FR2733233A1 - NOVEL QUINOLINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, THE NEW INTERMEDIATES OBTAINED, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS COMPRISING THEM - Google Patents

Abstract

The invention concerns products of formula (I), wherein: A represents H or -CH2-B in which B is selected from alkyl or (i) radicals, Z1 and Z2 represent H or form the radical (ii) in which Y1 and Y2, which may be identical or different, are selected from -O-, -S-, -N-, -NH-, -CH= or -CH2-, Y1 and Y2 forming a ring with the phenyl radical, Z represents -O- or -S-, X represents carboxy, tetrazolyl, -CO-NH-SO2-R6, R6 representing optionally substituted alkyl, alkenyl or phenyl, R represents, in particular, H, halogen, dioxol, carboxy, alkyl, phenylthioalkyl and phenylthio, which may be optionally substituted, R1, R2, R3, R4 and R5, which may be identical or different, represent in particular hydrogen, halogen, hydroxyl, alkyl, alkoxy, and R2 and R3 with the phenyl radical may likewise form the rings formed by Z1 and Z2, with the proviso that when A is H, Z1 and Z2 form (ii), products of formula (I) in all the isomeric forms, and the acid or base addition salts.

Description

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

dans laquelle Z1 et Z2 représentent un atome d'hydrogène ou forment le radical dans lequel

The subject of the present invention is the products of formula (I)

in which Z1 and Z2 represent a hydrogen atom or form the radical in which

Y1 and Y2, which are identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH = or -CH2-,
Y1 and Y2 forming a ring with two consecutive methine radicals of the phenyl radical to which they are attached and the dashed lines indicating the possible presence of a double bond,
Z represents an oxygen or sulfur atom,
X represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical or the -CO-NH-SO2-R6 radical, in which R6 represents an alkyl, alkenyl or phenyl radical optionally substituted with one or more radicals chosen among the halogen atoms, the hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free carboxy, salified or esterified, tetrazolyl or phenyl radicals, itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy and nitro radicals,
R1 is chosen from a) hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano, nitro, benzoyl, acyl, sulfo, free carboxy, salified or esterified, tetrazolyl radicals, b) alkyl radicals, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio, all these radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkoxy, trifluoromethyl and cyano radicals, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, pyrrolidinyl, pyridinyl, pyrrolidinylcarbonyl and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals, c) amino radicals, mono- or dialkylamino, carbamoyl, d) pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl, mor pholinocarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl, all piperazinyl radicals being optionally substituted on the second nitrogen atom by an alkyl or phenyl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, nitro radicals; alkyl or alkyloxy, trifluoromethyl, cyano, free carboxy, salified or esterified, tetrazolyl and isoxazolyl,
R 2, R 3, R 4 and R 5, which are identical or different, are chosen from a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkoxy, trifluoromethyl, cyano-nitro, free carboxy, salified or esterified radicals; , tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted with one or two radicals chosen from the radical - (CH2) pS (O) mZ-R7 as defined below and the alkyl and alkenyl radicals, c) the radical - (CH2) pS (O) mZ-R7 wherein p represents the values 0 and 1, m represents the values 0 to 2, Z represents the radicals -NH-, -NH-CO-, -NH-CO-NH- or a single bond and R7 represents an alkyl, alkenyl, alkynyl, pyridyl, phenyl, benzyl, phenethyl, tetrazolyl, piperidinyl or thiazolyl radical, all the alkyl, alkenyl, alkynyl, alkoxy, phenyl, benzyl and phenethyl radicals above being optionally substituted by one or more radicals selected from halogen atoms and hydroxyl radicals, alkoxy, trifluoromethyl, cyano, free carboxy, salified or esterified and tetrazolyl, the phenyl, benzyl and phenethyl radicals being further optionally substituted by one or more alkyl or alkenyl radicals, knowing that R2 and R3 may also form with two consecutive methine radicals of phenyl radical to which they are attached a ring selected from the rings that Y1 and Y2 form as defined above, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as salts of addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

dans laquelle Z, X, R1, R2, R3 R4 R52 Y1 et Y2 ont les significations indiquées ci-dessus.The products of formula (I) thus comprise in particular the products of formula (F)

wherein Z, X, R 1, R 2, R 3 R 4 R 52 Y 1 and Y 2 have the meanings given above.

dans lequel Y1 et Y2, identiques ou différents, sont choisis parmi les atomes d'oxygène, de soufre et d'azote et les radicaux -NH-, -CH= ou -CH2-,
Y1 et Y2 formant un cycle avec deux radicaux méthine consécutifs du radical phényle auquel ils sont attachés et les traits pointillés indiquant l'éventuelle présence d'une double liaison,
Z représente un atome d'oxygène ou de soufre,
X représente le radical carboxy libre, salifié, estérifié ou amidifié, le radical tétrazolyle libre ou salifié ou le radical -CO-NH-S02-R8 dans lequel R8 représente un radical alkyle ou phényle éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène, les radicaux hydroxyle, alkyle, alcoxy, trifluorométhyle, nitro, cyano, carboxy libre, salifié ou estérifié et tétrazolyle,
R1 est choisi parmi a) l'atome d'hydrogène, les atomes d'halogène, les radicaux hydroxyle, mercapto, cyano, nitro, benzoyle, acyle, sulfo, carboxy libre, salifié ou estérifié, tétrazolyle, b) les radicaux alkyle, alkényle, alkyloxy, alkylthio, phényle, naphtyle, benzoyle, phénéthyle, phénylthioalkyle et phénylthio, tous ces radicaux étant éventuellement substitués par un ou plusieurs radicaux identiques ou différents choisis parmi les atomes d'halogène et les radicaux hydroxyle, alcoxy, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié et tétrazolyle, pyridinyle et phényle lui-même éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alkyle et alcoxy, c) les radicaux amino, mono- ou dialkylamino, carbamoyle, R21 R3, R4 et R5 identiques ou différents, sont choisis parmi a) l'atome d'hydrogène, les atomes d'halogène, les radicaux hydroxyle, alkyle, alkényle, alcoxy, trifluorométhyle, cyano, nitro, carboxy libre, salifié ou estérifié, tétrazolyle, isoxazolyle, b) amino ou carbamoyle éventuellement substitués par un ou deux radicaux alkyle et alkényle, tous les radicaux alkyle, alkényle et alcoxy ci-dessus étant éventuellement substitués par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle, alcoxy, trifluorométhyle, cyano, carboxy libre, salifié ou estérifié et tétrazolyle, sachant que R2 et R3 peuvent également former avec deux radicaux méthine consécutifs du radical phényle auquel ils sont attachés un cycle choisi parmi les cycles que forment Y1 et Y2 tels que définis ci-dessus, 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 subject of the present invention is in particular the products of formula (I) as defined above, in which
Z1 and Z2 represent the radical

in which Y1 and Y2, which are identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH = or -CH2-,
Y1 and Y2 forming a ring with two consecutive methine radicals of the phenyl radical to which they are attached and the dashed lines indicating the possible presence of a double bond,
Z represents an oxygen or sulfur atom,
X represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical or the -CO-NH-SO2-R8 radical in which R8 represents an alkyl or phenyl radical optionally substituted with one or more radicals chosen from among the atoms; halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free carboxy, salified or esterified and tetrazolyl radicals,
R1 is chosen from a) hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano, nitro, benzoyl, acyl, sulfo, free carboxy, salified or esterified, tetrazolyl radicals, b) alkyl radicals, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzoyl, phenethyl, phenylthioalkyl and phenylthio, all these radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, trifluoromethyl and cyano radicals, free, salified or esterified carboxy and tetrazolyl, pyridinyl and phenyl itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals; c) amino, mono- or dialkylamino, carbamoyl radicals; , R21, R3, R4 and R5, which are identical or different, are chosen from a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkoxy and trifluoromethyl radicals; , cyano, nitro, carboxy free, salified or esterified, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted with one or two alkyl and alkenyl radicals, all the above alkyl, alkenyl and alkoxy radicals being optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkoxy, trifluoromethyl, cyano, free carboxy, salified or esterified radicals and tetrazolyl, wherein R2 and R3 may also form with two consecutive methine radicals of the phenyl radical to which they are attached a ring chosen from the rings that Y1 and Y2 form as defined above, 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).

 The subject of the present invention is particularly the products of formula (I) as defined above, in which Y 1 and Y 2 form a ring with two methine radicals located at the meta and para positions of the phenyl radical to which they are attached, said products of Formula (I) being in any isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic 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 "alkyl" denotes a linear or branched alkyl radical having at most 12 carbon atoms, such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl radicals, and the like -pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl.

 Alkyl radicals having at most 4 carbon atoms and in particular the methyl, ethyl, propyl, isopropyl or n-butyl radicals are preferred.

 The term "alkenyl radical" denotes a linear or branched radical containing at most 8 carbon atoms and preferably 4, such as, for example, the vinyl, allyl, 1-propenyl, butenyl and especially 1-butenyl radical.

 The term alkynyl radical denotes a linear or branched radical, containing at most 8 carbon atoms and preferably 4, such as for example the ethynyl, propargyl, butynyl radical.

 The term alkoxy denotes a linear or branched radical, containing at most 12 carbon atoms and preferably 4 such as for example the methoxy, ethoxy, propoxy or isopropoxy radicals, but also linear, secondary or tertiary butoxy.

 Halogen, of course, means the fluorine, chlorine, bromine or iodine atoms.

 The chlorine, bromine or fluorine atoms are preferred.

 As particular examples of alkyl or alkoxy radicals substituted by one or more halogens or haloalkyl, there may be mentioned monofluoro-, chloro-, bromo- or iodomethyl or -ethyl, difluoro-, dichloro-, dibromo- or trifluoromethyl or pentafluoroethyl radicals; bromoethoxy, trifluoromethoxy, trifluoroethoxy or pentafluoroethoxy radicals.

 The term "acyl radical" preferably means a radical having at most 7 carbon atoms, such as the formyl, acetyl, propionyl, butyryl or benzoyl radical, but also the valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical.

 The term alkylthio radical preferably denotes radicals in which the alkyl radical is as defined above such as, for example, in methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, isopentylthio or isohexylthio; the alkylthio radical is optionally substituted as for example in hydroxyethylthio, aminoethylthio, haloalkylthio such as preferably bromoethylthio, trifluoromethylthio, trifluoroethylthio or pentafluoroethylthio, arylalkylthio such as for example benzylthio or phenethylthio.

 The sulfur atoms may not be oxidized as in the alkylthio or phenylthio radicals or, on the contrary, be oxidized to give the alkylsulfinyl, phenylsulfinyl, alkylsulfonyl or phenylsulfonyl alkylsulphinyl and alkylsulfonyl radicals denote radicals in which the alkyl radical is chosen for example from values indicated above for the alkyl radical such as for example the methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl radicals.

 The carboxyl group (s) of the products of formula (I) may be esterified, amidated or salified, by the various groups known to those skilled in the art.

 By esterified carboxy is meant, for example, alkyloxycarbonyl radicals such as, for example, the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butyl, tert-butyloxycarbonyl or benzyloxycarbonyl radicals, these alkoxy radicals being capable of being substituted by one or more radicals chosen for example from among the atoms halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl groups such as, for example, in chloromethyl, hydroxypropyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.

 There may be mentioned radicals formed with easily cleavable ester residues such as the methoxymethyl, ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.

 A list of such ester radicals can be found, for example, in European Patent EP 0 034 536.

dans lesquels les radicaux R a et Rb identiques ou différents soit représentent un atome d'hydrogène ou un radical alkyle ayant de 1 à 4 atomes de carbone tels que les radicaux méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, secbutyle ou tert-butyle pour former notamment les radicaux amino, mono ou diméthylamino, mono ou diéthylamino, méthyléthylamino, monopropylamino, isopropylamino, monobutylamino, ou encore méthyléthylamino, les radicaux alkyle étant éventuellement substitués ainsi qu'il est indiqué ci-dessus et ci-après, soit forment ensemble un hétérocycle qui peut ou non comporter un hétéroatome supplémentaire. On peut citer les radicaux pyrrolyle, imidazolyle, indolyle, pipéridino, morpholino, pipérazinyle.On préfère les radicaux pipéridino, morpholino ou pipérazinyle éventuellement substitué ou le second atome d'azote, comme par exemple dans méthylpipérazinyle, fluorométhylpipérazinyle, éthylpipérazinyle, propylpipérazinyle, phénylpipérazinyle ou benzylpipérazinyle : dans ces deux derniers radicaux, les radicaux phényle et benzyle peuvent être substitués, comme par exemple dans chlorophényle ou trifluorophényle.By carboxy amidated means groups of the type

in which the radicals R a and Rb which are identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl or tert- butyl to form in particular the amino, mono or dimethylamino, mono or diethylamino, methylethylamino, monopropylamino, isopropylamino, monobutylamino or methylethylamino radicals, the alkyl radicals being optionally substituted as indicated above and below, or form together a heterocycle which may or may not comprise an additional heteroatom. Mention may be made of the pyrrolyl, imidazolyl, indolyl, piperidino, morpholino and piperazinyl radicals. The piperidino, morpholino or optionally substituted piperazinyl radicals or the second nitrogen atom, for example in methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl or phenylpiperazinyl, are preferred. benzylpiperazinyl: in these last two radicals, the phenyl and benzyl radicals may be substituted, for example in chlorophenyl or trifluorophenyl.

 By salified carboxy and tetrazolyl is meant salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

 The sodium or potassium salt is preferred.

formés à partir du radical hydroxyle -OH, selon les méthodes usuelles connues de l'homme du métier et dans lesquels
P représente un groupement protecteur et a11 a2 et a3 représentent notamment un radical alkyle, alkényîe, alkynyle, aryle ou arylalkyle, ayant au plus 12 atomes de carbone et éventuellement substitués ainsi qu'il est défini ci-dessus.The hydroxyl radical can be esterified, etherified or protected, to form the radicals

formed from the hydroxyl radical -OH, according to the usual methods known to those skilled in the art and in which
P represents a protective group and a11 a2 and a3 represent in particular an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, having at most 12 carbon atoms and optionally substituted as defined above.

 Examples of protecting group P, as well as the formation of the protected hydroxyl radical, are given in particular in the standard book of the specialist: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley Interscience Publishers, John Wiley & Sons.

 The protective group of the hydroxyl radical that can represent P, can be chosen for example from the list below formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Mention may also be made of ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, PP-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1-cyclopropylethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl, trityl, benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl and 1-methyl groups. methoxyethyl, phthaloyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, paranitrobenzoyl, para-tert-butylbenzoyl, caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl.

ou encore un dérivé du silicium tel que triméthylsilyle, triisopropylsilyle, tbutyldiphénylsilyle, ou tbutyldiméthylsilyle.P can in particular represent the radical

or a silicon derivative such as trimethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, or tbutyldimethylsilyl.

 The carbamoyl and amino radicals that may represent or carry one or more of the radicals defined in the products of formula (I) may take the values indicated above for -CON (Ra) (Rb) or -N (Ra) respectively. (Rb).

 By way of example and in a non-exhaustive manner - the substituted carbamoyl radical denotes Nmonoalkylcarbamoyl groups such as N-methylcarbamoyl, N-ethylcarbamoyl; N, N-dialkyl carbamoyl, such as N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl; N- (hydroxyalkylcarbamoyl, such as N- (hydroxyethyl) carbamoyl, phenylcarbamoylpyridylcarbamoyl, benzylcarbamoyl, N-methyl-N-phenylcarbamoyl, pyridylmethylcarbamoyl.

the substituted amino radical denotes the mono or dialkylamino radicals in which the alkyl radical (s) are ethylamino, optionally substituted, in particular, with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, cyano, free carboxy and salified radicals, esterified or amidified, and represent in particular the radicals hydroxyalkyl-, cyanoalkyl-, carboxyalkyl- or alkoxyalkylamino such as for example methoxymethylamino, methoxyethylamino or ethoxyethylamino.

 The substituted amino radical may also be an alkoxycarbonylamino radical, such as in particular tert-butyloxycarbonylamino or benzyloxycarbonylamino, or an acylamino radical in which the acyl radical represents an alkylcarbonyl or arylcarbonyl radical such as in particular in the acetylamino or benzoylamino radicals.

 The amino and carbamoyl radicals can in particular be substituted with alkenyl radicals such as allyl, alkanoyl such as pivaloyl, aryl, arylalkyl, alkyl- and arylsulphonamide and aryl- or alkylsulphonyl as defined above and hereinafter.

 Mention may in particular be made of arylsulphonylamino radicals in which the arylsulphonyl radical represents, for example, the para-toluenesulphonyl radical.

 When the products of formula (I) as defined above contain an amino salifiable by an acid it is understood that these acid salts are also part of the invention.

 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.

 There may be mentioned more particularly the salts formed with hydrochloric or methanesulphonic acid for example.

les traits pointillés indiquant l'éventuelle présence d'une double liaison,
Z représente un atome d'oxygène ou de soufre,
X représente le radical carboxy libre, estérifié, salifié ou amidifié, le radical tétrazolyle libre et salifié et le radical -CO-NH-SO2-R9 dans lequel Rg représente le radical méthyle, éthyle ou phényle éventuellement substitué par un ou plusieurs radicaux alkyle,
R1 est choisi parmi l'atome d'hydrogène, les atomes d'halogène, les radicaux carboxy libre, salifié ou estérifié et phénylthiométhyle éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle et alcoxy,
R4 et R5, identiques ou différents, sont choisis parmi l'atome d'hydrogène, les atomes d'halogène et les radicaux hydroxyle, alkyle et alcoxy éventuellement substitué par un radical carboxy libre, salifié ou estérifié,
R2 et R3 forment avec deux radicaux méthine consécutifs du radical phényle auquel ils sont attachés un cycle choisi parmi ceux que forment Y1 et Y2, ou bien identiques ou différents, sont choisis parmi les valeurs de R4 et R5, 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 subject of the present invention is particularly the products of formula (I) as defined above in which the ring formed by Y1 and Y2 is chosen from the following radicals:

the dotted lines indicating the possible presence of a double bond,
Z represents an oxygen or sulfur atom,
X represents the free, esterified, salified or amidified carboxy radical, the free and salified tetrazolyl radical and the -CO-NH-SO2-R9 radical in which Rg represents the methyl, ethyl or phenyl radical optionally substituted with one or more alkyl radicals,
R1 is chosen from hydrogen atom, halogen atoms, free, salified or esterified carboxy and phenylthiomethyl radicals optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl and alkoxy radicals,
R4 and R5, which are identical or different, are chosen from hydrogen, halogen atoms and hydroxyl, alkyl and alkoxy radicals optionally substituted with a free, salified or esterified carboxy radical,
R2 and R3 form with two consecutive methine radicals of the phenyl radical to which they are attached a ring selected from those which Y1 and Y2 form, or else identical or different, are chosen from the values of R4 and R5, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

attaché aux positions méta et para du radical phényle.The subject of the present invention is more particularly the products of formula (I) corresponding to formula (F) as defined above, in which Y 1 and Y 2 form the radical

attached to the meta and para positions of the phenyl radical.

 The subject of the present invention is particularly the following products - potassium salt of 1 - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-3 - ((4-methoxyphenyl) methyl) 4-oxoquinoline-2-carboxylic acid, - 3 - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-1 - ((4-methoxyphenyl) methyl) potassium salt -4-oxo-quinoline-2-carboxylic acid.

dans laquelle R'1 a la signification indiquée ci-dessus pour
R1 dans laquelle les éventuelles fonctions réactives sont éventuellement protégées par des groupements protecteurs, avec un composé de formule (III)

dans laquelle R'2 et R'3 ont les significations indiquées ci-dessus, respectivement pour R2 et R3 dans lesquelles les éventuelles fonctions réactives sont éventuellement protégées par des groupements protecteurs, et alk et alk11 identiques ou différents, représentent un radical alkyle renfermant au plus 6 atomes de carbone, pour obtenir un produit de formule (1V)

dans laquelle R'1, R'2, R'3 et alk ont les significations indiquées ci-dessus, que l'on fait réagir avec un composé de formule (V)

dans laquelle Z11 Z2 R'4 et R'5 ont les significations indiquées ci-dessus, respectivement pour R4 et R5 dans lesquelles les éventuelles fonctions réactives sont éventuellement protégées par des groupements protecteurs, pour obtenir un produit de formule (I')

dans laquelle Z11 Z2 R'1, R'21 R'3, R'41 R'5 et alk ont les significations indiquées 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 a) une réaction de transformation de fonction oxo C=O en fonction thioxo C=S, b) une réaction de saponification de fonction ester en fonction acide, c) une réaction de transformation de fonction alkyloxy en fonction hydroxyle, d) une réaction de transformation de la fonction cyano en fonction acide, e) une réaction de transformation de la fonction cyano en radical tétrazolyle, f) une réaction d'estérification ou d'amidification de fonction acide, g) une réaction de réduction de la fonction carboxy en fonction alcool, h) une réaction de transformation du radical CO2alk en radical -CO-NH-SO2-R6, tel que défini ci-dessus, i) une réaction de transformation du radical CO2alk en radical CONH2 puis si désiré en radical cyano, j) une réaction d'élimination des groupements protecteurs que peuvent porter les fonctions réactives protégées, k) une réaction de salification par un acide minéral ou organique ou par une base minérale ou organique pour obtenir le sel correspondant, 1) 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 present invention is also the process for the preparation of the products of formula (I) as defined above, characterized in that a compound of formula (II) is reacted:

in which R'1 has the meaning indicated above for
R1 in which the optional reactive functional groups are optionally protected by protective groups, with a compound of formula (III)

in which R'2 and R'3 have the meanings indicated above, respectively for R2 and R3 in which the optional reactive functional groups are optionally protected by protective groups, and alk and alk11, which may be identical or different, represent an alkyl radical containing at least plus 6 carbon atoms, to obtain a product of formula (1V)

in which R'1, R'2, R'3 and alk have the meanings indicated above, which is reacted with a compound of formula (V)

in which Z11 Z2 R'4 and R'5 have the meanings indicated above, respectively for R4 and R5 in which the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (I ')

in which Z11 Z2 R'1, R'21 R'3, R'41 R'5 and alk have the meanings indicated above, product of formula (I ') which is subjected, if desired and if necessary, to one or more of the following reactions, in any order a) an oxo C = O function conversion reaction in the C = S thioxo function, b) an acid functional ester saponification reaction, c) a reaction conversion of alkyloxy function to hydroxyl function, d) a conversion reaction of the cyano function to acid function, e) a conversion reaction of the cyano function to the tetrazolyl radical, f) an esterification reaction or amidification of function acid, g) a reduction reaction of the carboxy function as a function of alcohol, h) a conversion reaction of the radical CO2alk into the radical -CO-NH-SO2-R6, as defined above, i) a conversion reaction of the radical CO2alk in radical CONH2 then if desired in cyano radical, j) a reacti removing the protective groups that the protected reactive functions can carry, k) a salification reaction with an inorganic or organic acid or a mineral or organic base to obtain the corresponding salt, 1) a resolving reaction of the racemic forms, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

 Under preferred conditions of implementation of the invention, the process described above can be carried out as follows the action of the products of formula (III) on the products of formula (II) to obtain the product of formula (IV) can be carried out in a solvent such as for example toluene or xylene, in the presence of a catalytic amount of acid such as ptoluenesulphonic or camphorsulfonic acid, or in the presence of molecular sieve.

 The compound of formula (III) is thus fixed by its oxo function, alpha of the carboxyl function on the amine function of the compound of formula (II) and is cyclized by heating at elevated temperature, especially greater than 2000C.

 The reaction of the product of formula (IV) thus obtained with the compound of formula (V) can be carried out in a solvent such as for example dimethylformamide or acetone, in the presence of sodium or potassium carbonate, at room temperature or at reflux of the solvent.

de préférence lié aux positions méta et para du radical phényle.In the compound of formula (V), Hal is preferably a bromine or chlorine atom and Z1 and Z2 as defined above, especially represent the cyclic radical containing Y1 and Y2, as defined above, which constitutes especially the radical

preferably linked to the meta and para positions of the phenyl radical.

 Such a compound of formula (V) is, for example, piperonyl bromide.

 The reactions to which the products of formulas (I ') as defined above may be subjected, if desired or necessary, may be carried out, for example, as indicated below.

a) the conversion reaction of oxo function in thioxo function can be carried out in particular by the reagent of
LAWESSON in toluene.

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

c) The optional alkoxy functions, such as in particular methoxy, 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 trifluoroacetic acid under reflux.

d) 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, glacial acetic acid and water, these three compounds preferably being in equal proportions, or in a mixture of sodium hydroxide, ethanol and refluxing water.

e) The optional cyano functions may, if desired, be converted into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide such as, for example, sodium azide or azide. trialkyltin on the nitrile function as indicated in the method described in the referenced article as follows
J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S. et al.

f) The products described above may, if desired, be subject, 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 reaction of conversion of acid function to amide function can in particular be carried out by first forming an acid chloride, for example by the action of SOC12 then amidification, or by direct amidation of the acid according to the usual known conditions of the skilled person.

The amide thus obtained can then, if desired, be converted into thioamide by the action, in particular, of the reagent of
LAWESSON in toluene.

g) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced according to the alcohol by the methods known to those skilled in the art: thus, for example, the possible free carboxy functions, in particular by hydride boron and any esterified carboxy functions in particular with lithium aluminum hydride in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether.

 The possible alcohol functions of the products described above may, if desired, be converted into an aldehyde or acid function by oxidation under the usual conditions known to those skilled in the art, such as, for example, by the action of manganese oxide to obtain the aldehydes or Jones reagent to access the acids.

 The reactions of conversion of formyl radical to carbamoyl radical and carbamoyl radical to nitrile radical can be carried out according to the usual conditions known to those skilled in the art, such as for example by passage through the keto nitrile and displacement by an amine (Chem .

Comm. 1971, p. 733).

 The optional alkylthio or phenylthio groups of the products described above may, if desired, be converted into the corresponding sulfoxide or sulfone functions under the usual conditions known to those skilled in the art, such as, for example, peracids, for example acid. peracetic or metachloroperbenzoic acid or alternatively by ozone, oxone, sodium periodate in a solvent such as, for example, methylene chloride or dioxane at room temperature.

 The optional amine functions of the products described above can be, if desired, converted into the corresponding alkylamino, dialkylamino, acylamino, alkyl- and arylsulfonamide and aminosulphonyl functions, which are optionally substituted in the usual conditions known to those skilled in the art, by way of example the action of tosyl chloride in the presence of pyridine in methylene chloride can be cited to convert the amine to arylsulfonylamino function tosylamino.

que l'on peut transformer en radical

par exemple par action du composé Sn(Bu)3N3 dans le toluène.The reaction of conversion of acid function to tetrazolylcarboxy function can be carried out for example by prior conversion of the acid function to acid chloride as indicated above, then by action of Cu-C-N, according to common conditions known to those skilled in the art on the acid chloride thus obtained, the radical is thus obtained.

that we can transform into radical

for example by the action of the compound Sn (Bu) 3N3 in toluene.

 The etherification reactions of the hydroxyl function or ester function conversion as defined above can be carried out under the usual conditions known to those skilled in the art.

h) the CO 2alk radical can be converted into -CO-NH-SO 2 R 6 radical by reaction with NH 2 -SO 2 -R 6 in which R 6 has the meaning indicated above, under the usual conditions known to those skilled in the art such as, for example in a basic medium in the presence of sodium hydroxide or potassium hydroxide by phase transfer. The -CO2alk radical may also be converted to the -C02H then -COC1 radical that is reacted with the NH2-SO2-R6 compound as defined above and according to the usual conditions known to those skilled in the art to obtain the radical -CO-NH-SO2-R6.

i) the CO 2alk radical can be converted to the CONH 2 radical and then to the nitrile or tetrazolyl radical according to the usual conditions known to those skilled in the art.

j) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation.

 The phthalimido group can be removed by hydrazine.

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

k) The products described above may, if desired, be the subject of salification reactions for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art.

1) The possible optically active forms of the products described above may be prepared by resolution of the racemic agents according to the usual methods known to those skilled in the art.

 Illustrations of such reactions defined above are given in the preparation of the examples described below.

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

 The products of formula (I) as defined above, have endothelin receptor antagonist properties and are thus notably inhibitors of the effects of endothelin, in particular the vasoconstrictor and hypertensive effects induced by the endothelin. endothelin. In particular, an antiischemic effect is noted, the vasoconstrictor activity of endothelin being abolished.

 The products of formula (I) are also able to oppose the stimulating effects of endothelin in all cell types, including smooth muscle cells, neuronal cells and bone cells.

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

 The invention particularly relates, as medicaments, to the products of formula (F) as defined above, said products of formula (F) being in all isomeric forms possible racemic or optically active, as well as the salts of addition with the inorganic or organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (F).

les traits pointillés indiquant l'éventuelle présence d'une double liaison,
Z représente un atome d'oxygène ou de soufre,
X représente le radical carboxy libre, estérifié, salifié ou amidifié, le radical tétrazolyle libre et salifié et le radical -CO-NH-S02-R9 dans lequel Rg représente le radical méthyle, éthyle ou phényle éventuellement substitué par un ou plusieurs radicaux alkyle,
R1 est choisi parmi l'atome d'hydrogène, les atomes dthalo- gène, les radicaux carboxy libre, salifié ou estérifié et phénylthiométhyle éventuellement substitué par un ou plusieurs radicaux choisis parmi les atomes d'halogène et les radicaux hydroxyle et alcoxy,
R4 et R51 identiques ou différents, sont choisis parmi l'atome d'hydrogène, les atomes d'halogène et les radicaux hydroxyle, alkyle et alcoxy éventuellement substitué par un radical carboxy libre, salifié ou estérifié,
R2 et R3 forment avec deux radicaux méthine consécutifs du radical phényle auquel ils sont attachés un cycle choisi parmi ceux que forment Y1 et Y2, ou bien identiques ou différents, sont choisis parmi les valeurs de R4 et R5, 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 pharmaceutiquement acceptables desdits produits de formule (I).The invention more particularly relates, as medicaments, to the products of formula (I) as defined above, in which the ring formed by Y1 and Y2 is chosen from the following radicals:

the dotted lines indicating the possible presence of a double bond,
Z represents an oxygen or sulfur atom,
X represents the free, esterified, salified or amidified carboxy radical, the free and salified tetrazolyl radical and the -CO-NH-SO2-R9 radical in which Rg represents the methyl, ethyl or phenyl radical optionally substituted with one or more alkyl radicals,
R 1 is chosen from hydrogen atom, halogen atoms, free, salified or esterified carboxy and phenylthiomethyl radicals optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl and alkoxy radicals,
R4 and R51, which are identical or different, are chosen from hydrogen, halogen atoms and hydroxyl, alkyl and alkoxy radicals optionally substituted with a free, salified or esterified carboxy radical,
R2 and R3 form with two consecutive methine radicals of the phenyl radical to which they are attached a ring selected from those which Y1 and Y2 form, or else identical or different, are chosen from the values of R4 and R5, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, 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 following products of formula (I) - potassium salt of 1 - ((1,3-benzodioxol) -5-yl) methyl-1,4-dihydro-3 - ((4-methoxyphenyl) methyl) -4-oxoquinoline-2-carboxylic acid, - potassium salt of 3 - ((1,3-benzodioxol) 5-yl) methyl-1,4-dihydro-1- (4-methoxyphenyl) methyl) -4-oxoquinoline-2-carboxylic acid.

 The medicinal products which are the subject of the invention find, for example, their use in the treatment of all vascular spasms, in the treatment of post-cerebral hemorrhages, in the treatment of coronary spasms, peripheral vascular spasms and in treatment. kidney failure. These drugs can also be used in the treatment of myocardial infarction, congestive heart failure, prevention of post-angioplasty restenosis, treatment of atherosclerosis and certain forms of hypertension such as pulmonary hypertension, as well as in the treatment of asthma.

 The drugs, object of the invention, can also find an application in the treatment of osteoporosis, prostatic hyperplasia and as neural protectors.

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

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

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

 The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 1 to 300 mg per day in the adult, orally or from 1 to 100 mg per day per day. intravenous.

 The starting materials of formulas (II), (III), and (V) are for the most part commercial or can be prepared from commercial products by the usual methods known to those skilled in the art.

 The products of formula (II), aniline or derivatives of aniline, are mostly commercial such as in particular aniline itself and nitroaniline.

 Among the commercial products of formula (V), mention may in particular be made of 6-chloro piperonyl chloride, piperonyl chloride or bromide, 4-methoxy benzyl chloride, 3,4-dichlorobenzyl chloride, or else 3-chlorobenzyl bromide.

 The examples described below in the experimental section give illustrations, which are not exhaustive, of such starting materials, in particular the preparation of products of formula (III), for example those of the preparations I and II described below.

 Another subject of the present invention is, as new industrial products, the compounds of formula (IV).

 The subject of the invention is therefore particularly the use of the products of formula (I) as defined above, for the preparation of pharmaceutical compositions intended for the treatment of affections resulting from an abnormal stimulation of the endothelin receptors.

 The subject of the invention is in particular the use of the products of formula (I) as defined above, for the preparation of pharmaceutical compositions intended for the treatment of endothelin-induced hypertension, the treatment of all vascular spasms. , treatment of cerebral post-hemorrhage and renal insufficiency and treatment of myocardial infarction and prevention of post-angioplasty resterosis.

 The following examples illustrate the invention without limiting it.

Preparation I
Stage 1: ethyl 3- (4-methoxyphenyl) propionate
9.6 g of 3- (4-methoxyphenyl) propionic acid, 200 ml of methylene chloride, 160 ml of ethanol and 0.1 g of 4- (dimethylamino) pyridine are introduced.

 It is cooled to OOC and then 11.3 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl are introduced.

 It is stirred for about 2 days at room temperature, poured into 200 ml of water and then extracted with three times 100 ml of methylene chloride. Washed with 100 ml of 2N sodium hydroxide. 11.3 g of expected product are thus obtained.

Physical analyzes: IR CHCl3 (cl 1) 1727
Aromatic 1610-1594-1514
Step 2: Ethyl 2 - [(4-methoxyphenyl) methyl) -1-oxo-1,4-butanedioate
11.3 g of the product obtained in Stage 1 above, 7.7 g of sodium ethoxide and 150 ml of toluene are introduced.

 It is stirred for one hour at 800 ° C. and then 9 ml of ethyl oxalate are introduced. It is stirred for 1 hour at 800 ° C., poured into water + 2N hydrochloric acid, extracted with three times 200 ml of ethyl acetate and dried. Chromatography on silica in cyclohexane-ethyl acetate (8-2) and thus obtained 7.46 g of the expected product.

Physical Analvses: IR CHCI3 (cl 1)
C = O 1752-1732
Aromatic 1612-1585-1515
Preparation II
Stage 1: ethyl 3- (3,4-methylenedioxyphenyl) propionate
The procedure is as in Step 1 of Preparation I starting from 11.65 g of 3- (3,4-methylenedioxyphenyl) propionic acid, 200 ml of methylene chloride, 160 ml of ethanol and 0.1 g of 4 g. - (dimethylamino) pyridine, cooled to 0 ° C and introduced 12.6 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, HCl.

 11.5 g of expected product are thus obtained.

Physical Analvses: NMR (CDCl3, S, ppm)
Aromatic (m, 3H) 6,8-6,6
OCH2O (s, 2H) 5.9
OCH2 (q, J = 6.7 Hz, 2H) 4.15
CH2-CO (t, J = 8Hz, 2H) 2.9
Ar-CH2 (t, J = 8 Hz, 2H) 2.6
CH3 (t, J = 6.7 Hz, 3H) 1.25
Step 2: Ethyl 2- [(1, 3-benzodioxol) -5-yl-methyl] -3-oxo-1,4-butanedioate
The procedure is as for Stage 2 of Preparation I, starting with 7.38 g of sodium ethoxide, 130 ml of toluene, 10.965 g of the product obtained in Stage 1 above, stirring and refluxing for 20 minutes. , introduced 8.7 ml of ethyl oxalate, refluxed for 1 hour and cooled.

200 ml of 1N hydrochloric acid and 200 ml of ethyl acetate, decanted, reextracted the aqueous phase with 200 ml of ethyl acetate. Then wash and dry. Chromatography on silica in cyclohexane-ethyl acetate (7-3) gives 10.543 g of expected product (colorless oil).

Phvsial Analvses: IR CHCl3 (cl 1)
C = O 1755-1734
Aromatic 1612-1506-1492
EXAMPLE 1 Ethyl (1,3-benzodioxol-5-yl) methyl) 1,4-dihydro-3- ((4-methoxyphenyl) methyl) -4-oxoquinoline 2-carboxylate
Stage 1: (E, Z) 2 - [(4-Methoxyphenyl) methyl] -3- (phenylamino) ethyl 1,4-butanedioate
7.46 g of the product obtained in Stage 2 of Preparation I, 2.7 ml of aniline, 70 ml of toluene and 0.1 g of para-toluenesulphonic acid are introduced. Refluxed for 1 hour and then left overnight at room temperature. It is poured into about 200 ml of saturated sodium bicarbonate solution, extracted with three times 200 ml of ethyl acetate and dried. Chromatography on silica in the cyclohexane-ethyl acetate mixture (7-3) gives 7.5 g of expected product (oil).

Phvsic Analvses: IR CHCl3 (cal) = C-NH-3250> = O 1735-1658
C = C + aromatics 1608-1595-1582-1510-1502
Stage 2: Ethyl 1,4-dihydro-3 - ((4-methoxyphenyl) methyl) 4-oxoquinoline 2-carboxylate
7.5 g of the product obtained in Stage 1 above is heated at 2200 ° C. for 30 minutes, cooled, the crystals obtained are washed with hexane and then with ice-cold ethyl ether to thereby obtain 4.59 g of the expected product ( crystals).

Physical Analvses: IR CHCl3 (cal) = C-NH 3424-3378> = O 1744-1708
C = 0 + conj system 1623-1606-1589-1573-1531-1511 + Aromatic
Stage 3: 1 - ((1,3-Benzodioxol-5-yl) methyl) -1,4-dihydro-3- (4-methoxyphenyl) methyl) -4-oxo-quinoline 2-ethyl carboxylate
2.3 g of the product obtained in Stage 2 above, 60 ml of dimethylformamide and 2.4 g of piperonyl bromide are introduced, the mixture is stirred for 5 minutes at room temperature and then 1.9 g of potassium carbonate are introduced.

 It is stirred for 70 hours at room temperature, poured into 100 ml of water and then extracted with three times 100 ml of ethyl acetate and dried. Chromatography on silica in cyclohexane-ethyl acetate (6-4) and 0.25 g of expected product (oil).

Analvseschvsiques: IR CHCl3 (cal) 1727
Conj. 1610-1583-1562-1512-1504-1492 + aromatics
EXAMPLE 2 Potassium salt of 1 - ((1,3-benzodioxol-5-yl) methyl) 1,4-dihydro-3 - ((4-methoxyphenyl) methyl) 4-oxoquinoline 2-carboxylic acid
0.25 g of the product of Example 1, 6 ml of ethanol, 0.18 ml of 6N potassium hydroxide are introduced, the mixture is stirred and then concretized in ethyl ether and dried. 0.237 g of expected product (crystals) are thus obtained.

Physical Analvses: IR Nujol (cl 1)
Conj.

+ C00e 1612-1590-1565-1510-1490 + Aromatic
EXAMPLE 3 Ethyl 3 - ((1,3-benzodioxol-5-yl) methyl) 1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxoquinoline 2-carboxylate
Step 1: (E, Z) 2 - [(1,3-Benzodioxol-5-yl) methyl] -3- (phenylamino) -1,4-ethyl butanedioate
7.2 g of the product obtained in Stage 2 of Preparation II, 2 ml of aniline, 70 ml of toluene and 0.1 g of para-toluenesulfonic acid are introduced.

 Refluxed for 4 hours by distilling the water formed, poured into about 200 ml of saturated sodium bicarbonate solution, extracted with three times 100 ml of ethyl acetate and dried. Chromatography on silica in cyclohexane-ethyl acetate (8-2) and 6.2 g of expected product (oil).

Physical Analvses: IR CHCl3 (cal) = C-NH-3260> = O 1733-1656
C = 0 + aromatics 1610-1595-1583-1502-1489
Stage 2: 1, 4-Dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxoquinoline-2-carboxylic acid ethyl ester
6.2 g of the product obtained in Stage 1 above are heated at 2400C for 30 minutes and cooled. The crystals obtained are filtered and then washed with ice cold ethyl ether. 3.9 g of expected product (crystals) are thus obtained.

Physical Analvses: IR CHCl3 (cl 1) = C-NH 3424-3379> = O 1745-1708
Conj. + aromatics 1623-1608-1591-1573-1532-1503
Stage 3: 3 - ((1,3-benzodioxol-5-yl) methyl) -1,4-dihydro-1 ((4-methoxyphenyl) methyl) -4-oxoquinoline-2-carboxylic acid ethyl ester
1.8 g of the product obtained in Step 2 above, 50 ml of dimethylformamide, 1.4 ml of 4-methoxybenzyl chloride are added, the mixture is stirred for 5 minutes at room temperature and then 1.4 g of potassium carbonate are introduced. It is stirred at ambient temperature, poured into 100 ml of water and then extracted with three times 50 ml of ethyl acetate and dried. Chromatography on silica in cyclohexane-ethyl acetate (5-5) and 0.25 g of expected product (oil).

Physical Analvses: NMR (CDCl3, S, ppm)
COOCH2CH3 (t, 3H) 1.15
COOCH2CH3 (q, 2H) 4.3
OCH3 (s, 3H) 3.7
Ph-CH2-C = (s, 2H) 3.9 = CN-CH2-Ph (s, 2H) 5.2
PhO-CH2-O (s, 2H) 5.9
Aromatic 6.5 to 8.6
EXAMPLE 4 Potassium salt 3 - ((1,3-benzodioxol-5-yl) methyl) -1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxoquinoline-2-carboxylic acid
The procedure is as in Example 2, starting from 0.25 g of the product of Example 3, 6 ml of ethanol and 0.18 ml of 6N potassium hydroxide. Heat at 800C for 72 hours and leave about 2 days at room temperature. The crystals obtained are drained, washed with ethyl ether and then dried. 0.143 g of expected product (crystals) are thus obtained.

Analvses phvsiaues: IR Nujol (cal)> = O conj. 1606
Conj. + Aromatic 1592-1565-1535-1511-1501-1492
EXAMPLE 5: Pharmaceutical composition

Tablets having the following formula were prepared
Product of Example 2 ........................... 50 mg
Excipient for a tablet finished at .............. 200 mg (details of the excipient: lactose, talc, starch, magnesium stearate).

PHARMACOLOGICAL RESULTS:
STUDY OF ACTIVITY ON ENDOTHELIN RECEPTOR A
Membrane preparation is carried out from rat heart (ventricles). The tissue is ground with POLYTRON in a 50 mM Tris buffer pH = 7.4.

 After 30 minutes at 250 ° C. (B.M.) the homogenate is centrifuged at 30000 g for 15 minutes (2 centrifugations with intermediate recovery in Tris buffer pH 7.4).

 The pellets are resuspended in incubation buffer (25mM Tris, perpstatin A 5 microg / ml, aprotinin 3microg / ml, 0.1mM PMSF, 3mM EDTA, 1mM EGTA pH 7.4).

 2 ml aliquots are distributed in hemolysis tubes and 125 I endothelin (about 50000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10-5 M in triplicate). When the test product displaces receptor-specific radioactivity by more than 50%, it is tested again in a range of 7 concentrations to determine the concentration that inhibits receptor-specific radioactivity by 50%. The 50% inhibitory concentration is thus determined.

 Nonspecific binding is determined by addition of endothelin at 10-6 M (in triplicate). Incubated at 25 ° C. for 60 minutes, reslurried with OOC for 5 minutes, filtered under reduced pressure, rinsed with Tris buffer 7.4 and counted the radioactivity in the presence of Triton scintillant.

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

Result
TABLE I

<tb> Product <SEP> of <SEP> Example <SEP> Receptor <SEP> A <SEP> of <SEP> Endothelin <SEP>
<tb><SEP> IC50 <SEP> in <SEP> nanomoles
<tb><SEP> 2 <SEP> 10.6
<Tb>
STUDY OF ACTIVITY ON ENDOTHELIN RECEPTOR B
Membrane preparation is performed from posterior cortex plus rat cerebellum. The fabric is crushed
POLYTRON in a 50 mM Tris buffer pH = 7.4.

 After 30 minutes at 250 ° C. (B.M.) the homogenate is centrifuged at 30000 g for 15 minutes (2 centrifugations with intermediate recovery in Tris buffer pH 7.4).

 The pellets are resuspended in incubation buffer (25 mM Tris, 5 microg / ml pepstatin A, 3 microg / ml aprotinin, 0.1 mM PMSF, 3 mM EDTA, 1 mM EGTA pH 7.4).

 2 ml aliquots are distributed in hemolysis tubes and 125 I endothelin (about 50000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10 5M in triplicate). When the test product displaces receptor-specific radioactivity by more than 50%, it is tested again in a range of 7 concentrations to determine the concentration that inhibits receptor-specific radioactivity by 50%. The 50% inhibitory concentration is thus determined.

 Nonspecific binding is determined by addition of endothelin at 10-6 M (in triplicate). It is incubated at 250 ° C. for 60 minutes, put back on a water bath at 0 ° C. for 5 minutes, filtered under reduced pressure, rinsed with Tris buffer 7.4 and counts the radioactivity in the presence of Triton scintillant.

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

Result
TABLE I

<tb> Product <SEP> of <SEP> Example <SEP> Receptor <SEP> B <SEP> of <SEP> Endothelin
<tb><SEP> IC50 <SEP> in <SEP> nanomoles
<tb><SEP> 2 <SEP> 606
<Tb>

Claims (11)

R1 is chosen from a) hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano, nitro, benzoyl, acyl, sulfo, free carboxy, salified or esterified, tetrazolyl radicals, b) alkyl radicals, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio, all these radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkoxy, trifluoromethyl, cyano and free carboxy radicals; , salified or esterified, tetrazolyl, isoxazolyl, pyrrolidinyl, pyridinyl, pyrrolidinylcarbonyl and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals, c) amino, mono-, or dialkylamino, carbamoyl, d) pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl, mor pholinocarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl, all piperazinyl radicals being optionally substituted on the second nitrogen atom by an alkyl or phenyl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, nitro radicals; , alkyl or alkyloxy, trifluoromethyl, cyano, free carboxy, salified or esterified, tetrazolyl and isoxazolyl, R21 R31 R4 and R5 identical or different, are chosen from a) the hydrogen atom, the halogen atoms, the hydroxyl radicals; alkyl, alkenyl, alkoxy, trifluoromethyl, cyano, nitro, carboxy free, salified or esterified, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted by one or two radicals selected from - (CH2) pS (O) mZ- R7 as defined below and the alkyl and alkenyl radicals, c) the radical - (CH2) pS (O) mZ-R7 wherein p represents the values 0 and 1, m represents the values 0 to 2, Z represents the radicals -NH-, -NH-CO-, -NH-CO-NH- or a single bond and R7 represents an alkyl, alkenyl, alkynyl, pyridyl, phenyl, benzyl, phenethyl or tetrazolyl radical, piperidinyl, thiazolyl, all the alkyl, alkenyl, alkynyl, alkoxyphenyl, benzyl and phenethyl radicals above being optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, trifluoromethyl, cyano and free carboxy radicals; , salified or esterified and tetrazolyl, the phenyl, benzyl and phenethyl radicals being further optionally substituted by one or more alkyl or alkenyl radicals, knowing that R2 and R3 can also form with two consecutive methine radicals of the phenyl radical to which they are attached a ring. selected from the rings that Y1 and Y2 form as defined above, said products of formula (I) being in all isomeric possible racemic forms, enan tiomers 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). X represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical or the -CO-NH-SO2-R6 radical, in which R6 represents an alkyl, alkenyl or phenyl radical optionally substituted by one or more radicals chosen among the halogen atoms, the hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free carboxy, salified or esterified, tetrazolyl or phenyl radicals, itself optionally substituted with one or more radicals chosen from halogen atoms and the hydroxyl, alkoxy and nitro radicals, Z represents an oxygen or sulfur atom, Y1 and Y2 forming a ring with two consecutive methine radicals of the phenyl radical to which they are attached and the dashed lines indicating the possible presence of a double bond, Y1 and Y21, which are identical or different, are chosen from oxygen, sulfur and nitrogen atoms and radicals -NH-, -CH = or -CH2-,  in which

Z1 and Z2 represent a hydrogen atom or form the radical  in which

 CLAIMS 1) Products of formula (I) 2) Products of formula (I) as defined in claim 1, wherein Z1 and Z2 represent the radical

 in which Y1 and Y2, which are identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH = or -CH2-, Y1 and Y2 forming a ring with two consecutive methine radicals of the phenyl radical to which they are attached and the dashed lines indicating the possible presence of a double bond, Z represents an oxygen or sulfur atom, X represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical or the -CO-NH-SO2-R8 radical in which R8 represents an alkyl or phenyl radical optionally substituted with one or more radicals chosen from among the atoms; halogen, hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free carboxy, salified or esterified and tetrazolyl radicals, R1 is chosen from a) hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano, nitro, benzoyl, acyl, sulfo, free carboxy, salified or esterified, tetrazolyl radicals, b) alkyl radicals, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio, all these radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy and tetrazolyl, pyridinyl and phenyl itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals; c) amino, mono- or dialkylamino, carbamoyl radicals; , R 2, R 31, R 4 and R 5, which are identical or different, are chosen from a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkoxy, trifluoromethyl, cyano, nitro, free carboxy, salified or esterified radicals; , tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted with one or two alkyl and alkenyl radicals, all the above alkyl, alkenyl and alkoxy radicals being optionally substituted with one or more radicals chosen from halogen atoms and radicals hydroxyl, alkoxy, trifluoromethyl, cyano, carboxy free, salified or esterified and tetrazolyl, knowing that R2 and R3 can also form with two consecutive methine radicals of the phenyl radical to which they are attached a ring selected from the rings that Y and Y2 form such that defined above, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as addition salts with the inorganic 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 wherein Y1 and Y2 form a ring with two methine radicals located in the meta and para positions of the phenyl radical to which they are attached, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as addition salts with inorganic and organic acids 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 wherein the ring formed by Y1 and Y2 is selected from the following radicals

 the dotted lines indicating the possible presence of a double bond, Z represents an oxygen or sulfur atom, X represents the free, esterified, salified or amidified carboxy radical, the free and salified tetrazolyl radical and the -CO-NH-SO2-R9 radical in which Rg represents the methyl, ethyl or phenyl radical optionally substituted with one or more alkyl radicals, R1 is chosen from hydrogen atom, halogen atoms, free, salified or esterified carboxy and phenylthiomethyl radicals optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl and alkoxy radicals, R4 and R5, which are identical or different, are chosen from hydrogen, halogen atoms and hydroxyl, alkyl and alkoxy radicals optionally substituted with a free, salified or esterified carboxy radical, R2 and R3 form with two consecutive methine radicals of the phenyl radical to which they are attached a ring selected from those which Y1 and Y2 form, or else identical or different, are chosen from the values of R4 and R5, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). (5) The following products - Potassium salt of 1 - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-3 - ((4-methoxyphenyl) methyl) -4-oxoquinoline- 2-carboxylic acid, - 3 - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxoquinoline-2-potassium salt carboxylic acid. 6) Process for the preparation of the products of formula (I) as defined in claim 1, characterized in that a compound of formula (II) is reacted

 in which R'1 has the meaning indicated in claim 1 for R1 in which the optional reactive functional groups are optionally protected by protective groups, with a compound of formula (III)

 in which R'2 and R'3 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, and alk and alk1, which may be identical or different, represent an alkyl radical; containing not more than 6 carbon atoms, to obtain a product of formula (IV)

 in which R'1, R'2, R'3 and alk have the meanings indicated above, which is reacted with a compound of formula (V)

 in which Z11 Z2 R'4 and R'5 have the meanings indicated in claim 1, respectively for R4 and R5 in which the optional reactive functional groups are optionally protected by protecting groups, to obtain a product of formula (I ')

 in which Z11 Z2 R'11 R'2, R'3, R'4, R'5 and alk have the meanings indicated above, product of formula (I ') which is subjected, if desired and if necessary at one or more of the following reactions, in any order a) an oxo C = O function conversion reaction in the C = S thioxo function, b) an ester functional saponification reaction in the acid function, c) an conversion reaction of alkyloxy function to hydroxyl function, d) a reaction of conversion of the cyano function to acid function, e) a conversion reaction of the cyano function to the tetrazolyl radical, f) an esterification or amidation reaction of acid function, g) a reduction reaction of the carboxy function as a function of alcohol, h) a conversion reaction of the radical CO2alk into the radical -CO-NH-SO2-R6, as defined in claim 1, i) a reaction of transformation of the radical CO2alk in radical CONH2 then if desired in cyano radical (j) an elimination reaction of the protective groups which the protected reactive functions can carry, (k) a salification reaction with an inorganic or organic acid or with a mineral or organic base to obtain the corresponding salt, (1) a doubling reaction 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, and their addition salts with inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases. 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 (IV). 11) Use of the products of formula (I) as defined in claims 1 to 5, for the preparation of pharmaceutical compositions for the treatment of conditions resulting from abnormal stimulation of endothelin receptors.