EP1654252A2 - Substituted quinolines serving as antimicrobial agents - Google Patents

Abstract

The invention relates to substituted quinoline-4 derivatives of general formula (I) that are active as antimicrobial agents, in which: X1, X2, X3, X4 and X5 respectively represent >C-R'1 to >C-R'5 or one at most represents a nitrogen; Y represents CHR, CO, CROH, CRNH2, CRF or CF2; R being hydrogen or alkyl, m is 0, 1 or 2 and n is 0 or 1; R2 represents a radical R, -CO2R, -CH2CO2R, -CH2-CH2CO2R, -CONH2, -CH2-CONH2r -CH2-CH2-CONH2, -CH2OH, -CH2-CH2OH, -CH2-NH2 -CH2-CH2-NH2 or -CH2-CH2-CH2-NH2, R being as defined above; R3 represents phenyl, heteroaryl or alk-R DEG 3, or alk is alkyl and R DEG 3 represents various groups, in this case, oxygenated groups, sulfurated groups or amino groups in their enantiomeric or diastereoisomeric forms or mixtures thereof and/or, in this case, in the form of syn or anti or mixtures thereof as well as their salts.

Description

 DERIVATIVES OF 4-SUBSTITUTED QUINOLEINS, THEIR PROCESSES AND INTERMEDIATES AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM The present invention relates to quinoline-4-substituted derivatives of general formula:

who are active as antimicrobials. The invention also relates to their preparation processes and intermediates and to the pharmaceutical compositions containing them. In patent applications WO 99/37635 and WO 00/43383, quinolyl propyl piperidine antimicrobial derivatives of the general formula have been described:

in which the radical Ri is in particular alkoxy (Cl-6), R ₂ is hydrogen, R ₃ is in position -2 or -3 and represents alkyl (Cl-6) which may be optionally substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxy, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxy optionally substituted with alkyl, R is a group -CH ₂ -R _S for which R ₅ is selected from alkyl hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroarylalkyl, optionally substituted heteroaroyl ..., n is 0 to 2, m is 1 or 2 and A and B are in particular oxygen, sulfur, sulfinyl, sulfonyl, NRn, CR ₆ R for which R _s and R ₇ represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxy, amino, and Zi to Z ₅ are N

Other applications, in particular WO 00/21952, WO 00/21948, WO 01/07432, WO 01/07433, WO 03/010138, or also WO 02/40474 or WO 02/072572 describe other derivatives of 4— quinolyl propyl) piperidines, substituted in particular in 3 or disubstituted in 4, active in the same field. European application EP 30044 also describes related derivatives active in the cardiovascular field. It has now been found, and this is what is the subject of the present invention, that the compounds of general formula (I) in which:

X- _L , X ₂ , X ₃ , X and X ₅ represent respectively>C-R'ιto> C-R ' ₅ , or else one at most of them represents a nitrogen atom,

Ri, R'i, R ', R' _{3 /} R 'and R' ₅ are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or heteroarylthio mono or bicyclic, OH, SH, alcoyloxy, difluoromethoxy, trifluoromethoxy, alcoylthio, trifluoromethylthio, cycloalcoyloxy, cycloalcoylthio, acyl, acyloxy, acylthio, cyano, carboxy, alcoyloxycarbonyl, cycloalcarloxy or cycloalcoyloxy represent hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl or Ra and Rb form together with the nitrogen atom to which they are linked a 5 or 6-membered heterocycle which may optionally contain another heteroatom chosen from 0, S or N and bearing if necessary a mono or bicyclic alkyl, phenyl or heteroaryl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized in the sulfinyl or sulphonyl state), or represent a methylene radical substituted by fluoro, hydroxy, alkyloxy, alkylthio, cycloalkoyloxy, cycloalkoylthio, phenyl, mono or bicyclic heteroaryl, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb for which Ra and Rb are, as heteroxy, carboxy, carboxy, etc. R _x can also represent difluoromethoxy, or a radical of structure -C _m F _{2m +} ι, -SC _ra F _{2πι +} ι or -OC _m F _{2m +} ι for which m is an integer from 1 to 6 or else R ' ₅ • can also represent trifluoroacetyl, m is 0, 1 or 2; n is 0 or 1; Y represents a group CHR, C = 0 or, when m is equal to 1 or 2, CROH, CRNH ₂ , CRF or CF ₂ , R being a hydrogen atom or an alkyl radical (Cι- ₆ );

R ₂ represents a radical R, -C0 ₂ R, -CH ₂ C0 ₂ R, -CH ₂ -CH ₂ C0 ₂ R, -CONH ₂ , -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ , -CH ₂ OH, -CH ₂ -CH ₂ OH, -CH ₂ -NH ₂ -CH ₂ -CH ₂ -NH ₂ or -CH ₂ -CH ₂ -CH ₂ -NH ₂ , R being as defined above;

R ₃ represents a phenyl, mono or bicyclic heteroaryl radical, alk-R ° ₃ for which alk is an alkylene radical and R ° ₃ represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyloxy, cycloalkyloxy , cycloalkyllio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cycloalkyl) ₂ , acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsuifinyl, phenylsuifinyl, phenylsuifinyl, phenylsuifinyl -cycloalkyl N-phenyl amino, -N- (phenyl) ₂ , phénylalcoyloxy, phénylalcoylthio, phénylalcoylsuifinyle, phénylalcoylsulfonyle, phénylalcoylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl N-phenylalkyl Amino, benzoyl, mono or bicyclic heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, hétéroarylsuifonyle, heteroarylamino, N-alkyl N-heteroaryl amino , N- cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkoyloxy, heteroarylalkoylthio, heteroarylalkoylsulfinyl, heteroarylalkyl, heteroarylalkoylamino, n -alkylalkyl, aminoalkyl, alkyl bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb respectively represent hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl, or one of Ra or Rb represents hydroxy, alkyloyloxy, cycloalkoyloxy , where Ra and Rb form together with the nitrogen atom at which they are linked a 5 or 6-membered heterocycle which may optionally contain another heteroatom chosen from O, S and N and bearing, where appropriate, a mono or bicyclic alkyl, phenyl or heteroaryl substituent on the nitrogen atom or, the where appropriate, the sulfur atom of which is oxidized in the suifinyl or sulfonyl state, or else R ° ₃ represents -CR'b = CR 'cR' a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, the part of which heteroaryl is mono or bicyclic, phenoxyalkyl, phénylthioalcoyle, phenylsulfinylalcoyle, phenylsulfonylalcoyle, phénylaminoalcoyle, N-alkyl N-phenyl aminoalkyl, heteroaryloxyalkyl, hétéroarylthioalcoyle, hétéroarylsulfinylalcoyle, hétéroarylsulfonylalcoyle, hétéroarylaminoalcoyle, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, (the heteroaryl parts mentioned above being mono or bicyclic), phenylthio, phenylsulfinyle, phenylsuifonyl, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or else R ° ₃ represents a radical -C≡C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, ^' N-alkyl N-phenyl aminoalkyl, heteroaryl mono or bicyclic, heteroarylalkyl, heterûaryloxyalcoyl, heteroarylthioalkyl, heteroarylaminoalkyl or arylaryl orarycyl, although R ₃ represents a radical -CF ₂ -phenyl or -CF ₂ -heteroaryl mono or bicyclic, it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above are optionally substituted on the ring by 1 to 4 substituents chosen from halogen, hydroxy, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxy, alkylcarbonyl, cyano, alkyllamino, -NRaRb for which Ra and Rb are alkyl as above, alkyl, phenyl, alkyl, above alkyl, phenyl, alcoyl, phenyl, etc. , alkylsulfinylalkyl, alkylsuifonylalkyl; R4 represents a radical R, -CHO, -C0CH ₃ -CH ₂ C0 ₂ H or -COCH ₂ NH ₂ ; it being understood that the alkyl and acyl radicals and portions contain (except. special mention) 1 to 10 carbon atoms, in straight or branched chain, and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or where appropriate in syn or anti form or their mixture, as well as their salts, are very powerful anti-bacterial agents.

It is understood that when the radicals represent or carry a halogen atom, the halogen is chosen from fluorine, chlorine, bromine or iodine, and is preferably fluorine.

In the general formula above, when the radicals represent or carry a mono or bicyclic heteroaryl substituent, the latter contains 5 to 10 members and can be chosen (without limitation) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl , thiadiazolyle, oxadiazolyl, tetrazolyl, pyridyl, ^{'pyridazinyl,} pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuranyl indazolyl, benzothiazolyl, naphthyridinyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, benzoxazolyl, benzimidazolyl which may be optionally substituted by the substituents mentioned above.

Among the compounds of general formula (I), mention may in particular be made of those in which

Xi, X ₂ , X ₃ , X ₄ and X ₅ are as defined above,

Ri, R'i, R ' ₂ , R' ₃ , R ' ₄ , and R' ₅ , are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a radical alkyloxy-substituted methylene;

m is 1;

n is 1;

Y represents a CH ₂ , CHOH, CHF, CHNH ₂ or C = 0 radical;

R ₂ is as defined above, and

R ₃ represents an alk-R ° ₃ radical for which alk is an alkylene radical and R ° ₃ represents alkyloxy, alkylthio, alkylamino, dialkoylamino, cycloalkyloyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cyclo) ₂ , phenoxy, phenylthio, phenylamino, N-alkyl N-phenyl amino, N-cycloalkyl N-phenyl amino, phenylalkoyloxy, phenylalkoylthio, phenylalkoylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkylnoyloyloyloyloyloxy , heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkoyloxy, heteroarylalkoylthio,. heteroarylalkoylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N-heteroaryl aminoalkyl, (the heteroaryl parts mentioned above being mono or bicyclic), -NRaRb or -CO-NRaRb for which Ra- and Rb are defined as above, or else R ° ₃ represents -CR'b = CR 'cR' a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl, heteroaryloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyloyoyl the heteroaryl parts mentioned above being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or else R ° ₃ represents a radical -C≡C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phénylthioalcoyle, N-alkyl N-phenyl amino-alkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, hétéroarylthioalcoyle, hétéroarylaminoalcoyle, ^• N-alkyl N- heteroaryl aminoalkyl, (the heteroaryl parts mentioned above being mono or bicyclic), or else R ° ₃ represents a radical -CF ₂ -phenyl or -CF ₂ -heteroaryl mono or bicyclic;

R ₄ is as defined above; it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above can be optionally substituted as envisaged above,

in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in syn or anti form or their mixtures, as well as their salts, and more particularly those in which

Xi, X ₂ , X ₃ , X and X ₅ respectively represent>C-R'ιto> C-R ' _S ,

Ri, R'i, R ' ₂ / R' ₃ R ', - R'Ξ are the same or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted by alkyloxy ; m is equal to al; n is 1;

Y represents a radical CH _2, CHOH, ^'CHF, CHNH ₂ or C = 0;

R ₂ is as defined above, and R ₃ represents an alk-R ° ₃ radical for which alk is an alkylene radical and R ° ₃ represents cycloalkyloxy, cycloalkylthio, phenoxy, phenylthio, phenylalkyloxy, phenylalkoylthio, heteroaryl oxy, heteroaryloxy, heteroaryloxy , heteroarylalkoylthio, (the heteroaryl parts mentioned above being mono or bicyclic) or else R ₃ represents -CR'b = CR 'cR' a for which R 'a represents phenyl, phenylalkyl, heteroaryl, heteroarylalkyl, phenoxyalkyl, phenylthoyalkyloxy , heteroarylthioalkyl (the heteroaryl parts mentioned above being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or ^' cycloalkyl, or else R ° ₃ represents a radical -C≡C- Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenyl aminoalkyl, mono or bicyclic heteroaryl, heteroarylalkyl, hetero roaryloxyalcoyle, hétéroarylthioalcoyle, (the heteroaryl parts mentioned above being mono- or bicyclic); R ₄ represents a radical R; it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above may be optionally substituted, as envisaged above, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or if appropriate, in the form syn or anti or their mixtures, as well as their salts. Among the compounds of general formula (I), the subject of the invention is very particularly any one of those whose names follow: • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- fluoro-6-methoxy-4-quinoleinyl) -ethylamino] -3- acid carboxylic pyrrolidine; • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (6-methoxy-4 -quinolinyl) - ethylamino] -3 -pyrrolidine carboxylic acid; • 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3- fluoro-6-methoxy-4-quinoleinyl) -ethylamino] -3- pyrrolidine carboxylate methyl; • methyl 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (-6-methoxy-4-quinoleinyl) -ethylamino] -pyrrolidine carboxylate; . ^• • acid 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- chloro-6-methoxy-4-quinoleinyl) - ethylamino] - pyrrolidine methyl carboxylate; • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- chloro-6-methoxy-4-quinoleinyl) - ethylamino] -3- pyrrolidine carboxylate methyl;

in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in 'syn or anti form or their mixture, as well as their salts. Among the compounds of general formula (I), mention may also be made of those whose names follow:

• 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] methylamino] acid - Carboxylic 3-pyrrolidine; • 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3 - [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] formylamino] acid - Carboxylic 3-pyrrolidine; • 3- [(aminoacetyl) [2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -1- [(2Ξ) -3- (2, 5-difluorophenyl) 2-propenyl acid ] -3-pyrrolidinecarboxylic; • 3- [(carboxymethyl) [2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -l- ^' [(2E) -3- (2, 5-difluorophenyl) acid) • -2-propenyl] -3-pyrrolidinecarboxylic;

• N- [1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4-quinoline ethanamine; • N- [1- [(2.E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- pyrrolidinyl] -N- [2- (3-fluoro-6-methoxy-4- quinolinyl) ethyl] -glycine; • N- [1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-N-methyl -4-quinolineethanamine; • 1- [(2.B) -3- (2, 5-difluorophenyl) -2-propenyl] -3- [[2- (3- fluoro-6-methoxy-4-quinolinyl) ethyl] amino] - 3- pyrrolidine methanol; • 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- [[2- (3- fluoro-6-methoxy-4 -quinolinyl) ethyl] amino] -3- pyrrolidinecarboxamide; • N- [3- (aminomethyl) -1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3 -pyrrolidinyl] -3-fluoro-6-methoxy-4-quinolineethanamine; • a- [[[1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- pyrrolidinyl] amino] methyl] -3-fluoro-6-methoxy-4-quinoline methanol . in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in syn or anti form or their mixture, as well as their salts.

According to the invention, the products of general formula (I) can be obtained by condensation of the chain R ₃ on the quinoline-4-substituted derivative of general formula:

in which X _lt X ₂ , X ₃ , X, X ₅ , Ri, R ₂ , Y, m and n are defined as before, R ₂ and R ₄ being protected when they carry a carboxy radical, followed where appropriate by the elimination of the protective group of the carboxy radical, optionally by the separation of the enantiomeric or diastereoisomeric forms and / or where appropriate of the forms syn or anti and possibly the transformation of the product obtained into a salt. The condensation of the chain R ₃ on heterocyclic nitrogen is advantageously carried out by the action of a derivative of general formula: R ₃ -X (Ha)

in which R ₃ is defined as above and X represents a halogen atom, a methylsuifonyl radical, a trifluoromethylsulfonyl radical or p. toluenesulfonyl, operating in an anhydrous medium, preferably inert, in an organic solvent such as an amide (for example dimethylformamide), a ketone (for example acetone) or a nitrile (for example acetonitrile) in the presence of a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature between 20 ° C. and the reflux temperature of the solvent. The nitrogen atom of the pyrrolidine ring of the derivative of general formula (II) is optionally protected according to the usual methods compatible with the rest of the molecule or the reaction; the protection is carried out for example by a protective radical chosen from the benzyl, t .butoxycarbonyl and benzyloxycarbonyl groups, and this nitrogen atom is released before condensation with the derivative of formula (IIa), in particular by acid hydrolysis.

Preferably, a derivative of general formula (IIa) is made to act for which X is a chlorine, bromine or iodine atom. Conditions under which the condensation between the derivatives of general formulas (II) and (IIa) can be carried out are also described in application WO 02/40474. When R ₃ is a radical -alk-R ° ₃ in which R ° ₃ is a group -C≡C-Rd, in which Rd is as defined more above, an alkynyl halide is condensed, intermediate, then the desired radical is condensed on the alkyne thus obtained. When R ₃ represents a radical -alk-R ° ₃ for which alk is an alkyl radical and R ° ₃ represents a phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino radical, the chain can also be constructed by first condensing an HO-alk-X chain for which X is a halogen atom, preferably iodine, under the conditions described above for the reaction of the product of general formula (IIa), then, if necessary, by transforming the hydroxyalkyl chain into a haloalkyl, methanesulfonylalkyl or p. toluenesulfonylalkyl and finally by acting in basic medium an aromatic derivative of structure R ° ₃ H or R ° ₃ H ₂ . The transformation of the hydroxyl chain into a haloalkyl chain or p. toluenesulfonyl is carried out according to the usual methods of halogenation or sulfonylation, in particular a halogenating agent such as thionyl chloride, halogenated phosphorus derivatives (trichloride or phosphorus tribromide for example) or a sulfonylating agent is made to act for example methanesulfonyl chloride, p chloride. toluenesulfonyl or trifluoromethanesulfonic anhydride. The reaction is carried out in an organic solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature between 0 and 60 ° C. <In some cases it may be advantageous to operate in the presence of a base such as pyridine or triethylamine. The reaction of the aromatic derivative R ₃ H or R ₃ H ₂ is advantageously carried out as described above for the action of the derivative of general formula (IIa), in an organic solvent such as an amide (dimethylformamide for example), a ketone (acetone for example), a nitrile (acetonitrile for example), in the presence of a base such as an organic nitrogenous base (for example triethylamine) or a mineral base (alkali carbonate: potassium carbonate for example) at a temperature included between 20 ° C and the reflux temperature of the reaction mixture. It may be advantageous to operate in presence of potassium iodide. It is also possible to operate in an ether (tetrahydrofuran for example) under dehydration conditions in the presence, for example, of diisopropylcarbodiimide and triphenylphosphine. It is understood that, if the radicals R ₃ carry carboxy or amino substituents, the latter are previously protected, then released after the reaction. We operate according to methods well known to those skilled in the art which do not alter the rest of the molecule, in particular according to the methods described by TW Greene and PGM Wuts, Protective Groups in Organic Synthesis (2 ^nd ed.), A. Wiley - Interscience Publication (1991), or by Me Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). The protected carboxy radical carried by R ₂ or R ₄ can be chosen from easily hydrolyzable esters. By way of example, mention may be made of methyl, benzyl, tert-butyl esters, or else phenylpropyl or allyl esters. Possibly the protection of the carboxy radical takes place simultaneously with the reaction. Where appropriate, the protection of the amino radical is carried out by means of the usual protective radicals cited in the references above.

The establishment and removal of these protective radicals is carried out according to methods known to those skilled in the art. According to the invention, the derivatives of general formula (I) for which R ₂ is hydroxymethyl or hydroxyethyl can be prepared by the action of an appropriate reducing agent on a derivative for which R ₂ is carboxy or carboxymethyl or protected carboxy or carboxy methyl protected. Any ketone function that may be present must then be protected.

Also according to the invention, the products of general formula (I) for which R ₂ is carboxymethyl or carboxyethyl can also be prepared from the derivatives for which R ₂ is hydroxymethyl or hydroxyethyl, by action on the latter of an agent d halogenation or tosylation, then a cyanidation agent and finally a nitrile hydrolysis agent. Also according to the invention, the products of general formula (I) for which R ₂ is -CONH ₂ , -CH ₂ -CONH ₂ or -CH ₂ -CH ₂ -CONH ₂ can be prepared from the corresponding acids or esters by amidification with ammonia. Also according to the invention, the products of general formula (I) for which R ₂ is -CH ₂ -NH ₂ , - (CH ₂ ) ₂ -NH ₂ or - (CH ₂ ) ₃ -NH ₂ can be prepared from corresponding amides by reduction. The reduction of the protected carboxy can be carried out according to the usual methods which do not alter the rest of the molecule, in particular by the action of a hydride (aluminum and lithium hydride or diisobutyl aluminum hydride for example) in a solvent. such as an ether (tetrahydrofuran for example) at a temperature between 20 and 60 ° C. Intermediate protection and then deprotection of a ketone function which may be present according to conventional methods known to those skilled in the art, in particular via an acetal, cyclic or not. The reduction of the free carboxy can be carried out according to methods also known to those skilled in the art, for example by hydrogenation in the presence of a catalyst based on rhodium or ruthenium, by the action of sodium hydroboride in the presence of Lewis or aluminum hydride and lithium in ether. Preferably, the ketone function is also in this case temporarily protected. The transformation of the hydroxymethyl or hydroxyethyl radical into a carboxymethyl or carboxyethyl radical is carried out according to the usual methods which do not alter the rest of the molecule, in particular by the action of a halogenating agent such as, for example, thionyl chloride or phosphorus trichloride or phosphorus tribromide, or a tosylating agent, then an alkaline cyanide, for example (potassium cyanide or sodium cyanide, to prepare the corresponding cyanomethyl derivative, followed by hydrolysis of the nitrile. The halogenation can be carried out in a chlorinated solvent (dichloromethane or chloroform for example), at a temperature between 0 ° C. and the reflux temperature of the solvent. - The amidation reaction with ammonia ^is' made in ^• the usual conditions known to those skilled in the art. The operation is preferably carried out starting from the acid, for example in the presence of dicyclohexylcarbodiimide and of dimethylaminopyridine or of hydroxybenzotriazole, in an ether, for example tetrahydrofuran, of a chlorinated solvent, for example of dichloromethane, or dimethylformamide . The reduction to the amine is carried out, likewise, under conventional conditions, for example by the action of a hydride such as lithium aluminum hydride in an ether, for example tetrahydrofuran, or by the action of 'a borane in the presence of dimethylsulfide. When R is a hydrogen atom, the condensation of the chain R ₃ on the nitrogen of pyrrolidine or of azetidine does not in principle require that the nitrogen carrying R ₄ is protected taking into account the steric hindrance around this nitrogen. Where appropriate, in exceptional cases where this might prove necessary, a conventional protective grouping of amino functions such as those described in the work by TWGreene and PGM Wuts cited above can be used. According to the invention, the preparation of the products of general formula (II) for which Y is a CH ₂ group and m is equal to 1 or 2, is carried out by condensation of a heteroaromatic derivative of general formula:

O = 0-H

in which RI, XI, X2, X3, X4 and X5 are defined as above and m is equal to 1 or 2, on a derivative of general formula: • in which P is a protective group, n and R ₂ are defined as above and R ₂ represents a protected radical if R ₂ represents or carries a carboxylic acid function, followed by the removal of the protective groups and / or followed by the transformation, by subsequent operation, substituents of the aromatic bicycle of general formula (II) thus obtained, to lead to the derivative carrying the radical R _x , R '--- / R' i ι ^• R ' ₃ ^• R', R's expected, and if necessary elimination of the protective radical (s) still present on the molecule. P can be any protective group of the nitrogen atom compatible with the reaction (t-butyloxycarbonyl, benzyloxycarbonyl for example). The groups protecting from the acid functions are chosen from the usual groups, the establishment and elimination of which do not affect the rest of the molecule, in particular those mentioned in the references cited above.

The reaction can be carried out in the presence of an amino base such as triethylamine, in a halogenated solvent such as chloroform or dichloroethane and then a reducing agent such as sodium triacetoxybrohydride in the presence of acetic acid, operating at room temperature.

In the case where m is equal to 0, the preparation is carried out under similar conditions, initially using a derivative of general formula

in which R, X _lf X ₂ , X ₃ , X and X ₅ are defined as above. According to the invention, the products of general formula (II) for which Y is a CHR group, R being an alkyl, can be prepared starting from the corresponding compounds in which Y is CH ₂ , by the action of an alkyl halide , preferably an iodide- on the anion in α of quinoline prepared by the action of a strong base, for example an alkaline tertbutylate. Such reactions are known to those skilled in the art. According to the invention, the preparation of the products of general formula (II) for which Y is a CHOH group and m = 1 is carried out by condensation of a derivative of general formula

in which RI, XI, X2, X3, X4 and X5 are defined as above, on a derivative of general formula IV) as defined above. One can operate in the presence of lithium or sodium perchlorate in a solvent such as dimethylfornamide, hot.

The products of general formula (II) for which Y is a carbonyl group and m = 1 or 2 can be prepared by oxidation of the corresponding derivative of general formula (II) for which Y is a CHOH group. This oxidation is carried out for example by means of potassium permanganate, optionally in a sodium hydroxide solution (for example 3N sodium hydroxide), at a temperature between -20 and 20 ° C., or else by the action of oxalyl chloride in the presence of dimethyl sulfoxide, followed by the addition of an amine such as triethylamine, in an inert solvent such as dichloromethane, dimethyl sulfoxide at a temperature between -60 and 20 ° C by analogy with the method described by D. SWERN et al. , J. Org. Chem. , 44, 4148 (1979). The. products of general formula (II) for which Y is a carbonyl group and m = O can be obtained by a peptide coupling reaction of the amine of formula (IV) with a product of general formula

in which RI, XI, X2, X3, X4 and X5 are defined as above. One operates for example in the presence of dicyclohexylcarbodiimide and 1-hydroxybenzotriazole.

The products of general formula (II) in which Y is a CROH group, R being an alkyl, can be obtained from "products in which Y is a carbonyl group, by reaction of an appropriate alkyl magnesium halide, in conventional conditions known to those skilled in the art. This is done for example by the action of methyl magnesium chloride in an ether such as tetrahydrofuran. The products of general formula (II) in which Y is a CHR group, R being an alkyl , can also be obtained from products in which Y is a CROH group, obtained as described above, by elimination of the alcohol via a xanthate. The alcohol is reacted with a strong base , for example sodium hydride, then add carbon sulfide and then methyl iodide, then heat the xanthate thus obtained in the presence of tributyltin hydride. The derivative of general formula (II) for which l Y is a CRNH ₂ group can be prepared from the corresponding CROH derivative which is transformed into its tosylated derivative, on which ammonia is made to act. The reaction is carried out in an inert solvent such as N, N-dimethylformamide or dimethyl sulfoxide and preferably under pressure (2 to 20 atmospheres) at a temperature between 20 and 100 ° C. 'The tosyloxy derivative is obtained from the product of general formula (II) for which Y is CROH, by the action of tosyl chloride in pyridine, at a temperature between 5 _. -10 and 20 ° C. The derivatives of general formula (II) for which Y is a CRF or CF _{2 group} can be prepared by fluorination respectively from the derivative for which Y is a CROH group and from that for which Y is a carbonyl group. The

10 reaction is carried out in the presence of a sulfur fluoride [for example in the presence of an amino sulfur trifluoride (diethylamino sulfur trifluoride (Tetrahedron, 44_, 2875 (1988), bis (2-methoxyethyl) amino trifluoride 'sulfur (Deoxofluor0), trifluoride

Morpholino sulfur, for example) or alternatively in the presence of sulfur tetrafluoride (J. Org. Chem., 4JD, 3808 (1975)]. The fluorination reaction can also be carried out using a fluorinating agent such as hexafluoropropyl diethylamine (JP 2 039 546) or N- (2-chloro-trifluoro-1, 1, 2

Ethyl) diethylamine. Is carried out in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform) or in an ether (tetrahydrofuran or dioxane for example) at a temperature between -78 and 40 ° C (preferably ^'25 0 and 30 ° C). It is advantageous to operate under an inert atmosphere The products of general formula (II) for which Y represents a CHOH group and m = 1 or 2, can also be prepared by oxidation in basic medium of the corresponding derivative for which Y is a CH group ₂ . Oxidation

30 is carried out by the action of oxygen, preferably in an inert solvent such as dimethyl sulfoxide in the presence of tert-butanol and a base such as potassium or sodium tert-butoxide at a temperature between at 0 and 100 ° C. The above reactions intended to take place at the level of Y on the product of formula (II) are carried out, if necessary, after protection of the reactive functions of the pyrrolidine or of the azetidine and of the chain at the level of R. The protective groups used are in particular those mentioned above. The products of general formula (III) in which m = 1 prepared from the product of formula:

in which RI, XI, X2, X3, X4 and X5 are defined as above, which is made to act with allyltributyltin in the presence of tetrakistriphenylphosphine palladium and copper iodide in dimethylfornamide at 60 °, to obtain the product allylé of formula .-

which is oxidized with osmium tetraoxide in the presence of N-methylmorpholine N-oxide, in a water-acetone mixture at room temperature, to obtain the diol of formula:

which is oxidized with sodium periodate in a tetrahydrofunan-water mixture at room temperature. The starting product of general formula (V) can be obtained as described in patent application WO 02.40474 The product of general formula (III) in which m = 2 can be prepared starting from a product of formula (VI) such as defined above, which is subjected to a hydroboration reaction by treatment with 9-borabicyclo [3, 2, 1] octane, followed by oxidation with hydrogen peroxide, to obtain the product of general formula :

which is oxidized to the corresponding aldehyde of general formula:

for example by the so-called Swern method mentioned above. One can also use the so-called Dess-Martin method, consisting in treating alcohol under conditions given by periodinane (J. Org. Chem. 1983, p.48, 1.155-6). - The product of general formula (III ') can be obtained from the product of general formula:

in which R _x , Xi, X ₂ , X ₃ , X ₄ and X ₅ are defined as above, which are treated with a strong base, then act on the anion thus obtained dimethylformamide. The strong base is preferably butyllithium, sec-butyllithium, or lithium diisopropylamide, and the operation is carried out in a solvent such as an ether, tetrahydrofuran for example, at a temperature between -78 ° and -40 °. The condensation of this lithiated derivative on DMF takes place in the same solvent, at a temperature between -78 ° C and 0 ° C. The product of general formula (X) can be prepared according to a method described in patent application WO 02.40474.

The product of formula (III ") can be obtained starting from the product of general formula (X) as defined above, the anion of which is prepared in position 4 as above, which is treated with acetaldehyde to obtain general formula alcohol

which is oxidized to the corresponding ketone of formula (XII)

which are treated with bromine in the presence of concentrated sulfuric acid, to obtain the product of general formula

which is subjected to the action of a ketone-reducing agent to obtain the product of formula of general formula:

which is subjected to the action of a base to obtain the expected product.

The reducing agent for the ketone may in particular be boron hydride and the operation is carried out for example within tetrahydrofuran. The base used is in particular a carbonate or an alkali hydroxide and the operation is carried out, for example, in an alkanol. The product of- general formula (III '") can be obtained from the product of general formula (X) as defined above, the anion of which is prepared in position -4, which is treated with a chloroformate of alkyl, to obtain the ester of general formula

that we saponify by a base under conditions. classics.

Products corresponding to the products of general formula (IV) as defined above, in which the reactive functions are free as well as some in which they are protected are described and, for certain commercial, in the cases where n = 0 or 1 and R ₂ = H, CH ₃ , C ₂ H ₅ , COOH, COOCH ₃ , CH ₂ C0 ₂ CH ₃ , C0NH ₂ , CH ₂ OH. Among _. references from the literature, we can cite applications ^• WO 9414794, WO 0170734, WO 9907696, EP 536035, EP 326916, EP 242789, JP 63130594 A2 and JP 62030776 A2, as well as the references Synlett (1991), 11, 783 -4, Synthetic Comm. (1995), 25 (9), 1295-1302. The products of formula (IN) not described can generally be obtained by methods described in these references or, starting from the products described, by methods known to those skilled in the art. According to the invention, products of general formula (I) for which R is different from hydrogen can be obtained either as described above, starting from a product of general formula (II) for which R has the corresponding value, different from hydrogen, either from a product of general formula (I) for which R ₄ is hydrogen, by one or other of the methods described below. According to the invention, the products of general formula (II) for which R ₄ is different from hydrogen can be obtained from a product of general formula (II) for which R ₄ is hydrogen, by the same methods. Where appropriate, and in particular for the preparation of products of general formula (II), the implementation of these methods requires the intermediate protection of the reactive functions, in particular amino and / or carboxy and / or hydroxy. This, as well as deprotection, can be carried out according to the methods described above. The products for which R ₄ represents an alkyl radical can be obtained by the action of a corresponding aldehyde on the amine, in the presence of a reducing agent. This may for example be sodium borohydride or sodium cyanoborohydride or alternatively sodium triacetoxy borohydride and it may be carried out in a conventional halogenated solvent or in an alcohol. It may be advantageous to operate at a slightly acid pH, for example in the presence of acetic acid. The products for which R represents a CHO radical can be obtained by the action of formic acid in the presence of ^" acetic acid, or by the action of triethyl orthoformate in the presence of paratoluene sulfonic acid and triethylamine, on the amine. One can operate in a halogenated solvent or in tetrahydrofuran or in • dimethylformamide. Formylation can also be carried out according to a Vilsmeyer type method. Products for _. which R represents a COCH ₃ radical can be obtained by the action of an acetyl halide or acetic anhydride on the amine. The operation is carried out in the presence of a base such as triethylamine. The products for which R ₄ represents a CH ₂ C0 ₂ H radical can be obtained by the action of bromoacetic acid on the amine, by operating under the same conditions as above, or by the action of glyoxaldehyde on the amine then reduction with sodium cyanoborohydride by operating in the same type of solvents.

The products for which R represents a CO-CH ₂ -NH ₂ radical can be obtained by peptide coupling by action of glycine on the amine, in the presence for example of dicyclohexylcarbodiimide, and after having protected the amine function of the glycine, or also by action on the amine of the same protected glycine, the acid function of which is activated beforehand, in particular in the form of chloride, by the action of oxalyl chloride or of thionyl chloride. It is preferably carried out in a halogenated solvent or in tetrahydrofuran.

The intermediate products of general formula (II) for which the reactive functions are free or protected obtained during the implementation of the process according to the invention are new and, as such, form part of the invention. Similarly, intermediate products of general formulas

XI), (XII), (XIII) and (XIV) are also new and, as such, are also part of the invention. It is understood that the derivatives of general formula (I) and (II) can exist in enantiomeric or diastereoisomeric forms or in syn or anti form, which of course fall within the scope of the present invention. These forms can be separated according to the usual methods known to those skilled in the art, in particular by chiral chromatography or by High Performance Liquid Chromatography (HPLC). This is illustrated below in the experimental part. The derivatives of general formula (I) can be purified if necessary by physical methods such as crystallization or chromatography. The derivatives of general formula (I) can, where appropriate, be converted into addition salts with acids or with bases, by known methods. It is understood that these salts with acids or bases also fall within the scope of the present invention. As examples of addition salts with pharmaceutically acceptable acids, may be mentioned the salts formed with inorganic acids (e.g. hydrochlorides, hydrobromides, sulphates, nitrates or - phosphates) ^'or with organic acids (e.g., succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p. toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates). The derivatives of general formula (I) carrying a carboxy radical can be transformed into metal salts or into addition salts with nitrogenous bases according to the methods known per se. The salts can be obtained by the action of a metal base (for example alkaline or alkaline-earth), ammonia or an amine, on a product according to the invention, in a suitable solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid. The salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or lyophilization. Examples of pharmaceutically acceptable salts which may especially be mentioned are the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), the ammonium salt, the salts of nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-β-phenethylamine, NN '-dibenzylethylenediamine, diphenylenediamine, benzydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine). ^' The derivatives of general formula (I) according to the invention are particularly active antibacterial agents.

The study below demonstrates this. a) In vitro activity The method of dilutions in an agar medium in accordance with the NCCLS recommendations is used for the determination of the minimum inhibitory concentrations (C.M.I.) expressed in μg / ml. The activities of the compounds of Examples 1 to 4 are grouped in the following table:

In vitro, the compounds of the invention have therefore been shown to be quite remarkable in at _. both gram positive and negative germs. b) The products according to the invention are particularly advantageous because of their low toxicity. None of the products showed toxicity at a dose of 50 mg / kg subcutaneously or orally in mice (2 administrations / day). These properties make said products suitable, as well that their pharmaceutically acceptable salts of acids and bases, to be used as medicaments in the treatment of the affections with sensitive germs caused by bacteria with gram-positive and in particular in those with 5 staphylococcus, such as septicemia with staphylococci, staphylococci malignant facial or cutaneous, pyoderma, septic or suppurative wounds, carbuncles, phlegmons, erysipelas, acute primary or post influenza staphylococcias, bronchopneumonia, pulmonary suppurations, 10 as well as those with streptococci or enterococci. These products can also be used as drugs in the treatment of upper and lower respiratory infections caused by gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis. The subject of the present invention is therefore also, as medicaments and in particular medicaments intended for the treatment of bacterial infections in humans or animals, the compounds of general formula (I) as defined above as well as their pharmaceutically acceptable salts, and in particular the preferred compounds mentioned above. The present invention also relates to the pharmaceutical compositions containing at least one quinoline-4-substituted derivative according to the invention, where appropriate in the form of a salt, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. The compositions according to the invention can be used orally, parenterally, topically, rectally or in aerosols. As solid compositions for oral administration, tablets, pills, capsules, powders or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can comprise substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for a controlled release. As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products. The compositions for parenteral administration can be sterile solutions or emulsions. As solvent or vehicle, there may be used water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium. The compositions for topical administration can be, for example, creams, ointments, lotions or aerosols. The compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. The compositions can also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in sterile pyrogen-free water, in serum or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active ingredient is finely divided and associated with a water-soluble solid diluent or vehicle with a particle size of 30 to 80 μm, for example dextran, mannitol or lactose. In human therapy, the new quinoline-4-substituted derivatives according to the invention are particularly useful in the treatment of infections of bacterial origin. The doses depend on the desired effect and on the duration of the treatment. The doctor will determine the dosage he considers most appropriate based on the treatment, depending on the age, weight, degree of infection and other factors specific to the subject to be treated. Generally, the doses are between 750 mg and 3 g of active product in 2 or 3 taken per day by the oral route or between 400 mg and 1.2 g by the intravenous route for an adult. The following examples illustrate compositions according to the invention. a) A liquid composition intended for parenteral use is prepared according to the usual technique, comprising: • Acid -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- ( 3-fluoro- 6-methoxy-4-quinoleinyl) ethylamino] -3-pyrrolidine carboxylic 1 g

• Glucose qs 2.5% »sodium hydroxide qs pH = 4-4.5

• ppi water qs 20 ml b) A liquid composition intended for parenteral use is prepared according to the usual technique, comprising: • Acid -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] - 3- [2- (6-methoxy-4 -quinolinyl) -ethylamino] -3 -pyrrolidine carboxylic;

• glucose ._ _ _ qs 5% • sodium hydroxide qs pH = 4-4.5 • water ppi ^' qs 50 ml The following examples illustrate the invention. Example 1 Enantiomers A and B of 1- [(E) -3- (2, 5-difluorophenyl) -allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) acid ) - ethylamino] -3 -pyrrolidine carboxylic:

The A-enantiomer of 1- [(E) -3- (2,5-difluoro-phenyl) - allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) acid) ethylamino] - 3 -pyrrolidine carboxylic acid - can be prepared as follows:

To a solution containing 0.226 g (0.452 mmol) of the methyl ester of the A enantiomer of acid 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [- 2- (3-fluoro-6-methoxy-quinoline-4-yl) -ethylamino] -pyrrolidine-3 -carboxylic in 25 cm ³ of dioxane are added, with stirring, 3.80 cm ³ (19.00 mmol) d 'an aqueous solution ^' of 5N sodium hydroxide, and the yellow solution thus obtained is brought to reflux, and stirred for 18 hours at this temperature. The reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 15 cm of silica 20-45 μm at atmospheric pressure using as .eluent a chloroform / methanol / 28% aqueous ammonia mixture (12/3/0 , 5 by volume). The fractions containing the expected are combined and concentrated under reduced pressure to give 0.150 g of a pale yellow product which is taken up in 20 cm ³ of a dichloromethane / methanol mixture (9/1). The resulting solution is filtered on paper, the paper is washed with twice 10 cm ³ of a dichloromethane / methanol mixture (9/1), the filtrates are combined and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of isopropyl ether, then the resulting suspension is concentrated to dryness under reduced pressure to. give 0.138 g of the expected enantiomer A, in the form of a pale yellow amorphous solid.

[α] _D = + 25.5 ° +/- 0.7 (c = 0.5 in methanol) MS spectrum: IC m / z = 486 MH ⁺ basic peak NMR spectrum R (30 MHz, (CD ₃ ) ₂ SO, δ in ppm): 1.82 (mt: 1H); 2.24 (mt: 1H); 2.40 (mt: 1H); 2.73 (d, J = 11 Hz: 1H); 2.75 to 3.05 (mt: 4H); from 3.05 to 3.40 (mt: 4H); 3.96 (s: 3H); 6.41 (dt, J = 16 and 6 Hz: 1H); 6.58 (broad d, J = 16 Hz: 1H); 7.13 (mt: 1H); 7.23 (t

split, J = 9.5 and 5 Hz: 1H) ^' ; from 7.35 to 7.50 (mt: 1H); 7.38 (dd, J = 9 and 3 Hz: 1H); 7.48 (d, J = 3 Hz: 1H); 7.96 (d, J = 9.5 Hz: 1H); 8.70 (broad s: 1H). IR spectrum (KBr pellet): 2962; 2834; 1621; 1512; 1490; 1385; 1264; 1240 1145; 1033; 969; 825; 799 and 727 cm ^"1

The B-enantiomer of 1- [(E) -3- (2,5-difluoro-phenyl) - allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl)) acid ethylamino] - 3 -pyrrolidine carboxylic acid can be prepared as follows:

To a solution containing 0.229 g (0.458 mmol) of the methyl ester of the B enantiomer of acid 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [- 2- (3-fluoro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic in 25 cm ³ of dioxane are added, with stirring, 3.85 cm ³ (19.24 mmol) of a solution aqueous 5N sodium hydroxide, and the yellow solution thus obtained is brought to reflux and stirred for 18 hours at this temperature. The reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 21 cm of silica 20-45 μm at atmospheric pressure using as eluent a chloroform / methanol / 28% aqueous ammonia mixture (12/3/0 , 5 by volume). The fractions containing .1 'expected are combined and concentrated under pressure reduced to give 0.150 g of a pale yellow product which is taken up in 20 cm ³ of a dichloromethane / methanol mixture (9/1). The resulting solution is filtered on paper, the paper is washed with twice 10 cm ³ of a dichloromethane / methanol mixture (9/1), the filtrates are combined and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of isopropyl ether, then the resulting suspension is concentrated to dryness under reduced pressure to give 0.143 g of the expected enantiomer B in the form of a pale yellow amorphous solid.

[α] _D = -21.6 ° +/- 0.7 (c = 0.5 in methanol) MS spectrum: IC m / z ≈ 486 MH ⁺ basic peak 3-H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO with the addition of a few drops of CD ₃ C00D d4, δ in ppm): 2.02 (mt: 1H); 2.33 (mt: 1H); 2.65 (mt: 1H); 2.94 (d, J = 11 Hz: 1H); 3.00 to 3.20 (mt: 3H); 3.22 (d, J = 11 Hz: 1H); from 3.30 to 3.50 (mt: 4H); 3.93 (s: 3H); 6.41 (dt, J = 16 and 6 Hz: 1H); 6.67 (broad d, J = 16 Hz: 1H); ^'7.14 (mt: 1H); 7.23 (t split, J = 9.5 and 5 Hz: 1H); from 7.35 to 7.45 (mt: 1H);

7.38 (dd, J = 9 and 3 Hz: 1H); 7.44 (d, J = 3 Hz: 1H);

7.96 (d, J = 9.5 Hz: 1H); 8.70 (broad s: 1H).

IR spectrum (KBr pellet): 2928; 2835; 1621; 1510; 1490;

1384; 1264; 1239; 1146; 1032; 969; 825; 799 and 727 cm ^"1

The enantiomers A and B of the methyl ester of l -'- acid 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [-2- (3-fluoro-6 - 4-methoxy-quinolinyl) -ethylamino] -3 -pyrrolidine carboxylic acid can be prepared in the following manner:

To a solution containing 1.15 g (3.3 mmol) of 3- (RS) -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) -ethylamino acid methyl ester] -3 -pyrrolidine carboxylic acid in 90 cm ³ of anhydrous acetonitrile are added, with stirring and under an inert atmosphere: 2.3 g (16.5 mmol) of potassium carbonate, 0.603 g (3.63 mmol) of iodide potassium and, in 5 minutes, 30 cm ³ of a solution containing 1 g (3.8 mmol) of (2,5-difluoro-phenyl) -allyl chloride (prepared according to the method described in patent application WO 9307109) in anhydrous acetonitrile. The yellow suspension thus obtained is brought to reflux for 5 hours, then brought to a temperature in the region of 20 ° C. and stirred for 18 hours. The reaction medium is then filtered, the residue is rinsed with 3 times 30 cm ³ of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in 250 cm ³ of ethyl acetate, the organic phase is washed with water, dried over anhydrous magnesium sulfate, filtered on paper and concentrated under reduced pressure. The orange oil thus obtained is purified by chromatography on a column 3.5 cm in diameter containing 26 cm of silica 20-45 μm at atmospheric pressure using as eluent a mixture of ethyl acetate / methanol (90/10), then a dichloromethane / methanol mixture (95/5). The fractions containing the expected product are combined and concentrated under reduced pressure to give 0.427 g of the methyl ester of 3- (RS) - l - [(E) -3- (2,5-difluoro-phenyl) acid. -allyl] -3- [-2- (3-fluoro-6-methoxy-quinoline-4-yl) -ethylamino] -pyrrolidine-3-carboxylic acid in the form of a yellow viscous oil.

MS spectrum: IE m / z = 4'99 M ⁺ "; m / z = 440 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 346 (M - C ₉ H ₇ F ₂ ) ⁺ ; m / z = 279 (M - Cι ₂ Hι ₃ ON ₂ F) ⁺ '; m / z = 153 C ₉ H ₇ F ₂ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺ base peak 0H NMR spectrum (300 MHz , (CD ₃ ) ₂ SO, δ in ppm): 1.70 (mt: 1H); 2.20 (mt: 1H); 2.40 (mf: 1H); from 2.55 to 2.80 (mt : 4H); 3.03 (wide d, J = 10 Hz: 1H); from 3.10 to 3.20 (mt: 4H); 3.58 (s: 3H); 3.95 (s: 3H) ; 6.45 (dt, J = 16 and 6 Hz: 1H); 6.58 (wide d, J = 16 Hz: 1H); 7.13 (mt: 1H); 7.25 (split t, J = 9.5 and 5 Hz: 1H); 7.39 (dd, J = 9 and 3 Hz: 1H); 7.43 (d, J = 3 Hz: 1H); 7.50 (ddd, J = 9, 5 - 6 and 3 Hz: 1H); 7.96 (d, J = 9 Hz: 1H); 8.69 (broad s: 1H). IR spectrum (solution in CH ₂ C1 ₂ ): 2985; 2805; 1730; 1621; 1508; 1490; 1469; 1277; 1232; 1145; 1088; 1030; 972 and 834 cm ^"1

Are also recovered 0.294 g of ^'the methyl ester of 3- (RS) -1- [(E) -3- (2, 5-difluoro-phenyl) - allyl] -3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) -ethylamino] -. - 3-pyrrolidine carboxylic acid in the form of a yellow oil.

MS ^' spectrum: IE m / z = 499 M ^{+ "} ; m / z = 440 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 346 (M - C ₉ H ₇ F ₂ ) ⁺ ; m / z = 279 (M - C ^" ι ₂ Hι ₃ ON ₂ F) ⁺ -; m / z = 153 C ₉ H ₇ F ₂ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺ base peak

The latter product is ironed in its free base form by treatment of a solution in ethyl acetate containing it with an aqueous solution of sodium bicarbonate, decantation of the organic phase, drying over anhydrous magnesium sulfate and concentration under pressure. scaled down. The product thus obtained is mixed with the preceding fraction, then the two enantiomers are separated by chiral chromatography on the Chiracel OD 20 μm phase, eluting with a Heptane 95% iPrOH 5% TEA 0.5% mixture. Detection is carried out at 265 nm. Are thus obtained:

* 0.226 g of the A-enantiomer of the methyl ester of acid ^' 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [-2- (3- fluoro -6-methoxy-4-quinolinyl) -ethylamino] -3 -pyrrolidine carboxylic in the form of an amber gum

[α] _D = + 12.9 ° +/- 0.7 (c = 0.5 in methanol) MS spectrum: IE m / z = 499 M ⁺ "; m / z = 440 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 346 (M - C ₉ H ₇ F ₂ ) ⁺ ; m / z = 279 (M - d ₂ Hι ₃ ON ₂ F) ⁺ -; m / z = 153 C ₉ H ₇ F ₂ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺ base peak

^ -E NMR spectrum (300 MHz, (CD ₃ ) ₂ SO, δ in ppm): 1.70 (mt

: 1H); 2.20 (mt: 1H); 2.39 (d, J = 10 Hz: 1H); 2.48 (mt: 1H); 2.55 to 2.80 (mt: 4H); 3.03 (d, J = 10 Hz:

1H); 33,, 114 (d wide, ^' J = 6 Hz: 2H); 3.18 (wide t, J = 7.5

Hz: 2H) 3.59 (s: 3H); 3.97 (s: 3H); 6.45 (dt, J = 16 and 6 Hz: 1H); 6.59 (broad d, J = 16 Hz: 1H); 7.13 (mt:

1H); 77,, 225E (t split, J = 9.5 and 5 Hz: 1H); 7.39 (dd, J = 99 e e; tt 33 HHzz: 1H); 7.43 (d, J = 3 Hz: 1H); 7.50 (ddd, J =

9, 5 - 6 and 3 Hz: 1H); 7.96 (d, J = 9 Hz: 1H); 8.69

(large: 1H). IR spectrum (solution in CC1 ₄ ): 3077 ;. 3033; 2935; 2928; 2832; 2801; 1732 1622; 1507; 1490; 1469; 1431; 1263; 1232; 1217; 1140; 1034; 971; 909; 872 and 833 cm ^"1

^' * and 0.229 g of enantiomer B of the methyl ester of acid -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [-2- (3 - fluoro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic in the form of an amber gum [α] _D = - 5.2 ° +/- 0.7 (c = 0.5 in the methanol) MS spectrum: IE m / z = 499 M ⁺ "; m / z = 440 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 346 (M - C ₉ H ₇ F ₂ ) ⁺ ; m / z = 279 (M - Cι ₂ Hι ₃ ON ₂ F) ⁺ -; m / z = 153 C ₉ H ₇ F ₂ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺ base peak NMR spectrum ^ H (300 MHz ,. (CD ₃ ) ₂ SO, δ in ppm): 1.70 (mt: IH); 2.20 (mt: IH); 2.39 (d, J = 10 Hz: IH); 2.48 (t, J = 7.5 Hz: IH); from 2.55 to 2.80 (mt: 4H); 3.03 (d, J = 10 Hz: IH); 3.14 (d wide, J = 6 Hz: 2H); 3.18 (wide t, J = 7.5 Hz: 2H); 3.59 (s: 3H); 3.97 (s: 3H); 6, '45 (dt, J = 16 and 6 Hz: IH); 6.59 (wide d, J = 16 Hz: IH) 7, 13 (mt: IH); 7.25 (t split, J = 9.5 and 5 Hz: IH) / 7.39 (dd, J = 9 and 3 Hz: IH); 7.43 (d, J = 3 Hz: IH) / 7.40 (ddd, J = 9.5 - 6 and 3 Hz: 1H); 7.96 (d, J = 9 Hz; 1 H); 8.69 (broad s: 1H). IR spectrum (solution in CC1 ₄ ) ^' : 3077; 3033; 2935; 2928; 2831; 2800; 1733; 1622; 1507; 1490; 1469; 1431; 1263; 1232 ;. 1217; 1140; 1034; 971; 909; 873 and 833 cm ^"1

The methyl ester of 3- (RS) -3- [-2- (3-fluoro-6-methoxy-4 -quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid can be prepared in the following manner:

To a solution containing 1.8 g (4.114 mmol) of 3- (RS) -1-benzyl-3- [-2- (3-fluoro-6-methoxy-4 -quinolinyl) acid methyl ester - ethylamino] -3 -pyrrolidine carboxylic in 160 cm ³ of methanol are added, with stirring, 25 cm ³ of cyclohexene, then 1.8 g of palladium on carbon at 10%. The black suspension thus obtained is brought to reflux and stirred for one hour at this temperature, before being brought to a temperature close to 20 ° C. The reaction medium is. filtered on paper and the residue is washed with 5 times 30 cm ³ of methanol. The filtrate is concentrated under reduced pressure to give 1.15 g of the expected ester in the form of a yellow oil.

MS spectrum: IE m / z = 347 M ⁺ -; m / z = 305 (M - C ₂ H ₄ N) ⁺ '; m / z = 288 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 192 C _u HιιONF ⁺ base peak; m / z = 157 C ₇ Hι ₃ 0 ₂ N ₂ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺

The 3- (RS) -1-benzyl-3- [-2- (3-fluoro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid methyl ester can be prepared from as follows:

To a suspension containing 1.5 g (6.766 mmol) of (3-fluoro-6-methoxy-4 -quinolinyl) acetaldehyde in 70 cm ³ of anhydrous chloroform are added, with stirring and under an inert atmosphere (Argon) 2.08 g (6.766 mmol) of 3- (RS) -3-amino-3-pyrrolidine carboxylic acid methyl ester hydrochloride (acid prepared according to the method described by Mamoun et al. Synth Commun., 1995,

25 (9), 1295-1302) and, in 5 minutes, a solution containing 1.9 cm ³ (13.53 mmol) of triethylamine dissolved in 30 cm ³ of anhydrous chloroform. The suspension is stirred vigorously under an inert atmosphere at a temperature in the region of 20 ° C for 18 hours. The clear orange solution thus obtained is concentrated under reduced pressure to give a yellow residue which is taken up in 100 cm ³ of dichloro-1,2-ethane and stirred at a temperature close to 20 ° C. To the yellow suspension thus obtained 2.12 g (9.472 mmol) of sodium triacetoxyborohydride are added, followed by 0.547 cm ³ (9.472 mmol) of acetic acid. The suspension thus obtained is stirred at a temperature in the region of 20 ° C for 18 hours. The reaction medium is then diluted with 300 cm ³ of dichloromethane, the organic phase is washed with 5 times 150 ^' cm ³ of water, dried over anhydrous magnesium sulfate, filtered on paper and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica 70-200 μm at atmospheric pressure using as eluting an ethyl acetate / methanol mixture (95/5). The fractions containing the product are combined and concentrated under reduced pressure to give 1.8 g of the expected ester in the form of a yellow oil.

MS spectrum: IE m / z = 437 M ^{+ -} ; m / z = 378 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 346 (M - C ₇ H ₇ ) ⁺ ; m / z = 219 C ₁₃ Hι ₇ 0 ₂ N ⁺ -; m / z = 133 C ₉ H _U N; m / z = 91 C ₇ H ₇ ⁺ ; m / z = 42 C ₂ H ₄ N ⁺ base peak The (3-fluoro-6-methoxy-4-quinolinyl) acetaldehyde can be prepared as follows:

To a suspension containing 1.7 g (6.766 mmol) of 3- (3-fluroro-6-methoxy-4-quinolinyl) -propane-1,2-diol in 90 cm ³ - of tetrahydrofuran are added, with stirring, 90 cm ³ of distilled water then 7.3 g (33.83 mmol) of sodium periodate. The yellow suspension thus obtained is stirred for 90 minutes at a temperature in the region of 20 ° C. then diluted with 300 cm ³ of water. The aqueous phase is extracted with 3 times 200 cm ³ of ethyl acetate, the organic phases are combined, washed with 3 times 100 cm ³ of water. The emulsion thus created is taken up in 100 cm ³ of brine, decanted, and the organic phases are dried over anhydrous magnesium sulfate, filtered on paper and then concentrated to dryness under reduced pressure to give 1.5 g of the expected product, in the form a pale yellow solid used as is in the next step.

MS spectrum: IE m / z = 219 M ⁺ '; m / z = 191 (M - CO) ⁺ - base peak

3- (3-fluroro-6-methoxy-4-quinolinyl) -propane-1, 2 -diol can be prepared as follows:

To a solution containing 1.9 g (8.746 mmol) of 4-allyl-3-fluoro-6-methoxy quinoline in 75 cm ³ of acetone and 15 cm ³ of water are added, with stirring, 5.2 g ( 43.73 mmol) of N-methylmorpholine N-oxide and then 2 cm ³ of a 2% solution of osmium tetraoxide in alcohol -te-rt-butyl. The black solution is stirred overnight at a temperature close to of -20 ° C. The reaction medium is then cooled to a temperature in the region of 0 ° C., then treated with 30 cm ³ of an aqueous solution saturated with Na ₂ S0 ₃ .5H ₂ 0. The solution thus obtained is stirred 15 minutes at a temperature close to 0 ° C., then diluted with 150 cm ³ of ethyl acetate. The organic phase is decanted and the aqueous phase is extracted with 3 times 100 cm ³ of ethyl acetate. The organic phases are combined, washed with 3 times 50 cm ³ of water, then s _. dried over anhydrous magnesium sulfate, filtered on paper and concentrated to dryness under reduced pressure. The solid residue thus obtained is taken up in 50 cm ³ of ethyl acetate and stirred for 30 minutes at a temperature in the region of 20 ° C. The suspension thus obtained is filtered, the solid is washed with ethyl acetate, then with 1 isopropyl ether. The solid thus obtained is dried in a desiccator under vacuum for 2 hours to give 1.6 g of the expected product in the form of crystals of cream color, melting at 162 ° C.

MS spectrum: IE m / z = 251 M ⁺ "; m / z = 191 (M - C ₂ H ₄ 0 ₂ ) ⁺ - base peak; m / z = 61 C ₂ H ₅ 0 ₂ ⁺

4-allyl-3-fluoro-6-methoxy quinoline can be prepared as follows:

To a suspension containing 4.55 g (15 mmol) of 4-iodo-3-fluoro-6-methoxy quinoline (prepared according to the method described in patent application WO 0240474) in 150 cm ³ of DMF are added 7.2 cm ³ (22.5 mmol) of allyl -tributyltin, 0.88 g (0.75 mmol) of tetrakis (triphenylphosphine) palladium and 0.575 g (3 mmol) of iodine of copper (I). The suspension is stirred under an inert atmosphere (Argon) and at a temperature in the region of 60 ° C for 24 hours. The reaction medium is then brought to a temperature in the region of 20 ° C, diluted with 500 cm ³ of ethyl acetate and washed with 3 times 300 cm ³ of water. The emulsion which has formed is filtered through sintered glass No. 4, and the residue is washed with 3 times 100 cm ³ of water, then with 3 times 100 cm ³ of ethyl acetate. The organic phases are combined and dried over magnesium sulfate Anhydrous. The suspension is filtered on paper, and the solution is concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a silica column 20-45 μm at atmospheric pressure using a dichloromethane / ethyl acetate mixture (95/5 by volume) as eluent. The fractions containing the product are combined and ^" concentrated under reduced pressure. 1.9 g of expected product are obtained in the form of a yellow oil. MS spectrum: IC m / z = 218 MH ⁺ base peak

Example 2:

Acid sodium salt 3- (RS) -1- [(E) -3- (2, 5 ^ -difluorophenyl) -allyl] -3- [-2- (3 -chloro-6-methoxy -4-quinolinyl) - ethylamino] -3 -pyrrolidine carboxylic

To a solution containing 0.125 g (0.242 mmol) of the methyl ester of 3- (RS) acid -1- [(E) -3- (2, 5-difluoro-phenyl) - allyl] -3- [ -2- (3 -chloro-6-methoxy-4-quinolinyl) -ethylamino] - carboxylic pyrrolidine in 20 cm ³ of dioxane are added,

with stirring, 2.1 cm ³ (10.18 mmol) of an aqueous 5N sodium hydroxide solution, and the orange solution thus obtained is brought to reflux, and stirred for 18 hours at this temperature. The reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a column 2.5 cm in diameter containing 15 cm of 20-45 Dm silica at atmospheric pressure using as eluent a chloroform / methanol / 28% aqueous ammonia mixture (12/3 / 0.5). The fractions containing the expected are combined and concentrated under reduced pressure. 0.038 g of the expected sodium salt is obtained in the form of a pale yellow meringue Mass spectrum (IE): m / z = 501 M ⁺ '; m / z = 265 Cι ₄ Hι ₃ 0 ₂ NF ₂ ⁺ -; - m / z = 207 CιιHι ₀ ONCl ⁺ -; m / z = 153 C ₉ H ₇ F ₂ ⁺ (base peak); m / z = 42 C ₂ H ₄ N ^{+ 1} H NMR spectrum (300 -MHz, (CD ₃ ) ^' ₂ SO with the addition of a few drops of CD ₃ COOD d4, D eh ppm): 2.05 (mt: 1H); 2.35 (mt: 1H); 2.72 (mt: 1H); 3.00 (broad d, J = 10.5 Hz: 1 H); 3.00 to 3.20 and 3.30 to 3.65 (mts: 7H); 3.25 (broad d, J = 10.5 HZ: 1 H); 3.97 (s: 3H); 6.42 (dt, J = 16 and 7 Hz.: 1 H) -; 6.69 (broad d, J = 16 Hz: 1 H); from 7.05 to 7.30 (mt: 2H); from 7.35 to 7.45 (mt: 1H); 7.44 (broad dd, J = 9 and 3 Hz: 1 H); 7.50 (broad d, J = 3 Hz: 1 H); 7.97 (d, J = 9 Hz: 1 H); 8.68 (s: 1H). IR spectrum (KBr pellet): 3064; 2920; 2850; 2379; 1621; 1506; 1490; 1387; 1261; 1233; 1178; 1122; 1026; 971; 872; 825 and 727 _--- cm ^"1

3- (RS) -1- [(E) -3- (2,5-difluorophenyl) -allyl] -3- [-2- (3-chloro-6-methoxy) acid methyl ester -4-quinolinyl) - ethylamino] -3 -pyrrolidine carboxylic acid can be prepared as follows:

To a solution containing 0.240 g (0.66 mmol) of 3- (RS) -3- [-2- (3 -chloro-6-methoxy-4-quinolinyl) -ethylamino] -3 methyl acid ester -pyrrolidine carboxylic acid in 30 cm ³ of anhydrous acetonitrile are added, with stirring and under an inert atmosphere (Argon): 0.456 g (3.3 mmol) of potassium carbonate, 0.121 g (0.726 mmol) of potassium iodide and , in 5 minutes, 10 cm ³ of a solution containing 0.15 g (0.760 mmol) of (2,5-difluoro-phenyl) - - allyl chloride (prepared according to the method described in patent application WO 9307109) in anhydrous acetonitrile. The yellow suspension thus obtained is brought to reflux for 8 hours, then brought to a temperature in the region of 20 ° C. and stirred for 18 hours. The reaction medium is then filtered, the residue is rinsed with 3 times 15 cm ³ of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in 50 cm ³ of ethyl acetate, the organic phase is washed with 3 times 15 cm ³ of water, dried over anhydrous magnesium sulfate, filtered on paper and concentrated under reduced pressure. The orange oil thus obtained is. purified by chromatography on a column 2 cm in diameter containing 15 cm of silica. 20-45 μm at atmospheric pressure using as eluent an ethyl acetate / methanol mixture (95/5), then an ethyl acetate / methanol mixture (95/5). The fractions containing the product are combined and concentrated under reduced pressure. 0.147 g of expected product is obtained in the form of a yellow meringue.

IR spectrum (KBr pellet): 2953; 2651; 1731 1621; 1504; 1491; 1432; 1423; 1272; 1261; 1231; 1195; 1117; 1040; 1024; 973; 832 and 727 cm ^"1

The methyl ester of 3- (RS) -3- [-2- (3-chloro-6-methoxy-quinoline-4-yl) -ethylamino] -pyrolidine-3-carboxylic acid can be prepared in the following manner: next :

To a solution containing 1.03 g (2.044 mmol) of the methyl ester of l-vinyloxycarbonyl-3- {[2- (3-chloro-6-methoxy-4-quinolinyl) -ethyl] -vinyloxycarbonyl- amino} -3- carboxylic pyrolidine in 10 cm ³ of acetic acid under inert atmosphere and with stirring are added dropwise 1.1 cm ³ (6.132 mmol, 3 equivalents) of a 33% solution of hydrobromic acid in acetic acid in about 15 minutes and at a temperature in the region of 15 ° C. The orange solution thus obtained is stirred for 3 hours at a temperature in the region of 20 ° C. The reaction medium is then concentrated under reduced pressure, and the residue obtained East . taken up in 50 cm ³ of water, the pH of the solution is brought to a value close to 9 by an aqueous solution of NaHCO ₃ , and the aqueous phase thus obtained is extracted with 3 times 100 cm ³ of ethyl acetate . The organic phases are combined, washed with 3 times 30 cm ³ of water, dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica 20-45 μm at atmospheric pressure using as eluent dichloromethane / methanol (50/50). The fractions containing the product are combined and concentrated under reduced pressure. 0.240 g of expected ester is obtained in the form of an orange oil. Mass spectrum (CI): m / z = 364 MH ⁺ (base peak).

3- (RS) -1-vinyloxycarbonyl-3- {[2- (3-chloro-6-methoxy-4-quinolinyl) -ethyl] -vinyloxycarbonyl-amino} -3-pyrolidine carboxylic acid methyl ester can be prepared as follows:

To a solution containing 1.2 g (2.643 mmol) of methyl ester of 3- (RS) -1-benzyl-3- [-2- (3-chloro-6-methoxy-4-quinolinyl) acid - ethylamino] -3 -pyrrolidine carboxylic acid (prepared as below) in 100 cm ³ of dichloro-1,2,2-ethane under inert atmosphere and with stirring, are added 0.55 cm ³ (6.343 mmol, 2.2 equivalents) vinyloxycarbonyl chloride. The orange solution obtained is stirred for 1 hour at a temperature close to 20 ° C., then 3 hours at a temperature close to 100 ° C. The reaction medium is then concentrated under reduced pressure, and the residue thus obtained is purified by chromatography on silica 20-45 μm at atmospheric pressure using dichloromethane as eluent, then a dichloromethane / ethyl acetate mixture (95/5). The fractions containing the product are combined and concentrated under reduced pressure. 0.550 g of the expected ester is obtained, in the form of an orange oil.

Mass spectrum (CI): m / z = 504 MH ⁺ (base peak).

Example 3;

Acid 3- (RS) -1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [-2- (6-methoxy-4-quinolinyl) -ethylamino] -3 - carboxylic pyrrolidine

To a solution containing 0.44 g (0.914 mmol) of the 3- (RS) acid methyl ester -1- [(E) -3- (2, 5-difluoro-phenyl) - allyl] -3- [ -2- (6-methoxy-4 -quinolinyl) -ethylamino] -3- carboxylic pyrrolidine in 50 cm ³ of dioxane are added, with stirring, 7.7 cm ³ (38.39 mmol) of an aqueous sodium hydroxide solution 5N, and the orange solution thus obtained is brought at reflux, and stirred for 18 hours at this temperature. The reaction medium is then brought to a temperature in the region of 20 ° C., then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a column 2 cm in diameter containing 21 cm of 20-45 Dm silica at atmospheric pressure using as eluent a dichloromethane / methanol / 28% aqueous ammonia mixture (40/5/0, 5). The fractions containing the expected are combined and concentrated under reduced pressure to give 0.360 g of a pale yellow meringue which is taken up in 25 cm ³ of a dichloromethane / methanol mixture (9/1). The resulting solution is filtered, the filter is washed with a dichloromethane / methanol mixture (9/1), the filtrates are combined and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of isopropyl ether, stirred for 10 minutes, then the resulting suspension is concentrated to dryness under reduced pressure to give 0.330 g of the expected acid in the form of a pale yellow solid.

MS spectrum: IE m / z = 467 M ⁺ "; m / z = 282 (M - Cι ₂ HnON) ⁺ ; m / z

= 185 Cι ₂ HnON ⁺ - base peak; m / z = 42 C ₂ H ₄ N ⁺

NMR spectrum (300 MHz, (CD ₃ ) ₂ SO with the addition of a few drops of CD ₃ COOD, δ in ppm): 2.05 (mt: 1H); 2.34 (mt:

IH); 2.65 (mt: 1H); 2.95 (d, J = 11 Hz: 1 H); from 3.05 to 3.20 (mt: 3H); 3.25 (d, J ≈ 11 Hz: 1 H); from 3.30 to 3.50 (mt: 4H); 3.92 (s: 3H); 6.42 (dt, J = 16 and 6 Hz: 1 H);

6.67 (broad d, J = 16 Hz: 1 H); 7.13 (mt: 1H); 7.23 (t split, J = 9.5 and 5 Hz: 1 H); from 7.35 to 7.50 (mt: 4H);

7.95 (d, J = 9.5 Hz: 1 H); 8.66 (d, J = 4.5 Hz: 1 H). IR spectrum (KBr pellet): 2961; 2832; 1621; 1592; 1510;

1490; 1476; 1431; 1367; 1263; 1242; 1228; 1145; 10-82; 1030;

969; 847; 821 and 727 cm ^"1

3- (RS) -1- [(E) -3- (2,5-difluorophenyl) -allyl] -3- [-2- (6-methoxy-4-quinolinyl) acid methyl ester ) -ethylamino] -3- pyrrolidine carboxylic acid can be prepared as follows: To a solution containing 0.8 g (2.187 mmol) of the hydrochloride of the methyl ester of acid 3- (RS) -3- [-2- (6-methoxy-4-quinolinyl) -ethylamino] -3 - carboxylic pyrrolidine in 60 cm ³ of anhydrous acetonitrile are added, with stirring and under an inert atmosphere (Argon): 1.82 g (10.94 mmol) of potassium carbonate, 0.400 g (2.406 mmol) of potassium iodide and , in 5 minutes, 10 cm ³ of a solution containing 0.600 g (2.517 mmol) of (2,5-difluoro-phenyl) -allyl chloride (prepared according to the method described in patent application WO 9307109) in

1 anhydrous acetonitrile. The yellow suspension thus obtained is brought to reflux for 5 hours, then brought to a temperature in the region of 20 ° C. and stirred for 18 hours. The reaction medium is then filtered through sintered glass No. 4, the residue is rinsed with 3 times 30 cm ³ of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in 250 cm ³ of ethyl acetate, the organic phase is washed with 3 times 100 cm ³ of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The orange oil thus obtained is purified by chromatography on silica 70-200 μm at atmospheric pressure using as eluent a mixture of ethyl acetate / methanol (90/10), then a dichloromethane / methanol mixture (90/10). The fractions containing the expected product are combined and concentrated under reduced pressure. 0.460 g of the expected ester is obtained in the form of a yellow oil.

MS spectrum: ES m / z = 431 MH ⁺ base peak ¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO, δ in ppm): 1.27 (mt: 1H); 2.23 (mt: 1H); 2.46 (d, J = 10 Hz: 1 H); 2.50 _. 2.85 (mt: 5H); 3.05 (d, J = 10 Hz: 1 H); from 3.10 to 3.25 (mt: 4H); 3.60 (s: 3H); 3.95 (s: 3H); 6.47 (dt, J = 16 and 6 Hz: 1 H); 6.62 (broad d, J ^' = 16 Hz: 1 H); 7.14 (mt: 1H); 7.26 (t ^' split, J = 9.5 and 5 Hz: 1H); 7.35 (d, J = 4.5 Hz: 1 H); 7.40 (mt: 2H); 7.51 (ddd, J = 9, 5 - 6 and 3 Hz: 1 H); 7.94 (d, J = 9 Hz: 1 H); 8, 64 (d, J = 4.5 Hz: 1 H). IR spectrum (solution in CCl ₄ ): 3076; 3031; 2952; 2907; 2833; 2800; 1733; 1621; 1593; 1508; 1490; 1474; 1431; 1262; 1241; 1229; 1196; 1036; 971; 872 and 850 cm ^"1 The hydrochloride of 3- (RS) -3- [-2- (6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid methyl ester can be prepared from as follows:

To a solution containing 1.2 g (2.643 mmol) of methyl ester of 3- (RS) -1-benzyl-3- [-2- (3-chloro-6-methoxy-4-quinolinyl) acid - ethylamino] -3 -pyrrolidine carboxylic acid in 100 cm ³ of methanol are added, with stirring, 15 cm ³ of cyclohexene, then 1.2 g of palladium on carbon at 10%. The black suspension thus obtained is brought to reflux and stirred for one hour at this temperature, before being brought to a temperature in the region of 20 ° C. The reaction medium is filtered and the residue is washed with 5 times 20 cm ³ of methanol. The filtrate is concentrated under reduced pressure to give 0.8 g of the expected ester dihydrochloride in the form of a yellow oil.

MS spectrum: IE m / z = 329 M ⁺ -; m / z = 287 (M - C ₂ H ₄ N) ⁺ -; m / z = 270 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 173 CuH _u ON ⁺ - base peak; m / z = 42 C ₂ H ₄ N ⁺ ; m / z = 36 HC1 ⁺ -

The methyl ester of 3- (RS) -1-benzyl-3- [-2- (3-chloro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid can be prepared from as follows:

To a suspension containing 1.06 g (4.5 mmol) of (3-chloro-6-methoxy-4-quinolinyl) acetaldehyde in 45 cm ³ of anhydrous chloroform are added, with stirring and under an inert atmosphere (Argon) 1, 38 g (4.5 mmol) of hydrochloride of the methyl ester of 3- (RS) -3- amino-3-pyrrolidine carboxylic acid and, in 5 minutes, a solution containing 1.27 cm ³ (9 mmol) of triethylamine dissolved in 15 cm ³ of anhydrous chloroform. The suspension is stirred vigorously under an inert atmosphere at a temperature close to 20 ° C for 18 hours. The solution thus obtained is concentrated under reduced pressure to give a residue which is taken up in 60 cm ³ of dichloro-1, 2-dichloroethane and stirred at a temperature of 20 ° C. To the suspension thus obtained are added _1/4 g (6.3 mmol) of sodium triacetoxyborohydride, followed by 0.364 cm ³ (6.3 mmol) of acetic acid. The suspension thus obtained is stirred at a temperature in the region of 20 ° C for 18 hours. The reaction medium is then diluted with 250 cm ³ of dichloromethane, the organic phase is washed with 5 times 100 cm ³ of water, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica 70-200 μm at atmospheric pressure using as eluent a mixture of ethyl acetate / methanol (95/5). The fractions containing the product are combined and concentrated under reduced pressure. 1.2 g of the expected methyl ester are obtained in the form of a yellow oil.

MS spectrum: IE m / z = 453 M ⁺ "; m / z = 394 (M - C0 ₂ CH ₃ ) ⁺ ; m / z = 362 (M - C ₇ H ₇ ) ⁺ ; m / z = 219 Cι ₃ Hι ₇ 0 ₂ N ⁺ -; m / z = 133 C ₉ HnN ⁺ -; m / z = 91 C ₇ H ₇ ⁺ ; m / z ≈ 42 C ₂ H ₄ N ⁺ base peak

(3-Chloro-6-methoxy-4-quinolinyl) acetaldehyde can be prepared as follows:

To a suspension containing 1.2 g (4.55 mmol) of 3- (3-chloro-6-methoxy-4-quinolinyl) -propane-1,2-diol in 60 cm ³ of tetrahydrofuran are added, with stirring, 60 cm ³ of distilled water then 4.8 g (22.5 mmol) of sodium periodate. The yellow suspension thus obtained is stirred for 90 minutes at a temperature in the region of 20 ° C, then diluted with 280 cm ³ of water. The aqueous phase is extracted with 3 times 150 cm ³ of ethyl acetate, the organic phases are combined, washed with 3 times 100 cm ³ of water. The emulsion thus created is taken up in 1.00 cm ³ of brine, decanted, and the organic phases are dried over anhydrous magnesium sulphate, filtered on paper and then concentrated to dryness under pressure. reduced to give 1.1 g of the expected product in the form of a pale yellow solid used as it is in the next step.

MS spectrum: IE m / z = 235 M ⁺ -; m / z = 207 (M - CO) ⁺ "base peak

3- (3-chloro-6-methoxy-4-quinoline-4-yl) -propane-1, 2-diol can be prepared as follows:

To a solution, containing 1.85 g (7.916 mmol) of 4-allyl-3-chloro-6-methoxy quinoline in 75 cm ³ of acetone and 15 cm ³ of water are added, with stirring, 4.7 g (39> 58 mmol) of N-methylmorpholine N-oxide then 1.8 cm ³ of a 2% solution of osmium tetraoxide in tert-butyl alcohol. The black solution is stirred overnight at a temperature in the region of 20 ° C. The reaction medium is then cooled to a temperature in the region of 0 ° C, then treated with 30 cm ³ of an aqueous solution saturated with Νa ₂ S0 ₃ .5H ₂ 0. The solution thus obtained is stirred for 15 minutes at a temperature in the region of 0 ° C., then diluted with 150 cm ³ of ethyl acetate. The organic phase is decanted and the aqueous phase ^is extracted with 3 times 100 cm ³ of ethyl acetate. The organic phases are combined, washed with 3 times 50 cm ³ of water, then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The solid residue thus obtained is taken up in 50 cm ³ of ethyl acetate and stirred for 30 minutes at a temperature in the region of 20 ° C. The suspension thus obtained is filtered, the solid is washed with 3 times 10 cm ³ - d ethyl acetate, then with 3 times 10 cm ³ of isopropyl ether. The solid thus obtained is dried under reduced pressure for 2 hours. 1.2 g of expected product are obtained in the form of crystals, melting at 138 ° C.

MS spectrum: IE m / z = 267 M ⁺ '; m / z ≈ 207 (M - C ₂ H ₄ 0 ₂ ) ⁺ 'base peak; m / z = 61 C ₂ H ₅ 0 ₂ ⁺

4-allyl-3-chloro-6-methoxy quinoline can be prepared as follows: To a suspension containing 8.2 g (30 mmol) of 4-bromo-3-chloro-6-methoxy quinoline (prepared according to the method described in patent application WO 0240474) in 250 cm ³ of DMF are added 14, 14 4 cm ³ (45 mmol) of allyl-tributyltin, 1.75 g (1.5 mmol) of tetrakis (triphenylphosphine) alladium and 1.2 g (6 mmol) of copper iodide (I). The suspension is stirred under an inert atmosphere (Argon) and at a temperature in the region of 60 ° C for 48 hours. The reaction medium is then brought to a temperature in the region of 20 ° C, diluted with 500 cm ³ of ethyl acetate and washed with 3 times 300 cm ³ of water. The emulsion which has formed is filtered, and the residue is washed with 3 times 100 cm ³ of water, then with 3 times 100. cm ³ of ethyl acetate. The organic phases are combined and dried over anhydrous magnesium sulfate. It is filtered and concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a column 6 cm in diameter containing 30 cm of 40-63 μm silica at atmospheric pressure using dichloromethane as eluent. The ^fractions containing the product were x; éunies and obtained 1.85 g of the expected product as an oil.

MS spectrum: IC m / z = 234 MH ⁺ base peak

Claims

1) A derivative of quinoline-4-substituted, characterized in that it corresponds to the general formula

in which :

Xi, X ₂ , X ₃ , X ₄ and X ₅ represent respectively>C-R'ιto> C-R ' ₅ , or else one at most of them represents a nitrogen atom,

Ri, R'i, R ' ₂ , R' ₃ , R ' ₄ and R' ₅ are identical or different and represent a hydrogen or halogen atom or an alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or heteroarylthio radical mono or bicyclic, OH, SH, alkoyloxy, difluoromethoxy, trifluoromethoxy, alkoylthio, trifluoromethylthio, cycloalcoyloxy, cycloalcoylthio, acyl, acyloxy, acylthio, cyano, carboxy, alcoyloxycarbonyl, cycloalcaRobroNONa-carbonYroxy-carbonYroxy-carbonyl, or Rb may represent hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl or Ra and Rb together with the nitrogen atom to which they are linked form a 5 or 6-membered heterocycle which may optionally contain another heteroatom chosen from 0, S or N and carrying, where appropriate, a mono or bicyclic alkyl, phenyl or heteroaryl substituent on the nitrogen atom or, where appropriate, the sulfur atom of which is oxidized to the sulfinyl or sulfonyl state), or represents t a methylene radical substituted by fluoro, hydroxy, alkyloxy, alkylthio, cycloalkoyloxy, cycloalkoylthio, phenyl, mono or bicyclic heteroaryl, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb, for which Ra and Rb are, as heteroxy, carboxyloxy, heterocyclic, Ri can also represent difluoromethoxy, or a radical of structure -C _m F _{2m +} , -SC _m F _{2m +} ι or -0C _m F _{2m +} ι for which m is an integer from 1 to 6 or else R ' _s can also represent trifluoroacetyl,

m is equal to 0.1 or 2 -;

n is 0 or 1;

Y represents a group CHR, C = 0 or, when m is equal to 1 or 2, CROH, CRNH ₂ , CRF or CF ₂ , R being a hydrogen atom or an alkyl radical (Cι- ₆ );

R ₂ represents a radical R, -C0 ₂ R, -CH ₂ C0 ₂ R, -CH ₂ -CH ₂ C0 ₂ R, -CONH ₂ , -CH ₂ -CONH ₂ , -CH ₂ -CH ₂ -CONH ₂ , -CH ₂ OH, -CH ₂ -CH ₂ 0H, '-CH ₂ -NH ₂ -CH ₂ -CH ₂ -NH ₂ or -CH ₂ -CH ₂ -CH ₂ -NH ₂ , R being as defined above ;

R ₃ represents a phenyl, mono or bicyclic heteroaryl radical, alk-R ₃ for which alk is an alkylene radical and R ₃ represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkoylamino, cycloalkyloyl cycloalkyloyloxy , cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cycloalkyl) ₂ acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenyl-phenylnylcyl phenylsuifonyl N-phenyl amino, -N- (phenyl) ₂ , phenylalkyloxy, phenylalkoylthio, phenylalkylsuifinyl, phenylalkylsuifonyl, phenylalkylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl, mono-phenylalkyl, benzyl heteroarylthio, heteroarylsulfinyl, hétéroarylsuifonyle, heteroarylamino, N-alkyl N-heteroaryl amino, N-N-cycloalkyl amino heteroaryl, heteroarylcarbonyl, hétéroarylalcoyloxy, hétéroarylalcoylthio, hétéroarylalcoylsulfinyle, -hétéroarylalcoylsulfonyle, hétéroarylalcoylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N- heteroaryl aminoalkyl, (the heteroaryl parts mentioned above being mono or bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb represent respectively hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl, or l one of Ra or Rb represents hydroxy, alkyloxy, cycloalkyloxy, or Ra and Rb together with the nitrogen atom to which they are linked form a 5 or 6-membered heterocycle which may optionally contain another heteroatom chosen from O, S and N and carrying, where appropriate, a mono or bicyclic alkyl, phenyl or heteroaryl substituent on the ato me of nitrogen or, where appropriate, whose sulfur atom is oxidized in the sulfinyl or sulfonyl state, or else R ° ₃ represents -CR'b≈CR 'cR' a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl in which the heteroaryl part is mono- or bicyclic, phenoxyalkyl, phénylthioalcoyle, phenylsulfinylalcoyle, phenylsulfonyl-alkyl, phénylaminoalcoyle, N-alkyl N-phenyl aminoalkyl, heteroaryloxyalkyl, hétéroarylthioalcoyle, hétéroarylsulfinylalcoyle, hétéroarylsulfonylalcoyle, hétéroarylaminoalcoyle, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, (the heteroaryl parts mentioned above being mono- or bicyclic), phenylthio, phenylsulfinyl, phénylsuifonyle, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R ₃ represents a radical -C≡C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N- alkyl N-phenyl aminoalkyl, mono or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, (the parts heteroaryl mentioned above being mono or bicyclic), or else R ° ₃ represents a radical -CF ₂ -phenyl or -CF ₂ -heteroaryl mono or bicyclic, it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above above are optionally substituted on the cycle by 1 to 4 substituents chosen from halogen, hydroxy, alkyl, alkyloxy, alkyl-oxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxy, alkyoyloxycarbonyl, cyano, alkylRoya, are defined as above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl; R ₄ represents a radical R, -CHO, -COCH ₃ , -CH ₂ C0 ₂ H or -COCH ₂ NH ₂ ; it being understood that the alkyl and acyl radicals and portions contain (unless special mention) 1 to 10 carbon atoms, in straight or branched chain, and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or the mixtures of these forms, and / or, where appropriate, in syn or anti form or their mixtures, as well as their salts.

2) A derivative of general formula (I), as defined in claim 1, characterized in that:

Xi, X ₂ , X ₃ , X ₄ and X ₅ are as defined in claim

1, i / R'i / R ' ₂ / R' ₃ R 'R's, are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted by alkyloxy;

m is 1;

n is 1;

Y represents a CH ₂ , CHOH, CHF, CHNH ₂ or C = 0 radical; R ₂ is as defined in claim 1, and

R ₃ represents an alk-R ° ₃ radical for which alk is an alkyl radical and R ° ₃ represents alkyloxy, alkylthio, alkylamino, dialcoylamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N-alkyl amino, -N- cyclo ), phenoxy, phenylthio, phenylamino, N-alkyl N-phenyl amino, N-cycloalkyl N-phenyl amino, phenylalkoyloxy, phenylalkoylthio, phenylalkoylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl, amino-phenylalkyl, amino heteroarylthio, heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkoyloxy, heteroaryloyloyloyloyloyloyloylnoyloyloyloyloyloyloyloyloyl -before being mono or bicyclic), -NRaRb or -CO-NRaRb for which Ra and Rb are defined as in claim 1, or else R ° ₃ represents -CR'b = CR 'cR' a for which R'a represents phenyl, phenylalkyl, heteroaryl or • heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyll-phenyl aminoalkyl, mono-alkyl, heteroaryl, alkyl, alkyl, heteroaryl, alkyl or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen., alkyl or cycloalkyl, or else R ° ₃ represents a radical -C≡C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl , phénylthioalcoyle, N-alkyl N-phenyl aminoalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, hétéroarylthioalcoyle, hétéroarylaminoalcoyle, N-alkyl N-aminoalkyl heteroaryl, (the heteroaryl parts mentioned above being mono- or bicyclic), or alternatively R ° ₃ represents a radical -CF ₂ -phenyl or -CF ₂ -heteroaryl mono or bicyclic; R is as defined in claim 1; it being understood that the phenyl or benzyl radicals or portions, benzoyl or heteroaryl mentioned above may be optionally substituted as envisaged above, in their enantiomeric or diastereoisomeric forms or the mixtures of these forms., and / or, if appropriate, in syn or anti form or their mixtures, as well as their salts.

3) A derivative of general formula (I) as defined in claim 1, characterized in that:

Xi, X ₂ , X ₃ , X ₄ and X ₅ represent respectively>C-R'ιto> C-R ' ₅ ,

Ri, R'i, R ' ₂ r' 3, R 'and R' ₅ are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted by alkyloxy;

m is 1;

n is 1;

Y represents a CH ₂ , CHOH, CHF, CHNH ₂ or C = 0 radical;

R ₂ is as defined in claim 1;

R ₃ represents an alk-R ° ₃ radical for which alk is an alkylene radical and R ° ₃ represents cycloalkyloyloxy, cycloalkyloylthio, phenoxy, - phenylthio, phenylalkoyloxy, phenylalkoylthio, heteroaryl, oxy, heteroarylthio, heteroaryloylaryloxyaryloxyalkyloaryloxyaryloxy above being mono or bicyclic) or else R ° ₃ represents -CR'b = CR 'cR' a for which R'a represents phenyl, phenylthioalkyl, heteroaryl, heteroarylalkoyl, phenoxyalkyl, phenylthioalkyl, heteroaryloxyalkyl, heteroaryl-heteroaryl alkyl above being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or else R ° ₃ represents a -radical -C-≡C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenyl aminoalkyl, heteroaryl mono or bicyclic, heteroaryloyloyloyloyloyloxy , (the heteroaryl parts mentioned above being mono or bicyclic); R ₄ represents a radical R; it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above can be optionally substituted, as envisaged above, in its enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form syn or anti or their mixtures, as well as their salts.

4) Any one of the derivatives of general formula (I) according to claim 1, the names of which follow: • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] acid - 3- [2- (3- fluoro-6-methoxy-quinolin-4-yl) -ethylamino] - pyrrolidine-3 -carboxylic; • acid 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (6-methoxy-quinolin-4-yl) - ethylamino] -pyrrolidine-3- carboxylic; • 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (3-fluoro-6-methoxy-quinolin-4-yl) -ethylamino] -. methyl pyrrolidine-3-carboxylate; • 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (-6- methoxy-quinolin-4-yl) - ethylamino] -pyrrolidine-3-carboxylate methyl; • acid 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- chloro-6-methoxy-quinolin-4-yl) - ethylamino] - methyl pyrrolidine-3-carboxylate; • 1- [(E) -3- (2, 5-difluoro-phenyl) -allyl] -3- [2- (3- chloro-6-methoxy-quinolin-4-yl) - ethylamino] - pyrrolidine- Methyl 3-carboxylate; • 1- [(2E) -3- (2, 5-difluorophenyl) -2 -propenyl] -3- [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] methylamino] acid - 3-carboxylic pyrrolidine; • 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- acid [[2 - (3 - fluoro-6-methoxy-4 - quinolinyl) ethyl] formylamino] -3 -pyrrolidine. carboxylic; • 3- [(aminoacetyl) [2- (3-fluoro-6-methoxy-4- 5 quinolinyl) ethyl] amino] -1- [(2E) -3- (2,5- difluorophenyl) 2- propenyl] -3-pyrrolidine carboxylic; • 3- [(carboxymethyl) [2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -1- [(2E) -3- (2,5-

^'10 difluorophenyl) -2-propenyl] -3-pyrrolidine carboxylic acid; • N- [1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4-quinoline ethanamine;

15 • N- [1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- pyrrolidinyl] -N- [2- (3-fluoro-6-methoxy-4-quinolinyl) ) ethyl] -glycine; • N- [1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-f luoro- 6-methoxy-N-methyl -4 -

Quinolineethanamine; • 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -3- pyrrolidine methanol; • 1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- [[2- (3- 25 fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -3 - pyrrolidinecarboxamide; • N- [3- (aminomethyl) -1- [(2.Ξ) -3- (2, 5-difluorophenyl) -2- propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4- quinolineethanamine; 0 • a- [[[1- [(2E) -3- (2, 5-difluorophenyl) -2-propenyl] -3- pyrrolidinyl] amino] methyl] -3-fluoro-6-methoxy-4- quinoline methanol. in its enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in syn 5 or anti form or their mixture, as well as its salts.

5) Process for preparing the products of general formula (I) as defined in claim 1, characterized in that condensing the chain R ₃ defined in claim 1, on the substituted quinoline 4-derivative of general formula:

in which X _x , X ₂ , X ₃ , X, X5, Ri, R ₂ Y / m and n are defined in claim 1, R ₂ and R ₄ being protected when they carry a carboxy radical, then, if necessary where appropriate, eliminates the protecting group from the carboxy radical, and, where appropriate, separates the enantiomeric or diastereoisomeric forms and / or, where appropriate, the syn or anti forms and, where appropriate, transforms the product obtained into a salt.

6) Method according to claim 5, characterized in that the condensation of the chain R ₃ on heterocyclic nitrogen is carried out by the action of a derivative of general formula:

R ₃ -X (Ha)

wherein R ₃ is defined as in claim 1 and X represents a halogen atom, a methylsulfonyl radical, a trifluoromethylsulfonyl radical or p. toluenesulfonyl.

7) Method according to one of claims 5 and 6, characterized in that when R ₃ represents a radical

-alk-R ° ₃ for which alk is an alkyl radical and R ° ₃ represents a radical -C≡C-Rd in which Rd is as defined in claim 1, the reaction is carried out by condensation of a halide d alkyhyl HC≡C-alk-X for which alk is defined as above and X is a halogen atom, then substitution of the chain by an appropriate Rd radical. 8) A method according to one of claims 5 and 6-, characterized in that when R ₃ represents a radical -alk-R ₃ for which alk is an alkyl radical and R ₃ represents a phenoxy, phenylthio-, phenylamino radical, heteroaryloxy, heteroarylthio or heteroarylamino, the reaction is carried out by construction of the chain by first condensing a chain HO-alk-X for which X ^' is a halogen atom, then either by transforming the hydroxyalkyl chain obtained into a haloalkyl chain , methanesulfonylalkyl or p. toluenesulfonylalkyl and finally by causing an aromatic derivative of structure R ₃ H or R ₃ H _{2 to} act in basic medium, or by causing the aromatic derivative to act directly under dehydration conditions. 9) Process according to claim 5, characterized in that the derivatives of general formula (II) are prepared for which Y is a CH ₂ group and m is equal to 1 or 2 by condensation of a heteroaromatic derivative of general formula : 0 = CH

in which R _x , Xi, X ₂ , X ₃ , X and X ₅ are defined as in claim 1 and m is equal to 1 or 2, on a derivative of general formula:

in which P is a protective group, n and R ₂ are defined as in claim 1 and R ₂ represents a radical protected if R ₂ represents or carries an acid-carboxylic function, followed by the elimination of the protective groups and / or followed by the transformation, by subsequent operation, of the substituents of the aromatic bicycle of general formula (II) thus obtained, to lead to the derivative carrying the radical R _x , R'i, R'- ₂ , R ' ₃ , R' ₄ , R's expected, and if necessary, elimination of the protective radical (s) still present on the molecule. 10) The products of general formula (II):

in which X _lt X ₂ , X ₃ , X ₄ , X ₅ , R _lr R ₂ , m and n are defined as in claim 5.

11) The products of general formulas (XI), (XII), (XIII) and (XIV):

in which Xi, X ₂ , X ₃ , X, X ₅ and R _x are defined as in claim 1, Ri not being able to represent a hydrogen atom. 12) As medicaments, the derivatives of general formula (I) as defined in claim 1. -

13) As medicaments, the derivatives of general formula (I) as defined in any one of ^'claims 2 to 4.

14) Pharmaceutical composition characterized in that it contains at least one medicament according to claim 12, in the pure state or in combination with one or more diluents and / or adjuvants compatible and pharmaceutically acceptable.