CA2535020A1 - Substituted quinolines serving as antimicrobial agents - Google Patents

Abstract

The invention relates to substituted 4-quinoline derivatives of the general formula: (I) which are active as antimicrobials, wherein X1, X2, X3, X4 and X5 respectively represent> CR '1 to> C-R 5, or at most one is nitrogen, Y is CHR, CO, CROH, CRNH2, CRF or CF2, where R is 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 CH 2 -CH 2 -CH 2 -NH 2, R being as defined above; R 3 represents phenyl, heteroaryl or alk-R ~ 3, where alk is alkyl and R ~ 3 represents various groups, optionally oxygenated, sulfur-containing or amino, in their enantiomeric or diastereoisomeric forms or mixtures thereof, and / or where appropriate in syn or anti form or mixtures thereof, as well as their salts.

Description

QUINOLINE-4-SUBSTITUTED DERIVATIVES, PROCESSES THEREOF AND
PREPARATION INTERMEDIATES AND COMPOSITIONS
PHARMACEUTICALS CONTAINING THEM
The present invention relates to derivatives of 4-substituted quinoline compounds of the general formula X ~ NW X3.
4 ~~ 2 R ~
~ Y
(H2C ~
m N \ (I) (CH2) ~ R

which are active as antimicrobials. The invention relates to also their processes and intermediate preparation and the pharmaceutical compositions containing them.
In the patent applications WO 99/37635 and WO 00/43383 have quinolyl propyl piperidine derivatives have been described antimicrobials, of general formula.
AB- (CH2) ~ N-R4 AB- (CH2) ~ 'N-R4 ~ usz \ \ R R3 R ~~ z1 ~ ~ is R3 (R1) m 22 / NJ z ~~ zi N ~ z4 in which the radical R1 is in particular alkoxy (C1-6), R ~
is hydrogen, R3 is in position -2 or -3 and represents (C1-6) alkyl which may be optionally substituted with 1 to 3 substituents selected from thiol, halogen, alkylthio, trifluoromethyl, carboxy, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxy optionally substituted with alkyl, R4 is a group

2 -CH2-RS for which RS is. selected from alkyl hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, phenylalkenyl optionally substituted, optionally heteroarylalkyl substituted, optionally substituted heteroaroyl ..., n is 0 at 2, m is 1 or 2 and A and B are in particular oxygen, sulfur, sulfinyl, sulphonyl, NR11, CR6R ~ for which Rg and R ~
represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxy, amino, and Z1 to Z5 are N
or CRla. -.
Other applications, in particular WO 00/21952, WO 00/21948, WO 01/0743-2, WO 01/07433, WO 03/010138 or WO 02/40474 or WO 02/072572 disclose other 4-quinolyl derivatives propyl) piperidines, substituted in particular with 3 or disubstituted in 4, active in the same field. Requirement European Patent EP 30044 also describes derivatives related, active in the cardiovascular field.-It has now been found, and this is the subject of the present invention, that the compounds of general formula (I) in which.
Xl, Xz, X3, X4 and XS respectively represent> CR '1 to >C-R'S, or at most one of them represents an atom nitrogen, R 1, R '1, R' 2, R '3, R' 4 and R 'S are identical or different and represent a hydrogen or halogen atom or a radical alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or mono or cyclic heteroarylthio, OH, SH, alkyloxy, difluoro-romethoxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, acyl, acyloxy, acylthio, cyano, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, nitro, -NRaRb or -CONRaRb (for which Ra and Rb can represent hydrogen, alkyl, cycloalkyl, phenyl, mono or bicyclic heteroaryl or Ra and Rb together with the nitrogen atom to which they are attached a 5-membered heterocycle or 6 links that may possibly contain another heteroatom chosen from O, S or N and bearing as appropriate

3 an alkyl, phenyl or heteroaryl mono or to the nitrogen atom or, where appropriate, whose the sulfur atom is oxidized in the sulfinyl or sulphonyl state), or represent a methylene radical substituted with fluoro, hydroxy, alkyloxy, alkylthio, cycloalkyloxy;
cycloalkylthio, phenyl, mono or bicyclic heteroaryl, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb For which reason Ra and Rb are defined as previously, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or R1 can also represent difluoromethoxy, or a radical of structure -CmF2m + i. -SCmFzm + i or -OCmF2m + i for which m is an integer from 1 to 6 or R'S
can also represent trifluoroacetyl, m is 0.1 or 2 ';
n is 0 or 1;
Y represents a group CHR, C = O or, when m is equal to 1 or 2, CROH, CRNHz, CRF or CF2, where R is a hydrogen atom or a alkyl radical (C 1 -C 4);
Rz represents a radical R, -CO2R, -CH2COZR, -CHI-CH2CO2R, -CONH 2, -CHI-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 high ;
R3 represents a phenyl radical, mono heteroaryl or bicyclic, alk-R ° 3 for which ~ alk is an alkylene radical and R 3 represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulphinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cycloalkyl), acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino, -N- (phenyl) -,

4 phenylalkyloxy, phenylalkylthio, phenylalkylsulphinyl, phenylalkylsulfonyl, phenylalkylamino ,. N-alkyl N-phenyl aminoalkyl, N-cycloalkyl N-phenylalkylamino, benzoyl, mono or bicyclic heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylalkylsulfinyl, heteroarylalkylsulfonyl, heteroarylalkylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N-heteroaryl aminoalkyl, (the parts heteroaryl mentioned above being mono or bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb respectively represent hydrogen, alkyl, cycloalkyl, phenyl, heteroaryl mono or bicyclic, or one of Ra or Rb is hydroxy, alkyloxy, cycloalkyloxy, or Ra and Rb together with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle links which may optionally contain another heteroatom chosen from O, S and N and, where appropriate, a alkyl substituent, phenyl or mono heteroaryl or to the nitrogen atom or, where appropriate, whose The sulfur atom is oxidized in the sulfinyl or sulphonyl state, or else R ° 3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroarray or heteroarylalkyl, the heteroaryl part of which is mono or bicyclic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylsulphinylalkyl, heteroarylsulfonylalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, (the heteroaryl moieties cited above are mono or bicyclic), phenylthio, phenylsulphinyl, phenylsulfonyl, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R 3 represents a radical -C --- C-Rd for where Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenylaminoalkyl, mono or heteroaryl bicyclic, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl,

N-alkyl N-heteroaryl aminoalkyl, (the heteroaryl moieties cited above being mono-aromatic or cyclic), or R 3 is a -CF 2 -phenyl radical or -CF2-mono or cyclic heteroaryl, it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above are possibly substituted on the cycle by 1 to 4 substitutes selected from halogen, hydroxy, alkyl, alkyloxy, alkoxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxy, alkyloxy carbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are defined as above, phenyl, hydro ~ yalco ~ le, alkylthioalkyl, alkylsulfinylalkyl, alkylsulphonyl-alkyl; ' R4 represents a radical R, -CHO, -COCH3, -CHZCO2H or -COCHZNHZ;
it being understood that the radicals and alkyl or acyl portions contain (except special mention) 1 to 10 carbon atoms, in straight or branched chain, and that the radicals cycloalkyls contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, syn or anti or their mixture, as well as their salts, are very powerful anti-bacterial agents.
It is understood that when radicals represent or carry a halogen atom, the halogen is selected from fluorine, chlorine, bromine or iodine, and is preferably fluorine.
In the general formula above, when the radicals represent or carry a mono heteroaryl substituent or bicyclic, the latter contains 5 to 10 links and may be chosen (non-limiting) among thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, WO 2005/01691

6 PCT / FR2004 / 002090 oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuranyl indazolyl, benzothiazolyl, naphthyridinyl, quinolinyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, benzoxazolyl, benzimidazolyl possibly being substituted with the substituents mentioned above.
Among the compounds of general formula (I), it is possible in particular cite those in which X1, X2, X3, X4 and XS are as defined above, R1, R '1, R' 2, R '3, R' 4, and R 'S, are identical or different and represent a hydrogen or halogen atom or a alkyl or alkyloxy radical, or represent a radical methylene substituted with alkyloxy;
m is 1;
n is equal to;
Y represents a radical CHz, CHOH, CHF, CHNHz or C = O;
R2 is as previously defined, and R3 represents a radical alk-R ° 3 for which alk is a alkylene radical and R 3 represents alkyloxy, alkylthio, alkylamino, dialkylamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N-alkylamino, N- (cycloalkyl) 2, phenoxy, phenylthio, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino, phenylalkyloxy, phenylalkylthio, phenylalkylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl N-phenylalkyl amino, heteroaryloxy, heteroarylthio, heteroarylamino.
N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio ,. hétéroarylalcoylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl

7 N-heteroaryl aminoalkyl, (the heteroaryl moieties cited above being mono or bicyclic), -NRaRb or -C0-NRaRb for which Ra and Rb are defined as higher or R 3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, heteroaryl moieties mentioned above being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R 3 represents a -C --- C-Rd radical for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenylamino-alkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, ~
N-alkyl N-heteroaryl aminoalkyl, (the heteroaryl moieties quoted above being mono or bicyclic), or else R ° 3 represents a radical -CF2-phenyl or = CF2-heteroaryl mono or bic ~ rclique;
R4 is as defined previously;
it being understood that the phenyl radicals or portions, benzyl, benzoyl or heteroaryl mentioned above may be possibly substituted as envisaged above, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form of syn or anti-mixtures thereof, as well as their salts, and more especially those in which Xl, X ~, X3, X4 and Xs respectively represent> CR '1 to >C-R's, R 1, R '1, R' 2, R '3, R' 4, R 'are identical or different and represent a hydrogen or halogen atom or a radical alkyl or alkyloxy, or represent a methylene radical substituted with alkyloxy;

8 m is 1;
n is 1;
Y represents a radical CH2, CHOH, CHF, CHNH - or C = O;
R2 is as defined above, and R3 represents a radical alk-R ° 3 for which alk is a alkylene radical and R 3 represents cycloalkyloxy, cycloalkylthio, phenoxy, phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryloxy, heteroarylthio, heteroarylalkyloxy, heteroarylalkylthio, (the parts heteroaryls mentioned above being mono or bicyclic) or R3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroaryl, heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, heteroaryloxyalkyl, heteroarylthioalkyl (the heteroaryl moieties listed before being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R 3 represents a radical -C --- C-Rd for where Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenylamino alkyl, mono or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, (the parts heteroaryls mentioned above being mono or bicyclic);
R4 represents a radical R;
it being understood that the phenyl radicals or portions, ben ~ yl, benzoyl or heteroaryl mentioned above may be possibly substituted named as envisaged above, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form of syn or anti or mixtures thereof, as well as ~ .eurs salts.
Among the compounds of general formula (I), the invention is particularly concerned with any of those whose names follow.

9 1- [(E) -3- (2,5-Difluoro-phenyl) -allyl] -3- [2- (3-fluoro-6-methoxy-4-quinolinyl) ethylamino] -3 pyrrolidine carboxylic acid;
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-quinolinyl) ethylamino] -3 pyrrolidine carboxylate of methyl;
~ 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (-6-) Methoxy-4-quinolinyl) ethylamino-pyrrolidine methyl carboxylate 1- [(E) -3- (2,5-Difluoro-phenyl) -allyl] -3- [2- (3-chloro-6-methoxy-4-quinolinyl) ethylamino] -methyl pyrrolidine carboxylate;
1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3-chloro-6-methoxy-4-quinolinyl) ethylamino] -3-methyl pyrrolidine carboxylate;
in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form of syn or anti or their mixture, as well as their salts.
Among the compounds of general formula (I), again mention those whose names follow.
1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-[[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] methylamino] -3-pyrrolidine carboxylic acid;
1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-[[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] formylamino] -3-pyrrolidine carboxylic acid;
~ 3 - [(aminoacetyl) [2- (3-fluoro-6-methoxy) -4-quinolinyl) ethyl] amino] -1- [(2E) -3- (2,5-difluorophenyl) 2-propenyl] -3-pyrrolidinecarboxylic acid;
~ 3 - [(carboxymethyl) [2- (3-fluoro-6-methoxy) -4-quinolinyl) ethyl] amino] -1- [[2E] -3- (2,5-difluorophenyl)]

-2-propenyl] -3-pyrrolidinecarboxylic acid;
N- [1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4-quinoline Ethanamine;
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-fluoro-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-pyrrolidinemethanol; .
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-quinolinemethanol.
in their enantiomeric forms ~ s or diastereoisomers or the mixtures of these forms, and / or, where appropriate, in the form of or anti or their mixture, and their salts.
According to the invention, the products of general formula (I) can be obtained by condensation of the R3 chain on the 4-substituted quinoline derivative of general formula.
~ (CHz) m \ (CHz) ~
I Rz N
x R ~ ~~ \ X R4 H
3 5 ~ (II) Xz ~ X ~ NiXa wherein X1, Xz, X3, X4, X5, R1, Rz, Y, m and n are defined

11 -as before, Rz and R4 being protected when wearing a carboxy radical, followed, where appropriate, by the elimination of protecting group of the carboxy radical, possibly the separation of the enantiomeric or diastereoisomeric forms and / or where appropriate, syn or anti forms and possibly transformation of the product obtained into a salt.
Condensation of the R3 chain on heterocyclic nitrogen is advantageously carried out by the action of a derivative of formula general.
R3-X (IIa) in which R3 is defined as above and X represents a halogen atom, a methylsulfonyl radical, a radical trifluoromethylsulfonyl or p-toluenesulfonyl, by operating anhydrous, preferably inert, medium in a solvent organic compound such as an amide (dimethylformamide for example), a ketone (acetone for example) or a nitrile (acetonitrile for example) in the presence of a base such as a base organic nitrogen (eg triethylamine) or a base mineral (alkali carbonate, potassium carbonate by example) at a temperature of between 20 ° C and reflux temperature of the solvent. The nitrogen atom of the cycle pyrrolidine derivative of the general formula (II) is possibly 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 selected from benzyl, t.butoxycarbonyl and benzyloxycarbonyl, and this nitrogen atom is released prior to condensation with the derivative of formula (IIa), in particular by acid hydrolysis.
Preferably, a derivative of general formula is (IIa) for which X is a chlorine, bromine or diode.
Conditions under which the condensation between the derivatives of general formulas (II) and (IIa) are also described in the application WO 02/40474.
When R3 is a -alk-R3 radical in which R3 is a grouping -C = C-Rd, where Rd is as defined more

12 top, an alkynyl halide is intermediately condensed then the desired radical is condensed on the alkyne thus obtained.
When R3 represents a radical -alk-R ° 3 for which alk is an alkyl radical and R 3 represents a phenoxy radical, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino, one can also build the chain in condensing first a chain HO-alk-X for which X is a halogen atom, preferably iodine, under the conditions described above for the reaction of the formula product (IIa), and, where appropriate, by transforming the . ~ hydroxyalkyl chain into a haloalkyl chain, methanesulfonyla.lcoyl or p.toluenesulfonylalkyl and finally by acting in a basic medium an aromatic derivative of structure R ° 3H or R ° 3H2.
l5 Transformation of the hydroxyl chain into a chain haloalkyl or p-toluenesulfonyl is carried out according to usual methods of halogenation or sulphonylation, in particular, a halogenating agent is made to act as the thionyl chloride, halogenated phosphorus derivatives (for example, trichloride or phosphorus tribromide) or sulfonylating agent such as, for example, methanesulfonyl, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride. The reactiom is carried out in an organic solvent such as a chlorinated solvent (for example, dichloromethane or chloroform), temperature between 0 and 60 ° C. ~ In some cases it can be advantageous to operate in the presence of a base such as pyridine or triethylamine.
The reaction of the aromatic derivative R3H or R3H2 is carried out advantageously as previously described 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 nitrite (acetonitrile for example), in the presence of a base such as a nitrogenous organic base (for example triethylamine) or a mineral base (carbonate alkaline. potassium carbonate for example) at a temperature of . . between 20 ° C and the reflux temperature of reaction mixture. It may be advantageous to operate in

13 presence of potassium iodide. We can still operate in a ether (tetrahydrofuran, for example) under conditions of dehydration in the presence, for example, of diisopropyl-carbodiimide and triphenylphosphine.
It is understood that if the radicals R3 bear carboxy or amino substituents, these are previously protected, and then released after the reaction. We operates according to the well known methods of the business man which do not alter the rest of the molecule, especially according to the methods described by TW Greene and PGM Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wiley -Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).
The protected carboxy radical carried by R2 or R4 can be chosen among the easily hydrolysable esters. For exemple mention may be made of methyl, benzyl, tert-butyl esters, or phenylpropyl esters or allyl. Possibly the protection of the carboxy radical occurs simultaneously with the reaction.
If necessary, the protection of the amino radical is carried out at average of the usual protective radicals mentioned in references above.
The establishment and elimination of these protective radicals is carried out according to the methods known to those skilled in the art.
According to the invention, the derivatives of general formula (I) for which R ~ is hydroxymethyl or hydroxyethyl may be prepared by the action of an appropriate reducing agent on a derivative for which RZ is carboxy or carboxymethyl or carboxy protected or carboxy methyl ~ protected. A ketone function possibly present must then be intermediately protected.
Also according to the invention, the products of general formula (I) for which Ra is carboxymethyl or carboxyethyl can also be prepared from derivatives for which R2 is hydroxymethyl or hydroxyethyl, by on it of a halogenating agent or tosylation, then a cyanidation agent and finally a hydrolysis agent ~
nitrile.

14 Also according to the invent-ion, the products of formula (I) for which Rz is -CONH2, -CHz-CONHZ or -CH2-CH2-CONHZ can be prepared from the acids or corresponding esters by amidation by ammonia.
Also according to the invention, the products of formula (I) for which Rz is -CH2-NH2, - (CHZ) ~ 2-NHz or -(CH ~) 3-NHz can be prepared from amides corresponants by reduction.
The reduction of the protected carboxy can be carried out according to the usual methods that do not alter the rest of the molecule, in particular by the action of a hydride (hydride of aluminum and aluminum or aluminum diisobutyl hydride for example) in a solvent such as an ether (eg tetrahydrofuran) at a temperature of between 20 and 60 ° C. It protects intermediately then deprotège a ketone function possibly present according to conventional methods known to those skilled in the art, in particular via an acetal, cyclic or not.
The reduction of free carboxy can be carried out according to methods also known to those skilled in the art, by hydrogenation in the presence of a catalyst.
of rhodium or ruthenium by hydroboride sodium in the presence of Lewis acid or aluminum hydride and lithium in ether. Preferably, the ketone function is in this case also intermediately protected.
The transformation of the hydroxymethyl radical or hydroxyethyl in a carboxymethyl or carboxyethyl radical is carried out according to the usual methods that do not alter the rest of the molecule, especially by the action of an agent halogenation, for example thionyl chloride or phosphorus trichloride or phosphorus tribromate, or of a tosylation agent, then an alkaline cyanide, by example (potassium cyanide or sodium cyanide, for prepare the corresponding cyanomethyl derivative, followed by hydrolysis of nitrite.
Halogenation can be carried out in a solvent chlorine (eg dichloromethane or chloroform) at a temperature between 0 ° C and the reflux temperature of solvent..
The amidification reaction with ammonia is carried out under the usual conditions known to man of career. The procedure is preferably carried out starting from the acid, for Example in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine or hydroxybenzotriazole, within a ether, for example tetrahydrofuran, with a chlorinated solvent, for example dichloromethane, or dimethylformamide.
The reduction in amine is carried out, likewise, in Conventional conditions, for example by the action of a hydride such as lithium aluminum hydride within a ether.,. for example tetrahydrofuran, or by action of a borane in the presence of dimethylsulfide.
When R4 is a hydrogen atom, the condensation of

The R3 chain on the nitrogen of pyrrolidine or azetidine does not in principle require that the carrier nitrogen of R4 be protected given the steric hindrance around this nitrogen. Where appropriate, in exceptional cases where this might be necessary, a protective group classical amine functions such as those described in the work of TWGreene and PGM Wuts mentioned above can to be used.
According to the invention, the preparation of the products of general formula (II) for which Y is a CHI group and m is equal to 1 or 2, is carried out by condensation of a derivative heteroaromatic of general formula.
O = CH
3 0 (CHZ) m x ~ X
(III) XZ \ X / N ~ X4 wherein R1, X1, X2, X3, X4 and X5 are defined as previously and m is equal to 1 or 2, on a derivative of general formula.

WO 2005/0169

16 PCT / FR2004 / 002090 H
H- N (OHz) ~
Rz ~ N
\ P
(IV) in which P is a group -protector, n and Rz are defined as before and Rz represents a protected radical if RZ represents or carries a carboxylic acid function, followed by the elimination of protective groups and / or followed by the subsequent processing of the substituents of the aromatic bicycle of formula, general (II) thus obtained, to give the derivative carrying the radical R 1, R'1, R'2, R'3, R'4, R's expected, and if applicable elimination protective radical (s) still present on the molecule.
P can be any protecting group of the nitrogen atom compatible with the reaction (t-butyloxycarbonyl, benzyloxycarbo, nyl for example). Protective groups acidic functions are selected from groups the establishment and elimination of which do not affect not the rest of the molecule, especially those mentioned in references cited above.
The reaction can be carried out in the presence of an amino base such as triethylamine, in a halogenated solvent.
than chloroform or dichloroethane then a reductant such as sodium triacetoxyhydride in the presence of acid acetic acid, operating at room temperature.
In the case where m is equal to O, the preparation is carried out in similar conditions, using a derivative from the outset of general formula p \ C ~ H
w 3 5 ~ R ~ XW ~ X
(III ') Xz.X ~ NiXa

17 wherein R1, X1, X2, X3, X4 and XS are defined as previously.
According to the invention, the products of general formula (II) for Y is a CHR group, R being alkyl, be prepared from the corresponding compounds in Y is CH2 by the action of an alkyl halide, preferably an iodide. on the anion in has quinoline prepared by action of a strong base, for example a alkaline tertbutylate. Such reactions are known to the skilled person.
According to the invention, the preparation of formula products (II) for which Y is CHOH and m = 1 is carried out by condensation of a derivative of general formula O
x R ~~ '~ ~ X
(III ") Xa ~ X / NiX4 wherein R1, X1, X2, X3, X4 and X5 are defined as previously, on a derivative of general formula IV) such that previously defined. ' We can operate in the presence of lithium or sodium perchlorate in a solvent such as Methylformamide, hot.
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 solution of soda (for example soda 3N), at a temperature between -20 and 20 ° C, or by action of oxalyl chloride in the presence of dimethylsulfoxide, followed by the addition of an amine such as triethylamines, in an inert solvent such as dichloromethane, dimethylsulfoxide at a temperature of between -60 and 20 ° C by analogy with the method described by D. SWERN and coll., J. Org. Chem., 44, 4148 (1979).

1g 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 the general formula -OH
O ~ O
R ~~ X ~~ ~ X

~ (III ~~~) X2 ~ X ~ NiX4 wherein R1, X1, X2, X3, X4 and X5 are defined as previously.
For example, in the presence of dicyclohex-1-carbodiimide and 1-hydroxybenzotriazole.
Products of the general formula (II) in which Y is a CROH group, R being an alkyl, can be obtained at -departing products in which Y is a carbonyl group, by reaction of a suitable alkyl magnesium halide, under standard conditions known to those skilled in the art.
One operates for example by action of methyl chloride magnesium in an ether such as tetrahydrofuran.
Products of the general formula (II) in which Y is a 25 ~ CHR group, R being an alkyl, can still be obtained from the products in which Y is a C ~ ROH group, obtained as described above, by elimination of the alcohol via a xanthate. Alcohol is reacted with a strong base, for example sodium hydride, and then adds sulfur of carbon and then iodide of methyl. The xanthate thus obtained is then heated to presence of tributyltin hydride.
The derivative of general formula (II) for which Y is a CRNH2 group can be prepared from CROH derivative corresponding that is transformed into its tosyl derivative, on which is made to act ammonia. We operate in a solvent inert such as N, N-dimethylformamide or dimethylsulfoxide 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 the formula (II) for which Y is CROH, by action of chloride of tosyl in pyridin, at a temperature between -10 and 20 ° C.
The derivatives of general formula (II) for which Y is a CRF or CF2 group can be prepared by fluoridation respectively from the derivative for which Y is a group CROH and that for which Y is a carbonyl group. The reaction is carried out in the presence of a fluoride of sulfur [for example in the presence of a trifluoride Aminosulfur (diethylamino trifluoride sulfur (Tetrahedron, 44, 2875 (1988), bis trifluoride (2-methoxyethyl) amino sulfur (Deoxofluor), trifluoride morpholino sulfur for example) or alternatively in the presence sulfur tetrafluoride (J. Org Chem., 40, 3808 (1975)].
The fluorination reaction can still be carried out by means of a fluorinating agent such as hexafluoropropyl ethylamine (JP 2,039,546) or N- (2-chloro-1,1,2-trifluoro) ethyl) diethylamine.
It is carried out in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform) or in an ether (tetrahydrofuran, dioxane for example) to a temperature between -78 and 40 ° C (preferably between 0 and 30 ° C). It is advantageous to operate under an inert atmosphere Products of general formula (II) for which Y
represents a CHOH group and m = 1 or 2, can still be prepared by oxidation in a basic medium of the derivative corresponding for which Y is a group CH2. oxidation is carried out by the action of oxygen, preferably within an inert solvent such as dimethylsulfoxide in the presence tert-butanol and a base such as tert-butylate potassium or sodium at a temperature between 0 and and 100 ° C.
The above reactions intended to intervene at of Y on the product of formula (II) are conducted, where appropriate, after the protection of the reactive functions of the pyrrolidine or azetidine and the chain at R4.

The protective groups used are particularly those mentioned above.
Products of the general formula (III) in which m = 1 prepared from the product of formula.

z X.
R ~~ X
(V) Xa ~ / ~ Xa wherein R1, X1, X2, X3, X4 and X5 are defined as previously, that one makes act with allyltributyltin in presence of tetrakistriphenylphosphine palladium and iodide of copper in dimethylformamide at 60 °, to obtain the allyl product of formula.
x R ~~ y \ X
5, (VI) X2wX / N iXa that is oxidized by osmium tetroxide in the presence of N-methylmorpholine N-oxide in a water-acetone ambient temperature, to obtain the diol of formula.
H
3 0 ~ H
R ~ X
(VII) X2 ~ X3 that is oxidized by sodium periodate in a mixture tetrahydrofunan-water at room temperature.

The starting material of general formula (V) can be obtained ~ as described in the patent application WO 02.40474 The product of general formula (III) in which m = 2 can be prepared from a product of formula (VI) as defined above, which is subject to a reaction hydroboration by treatment with 9-borabicyclo [3,2,1] octane, suviye oxidation with oxygenated water, to obtain the product of general formula.
15 (VIII) X2 \
that is oxidized to the corresponding aldehyde of formula general.
H
x R ~
(IX) X2 \ X3 N
for example by the so-called Swern method mentioned above.
We can still use the method called Dess-Martin, of treating the alcohol under conditions given by periodinane (J.Org Chem 1983, p.48, 1.155-6).
The product of general formula (III ') can be obtained at departure of the product of general formula.
x ~ X
s (X) X2 ~ X ~ N / Xa wherein R1, Xr, Xz, X3, X4 and X5 are defined as previously, that one deals with a strong base, and then makes act on the anion thus obtained dimethylformamide. The base strong is preferably butyllithium, sec-butyllithium, or lithium diisopropylamide, and one operates in a solvent such as an ether, tetrahydrofuran for example, at a temperature between -7B ° and -40 °. The condensation of this derivative, which is lithiated on the DMF, is in the same solvent, 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 product of general formula (X) as defined above, which we prepare the anion in position 4 as before, that treated with acetaldehyde to obtain the alcohol of general formula HO ~ ~
2 0 RX ~ ~, ~ 5 (XI) Xa ~ X ~ N / Xa that is oxidized to the corresponding ketone of formula (XII) 2 5. O CH3 x 5 (XII) Xz ~ X ~ NeXa that is treated with bromine in the presence of sulfuric acid concentrated, to obtain the product of general formula O Br x ¿~ 1 ~ 1 X
5 (X111) XZ ~ X ~ NiXa that is subjected to the action of a reducing agent of ketone to obtain the product of formula of general formula HO
Br w R ~. X ~ ~ \ X
(XIV) X2 \ X / NsX4 s that one submits to the action of a base to obtain the product expected.
The reducing agent of the ketone may especially be hydride boron and is carried out for example in tetrahydrofuran.
The base used is, for example, a carbonate or a hydroxide alkali and operates, for example, in an alkanol.
The product of general formula (III "') can be obtained at starting of the product of general formula (X) as defined previously, whose anion is prepared in position 4, which is treated with an alkyl chloroformate, to obtain the ester of general formula O Oal x R ~~ 1 ~ \ X _ (XV) Xa ~ X / NiX4 that is saponified by a base under conditions.
classics.
Products corresponding to formula products (IV) as defined above, in which the reactive functions are free as well as some in which they are protected are described and, for some in cases where n = 0 or 1 and R2 = H, CH3, C2H5, COOH, COOCH 3, CH 2 CO 2 CH 3, CONH 2, CH 2 OH.

Among the references in the literature are the WO 9414794, WO 0170734, WO 9907696, EP 536035, EP
326916, EP 242789, JP 63130594 A2 and JP 62030776 A2, and that references Synlett (1991), 11, 783-4, Synthetic Comm.
(1995), 25 (9), 1295-1302.
The -products ~ of formia.le (IV ~) not described can in general ' be obtained by methods described in these references or, initially, the described products, by known methods of the skilled person.
According to the invention, products of general formula (I) for Which R 4 is hydrogen can be obtained as described above, from a product of general formula (II) for which R4 has the value corresponding, different from hydrogen, either from a product of general formula (I) for which R4 is hydrogen, by either of the methods described hereinafter.
According to the invention, the products of general formula (II) for which R4 is different from hydrogen can be obtained at starting of a product of general formula (II) for which R4 is hydrogen; by the same methods.
Where appropriate, and in particular for the preparation of the products of general formula (II), the implementation of these processes requires the intermediate protection of the functions reactive agents, especially amino and / or carboxy and / or hydroxy.
This, as well as deprotection, can be performed according to the methods described above.
Products for which R4 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 one can be for example sodium borohydride or sodium cyanoborohydride or triacetoxy sodium borohydride and can be operated in a solvent halogen classic or in a. alcohol. It can be advantageous to operate at slightly acidic pH, for example in the presence acetic acid.
Products for which R4 represents a radical CHO
can be obtained by the action of formic acid in the presence of acetic acid, or by the action of triethylorthoformate in the presence of paratoluene sulphonic acid and triethylamine, on the amine. We can operate in a solvent halogenated or in tetrahydrofuran or in the dimethylformamide. We can still perform the formylation 5 according to a Vilsmeyer type method.
The products for which R4 represents a COCH3 radical can be obtained by the action of an acetyl halide or of acetic anhydride on the amine. We operate in the presence of a base such as triethylamine.
The products for which R4 represents a CH2CO2H radical can be obtained by the action of bromoacetic acid on amine, operating under the same conditions as above, or by action of glyoxaldehyde on the amine then reduction by sodium cyanoborohydride operating in the same type of Solvents.
Products for which R4 represents a radical CO-CHZ-NH2 can be obtained by peptide coupling by action of the glycine on the amine, for example in the presence of dicyclohexylcarbodiimide, and after having protected the function Amine glycine, or by action on the amine of the same protected glycine, which is previously acid function, especially in chloride form, by action oxalyl chloride or thionyl chloride. We operate from preferably in a halogenated solvent or in the Tetrahydrofuran.
Intermediate products of general formula (II) for which reactive functions are free or protected obtained during the implementation of the process according to the invention are new and, as such, are part of the invitation.
Similarly, intermediate products of general formulas XI), (XII), (XIII) and (XIV) are also new, and title, are also part of the invention.
It is understood that the derivatives of general formula (I) and (II), may exist in enantiomeric forms or diastereoisomers or in syn or anti form, which are of course within the scope of the present invention.
These forms may be separated according to the methods usual, known to those skilled in the art, in particular by ~ chiral chromatography or by high liquid chromatography Performance (HPLC). This is illustrated ci ~ -after in the part EXPERIMENTAL.
The derivatives of general formula (I) can be purified where appropriate by physical methods such as crystallization or chromatography.
The derivatives of general formula (I) may be the case optionally converted to additone salts with the acids or with bases, by known methods. It is understood that these salts with acids or bases are also included in of the present invention.
Examples of addition salts with acids pharmaceutically acceptable salts may be cited formed with mineral acids (eg hydrochlorides, hydrobromides, sulphates, nitrates or 'phosphates' or with organic acids (eg succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates) or with derivatives substitution of these acids.
Derivatives of general formula (I) carrying a radical carboxy can be converted to metal salts or addition salts with nitrogenous bases according to the methods known per se. Salts can be obtained by action metal base (for example alkaline or alkaline earthy), ammonia or an amine, on a product the invention, in a suitable solvent such as an alcohol, a ether or water, or by exchange reaction with a salt of a organic acid. The salt formed pre-irritates after concentration eventual solution, it is separated by filtration, decantation or lyophilization. Examples of salts pharmaceutically acceptable can be cited salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (magnesium, calcium), ammonium salt, nitrogenous base salts (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl- (3-phenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benzydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).
5 ~ The derivatives of general formula (I) according to the invention are particularly active antibacterial agents.
The following study demonstrates this.
a) In vitro activity The method of dilutïons in agar medium in agreement with NCCLS recommendations are used for the determination minimum inhibitory concentrations (MIC) expressed in ~ .g / ml.
The activities of the compounds of Examples 1 to 4 are grouped in the following table.
Grain-positive MIC ~, g / ml 24 hours S. aureus TP8203 sensitive 0.06 - 4 S. aureus AS 5155 0.06 - 4 methicillin resistant S. pneumoniae 6254-Ol 0.012 - 2 MLSB resistant E. faecalis ATCC29212 0.5 - 4 vancomycin resistant Grain-negative CMI ~, g / ml 48 hours M. catarrhales IPA151 sensitive 0.25 - 4 H. influenzae 87169 sensitive 4 - 32 In vitro, the compounds of the invention have therefore been shown quite noteworthy on both positive grain germs only on negative germs.
b) The products according to the invention are particularly interesting because of their low toxicity. None of The products did not demonstrate toxicity at a dose of 50 mg / kg subcutaneously or by oral route in mice (2 administrations / day).
These properties make these products suitable, as well as that their salts of acids and bases pharmaceutically acceptable, to be used as medicinal products in the treatment of diseases caused by susceptible germs caused by gram-positive bacteria and especially those with staphylococci, such as staphylococcal septicemia, malignant staphylococcal disease of the face or cutaneous, pyoderma, septic or festering wounds, anthrax, phlegmons, erysipelas, acute primitive staphylococci or post influenza, bronchopneumonia, pulmonary suppuration, as well as those with streptococci or enterococci.
These products can also be used as medicines in the treatment of respiratory infections high and low caused by gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhales.
The present invention therefore also aims, at as medicinal products, and in particular medicinal products intended treatment of bacterial infections in humans or the animal, the compounds of general formula (I) such that defined above and their pharmaceutically acceptable salts acceptable, and especially the preferred compounds mentioned upper.
The present invention also relates to pharmaceutical compositions containing at least one derivative of quinoline-4-substituted according to the invention, if appropriate 25. In salt form, in pure form or in the form of a combination with one or more diluents or adjuvants compatible and pharmaceutically acceptable.
The compositions according to the invention can be used orally, parenterally, topically, rectally or in combination with aerosols.
As solid compositions for oral administration can be used tablets, pills, capsules, ~ powders or granules. In these compositions, the active product according to the invention is mixed with one or several inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions may include substances other than thinner, for example a lubricant such as magnesium stearate or a coating intended for controlled release.
As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions acceptable, 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 for example wetting, sweetening or flavoring products.
The compositions for parenteral administration, can be sterile solutions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, organic esters injectables, for example ethyl oleate. These compositions may also contain adjuvants, particularly wetting agents, isotonizing agents, emulsifiers, dispersants and stabilizers.
Sterilization can be done in many ways, for example using a bacteriological filter, by irradiation or by heating. They can also be prepared under form of sterile solid compositions that can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Compositions for topical administration may for example creams, ointments, lotions or aerosols.
The compositions for rectal administration are the suppositories or rectal capsules, which contain additionally the active ingredient, excipients such as butter cocoa, semi-synthetic glycerides or polyethylene glycols.
The compositions may also be aerosols.
For use in the form of liquid aerosols, the compositions can be stable sterile solutions or .35 solid compositions dissolved at the time of use in sterile pyrogen-free water, in serum or any other vehicle pharmaceutically acceptable. For use in form dry aerosols intended to be directly inhaled, the active ingredient is finely divided and associated with an effluent or water-soluble solid vehicle with a particle size of 30 to 80 , um, for example dextran, mannitol or lactose.
In human therapy, the new derivatives of Quinoline-4-substituted according to the invention are particularly useful in the treatment of infections of bacterial origin. Doses depend on the effect sought and duration of treatment. Doctor determine the dosage he considers most appropriate in 10 the function of the treatment, according to age, weight, degree of infection and other factors specific to the subject treat. Generally, the doses are between 750 mg and 3 g of active product in 2 or 3 doses per day oral route or between 4'00 mg and 1.2 g intravenously 15 for an adult.
The following examples illustrate compositions according to 'The invention.
a) Preparing according to the usual technique a liquid composition for parenteral use Including 20 ~ -1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3-fluorophenyl) -1-6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic .._._._._._._._._._._._._._._._._._._._._._._._._ ._._._._._._._._._ .. 1 g ~
Glucose................................................. ............ ..........
................................. qs 2, 5 0 25 ~ hydroxide .de sodium:.............................................:.. .......................
qsp pH = 4-4, 5 ~ water ppi ................................................. ...........................
................................ qs 2 0 ml (b) The usual technique is to prepare liquid composition for parenteral use Comprising ~ -1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid;
~ a glucbse .._._._._._._._._._._._._._._._._._._._._._._._ .. .._._._._._._._._._._._ ._._._ .. qsp 5 0 ~ sodium hydroxide ._._._._._._._._._._._._._._._._._._._ ._...._._ ..
qsp pH = 4 -4.5 ~ water ppi .._._._._._._._._._._._._._._._._._._._._._._._._ ._._._._._._._._._._._._._.
_ .. qsp 50 ml 31 _ The following examples illustrate the invention.
Example 1 Enantiomers A and B of 1 - [. (E) -3- (2,5-difluoro-phenyl) -A11 ~ 1] -3 - [- 2- (3-fluoro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid.
The enantiomer A of 1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3 - [- 2- (3-fluoro-6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid can be prepared in the next .
To a solution containing 0.226 g (0.452 mmol) of the ester of the enantiomer A of 1 - [(E) -3- (2,5-difluoro-phériyl) -allyl] -3 - [- 2- (3-fluoro-6-methoxy-quinoline 4-yl) -ethylamino] -pyrrolidine-3-carboxylic acid in 25 cm3 of of the oxane are added, with stirring, 3.80 cm3 (19.00 mmol) aqueous solution of 5N sodium hydroxide, and the yellow solution thus obtained is refluxed and agitated for 18 hours at this temperature. The reaction medium is then reduced to a temperature close to 20 ° C, then concentrated to dry under reduced pressure. The residue thus obtained is purified by chromatography on a 2 cm diameter column containing 15 cm of silica 20-45 ~, m at atmospheric pressure in using as eluent a chloroform / methanol /
aqueous ammonia at 28% (12/3 / 0.5 by volume). Fractions containing the expected are combined and concentrated under pressure reduced to give 0.150 g of a pale yellow product that is taken up in 20 cm3 of a dichloromethane / methanol mixture (9/1). The resulting solution is filtered on paper, the paper is washed twice with 10 cm3 of a mixture dichloromethane / methanol (9/1), the filtrates are combined then concentrated to dryness under reduced pressure. The residue is taken up 50 cm3 of isopropyl ether and then the suspension resulting is concentrated to dryness under reduced pressure for.

give 0.138 g of the expected enantiomer A, in the form of a pale yellow amorphous solid.
[a] D = + 25.5 ° +/- 0.7 (c = 0.5 in methanol) MS spectrum: IC m / z = 486 MH + base peak 1H NMR spectrum (3'00 MHz, ~ (CD3) zSO, 8 in .ppm). 1, 82 (mt . 1H); 2.24 (mt, 1H); 2.40 (mt 1H); 2.73 (d, J = 11 Hz. 1H); from 2.75 to 3.05 (mt.4H); from 3.05 to 3.40 (mt.
4H); 3, 96 (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 doubled, J = 9.5 and 5 Hz. 1H); 7.35 to 7.50 (mt 1H);
7.38 (dd, J = 9 and 3 Hz. 1H); 7.48 (d, J = 3Hz. 1H);
7.96 (d, J = 9.5 Hz. 1H); 8.70 (s, 1H).
IR spectrum (KBr pellet). 2962; 2834; 1621; 1512; 1490;
1385; 1264; 1240 1145; 1033; 969; 825; 799 and 727 crril The enantiomer B of 1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3 - [- 2- (3-fluoro-6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid can be prepared in the manner next .
To a solution containing 0.229 g (0.458 mmol) of the ester of the enantiomer B of the acid 1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3 - [- 2- (3-fluoro-6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in cm 3 of dioxane are added, with stirring, 3.85 cm 3 (19.24 mmol) of a 5N aqueous sodium hydroxide solution, and the solution yellow thus obtained is brought to reflux, and stirred 18 hours at this temperature. The reaction medium is then reduced to a temperature close to 20 ° C, then concentrated to dry under reduced pressure. The residue thus obtained is purified by chromatography on a column of 2 ~ cm diameter containing 21 cm of silica 20-45 ~, m at atmospheric pressure in using as eluent a chloroform / methanol /
aqueous ammonia at 28 ~ (12/3 / 0..5 by volume). Fractions container. the expected are gathered and concentrated under pressure reduced to give 0.150 g of a pale yellow product that is taken up in 20 cm3 of a dichloromethane / methanol mixture (9/1). The resulting solution is filtered on paper, the paper is washed twice with 10 cm3 of a mixture dichloromethane / methanol (9/1), the filtrates are combined then concentrated to dryness under reduced pressure. The residue is taken up 50 cm3 of isopropyl ether and then the suspension resulting 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.
[a] D = -21.6 +/- 0.7 (c = 0.5 in methanol) MS spectrum: IC m / z = 486 MH + base peak - 1H NMR spectrum (300 MHz, (CD3) ~ SO with some additional drops of CD3COOD d4, b in ppm). 2.02 (mt 1H) 2.33 (mt.
. ;

1H); 2.65 (mt, 1H); 2.94 (d, J = 11 Hz 1H) of 3.00 . ;

3.20 (mt 3H); 3.22 (d, J = 11 Hz. 1H) from 0 ~ 3.50 ; 3.3 (mt 4H); 3.93 (3H),; 6.41 (dt, J = and Hz. 1H) 6, 67 (broad d, 1H) 7, 23 (t J = 16 Hz. 1H);
; ~ 7, 14 (mt.

ddoubl, J = 9.5 and 5 Hz. 1H); 7.35 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 (s wide 1H).
.

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

1384; 1264; 1239; 1146; 1032; 969; 825; 799 and cnil The enantiomers A and B of the methyl ester of 1 -'-acid 1- [(E) -3- (2,5-Difluoro-phenyl) -allyl] -3- [-2- (3-fluoro) -6-Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid can be prepared in the following manner.
To a solution containing 1.15 g (3.3 mmol) of ester 3- (RS) -3 - [- 2- (3-fluoro-6-methoxy-4-) methylmethylate quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in 90 cm3 of anhydrous acetonitrile are added, with stirring and under an inert atmosphere. 2.3 g (16.5 mmol) of carbonate of potassium, 0.603 g (3.63 mmol) of potassium iodide and, in 5 minutes, 30 cm3 of a solution containing 1 g (3.8 mmol) of (2,5-difluoro-phenyl) -allyl chloride (prepared according to method described in patent application WO 9307109) in anhydrous acetonitrile. The yellow suspension thus obtained is refluxed for 5 hours, then brought back to a temperature around 20 ° C and stirred 18 hours. The environment The reaction mixture is then filtered and the residue is rinsed 3 times.
30 cm3 of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is recovered.
cm 3 of ethyl acetate, the organic phase is washed with water, dried over anhydrous magnesium sulphate, filtered on paper and concentrated under reduced pressure. The orange oil as well obtained is purified by chromatography on a column of 3.5 cm in diameter containing 26 cm of silica 20-45 ~, m to atmospheric pressure using as eluent a mixture ethyl acetate / methanol (90/10), then a mixture dichloromethane / methanol (95/5). Containing fractions the expected are gathered and concentrated under reduced pressure to give 0.427 g of the methyl ester of 3- (RS) -1- [(E) -3- (2,5-Difluoro-phenyl) -allyl] -3- [-2- (3-fluoro) -6-methoxy-quinolin-4-yl) -ethylamino] -pyrrolidine-3 ~ -carboxylic acid as a viscous yellow oil.
MS spectrum. IE m / z = 499 M + '; m / z = 440 (M-CO 2 CH 3) +; m / z =
346 (M-C9H ~ F ~) +; m / z = 279 (M-C 12 H 30 O 2 F) + ': m / z = 153 C9H ~ F ~ +; m / z = 42 C2H4N + base peak 1 H NMR spectrum (300 MHz, (CD3) 250, b in ppm). 1, 70 (mt . 1H); 2.20 (mt, 1H); 2.40 (m, 1H); from 2.55 to 2.80 (mt 4H); 3.03 (broad d, J - 10 Hz. 1H); from 3, 10 to 3, 20 (mt 4H); 3. 58 (3H); 3.95 (3H); 6, 45 (dt, J = 16) and 6 Hz. 1H); 6.58 (broad d, J - 16 Hz. 1H); 7.13 (mt.
1H); 7.25 (t split, 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 (wide 1H).
IR spectrum (solution in CH2Cl2). 2985; 2805; 1730; 1621;
1508; 1490; 1469; 1277; 1232; 1145; 1088; 1030; 972 and 834 cm 1 0.294 g of ester hydrochloride are also recovered.
3- (RS) -1- [(E) -3- (2,5-difluoro-phenyl) methyl) allyl] -3- [2- (3-fluoro-6-methoxy-4-quinolinyl) ethylamino] -.
3-pyrrolidine carboxylic acid as a yellow oil.
MS spectrum. IE m / z - 499 M + '; m / z = 440 (M-CO 2 CH 3) +; m / z = 346 (M-C9H-F2) +; m / z = 279 (M-Cl2H130N2F) + '; m / z = 153 C9H-F2 +;
m / z = 42 C2H4N + base peak This last product is ironed in its free base form by treatment of a solution in ethyl acetate on 10 containing an aqueous solution of sodium bicarbonate, decantation of the organic phase, drying over anhydrous magnesium and concentration under reduced pressure. The product thus obtained is mixed with the preceding fraction, then the two enantiomers are separated by chromatography Chiracel phase chiral OD 20 ~ m eluting with a mixture Heptane 95% iPrOH 5% TEA 0.5%. Detection is carried out at 265 nm. Are thus obtained.
0.226 g of the enantiomer A of the methyl ester of 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 an amber gum [a] D = + 12.9 +/- 0.7 (c = 0.5 in methanol) MS spectrum. IE m / z = 499 M + '; m / z = 440 (M-CO 2 CH 3) +; m / z =

346 (M-C9H-Fz) +; m / z = 279 (M C1 + H130NaF) + '; m / z = 153 -CgH ~ F2 +; m / z = 42 CZH4N + peak of based 1H NMR Spectrum (300 MHz, (CD3) ~ SO, 8 ppm). 1, 70 (mt 1H); 2.20 (mt, 1H); 2.39 (d, J = 10 Hz, 1H); 2.48 (Mt 1H); 2.252 (mt.4H); 3, 03 (d, J = 10 Hz 1H); 3, 14 (broad, J = 6 Hz 2H); 3, 18 (t wide, J =
. 7, 5 Hz. 2H); 3.59 (3H); 3.97 (3H); 6.45 (dt, J = 16) and 6 Hz. 1H); 6.59 (broad d, J - 16 Hz. 1H); 7.13 (mt) .

1H); 7.25 (tddoubl, 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, (d, J - 9 Hz, 1H); 8, 69 (wide 1H).

IR spectrum (solution in CC14). 3077 ;. 3033; 2935; 2928;
2832; 2801; 1732 1622; 1507; 1490; 1469; 1431; 1263; 1232;
1217; 1140; 1034; 971; 909; 872 and 833 crnl 5 '* and 0.229 g of the enantiomer B of the methyl ester of -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 an amber gum [a,] D = -5, 2 ° +/- 0.7 (c = 0.5 in methanol) MS spectrum. IE m / z = 499 M + '; m / z = 440 (M-CO 2 CH 3) +; m / z -346 (M-C9H-Fz); m / z - 279 (M +/- C14H13N0F) + '; m / z C9H ~ Fz +; m / z = 42 CZH4N + base peak 1H NMR Spectrum (300 MHz, (CD3) zSO 8 in ppm). 1, 70 (mt . 1H); 2.20 (mt 1H); 2.39 J = 10 Hz. 1H); 2.48 (t, (D, J = 7.5 Hz. 1H); 2.55 2.80 (mt.4H); 3.03 (d, J =

Hz. 1H); 3, 14 (d wide, J = 6 Hz . 2H); 3, 18 (t wide, J

- 7.5 Hz. 2H); 3.59 (3H); 3.97 (3H); 6.45 (dt, J = 16 and 6 Hz. 1H); 6, 59 (d wide, J = 16 Hz. 1H); 7, 13 (mt 1H); 7.25, (tddoubl, 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 3Hz. 1H); 7, 96 (d, J = 9 Hz. 1H) ;

8.69 (bs, 1H).

IR spectrum (solution in CC14) ~. 3077; 3033; 2935; 2928;

2831; 2800; 1733; 1622; 1507; 1490; 1469; 1431; 1263; 1232 ;, 1217; 1140; 1034; 971; 909; 873 and 833 cm -1 3- (RS) -3 - [- 2- (3-fluoro-6) methyl ester Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid can be prepared as follows.
To a solution containing 1.8 g (4.114 mmol) of ester 3- (RS) -1-benzyl-3 - [- 2- (3-fluoro-6-) methyl acid Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in 160 cm3 of methanol are added, with stirring, 25 cm3 of cyclohexene, followed by 1.8 g of 10% palladium on charcoal.
The black suspension thus obtained is brought to reflux and stirred an hour at this temperature, before being brought back to a temperature close to 20 ° C. The reaction medium is.
filtered paper sia.r and the residue is washed by 5 times 30 ~ cm3 of methanol. The filtrate is concentrated under reduced pressure to give 1.15 g of the expected ester as a yellow oil.
MS spectrum. IE m / z = 347M + '; m / z = 305 (M-C14H4N) + '; m / z =
288 (M - C02CH3) +; m / z = 192 C11H11 ~ NF + base peak; m / z = 157 C ~ Hi30zNz +; m / z = 4 2 C2H4N +
The methyl ester of 3- (RS) -1-benzyl-3 - [- 2- (3-fluoro-6-méthox ~ r-4-quinolinyl) ethylamino] -3-pyrrolidine The carboxylic acid can be prepared in the following manner.
To a suspension containing 1.5 g (6.76 mmol) of (3-fluoro) 6-methoxy-4-quinolinyl) acetaldehyde in 70 cm3 of anhydrous chloroform are added, with stirring and under inert atmosphere (Argon) 2.08 g (6.766 mmol) of 3- (RS) -3- methyl ester dihydrochloride amino-3-pyrrolidine carboxylic acid (acid prepared according to method described by Mamoun and roll. Common Synth., 1995, 25 (9), 1295-1302) and, in 5 minutes, a solution containing 1.9 cm3 (13.53 mmol) of triethylamine dissolved in 30 cm3 of anhydrous chloroform. The suspension is agitated under an inert atmosphere at a temperature of 20 ° C
for 18 hours. The clear orange solution thus obtained is concentrated under reduced pressure to give a residue yellow which is taken up in 100 cm3 of 1,2-dichloroethane and stirred at a similar temperature. from 20 ° C. To the suspension obtained in this way are added 2.12 g (9.472 mmol) of sodium triacetoxyborohydride followed by 0.547 cins3 (9.472 mmol) of acetic acid. The suspension thus obtained is stirred at a temperature of 20 ° C for 18 hours.
The reaction medium is then diluted with 300 cm3 of dichloromethane, the organic phase is washed 5 times cm3 of water, dried over anhydrous magnesium sulphate, filtered on paper and then concentrated to dryness under reduced pressure. The The residue thus obtained is purified by chromatography on 70-200 ~ silica, m at atmospheric pressure using as eluting a mixture of ethyl acetate / methanol (95/5):
Fractions containing the product are pooled and concentrated under pressure ~ reduced to give 1.8 g of estes expected in the form of a yellow oil.
MS spectrum. IE m / z = 437M + '; m / z = 378 (M-CO 2 CH 3) +; m / z =
346 (M - C + H) +; m / z = 219 C13H1 ~ 02N + -; m / z = 133 C9H11N + '; m / z - 91 C ~ H ~ *; m / z = 42 C2H4N + base peak (3-Fluoro-6-methoxy-4-quinolinyl) acetaldehyde can be prepared in the following manner.
To a suspension containing 1.7 g (6.766 mmol) of 3- (3-fluroro-6-methoxy-4-quinolinyl) propan-1,2-diol in 90 cc of tetrahydrofuran are added, with stirring, 90 cm3 distilled water and then 7.3 g (33.83 mmol) of sodium. The yellow suspension thus obtained is stirred 90 minutes at a temperature in the region of 20 ° C. then diluted by 300 cm3 of water. The aqueous phase is extracted 3 × 200 times cm3 of ethyl acetate, the organic phases are combined, washed with 3 times 100 cm3 of water. The emulsion thus created is recovery by 100 cm3 of brine, decanted, and phases organics are dried over anhydrous magnesium sulphate, filtered on paper and then concentrated to dryness under pressure reduced to give 1.5 g of expected product, in the form of a solid yellow_pale 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) propan-1,2-diol can be prepared as follows.
To a solution containing 1.9 g (8.746 mmol) of 4-allyl-3-fluoro-6-methoxyquinoline in 75 cm3 of acetone and 15 cm3 of water are added, with stirring, 5.2 g (43.73 mmol) of N-methylmorpholine N-oxide and then 2 cm3 of a 2% solution of osmium tetraoxide in alcohol, aert-butyl alcohol. the ~
black solution is stirred overnight at a nearby temperature The reaction medium is then cooled to a temperature of temperature close to 0 ° C, then treated with 30 cm3 of a aqueous solution. saturated with Na2SO3.5H2O. The solution obtained is stirred for 15 minutes at a temperature of 0 °
C, then diluted with 150 cm3 of ethyl acetate. The sentence organic matter is decanted and the aqueous phase is extracted by 3 100 cm3 of ethyl acetate. The organic phases are reunited, washed with 3 times 50 cm3 of water, then dried on anhydrous magnesium sulphate, filtered on paper and concentrated to dryness under reduced pressure. The solid residue thus obtained is taken up in 50 cm3 of ethyl acetate and stirred for 30 minutes at a temperature of 20 ° C.
suspension thus obtained is filtered, the solid is washed with ethyl acetate and then with isopropyl ether. The solid thus obtained is dried in a desiccator under vacuum for 2 hours to give 1.6 g of expected product in the form of cream-colored crystals melting at 162 ° C.
MS spectrum. IE m / z = 251 M + '; m / z = 191 (M-C 2 H 4 O 2) + peak of Base; m / z = 61C ~ H502 +
4-Allyl-3-fluoro-6-methoxyquinoline can be prepared as follows .
To a suspension containing 4.55 g (15 mmol) of 4-iodo-3-fluoro-6-methoxyquinoline (prepared according to the method described in the patent application WO 0240474) in 150 cm3 of DMF is added 7.2 cm3 (22.5 mmol) of allyl-tributyltin, 0.88 g (0.75 mmol) of tetrakis (triphenylphosphine) palladium and 0.575 g (3 mmol) of copper iodine (I). Suspension is stirred under an inert atmosphere (Argon) and at a temperature close to 60 ° C for 24 hours. The environment reaction is then reduced to a temperature of 20 °
C., diluted with 500 cm3 of ethyl acetate and washed 3 times with 300 cm3 of water. The emulsion that has formed is filtered on glass sintered No. 4, and the residue is washed with 3 times 100 cm3 of water, then 3 times 100 cm3 of ethyl acetate. The phases organic are combined and dried over magnesium sulphate 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 ~, m at atmospheric pressure using as eluent Dichloromethane / ethyl acetate (95/5 by volume).
The fractions containing the product are combined and concentrated under reduced pressure. 1.9 g of expected product as a yellow oil.
MS spectrum. IC m / z = 218 MH + base peak Example 2 Sodium salt of 3- (RS) -1- [(E) -3- (2,5-difluoro-Phenyl) -allyl] -3 - [- 2- (3-chloro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid To a solution containing 0.125 g (0.242 mmol) of the ester 3- (RS) -1 - [(E) -3- (2,5-difluoro-phenyl)) methyl ester Allyl] -3 - [- 2- (3-chloro-6-methoxy-4-quinolinyl) ethylamino] -pyrrolidine carboxylic acid in 20 cm3 of dioxane are added, with stirring, 2.1 cm3 (10.18 mmol) of an aqueous solution 5N sodium hydroxide solution, and the resulting orange solution is at reflux, and stirred 18 hours at this temperature. The environment The reaction is then brought back to a temperature in the region of 20 ° C.
C. and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by column chromatography 2.5 cm in diameter containing 15 cm of silica 20-45 Om to atmospheric pressure using as eluent a mixture Chloroform / methanol / aqueous ammonia at 28 ~ (12/3 / 0.5). The fractions containing the expected are gathered and concentrated under reduced pressure. 0.038 g of the sodium salt is obtained expected in the form of a pale yellow meringue Mass spectrum (IE). m / z = 501 M + '; m / z = 265 C14H130 ~ NF2 +.
m / z = 207 ClIHIOONCl + '; m / z = 153 C9H ~ F2 + (base peak); m / z = 42 C2H4N +

1H NMR Spectrum (300 .MHz, (CD3) .2SO with addition of some drops of CD3COOD d4, ~ eri ppm). 2.05 (mt 1H); 2.35 (mt 1H); 2.72 (mt, 1H); 3.00 (d wide, J = 10.5 Hz 1H); 3.00 to 3.20 and 3.30 to 3.65 (mts, 7H); 3.25 (d wide, J = 10.5 ~ Hz. 1H); 3.97 (3H); 6.42 (dt, J = 16 and 7) Hz 1H); 6.69 (broad d, J = 16 Hz, 1H); from 7.05 to 7.30 (mt 2H); 7.35 to 7.45 (mt, 1H); 7.44 (broad dd, J = 9 and 3 Hz. 1H); 7.50 (broad d, J = 3 Hz. 1H); 7.97 (d, J =
9 Hz. 1H); 8, 68 (1H).
IR spectrum (KBr pellet). 3064; 2920; 2850; 2379; 1621;
1506; 1490; 1387; 1261; 1233; 1178; 1122; 1026; 971; 872; 825 and 72 'crri i.
L. ' methyl ester of 3- (RS) -1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3 - [- 2- (3-chloro-6-methoxy-4-quinolinyl) -ethylamino] -3-pyrrolidine carboxylic acid can be prepared from the following way.
To a solution containing 0.240 g (0.66 mmol) of ester 3- (RS) -3 - [- 2- (3-chloro-6-methoxy-4-) methyl acid quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in cm3 of anhydrous acetonitrile are added, with stirring and under inert atmosphere (Argon). 0.456 g (3.3 mmol) of potassium carbonate, 0.121 g (0.726 mmol) of iodide Potassium and, in 5 minutes, 10 cm3 of a solution containing 0.15 g (0.760 mmol) of (2,5-difluoro-phenyl) chloride allyl (prepared according to the method described in the application for WO 9307109) in anhydrous acetonitrile. Suspension yellow thus obtained is refluxed for 8 hours, 30 then brought back to a temperature of 20 ° C and stirred 18 hours. The reaction medium is then filtered, the residue is rinsed with 3 times 15 cm3 of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in 50 cm3 of ethyl acetate, the organic phase is washed with 3 times 15 cm3 of water, dried over magnesium sulphate anhydrous, filtered on paper and concentrated under pressure scaled down. The orange oil thus obtained is purified by chromatography on a column 2 cm in diameter. containing 15 .cm of silica.20-45 ~ .m at atmospheric pressure in using as eluent a mixture of ethyl acetate / methanol (95/5), then an ethyl acetate / methanol mixture (95/5). The , Fractons containing the product are pooled and concentrated under reduced pressure. 0.147 g of expected product is obtained under 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-quinolin-4-yl) ethylamino] -pyrolidine-3-carboxylic acid can be prepared in the following manner To a solution containing 1.03 g (2.044 mmol) of the ester 1-vinyloxycarbonyl-3- ~ [2- (3-chloro-6-yl) methyl ester methoxy-4-quinolinyl) -ethyl] -vinylôxycarbonyl-amino ~ -3-pyrolidine carboxylic acid in 10 cm3 of acetic acid under inert atmosphere and with stirring are added drop to drop, 1.1 cm 3 (6.132 mmol, 3 equivalents) of a solution of 33 ~ of hydrobromic acid in acetic acid in about 15 minutes and at a temperature of about 15 ° C. The solution orange thus obtained is stirred for 3 hours at a temperature close to 20 ° C. The reaction medium is then concentrated under reduced pressure, and the residue obtained is.repres in 50 cm3 of water, the pH of the solution is brought to a similar value of 9 with an aqueous solution of NaHCO 3, and the aqueous phase thus obtained is extracted with 3 times 100 cm3 of acetate ethyl. The organic phases are combined, washed by 3 30 cm3 of water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue thus obtained is purified by chromatography on silica 20-45 ~, m at pressure atmospheric in. using as eluent mixture dichloromethane / methanol (50/50). Fractions containing the product are combined and concentrated under reduced pressure. We 0.240 g of expected ester is obtained in the form of an oil orange.

Mass spectrum (IC). m / z = 364 MH + (base peak).
Methyl ester of 3- (RS) -1-vinyloxycarbonyl-3- acid f [2- (3-chloro-6-methoxy-4-quinolinyl) -ethyl] -vinyloxycarbonyl-amino ~ -3-pyrolidine carboxylic can be prepared in the following manner.
To a solution containing 1.2 g (2,643 mmol) of ester 3- (RS) -Z-benzyl-3 - [- 2- (3-chloro-6-) methyl acid Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid (prepared as below) in 100 cm3 of 1,2-dichloroethane under an inert atmosphere and with stirring, are added 0.55 cm3 (6.343 mmol, 2.2 equivalents) of sodium chloride.
vinyloxycarbonyl. The resulting orange solution is stirred 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 ~ .m to atmospheric pressure using as eluent the dichloromethane, then a dichloromethane / acetate mixture of ethyl (95/5). The fraçtions containing the product are pooled and concentrated under reduced pressure. We obtain 0.550 g of the expected ester, in the form of an orange oil.
Mass spectrum (IC). m / z = 504 MH +, (base peak).
Example 3 3- (RS) -1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [-2- (6-Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid To a solution containing 0.44 g (0.914 mmol) of the ester 3- (RS) -1 - [(E) -3- (2,5-difluoro-phenyl)) methyl ester allyl] -3 - [- 2- (6-methoxy-4-quinolinyl) ethylamino] -3 pyrrolidine carboxylic acid in 50 cm3 of dioxane are added, with stirring, 7.7 cm3 (38.39 mmol) of an aqueous solution 5N sodium hydroxide solution, and the resulting orange solution is at reflux, and stirred 18 hours at this temperature .. The medium reaction is then rerun at a temperature of 20 °
. C. and then concentrated to dryness under reduced pressure. The residue thus obtained is purified by column chromatography 2 cm in diameter containing 2l, cm of silica 20-45 Om at atmospheric pression using as eluent a mixture dichloromethane / methanol / 28% aqueous ammonia (40/5 / 0.5).
Fractions containing the expected are combined and concentrated under reduced pressure to give 0.360 g of meringue pale yellow which is taken up in 25 cm3 of a mixture dichloromethane / methanol (9/1). The resulting solution is filtered, the filter is washed with a mixture dichloromethane / methanol (9/1), the filtrates are combined then concentrated to dryness under reduced pressure. The residue is taken up 50 cm3 of isopropyl ether, stirred for 10 minutes, then the resulting suspension is concentrated to dryness under pressure reduced 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 - C12H11ON) +;
(M m / z - 185 C1 ~ H110N + ' base peak ; m / z = 42 CH N +

NMR Spectrum (300 MHz, (CD3) 2SO with addition of some drops of CD3COOD, 8 in ppm). 2.05 (mt 1H); 2.34 (mt . .

1H); 2.65 (mt; 2.95 (d, J = 11Hz. 1H);
1H) 05 3.20 (mt 3H); ; from 3.30 to 3.50 . 3.25 (d, J

Hz.
1H) (mt 4H); 3, 92. 3H); 6, 42 (dt, J
(s = 16 and 6 Hz. 1H);

, 6.67 (bd, 16Hz. 1H); 7.13 (mt 1H); 7.23 (t J -ddoubl, J = 9.5 Hz. 1H); 7, 35 7, 50 (mt 4H) and;

7.95 (d, J = 9.5H); 8.66 (d, J = 4.5 Hz. 1H).
Hz.

IR spectrum (KBr). 2961; 2832;
1621; 1592; 1510;

1490; 1476; 1431; 5; 10.82; 1030;
1367;
1263;
1242;
1228;

969; 847; 821 cm-i and 727 The methyl ester of 3- (RS) -1 - [(E) -3- (2,5-difluoro-phenyl) -allyl] -3 - [- 2- (6-methoxy-4-quinolinyl) ethylamino] -3 pyrrolidine carboxylic acid can be prepared in the next .

To a solution containing 0.8 g (2.187 mmol) of 3- (RS) -3 - [- 2- Methyl methyl ester dihydrochloride (6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in 60 cm3 of anhydrous acetonitrile are added, Under stirring and under an inert atmosphere (Argon). 1.82 g (10.94 mmol) potassium carbonate, 0.400 g (2.406 g) mmol) of potassium iodide and, in 5 minutes, 10 cm3 of solution containing 0.600 g (2.517 mmol) of (2,5-difluoro-phenyl) -allyl (prepared according to the method 10 described in the patent application WO 9307109) in anhydrous acetonitrile. The yellow suspension thus obtained is refluxed for 5 hours, then brought back to a temperature of 20 ° C and stirred 18 hours. The environment The reaction is then filtered on a sintered glass. No. 4, the residue Is rinsed with 3 times 30 cm3 of acetonitrile and the filtrate is concentrated under reduced pressure. The residue thus obtained is taken up in 250 cm3 of ethyl acetate; the organic phase is washed with 3 times 100 cm3 of water, dried over sodium sulphate anhydrous magnesium, filtered and concentrated under pressure Reduced. The orange oil thus obtained is purified by chromatography on silica 70-200 ~, m at atmospheric pressure using as eluent an acetate mixture of ethyl / methanol (90/10), then a mixture dichloromethane / methanol (90/10). Fractions containing the 25 expected product are combined and concentrated under pressure scaled down. 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 1H NMR Spectrum (300 MHz, (CD3) 250, 8 in ppm). 1.27 (mt) . 1H); 2.23. ; from 2.50 (mt 1H) 1H) ; 2.46 (d, J = 10 Hz 2.85 (mt, 5H); 3.05 (d, J - 10 Hz, 1H); 3, 10 3, (mt 4H); 3.60 (s, 3H); 3, 95 (3H) 6, (dt, J =
; 47 16 and 6 Hz. 1H); 6.62 (broad d, J - 16 Hz. 1H); 7.14 (mt) .

1H); 7.26 (tddoubl, J = 9.5 and 5 Hz. 1H) 7.35 (d, ; J =

4.5 Hz. 1H) J 9.5 - 6 and ; 7.40 (mt -. 2H); 7.51 (Ddd, 3 Hz. 1H); 7.44 (d, J = 9Hz. 1H); 8, (d, J = 4, 5 64 Hz 1H).

IR spec (solution in C14). 3076; 3031; 2952; 2907;
2833; 2800; 1733; 1621; 1593; 1508; 1490; 1474; 1431; 1262;
1241; 1229; 1196; 1036; 971; 872 and 850 cm 1 3- (RS) -3- methyl ester dihydrochloride [2- (6-methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine The carboxylic acid can be prepared in the following manner.
To a solution containing 1.2 g (2,643 mmol) of ester 3- (RS) -1-benzyl-3 - [- 2- (3-chloro-6-) methyl acid Methoxy-4-quinolinyl) ethylamino] -3-pyrrolidine carboxylic acid in 100 cm3 of methanol are added, with stirring, 15 cm3 cyclohexene, then 1.2 g of 10% palladium on carbon.
The black suspension thus obtained is brought to reflux and stirred an hour at this temperature, before being brought back to a temperature close to 20 ° C. The reaction medium is filtered and the residue is washed with 5 times 20 cm3 of methanol. The filtrate is concentrated under reduced pressure to give 0.8 g of the dihydrochloride of the expected ester in the form of an oil 2 0 days.
MS spectrum. IE m / z = 329 M + '; m / z = 287 (M-C 2 H 4 N) + '; m / z =
270 (M - CO - CH3) +; m / z = 173 C11H11ON + base peak; m / z = .42 C2H4N +; m / z = 36 HCl +
The methyl ester. 3- (RS) -1-benzyl-3- [-2- (3-chloro-6-methoxy-4-quinolinyl) -éthyTamino] -3-pyrrolidine The carboxylic acid can be prepared in the following manner.
To a suspension containing 1.06 g (4.5 mmol) of (3-chloro 6-methoxy-4-quinolinyl) acetaldehyde in 45 cm3 of anhydrous chloroform are added, with stirring and under inert atmosphere (Argon) 1.38 g (4.5 mmol) from 3- (RS) -3- methyl ester dihydrochloride amino-3-pyrrolidine carboxylic acid and in 5 minutes a solution containing 1.27 cm3 (9 mmol) of triethylamine in solution in 15 cm3 of anhydrous chloroform. The suspension is stirred vigorously under 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 cm3 of 1,2-dichloroethane and agitated with a temperature close to 20 ° C. To the suspension as well obtained are added 1; 4 g (6.3 mmol) of sodium triacetoxyborohydride followed by 0.364 cm3 (6.3 mmol) of acetic acid. The suspension thus obtained is stirred at a temperature of 20 ° C for 18 hours.
The reaction medium is then diluted with 250 cm3 of dichloromethane, the organic phase is washed 5 times with 100 cm3 of water, dried over anhydrous magnesium sulphate, filtered then concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica 70-200 ~, m at atmospheric pressure using as eluent an ethyl acetate / methanol mixture (95/5). Fractions containing the product are gathered and concentrated under reduced pressure. 1.2 g of the methyl ester are obtained expected in the form of a yellow oil.
MS spectrum. IE m / z = 453 M + '; m / z = 394 (M-COZCH3) +; m / z =
62 (M-C7H +); m / z = 219 C13H1 ~ 02N + '; m / z = 13 C9H11N +; m / z 91 C ~ H ~ +; m / z = 42 C2H4N + base peak (3-Chloro-6-methoxy-4-quinolinyl) acetaldehyde can be prepared in the following manner.
To a suspension containing 1.2 g (4.55 mmol) of 3 ° - (3-chloro-6-methoxy-4-quinolinyl) propan-1,2-diol in 60 cc of tetrahydrofuran are added, with stirring, 60 cm3 of distilled water and then 4.8 g (22.5 mmol) of sodium. The yellow suspension thus obtained is stirred 90 minutes at a temperature of 20 ° C, then diluted with 280 cm3 of water. The aqueous phase is extracted three times cm3 of ethyl acetate, the organic phases are combined, washed with 3 times 100 cm3 of water. The emulsion thus created is taken up with 1.00 cm3 of brine, decanted, and the phases organics are dried over anhydrous magnesium filtered on paper and then concentrated to dryness under pressure reduced to give 1.1 g of. expected product in the form of a pale yellow solid used ~ as is in the next step.
MS spectrum. IE m / z = 235 M + '; m / z = 207 (M-CO) + 'peak of based 3- (3-Chloro-6-methoxy-4-quinolin-4-yl) propan-1,2-diol can be prepared as follows.
To a solution. containing 1.85 g (7.916 mmol) of 4-allyl-3-chloro-6-methoxyquinoline in 75 cc of acetone and 15 cc 4.7 g (39.58 mmol) of water are added with stirring.
N-methylmorpholine N-oxide and then 1.8 cm3 of a 2% solution of osmium tetraoxide in tert-butyl alcohol. The black solution is stirred overnight at a nearby temperature The reaction medium is then cooled to a temperature of temperature close to 0 ° C, then treated with 30 cm3 of a saturated aqueous solution of Na2SO3.5H2O. The solution obtained is stirred for 15 minutes at a temperature of 0 °
C, then diluted with 150 cm3 of ethyl acetate. The sentence organic matter is decanted and the aqueous phase is extracted by 3 100 cm3 of ethyl acetate. The organic phases are rinsed, washed with 3 times 50 cm3 of water and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under pressure, reduced. The solid residue as well. got is taken up in 50 cm3 of ethyl acetate and stirred for 30 minutes at a temperature close to 20 ° C. The suspension thus obtained is filtered, the solid is washed with 3 times 10 cm3-acetate of ethyl, then with 3 times 10 cm3 of isopropyl ether. The solid thus obtained is dried under reduced pressure for 2 hours.
hours. 1.2 g of expected product is obtained in the form of crystals melting at 138 ° C.
MS spectrum. IE m / z = 267M + '; m / z = 207 (M - C 2 H 4 +) +
base peak; m / z = 61 CaH502 +
4-Allyl-3-chloro-6-methoxyquinoline can be prepared as follows .

Has a suspension. containing 8.2 g (30 mmol) of 4-bromo-3-chloro-6-methoxyquinoline (prepared according to the method described in the patent application VJO 0240474) in 250 cm3 of DMF are added 14.4 cm3 (45 mmol) of allyl-tributyltin, 1.75 g (1.5 mmol) tetrakis (triphenylphosphine) palladium and 1.2 g (6 mmol) of copper iodide (I). The suspension is agitated under an inert atmosphere (Argon) and at a nearby temperature 60 ° C for 48 hours. The reaction medium is then brought to a temperature close to 20 ° C, diluted by 500 cm3 of ethyl acetate and washed 3 times with 300 cm3 of water.
The emulsion that has formed is filtered, and the residue is washed with 3 times 100 cm3 of water, then 3 times 100_ cm3 of ethyl acetate. The organic phases are united and dried over anhydrous magnesium sulfate. We filter and concentrated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on a 6 cm column of Diameter containing 30 cm of silica 40-63 ~ m under pressure atmospheric using dichloromethane as eluent.
The fractions containing the product are combined. and we get Z, 85 g of expected product in the form of an oil.
MS spectrum. IC m / ~ = 234 MH + base peak

Claims (14)

1) A quinoline-4-substituted derivative, characterized in that that he answers the general formula in which :
X1, X2, X3, X4 and X5 respectively represent>C-R'1 to >C-R'5, or at most one of them represents an atom nitrogen, R1, R'1, R'2, R'3, R'4 and R'5 are the same or different and represent a hydrogen or halogen atom or a radical alkyl, cycloalkyl, phenyl, phenylthio, heteroaryl or mono or bicyclic heteroarylthio, OH, SH, alkyloxy, difluoromethoxy, trifluoromethoxy, alkylthio, trifluoro-methylthio, cycloalkyloxy, cycloalkylthio, acyl, acyloxy, acylthio, cyano, carboxy, alkyloxycarbonyl, cycloalkyloxy carbonyl, nitro, -NRaRb or -CONRaRb (for which Ra and Rb can 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 contain another heteroatom selected from O, S or N and bearing the case optionally an alkyl substituent, phenyl or heteroaryl mono or bicyclic on the nitrogen atom or, where appropriate, the sulfur atom is oxidized in the sulfinyl or sulphonyl state), or represent a methylene radical substituted with fluoro, hydroxy, alkyloxy, alkylthio, cycloalkyloxy, cycloalkylthio, phenyl, mono or bicyclic heteroaryl, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, -NRaRb or -CONRaRb for which Ra and Rb are defined as previously, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or R1 can also represent difluoromethoxy, or a radical of structure -C m F2m + 1, -SC m F2m + 1 or -OC m F2m + 1 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 = O or, when m is equal to 1 or 2, CROH, CRNH2, CRF or CF2, R being a hydrogen atom or a alkyl radical (C1-6);
R2 represents a radical R, -CO2R, -CH2CO2R, -CH2-CH2CO2R, -CONH2, -CH2-CONH2, -CH2-CH2-CONH2, -CH2OH, -CH2-CH2OH, -CH2-NH2 -CH 2 -CH 2 -NH 2 or -CH 2 -CH 2 -CH 2 -NH 2, R being as defined above high;
R3 represents a phenyl radical, mono heteroaryl or bicyclic, alk-R3 for which alk is an alkylene radical and R3 represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulphinyl, alkylsulfonyl, alkylamino, dialkylamino, cycloalkyl, cycloalkyloxy, cycloalkylthio, cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylamino, N-cycloalkyl N-alkylamino, -N- (cycloalkyl) 2, acyl, cycloalkylcarbonyl, phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino; -N (phenyl) 2, phenylalkyloxy, phenylalkylthio, phenylalkylsulphinyl, phenylalkylsulfonyl, phenylalkylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl N-phenylalkylamino, benzoyl, mono or bicyclic heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylalkylsulfinyl, heteroarylalkylsulfonyl, heteroarylalkylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N-heteroaryl aminoalkyl, (the parts heteroaryl mentioned above being mono or bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb respectively represent hydrogen, alkyl, cycloalkyl, phenyl, heteroaryl mono or bicyclic, or one of Ra or Rb represents hydroxy, alkyloxy, cycloalkyloxy, or Ra and Rb together with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle links which may optionally contain another heteroatom chosen from O, S and N and bearing, where appropriate, a alkyl substituent, phenyl or heteroaryl mono or to the nitrogen atom or, where appropriate, whose the sulfur atom is oxidized in the sulfinyl or sulphonyl state, or else R ° 3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, the heteroaryl part of which is mono or bicyclic, phenoxyalkyl, phenylthioalkyl, phenyl sulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylsulphinylalkyl, heteroarylsulfonylalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, (the parts heteroaryl mentioned above being mono or bicyclic), phenylthio, phenylsulphinyl, phenylsulfonyl, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R3 represents a -C.ident.C-Rd radical for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenylaminoalkyl, mono or bicyclic heteroaryl, heteroarylalkyl, heteroaryl aryloxyalkyl, heteroarylthioalkyl, heteroarylamino-alkyl, N-alkyl N-heteroaryl aminoalkyl, (the parts heteroaryl mentioned above being mono or bicyclic), or R 0 3 represents a -CF 2 -phenyl radical or -CF2-mono or bicyclic heteroaryl, 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 selected from halogen, hydroxy, alkyl, alkyloxy, alkyl, oxyalkyl, haloalkyl, trifluoromethyl, trifluoro-methoxy, trifluoromethylthio, carboxy, alkyloxycarbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are defined as above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulphinylalkyl, alkylsulfonylalkyl;
R4 represents a radical R, -CHO, -COCH3, -CH2CO2H or -COCH2NH2;
it being understood that the radicals and alkyl or acyl portions contain (unless otherwise stated) 1 to 10 carbon atoms, in straight or branched chain, and that the radicals cycloalkyls contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form of syn or anti or mixtures thereof, as well as their salts.

2) A derivative of general formula (I), as defined in claim 1, characterized in that:
X1, X2, X3, X4 and X5 are as defined in claim R1, R'1, R'2, R'3, R'4, R'5, are identical or different and represent a hydrogen or halogen atom or a radical alkyl or alkyloxy, or represent a methylene radical substituted with alkyloxy;
m is 1;
n is 1;
Y represents a radical CH2, CHOH, CHF, CHNH2 or C = O;

R2 is as defined in claim 1, and R3 represents an alk-R o3 radical for which alk is a alkylene radical and R o3 represents alkyloxy, alkylthio, alkylamino, dialkylamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl N-alkylamino, N- (cycloalkyl) 2, phenoxy, phenylthio, phenylamino, N-alkyl N-phenylamino, N-cycloalkyl N-phenylamino, phenylalkyloxy, phenylalkylthio, phenylalkylamino, N-alkyl N-phenyl aminoalkyl, N-cycloalkyl N-phenylalkyl amino, heteroaryl, oxy, heteroarylthio, heteroarylamino, N-alkyl N-heteroaryl amino, N-cycloalkyl N-heteroaryl amino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylalkylamino, N-alkyl N-heteroaryl aminoalkyl, N-cycloalkyl N-heteroaryl aminoalkyl, (the heteroaryl moieties cited above being mono or bicyclic), -NRaRb or -CO-NRaRb for which Ra and Rb are defined as in the claim 1, or R o3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, heteroarylthio, (the heteroaryl moieties mentioned above being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or well R o3 represents a radical -C.ident.C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylamino-alkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl N-heteroaryl aminoalkyl, (the heteroaryl moieties mentioned above being mono or bicyclic), or R o3 represents a radical -CF2-phenyl or -CF2-heteroaryl mono or bicyclic;
R4 is as defined in claim 1;
it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above may be possibly substituted as envisaged above, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and / or, where appropriate, in the form of syn or anti or mixtures thereof, as well as their salts. 3) A derivative of general formula (I) as defined in claim 1, characterized in that:
X1, X2, X3, X4 and X5 respectively represent>C-R'1 to >C-R'5, R1, R'1, R'2, R'3, R'4 and R'5 are the same or different and represent a hydrogen or halogen atom or a radical alkyl or alkyloxy, or represent a methylene radical substituted with alkyloxy;
m is 1;
n is 1;
Y represents a radical CH2, CHOH, CHF, CHNH2 or C = O;
R2 is as defined in claim 1;
R3 represents an alk-R-3 radical for which alk is a alkylene radical and R3 represents cycloalkyloxy, cycloalkylthio, phenoxy; phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryl, oxy, heteroarylthio, heteroarylalkyloxy, heteroarylalkylthio, (the parts heteroaryls mentioned above being mono or bicyclic) or R ~ 3 represents -CR'b = CR'c-R'a for which R'a represents phenyl, phenylthioalkyl, heteroaryl, heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, heteroaryloxyalkyl, heteroarylthioalkyl (the heteroaryl moieties listed before being mono or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or R 3 represents a radical -C.ident.C-Rd for where Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl N-phenylamino alkyl, mono or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, (the parts heteroaryls mentioned above being mono or bicyclic);
R4 represents a radical R;
it being understood that the radicals or portions phenyl, benzyl, benzoyl or heteroaryl mentioned above may be possibly substituted as envisaged above, in its enantiomeric or diastereoisomeric forms or the mixtures of these forms, and / or, where appropriate, in the form of syn or anti or mixtures thereof, as well as their salts. 4) Any one of the derivatives of general formula (I) according to claim 1, whose names follow:
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3-fluoro-6-methoxy-quinolin-4-yl) ethylamino] -pyrrolidine-3-carboxylic acid;
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (6-Methoxy-quinolin-4-yl) -ethylamino] -pyrrolidine-3-carboxylic acid;
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (3-fluoro-6-methoxy-quinolin-4-yl) ethylamino] -methyl pyrrolidine-3-carboxylate;
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -alkyl] -3- [2- (-6-) Methoxy-quinolin-4-yl) -ethylamino] -pyrrolidine-3-methyl carboxylate;
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3-chloro-6-methoxy-quinolin-4-yl) -ethylamino] -methyl pyrrolidine-3-carboxylate;
.cndot. 1- [(E) -3- (2,5-difluoro-phenyl) -allyl] -3- [2- (3-chloro-6-methoxy-quinolin-4-yl) -ethylamino] -methyl pyrrolidine-3-carboxylate;
.cndot. 1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-[[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl]
methylamino] -3-pyrrolidine carboxylic acid;
.cndot. 1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-[[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] formylamino] -3-pyrrolidine carboxylic acid;
.cndot. 3 - [(aminoacetyl) [2- (3-fluoro-6-methoxy) -4-quinolinyl) ethyl] amino] -1- [(2E) -3- (2,5-difluorophenyl) 2-propenyl] -3-pyrrolidine carboxylic acid;
.cndot.acid 3 - [(carboxymethyl) [2- (3-fluoro-6-methoxy) -4-quinolinyl) ethyl] amino] -1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidine carboxylic acid;
.cndot.N- [1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4-quinoline ethanamine;
.cndot.N- [1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -N- [2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] glycine;
.cndot.N- [1 - [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-N-methyl-4-quinolineethanamine;
.cndot.le 1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -3-pyrrolidinemethanol;
.cndot.le 1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3- [[2- (3-fluoro-6-methoxy-4-quinolinyl) ethyl] amino] -3-pyrrolidinecarboxamide;
.cndot.N- [3- (aminomethyl) -1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] -3-fluoro-6-methoxy-4-quinolineethanamine;
.cndot.alpha.- [[[1- [(2E) -3- (2,5-difluorophenyl) -2-propenyl] -3-pyrrolidinyl] amino] methyl] -3-fluoro-6-methoxy-4-quinolinemethanol.
in its enantiomeric or diastereoisomeric forms or the mixtures of these forms, and / or, where appropriate, in the form of syn or anti 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 that we condense the chain R3 defined in the claim 1, on the 4-substituted quinoline derivative of the formula general:
wherein X1, X2, X3, X4, X5, R1, R2, y, m and n are defined in claim 1, R2 and R4 being protected when carry a carboxy radical and then, if necessary, eliminate the protecting group of the carboxy radical, and, where appropriate, separates the enantiomeric or diastereoisomeric forms and / or the where appropriate, the syn or anti forms and, where appropriate, converts the product obtained into a salt. 6) Process according to claim 5, characterized in that the condensation of the R3 chain on the heterocyclic nitrogen is carried out by action of a derivative of general formula:
R3-X (IIa) wherein R3 is defined as in claim 1 and X
represents a halogen atom, a methylsulfonyl radical, a trifluoromethylsulfonyl or p-toluenesulfonyl radical. 7) Method according to one of claims 5 and 6, characterized in that when R3 represents a radical -alk-R ~ 3 for which alk is an alkyl radical and R ~ 3 represents a radical -C.ident.C-Rd in which Rd is such that defined in claim 1, the reaction is carried out by condensation of an alkynyl halide HC.ident.C-alk-X for which alk is defined as above and X is an atom of halogen, then substitution of the chain by a radical Rd appropriate. 8) A method according to one of claims 5 and 6, characterized in that when R3 represents a radical -alk-R3 for which alk is an alkyl radical and R3 represents a phenoxy, phenylthio, phenylamino, heteroaryloxy radical, heteroarylthio or heteroarylamino, the reaction is carried out by chain construction by first condensing a HO-alk-X chain for which X is a halogen atom, then by transforming the hydroxyalkyl chain obtained into a haloalkyl, methanesulphonylalkyl or p.toluenesulfonylalkyl and finally by acting in medium basic aromatic derivative of structure R3H or R3H2, either in causing the aromatic derivative to act directly in dehydration conditions. 9) Method according to claim 5, characterized in that the derivatives of general formula (II) are prepared for where Y is CH2 and m is 1 or 2 by condensation of a heteroaromatic derivative of formula general:

wherein R1, X1, X2, X3, X4 and X5 are defined as a claim 1 and m is 1 or 2, on a derivative of general formula:

wherein P is a protecting group, n and R2 are defined as in claim 1 and R2 represents a radical protected if R2 represents or carries an acid function carboxylic acid, followed by the elimination of protectors and / or followed by processing, by operation subsequent substituents of the aromatic bicycle of general formula (II) thus obtained, to lead to the derivative carrying the radical R1, R'1, R'2, R'3, R'4, R'5 expected, and the where appropriate, removal of the protective radical (s) present on the molecule. 10) The products of general formula (II):

wherein X1, X2, X3, X4, X5, R1, R2, m and n are defined as in claim 5. 11) Products of general formulas (XI), (XII), (XIII) and (XIV):

in which X1, X2, X3, X4, X5 and R1 are defined as in claim 1, R1 not being able to represent an atom hydrogen. 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 at 4. 14) Pharmaceutical composition characterized in that it contains at least one medicament according to claim 12, pure or in combination with one or more diluents and / or compatible adjuvants and pharmaceutically acceptable.