cm-1 1610 cm-1 1580 cm-1 1546 cm-1 1520 cm-1
Stage E: 4- (<3-butyl-8-bromo-4-quinolinyl) oxy] benzyl.

 Refluxed 5 hours, 2 g of the product obtained in Step D above, in 100 cm3 of acetone with 1 cm3 of benzyl bromide and 2 g of potassium carbonate. After chromatography on silica (eluent: methylene chloride) 2.12 g of the desired product is obtained.

1598 cm-1 1554 cm-1 1498 cm-1
EXEMPLE 18 : Acide 4'-((3-butyl 1,4-dihydro 8-bromo 4-oxo 1quinoléinyl) méthyl) (1,1'-biphényl) 2-carboxylique
On opère comme à l'exemple 2, à partir de 380 mg du produit obtenu à l'exemple 17, en utilisant 10 cm3 de soude N et 5 cm3 d'éthanol, on obtient 120 mg du produit recherché.IR spectrum (CHC1 <) C = c
Aromatic

1598 cm -1 1554 cm -1 1498 cm -1
EXAMPLE 18 4 '- ((3-Butyl-1,4-dihydro-8-bromo-4-oxo-1-quinolinyl) methyl) (1,1'-biphenyl) -2-carboxylic acid
The procedure is as in Example 2, from 380 mg of the product obtained in Example 17, using 10 cm3 of N sodium hydroxide and 5 cm3 of ethanol, 120 mg of the desired product is obtained.

Mp = 1800 ° C., recrystallized from ethyl acetate.

1622 cm1 1602 cm-1 1556 cm-1 1528 cm-1
EXEMPLE 19 z 4'-E(2-butYl 1,4-dihydro 4-oxo 1-quinoléinyl) méthyl) (l,l'-biphényl) 2-carboxylate de méthyle
On chauffe 15 heures à 1300C, un mélange de 1 g de 4-((2- butyl 4-quinoléinyl) oxy] benzyle (préparation ci-après) et 1,4 g de bromométhyl (l,1'-biphényl) 2-carboxylate de méthyle.Analysis for C27H24NO3Br = 490.45
CHN Br% calculated 66.13 4.93 2.86 16.29% found 66.4 4.9 2.8 16.2
IR spectrum (Nujol)
C = O 1706 cm -1
C = C
Aromatic

1622 cm1 1602 cm-1 1556 cm-1 1528 cm-1
EXAMPLE 19 Methyl 4'-E (2-butyl-1,4-dihydro-4-oxo-1-quinolinyl) methyl) (1,1'-biphenyl) -2-carboxylate
A mixture of 1 g of 4 - ((2-butyl-4-quinolinyl) oxy] benzyl (preparation below) and 1.4 g of bromomethyl (1,1'-biphenyl) 2 was heated for 15 hours at 130 ° C. methyl carboxylate.

After chromatography on silica, 1.3 g of the desired compound are obtained.

1623 cm-1 1602 cm-1 1575 cm-1 1555 cm-1
Préparation de 1'exemple 19 : 4-(E(2-butyl 4-quinoleinyl) oxy) méthyl) benzoyle
Stade A : 3-oxo heptanoate d'éthyle
A une suspension de 27,3 g d'hydrure de sodium (à 50 % dans l'huile, lavé 3 fois avec de l'hexane) dans 250 cm3 d'éther, on ajoute 70,8 g de carbonate d'éthyle en solution dans 50 cm3 d'éther. On agite 10 minutes et on ajoute 30 g d'hexanone. On chauffe 2 heures au reflux. On ajoute une solution de 35 cm3 d'éther contenant 12 cm3 d'éthanol.On refroidit la solution à 0 C et ajoute une solution de 36 cm3 d'acide acétique dans 300 cm3 d'eau, on ajoute 12 cm3 d'une solution saturée de bicarbonate de sodium, on extrait avec de l'éther, lave à l'eau, sèche, filtre et évapore à sec sous pression réduite. On obtient 100 g d'huile que l'on distille sous une pression de 3 mbar à 70 C. On obtient 32,5 g de produit recherché.IR spectrum (CHC13)
C = O 1725 cm-1
Conjugate system
+
Aromatic

1623 cm-1 1602 cm-1 1575 cm-1 1555 cm-1
Preparation of Example 19: 4- (E (2-butyl-4-quinolinyl) oxy) methyl) benzoyl
Stage A: 3-oxo ethyl heptanoate
To a suspension of 27.3 g of sodium hydride (50% in oil, washed 3 times with hexane) in 250 cm3 of ether, 70.8 g of ethyl carbonate are added. solution in 50 cm3 of ether. Stir 10 minutes and add 30 g of hexanone. It is heated for 2 hours under reflux. A solution of 35 cm3 of ether containing 12 cm3 of ethanol is added. The solution is cooled to 0.degree. C. and a solution of 36 cm.sup.3 of acetic acid in 300 cm.sup.3 of water is added, 12 cm.sup.3 of a solution is added. saturated with sodium bicarbonate, extracted with ether, washed with water, dried, filtered and evaporated to dryness under reduced pressure. 100 g of oil are obtained which is distilled under a pressure of 3 mbar at 70 ° C. 32.5 g of desired product are obtained.

2,55 ppm (t) COEt 1,28 ppm (t)
4,20 ppm (q)

3,44 ppm (s)
Stade B : 3-(phénylamino) 2-heptanoate d'éthyle
On agite pendant 48 heures un mélange de 17,9 g d'aniline avec 45 g de 3-one heptanoate d'éthyle obtenu comme au stade
A, en présence de 5 g de siliporite activée. Le mélange réactionnel est chromatographié sur silice (éluant : hexaneacétate d'éthyle (95-5)). On obtient 28,7 g du produit recherché.CDC13 NMR spectrum (250 MHz)
CH3-CH2 0.91 ppm Central CH2 1.34 - 1.59 ppm

2.55 ppm (t) COEt 1.28 ppm (t)
4.20 ppm (q)

3.44 ppm (s)
Stage B: 3- (phenylamino) ethyl 2-heptanoate
A mixture of 17.9 g of aniline is stirred for 48 hours with 45 g of ethyl 3-one heptanoate obtained as at the stage
A, in the presence of 5 g of activated siliporite. The reaction mixture is chromatographed on silica (eluent: ethyl hexaneacetate (95-5)). 28.7 g of the desired product are obtained.

1612 cm'l 1594 cm'l 1588 cm-1
Stade C : 2-butyl 4(1H)-quinoléinone
On chauffe pendant 45 minutes à 250 C, une solution de 28,7 g du composé obtenu au stade B ci-dessus, dans 60 cm3 de phényl éther. On laisse refroidir, empâte dans 400 cm3 de pentane, essore et lave avec du pentane. On obtient 16,95 g de produit recherché. F = 140 C.IR spectrum (CHC13)
NH 3260 cm-1
C = O 1648 cm -1
C = C
Aromatic

1612 cm -1 1594 cm -1 1588 cm -1
Stage C: 2-butyl 4 (1H) -quinolinone
A solution of 28.7 g of the compound obtained in Step B above in 60 cm3 of phenyl ether is heated for 45 minutes at 250 ° C. It is allowed to cool, to paste in 400 cm3 of pentane, drained and washed with pentane. 16.95 g of desired product are obtained. F = 140 C.

1636 cm'l 1606 cm-1 1596 cm-I 1547 cm-1 1502 cm-1
Stade D : 4-[t(2-butyl 4-quinoléinyl) oxy] méthyl] benzyle
On agite 5 heures au reflux 3 g du produit obtenu au stade C, 2,8 cm3 de bromure de benzyle et 4,1 g de carbonate de potassium dans 70 cm3 d'acétone. On coule dans 100 cm3 d'eau, extrait à l'acétate d'éthyle. Après chromatographie sur silice (éluant : chlorure de méthylène - méthanol (95-5)) on obtient 3,2 g du produit recherché.IR spectrum (CHCl 3) = C-NH 3428 cm -1
C = O + c = c + C = -N +
Aromatic

1636 cm -1 1606 cm -1 1596 cm -1 1547 cm -1 1502 cm -1
Stage D: 4- [t (2-butyl-4-quinolinyl) oxy] methyl] benzyl
3 g of the product obtained in Stage C, 2.8 cm 3 of benzyl bromide and 4.1 g of potassium carbonate in 70 cm 3 of acetone are stirred under reflux for 5 hours. Poured into 100 cm3 of water, extracted with ethyl acetate. After chromatography on silica (eluent: methylene chloride - methanol (95-5)) 3.2 g of the desired product are obtained.

1620 cm-1 1598 cm1 1568 cm-1 1508 cm-1
EXEMPLE 20 : Acide 4 (2-butyl 1,4-dihydro 4-oxo l-quino leinyl) méthyl) (l,l'-biphonyll 2-carboxylique
On opère comme à l'exemple 2, à partir du produit obtenu à l'exemple 19, en utilisant 3 cm3 de soude N et 2 cm3 d'éthanol.IR spectrum (CHC13)
Absence of OH
C = C
Aromatic

1620 cm-1 1598 cm1 1568 cm -1 1508 cm -1
EXAMPLE 20: 4 (2-Butyl-1,4-dihydro-4-oxo-1-quinolinyl) methyl) (1,1'-biphony-2-carboxylic acid)
The procedure is as in Example 2, from the product obtained in Example 19, using 3 cm3 of sodium hydroxide and 2 cm3 of ethanol.

 After recrystallization from dimethylformamide, 155 mg of the desired product is obtained (mp> 260 ° C.).

1616 cm-1 1596 cm-1 1550 cm-1 1532 cm-1 1496 cm-1
EXEMPLE 21 : de composition pharmaceutique
On a préparé des comprimés répondant à la formule suivante
Produit de l'exemple 10 ......................... 10 mg
Excipient pour un comprimé terminé à ............ 100 mg (détail de l'excipient : lactose, talc, amidon, stéarate de magnésium)
RESULTATS PHARNACOLOGIOUE8 : 1) Test sur le récepteur de l'ancriotensine II
On utilise une préparation membranaire fraîche obtenue à partir de foie de rat.Le tissu est broyé au polytron dans un tampon Tris 50 mM pH 7,4 le broyage est suivi de 3 centrifugations à 30 000 g 15 minutes avec reprises intermédiaires des culots dans le tampon Tris pH 7,4.Analysis for C27H25NO3 = 411.48
CHN% calculated 78.80 6.12 3.4% found 78.6 6.0 3.3
IR spectrum (Nujol)
C = O 1692 cm-1 c = O
C = C
+
Aromatic

1616 cm -1 1596 cm -1 1550 cm -1 1532 cm -1 1496 cm -1
EXAMPLE 21: Pharmaceutical composition
Tablets having the following formula were prepared
Product of Example 10 ......................... 10 mg
Excipient for a tablet finished at ........... 100 mg (details of the excipient: lactose, talc, starch, magnesium stearate)
PHARNACOLOGICAL RESULTS8: 1) Ancriotensin II Receptor Assay
A fresh membrane preparation obtained from rat liver is used. The tissue is crushed with polytron in 50 mM Tris buffer pH 7.4, the grinding is followed by 3 centrifugations at 30,000 g for 15 minutes with intermediate re-slips of the pellets. 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 bistrimethylsilylacetamide 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 DM 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.

Non-specific binding is determined by adding the product of Example 94 of European Patent 0253310 to 10M (in triplicate). Incubated at 25 ° C. for 150 minutes, put back in the bath at 0 ° C. for 5 minutes, filtered under vacuum, rinsed with Tris buffer pH 7.4 and counted the radioactivity in the presence of the scintillant
Triton.

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

Result

<tb> | <SEP> Product <SEP> of <SEP> example <SEP>(<SEP> IC50 <SEP> in <SEP> nanomoles <SEP> | <SEP>
<tb><SEP> 10 <SEP> 1 <SEP> 92
<tb><SEP> 4 <SEP> 1 <SEP> 1 <SEP> 180
<tb><SEP> 6 <SEP> 1 <SEP> 1 <SEP> 400
<tb> 2 - Demonstration of angiotensin II antagonistic activity on the isolated portal vein
The portal vein is removed from Wistar male rats (approximately 350 g) (IFFA Crédo France) 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 25 - glucose 11.1 - CaCl2 2, 5) the medium is maintained at 37 C and oxygenated with a mixture of 95% O2 and 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.

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

Results

<tb> Product <SEP> of <SEP> Example <SEP> IC50 <SEP> in <SEP> nanomoles
<tb><SEP> 10 <SEP> 1 <SEP> 31
<tb><SEP> 4 <SEP> 96.5 <SEP>
<tb><SEP> 6 <SEP> 66
<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 (60 mg / kg). Diastolic blood pressure is recorded using a heparinised (PE50) catheter introduced into the left carotid of the animal, and connected to a pressure calculator (Gould, Pressure Processor) via a Gould pressure sensor.

 A catheter is introduced into the right jugular of the animal for 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 sufficient period of stabilization, the study of the antagonism of the compounds with respect to angiotensin II (Hypertensine Ciba) is approached as follows.

1 - Three consecutive injections of angiotensin II (0.75 micrograms / kg) spaced by 15 minutes make it possible to obtain a reproducible and stable press response.

2 - While keeping a periodicity of 15 minutes for the administration of angiotensin II, the molecules to be studied are injected 5 minutes before angiotensin II.

The pressor effects of angiotensin II in the presence of the antagonist are expressed as a percentage of the pressure effects of angiotensin II administered alone. The inhibitory dose at 50% of the effect studied is thus determined
Each animal is considered as its own witness.

Results

<tb> Product <SEP> of <SEP> Example <SEP> | <SEP> Dose <SEP> inhibitory <SEP> to <SEP> 50 <SEP>%
<tb><SEP> (mg / kg)
<tb><SEP> 10 <SEP> 1.27
<tb><SEP> 4 <SEP> 1 <SEP> 7.55
<tb><SEP> 6 <SEP> 6.65 <SEP>
<Tb>

Claims (13)

Y2 represents either, if B represents a single bond, a hydrogen or halogen atom, a hydroxyl, cyano, nitro, trifluoromethyl, free carboxy, salified or esterified, tetrazole or isoxazole radical, or, whatever the value of B and Y2 being identical to or different from Y1, the values defined for Y1, it being understood that the products of formula (I) can not represent the products in which X represents an oxygen atom and such that A represents a radical CH substituted by a methyl radical itself substituted with a free or esterified carboxy radical, R1, R2 and R3 are identical and all represent a hydrogen atom and -R5-Y represents a benzyl radical substituted with a fluorine atom, or A represents a radical CH, R1, R2 and R3, identical are all three a methyl radical and -R5 -Y represents a benzyl radical, or A represents a nitrogen atom, R1 represents an ethyl radical substituted by a free or esterified carboxy, cyano or carbamoyl radical, one of R 2 and R 3 represents a hydrogen atom and the other represents an alkyl, alkyloxy or phenyl radical, -R 5 -Y represents a benzyl radical optionally substituted by an alkyl radical; , alkyloxy or phenyl, 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 or with the inorganic and organic bases of said products of formula ( I). B represents either a single bond between Y1 and Y2, or one of the following divalent radicals: -CO-, -NH-CO-, -CO-NH-, -O- (CH2) n- or -S- (CHZ ), with n representing the values 0 to 4, Y1 represents a monocyclic aryl radical comprising 5 or 6 members or constituted by fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms, and being optionally substituted by one or more radicals chosen from radicals that can represent R2 or R3, Y represents the radical -Y1-B-Y2 in which R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms, R4 can take the same values as the radical R1, it being understood that when A represents a nitrogen atom or a radical CH, R1 does not represent a hydrogen atom, A represents a nitrogen atom or a radical C-R4 in which X represents an oxygen atom or a sulfur atom, R7 represents an acyl radical derived from a carboxylic acid containing at most 6 carbon atoms,   in which either R6 and R7 or R8 and Rg, which are identical or different, represent - a hydrogen atom, - an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted with one or more radicals chosen from the atoms of halogen and the hydroxyl radical, - an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms, - an aryl or arylalkyl radical in which the linear or branched alkyl radical contains at least plus 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals selected from among the atoms halogen, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radical, or R6 and R7 radicals. or R8 and Rg respectively together with the nitrogen atom to which they are attached form a monocytic radical comprising 5 to 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more selected heteroatoms; among the oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, aikenyl, alkyloxy and alkylthio radicals; and acyl, these radicals containing at most 6 carbon atoms, the free carboxy radical, salified or esterified, or R8 and Rg, identical or different or one of R6 or

R2 and R3, which may be identical or different, represent a; a hydrogen atom, a halogen atom, a hydroxyl radical, mercapto, cyano, nitro, sulfo, formyl, benzoyl, acyl having at most 12 carbon atoms, carboxy free, salified or esterified, cycloalkyl containing from 3 to 7 carbon atoms, b) an alkyl, alkenyl, alkyl, alkyloxy or alkylthio radical, these radicals being linear or branched, containing at most 6 carbon atoms and being optionally substituted, c) an aryl, arylalkyl, arylalkenyl, aryloxy or arylthio radical in which the linear or branched alkyl and alkenyl radicals contain at most 6 carbon atoms, these aryl, arylalkyl, arylalkenyl or arylthio radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 ring members or a radical consisting of rings 8 to 10-membered condensed radicals, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and optionally being substituted, d) a radical R1 represents a hydrogen atom, an alkyl, alkenyl or alkynyl linear or branched radical containing at most 6 carbon atoms and optionally substituted, or an acyl, cyano, free carboxy, salified or esterified,  in which

 CLAIMS 1) Products of formula (I): 2) Products of formula (I) as defined in claim 1, characterized in that the substituent or substituents, which may be identical or different, may bear (a) the alkyl, alkenyl and alkynyl radicals which R1, b) may represent, the alkyl radicals, alkenyl, aikynyl, alkyloxy and alkylthio that can represent R2 and R3, c) the aryl, arylalkyl, arylalkenyl, aryloxy and arylthio radicals that can represent R2 and R3, are chosen from the group formed by - the halogen atoms, the radicals hydroxyl, cyano, nitro, formyl, acyl or acyloxy having not more than 6 carbon atoms, benzoyl, free carboxy, salified or esterified by an alkyl radical containing not more than 6 carbon atoms, - alkyl and alkenyl radicals containing not more than 6 atoms of carbon and optionally substituted by one or more substituents chosen from halogen atoms, hydroxyl radical, alkyloxy radicals containing at most 6 carbon atoms, carbamoyl, carboxy or esterified tetrazole, - linear and branched alkyloxy and alkylthio radicals containing at most 6 carbon atoms, - aryl and arylalkyl radicals in which the linear or branched alkyl radical contains at most 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms, the radicals carboxy free, salified or esterified, - radicals

 in which R10 and R11 or R12 and R13, which are identical or different, represent: a hydrogen atom, an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted by one or more radicals chosen from halogen atoms and the hydroxyl radical; an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms; an aryl or arylalkyl radical in which the linear or branched alkyl radical; contains at most 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen among the oxygen, nitrogen and sulfur atoms, and being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, akenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radicals, or R10 and R11 or R12 and R13 respectively form, with the nitrogen atom to which they are bonded, a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from the atoms of oxygen, nitrogen and sulfur, and being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy and acyl radicals, these radicals containing at most 6 carbon atoms, the free, salified or esterified carboxy radicals, or R12 and R13, which are identical or different, or one of R10 and R11, represent an acyl radical derived from a carboxylic acid containing at most 6 carbon atoms, 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 or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in claims 1 and 2 and corresponding to formula (ira):

 Rla represents an n-butyl or butenyl radical, R2a and R3at, which are identical or different, are chosen from the group formed by - the hydrogen atom, - the halogen atoms, - the hydroxyl radical, - the mercapto, cyano, nitro, formyl, benzoyl, acyl radical having at least plus 6 carbon atoms, sulfo, - free carboxy radicals, salified or esterified by a linear or branched alkyl radical containing not more than 4 carbon atoms, tetrazole, - linear or branched alkyl, alkyloxy and alkylthio radicals containing not more than 6 atoms of carbon, phenyl, naphthyl, benzyl and phenylthio, all these radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radical, alkyloxy radicals containing at most 4 carbon atoms, trifluoromethyl, cyano, carboxy free, salified or esterified, tetrazole and isoxazole, - amino, mono- or dialkylamino, carbamoyl, pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morphol radicals inomethyl, piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl, piperazinylcarbonyl, all piperazinyl radicals being optionally substituted on the second nitrogen atom by an alkyl or phenyl radical, these alkyl and phenyl radicals being themselves optionally substituted by one or more radicals chosen from hydroxyl, halogen, nitro, alkyl or alkyloxy atoms containing at most 4 carbon atoms, trifluoromethyl, cyano, free carboxy, salified or esterified, tetrazole and isoxazole, A a represents a nitrogen atom or a C-R4a radical in which R4a represents a hydrogen atom, an acyl radical containing at most 6 carbon atoms, cyano, free carboxy, salified or esterified with an alkyl radical containing at most 4 carbon atoms or alkyl containing at most 6 carbon atoms optionally substituted by one or more radicals chosen from the hydroxyl radical and the halogen atoms, X represents an oxygen atom or a sulfur atom, R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms, Y a represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from hydroxyl, halogen, alkyl and alkyloxy radicals containing at most 4 atoms of carbon, trifluoromethyl, cyano, nitro, free carboxy, salified or esterified, tetrazole and isoxazole, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic or with the inorganic and organic bases of said products of formula (I). 4) Products of formula (I) as defined in claims 1 to 3 in which R1 represents an n-butyl radical, R2 and R3, which are identical or different, are chosen from the group formed by the hydrogen atom, the mercapto and alkylthio radicals, the linear or branched alkyl radicals containing at most 6 carbon atoms and optionally substituted with one or several identical or different substituents chosen from halogen atoms, the hydroxyl radical, the amino, mono- and dialkylamino radical, pyrrolidine, morpholine, piperidine, the free carboxy radical, salified or esterified by a linear or branched alkyl radical containing at most 4 carbon atoms, pyrrolidinylcarbonyl, morpholinylcarbonyl, carbamoyl, dialkylcarbamoyl, piperidynylcarbonyl, A represents a nitrogen atom or a CH radical, X represents an oxygen atom or a sulfur atom, R5 represents a methylene radical, Y represents a phenyl or biphenyl radical optionally substituted by one or more radicals chosen from cyano, free carboxy, salified and esterified, tetrazole and isoxazole radicals, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms; as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases, pharmaceutically acceptable, of said products of formula (I). 5) The products of formula (I) having the following definitions: 4 '- [(3-butyl-1,4-dihydro-4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -2 carboxylic acid 4 '- [(3-butyl-1,4-dihydro-4-thioxo-1-quinolinyl) methyl] (1,1'-biphenyl) -2-carboxylic acid 3-butyl 1 - [( 2'-carboxy (1,1'-biphenyl) -4-yl) methyl] 1,4-dihydro-4-oxo-7-quinolinecarboxylic acid 4 '- ((3-butyl-1,4-dihydro-8-bromo) 4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) -2-carboxylic acid 4 '- [(3-butyl-1,4-dihydro-7- (hydroxymethyl) -4-oxo-1-quinolinyl) methyl] (1,1'-biphenyl) 2-carboxylic acid 4 '- [(3-butyl-1,4-dihydro-4-oxo-7 - [(1-pyrrolidinyl) carbonyl] -1-quinolinyl) methyl (1, 1') biphenyl) 2-carboxylic acid. 6) Process for the preparation of products of formula (I) as defined in claim 1, characterized in that either a product of formula (II) is reacted:

 in which R2, and R3, have the meanings given in claim 1 respectively for R2 and R3 in which the optional reactive functional groups are optionally protected by protective groups, with a product of formula (III)

 in which R 1 and R 4 have the meanings given in claim 1 for R 1 and R 4, respectively, in which the optional reactive functional groups are optionally protected by protective groups and alk represents an alkyl radical containing at most 6 carbon atoms, in order to obtain products of formula (IV) ::

 in which R 1 ', R 2, R 3', R 4, and alk have the meanings indicated above, which is cyclized to obtain products of formula (V)

 in which R 1 ', R 2', R 3, and R 4 'have the meanings indicated above, or a product of formula (VI) is reacted

 in which R2, and R3 'have the meanings indicated above, with a product of formula (VII): R1 1-C-CH (VII) in which R1' has the meaning indicated above, to obtain products of formula (VIII) ::

 wherein R 1 ', R 2' and R 3, have the meanings indicated above, which is subjected to a cyclization reaction to obtain a product of formula (IX)

 in which R 1, R 2 'and R 3, have the meanings indicated above, products of formula (V) and (IX) that, if desired, is subjected to a conversion reaction of the oxo function to a thioxo function and reacting with a compound of formula (X) ::  Hal-R5'-Y '(X) in which R5' and Y 'have the meanings given in claim 1 respectively for R5 and Y in which the optional reactive functions are optionally protected by protective groups, to obtain a product of formula ( I ') ::

 in which R 1 ', R 2, R 3, R 4', R 5 'and Y' have the meaning indicated above and wherein A represents the radical C-R 4 'or a nitrogen atom, and X has the indicated meaning in claim 1, product of formula (I ') which is subjected, if desired and if necessary, to one or more of the following reactions, in any order - an oxo C = O function conversion reaction in thioxo function C = S, - a removal reaction of the protective groups that can carry the protected reactive functions, - a salification reaction with a mineral or organic acid or a mineral or organic base to obtain the corresponding salt, - a reaction acid function esterification, - acid functional ester saponification reaction, - alkyloxy functional conversion reaction to hydroxyl function, - a reaction reaction of the cyano function to acid function, - a reduction reaction of e the carboxy function in alcohol function, - a resolving reaction of the racemic forms, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers. 7) As medicaments, the products as defined by the formula (I) of claim 1, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with the inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 8) As medicaments, the products of formula (I) as defined in claims 2 to 5, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula ( I). 9) The pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined in any one of claims 7 and 8. 10) As new industrial products, the compounds of formula (in), (V> and (IX). 11) Use of the products of formula (F):

 in which R1 represents a hydrogen atom, a linear or branched alkyl, alkenyl or alkynyl radical containing at most 6 carbon atoms and optionally substituted, acyl, cyano, free carboxy, salified or esterified, R2 and R3, which may be identical or different, represent a; a hydrogen atom, a halogen atom, a hydroxyl radical, mercapto, cyano, nitro, sulfo, formyl, benzoyl, acyl having at most 12 carbon atoms, carboxy free, salified or esterified, cycloalkyl containing from 3 to 7 carbon atoms, b) an alkyl, aikenyl, alkylynoxy, alkyloxy or alkylthio radical, these radicals being linear or branched, containing at most 6 carbon atoms and being optionally substituted, c) an aryl, arylalkyl, arylalkenyl, aryloxy or arylthio radical in which the linear or branched alkyl and alkenyl radicals contain at most 6 carbon atoms, these aryl, arylalkyl, arylalkenyl or arylthio radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 ring members or a radical consisting of rings 8 to 10-membered condensed radicals, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being ntually substituted, d) a radical

 in which either R6 and R7 or R8 and Rg, which are identical or different, represent - a hydrogen atom, - an alkyl or alkenyl radical containing at most 6 carbon atoms and optionally substituted with one or more radicals chosen from the atoms of halogen and the hydroxyl radical, - an alkyl or alkenyl radical containing from 2 to 6 carbon atoms substituted by an alkyloxy radical containing at most 6 carbon atoms, - an aryl or arylalkyl radical in which the linear or branched alkyl radical contains at least plus 6 carbon atoms, these aryl and arylalkyl radicals being such that the aryl radical represents a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals selected from among the atoms Halogen radicals, hydroxyl, cyano, trifluoromethyl, nitro radicals, alkyl, alkenyl, alkyloxy, alkylthio and acyl radicals, radicals containing at most 6 carbon atoms, carboxy radical free, salified or esterified, or R6 and R7 or R8 and Rg respectively form together with the nitrogen atom to which they are attached a monocyclic radical comprising 5 or 6 members or a radical consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from the oxygen, nitrogen and sulfur atoms, and being optionally substituted with one or more radicals chosen from halogen atoms, hydroxyl, cyano, trifluoromethyl and nitro radicals, and alkyl, alkenyl, alkyloxy and alkylthio radicals; acyl, these radicals containing at most 6 carbon atoms, the free carboxy radical, salified or esterified, or R8 and Rg, identical or different, represent a radical acyl carboxylic acid derivative having not more than 6 carbon atoms, X represents an oxygen atom or a sulfur atom, A represents a nitrogen atom or a radical = C-R4 in which R4 can take the same values as the radical R1, it being understood that when A represents a nitrogen atom or a radical = C-H, R1 does not represent a hydrogen atom, R5 represents a divalent alkylene radical, linear or branched, containing at most 4 carbon atoms, Y represents the radical -Y1-B-Y2 in which Y1 represents a monocyclic aryl radical comprising 5 or 6 members or consisting of fused rings comprising 8 to 10 members, these radicals optionally containing one or more heteroatoms chosen from oxygen, nitrogen and sulfur atoms, and being optionally substituted by one or more radicals chosen from radicals that may represent R2 or R3, B represents either a single bond between Y1 and Y2, or one of the following divalent radicals: -CO-, -NH-CO-, -CO-NH-, -O- (CH2) n- or -S- (CHZ ), with n representing the values 0 to 4, Y 2 represents either, if B represents a single bond, a hydrogen or halogen atom, a hydroxyl, cyano, nitro, trifluoromethyl, free carboxy, salified or esterified, tetrazole or isoxazole radical, or, whatever the value of B and Y2 being identical to or different from Y1, the values defined for Y1, said products of formula (F) being, in all possible isomeric racemic forms, enantiomers and diastereoispmers, as well as the addition salts with mineral and organic acids; or with the inorganic and organic bases of said products of formula (F) for the preparation of medicaments, intended either for the treatment of arterial hypertension, cardiac insufficiency, renal insufficiency and in the prevention of post-angioplasty restenosis, either at treatment of certain gastrointestinal or gynecological disorders. 12) Use as defined in claim 11 characterized in that the products of formula (F) are used in the preparation of medicaments for the treatment of arterial hypertension, heart failure, renal failure and in the prevention of restenosis post-angioplasty. 13) Use as defined in claims 11 and 12 characterized in that the products of formula (F) correspond to formulas (Ia) and (I) <I> as defined in claims 3 and 4.