WO1996033190A1

WO1996033190A1 - Quinoline derivatives, process for their preparation, the resultant intermediates, their use as medicaments and the pharmaceutical compositions containing them

Info

Publication number: WO1996033190A1
Application number: PCT/FR1996/000591
Authority: WO
Inventors: Jean-Luc Haesslein
Original assignee: Roussel Uclaf
Priority date: 1995-04-20
Filing date: 1996-04-18
Publication date: 1996-10-24
Also published as: FR2733233B1; FR2733233A1

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

Quinoline derivatives, their preparation process, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them.

The present invention relates to new quinoline derivatives, their preparation process and the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them. The subject of the present invention is the products of formula (I):

in which :

A represents a hydrogen atom or a radical -CH ₂ -B in which B is chosen from the radicals

and linear or branched alkyl radicals containing plus 5 carbon atoms, optionally substituted by a hydroxy, carboxy or tetrazolyl radical, these radicals being optionally free, esterified or salified, ZL and Z ₂ represent a hydrogen atom or else linked to two consecutive carbons of the phenyl radical, form the radical

^'Y 2 in which ^γ l ^{and γ} 2', identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH "or -CH ₂ -, and the dotted 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 radical -CO-NH-S0 ₂ -R ₆ , in which R ₆ represents a alkyl, alkenyl or phenyl radical optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl, alkoxy, trifluoro ethyl, nitro, cyano, free, salified or esterified carboxy, tetrazolyl or phenyl radicals even optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkoxy and nitro radicals, R is chosen from: a) the hydrogen atom, halogen atoms, hydroxyl radicals, mercapto, cyano, nitro, benzoyl, acyl, βulfo, free, salified or esterified carboxy, tetrazolyl, b) alkyl, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio radicals, all these radicals both optionally substituted with one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkoxy, trifluoromethyl, cyano, carboxy free, salified or esterified, tetrazolyl, isoxazolyl, pyrrolidinyl, pyridinyl, pyrrolidinyl 3 dinylcarbonyl 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 radicals, d) the dioxol radical linked to two consecutive carbons of the cycle which carries it, e) the pyrrolyl, orpholino, piperazinyl, pyrrolyl ethyl, morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl radicals, all the piperazinyl radicals 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, alkyl or alkyloxy, trifluoromethyl, cyano, carboxy radicals free, salified or esterified, tetrazolyl and isoxazolyl,

R _lf R ₂ , R ₃ , R ₄ and R _{5, which may be} identical or different, are chosen from: a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, trifluoro¬ radicals methyl, cyano, nitro, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted by one or two radicals chosen from the radical - (CH ₂ ) _p -S (0) _{] n} -ZR ₇ such as defined below and the alkyl and alkenyl radicals, c) the radical - (CH ₂ ) pS (0) _m -ZR ₇ in which 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 R ₇ represents an alkyl, alkenyl, alkynyl, pyridyl, phenyl, benzyl, phenethyl, tetrazolyl, piperidiny e, thiazolyl radical , all alkyl, alkenyl, alkynyl, alkoxy, phenyl, benzyl and phenethyl radicals above being optionally substituted by one or more radicals chosen from a halogen tomes and the hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy and tetrazolyl radicals, the phenyl, benzyl and phenethyl radicals being optionally substituted by one or more alkyl or alkenyl radicals, or alternatively R ₂ and R ₃ linked to two consecutive carbons of the phenyl radical can form a ring chosen from the rings formed by Z and Z ₂ as defined above, it being understood that when A represents an atom d 'hydrogen, Z ₁ and Z form the radical

> as defined above, ^γ ₂ said products of formula (I) being in all the possible raceric, enantioeric and diastereoisomeric isomeric forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I).

In the products of formula (I) and in the following: The term alkyl designates a linear or branched alkyl radical, having at most 12 carbon atoms, such as for example the methyl, ethyl, propyl, isopropyl, butyl, isobutyl radicals , sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, iso-hexyl, sec-hexyl, tert-hexyl, heptyl, octyl, decyl, undecyl, dodecyl .

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

The term alkenyl radical designates 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 particularly 1-butenyl radical.

The term alkynyl radical designates 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 designates 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.

By halogen is understood, of course, the atoms of fluorine, chlorine, bromine or iodine.

Chlorine, bromine or fluorine atoms are preferred. As specific examples of alkyl or alkoxy radicals substituted by one or more halogens or haloalkyl, mention may be made of the monofluoro-, chloro-, bro o- or iodomethyl or -ethyl, difluoro-, dichloro-, dibromo- or tri¬ radicals. fluoromethyl or pentafluoroethyl; bromoethoxy, trifluoromethoxy, trifluoroethoxy or even 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 carba¬ hub radical.

The term alkylthio radical preferably designates the radicals in which the alkyl radical is as defined above, 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 also 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, may be oxidized to give the alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, or phenylsulfonyl radicals: alkylsulfinyl and alkylsulfonyl denote the radicals in which the alkyl radical is chosen for example from the values indicated above for the alkyl radical such as for example the ethylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl radicals.

The carboxy radical (s) of the products of formula (I) can be esterified, amidified or salified, by various grou¬ pements known to those skilled in the art. By esterified carboxy is meant for example the alkyloxycarbonyl radicals such as for example the ethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butyl-, tert-butyloxycarbonyl, or even benzyloxycarbonyl radicals, these alkoxy radicals being able to be substituted by one or more radicals chosen by example among the halogen atoms, the hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, in the chloromethyl, hydroxypropyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.

Mention may be made of radicals formed with easily cleavable ester residues such as the methoxymethyl and ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxy ethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkylalkylcarbonyloxyalkyl 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. By amidified carboxy is meant groups of the type

in which the radicals R _a and R _j -, identical or different, either represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dry radicals - butyl or tert-butyl to form in particular the amino, mono or dimethylamino, mono or diethylamino, methyl-ethylamino, monopropylamino, isopropylamino, monobutylamino, or also methylethylamino radicals, the alkyl radicals being optionally substituted as indicated below above and below, either together form a heterocycle which may or may not comprise an additional heteroatom. We can cite the radicals pyrrolyle, imidazolyle, indolyle, pipéridino, morpholino, pipérazinyle. The piperidino, morpholino or piperazinyl radicals which are optionally substituted on the second nitrogen atom are preferred, as for example in methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl; substituted, as for example in chlorophenyl or trifluorophenyl. By salified carboxy and tetrazolyl is meant the salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hyάroxymethyl) amino methane, l ethanolamine, pyridine, picoline, dicyclohexyl- a ine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine. The sodium or potassium salt is preferred.

The hydroxyl radical can be esterified, etherified or protected, to form the radicals -OCo ^, -0-α ₂ or -OP,

IO according to the usual methods known to a person skilled in the art and in which P represents a protective group and a ± and α represent in particular an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, having at most 12 carbon atoms and optionally substituted thus that it is defined above.

Examples of protective group P, as well as the formation of the protected hydroxyl radical, are given in particular in the usual book of those skilled in the art: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley- Interscience Publishers, John iley & Sons.

The hydroxyl radical protection group that may represent P, may be chosen for example from the list below: formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. One can also cite the ethoxycarbonyl, xycarbonyle methodical, propoxycarbonyl, βββ-trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethoxycarbonyl l-cyclo propyl, tetrahydropyranyl, tétrahydrothiopyran- nyle, methoxytetrahydropyranyl, trityl, benzyl, 4-methodical xybenzyle, benzhydryl , trichloroethyl, l-methyl 1-methoxyethyl, phthaloyl, propionyl, butyryl, isobutyryl, valé¬ ryle, isovaleryl, oxalyl, succinyl and pivaloyl, phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para¬ nitrobenzoyl butylbenzoyl, caprylyl, acryloyl, ethylcarbamoyl, phenylcarbamoyl, naphthylcarba oyle. P can in particular represent the radical

or a silicon derivative such as trimethylsilyl, triisopropylsilyl, tbutyldiphenylsilyl, or tbutyldimethylsilyl. The carbamoyl and amino radicals which can represent or carry one or more of the radicals defined in the products of formula (I) can respectively take the values indicated above for -C0N (R _a ) (R _b ) or -N ( R _a ) (R _b ). By way of example and in a non-exhaustive manner: - the substituted carbamoyl radical denotes the N-monoalkylcarbamoyl groups such as N-methylcarbamoyl, N-ethylcarbamoyl; N, N-dialkyl carbamoyl, such as N, N-dimethylcarba- oyl, N, N-diethylcarbamoyl; N- (hydroxyalkyl carbamoyl, such as N- (hydroxyethyl) carbamoyl; phenylcarbamoyl; pyridylcarbamoyl; benzylcarbamoyl; N-methyl 1 N-phenylcarbamoyl; pyridylmethylcarbamoyl.

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

The substituted amino radical can 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 acetylamino or benzoylamino radicals.

The amino and carbamoyl radicals can in particular be substituted by alkenyl radicals such as allyl, alkanuclei such as pivaloyl, aryl, arylalkyl, alkyl- and arylsulfonamide and aryl- or alkylsulfonyl as defined above and below.

Mention may in particular be made of the arylsulfonylamino radicals in which the arylsulfonyl radical represents, for example, the paratoluene sulfonyl radical.

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

The addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic or formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as for example ethanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkoyldisulfonic acids such as by example methanedisulfonic acid, alpha acid, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids. Mention may more particularly be made of the salts formed with hydrochloric or methanesulfonic acids for example.

The present invention particularly relates to the products of formula (I) as defined above, in which

A represents a hydrogen atom or a radical -CH -Ba in which Ba is chosen from the radicals

and linear or branched alkyl radicals containing at most 4 carbon atoms and optionally substituted by the free, esterified or salified carboxy radical Z ₁ and Z ₂ linked & two consecutive carbons of the phenyl radical represent the radical

in which 2

YL and Y ₂ , identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH≈ or -CH ₂ -, and the dotted lines indicating the eventual 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 radical -CO-NH-S0 ₂ -R ₈ , in which R ₈ represents an alkyl or phenyl radical optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free, salified or esterified and tetrazolyl carboxy radicals, R is chosen from: a) the hydrogen atom, the halogen atoms, the hydroxyl radicals, ercapto, cyano, nitro, benzoyl, acyl, sul o, free, salified or esterified carboxy, tetrazolyl, b) the alkyl, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio radicals, all of these radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, the radicals hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy, tetrazolyl, pyridinyl and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals, c) radicals amino, mono- or dialkylamino, carbamoyl, d) the dioxol radical linked to two consecutive carbons of the cycle which carries it,

R _j , R ₂ , R ₃ , R ₄ and R _{5, which may be} identical or different, are chosen from: a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkoxy, trifluoromethyl, cyano radicals , nitro, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted by one or two alkyl and alkenyl radicals, all of the above alkyl, alkenyl and alkoxy radicals being optionally substituted by one or more chosen radicals ¬ located among the halogen atoms and the hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy and tetrazolyl radicals, knowing that R and R ₃ linked to two consecutive carbons of the phenyl radical can form a ring chosen from the rings that form Z- and Z ₂ as defined above, said products of formula (I) being in all the possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the s mineral and organic acids or with the mineral and organic bases of said products of formula (I).

The present invention particularly relates to the products of formula

(I) as defined above, in which Z _χ and Z ₂ are linked to two carbons located in meta and para of the radical X ⁾

as defined above and the other substituents are as defined above, the said products of formula (I) being in all the racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I).

A more particular subject of the present invention is the products of formula (I) as defined above in which:

A represents a radical -CH ₂ -Ba in which Ba is defined as indicated above, Z ₁ and Z ₂ form a radical

'

"Y chosen from the following radicals

5

)> ">

NH

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 radical -CO-NH-S0 ₂ -R ₉ in which R ₉ represents the radical methyl, ethyl or phenyl optionally substituted by one or more alkyl radicals,

R is chosen from the hydrogen atom, the halogen atoms, the free, salified or esterified carboxy radicals and phenylthiomethyl optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals and alkoxy,

R ^, R ₄ and R ₅ , identical or different, are chosen from the hydrogen atom, the halogen atoms and the hydroxyl, free, salified or esterified carboxy radicals and the alkyl and alkoxy radicals optionally substituted by a radical free, salified or esterified carboxy, R ₂ and R ₃ linked to two consecutive carbons of the phenyl radical form a cycle chosen from those formed by Z and Z ₂ , or else identical or different, are chosen from the values of R _χ , R ₄ and R ₅ , said products of formula (I) being in all the possible racemic isomeric, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with inorganic and organic bases of said products of formula (I).

A very particular subject of the present invention is the products of formula (I) as defined above in which A represents the radical

in which R ₂ and R ₃ have the meaning indicated above and the other substituents have the meanings indicated above, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisers, thus as addition salts with mineral and organic acids or with mineral and organic bases ques of said products of formula (I).

The products of formula (I) thus especially include the products of formula (F)

in which Z, X, R, R ₂ , R ₃ , ^< 4 'and Y ₂ have the meanings indicated above, and in particular the products of formula (I) as defined above, in which Z and Z form together the radical

linked to the meta and para positions of the phenyl radical, as well as the products of formula (I) as defined above in which X represents a —COOH radical optionally esterified or salified or a radical

-C0 ₂ alk ₁ -0-CO-0-alk ₂

in which alk- ^ represents an alkyl radical, for example a methyl or ethyl radical and alk ₂ represents an alkyl radical, in particular an isopropyl radical, or alternatively X represents a radical

in which alkyl represents an alkyl radical, in particular an isopropyl radical.

The present invention particularly relates to the following products:

- potassium salt of l - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-3 - ((4-methoxyphenyl) methyl) -4-oxo-quinoline-2-carboxylic acid ,

- potassium salt of 3 - ((1,3-benzodioxol-5-yl) methyl- 1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxo-quinoline-2-carboxylic acid ,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid, - potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3- (phenylmethyl) quinoline 2-carboxylic acid,

- potassium salt of 1,4-dihydro acid 1 - ((6-ethylene 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3 - ((3,4,5-trimethoxyphenyl) methyl) quinoline 2-carboxylic,

- dipotassiu salt of acid l - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 3 - ((4-carboxyphenyl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid,

- potassium salt of acid 1 - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 3- (cyclohexylmethyl) 1,4-dihydro 4-oxo quinoline 2-carboxyic, - potassium salt of 3 - ((4-bromophenyl) methyl) 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid,

- dipotassium salt of 3 - ((3-carboxyphenyl) methyl) acid l - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 1H-quinoline 2-carboxylic,

- potassium salt of 1,4-dihydro acid 1 - ((6-ethyl 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 3- (2-furanylmethyl) 4-oxo quinoline 2-carboxylic acid,

- dipotassium salt of 3 - ((3-carboxyphenyl) methyl) 1,4-dihydro l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 4-oxo quinoline 2-carboxylic acid, said products being in all possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as the corresponding bases of said products and the addition salts of said bases with mineral and organic acids or with mineral and organic bases.

The present invention also relates to the process for the preparation of the products of formula (I) as defined above, characterized in that - either a compound of formula (II) is reacted:

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

HC C — 0 | | ⁽ "D a O _^ C CO _^ al-, in which A 'has the meaning indicated above for A in which the possible reactive functions are evenly protected by protective groups, and identical and different alk and al _lf represent an alkyl radical containing at most 6 carbon atoms, to obtain a product of formula (IV):

in which R ', A' and alk have the meanings indicated above, which are reacted with a compound of formula (V):

in which Z- ^, Z ₂ have the meanings indicated above and R ' ₄ and R' ₅ have the meanings indicated above, respectively for R ₄ and R ₅ in which the possible reactive functions are optionally protected by groups protectors, to obtain a product of formula (I '):

in which Z _χ , Z ₂ , A ', R', R ' ₄ , R' ₅ and alk have the meanings indicated above,

- either react a compound of formula (VI):

in which R 'has the meaning indicated above, with a compound of formula (VII):

B'-CHO (VII)

in which B 'has the meaning indicated above for B in which the possible reactive functions are evenly protected, in order to obtain the product of formula (VIII):

(VIII)

in which R 'and B' have the meanings indicated above, which are subjected to a reducing agent, to obtain a product of formula (IX):

in which R 'and B' have the meanings indicated above, which are reacted with a compound of formula (X):

in which Z _{1 #} Z ₂ , R ' ₄ and R' ₅ have the meanings indicated above, to obtain a product of formula (XI):

in which B ', R', R ' ₄ , R' ₅ , Z and Z ₂ have the meanings indicated above, - either a compound of formula (XIII) is reacted:

in which R 'has the meaning indicated above, with a compound of formula (V) as defined above, to obtain a product of formula (XIV):

in which R ', R' _{4 "} 's - Z ^ and Z ₂ have the meanings indicated above, products of formula (XI) or (XIV) as defined above, which are subjected to the action of '' an acid chloride of formula:

Cl-CO-C0 ₂ -alk

in which alk represents a linear or branched alkyl radical containing at most 6 carbon atoms, to obtain a product of formula (XV):

in which Z _χ , Z ₂ , R ', R' ₄ , R ' ₅ and alk have the meanings indicated above and A' represents a hydrogen atom or the radical -CH ₂ -B 'such as defined above, which is subjected to the action of a cyclization agent, to obtain a product of formula (I ') as defined above, product of formula (I') which is subject, if desired and if necessary, to one or more of the following reactions, in an appropriate order: a) a transformation reaction of oxo OO function into thioxo OS function, b) a saponification reaction of ester function into acid function , c) a reaction for transforming an alkyloxy function into a hydroxyl function, d) a reaction for transforming the cyano function into an acid function, e) a reaction for transforming the cyano function into a tetrazolyl radical, f) an esterification reaction or of amidification of acid function, g) a reduction reaction of the carboxy function in alcohol function, h ) a reaction for converting the radical C0 ₂ alk into radi¬ cal -CO-NH-S0 ₂ -R ₆ , as defined above, i) a reaction for transforming the radical C0 ₂ alk into radical cal CONH ₂ then, if desired as a cyano radical, j) a reaction for eliminating the protective groups which the protected reactive functions can carry, k) a salification reaction with a mineral or organic acid or with a mineral or organic base for get the corresponding salt,

1) a resolution reaction of racemic forms, said products of formula (I) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereoisomers.

A more specific subject of the invention is the process for preparing the products of formula (I) as defined above, characterized in that a compound of formula (II) is reacted:

as defined above with a compound of formula (III '):

in which R ' ₂ and R' ₃ have the meanings indicated above, respectively for R ₂ and R ₃ in which the possible reactive functions are optionally protected by protective groups, and identical and different alk and alk _lf represent a radical alkyl containing at most 6 carbon atoms, to obtain a product of formula (IV):

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

as defined above, to obtain a product of formula (I "):

in which Z _χ , Z ₂ , R ' ₁ R' ₂ , R ' ₃ , R' ₄ , R ' ₅ and alk have the meanings indicated above, product of formula (I ^M ) which is submitted, if desired and if necessary for one or more of the reactions indicated above for the products of formula (I ').

Under preferential conditions for implementing the invention, the process described above can be carried out as follows: the action of the products of formula (III) or (III ') on the products of formula (II) to obtain the product of formula (IV) or (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 ptoluenesulfonic or camphorsulfonic acid, or alternatively in the presence of molecular sieve.

The compound of formula (III) or (III ') is thus fixed by its oxo function, in alpha of the carboxy function, on the amine function of the compound of formula (II) and is cyclized by heating at high temperature in particular above 200 ° C.

The reaction of the product of formula (IV) or (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.

In the compound of formula (V), Hal preferably represents a bromine or chlorine atom and Z and Z ₂ , as defined above, represent in particular the cyclic radical containing Y ^ and Y ₂ , as defined above, and more particularly the radical

>

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

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

The reaction of the compound of formula (VI) with the compound of formula (VII) can be carried out using dilute sodium hydroxide or else in the presence of a catalytic amount of piperidine and acetic acid in an organic solvent at reflux, for example toluene.

The reduction of the ethylenic bond and of the nitrile group to the amine is carried out by hydrogenation in the presence of a catalyst such as platinum oxide in an organic solvent, for example ethyl acetate.

During the reaction of the compound of formula (IX) with the compound of formula (X), the reductive amination is carried out in a solvent such as dichloromethane in the presence of acetic acid for the formation of the intermediate imine then in a lower alcohol in the presence of sodium borohydride.

The aldehyde of formula (X) is for example 5-chloro or

6-chloro piperonal, 5-bromo or 6-bromo piperonal or even 5-methoxy piperonal.

The reaction of the compound of formula (XIII) with the compound of formula (V) is carried out in an organic solvent, for example dichloromethane in the presence of a base, in particular an amine base such as triethylamine. The ketoester of formula (XV) is obtained by the action of the compound of formula (XI) or (XIV) with a derivative of oxalyl chloride in the presence of triethylamine in an organic solvent such as tetrahydrofuran.

The cyclization of the compound of formula (XV) is carried out by the action of potassium carbonate in ethanol or by the action of sodium ethylate in an organic solvent, for example toluene.

The reactions to which the products of formula (I ') or

(I "), as defined above can be subjected, if desired or if necessary, can be carried out, for example, as indicated below. A) the transformation reaction from oxo function to thioxo function can be carried out in particular by the reagent of

LAWESSON in toluene. b) Any transformations of ester functions into acid functions of the products described above can be, if desired, carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis for example by soda or potash in an alcoholic medium such as, for example, in methanol or also by hydrochloric or sulfuric acid. c) The possible alkoxy functions such as in particular the methoxy of the products described above can be, if desired, transformed into a 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 pyridine hydrobromide or hydrochloride or alternatively with hydrobromic or hydrochloric acid in water or trifluoro acetic acid at reflux. d) The possible cyano functions of the products described above can, if desired, be transformed into an acid function under the usual conditions known to those skilled in the art, for example by double hydrolysis carried out in an acid medium such as, for example, in a mixture sulfuric acid, glacial acetic acid and water, these three compounds preferably being in equal proportions, or alternatively in a mixture of soda, ethanol and water at reflux. e) The possible cyano functions can be, if desired, transformed 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 an azide of trialkyltin on the nitrile function as indicated in the method described in the article referenced as follows: J. Organometallic Chemistry. , 21, 337 (1971) KOZIMA S. & al. f) The products described above can, if desired, be the subject, on any carboxy functions, of esterification reactions which can be carried out according to the usual methods known to those skilled in the art.

The reaction for transforming an acid function into an ide function can in particular be carried out by first forming an acid chloride, for example by the action of SOCl ₂ then amidification, or even by direct amidification of the acid according to the usual conditions known to those skilled in the art.

The amide thus obtained can then, if desired, be trans- formed into thioamide by action in particular of the LA ESSON reagent in toluene. g) The possible free or esterified carboxy functions of the products described above can, if desired, be reduced to the alcohol function by methods known to those skilled in the art: thus for example the possible free carboxy functions in particular by hydride boron and any carboxy functions esterified in particular with lithium aluminum hydride in a solvent such as for example tetrahydrofuran or even dioxane or ethyl ether. The possible alcohol functions of the products described above can, 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 acids.

The reactions for converting from a formyl radical to a carbamoyl radical and from a carbamoyl radical to a 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 nitrile keto and displacement by an amine (Chem. Comm. 1971, p. 733).

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

The possible amine functions of the products described above can, if desired, be converted into the alkylamino, dialkylamino, acylamino, alkyl- and arylsulfonamide and aminosulfonyl functions, optionally substituted corresponding under the usual conditions known to those skilled in the art. , by way of example, mention may be made of the action of tosyl chloride in the presence of pyridine in methyl chloride. lene to transform the amine into an arylsulfonylamino function here tosylamino.

The reaction for transforming an acid function into a tetrazolylcarboxy function can be carried out for example by prior transformation of the acid function into acid chloride as indicated above, then by the action of Cu-C "N, according to the usual conditions known to those skilled in the art to thereby obtain the radical -CC-BN which can be

turn into radical

0 ^ N N

H for example by action of the compound Sn (Bu) ₃ N ₃ in toluene. The etherification reactions of the hydroxyl function or of transformation of the ester function as defined above can be carried out under the usual conditions known to those skilled in the art. h) the radical C0 ₂ alk can be transformed into radical -CO-NH-S0 ₂ R ₆ by reaction with NH ₂ -S0 ₂ -R ₆ in which R ₆ has the meaning indicated above, under the usual conditions known from a person 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 radical -C0 ₂ alk can also be transformed into radical -C0 ₂ H then -C0C1 which is reacted with the compound NH ₂ -S0 -R ₆ as defined above and according to the usual conditions known from the skilled in the art to obtain the radical -C0-NH-S0 ₂ -R ₆ . i) the C0 ₂ alk radical can be transformed into a C0NH ₂ radical and then into a nitrile or tetrazolyl radical according to the usual conditions known to those skilled in the art. j) The removal 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 an acid hydrolysis carried out with an acid such as hydrochloric acid, sulfonic benzene or sulfonic para-toluene, formic or trifluoroacetic or also by catalytic hydrogenation. The phthalimido group can be eliminated by hydrazine.

A list of different protective groups can be found, which can be used for example in patent BF 2,499,995. K) The products described above can, if desired, undergo salification reactions, for example with a mineral or organic acid. or by an inorganic or organic base according to the usual methods known to those skilled in the art. 1) Any optically active forms of the products described above can be prepared by splitting the racemates 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 as well as their addition salts with acids have interesting pharmacological properties.

The products of formula (I) as defined above are endowed with antagonistic properties for endothelin receptors and are thus in particular inhibitors of the effects of endothelin, in particular of vaso-constrictive and hypertensive effects induced by endothelin. In particular, an antiischemic effect is noted, the vasoconstrictive activity of endothelin being abolished. The products of formula (I) are also capable of opposing the stimulating effects of endothelin at the level of all cell types, in particular 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 formula (I) above, said products of formula (I) being in all forms. possible racemic, enantiomeric and diastere isomeric forms reoisomers, as well as addition salts with mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I).

The subject of the present invention is especially, as a medicament, the products of formula (I) as defined above corresponding to formula (F):

in which Z, X, R, R ₂ , R ₃ , R ₄ , R ₅ , Y _χ and Y ₂ have the meanings indicated above, and more especially the products of formula (I) as defined above, in which Z ^ and Z ₂ together form the radical

) linked to the meta and para positions of the phenyl radical. A subject of the invention is very particularly, as medicaments, the products described below in the examples and in particular the following products of formula (I):

- potassium salt of 3 - ((1,3-benzodioxol-5-yl) methyl- 1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-oxo-quinoline-2-carboxylic acid . 31

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxy,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3- (phenylmethyl) quinoline 2-carboxylic acid,

- potassium salt of 1,4-dihydro acid 1 - ((6-ethylene 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid, - potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3 - ((3,4,5-trimethoxyphenyl) methyl) quinoline 2-carboxylic,

- dipotassium salt of l - (((6-chloro 1,3-benzodioxol-5-yl) methyl) 3 - ((4-carboxyphenyl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 3- (cyclohexylmethyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid,

- potassium salt of 3 - ((4-bromophenyl) methyl) 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid,

- dipotassium salt of acid 3 - ((3-carboxyphenyl) methyl) l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 1H-quinoline 2- carboxylic, - potassium salt of 1,4-dihydro acid l - ((6-ethyl 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2- carboxylic,

- dipotassium salt of 3 - ((3-carboxyphenyl) methyl) 1,4-dihydro l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 4-oxo quinoline 2-carboxylic acid, said products being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as the corresponding bases of said products and the addition salts of said bases with mineral and organic acids or with mineral and organic bases pharmaceutically acceptable.

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

The drugs which are the subject of the invention can also find an application in the treatment of osteoporosis, prostatic hyperplasia and as neuronal protectors.

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

These pharmaceutical compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and the mucous membranes or by injection by intravenous or intramuscular route.

These compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in human medicine such as, for example, simple 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 therein 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, which varies according to the product used, the subject treated and the condition in question, can be, for example, from 1 to 300 mg per day in adults, orally or. from 1 to 100 mg per day intravenously.

The starting materials of formulas (II), (III), (III '), (V), (VI), (VII), (X) and (XIII) are mostly commercial or can be prepared from commercial products by the usual methods known to those skilled in the art.

Among the products of formula (II), derived from aniline, there may be mentioned in particular aniline and nitroaniline.

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

The examples described below in the experimental part give illustrations, which are moreover not exhaustive, of such starting materials, in particular the preparation of products of formula (III).

The present invention finally relates as new industrial products, the compounds of formula (IV), (VIII), (IX), (XI), (XIV) and (XV).

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

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 hypertension induced by endothelin, for the treatment of all vascular spasms , to the treatment of cerebral post-hemorrhages and renal insufficiencies and to the treatment of myocardial infarction and to the prevention of post-angioplasty resteroses. The following examples illustrate the invention without, however, 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 are introduced. g of 4- (dimethylamino) pyridine. Cooled to 0 ^β C and then introduced 11.3 g of 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide HCl. The mixture is stirred for approximately 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. Phvsiσues analyzes: IR CHC1 ₃ (cm ^-1 )> -0 1727 Aromatics 1610-1594-1514

Stage 2: Ethyl 2- [(4-methoxyphenyl) methyl)] -3-oxo-1,4-butane-dioate

11.3 g of the product obtained in stage 1 above, 7.7 g of sodium ethylate and 150 ml of toluene are introduced. The mixture is stirred for one hour at 80 ° C. and then 9 ml of ethyl oxalate are introduced. The mixture is stirred for one hour at 80 ° C., poured onto water + 2N hydrochloric acid, extracted with three times 200 ml of ethyl acetate and dried. Chromatography on silica in a cyclohexane-ethyl acetate mixture (8-2) and thus 7.46 g of expected product is obtained.

Physical analyzes: IR CHC1 ₃ (cm " ¹ ) C" 0 1752-1732

Aromatics 1612-1585-1515 Preparation II t Stage 1: 3- (3,4-methylenedioxyphenyl) ethyl propionate

The procedure is carried out as in stage 1 of preparation I 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 - (dimethylamino) pyridine, cools to 0 "C and introduces 12.6 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, HCl. This gives 11.5 g of the expected product. Physical analyzes: NMR (CDC1 ₃ , S, ppm) Aromatics (m, 3H) 6.8-6.6 OCH ₂ 0 (s, 2H) 5.9

OCH ₂ (q, J = 6.7 Hz, 2H) 4.15 CH ₂ -CO (t, J = 8 Hz, 2H) 2.9 Ar-CH ₂ (t, J »8 Hz, 2H) 2, 6 CH ₃ (t, J = 6.7 HZ, 3H) 1.25

Stage 2: 2 - [(1,3-benzodioxol) -5-yl-methyl] -3-oxo-1,4-butane-ethyl dioate

The procedure is carried out as in stage 2 of preparation I, starting from 7.38 g of sodium ethylate, 130 ml of toluene, 10.965 g of the product obtained in stage 1 above, stirring, bringing to reflux for 20 minutes , introduced 8.7 ml of ethyl oxalate, left to reflux for 1 hour and cooled. 200 ml of IN hydrochloric acid and 200 ml of ethyl acetate, decanted, are added, the aqueous phase is re-extracted with 200 ml of ethyl acetate. Then wash and dry. Chromatography on silica in cyclohexane-ethyl acetate (7-3) and 10.543 g of expected product is obtained (colorless oil). Physical analyzes: IR CHC1 ₃ (cm ' ¹ ) C-0 1755-1734 Aromatics 1612-1506-1492

EXAMPLE 1: 1 - ((1,3-bβnzodioxol 5-yl) methyl) 1,4-dihydro 3- ((4-methoxyphenyl) methyl) 4-oxo-quinoline 2-carboxyl t * ethyl Stage 1: ( E, Z) ethyl 2 - [(4-methoxyphenyl) methyl] -3- (phenylamino) 1,4-butanedioate

7.46 g of the product obtained in stage 2 of preparation I are introduced, 2.7 ml of aniline, 70 ml of toluene and 0.1 g of paratoluene sulfonic acid. The mixture is brought to reflux for 1 hour and then left overnight at room temperature. Poured onto approximately 200 ml of saturated sodium bicarbonate solution, extracted with three times 200 ml of ethyl acetate and dried. Chromatography on silica in a cyclo¬ hexane-ethyl acetate mixture (7-3) and 7.5 g of the expected product (oil) are obtained. Physical analyzes: IR CHC1 ₃ (cm ^{* 1} ) “C-NH - 3250

> »0 1735-1658

OC + aromatics 1608-1595-1582-1510-1502 Stage 2: 1,4-dihydro 3- ((4-methoxyphenyl) methyl) 4-oxo-quinoline 2-ethyl carboxylate

Heated 7.5 g of the product obtained in stage i above, at 220 ^β C for 30 minutes, cooled, the crystals obtained washed with hexane and then with ethyl ether and ice thus obtained 4.59 g of product expected (crystals). Physical analyzes: IR CHC1 ₃ (cm ^-1 ) ^« C-NH 3424-3378

> -0 1744-1708 C = 0 + conj. System 1623-1606-1589-1573-1531-1511 + Aromatics

Stage 3: 1- (1, 3-benzodioxol-5-yl) methyl) -1,4-dihydro 3- ((4-methoxyphenyl) methyl) -4-ethyl oxo-quinoline 2-carboxylate 2 are introduced , 3 g of the product obtained in stage 2 above, 60 ml of dimethylformamide, 2.4 g of piperonyl bromide, stirred for 5 minutes at room temperature and then introduced 1.9 g of potassium carbonate. The mixture 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 the cyclohexane-ethyl acetate mixture (6-4) and 0.25 g of expected product (oil) is obtained. Physical analyzes: IR CHC1 ₃ (cm " ¹ )> -0 1727 System conj. 1610-1583-1562-1512-1504-1492 + aromatics

EXAMPLE 2 Potassium salt of l - ((1,3-benzodioxol 5-yl) methyl) 1, -dihydro 3- ((4-methoxyphenyl) methyl) 4-oxo-quinoline 2-carboxylic acid We introduce 0 , 25 g of the product of Example 1, 6 ml of ethanol, 0.18 ml of 6N potassium hydroxide, stirred and then concrete in ethyl ether and dried. 0.237 g of expected product is thus obtained (crystals). Physical analyzes: IR Nujol (cm ^-1 ) Conj.

+ C00 ^θ 1612-1590-1565-1510-1490

+ Aromatics

EXEM _P LE 3: 3 - ((1,3-bβnzodioxol 5-yl) methyl) 1,4-dihydro i- ((4-methoxyphenyl) methyl) ethyl 4-oxo-quinoline 2-carbox late

Stage 1: (E, Z) 2- [(1,3-benzodioxol-5-yl) methyl] -3- (phenylamino) -1,4-ethyl butanedioate 7.2 g of the product obtained are introduced in stage 2 of preparation II, 2 ml of aniline, 70 ml of toluene and 0.1 g of para-toluene sulfonic acid. The mixture is brought to reflux for 4 hours, eliminating the water formed, poured onto approximately 200 ml of saturated sodium bicarbonate solution, extracted with three times 100 ml of ethyl acetate and dried. Chromatography on silica in a cyclohexane-ethyl acetate mixture (8-2) and 6.2 g of the expected product (oil) are obtained. Physical analyzes: IR CHC1 ₃ (cm ^-1 ) ^" C-NH - 3260>^" 0 1733-1656

C≈O + Aromatics 1610-1595-1583-1502-1489

Stage 2: 1,4-dihydro-1 - ((4-methoxyphenyl) methyl) -4-ethyl oxo-quinoline-2-carboxylate

6.2 g of the product obtained in stage l above is heated at 240 ° C. for 30 minutes and cooled. The crystals obtained are filtered and then washed with ice-cold ethyl ether. 3.9 g of expected product are thus obtained (crystals). Physical analyzes: IR CHC1 ₃ (cm ^-1 ) -C-NH 3424-3379>"0 1745-1708

System conj. + aromatic 1623-1608-1591-1573-1532-1503 Stage 3: 3 - ((1,3-benzodioxol-5-yl) methyl) -1,4-dihydro-l- ((4-methoxyphenyl) methyl) - Ethyl 4-oxo-quinoline-2-carboxylate 1.8 g of the product obtained in stage 2 above are introduced, 50 ml of dimethylformamide, 1.4 ml of 4-ethoxy benzyl chloride, stirred for 5 minutes at room temperature then introduced 1.4 g of potassium carbonate. The mixture is stirred at room temperature, poured into 100 ml of water and then extracted with three times 50 ml of ethyl acetate and dried. Chromatography on silica in a cyclohexane-ethyl acetate mixture (5-5) and 0.25 g of expected product (oil) is obtained. Phvsiσues analyzes: NMR (CDC1 ₃ , S, ppm) COOCH ₂ CH ₃ (t, 3H) 1.15

COOCH ₂ CH ₃ (q, 2H) 4.3

OCH ₃ (S, 3H) 3.7

Ph-CH ₂ -C = (S, 2H) 3.9 -CN-CH ₂ -Ph (s, 2H) 5.2

PhO-CH ₂ -0 (s, 2H) 5.9

Aromatic 6.5 to 8.6

EXAMPLE 4 potassium salt 3 - ((1,3-benzodioxol-5-yl) methyl) -1,4-dihydro-l - ((4-methoxyphenyl) methyl) -4-oxo-quinoline-2-carboxylic

The procedure is as in Example 2, starting with 0.25 g of the product of Example 3, 6 ml of ethanol and 0.18 ml of potassium hydroxide

6N. It is heated to 80 ^β C for 72 hours and then left for approximately 2 days at room temperature. The crystals obtained are drained, washed with ethyl ether and then dried. 0.143 g of expected product is thus obtained (crystals).

Physical analyzes: IR Nujol (cm ^-1 )

> »0 conj. 1606

System conj. + Aromatics 1592-1565-1535-1511-1501-1492 EXAMPLE 5: acid 3 - ((2- (carboxymethoxy) 4-methoxyphenyl) methyl) l - ((6-chloro ι, 3-benzodioxol-5-yl) methyl ) 1,4-dihydro 4-oxo quinoline 2-carboxylic.

Stage A; 2- (5-methoxy 2- (3- (2-nitrophenyl) 3-oxo 1-propenyl) phenoxy) ethyl acetate. 1.32 g of 2-nitro acetophenone and 2.12 g of

2- (2-formyl 5-methoxyphenoxy) ethyl acetate in 10 ml of toluene then add 0.1 ml of concentrated acetic acid and 0.1 ml of piperidine and heat under reflux for 24 hours. The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate

6-4), takes up the residue in ether and collects 2.05 g of the expected product.

IR spectrum (CHC1 ₃ , cm ^"1 )

CO 1758, 1736 ester 1672 (ep.), 1646 (max) aromatic conjugated ketone + C = C + N0 ₂ 1604 (F), 1574, 1567 (F), 1504

CH-CH 983.

_S tade B: 2- (2- (3- (2-aminophenyl) 3-oxopropyl) 5-methoxy- 39 phenoxy) ethyl acetate.

0.5 g of 82% platinum oxide is added in a solution comprising 1.7 g of the product obtained in stage A in 30 ml of ethyl acetate and then hydrogen for 3 hours. The catalyst is filtered, the solvent is evaporated, the residue is taken up in dichloromethane and crystallized by adding ether. 0.66 g of product is obtained. After chromatography on silica of the filtrate (eluent: cyclohexane-ethyl acetate 6-4) and taking up the residue in ether, 0.65 g of additional product is obtained.

IR spectrum (CHC1 ₃ , cm " ¹ )

-C-NH ₂ 3499, 3355

C ^“ 0 1757, 1734, 1647 aromatic + NH ₂ (def) 1615, 1584, 1550, 1507. Stage C: 2- (2- (3 - (((2- (6-chloro l, 3-benzodioxol-5 -yl) methyl) amino) phenyl) 3-oxopropyl) 5-methoxyphenoxy) ethyl acetate.

0.2 g of product obtained in stage B is dissolved in 2 ml of dichloromethane and 0.1 ml of concentrated acetic acid and 0.132 g of 6-chloropiperonal added in 1 l of dichloromethane is added. The mixture is stirred for 3 hours at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in 3 ml of methanol, 0.05 g of sodium cyanoborohydride is added, the mixture is stirred for 1.5 hours, the precipitate formed is drained, rinsed with methanol, dries and obtains 0.136 g of the expected product, used as it is for the following stage. IR spectrum (CHC1 ₃ , cm ^"1 ) NH complex ≈ 3319

OO 1757, 1734, 1636 aromatic 1616, 1589, 1575, 1520, 1505, 1481.

Stage D: 2 - ((2 - ((2- (2-ethoxy 2-oxoethoxy) 4-methoxyphenyl) propionyl) pehnyl) (6-chloro 1,3-benzodioxol-5-yl) methyl) amino) 2-oxo ethyl acetate.

0.185 ml of ethyloxalyl chloride is added to 0.575 g of the product obtained in Stage C in 30 ml of tetrahydrofuran in the presence of 0.23 ml of triethylamine. Agitation is carried out for 3.5 hours at room temperature, again 0.2 ml of triethylamine and 0.2 ml of ethyloxalyl chloride are added, again 30 minutes and add 5 ml of water. The tetra¬ hydrofuran is evaporated, extracted with ethyl acetate, the organic phase is washed with salt water, dried and the solvent is evaporated off under reduced pressure. The residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate 7-3) and 0.276 g of the expected product is obtained. IR spectrum (CHC1 ₃ , cm ^"1 )

C≈O 1754, 1741, 1682, 1669 aromatic 1615, 1598, 1589, 1575 (ep.f), 1506 (F), 1480 (F)

Stage E: acid 3 - ((2- (carboxymethoxy) 4-methoxyphenyl) methyl) l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic .

- Cyclization 0.09 g of potassium carbonate is added to 0.276 g of product obtained in the preceding stage in 8 ml of ethanol and 1 ml of tetrahydrofuran and the mixture is stirred for 2.5 hours at room temperature.

- Saponification 2 ml of 6N potassium hydroxide are added, the mixture is stirred for 30 minutes, the solvents are evaporated off under reduced pressure and 5 ml of water are added. Acidified to pH 1 with 2N hydrochloric acid, extracted with ethyl acetate, washed with salt water, dried and the solvent evaporated under reduced pressure. The residue is chromatographed on silica (eluent: acetone-ethyl acetate-water 5-4-1) and the expected product is obtained in the form of a monoester. 0.16 g of this product is taken up in 15 ml of ethanol and 3 ml of tetrahydrofuran and 0.9 ml of 6N potassium hydroxide is added and the suspension is heated to reflux for 7 days. Filtered, the solvent is evaporated off under reduced pressure, the residue is taken up in water, acidified slowly to pH - 1 with 2N hydrochloric acid, filtered and dried the precipitate obtained which is purified by chromatography on silica (eluent: acetone-ethyl acetate-water 5-4-1). 0.04 g of expected product is recovered.

IR spectrum (Nujol, cm ^"1 ) absorption NH / OH conjugated ketone + 43

By operating as in Example 5 using 5-bromopiperonal from stage C, the following compound was prepared: EXAMPLE 20: 1 - ((7-bromo 1,3,3-benzodioxol-5-yl) methyl) 1 , 4- dihydro 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2- potassium potassium carbox late.

F> 260 ^* C. rf - 0.47 (acetone-ethyl acetate-H ₂ 0 5-4-1) Preparation of 5-bromopipôronal.

0.217 g of 3,4-dihydroxy 5-bromo benzaldehyde in 10 ml of dimethylformamide with 0.116 g of potassium fluoride and 0.7 ml of dibromomethane are heated for 100 hours at 100-110 ° C. The mixture is left to return to ambient temperature, poured into a water-ice-hydrochloric acid 2N mixture and then extracted with ethyl acetate. The solvent is evaporated off under reduced pressure, the residue is chromatographed on silica (eluent: cyclohexane-ethyl acetate 8-2) and 0.11 g of expected product is obtained. F »127 ^* C.

EXAMPLE 21 potassium salt of 1,4-dihydro acid l - ((6-ethyldne 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxypbenyl) methyl) 4-oxo quinoline 2- carboxylic. Stage A: 1,4-dihydro l - ((6-ethenyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylate ethyl.

To a suspension in 25 ml of toluene of 1.27 g of 1,4-dihydro l - ((6-bromo l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4- ethyl oxo quinoline 2-carboxylate obtained during the synthesis of the product prepared In Example 19, 1.01 ml of vinyltributyltin and 53 mg of tetrakis (triphenylphosphine) palladium (o) are added and then heated to 110-120 ′ C for 19 hours. 0.5 ml of tributyltin is added and heating is continued for 23 hours. The mixture is allowed to return to room temperature, poured into a water-ice-ammonia mixture at 20%, filter, extract with ethyl acetate, wash with water, dry and evaporate the solvent under reduced pressure. After washing the residue with hexane and chromatography on silica (eluent: cyclohexane-CHCl ₃ -AcOEt 6-2-2), 0.9 g of expected product is recovered. F - 118 ^* C. Stage B: potassium salt of 1,4-dihydro acid l - ((6-ethylene l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) 41

C "C + aromatic

+ COO 1613, 1588, 1558, 1508, 1498 rf - 0.25 (acetone-ethyl acetate-H ₂ 0 5-4-1).

By operating as indicated in Example 5, initially using 2-nitro acetophenone, the appropriate aldehyde and 6-chloro piperonal, the following compounds were prepared:

EXAMPLE 6 potassium salt of 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3- ((4-methyloxyphenyl) methyl) 4-oxo quinoline acid 2- carboxylic, F> 260 ^* C.

EXAMPLE 7: 1 - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 3-

((2,3-dichlorophenyl) methyl) potassium 1,4-dihydro 4-oxo 2-quinoline carboxylate.

F> 250 ^* C. EXAMPLE 8 potassium salt of the acid l - ((6-chloro 1,3- bβnzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3- (phenylmethyl) quinoline 2 -carboxylic. rf - 0.44 (acetone-AcOEt-H ₂ 0 5-4-1)

EXAMPLE 9 potassium salt of the acid l - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3- ((4-methoxyphenyl) methyl) 4-oxo l, 3 -dioxolo (4,5-g) quinoline 2-carboxylic acid. rf - 0.3 (CH ₂ Cl ₂ -MeOH 80-20)

EXAMPLE 10 t potassium salt of l- (6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 3- (3-pyridinylmethyl) quinoline 2-carboxylic acid .

F> 260 ^* C. rf “0.57 (CH ₂ Cl ₂ -MeOH 80-20)

EXAMPLE 11: potassium salt of 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 3- (cyclohexylmethyl) 1,4-dihydro-4-oxo quinoline 2-carboxylic acid. rf - 0.7 (acetone-AcOEt-H ₂ θ 5-4-1)

EXAMPLE 12 dipotassium salt of l - {(6-chloro 1,3-benzodioxol-5-yl) methyl) 3 - ((4-carboxyphenyl) methyl) 1,4-dihydro 4-oxo quinoline 2- carboxylic. rf = 0.43 (acetone-AcOEt-H ₂ 0 5-4-1) EXAMPLE 13: potassium salt of acid l - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1, 4-dihydro 4-oxo 3 - ((3,4,5-trimethoxyphenyl) methyl) quinoline 2-carboxylic acid.

F - 267 ^* C. rf - 0.18 (acetone-AcOEt-H ₂ 0 5-4-1) 42

EXAMPLE 14: potassium salt of 3 - (((4-bromophenyl) methyl) acid) l - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2- carboxylic. F> 250 ^* C. rf ≈ 0.13 (CH ₂ Cl ₂ -Me0H 9-1) EXAMPLE 15: dipotassium salt of 3 - (((3-carboxyphenyl) methyl) acid) l - ((6- chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo 1H-quinolinβ 2-carboxylic. rf "0.4 (acetone-AcOEt-H ₂ 0 5-4-1) EXAMPLE 16: dipotassium salt of 2-carboxy acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl ) 1,4-dihydro 4-oxo quinoline 3-hβxanoïquβ. F> 250 ^* C. rf ^“ 0.4 (AcOEt-AcOH 100-25)

EXAMPLE 17 Potassium salt of 1 - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3- (2-furanylmethyl) 4-oxo quinoline 2-carboxylic acid. rf - 0.35 (acetone-AcOEt-H ₂ 0 5-4-1)

EXAMPLE is: 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-methoxyphenyl) methyl) -oxo quinoline 2- carboxylate 1- ((((1 -methylethoxy) carbonyl) oxy) ethyl. 0.19 g of the acid obtained from the compound of Example 6 in 5 ml of dimethylacetamide is cooled to 0 ° C. in the presence of 0.17 ml of dicyclohexylamine. 0.2 g of (1-iodoethyl) (1-methylethyl) carbonate is added in 2 ml of dimethylacetamide. The mixture is left to return to ambient temperature, stirred for 2 hours, poured the reaction medium into water with 2N hydrochloric acid, extracted with ethyl acetate, dried, evaporated the solvent under reduced pressure, chromatographs the residue. on silica (eluent: cyclohexane-ethyl acetate 7-3), takes up in pentane supplemented with dichloromethane and obtains 0.17 g of the expected product. F "170 ^* C. rf" 0.3 (cyclohexane-ethyl acetate 7-3)

By operating as in Example 5, using 6-bromopiperonal from stage C, the following compound was prepared: EXAMPLE 19: l - ((6-broπ.o ι, 3-benzodioxol-5-yl) methyl ) 1,4- dihydro 3 - ((4-methoxyρhenyl) methyl) 4-oxo quinoline 2- potassium carboxylatβ. F> 260 ^* C. rf - 0.55 (acetone-ethyl acetate-H ₂ 0 5-4-1) methyl) 4-oxo quinoline 2-carboxylic.

0.4 g of ester obtained in Stage A is heated at reflux for 66 hours in 8 ml of ethanol in the presence of 0.14 ml of 6N potassium hydroxide. After adding 0.07 ml of additional 6N potassium hydroxide, the heating is continued for 24 hours, the mixture is allowed to return to ambient temperature, the product crystallized, the product is washed with ethanol, dried and recovered 0.32 g of the expected product. F> 250 ^* C. IR spectrum (Nujol, cm ^"1 ) conjugated ketone + COO" + aromatic and OC 1612, 1588, 1570, 1532, 1508,

1496, 1484 EXAMPLE 22: potassium salt of acid 1, -dihydro l - ((6- ethyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic. Stage A: 1,4-dihydro l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylate ethyl. 0.3 g of product obtained in Stage A of Example 21 is dissolved in 20 ml of ethyl acetate, 0.03 g of palladium on activated carbon is added, followed by hydrogen under 1800 mbar. Filtered, rinsed With ethyl acetate, the solvent is evaporated off under reduced pressure and 0.3 g of the expected product is obtained. F - 148 ^* C.

Stage B: potassium salt of 1,4-dihydro acid l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4- oxo quinoline 2- carboxylic.

The procedure is carried out as in stage B of example 21 using 0.41 g of ester prepared as in stage A above and 0.21 ml of 6N potassium hydroxide. 0.37 g of acid is obtained which is chromatographed on silica (eluent: CH ₂ Cl ₂ -MeOH 8-2). The residue is taken up in 2.2 ml of ethanol, 0.12 ml of 6N potassium hydroxide is added and the mixture is heated for 16 hours at reflux. The mixture is allowed to cool to room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in acetonitrile, the product is filtered off and dried. 0.23 g of expected product is obtained. F> 280 ^* C. IR spectrum (Nujol, cm ^"1 ) OH / NH absorption

00 1638 aromatic + OC + C00 ^" 1612, 1588, 1574, 1532, 1511, 1488

EXAMPLE 23 Potassium salt of 1,4-dihydro acid 1 - ((7-ethenyl 1,3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2- carboxylic. stage A: 1,4-dihydro l - ((7-ethenyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylate ethyl. The procedure is carried out as in stage A of example 21, using initially 0.275 g of 1,4-dihydro l - (((7-bromo 1,3-benzodioxol-

5-yl) methyl) 3 - ((4-methoxyphenyl) methyl 4-oxo quinoline 2-ethyl carboxylate obtained during Example 20. 0.060 g of expected product is obtained Stage B: potassium salt of 1 1,4-dihydro 1 - ((7-ethenyl 1,3-benzodioxol-5-yl) methyl) 3- ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid.

The procedure is carried out as in stage B of example 21 using initially 0.331 g of product prepared as in stage A above and 0.116 g of acid is obtained then 0.082 g of expected potassium salt. F>260'C. rf - 0.05 (CH ₂ Cl ₂ -MeOH 9-1).

EXAMPLE 24 s potassium salt of 1,4-dihydro acid l - ((7-ethyl l, 3-bβnzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2- carbox lique. Stage A: 1,4-dihydro l - ((7-ethyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylate ethyl.

The procedure is carried out as in Stage A of Example 22, using 0.69 g of the ester obtained in Stage A of Example 23 at the start. 0.648 g of expected product is obtained.

Stage B: potassium salt of 1,4-dihydro acid l - ((7-ethyl l, 3-benzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4- oxo quinoline 2- carboxylic.

The procedure is carried out as in stage B of example 22 using 0.620 g of product from stage A and obtained 0.554 g of acid then

0.568 g of expected potassium salt. F> 260 ^* C. rf - 0.37 (AcOEt-EtOH-H ₂ 0 7-2-1)

EXAMPLE 25 potassium salt of 1,4-dihydro l - (((7- methoxy 1,3-bβnzodioxol-5-yl) methyl) 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic.

The procedure is as in Example 5 using, starting from stage C, 5-methoxypiperonal and the expected product is obtained. rf - 0.5 (CH ₂ Cl ₂ -MeOH 8-2)

EXAMPLE 26 potassium salt of the acid 1 - ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-ethenylphenyl) methyl) -oxo quinoline 2-carbox lique. Stage A: 1- ((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-ethenylphenyl) methyl) 4-oxo quinoline 2-carboxylate ethyl.

The procedure is as in Example 21, starting with 0.554 g of 3 - ((4-bromophenyl) methyl) l - ((6-chloro 1,3-benzo-dioxil-5-yl) methyl) 1,4- ethyl dihydro 4-oxo quinoline 2-carboxylate prepared during the synthesis of the product of Example 14, 1.45 ml of vinyltributyltin and 23 mg of tetrakis (triphenylphosphine) palladium. 0.26 g of the expected ester is obtained. Stage B: potassium salt of the acid 1 - ((6-chloro 1,3-benzo-dioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-ethenylphenyl) methyl) 4-oxo quinoline 2-carboxylic.

The procedure is as in Example 21 stage B using 0.46 g of the ester prepared above in ethanol and 0.15 ml of 6N potassium hydroxide. 0.16 g of expected product is obtained. F> 260 ^* C. rf - 0.38 (acetone-AcOEt-H ₂ 05-4-1)

By operating as in the previous examples, using the appropriate compounds at the start, the following compounds were prepared: EXAMPLE 27 t acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1, 4-dihydro 3 - (((3-methoxycarbonyl) phenyl) methyl) -oxo quinoline 2-carboxylic.

F> 260 ^* C. rf - 0.6 (acetone-AcOEt-H ₂ 05-4-1) EXAMPLE 28: dipotassium salt of 3 - (((3-carboxyphenyl) methyl) acid 1,4- dihydro l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 4-oxo quinoline 2-carboxylic,

F> 250 ^* C. (dec) rf - 0.21 (acetone-AcOEt-H ₂ 0 5-4-1) EXAMPLE ₂ 9: acid 3 - ((4- (carboxymethyl) cyclohexyl) methyl) l - (( _6- chloro ι, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid. rf »0.2 (acetone-AcOEt-H ₂ 0 5-4-1)

EXAMPLE 30 x potassium salt of l - (((6-chloro 1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4 - ((ethoxycarbonyl) methyl) eyclohexyl) methyl) acid) 4-oxo quinoline 2-carboxylic. rf - 0.4 (acetone-AcOEt-H ₂ 0 5-4-1)

EXAMPLE 31 potassium salt of l - ((1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid. Stage A: N- (2-acetylphenyl) 1,3-bensodioxol 5-methaneamine. 1.2 ml of 2-aminoacetophenone in 20 ml of dichloromethane are stirred for 1 hour at room temperature with 1.5 ml of triethylamine and 2.4 g of piperonyl bromide. 1.63 g of piperonyl bromide are again added, the mixture is stirred for 16 hours at room temperature, poured into water, extracted with ethyl acetate, dried, the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica ( eluent: cyclohexane-ethyl acetate-dichloromethane 8-1-1) and obtained 2.4 g of the expected product. Stage B: 2 - ((2-acetylphenyl) ((1,3-benzodioxol-5-yl) methyl) amino) 2-oxo ethyl acetate.

0.7 ml of ethyl oxalyl chloride is added drop by drop to 1.6 g of product obtained in stage A in 100 ml of tetrahydrofuran in the presence of 0.9 ml of triethylamine. Stir 2 hours at room temperature, pour into water, extract with ethyl acetate, dry, evaporate the solvent under reduced pressure, chromatograph the residue on silica (eluent: cyclohexane-ethyl acetate 6-4) and obtains 1 g of the expected product. Stage C: 1 - ((1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-ethyl carboxylate.

1 g of product obtained in Stage B in 50 ml of toluene with 0.23 g of sodium ethylate is stirred for 30 minutes at room temperature. Then heated for 2 hours at reflux, pour the reaction medium into water with 2N hydrochloric acid. Extracted with ethyl acetate, dried, the solvent evaporated, collected 0.16 g of acid which is washed with ethyl acetate, filtered and dried. The filtrate is chromatographed on silica (eluent: cyclohexane-ethyl acetate 6-4) and collects 0.36 g of the expected product used as it is for the next stage.

Stage D: potassium salt of l - ((1,3-benzodioxol-5-yl) methyl) 1,4-dihydro 4-oxo quinoline 2-carboxylic acid. The product obtained in Stage C is stirred for 4 hours at room temperature in 10 ml of ethanol with 0.16 ml of potassium hydroxide. The mixture is partially concentrated, the crystals are drained, washed with ether, dried at 50 ° C. under reduced pressure and collected 0.23 g of the expected product. IR spectrum (Nujol, cm ^"1 ) OO + conj.

+ aromatics + COO ^" 1620, 1590, 1558, 1498, 1488 EXAMPLE 32: l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4- dihydro" - ((4- (l- methylethyl) phenyl) sulfonyl) 4-oxo quinoline 2-carboxamide.

0.78 g of carbonyldiimidazole in 5 ml of tetrahydro¬ furan is added dropwise 0.7 g of acid obtained from the corresponding ester prepared as indicated in Example 31 for the non-chlorinated derivative, in suspension in 20 ml of tetrahydrofuran. The mixture is heated for 1 hour at reflux, allowed to return to room temperature, 0.6 g of sulfonamide is added, the mixture is stirred for 10 minutes at reflux and again allowed to return to room temperature. 0.45 ml of 1,8-diazabicyclo- [5,4,0] undec-7-ene is added in 5 ml of tetrahydrofuran, the mixture is stirred for 30 minutes at reflux, and left for 16 hours at room temperature. The reaction medium is poured into water added with hydrochloric acid, extracted with ethyl acetate, filtered, dried, the solvent is evaporated under reduced pressure, the residue is chromatographed on silica (eluent: acetone-acetate d 'ethyl-water 5-4-1) and obtains 0.25 g of crude product which is taken up in a mixture of ethyl acetate / water and concentrated hydrochloric acid. The organic phase is separated, dried, evaporated to dryness and the residue is recrystallized from hot ethyl acetate. 0.1 g of pure expected product is collected.

IR spectrum (Nujol, cm ^"1 ) OO 1638

OO + syst. conj. + aromatic + OC + amide II 1600 (max), 1560 (ep), 1500, 1420

EXAMPLE 33: of pharmaceutical composition.

Tablets corresponding to the following formula were prepared:

Product of Example 2 50 mg

Excipient for one tablet finished at 200 mg

(detail of excipient: lactose, talc, starch, magnesium stearate). PHARMACOLOGICAL RESULTS t

STUDY OF ENDOTHELIN RECEPTOR ACTIVITY

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 25 ° C (B.M.) the homogenate is centrifuged at 30,000 g for 15 minutes (2 centrifugations with intermediate recovery in the Tris pH 7.4 buffer).

The pellets are resuspended in an incubation buffer (Tris 25mM, perpstatin A 5 microg / ml, aprotinin 3 microg / ml, PMSF 0.1 mM, EDTA 3mM, EGTA ImM pH 7.4). Aliquots of 2 ml are distributed in hemolysis tubes and 1251 Endothelin (approximately 50,000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10 ~ ⁵ M in triplicate). When the tested product displaces the radioactivity linked specifically to the receptor by more than 50%, it is tested again according to a range of 7 concentrations in order to determine the concentration which inhibits by 50% the radioactivity linked specifically to the receptor. The inhibitory concentration 50% is thus determined. Nonspecific binding is determined by adding 10-6 M endothelin (in triplicate). Incubate at 25 ° C for 60 minutes, return to a water bath at 0 ° C for 5 minutes, filter under reduced pressure, rinse with Tris 7.4 buffer and count the radioactivity in the presence of the scintillant Triton. The result is expressed directly in inhibitory concentration 50% (IC50), that is to say in concentration of studied product expressed in nM, necessary to displace 50% of the specific radioactivity fixed on the receptor studied. Result:

Tftgfcga ^p i

Product of the example A ₅ o endothelin receptor in nanomoleβ

2 10.6

6 1.6

8 4.1

11 1.1

12 4.6

13 1.9

14 5.7

15 3

17 5.7

21 1.8

22 1

STUDY OF ACTIVITY ON ENDOTHELIN RECEPTOR B

A membrane preparation is carried out from the posterior cortex plus rat cerebellum. The tissue is ground with POLYTRON in a 50 mM Tris buffer pH "7.4.

After 30 minutes At 25 ^β C (BM), the homogenate is centrifuged at 30,000 g for 15 minutes (2 centrifugations with intermediate recovery in the Tris pH 7.4 buffer). The pellets are resuspended in an incubation buffer (Tris 25 mM, pepstatin A 5 microg / ml, aprotinin 3 microg / ml, PMSF 0.1 mM, EDTA 3mM, EGTA ImM pH 7.4).

Aliquots of 2 ml are distributed into hemolysis tubes and 1251 Endothelin (approximately 50,000 dpm / tube) and the product to be studied are added. (The product is first tested at 3 * 10 " ⁵ M in triplicate.) When the tested product displaces the radioactivity linked specifically to the receptor by more than 50%, it is tested again according to a range of 7 concentrations in order to determine the concentration which inhibits the radioactivity linked specifically to the receptor by 50%, thereby determining the inhibitory concentration 50%.

Nonspecific binding is determined by addition endothelin A 10 ~ ⁶ M (in triplicate). Incubated at 25 ^β C for 60 minutes, returned to a water bath at 0 ° C for 5 minutes, filtered under reduced pressure, rinsed with Tris 7.4 buffer and counted the radioactivity in the presence of the scintillant Triton. The result is expressed directly in inhibitory concentration 50% (IC50), that is to say in concentration of studied product expressed in nM, necessary to displace 50% of the specific radioactivity fixed on the receptor studied. Result:

TABftEAP II

Product of the example Endothelin CI ₅₀ receptor in nanoscale

2,606

13 789 11 102

Claims

1) Products of formula (I)

in which :

and linear or branched alkyl radicals containing at most 5 carbon atoms, optionally substituted by a hydroxy, carboxy or tetrazolyl radical, these radicals being optionally free, esterified or salified, Z _j and Z ₂ represent a hydrogen atom or well bonded to two consecutive carbons of the phenyl radical, form the radical

in which and Y, which are identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH≈ or -CH ₂ -, and the dotted 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 radical -CO-NH-S0 ₂ -R ₆ , in which R ₆ represents a alkyl, alkenyl or phenyl radical optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free, salified or esterified carboxy, tetrazo¬ or phenyl radicals itself optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkoxy and nitro radicals, R is chosen from: a) the hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano radicals , nitro, benzoyl, acyl, sulfo, free, salified or esterified carboxy, tetrazolyl, b) alkyl, alkenyl, alkyloxy, alkylthio, phenyl, naphthyl, benzyl, phenethyl, phenylthioalkyl and phenylthio radicals, all these radicals optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, pyrrolidinyl, pyridinyl, pyrrolinylcarbonyl and phenyl radicals - even optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals, c) amino, mono- or ialkylamino, carbamoyl radicals, d) the dioxol radical linked to two consecutive carbons of the cycle that carries it. e) the pyrrolyl, morpholino, piperazinyl, pyrrolylmethyl, morpholinomethyl, piperazinylmethyl, pyrrolylcarbonyl, morpholinocarbonyl, pyrrolidinylcarbonyl, piperazinylcarbonyl radicals, all the piperazinyl radicals being optionally substituted with the second nitrogen atom or phenyl, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, nitro, alkyl or alkyloxy, trifluoromethyl, cyano, free, salified or esterified carboxy, tetrazolyl and isoxazolyl radicals,

R _1f R, R ₃ , R and R ₅ , which are identical or different, are chosen from: a) the hydrogen atom, the halogen atoms, the hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, trifluoromethyl radicals, cyano, nitro, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted by one or two radicals chosen from the radical - (CH ₂ ) _p -S (0) _m -ZR ₇ as defined above - below and the alkyl and alkenyl radicals, c) the radical - (CH ₂ ) - S (0) _m -ZR ₇ in which p represents the values 0 and 1, m represents the values 0 A 2, Z represents the radicals -NH-, -NH-CO-, -NH-CO-NH- or a single bond and R ₇ represents an alkyl, alkenyl, alkynyl, pyridyl, phenyl, benzyl, phenethyl, tetrazolyl, piperinyl, thiazolyl radical, all the alkyl, alkenyl, alkynyl, alkoxy, phenyl, benzyl and phenethyl radicals above being optionally substituted by one or more radicals chosen from atoms of halogen and the hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy and tetrazolyl radicals, the phenyl, benzyl and phenethyl radicals being additionally optionally substituted by one or more alkyl or alkenyl radicals, or alternatively R ₂ and R ₃ linked to two consecutive carbons of the phenyl radical can form a ring chosen from the rings formed by <and Z ₂ as defined above, it being understood that when A represents a hydrogen atom, ^z l ^{and z} 2 f ^{form the} radical

as defined above, said products of formula (I) being in all the possible racemic isomeric, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases ques of said products of formula (I).

2) Products of formula (I) as defined in claim 1, in which A represents a hydrogen atom or a -CH ₂ -Ba radical in which Ba is chosen from the radicals

and linear or branched alkyl radicals containing at most 4 carbon atoms and optionally substituted by the free, esterified or salified carboxy radical, Z 1 and Z bonded to two consecutive carbons of the phenyl radical represent the radical

> in which ²

Y ₁ and Y ₂ , identical or different, are chosen from oxygen, sulfur and nitrogen atoms and the radicals -NH-, -CH≈ or -CH ₂ -, and the dotted lines indicating the event the 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 radical -CO-NH-S0 ₂ -R ₈ , in which R ₈ represents a radical alkyl or phenyl optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl, alkoxy, trifluoromethyl, nitro, cyano, free, salified or esterified carboxy radicals and tetrazolyl, R is chosen from: a) - l hydrogen atom, halogen atoms, hydroxyl, mercapto, cyano, nitro, benzoyl, acyl, sulfo, free, salified or esterified carboxy, tetrazolyl, b) - alkyl, alkenyl, alkyloxy, alkylthio radicals, 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, cyano, free carboxy, salified radicals or esterified, tetrazolyl, pyridinyl and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkox radicals y, c) - amino, mono- or dialkylamino, carbamoyl radicals, d) - the dioxol radical linked to two consecutive carbons of the cycle which carries it,

^R l '2' 3 '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 radicals, free, salified or esterified carboxy, tetrazolyl, isoxazolyl, b) amino or carbamoyl optionally substituted by one or two alkyl and alkenyl radicals, all of the above alkyl, alkenyl and alkoxy radicals being optionally substituted by one or more radicals chosen from the halogen atoms and the hydroxyl, alkoxy, trifluoromethyl, cyano, free, salified or esterified carboxy and tetrazolyl radicals, knowing that R ₂ and R ₃ linked to two consecutive carbons of the phenyl radical can form a ring chosen from the rings which form Z ^ and Z ₂ as defined above, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric forms isomers, as well as addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I).

3) Products of formula (I) as defined in claim 1 or 2, in which Z ± and Z ₂ are linked to two carbons located in meta and para of the phenyl radical when they represent the radical

as defined in claim 1 or 2 and the other substituents are as defined in claim 1 or 2, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I). 4) Products of formula (I) as defined in any one of claims 1 to 3, in which:

A represents a radical -CH ₂ -Ba in which Ba is defined as indicated In claim 2, Z ₁ and Z ₂ form a radical

\)

chosen from the following radicals:

3

))>

'NH

>"

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 radical -CO-NH-S0 ₂ -R _g in which R ₉ represents the radical methyl, ethyl or phenyl optionally substituted by one or more alkyl radicals, R is chosen from the hydrogen atom, the halogen atoms, the free, salified or esterified carboxy radicals and phenylthiomethyl optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl and alkoxy radicals, _{1 #} R ₄ and R ₅ , identical or different, are chosen from the hydrogen atom, halogen atoms and hydroxyl radicals, free carboxy , salified or esterified and the alkyl and alkoxy radicals optionally substituted by a free, salified or esterified carboxy radical, R ₂ and R ₃ linked to two consecutive carbons of the phenyl radical form a ring chosen from those which form Z ^ and Z ₂ , or else identical or different, are chosen from the values of R _χ , R ₄ and R ₅ , said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I). 5) Products of formula (I) as defined in any one of claims 1 to 4, in which A represents the radical

in which R ₂ and R ₃ have the meaning given to one any of claims 1 to 4, the other substituents having the meanings indicated in any one of claims 1 to 4, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I). 6) The following products: - potassium salt of acid l - ((1,3-benzodioxol-5-yl) methyl-1,4-dihydro-3 - ((4-methoxyphenyl) methyl) -4-oxo - quinoline-2-carboxylic acid,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 3 - ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid,

- potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 3- (cyclohexylmethyl) 1,4-dihydro -oxo quinoline 2-carboxyic,

- dipotassium salt of acid 3 - ((3-carboxyphenyl) methyl) l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro -oxo 1H-quinoline 2-carboxylic acid,

- potassium salt of 1,4-άihydro l acid - ((6-ethyl 1,3-benzodioxol-5-yl) methyl) 3- ((4-methoxyphenyl) methyl) 4-oxo quinoline 2-carboxylic acid, - potassium salt of the acid l - ((6-chloro l, 3-benzodioxol-5-yl) methyl) 1,4-dihydro 3- (2-furanylmethyl) 4-oxo quinoline 2-carboxylic acid,

- dipotassium salt of 3- ((3-carboxyphenyl) methyl) 1,4-dihydro l - ((6-ethyl l, 3-benzodioxol-5-yl) methyl) 4-oxo quinoline 2-carboxylic acid, said products being in all possible racemic, enantiomeric and diastereoisomeric isomeric forms, as well as the corresponding bases of said products and the addition salts of said bases with mineral and organic acids or with mineral and organic bases.

7) Process for the preparation of products of formula (I) as defined in claim 1, characterized in that

- either react a compound of formula (II):

in which R ′ has the meaning indicated above for R in which the possible reactive functions are evenly protected by protective groups, with a compound of formula (III):

a 1 OJ „C C0 ₂ a IX

in which A 'has the meaning indicated above for A in which the possible reactive functions are tually protected by protective groups, and alk and alk _j , identical or different, represent an alkyl radical containing at most 6 carbon atoms, to obtain a product of formula (IV):

in which Z _lt Z ₂ have the meanings indicated above and R ' ₄ and R' ₅ have the meanings indicated above, respectively for R ₄ and R ₅ in which the possible reactive functions are optionally protected by protective groups, to obtain a product of formula (I '):

in which z ₁ , Z ₂ , A ', R', R ' ₄ , R' ₅ and alk have the meanings indicated above,

- either react a compound of formula (VI):

in which R 'has the meaning indicated above, with a compound of formula (VII):

B'-CHO (VII)

(VIII)

in which Z _lt Z, R ' ₄ and R' ₅ have the meanings indicated above, to obtain a product of formula (XI):

in which B ', R', R ' ₄ , R' ₅ , Z ₁ and Z ₂ have the meanings indicated above, - either a compound of formula (XIII) is reacted:

wherein R ', ^R' 5, Z ^ and Z ₂ have the meanings indicated above, products of formula (XI) or (XIV) as defined above, which is subjected to the action of an acid chloride of formula:

Cl-C0-C0 ₂ -alk

in which Z _χ , Z ₂ , R ', R' ₄ , R ' ₅ and alk have the meanings indicated above and A' represents a hydrogen atom or the radical -CH ₂ -B 'such as defined above, which is subjected to the action of a cyclization agent, to obtain a product of formula (I ') as defined above, product of formula (I') which is subject, if desired and if necessary, to one or more of the following reactions, in an appropriate order: a) a transformation reaction of oxo OO function into thioxo OS function, b) a saponification reaction of ester function into acid function , c) a reaction for transforming an alkyloxy function into a hydroxyl function, d) a reaction for transforming the cyano function into an acid function, e) a reaction for transforming the cyano function into a tetrazolyl radical, f) an esterification reaction of amidification of acid function, g) a reduction reaction of the carboxy function in alcohol function, h) u ne reaction for converting the radical C0 ₂ alk into radi¬ cal -C0-NH-S0 ₂ -R ₆ , as defined above, i) a reaction for transforming the radical C0 ₂ alk into radi- cal CONH ₂ then, if desired as a cyano radical, j) a reaction for eliminating the protective groups which the protected reactive functions can carry, ^* * k) a salification reaction with a mineral or organic acid or with a mineral base or organic to obtain the corresponding salt,

I) a splitting reaction of the racemic forms, the said products of formula (I) thus obtained being in all the possible racemic, enantiomeric and diastereoisomeric isomeric forms.

8) As medicaments, the products as defined by formula (I) of claim 1, said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with the pharmaceutically acceptable mineral and organic bases of said products of formula (I).

9) As medicaments, the products of formula (I) as defined in claims 2 to 5, as well as their addition salts with mineral and organic acids or with pharmaceutically acceptable mineral and organic bases.

10) Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in any one of claims 8 and 9.

II) As new industrial products, the compounds of formula (IV), (VIII), (IX), (XI), (XIV) and (XV).

12) Use of the products of formula (I) as defined in claims 1 to 5, for the preparation of pharmaceutical compositions intended for the treatment of conditions resulting from abnormal stimulation of the endothelin receptors.