RS20050806A - 4-substituted quinolein derivatives,preparation methods and intermediates and pharmaceutical compositions compraising same - Google Patents

Abstract

The invention concerns 4-substituted quinoline derivatives active as antimicrobial agents, of general formula (I), wherein: X1, X2, X3, X4 and X5 respectively represent >C-R'1 to >C-R'5, or not more than one represents N; Y represents CHR, CO, CROH, CRNH2, CRF or CF2, R being hydrogen or alkyl; m is 1, 2, or 3 and n is 0, 1 or 2; Z is CH2 or Z represents O, S, SO, SO2 and, in that case, n is equal to 2; R2 represents -CO2R, -CH2CO2R, -CH2-CH2CO2R, -CH2OH or -CH2-CH2OH, R being as defined above; R3 represents phenyl, heteroaryl or alk-R°3, wherein alk is an alkyl and R°3 represents various groups, optionally oxygenated, sulphured or aminated, in their enantiomeric or diastereoisomeric forms or mixtures thereof, and optionally in their syn or anti forms or mixtures thereof, as well as their salts.

Description

4- SUBST1TUISAN1 QUINOLINE DERIVATIVES, METHOD OF ITNTERMBDIERS FOR THEM

REFUTATION AND PHARMACEUTICAL FORMS CONTAINING THEM

This invention relates to 4-quinoline derivatives of the general formula:

which have antimicrobial activity. This invention also relates to the method and intermediates for their preparation and to the pharmaceutical forms containing them.

Patent applications WO 99/37635 and WO 00/43383 describe antimicrobial quinolylpropylpiperidine derivatives of the general formula:

where the radical is specific alkoxy (Cl-6), preferably hydrogen, R3 is in position 2 or 3 and represents alkyl (Cl-6) which can be optionally substituted with 1-3 adabrane substituents from thiol, halogen, alkylthio, trifluoromethyl, carboxy, alkyloxycarbonyl, alkylcarbonyl,

alkenyloxycarbonyl, alkenylcarbonyl, hydroxy optionally substituted with alkyl, R4 is a group - CH2-R5 for which R5 is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted heteroaryl..., n 0 to 2, m is 1 or 2 and A and B are especially oxygen, sulfur, sulfinyl, sulfonyl, NRn, CR6R7 in which R6 and R7 are H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxy, amino, and Zido Z5 is N or CRia...

Other applications, in particular WO 00/21952, WO 00/21948, WO 01/07432, WO 01/07433, WO 03/010138, or alternatively WO 02/072572 describe other 4-(quinolylpropyl)piperidine derivatives, substituted specifically at position 3 or disubstituted at position 4, which are active in the same field. European application EP 30044 also describes similar derivatives that are active in the field of cardiovascular diseases.

A derivative in which the piperidine ring has been modified in the manner given in formula (I) above has not yet been described.

It has been established, and this is the subject of this invention, that the compounds of the general formula (I) where: X], X2, X3, X4 and X5 represent >C-R' and >C-R' in the middle, or alternatively at least one of them represents a nitrogen atom,

Ri, R'i, R'2, R3, R'4 and R'5 are the same or different and represent a hydrogen or halogen atom or one alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic heteroaryl or heteroarylthio, OH, SH, alkyloxy, difluoromethoxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, acyl, acyloxy, acylthio, cyano, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, nitro, -NraRb or -CONRaRb radical ( for which Ra and Rb can be hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic heteroaryl or Ra and Rb form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle which may optionally contain another heteroatom selected from O, S or N and bearing, when appropriate, one alkyl, phenyl or mono- or bicyclic heteroaryl substituted on the nitrogen atom or when appropriate, when the sulfur atom is oxidized to the sulfinyl or sulfonyl state, or represents 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 above, or represents phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or alternatively R| may also represent difluoromethoxy or a radical having the structure -CmF2m+i, -SCmF2m+i or -OCmF2m+iza where m is an integer from 1 to 6 or alternatively R'5 may also represent trifluoroacetyl,

m is equal to 1, 2 or 3;

n is equal to 0, 1 or 2;

Y represents the group CHR, CO, CROH, CRNH 2 , CRF or CF 2 , R is a hydrogen atom or an alkyl (C 1-6 ) radical;

Z represents a CH 2 group or alternatively Z represents an oxygen atom, a sulfur atom or an SO group or one SO 2 group and in that case, n equal to 2;

R2 represents the radical -CO2R, -CH2CO2R, -CH2-CH2CO2R, -CH2OH or -CH2-CH2OH, R as described above;

R3 represents a phenyl radical, mono- or bicyclic heteroaryl, alk-R°3 for which alk is one alkylene radical and R°3 represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfinyl, 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, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylamino, N-alkyl-N-phenylamino, -N-(phenyl)2, N-cycloalkyl-N-phenylalkylamino, benzoyl, mono- or bicyclic heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino, N-alkyl-N-heteroarylamino, N-cycloalkyl-N-heteroarylamino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylsulfonyl, heteroarylsulfonyl, heteroarylamino, N-alkyl-N-heteroarylaminoalkyl, N-cycloalkyl-N-heteroarylaminoalkyl, (the heteroaryl moieties mentioned above can be mono- or bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CONRaRb for which Ra and Rb respectively represent hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic heteroaryl, or one of Ra or Rb represents hydroxy, alkyloxy, cycloalkyloxy, or Ra and Rb form together with the nitrogen atom to which they are attached 5- or 6-

membered heterocycle which may optionally contain another heteroatom selected from O, S and N and carries when appropriate, one alkyl, alkyl, phenyl or mono- or bicyclic heteroaryl substituent on the nitrogen atom or when appropriate, when the sulfur atom is oxidized to the sulfinyl or sulfonyl state, or alternatively R°3 represents -CR'b=CR'c-R<*>a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl where the heteroaryl moiety is mono- or bicyclic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, heteroarylthio, heteroarylsulfonyl, heteroarylsulfonyl, (the heteroaryl moieties mentioned above can be mono- or bicyclic), phenylthio, phenylsulfinyl, phenylsulfonyl, and for which R'b and R'c represent hydrogen hydrogen, alkyl or cycloalkyl, or alternatively R°3 represents the radical -OC-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, (the heteroaryl moieties mentioned above are mono- or bicyclic aromatics), or alternatively R°3 represents the radical -CF2-phenyl or mono- or bicyclic -CF2-heteroaryl,

where it is understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or moieties mentioned above may be optionally substituted on the ring with 1 to 4 substituents selected from halogen, hydroxy, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxy, alkyloxycarbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are as defined above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,

where it is understood that the alkyl or acyl radicals and moieties contain (unless otherwise indicated) 1 to 10 carbon atoms in the form of a straight or branched chain and that the cycloalkyl radicals contain 3 to 6 carbon atoms,

in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or when appropriate syn or anti forms or mixtures thereof, and their salts, which are very potent antibacterial agents.

It is understood that when the radical represents or carries on it a halogen atom, this can be selected from fluorine, chlorine, bromine and iodine, and it is most suitable to be fluorine.

In the previous general formula, when the radical represents or carries a mono- or bicyclic

heteroaryl substituent, this contains 5 to 10 members and may be selected (without limitation) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, benzothienyl, benzofuranyl, indazolyl, benzothiazolyl, naphthyridinyl, quinolyl, isoquinolyl, quinolyl, quinazolyl, quinoxalyl, benzoxazolyl and benzimidazolyl which are optionally substituted with the above substituents.

Of the compounds of the general formula (I), we can mention in particular those in which

Xi, X2, X3, X4 and X5 are as defined above,

Ri, R'i, R'2, R'3, R'4 and R'5, which are the same or different, represent a hydrogen or halogen atom, an alkyl or alkyloxy radical, or a methylene radical substituted with alkyloxy: Y represents a CH2, CHOH, CHF, CHNH2 or C=0 radical;

m is equal to 1;

as defined above;

Z is a CH2 group or an oxygen atom and in the latter case, it is equal to 2;

R2 is defined as before, i

R3represents the radical alk-R°3for which alk is one alkylene radical and R°3represents 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, phenoxy and lamino, N-alkyl-N-phenylaminoalkyl, N-cycloalkyl-N-phenylalkylamino, heteroaryloxy, heteroarylthio, heteroarylamino, N-alkyl-N-heteroarylamino, N-cycloalkyl-N-heteroarylamino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylalkylamino. N-alkyl-N-heteroarylaminoalkyl, N-cycloalkyl-N-heteroarylaminoalkyl, (wherein the heteroaryl moieties mentioned above may be mono- or bicyclic), -NRaRb or -CO-NRaRb for which Ra and Rb are as defined above, or alternatively R°3 is -CR'b=CR'c-R'a where R'a is phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, heteroarylthio, (wherein the heteroaryl moieties mentioned above may be mono- or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or alternatively R°3 represents the radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, (where the heteroaryl moieties mentioned above may be mono- or bicyclic), or alternatively R°3 represents -CF2-phenyl or mono- or bicyclic -CF2-heteroaryl radical, where it is understood that phenyl, benzyl, benzoyl or the heteroaryl radicals or moieties mentioned above may be optionally substituted as described above,

in its enantiomeric and diastereoisomeric form or a mixture of these forms and/or when appropriate in the syn or anti form or their mixture, and their salts and especially those in which Xi, X2, X3, X4 and X5 represent >C-R'i to >C-R'5 respectively,

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

Y represents the radical CH2, CHOH, CHF, CHNH2 or C=0;

m is equal to 1;

not as described above;

Z is a CH2 group or an oxygen atom and in that case, it equals 2;

R2 is as defined above, i

R3represents the radical alk-R°3za where alk is one alkylene radical and R°3represents cycloalkyloxy, cycloalkylthio, phenoxy, phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryloxy, heteroarylthio, heteroarylalkyloxy, heteroarylalkylthio, (heteroaryl moieties mentioned above are mono- or bicyclic) or alternatively R3represents -CR'b=CR'c-R'za where R'represents phenyl, phenylalkyl, heteroaryl, heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylthio (wherein the heteroaryl moieties mentioned above may be mono- or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl,

or alternatively R°3 represents the radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl,

where the heteroaryl moieties mentioned above may be mono- or bicyclic,

wherein it is understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or moieties mentioned above may be optionally substituted as previously described,

in their enantiomeric or diastereoisomeric form or mixtures thereof and/or in the corresponding syn or anti form or mixtures thereof and their salts.

Of the compounds of general formula (I), the subject of this invention are especially those whose names are listed below: • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-hydroxy-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenylsulfanyl)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenyloxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(thiophen-2-ylsulfanyl)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-hydroxy-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-hydroxy-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenylsulfanyl)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenyloxy)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(thiophen-2-ylsulfanyl)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid; • 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid; • 1-[3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid; • 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid;

in their enantiomeric or diastereoisomeric forms or their mixtures, and/or the corresponding syn or anti forms or their mixtures as well as their salts

According to the invention, products of the general formula (I) can be obtained by condensation of a series of R3 with a 4-substituted quinoline derivative of the general formula:

where Xi, X2, X3, X4>X5, Ri, R2, Y, Z, m and n are as defined above, R2 is protected when it bears a carboxy radical, followed when appropriate by removal of the carboxy radical protecting group, optionally by resolution of enantiomeric or diastereoisomeric forms and/or when appropriate syn and anti forms, and optionally by converting the resulting product into a salt.

Condensation of a series of R3 with heterocyclic nitrogen is most conveniently carried out by the action of derivatives of the general formula:

where R 3 is as defined above and X represents a halogen atom, methylsulfonyl radical, trifluoromethylsulfonyl or p-toluenesulfonyl radical, where the reaction takes place in an anhydrous, preferably inert medium in an organic solvent 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 sodium organic base (triethylamine for example) or an inorganic base (alkali metal carbonate: potassium carbonate for example) at a temperature between 20°C and the reflux temperature of the solvent. The nitrogen atom of the pyrrolidine ring of the derivative of general formula (II) is optionally protected according to the usual methods compatible with the rest of the molecule or with the reaction; protection is carried out, for example, with a protecting radical selected from t-butoxycarbonyl and benzyloxycarbonyl and this nitrogen atom is liberated before condensation with a derivative of formula (Ha), and in particular by acid hydrolysis.

It is preferable that a derivative of the general formula (Ha) for which X is a chlorine, bromine or iodine atom enters the reaction.

The conditions under which it is possible to carry out the condensation between the derivatives of the general formula (II) and (Ha) are also described in the application WO 02/40474.

When R3 is the radical -alk-R°3 where R°3 is the group -OC-Rd, where Rd is defined as above, one alkynyl halide of the formula HOC-alk-X is intermediately condensed and then the corresponding radical Rd is condensed with the thus obtained alkyne.

When R3 represents the radical -alk-R°3 for which alk is one alkyl radical and R°3 represents a phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino radical, it is also possible to construct a series by first condensing the series HO-alk-X for which X is a halogen atom, preferably iodine, under the conditions described above for the reaction of the product of the general formula (Ha), and then, when appropriate, converting the hydroxyalkyl series into haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl series and finally promote the reaction of an aromatic derivative having the structure R°3H or R°3H2 to act in a basic medium.

The conversion of the hydrated chain into a haloalkyl or p-toluenesulfonyl chain is carried out according to the usual methods for halogenation or sulfonation, in particular with halogenating agents such as thionyl chloride, halogen derivatives of phosphorus (phosphorus trichloride or tribromide for example) or with sulfonating agents such as for example methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl anhydride are employed. The reaction takes place in an organic solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature between 0 and 60°C. In some cases, it may be convenient to carry out the reaction in the presence of a base such as pyridine or triethylamine.

The reaction of the aromatic derivative R3H or R3H2 most conveniently takes place as described above, by the action of the derivative of the general formula (Ha), in an organic solvent such as an amide (dimethylformamide for example), a ketone (acetone for example), a nitrile (acetonitrile for example), in the presence of a base such as a nitrogenous organic base (for example triethylamine) or an inorganic base (alkali metal carbonate: potassium carbonate for example) at a temperature of between 20°C and reflux of the reaction mixture. It may be useful to carry out the reaction in the presence of potassium iodide.

It is also possible to carry out the reaction in ether (tetrahydrofuran for example) under dehydrated conditions in the presence of for example diisopropylamide and triphenylphosphine.

It goes without saying that if the radicals R3 carry carboxy or amino substituents, they must be protected beforehand and then released after the reaction is over. This procedure is carried out according to methods well known to those skilled in the art, which will not affect the rest of the molecule, and in particular according to the methods described in T.W. Green and P.G.M. Woots. Protective Groups in Organic Synthesis (2nd cd.), A. Wiley - Interscience Publication

(1991), or Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

The protected carboxyl radical carried on R2 may be selected from hydrolyzable esters. Examples include methyl, benzyl or tert-butyl ester, or alternatively phenylpropyl or -2-propenyl esters. Optionally, protection of the carboxyl radical is performed simultaneously with the reaction.

When appropriate, the protection of the amino radical is carried out by the usual means for radical protection mentioned above in the references.

The introduction and removal of protective radicals is carried out by methods known to those skilled in the art. According to the invention, derivatives of general formula (I) for which R 2 is hydroxymethyl or hydroxyethyl can be obtained by the action of a suitable reducing agent on derivatives for which R? is carboxy or carboxymethyl or protected carboxy or protected carboxymethyl. A keto functional group that may be present should be intermediately protected. Also according to the invention, products of the general formula (I) for which R 2 is carboxymethyl or carboxyethyl can also be obtained from derivatives for which R 2 is hydroxymethyl or hydroxyethyl, by treating the latter with a halogenating or tosylate agent and then with a cyanate agent and finally hydrolysis of the nitrile.

It is possible to carry out the reduction of the protected carboxylate according to the usual methods that otherwise do not disturb the rest of the molecule, in particular it refers to the use of a hydride (lithium aluminum hydride or diisobutyl aluminum hydride for example) in a solution such as ether (tetrahydrofuran for example) at a temperature of between 20 and 60°C. A keto functional group that may be present is intermediately protected according to conventional methods known to those skilled in the art, particularly via cyclic or noncyclic acetals.

Reduction of the free carboxyl can be carried out according to methods also known to those skilled in the art, for example by hydrogenation in the presence of rhodium- or ruthenium-based borohydrides in the presence of a Lewis acid or lithium aluminum hydride in ether. It is preferable that the keto functional group in that case is also protected in the intermediate phase.

The conservation of the hydroxymethyl or hydroxyethyl radical into the carboxymethyl or carboxyethyl radical takes place according to the usual methods that do not affect the rest of the molecule, in particular by the action of a halogenating agent such as for example thionyl chloride or phosphorus trichloride or phosphorus tribromide or a tosyl agent, followed by an alkali metal cyanide, for example potassium cyanide to obtain the corresponding cyanomethyl derivative, followed by hydrolysis of the nitrile.

Halogenation can be carried out in a chlorinated solvent (dichloromethane or chloroform for example), at a temperature between 0°C and the reflux temperature of the solvent.

According to the invention, the product of the general formula (II) for which Y is a CHR group is obtained by condensation of heteroaromatic derivatives of the general formula: in which Ri, Xi, X2, X3, X4 and Xssu defined as above and Hal represents a halogen atom, with a derivative of the general formula:

where P is a protecting group and R, Z, m, n and R 2 are as defined above or R 2 represents a protected radical if R 2 represents or carries a carboxylic acid functional group, followed by removal of the protecting group and/or followed by conversion, by successive operations, of the substituents of the aromatic cycle of the general formula (II) thus obtained, in order to obtain the expected derivatives bearing the radicals Ri, R'i, R'2, R'3, R'4, R'5, with appropriate removal of the protecting radical(s) still present in the molecule.

P can be any nitrogen protecting group compatible with the reaction (t-butyloxycarbonyl, benzyloxycarbonyl for example). Groups protecting the acidic functional group are selected from common groups whose introduction and removal do not affect the rest of the molecule, particularly those mentioned in the references cited above.

The reaction can be carried out especially by successive action, on derivatives of the general formula (II), of one organoborane (9-borabicyclo[3.3.1]nonane for example) in a solvent such as ether (tetrahydrofuran or dioxane for example) at a temperature of about -20 to 20°C and then of a bicyclic derivative of the general formula (III) for which Hal represents a chlorine atom or preferably a bromine or iodine atom, by analogy with the methods described by Suzuki et al. Pure and Appl. Chem., 57, 1749 (1985). The reaction generally takes place in the presence of a palladium salt (diphenylphosphoferrocene-palladium chloride for example) and a base such as potassium phosphate at a temperature between 20°C and the reflux temperature of the solvent.

According to the invention, products of the general formula (II) for which Y represents the CROH group can be obtained by oxidation, in a basic medium, of the corresponding derivative for which Y is the CHR group. Oxidation is carried out by the action of oxygen. preferably in an inert solvent such as dimethyl sulfoxide, in the presence of tert-butanol and a base such as potassium or sodium tert-butoxide at a temperature of between 0 and 100°C.

Derivatives of the general formula (II) for which Y is the group CRF or CF2 can be obtained by fluorination from derivatives for which Y is the group CROH and for which Y is the carbonyl group. The reaction takes place in the presence of sulfur fluoride [for example in the presence of aminosulfur trifluoride (diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988), bis(2-methoxyethyl)-aminosulfur trifluoride (Deoxofluor<®>), morpholinosulfur trifluoride for example) or alternatively in the presence of sulfur tetrafluoride (J. Org. Chem., 40, 3808 (1975)).Fluorination can also be carried out using a fluorinating agent such as hexafluoropropyl diethylamine (JP 2 039 546) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine.

The process 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) at a temperature between -78 and 40°C (preferably between 0 and 30°C). Reactions that take place in an inert medium (argon or nitrogen in particular) are preferred.

Derivatives of the general formula (II) for which Y is a carbonyl group can be obtained by oxidation of the corresponding derivative of the general formula (II) for which Y is a CHOH group. This oxidation takes place for example using potassium permanganate, optionally in a sodium hydroxide solution (for example 3 N sodium hydroxide), at a temperature between -20 and 20°C, or alternatively by the action of oxalyl chloride in the presence of dimethyl sulfoxide, followed by the addition of an amine such as triethylamine, in an inert solvent such as dichloromethane, dimethyl sulfoxide at a temperature between -60 and 20°C by analogy with the method described in D. SWERN et al., .1. Org. Chem., 44, 4148 (1979).

These derivatives can also be obtained by condensation of derivatives containing lithium in the 4-position of a heteroatom derivative of the general formula: where R1, X1, X2, X3, X4 and Xssu as defined above, with derivatives of the general formula:

where P, R2, m and n are as defined in formula (IV) and alk represents an alkyl radical containing from 1 to 4 carbon atoms, preferably methyl, followed by deprotection and/or conversion, successive operations, of substituents

of the aromatic bicycle of the general formula (II) thus obtained, in order to obtain the expected derivative bearing the radical Ri, R'i, R'2, R'3, R'4, R's, and when appropriate, removal of the protecting radical(s) still present in the molecule.

The formation of derivatives containing lithium at the 4-position of derivative (III') takes place with the help of a strong lithium base such as butyllithium, sec-butyllithium, or preferably lithium diisopropylamide, in a solvent such as ether, tetrahydrofuran for example, at a temperature of between -78°C and -40°C. Condensation of this lithium derivative with ester (IV) takes place in the same solvent, at a temperature between -78°C and 0°C.

Derivatives of general formula (III') can be obtained according to the method described in patent application WO 02/40474.

Derivatives of general formula (II) for which Y is the group CRNH 2 can be obtained from the corresponding CHOH derivative which is changed into its tosyl derivative, which reacts with ammonia. The process takes place in an inert solvent such as N,N-dimethylformamide or dimethyl sulfoxide, and preferably under pressure (2 to 20 atmospheres) at a temperature of between 20 and 100°C.

Tosyloxy derivatives are obtained from products of the general formula (II) for which Y is CROH, by the action of tosyl chloride in pyridine, at a temperature between -10 and 20°C.

Login

WO 02/40474 provides methods for obtaining different values for R 1 , X] , X 2 , X 3 , X 4 and X 5 in derivatives of general formula (II) and (III) and Hal in derivatives of general formula (III).

Derivatives of the general formula (IV) can be obtained by condensation with derivatives of the general formula: where n and P are defined as above and R2 is as defined for the general formula (IV) or (IV), a product of the general formula where Hal represents a halogen atom, preferably a bromine atom and m and R are as defined above. The process is most conveniently carried out in the presence of a strong base, especially an alkali metal amide, for example lithium bis(trimethylsilyl)amide, or a lithium compound, for example butyllithium, in an organic solvent which can be especially an ether such as tetrahydrofuran or dioxane.

In the case where m=l, the procedure is most conveniently carried out by condensing the derivative of the general formula (V) as defined above with the product of the dibromoethane type of the general formula:

where R is as defined above, followed by removal of the hydrobromide from the product obtained by a method known to those skilled in the art. References that can be cited for this method are for example R.A.Bunce et al. Organic Preparations Procedure Internationale 1999-31 (l)p. 99-106.

Other methods enabling the preparation of derivatives of general formula (IV) are described in WO 02/40474. The procedure takes place starting from the corresponding nitrogen heterocyclic derivative.

Examples are given ahead in the experimental section.

The intermediate derivatives of general formulas (II) and (IV) obtained during the use of the method according to the present invention are novel and as such form part of the present invention.

Derivatives of general formula (V) are generally known (references EP 405506 or WO 00/37458 can be cited) and some of them are commercially available. Their obtaining is given in the experimental part.

It is understood that the derivatives of general formula (I) and (II) can exist in enantiomeric or diastereoisomeric form or in syn or anti form, which is also part of the present invention. These forms can be separated by conventional methods known to those skilled in the art, particularly chiral chromatography or High Performance Liquid Chromatography (HPLC).

Derivatives of general formula (I) can be purified, when appropriate, by physical methods such as crystallization or chromatography.

Derivatives of the general formula (I) can be when appropriate, convert to addition salts with acids or bases by known methods. It is understood that these salts with acids or bases also form part of the present invention.

As an example of addition salts with pharmaceutically acceptable acids, mention may be made of salts formed with inorganic acids (for example hydrochlorides, hydrobromides, sulfates, nitrates or phosphates) or with organic acids (for example succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methane sulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates,

isethionates, naphthylsulfonates or camphorsulfonates) or with substituted derivatives of these acids.

Derivatives of the general formula (I) carry a carboxyl radical that can be converted into a metal salt or an addition salt with a nitrogen base according to already known methods. Salts can be obtained by the action of metal (for example alkali or alkaline earth metal) bases, ammonia or amines, on the product according to the invention, in a suitable solvent such as alcohol, ether or water or by a substitution reaction with an organic acid salt. The obtained salt is precipitated after obtaining the optional concentration of the solution, separated by filtration, decantation or lyophilization. As an example of pharmaceutically acceptable salts, we can mention especially salts of alkali metals (sodium, potassium, lithium) or alkaline earth metals (magnesium, calcium), ammonium salts, salts of nitro bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-P-phenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, benzhydramine, quinine, choline, arginine, lysine, leucine, dibenzylamine).

Derivatives of general formula (I) according to the invention are particularly active antibacterial agents.

The following study clearly shows this.

a) Activity in vitro The agar dilution method in accordance with NCCLS recommendations was used to determine the minimum inhibitory concentration (MIC).

expressed in ug/ml.

The activities of the compounds of Examples 1 to 4 are grouped together in the following table:

In vitro, the compounds of the present invention have shown remarkable results against both Gram-positive and Gram-negative microorganisms.

b) In vivo activities

Certain derivatives have been shown to be active on experimental infections in mice with

Staphvlococcus aureus IP8203 in doses between 5 and 50 mg/kg subcutaneously or orally.

c) The product according to the invention is particularly suitable due to its low non-toxicity. None of the products showed toxicity at doses of 50 mg/kg subcutaneously or

orally in mice (2 doses/day).

These properties make the products, and their salts with pharmaceutically acceptable acids and bases, suitable for use in the medical treatment of conditions caused by sensitive microorganisms caused by Gram-positive bacteria, especially those caused by staphvlococci, such as staphvlococcal septicemia, facial or cutaneous malignant staphvlococcia, pvoderma, septic or purulent ulcers, anthrax, phlegmons, erysipelas, primitive or post-influenza acute staphvlococcia, bronchopneumonia, pneumonia, and those caused by streptococci or enterococci.

These products can also be used as medicines in the treatment of upper and lower respiratory infections caused by Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis.

The subject of this invention is therefore also drugs and in particular drugs intended for the treatment of bacterial infections in humans and animals, compounds of the general formula (I) as defined above and their pharmaceutically acceptable salts, and in particular as defined previously as I their pharmaceutically acceptable salts, and in particular the compounds mentioned above.

This invention also relates to pharmaceutical compounds containing at least one 4-substituted quinoline derivative according to the invention, when suitable in salt form, in pure form, or in combination with one or more pharmaceutically acceptable diluents or additives.

The compounds of the invention can be used orally, parenterally, topically or rectally or as aerosols.

All solid forms for oral use, can be used as tablets, pills, gelatinized

capsules, powders or granules. In these forms, the active product according to the invention is mixed with one or more inert diluents or additives, such as sugar, lactose or starch. These compounds may contain substances other than diluents, for example lubricants such as magnesium stearate or controlled release coatings.

As liquid compounds for oral use, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compounds may also contain substances other than diluents, for example wetting agents, sweeteners or artificial flavors.

Compounds for parenteral use may be sterile solutions or emulsions. As a solvent or binder, it is possible to use water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, organic esters for injection, for example ethyl oleate. These compounds may also contain additives and in particular humectants, isotonics, emulsifiers, dispersing agents and stabilizing agents.

Sterilization can be done in several ways, for example using a bacteriological filter, irradiation or heating. It may also be obtained as a sterile solid which may be dissolved prior to use in sterile water or any sterile injection medium.

Pharmaceutical forms for topical application can be, for example, oil creams, lotions or aerosols.

Compounds for rectal administration are suppositories or rectal capsules containing, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Pharmaceutical forms can also be in the form of an aerosol. For use in the form of liquid aerosols, the compounds may be stable sterile solutions or solid compounds dissolved prior to use in sterile water, saturated sodium chloride solution, or some other pharmaceutically acceptable carrier. For use in the form of dry aerosols intended for direct inhalation, the active ingredients are finely powdered and mixed with a water-soluble diluent or carrier having a particle size of 30 to 80 µm, for example dextran, mannitol or lactose.

In human therapy, the new 4-substituted quinoline derivatives according to the invention are particularly useful in the treatment of infections of bacterial origin. Doses depend on the desired effect and duration of treatment. The doctor should determine the dosage method that is considered appropriate for treatment, according to the age, weight, degree of infection and other factors specific to each patient. In general, doses are between 750 mg and 3 g of the active product in 2 or 3 doses per day orally or between 400 mg and 1.2 g intravenously for adults.

The following examples illustrate the pharmaceutical forms according to the invention.

a) Liquid pharmaceutical form intended for parenteral use, prepared in the usual way, contains: • (±)-1-[(2E)-3-(2,5-difluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxy-quinolin-4-yl)-propyl]pyrrolidine-3-carboxylic acid 1 g

• Glucose 2.5%

• Sodium hydroxide pH = 4-4.5

• Water for injection 20 ml

b) Liquid form for parenteral use is obtained according to usual techniques and contains:

• 2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-4-[2-(2,5-difluorophenyl-sulfanyl)ethyl]morpholine-2-carboxylic acid 500 mg

• Glucose 5%

• Sodium hydroxide pH = 4-4.5

• Water for injection 50 ml The following examples illustrate the invention.

Example 1

(±)-1-[(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]

3-pyrrolidinecarboxylic acid:

14.2 cm<3>5 N aqueous sodium hydroxide solution is added, at a temperature of about 20°C, to 1.25 g (2.336 mmol) of methyl (±)-1-[(2£')-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-meloxyquinolin-4-yl)-propyl]-3-pyrrolidinecarboxylate in a solution of 25 cm<3>dioxane. After stirring under reflux for 16 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up with 40 cm<3>acetonitrile. After stirring for 0.5 hours at a temperature of about 0°C, the orange solid in suspension was filtered, washed twice with 7 cm<3>acetonitrile and then dissolved in 55 cm<3>water. The aqueous phase is then acidified with 1 N hydrochloric acid to a pH of 6-7 and then extracted twice with 20 cm<3>dichloromethane each. The organic phases were combined, washed twice with 10 L of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.55 g. (±)-1-[(2£')-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-3-pyrrolidinecarboxylic acid, as a yellow solid melting at 77°C.

HNMR (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): 1.59 (mt: 4H); 1.81 (mt: 2H); 2.25 (mt: IH); 2.38 (wide d, J = 9Hz: IH); 2.57 (mt: IH); 2.96 (wide d, J = 9 Hz : IH); 3.07 (broad t, J = 7.5 Hz : 2H); 3.21 (broad d, J= 6 Hz : 2H); 3.94 (s : 3H); 6.47 (dt, J = 16 and 6 Hz : IH): 6.61 (broad d, J = 16 Hz: IH); 7.12 (mt: IH); 7.24 (split t, J = 9.5 and 4.5 Hz : IH);

7.35 (d, J = 3 Hz : IH); 7.39 (dd, J = 9 and 3 Hz : IH); 7.50 (mt: IH); 7.96 (d, J = 9 Hz : IH); 8.68 (wide s : IH).

C m / z = 485 (MH<+>).

Methyl (±)-14(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxy-4-quinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be prepared as described in Example 2.

Example 2

Methyl (±)-1-[(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be prepared as described in Example 2 below.

3.92 g of potassium carbonate, 1.03 g of potassium iodide and then a freshly prepared solution of 2-[(1E)-3-chloro-l-propenyl]-1,4-difluorobenzene (7.34 mmol) in dichloromethane were added at a temperature of about 20°C under an argon atmosphere to 2.171 g (5.67 mmol) of methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate dihydrochloride dissolved in

150 cm<3>acetonitrile. After stirring under reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up with 200 cm<3> of dichloromethane, washed 3 times with 100 cm<3> of water and then with 75 cm<3> of saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 2.6 g of an orange oil which was purified by flash chromatography [eluent: cyclohexane/ethyl acetate (1/1 by volume)]. After concentrating the fractions under reduced pressure, 1.45 g of methyl (±)-1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate were obtained as a yellow oil;

1 H NMR (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): from 1.40 to 1.70 (mt: 3H); 1.81 (mt: 211); 2.26 (mt: IH); 2.36 (d, J = 9.5 Hz : IH); from 2.40 to 2.65 (mt: 2H); 2.95 (d, J = 9.5 Hz : IH); 3.06 (wide t, J = 7.5 Hz : 2h); 3.18 (d, J = 6 Hz : 2H); 3.53 (s : 3H); 3.95 (s : 3H); 6.45 (dt, J = 16.5 and 6 Hz : IH); 6.60 (wide d, J = 16.5 Hz : IH); 7.12 (mt: IH); 7.23 (split t, J = 9.5 and 4.5 Hz : IH); 7.34 (d, J = 3 Hz : IH); 7.39 (dd, J = 9 and 3 Hz : IH); 7.49 (ddd, J = 9.5 - 6 and 3 Hz : IH); 7.96 (d, J = 9Hz: IH); 8.68 (wide s : IH).

EIm/z=498 (M<+>), 439(M-C02CH3<+>), 153(C9H7F2<+>).

A solution of 2-[(lE)-3-chloro-l-propenyl]-l,4-difluorobenzene (7.34 mmol) in dichloromethane can be obtained as follows: A solution of 0.66 cm<3>(9.07 mmol) of thionyl chloride and 1.08 g (9.07 mmol) of benzotriazole in 70 cm<3>of dichloromethane is added at a temperature of about 20°C, under an atmosphere argon, in 1.25 g (7.34 mmol) of 2,5-difluorocinnamyl alcohol in a solution of 130 cm<3>dichloromethane. After stirring for 10 minutes, the reaction mixture was filtered on a No. 3 sintered glass and the solid residue is washed twice with 20 cm<3>dichloromethane each. The phytrate is washed 3 times with 75 cm<3> of water each. The organic phase was dried over anhydrous magnesium sulfate and filtered to give a solution of 2-[(1E)-3-chloro-1-propenyl]-1,4-difluorobenzene (7.34 mmol) which was used immediately in the next step.

Methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-3-pyrrolidinecarboxylate dihydrochloride can be obtained as follows: 8.117 cm<3>4 N hydrochloric acid in dioxane is added at a temperature of about 20°C to 2.9g (6.495 mmol) of l-(l,l-dimethylethyl) and 3-Methyl(±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate in a solution of 20cm<3>methanol. After stirring for 4 hours at about 20°C, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give 2.38 g of methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-3-pyrrolidinecarboxylate dihydrochloride as a yellow solid.

EIm/z=346 (M<+>), 315 (M-OCH3 ), 304 (M-C2H4N<+>), 204 (Ci2HnONF<+>). 1-(1,1-dimethylethyl) and 3-methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate can be obtained as follows: A solution of 2.23 g (8,279 mmol) of 1-(1,1-dimethylethyl) and 3-methyl (±)-3-(2-propenyl)-1,3-pyrrolidinedicarboxylate in 30 cm of tetrahydrofuran are added at a temperature of about 0°C, under an argon atmosphere, to 24.84 cm<3>(12.42 mmol) of a 0.5 M solution of 9-BBN (9-borabicyclo[3.3.1]nonane/THF. After heating the reaction mixture to a temperature of about 20°C and stirring for 3 hours at a temperature of about 20°C, 2.509 g (8.279 mmol) 3-Fluoro-4-iodo-6-methoxyquinoline in suspension in 70 cm<3>tetrahydrofuran and then 5.27 g (24.84 mmol) potassium phosphate and 0.182 g (0.248 mmol) PdCl2dppf (1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride) are added successively. After stirring for 16 hours at reflux temperature, the reaction mixture was cooled and then filtered at

Celite<®>. The cells are washed 3 times with 25 cm<3>tetrahydrofuran each. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with 100 cm<3> of dichloromethane, washed 3 times with 40 cm<3> of water and then with 50 cm<3> of a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 5.7 g of an orange oil which was purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 v/v)]. After concentrating the fractions under reduced pressure, 2.9 g of 1-(1,1-dimethylethyl) and 3-methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate were obtained in the form of a yellow oil.

EIm/z=446 (M<+>), 390 (M-C4H8<+>), 345 (390-CO2H<+>), 204 (CuHnONF<+>).

3-Fluoro-4-iodo-6-methoxyquinoline can be obtained according to the method described in patent application WO 02/40474.

1-(1,1-Dimethylethyl) and 3-methyl (±)-3-(2-propenyl)-1,3-pyrrolidine dicarboxylate can be obtained as follows: 12.23 cm<3> (12.23 mmol) of lithium bis(trimethylsilyl)amide as a 1 M solution in tetrahydrofuran is added dropwise at a temperature of about -78°C, under argon, to 2.55 g (11.12 mmol) of 1-(1,1-dimethylethyl) and 3-methyl 1,3-pyrrolidine dicarboxylate dissolved in 30 cm<3>tetrahydrofuran. After stirring for 0.25 hours at a temperature of about -78°C, 1,486 cm<3>(16.68 mmol) of 2-propenyl bromide was added and then the temperature was changed from about -78°C to a temperature of about 20°C for 1.5 hours. The reaction mixture is then hydrolyzed with 10 cm<3>1 N aqueous hydrochloric acid and the solution is then concentrated to three quarters under reduced pressure (2.7 kPa). The concentrate is then taken up with 50 cm<3>ethyl acetate. The organic phase was separated by decantation, washed successively with 15 cm<3>1 N aqueous hydrochloric acid solution, 20 cm<3>water and twice with 20 cm<3>saturated aqueous sodium bicarbonate solution, dried under anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 2.5 g of a yellow oil which was purified by flash chromatography. [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. After concentration of the fractions under reduced pressure, 2.23 g of 1-(1,1-dimethylethyl) and 3-methyl (±)-3-(2-propenyl)-1,3-pyrrolidinedicarboxylate were obtained as a colorless oil.

CI m/z 287 (MNH4<+>), 270 (MH<+>), 231 (MNH4<+->C4H8).

1-(1,1-Dimethylethyl) and 3-methyl 1,3-pyrrolidinedicarboxylate can be obtained as follows:

3 cm<3>triethylamine and then 4.649 g of di-tert-butyl dicarbonate in a solution of 30 cm<3>dichloromethane are successively added at a temperature of about 20°C, in an argon atmosphere to 2.5 g (19.36 mmol) of methyl (±)-3-pyrrolidinecarboxylate dissolved in 50 cm<3>dichloromethane. After stirring for 20 hours at a temperature of about 20°C, the reaction mixture is successively washed 3 times with 50 cm 3 of water and 50 cm 3 of a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 3.08 g of a colorless oil which was purified by flash chromatography [eluent: cyclohexane/ethyl acetate (6/4 by volume)]. After concentrating the fractions under reduced pressure, 2.55 g of 1-(1,1-dimethylethyl and 3-methyl 1,3-pyrrolidinedicarboxylate) were obtained in the form of a colorless oil.

CI m/z 247 (MNH4<+>), 230 (MH<+>), 191 (MNH4<+->C4H8), 174 (MH<+->C4H8).

Methyl (±)-3-pyrrolidinecarboxylate can be obtained as follows:

0.704 g of 10% palladium on carbon (Pd/C) and then 11.5 g of ammonium formate are successively added at a temperature of about 20°C, in an argon atmosphere, to 5 g (22.8 mmol) of methyl (±)-l-(phenylmethyl)-3-pyrrolidinecarboxylate dissolved in 100 cm<3>methanol. After stirring for 3 hours at reflux temperature, the reaction mixture was filtered on Celite<®>. Cells<®>are washed 3 times with 20 cm<3>methanol each. The filtrate was then concentrated to dryness under reduced pressure (2.7 kPa) to give 2.5 g of methyl (±)-3-pyrrolidinecarboxylate as a colorless oil.

CI m/z 130 (MH<+>).

Methyl (±)-1-(phenylmethyl)-3-pyrrolidinecarboxylate can be obtained as follows

0.213 cm<J> (2.758 mmol) of trifluoroacetic acid was added dropwise at a temperature of about 20°C, under an argon atmosphere, to 9.496 g (110.3 mmol) of methyl acrylate and 32.37 g (115.8

mmol) of N-butoxymethyl-N-trimethylsilylmethylbenzylamine (Ashiw's dipole) dissolved in 350 cm<3>dichloromethane. The reaction is highly exothermic; after stirring for 4 hours at a temperature of about 20°C, 15 g of potassium carbonate is added, after stirring for 15 minutes at a temperature of about 20°C, the reaction mixture is successively washed 3 times with 150 cm<3> of water and 150 cm<3> of a saturated aqueous solution of sodium chloride. The organic phases are dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness

under reduced pressure (2.7 kPa) to give 26 g of a yellow oil which was purified by flash chromatography [eluent: cyclohexane/ethyl acetate (gradient 7/3 to 6/4 by volume)]. After concentrating the fractions under reduced pressure, 24.5 g of methyl (±)-1-(phenylmethyl)-3-pyrrolidinecarboxylate were obtained in the form of a yellow oil.

EI m/z219(M<+>), 188(M-CH30<+>), 142(M-C6H5<+>), 128(M-C7H7<+>).

N-Butoxymethyl-N-trimethylsilylmethylbenzylamine (Ashiw's dipole) can be obtained according to the method described by Terao, Y., Kotaki, H., Imai, N., Achiwa, K.Chem. Pharm. Bully

1985, 33, 896.

Example 3

Enantiomer A 1 -[(2it)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid

1.17 cm<3>5 N aqueous sodium hydroxide solution, added at a temperature of about 20°C to 0.0693 g (0.139 mmol) of enantiomer A (left-handed) methyl 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate dissolved in 3 cm<3>dioxane. After stirring under reflux for 48 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up with 5 cm<3>water and 5 cm<3>dichloromethane. The aqueous phase was acidified with 5 N and then with 1 N hydrochloric acid to a pH of about 7. The organic phase was separated by decantation and then the aqueous phase was concentrated to dryness under reduced pressure (2.7 kPa) to give 0.067 g of a residue which was purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (60/20/20 by volume)]. After concentrating the fractions under reduced pressure, 0.059 g of a beige solid is obtained, which is taken up with 5 cm<3> of water and 5 cm<3> of dichloromethane. The pH of the aqueous phase was adjusted to 7 with 0.01 N aqueous sodium hydroxide solution. The aqueous phase is extracted twice with 5 cm<3>dichloromethane each. The organic phases are combined, washed with 5 cm<3> of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.04 g of enantiomer A. 1-[(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a beige solid melting at 76-80°C.

[oc]D<20>+7.3 +/- 0.4 [dichloromethane (c = 0.5), 589 nm];

1 H NMR (300 MHz, (CD 3 ) 2 SO d 6 , 6 in ppm): 1.66 (mt: 4H); 1.79 (mt: 2H); 2.24 (mt: IH); 2.35 (d, J = 9 Hz : IH); from m 2.40 to 2.60 (mt: IH); 2.94 (d, J = 9 Hz : IH); 3.06 (wide t, J = 7 Hz : 2H); 3.19 (d, J = 6 Hz: 2H); 3.95 (s : 3H); 6.48 (dt, J = 16 and 6 Hz : IH); 6.61 (wide d, J = 16 Hz : IH); 7.14 (mt: IH); 7.25 (split t. J = 9.5 and 5 Hz : IH); from 7.30 to 7.45 (mt: 2H); 7.51 (ddd, J = 9.5 - 6 and d 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.69 (with :

IH).

EI m/z484(M<+>),439(M-C02H<+>),153(C9H7F2<+>).

Enantiomer A (levorogyry) methyl 1-[(2R')-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained as described in Examples 5 and 6 below.

Example 4

Enantiomer B 1-[(2iT)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid

1.137 cm<J>5 N aqueous sodium hydroxide solution was added at a temperature of about 20°C to 0.0675 g (0.135 mmol) of enantiomer B (dextrorotatory) methyl 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate dissolved in 3 cm<3>dioxane. After stirring under reflux for 48 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up with 2 cm<3>water and 5 cm<3>dichloromethane. The aqueous phase is acidified with 1 N and then with 0.1 N hydrochloric acid to pH 7. The aqueous phase is extracted twice with 5 cm<3>dichloromethane each. The organic phases are combined, washed twice with 5 cm<3>water each, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.035 g of enantiomer B 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration not determined) as a beige solid melting at 80-84°C.

[a]D<2>° -7.7 +/- 0.4 [dichloromethane (c = 0.5), 589 nm].

1 H NMR (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): 1.58 (mt: 4H); 1.80 (mt: 2H); 2.25 (mt: IH); 2.36 (wide d, J = 9 Hz: IH); from 2.45 to 2.65 (mt: IH); 2.93 (wide d, J = 9 Hz : IH); 3.07 (wide t, J = 7 Hz : 2H); 3.18 (d, J = 6 Hz : 2H); 3.94 (s : 3H); 6.47 (dt, J = 16 and 6 Hz : IH); 6.61 (wide d, J = 16 Hz : IH); 7.12 (mt: IH); 7.24 (split t, J = 9.5 and 4.5 Hz : IH); 7.35 (mt: IH); 7.38 (dd, J = 9 and 3 Hz : IH); 7.50 (ddd, J = 9.5 - 6 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.69 (wide s : IH).

EI mz484(M<+>),439(M-C02H<+>),153(C9H7F2+).

Enantiomer B (right-handed) methyl 1-[(2i?)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be prepared as described in Examples 5 and 6.

Examples 5 and 6

Enantiomers A (levorotatory) and B (dextrorotatory) methyl 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate Methyl (±)-1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate (0.155 g) is injected onto a column 80 cm in diameter and 35 cm high containing 1200 g of a chiral stationary phase: Chiralpak AD TM which has a particle size of 20 µm. mobile phase [heptane/2-propanol/methanol (92/5/3 by volume)] at a flow rate of 120 ml/min, detection with UV at 254 n.m. Enantiomer A (levogyric), having an undefined absolute configuration, which was eluted in the first stage, was regenerated and concentrated under vacuum to give 0.069 g of a colorless oil.

EI mz498(M<+>),439(M-C02CH3<+>),153(C9H7F2<+>).

[a]D<20>-11.6 +/- 0.4 [methanol (c = 0.5), 589 nm].

Enantiomer B (right-handed), which has an undefined absolute configuration, eluted in the second phase and was regenerated and then concentrated under vacuum to give 0.067 g of a colorless oil.

EI mz498(M<+>),439(M-C02CH3<+>),153(C9H7F2<+>).

[a]D<20>-11.5 +/- 0.4 [methanol (c = 0.5), 589 nm].

Methyl (±)-1-[(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-^yl)propyl]-3-pyrrolidinecarboxylate can be prepared as described in Example 2.

Example7

Enantiomer A of 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2-morpholinecarboxylic acid (undefined absolute configuration) Solution of 0.21 g of enantiomer A methyl 4-[2-[2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxy-4-quinolin-4-yl)propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm<3>methanol and 1.18 cm<3>5 N sodium hydroxide is heated at a temperature of about 80°C, with stirring and in an inert atmosphere, for a duration of 12 hours. After cooling to about 20°C, the reaction mixture was evaporated under reduced pressure (2 kPa; 45°C) to give an off-white crust. The residue is taken up with 25 cm 3 of dichloromethane and 10 cm 3 of distilled water and then neutralized with 1.2 cm<3>5 N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30°C. The resulting residue is purified by chromatography on a silica gel column (particle size 70-200 µm, diameter 2 cm), eluting with a chloroform-methanol-aqueous ammonia solution (28%) (12/3/0.5 by volume) mixture and taking fractions of 10 cm<3>. Fractions containing the expected product are pooled and then combined according to the conditions given above. 0.18 g of enantiomer A of 4-[2-[(2,5-difluorophenyl)-thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2-morpholinecarboxylic acid is obtained in the form of a white solid.

1H NMR spectrum (300 MHz, (CD3)2SO d6 with addition of a few drops of CD3COOD d4, 5 in ppm): from 1.45 to 1.90 (mt: 4H); 2.04 (d, J = 11 Hz : IH); 2.12 (wide t, J = 11 Hz : IH); from 2.40 to 2.60 (mt: 2H); 2.63 (wide d, J = 11 Hz : IH); from 2.95 to 3.05 (mt: 2H); 3.04 (t, J = 7.5 Hz : 2H); 3.12 (d, J = 11 Hz : IH); 3.52 (very wide d, J = 11 Hz : IH); 3.77 (wide t, J = 11 Hz : IH); 3.85 (s : 3H); 7.20 (mt: IH); from 7.30 to 7.50 (mt: 2H); from 7.50 to 7.60 (mt: 2H); 8.08 (d, J = 9 Hz : IH); 8.73 (wide s : IH).

aD<20=>-12.7°<+/>- 0.6 in methanol at 0.5%.

Example 8

Enantiomer B of 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid (undefined absolute configuration)

A solution of 0.22 g of enantiomer B methyl 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm<3>methanol and 1.23 cm<3>5 N sodium hydroxide is heated at a temperature of about 80°C with stirring. in an inert atmosphere for 12 hours. After cooling to about 20°C, the reaction mixture was evaporated under reduced pressure (2 kPa; 45°C) to give an off-white crust. The residue is taken up with 25 cm 3 of dichloromethane * and 10 cm 3 of distilled water and then neutralized with 1.2 cm<3>5 N hydrochloric acid and extracted with 25 cm<3>diethyl ether. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30°C. The resulting residue is purified by chromatography on a silica gel column (particle size 70-200 µm; diameter 2 cm), eluting with a chloroform-methanol-aqueous ammonia solution (28%) (12/3/0.5 by volume) mixture, collecting fractions of 10 cm each<3.> The fractions containing the expected product are combined and then evaporated according to the conditions described above. 0.2 g of enantiomer B 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl-2-morpholinecarboxylic acid is obtained in the form of a white solid.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.50 to 1.85 (mt: 4H); 1.96 (d, J = 11 Hz : IH); 2.08 (wide t, J = 11 Hz : IH); from 2.45 to 2.55 (mt: 2H); 2.60 (wide d, J = 11 Hz : IH); 3.07 (mt: 2H); 3.10 (t, J = 7.5 Hz : 2H); from 3.10 to 3.20 (mt: 2H); 3.54 (very wide d, J = 11 Hz : IH); 3.91 (wide t, J = 11 Hz : IH); 3.98 (s : 3H); 7.07 (mt: IH); from 7.20 to 7.35 (mt: 2H); from 7.35 to 7.45 (mt: 2H); 7.96 (d, J = 9 Hz : IH); 8.68 (with :

IH).

aD<20=>+16.0 +/- 0.5 in 0.5% methanol.

Preparation of enantiomers A and B methyl 4-[2-[(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2-morpholinecarboxylate: Mixture of 0.7 g of methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate (racemic mixture of enantiomers A and B), 0.59 g 2-(2-Bromoethyl)thio]-1,4-difluorobenzene, 0.32 g of potassium iodide and 1.33 g of potassium carbonate in 45 cm<3>acetonitrile is heated, with stirring and in an inert atmosphere, for 20 hours at a temperature of about 75°C. After cooling to a temperature of about 20°C, the reaction mixture is filtered and the insoluble residue is washed twice with 10 cm<3>acetonitrile each. The filtrate is evaporated under reduced pressure (2 kPa) at a temperature of about 40°C. The residue after evaporation is taken up with 50 cm<J>of distilled water and 100 cm<3>of ethyl acetate. The organic phase is washed 3 times with 30 cm<3> of distilled water and twice with 50 cm<3> of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated according to the conditions described above. The obtained oil is purified by chromatography on a silica gel column (particle size is 70-200 um; diameter 2.5 cm), eluting with a mixture of dichloromethane-ethyl acetate (90/10 by volume) while collecting fractions of 10 cm each<3.> Fractions containing the desired product are combined and then evaporated under reduced pressure (2 kPa) at a temperature of about 40°C. 0.52 g of methyl (±)-4-[2-(2,5-difluorophenyl)thio]ethyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate is obtained in the form of a colorless thick oil (racemic mixture of enantiomers A and B).

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): from 1.40 to 1.60 (mt : 1H); 1.73 (mt :

3H); 2.01 (d, J= 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : IH); from 2.50 to 2.60 (mt: 2H); 2.64 (wide d, J = 11 Hz : IH); 3.06 (mt: 2H); 3.10 (t, J = 7 Hz : 2H); 3.17 (wide d, J = 11 Hz : IH); 3.59 (s : 3H); 3.64 (very wide d, J = 7 Hz : IH); 3.81 (split t, J = 11 and 3 Hz : IH); 3.97 (s : 3H); 7.65 (mt: IH); from 7.20 to 7.35 (mt: 2H); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.68 (wide s : IH). 1-[(2-Bromoethyl)thio]-(2,5-difluoro)benzene is obtained according to the method described in patent application WO 02/40474.

Starting with the racemic mixture of enantiomers A and B obtained above, separation of each enantiomer is performed using HPLC.

The separation of the 2 enantiomers A and B takes place in the stationary phase Chiracel OD TA/C18 starting with 0.52 g of the mixture A, B described above, particle size 20 µm; diameter 80 mm and length 350 mm; mass of stationary gauze 1200 g), the mobile phase consists of a mixture of heptane/ethanol/triethylamine (95/05/0.05 by volume) having a flow rate of 110 cm<3>per minute and a wavelength on the UV detector set at 265 nm.

Fractions containing the first enantiomer (enantiomer A) were eluted in the first position, levorotated, combined and evaporated under reduced pressure (2 kPa) at a temperature in the region of about 40°C to give 0.224 g of a colorless oil. Fractions containing the other enantiomer

(enantiomer B) are eluted in the second position, right-handed, combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40°C to give 236 g of a colorless oil.

Enantiomer A

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.40 to 1.60 (mt: 1H); 1.73 (mt: 3H); 2.01 (d, J = 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : 1H); from 2.50 to 2.60 (mt: 2H); 2.64 (wide d, J = 11 Hz : IH); 3.05 (mt: 2H); 3.10 (t, J = 7 Hz : 2H); 3.17 (broad d, J = 11 Hz : IH); 3.59 (s : 3H); 3.64 (very wide d, J = 11 Hz : IH); 3.81 (broad t, J = 11 and 3 Hz : III); 3.97 (s : 3H); 7.05 (mt: IH); from 7.20 to 7.35 (mt: 211); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.68 (wide s : IH).

aD<20=>-17.5° +/- in DMSO at 0.6%.

Enantiomer B

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.40 to 1.60 (mt: 1H); 1.73 (mt: 3H); 2.01 (d, J = 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : IH); from 2.50 to 2.60 (mt: 2H); 2.64 (wide d, J = 11 Hz : IH); 3.06 (mt: 2H); 3.10 (t, J = 7 Hz : 2H); 3.17 (wide d, J = 11 Hz : IH); 3.59 (s : 3H); 3.64 (very wide d, J = 11 Hz : IH); 3.81 (split t, J = 11 and 3 Hz : IH); 3.97 (s : 3H); 7.05 (mt: IH); from 7.20 to 7.35 (mt: 2H); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.68 (wide s : IH).

aD<2>°= +24.1° +/- 0.9% in DMSO at 0.5%.

Methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2-morpholinecarboxylate

17.3 cm<3>of 4 N dioxane hydrochloride was added to a solution of 3.2 g of 4-(],1-dimethylethyl) and 2-methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2,4-morphodicarboxylate in 70 cm<3>of dioxane, and then the medium was stirred at 20°C for 16 hours. The reaction medium is then evaporated under reduced pressure (45°C; 5 kPa). The residue is taken up in 30 cm<3>ethyl acetate and 20 cm<3>distilled water and then neutralized with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 40°C. The obtained residue is purified by chromatography on a silica gel column (particle size 70-200 µm; diameter 2.5 cm), eluting with a dichloromethane-methanol mixture (95/5 by volume) with collection

fraction of 10 cm each<3>. Fractions containing the desired product are combined and combined according to the conditions described above. 1.8 g of methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate is obtained in the form of a thick brown oil.

1H NMR spectrum (300 MHz, (CD3)2SO d6, 5 in ppm): from 1.35 to 1.60 (mt: IH; 1.69 (mt: 3H); from 2.55 to 2.70 (mt: IH); 3.04 (mt: 2H); 3.19 (mt: 2H); from 3.30 to 3.35 (mt: IH); 3.55 (very wide d, 11 Hz); 3.70 (s: 3H); 7.40 (d, 3 Hz: IH); 8.68 (broad s: IH).

4-(1,1-dimethylethyl) and 2-methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-2,4-morphodicarboxylate 32 cm<3>0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran was added to a solution of 3.9 g of 4-(1,1-dimethylethyl) and 2-methyl (±)-2-(2-propenyl)-2,4-morpholindicarboxylate in 40 cm<3>tetrahydrofuran with stirring and in an inert atmosphere and after cooling to -10°C. The mixture is then brought to a temperature of about 20°C with stirring for another 4 hours. 4.35 g of 4-iodo-3-chloro-6-methoxyquinoline in a solution of 30 cm<3>tetrahydrofuran is added for 45 minutes, then 260 mg of diphenylphosphinoferrocenepalladium chloride and finally 7.54 g of tribasic potassium phosphate. The reaction mixture was heated under reflux for 15 hours and then filtered while hot on sintered glass. The filtrate is taken up 4 times with 20 cm<3>ethyl acetate each and concentrated to dryness under reduced pressure (40°C; 5 kPa). The residue is taken up with 250 cm<3>ethyl acetate and 200 cm<3>water. The organic phase is separated by decantation, washed 3 times with 50 cm of distilled water and twice with 100 cm of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (45°C; 5 kPa). The residue is purified by chromatography on a silica gel column (particle size 70-200 (im; diameter 2.8 cm), eluting with dichloromethane and then with a mixture of dichloromethane-ethyl acetate (90/10 by volume) collecting fractions of 200 cm<3.> Fractions containing the desired product are combined and then concentrated under reduced pressure (40°C; 5 kPa). 3.22 g 4-(1,1-dimethylethyl) and 2-methyl (±)-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2,4-morphodicarboxylate are obtained as a yellow viscous oil.

1H-NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.35 to 1.85 (mt: 4H); 1.38 (s : 9H); from 2.85 to 3.05 (mt: IH); 3.07 (mt: 2H); 3.61 (s : 3H); 3.67 (mt: 4H); 3.97 (s : 3H);

4.17 (d, J = 13.5 Hz : IH); from 7.35 to 7.45 (mt: 2H); 7.97 (d, J = 9 Hz : IH); 8.69 (wide s : IH).

4-(1,1-Dimethylethyl) and 2-methyl (±)-2-(2-propenyl)-2,4-morpholindicarboxylate (racemate)

15 cm<3>1.6 M solution of butyllithium in hexane was added dropwise to a solution of 3.7 cm<3>diisopropylamine in 50 cm<3>tetrahydrofuran with stirring and in an inert atmosphere after cooling to -70°C. The mixture is stirred at this temperature for 70 minutes. 5 g of 4-(1,1-dimethylethyl) and 2-methyl 2,4-morphodicarboxylate in dissolved in 40 cm<3>tetrahydrofuran is added dropwise over 40 minutes. The mixture is stirred at the same temperature for 40 minutes. 3.2 g of -2-propenyl bromide in a solution of 10 cm<3>THF is added drop by drop for 25 minutes, the mixture is stirred at the same temperature for 70 minutes. The mixture is then brought to a temperature of about 20°C while stirring is continued for another 2 hours. 15 cm of saturated ammonium chloride solution is added drop by drop. The temperature rises to 25°C. The organic phase is separated by decantation, washed once with 50 cm<3> of distilled water and twice with 100 cm<3> of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and then concentrated under reduced pressure (45°C; 5 kPa). The residue is purified by chromatography on a silica gel column (particle size 70-200 utn; diameter 2.8 cm), eluted with dichloromethane and fractions of 50 cm each are collected <3.> Fractions containing the desired product are combined and then concentrated under reduced pressure (45°C; 5 kPa). 3.5 g of 4-(1,1-dimethylethyl) and 2-methyl (±)-2-(2-propenyl)-2,4-morphodicarboxylate were obtained as a colorless oil.

<*>H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): 1.40 (s : 9H); 2.38 (d, J = 7.5 Hz : 2H); from 2.80 to 3.05 (mt: 2H); from 3.55 to 3.80 (mt: 311); 3.66 (s : 3H); 4.20 (d, J = 13 Hz : IH); from 5.00 to 5.20 (mt: 2H); 5.70 (mt: IH).

4-(1,1-Dimethylethyl) and 2-methyl (±)-2,4-morphodicarboxylate

13.5 cm3 of iodomethane and then 7 g of cesium carbonate were added to a solution of 10 g of 4-(1,1-dimethylethyl) 2,4-morpholindicarboxylate in 200 cm3 of acetonitrile with stirring and in an inert atmosphere, at a temperature of about 20°C. The mixture is stirred at the same temperature for 24 hours. The mixture is then filtered on Celite and the filtrate is concentrated to dryness under reduced pressure (45°C; 5 kPa). The residue is taken up with 250 cm 3 of dichloromethane and 200 cm 3 of water. The organic phase is separated by decantation, washed 3 times with 50 cm each of distilled water and

twice with 100 cm 3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (35°C; 5 kPa). 5 g of 4-(1,1-dimethylethyl) and 2-methyl 2,4-morphodicarboxylate is obtained in the form of a yellow viscous oil that crystallizes slowly. The melting point is 68°C.

1H NMR spectrum (400 MHz, (CD3)2SO d6 at a temperature of about 373K, 8 in ppm): 1.45 (s : 9H); 3.18 (split dd, J = 13.5 - 9 and 3 Hz : IH); 3.28 (dd, J = 13.5 and 8 Hz : IH); 3.53 (mt: 2H); 3.71 (s: 3H); 3.80 (dd, J= 13.5 and 3 Hz : IH); 3.89 (dt, J = 11 and 4 Hz : IH); 4.17 (dd, J = 8 and 3 Hz : IH).

Example 9

Enantiomer A 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid (undetermined absolute configuration) Solution of 0.21 g of enantiomer A methyl 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm<3>methanol and 1.22 cm<J>5 N sodium hydroxide is heated at a temperature of about 80°C.

with stirring in an inert atmosphere for 12 hours. After cooling to about 20°C, the reaction medium is evaporated under reduced pressure (2 kPa; 45°C) to give a whitish crust. The residue is taken up with 25 cm<3> of dichloromethane and then with 10 cm<3> of distilled water and then neutralized with 1.23 cm<3> of 5 N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30°C. The resulting residue was purified by chromatography on silica gel (particle size 70-200 (im; diameter 2 cm), eluting with a mixture of chloroform-methanol-aqueous ammonia solution (28%) (12/3/0.5 by volume) collecting fractions of 10 cm<3.> The fractions containing the desired product were combined and then evaporated according to the conditions described above. 0.13 g of enantiomer A 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl-2-morolinecarboxylic acid is obtained as a yellow glaze.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.45 to 1.60 (mt: 1H); from 1.65 to 1.90 (mt: 3H); 1.95 (d, J = 11 Hz : IH); 2.09 (split t, J = 11 and 3.5 Hz : IH); 2.63 (wide d, J = 11 Hz : IH); from 2.95 to 3.15 (mt: 4H); 3.17 (wide d, J = 11 Hz : IH); 3.63 (very wide d, J = 11 Hz : IH); 3.90 (very wide t, J = 11 Hz : IH); 3.96 (s : 3H); 6.41

(dt, J = 7 and 16.5 Hz : IH); 6.62 (wide d, J = 16.5 Hz : IH); 7.13 (mt: IH); 7.24 (broad t, J = 10 and 4.5 Hz : IH); 7.39 (mt: 2H); 7.48 (mt: IH); 7.96 (d, J = 10 Hz : IH); 8.68 (s : IH). aD<20>= -12.6° +/- 0.7 in methanol at 0.5%.

Example 10

Enantiomer B 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid (undetermined absolute configuration) Solution of 0.21 g enantiomer B methyl 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate in a mixture of 10 cm3 of 1,4-dioxane, 10 cm<J>methanol and 1.22 cm<3>5 N sodium hydroxide is heated at a temperature of about 80°C with stirring and in an inert atmosphere for 12 hours. After cooling to about 20°C, the reaction mixture was evaporated under reduced pressure (2 kPa; 45°C) to give an off-white crust. The residue is taken up with 25 cm<3>dichloromethane and 10 cm<J>distilled water and then neutralized with 1.2 cm<3>5 N hydrochloric acid. The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2 kPa) at a temperature of about 30°C. The residue was purified by column chromatography on silica gel (particle size 70-200 (im; diameter 2 cm), eluting with a mixture of chloroform-methanol-aqueous ammonia (28%) (12/3/0.5 by volume) and collecting fractions of 10 cm<3>. The fractions containing the expected product were combined and then evaporated under the conditions described above. 0.14 g of enantiomer B 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylic acid is obtained as a thick orange oil.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): from 1.45 to 1.60 (mt: 1H); from 1.65 to 1.85 (mt: 3H); 1.95 (d, J = 11 Hz : IH); 2.09 (split t, J = 11 and 2.5 Hz : IH); 2.62 (wide d, J= 11 Hz: IH); from 2.95 to 3.15 (mt: 4H): 3.17 (broad d, J= 11 Hz: IH); 3.62 (wide d, J = 11 Hz : IH); 3.91 (very wide t, J = 11 Hz : IH); 3.96 (s : 3H); 6.40 (dt, J = 16 and 7 Hz : IH); 6.62 (wide d, J = 16 Hz : IH); 7.13 (mt: IH); 7.24 (wide t, J = 10 and 5 Hz : IH); 7.39 (mt: 2H); 7.48 (mt: IH); 7.96 (d, J = 10 Hz : IH); 8.68 (wide s : IH).

aD<20>= +12.4° +/- 0.6 in methanol at 0.5%.

Preparation of enantiomers A and B methyl 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate: A solution of 0.62 g of benzotriazole and 0.62 g of thionyl chloride in a solution of 30 cm<3>chloroform is added dropwise to 0.7 g of 2,5-difluorocinnamyl alcohol. dissolved in 90 cm of chloroform, with stirring under an inert atmosphere, at a temperature of about 23°C. The mixture is then stirred at the same temperature for 2 hours. The reaction mixture was taken up with 75 cm<3> of saturated sodium bicarbonate solution, and * ti* m with 75 cm 3 of distilled water and finally dried over magnesium sulfate to obtain a yellow solution S. This solution S was added to a mixture of 1.1 g of methyl 2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate, 0.5 g of potassium iodide and 2.1 g potassium carbonate in 150 cm<3>acetonitrile and then heated with stirring in an inert atmosphere for 20 hours at a temperature of about 75°C. After cooling to a temperature of about 20°C, the reaction mixture is filtered and the insoluble part is washed twice with 10 cm<3>acetonitrile each. The filtrate is evaporated under reduced pressure (2 kPa) at a temperature of about 40°C. The residue after evaporation is taken up with 50 cm<3> of distilled water and 100 cm<3> of ethyl acetate. The organic phase is washed 3 times with 30 cm<3> of distilled water and twice with 50 cm<3> of a saturated solution of magnesium sulfate and evaporated under the conditions described previously. The resulting oil is purified by chromatography on a silica gel column (particle size 70-200 um; diameter 2.5 cm), eluting with a mixture of dichloromethane-ethyl acetate (80/20 by volume) and collecting fractions of 10 cm each. Fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa) at a temperature of about 40°C. 0.48 g of methyl 4-[3-(2,5-difluorophenyl)-2-propenyl]-2-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-2-morpholinecarboxylate is recovered as a brown gum (racemic mixture of enantiomers A and B).

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): from 1.40 to 1.60 (mt: 1H); 1.73 (mt: 3H); 1.99 (d, J = 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : IH); 2.64 (wide d, J = 11 Hz : IH); 3.05 (mt: 2H); from 3.05 to 3.15 (mt: 2H); 3.18 (wide d, J = 11 Hz : IH); 3.61 (s : 3H); 3.67 (very wide d, J = 11 Hz : IH); 3.83 (split t, J = 11 and 2.5 Hz : IH); 3.96 (s : 3H); 6.39 (dt, J = 16.5 and 7 Hz : IH); 6.61 (broad d, J = 16.5 Hz : IH); 7.13 (mt: IH); 7.24 (split t, J = 10 and 5 Hz : IH); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.49 (mt: IH); 7.96 (d, J = 9 Hz : IH); 8.68 (wide s : IH).

Starting from the racemic mixture of enantiomers A and B obtained previously, the separation of each enantiomer is carried out by HPLC.

The separation of the 2 enantiomers A and B takes place on the stationary phase Chiracel OD IM Cl 8 starting from 0.52 g of the mixture A, B described previously, particle size 20 µm; diameter 80 mm, length 350 mm; the mass of the stationary phase is 1200 g, the bulk phase consists of a mixture of heptane/methanol/propanol (95/01/04 in volumes) having a flow rate of 100 cm per minute and the UV detector is set at a wavelength of 254 nm.

Fractions containing the first enantiomer are eluted in the first position (called enantiomer A), levorotatory, combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40°C to give 0.217 g of a colorless oil.

Fractions containing the other enantiomer are eluted at the second position (called enantiomer B), right-handed, combined and evaporated under reduced pressure (2 kPa) at a temperature of about 40°C to give 0.212 g of a colorless oil.

EnantiomerA

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): from 1.40 to 1.60 (mt: 1H); 1.73 (mt: 3H); 1.99 (d, J = 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : IH); 2.64 (wide d, J = 11 Hz : IH); 3.05 (mt: 2H); from 3.05 to 3.15 (mt: 2H); 3.18 (d, J = 11 Hz : IH); 3.61 (s : 3H); 3.67 (very wide d, J = 11 Hz : IH); 3.83 (broad t, J = 11 and 2.5 Hz : IH); 3.96 (s : 3H); 6.39 (dt, J = 16 and 6.5 Hz : IH); 6.61 (wide d, J = 16 Hz : IH); 7.13 (mt: IH); 7.24 (split t, J = 10 and 4.5 Hz : IH); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.49 (mt: IH); 7.96 (d, J = 9 Hz : IH); 8.68 (s : IH).

Enantiomer B

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , S in ppm): from 1.40 to 1.60 (mt: 1H); 1.73 (mt: 3H); 1.99 (d, J = 11 Hz : IH); 2.12 (split t, J = 11 and 3.5 Hz : IH); 2.64 (wide d, J = 11 Hz : IH); 3.05 (mt: 2H); from 3.05 to 3.15 (mt: 2H); 3.18 (wide d, J = 11 Hz : IH); 3.61 (s : 3H); 3.67 (very wide d, J = 11 Hz : IH); 3.83 (broad t, J = 11 and 2.5 Hz : IH); 3.96 (s : 3H); 6.39 (dt, J= 16 and 7 Hz: IH); 6.61 (wide d, J=16Hz: IH); 7.13 (mt: IH);

7.24 (split t, J = 10 and 5 Hz : IH); 7.36 (d, J = 3 Hz : IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.49 (mt: IH); 7.96 (d, J = 9 Hz : IH); 8.68 (s : IH).

Example 11

1-[(2R)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylic acid

5 cm<3>5 N aqueous sodium hydroxide solution was added at a temperature of about 20°C to 614 mg (1,267 mmol) of methyl 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylate in a solution of 20 cm<3>dioxane. After stirring at reflux for 1.5 hours, 6 cm<3>5 N aqueous sodium hydroxide solution is added again and the medium is kept under reflux for another 3 hours; the reaction medium is cooled and 4.5 cm<3> of 37% hydrochloric acid is added, and then it is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography on a 200 cm<3> column of fine silica gel [eluent: solvent gradient : (dichloromethane-methanol-aqueous ammonia solution of 28%) (from 100-0-0 to 72-24-4 in volumes)]. Fractions containing the desired product are combined to dryness (2.7 kPa). The residue (530 mg) was taken up with 10 cm<3>dichloromethane, quenched with 25 cm<3>diethyl ether to give 445 mg of 1-[(2R')-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylic acid as a slightly pink substance melting at 211°C.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): 1.60 (mt: 2H); 1.99 (mt: 2H); from

2.95 to 3.55 (mt: 2H); 3.09 (d, J = 7 Hz : 2H); 3.19 (wide d, J = 5.5 Hz : 2H); 3.37 (d, J = 7 Hz : 2H); 3.96 (s : 3H); 6.35 (dt, J = 16.5 and 5.5 Hz : IH); 6.57 (wide d, J = 16.5 Hz : IH); 7.13 (mt: IH); 7.25 (wide t, J = 9.5 and 5 Hz : IH); from 7.35 to 7.45 (mt: 2H); 7.49 (ddd, J = 9.5 - 6 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.70 (wide s: IH).

CI mass spectrum: m/z 471 (M+H)<+>(main peak).

Methyl 1-[(2 R )-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylate can be prepared as described in Example 12.

Example 12

Methyl 1-[(2N)-3-(2,5-difluorophenyl)-2-propenyl]-343-(3-fluoro-6-methoxyquinolin-4-11)propyl]-3-azetidinecarboxylate 2 g of potassium carbonate, 0.531 g of potassium iodide and then a freshly prepared solution of 2-[(1N)-3-chloropropenyl]-1,4-difluorobenzene (3.8 mmol) in 1.18 g (2.91 mmol) of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylate dihydrochloride is added to a solution of 70 cm of acetonitrile at a temperature of about 20°C in an argon atmosphere. After stirring under reflux for 3 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up with 100 cm<3> of water, extracted 6 times with 100 cm<3> of dichloromethane which is concentrated to dryness under reduced pressure (2.7 kPa) to give 1.546 g of a brown oil which is purified by flash chromatography. on 240 ml of fine silica gel [eluent: gradient cyclohexane/ethyl acetate (from 50-50 to 40-60 by volume)]. After concentrating the fractions under reduced pressure, 0.799 g of methyl 1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylate is obtained as a yellow oil.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 6 in ppm): 1.57 (mt: 2H); 2.00 (mt: 2H); from 3.00 to 3.15 (mt: 2H); 3.10 (d, J = 7.5 Hz : 2H); 3.17 (wide d, J = 6 Hz : 2H); 3.38 (d, J = 6 Hz : 2H); 3.60 (s : 3H); 3.96 (s : 3H); 6.35 (dt, .1 = 16.5 and 6 Hz : IH); 6.55 (wide d, J = 16.5 Hz : IH); 7.12 (mt: IH); 7.24 (wide t, J = 9.5 and 5 Hz : IH); from 7.30 to 7.45 (mt: 2H); 7.48 (ddd, J = 9.5 - 6 and 3 Hz : IH); 7.96 (d, J = 9 Hz : IH); 8.70 (d, J = 1 Hz : IH).

Mass spectrum: m/z484(M<+>) m/z 191 (main peak).

A solution of 2-[(1£)-3-chloro-1-propenyl]-1,4-difluorobenzene (3.8 mmol) in acetonitrile can

can be obtained as follows:

A solution of 0.34 cm<3>(4.66 mmol) of thionyl chloride and 0.555 g (4.66 mmol) of benzotriazole in 40 cm<3>dichloromethane is added at a temperature of about 20°C in an argon atmosphere to 0.646 g (3.8 mmol) of 2,5-difluorocinnamyl alcohol dissolved in 40 cm of dichloromethane. After stirring for 10 minutes, the reaction mixture was filtered on a No. 3 sintered glass and the solid residue is washed twice with 10 cm<3>dichloromethane each. The filtrate is washed 3 times with 30 cm<3> of water. The organic phase is dried over magnesium sulfate and filtered to give a solution of 2-[(l£)-3-chloro-l-propenyl]-1,4-difluorobenzene (3.8 mmol) which is then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of about 20°C, before dissolving in acetonitrile.

Methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylate dihydrochloride can be obtained as follows: 10 cm<3>4 N hydrochloric acid in dioxane is added at a temperature of about 20°C to 1.325 g (3.06 mmol) of l-(1,1-dimethylethyl) and 3-methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]1,3-azetidine dicarboxylate dissolved in 10 cm<3>methanol. After stirring for 4 hours at a temperature of about 20°C, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give 1.19 g of methyl 3-|3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylate dihydrochloride as a bright yellow foam.

EMass spectrum: m/z 332 (M+ ), m/z304, 204 (basic peak), i191.1-(1,1-Dimethylethyl) and 3-methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-azetidine dicarboxylate can be obtained as follows: A solution of 1.021 g (4 mmol) of l-( 1,1-dimethylethyl) and 3-methyl 3-(2-propenyl)-1,3-azetidine dicarboxylate in 15 cm<3>tetrahydrofuran is added at a temperature of about 3°C, in an argon atmosphere, to 12 cm<3>(6 mmol) of a 0.5 M solution of 9-BBN

(9-borabicyclo[3.3.1]nonane)/THF. After heating the reaction mixture to a temperature of about 20°C and stirring for 3 hours at a temperature of about 20°C, 2.34 g (4.4 mmol) of 3-fluoro-4-iodo-6-methoxyquinoline in suspension with 35 cm<3>tetrahydrofuran and then 2.55 g (12 mmol) of potassium phosphate and 0.09 g (0.123 mmol) were added sequentially. PdCbdppf (l,r-bis(diphenylphosphino)ferrocenepalladium dichloride). After stirring for 19 hours at reflux, the reaction mixture was cooled and then filtered on sintered glass, which was subsequently washed with tetrahydrofuran and ethyl acetate. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 3.09 g of a black oil which is purified by flash chromatography on 300 cm<3>fine silica gel [eluent: gradient cyclohexane/ethyl acetate (from 75-25 to 60-40 by volume)]. After concentrating the fractions under reduced pressure, 1,334 g of 1-(1,1-dimethylethyl) and 3-methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-azetidinedicarboxylate were obtained as a yellow oil.

Mass spectrum: m/z 433 (M+H)<+> (main peak).

1-(1,1-Dimethylethyl) and 3-methyl 3-(2-propenyl)-1,3-azetidine dicarboxylate can be obtained as follows: 20 cm<3> (20 mmol) of lithium bis(trimethylsilyl)amide as a 1 M solution in tetrahydrofuran is added dropwise at a temperature of about -78°C, in an argon atmosphere, to 3.601 g (16.73 mmol) 1-(1,1-dimethylethyl) and 3-methyl 1,3-azetidine dicarboxylate dissolved in 40 cm<3>tetrahydrofuran. After stirring for 10 minutes at about -78°C, 2.2 cm (25.4 mmol) of 2-propenyl bromide was added and the temperature was then allowed to rise from -78°C to about 20°C, where the mixture was stirred for an additional 17 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa). the residue is taken up with 50 cm<3> of water and then extracted 3 times with 50 cm<3> of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.525 g of a yellow oil which is purified by flash chromatography [eluent: gradient cyclohexane/ethyl acetate (from 90-10 to 80-20 in volumes)]. After concentrating the fractions under reduced pressure, 2.75 g of -dimethylethyl) and 3-methyl 3-(2-propenyl)-1,3-azetidinedicarboxylate were obtained in the form of a colorless oil.

CI mass spectrum: m/z 256 (M+H)<+>, m/z 273 (M+NH4)<+> (main peak).

1-(1,1-Dimethylethyl) and 3-methyl 1,3-azetidinedicarboxylate can be obtained as follows:

0.9 cm<3> (0.9 mmol) of a molar solution of tetrabutylammonium fluoride is added to a solution of 3.513 g (17.46 mmol) of I-(1,1-dimethylethyl) 1,3-azetidinedicarboxylate dissolved in 30 cm<3>methanol; the mixture is cooled to a temperature of about 5°C, and then 10 cm<3>(20 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane is added and then after thirty minutes, another 15 cm'' (30 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane is added. After decolorization, the solvents were evaporated under reduced pressure (2.7 kPa) to give 4.205 g of a brown liquid which was purified by flash chromatography on 320 ml of fine silica gel [eluent: cyclohexane/ethyl acetate (80/20 by volume)]. After concentrating the fractions under reduced pressure, 3,456 g of 1-(1,1-dimethylethyl) and 3-methyl 1,3-azetidinedicarboxylate were obtained in the form of a colorless liquid.

CI mass spectrum: m/z 216 (M+H)<+>, m/z 233 (M+NH4)<+> (main peak).

Example 13

3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-propyl]-1-[2-(2-thienylthio)ethyl]-3-azetidinecarboxylic acid sodium salt

The procedure is carried out as in Example 11, but starting with 512.4 mg (1.08 mmol) of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]azetidine-3-carboxylate, 20 cm<3>dioxane and 10 cm<3>5 N aqueous sodium hydroxide solution. 1.5 hours under reflux. The mixture is then cooled and then 5 cm<3>hydrochloric acid is added, followed by aqueous ammonia until pH > 8 is reached. The solvents are evaporated under reduced pressure (2.7 kPa), but not to dryness. The mixture is taken up with 20 cm<3> of water and left to stand, before filtering, washing with water and diethyl ether. 473 mg of the sodium salt of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)-ethyl]-3-azetidinecarboxylic acid is obtained in the form of a white powder that melts at about 67°C.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm): 1.57 (mt: 2H); 1.96 (mt: 2H); 2.57 (broad t, J = 7 Hz : 2H); 2.74 (broad t, J = 7 Hz : 2H); from 2.95 to 3.10 (mt: 2H); 3.05 (broad d, J - 7 Hz : 2H); 3.32 (broad d, J = 7 Hz : 2H); 3.97 (s : 3H): 7.04 (dd, J = 5.5 and 3.5 Hz : IH); 7.17 (broad d, J = 3.5 Hz : IH); 7.38 (mt: IH); 7.40 (dd, J = 9 and 3 Hz : IH); 7.60 (broad d, J = 5.5 Hz : IH); 7.97 (d, J = 9 Hz : IH); 8.70 (broad s : IH).

EI mass spectrum: m/z 460 (M<+>), m/z 331 (base peak).

Example 14

Methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-azetidinecarboxylate

A solution of 0.53 cm<3>(2.7 mmol) of diisopropylcarbodiimide in 5 cm<3>tetrahydrofuran was added at a temperature of about 20°C to a solution of 508 mg (1.35 mmol) of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)-3-azetidinecarboxylate, 314 mg (2.7 mmol). 2-thiophenethiol and 708 mg (2.7 mmol) of triphenylphosphine in 5 cm<3>tetrahydrofuran and the mixture is stirred for about 22 hours at a temperature of about 20°C. 30 cm<3> of diethyl ether is then added to the reaction mixture and the mixture is extracted twice with 30 cm<3> of water supplemented with 0.5 cm<3> of concentrated methanesulfonic acid, and then twice with 30 cm<3> of water. This acidic aqueous phase, after the phases have been combined, is washed twice with 30 cm<3>diethyl ether each, and then alkyned to pH > 11; the mixture is then extracted 5 times with 50 cm<J>dichloromethane each, before being evaporated to dryness under reduced pressure (2.7 kPa). The residue (693 mg) was purified by flash chromatography on 150 cm of fine silica gel [eluent: cyclohexane/ethyl acetate (1/1 by volume)]. After concentration of the fractions under reduced pressure, 340 mg of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-azetidinecarboxylate were obtained in the form of an almost colorless oil.

1 H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm): 1.53 (mt: 211); 1.97 (mt: 2H); 2.56 (t, J = 7 Hz : 2H); 2.74 (t, J = 7 Hz : 2H); from 3.00 to 3.15 (mt: 2H); 3.06 (d, J = 7 Hz : 2H); 3.33 (d, J = 7 Hz : 2H); 3.59 (s : 3H); 3.97 (s : 3H); 7.04 (dd, J = 5.5 and 3.5 Hz : IH); 7.17 (dd, J = 3.5 and 1 Hz : IH); 7.37 (wide d, J = 3 Hz : IH); 7.41 (broad dd, J = 9 and 3 Hz : 1H); 7.60 (dd, J = 5.5 and 1 Hz : IH); 7.97 (d, J = 9 Hz : IH); 8.70 (d, J = 1 Hz : IH).

EI mass spectrum: m/z474(M+ ), m/z345 (main peak).

Methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)-3-azetidinecarboxylate can be obtained as follows: 3.51 g of potassium carbonate (24.4 mmol) is added to a solution of 2.57 g (6.347 mmol) of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-azetidinecarboxylate. dihydrochloride and 0.75 cm<3>(9.6 mmol) of 2-iodoethanol in 100 cm<3>acetonitrile and the mixture was stirred for 20 hours at a temperature of about 20°C, before heating for 1.25 hours under reflux and evaporation of the solvent under reduced pressure. The residue is taken up in 100 cm<3> of water and extracted 3 times with 100 cm<3> of dichloromethane each, which is evaporated under reduced pressure (2.7 kPa). 2.88 g of a pink oil is obtained, which is purified by flash chromatography on 300 ml of fine silica gel [eluent: gradient dichloromethane/methanol/aqueous ammonia solution of 28% (from 100-0-0 to 86-12-2 by volume)]. After concentrating the fractions under reduced pressure, 1,748 g of methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-hydroxyethyl)-3-azetidinecarboxylate were obtained as a pink oil.

EI mass spectrum: m/z 376 (M+ ), m/z 345 (main peak).

Example 15

(±)-3-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2R')-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid sodium salt

Following the method described in Example 1, but starting from 4-bromo-3-chloro-6-methoxyquinoline (which can be obtained according to the method described in the patent WO200240474-A2, the sodium salt is obtained (±)-3-[3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2R')-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid as a solid melting at 77°C.

EI mass spectrum: m/z=500 M+, m/z=153 C9H7F2+basic peak.

Infrared spectrum KBr: 2936; 1621; 1504; 1491; 1230; 1117; 831; 743 and 728 cm"1.

Example 16

Sodium salt of (±)-1-[(2i?)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid

Proceeding according to the method described in Example 1, but starting from 4-bromo-6-methoxyquinoline, the sodium salt of (±)-1-[(2£)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid is obtained in the form of a solid which melts at about 109-112°C.

CI mass spectrum m/z=467 MH<+>basic peak Infrared spectrum KBr: 2941; 1621; 1591; 1509; 1490; 1242; 1228; 1031; 845 and 728 cm"<1>.

Example 17

Enantiomer A (levogyric) 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylic acid (undetermined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate, enantiomer A (levogyr) 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate is obtained. acid (undefined absolute configuration) in the form of a white solid that melts at 160°C.

[a]D<2>° = - 36.3 +/- 0.8 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) 2937; 1620; 1508; 1228; 1031; 847; 832; 809; 785; 708 and 452 cm"'.

EI mass spectrum: m/z = 474 (M+); 345 (M - C5H5S2 )+ basic peak.

Methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienithio)ethyl]-3-pyrrolidinecarboxylate can be prepared as described in Example 2, but starting from 2-[(2-bromoethyl)thio]thiophene. A yellow oil is obtained.

EI mass spectrum: m/z 488 (M+).

2-[(2-Bromoethyl)thio]thiophene can be obtained according to the method described in patent VV0240474-A2.

Example 18

Enantiomer B (right-handed) 343-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate, enantiomer B (right-handed) 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate is obtained. acid (undefined absolute configuration) as a white solid melting at 172°C.

[a]D<2>° = + 36.3 +/- 0.8 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) 2937; 1620; 1508; 1228; 1031; 847; 832; 809; 785; 708 and 452 cm"1.

EI mass spectrum: m/z = 474 (M+); 345 (M - C5H5S2)+ basic peak .

Example 19

Enantiomer A (right-handed) sodium salt of l-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, the enantiomer A (right-handed) sodium salt is obtained 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration) as a white solid.

[a]D<2>° = + 15.3 +/- 0.8 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) 2934; 1620; 1509; 1483; 1361; 1230; 1187; 1030; 909; 831 and 757 cm"1.

CI mass spectrum m/z = 505 (MH)+ base peak.

Methyl (±)-1-[24(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be prepared as described in Example 2, starting from 2-[(2-bromoethyl)thio]-1,4-difluorobenzene. A bright yellow oil is obtained.

EI mass spectrum: m/z 518 (M+).

2-[(2-Bromoethyl)thio]-1,4-difluorobenzene can be obtained according to the method described in patent V/O200240474-A2.

Example 20

Enantiomer B (levogyric) sodium salt of l-[24L(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, the enantiomer B (levogyr) sodium salt is obtained 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration) as a white solid.

[a]D20 = - 17.5 +/- 0.7 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) 2934; 1620; 1509; 1483; 1361; 1230; 1187; 1030; 909; 831 and 757 cm"<1>.

CI mass spectrum m/z = 505 (MH)+ base peak.

Example 21

Enantiomer A (levogyric) 1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (levogyr) is obtained 1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration) in the form of a white lacquer.

[a]D2° = - 18.9+/- 0.7 [methanol (c = 0.5), 589 nm].

IR spectrum (CC14)cm-1 2929; 1621; 1507; 1499; 1477; 1292; 1231; 1031; 1008; 908 and 832 cm"1.

CI mass spectrum m/z = 489 (MH)+ base peak.

Methyl (±)-1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained according to the method described in Example 2, but starting from 2-(2-bromoethoxy)-1,3-difluorobenzene. A yellow oil is obtained.

EI mass spectrum: m/z 502 (M+).

2-(2-Bromoethoxy)-1,3-difluorobenzene can be obtained according to the method described in the patent.

Example 22

Enantiomer B (right-handed) 1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidine carboxylic acid (undefined absolute configuration)

Following the method described in Example 3, but starting from methyl (±)-1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B (right-handed) is obtained 1-[2-(2,6-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration) in the form of white lacquer.

[a]D<20>= + 18.3<+/->0.7 [methanol (c = 0.5), 589 nm].

IR spectrum (CC14) cm"1 2929; 1621; 1507; 1499; 1477; 1292; 1231; 1031; 1008; 908 and 832

cm"1.

Cl mass spectrum m/z = 489 (MH)+ basic peak.

Example23

Enantiomer A of 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration)

8.3 cm<3>5 N aqueous sodium hydroxide was added at a temperature of about 20°C to 0.49 g (0.987 mmol) of enantiomer A methyl 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in a solution of 30 cm dioxane. After stirring under reflux for 16 hours, the reaction mixture was concentrated under reduced pressure (2.7 kPa), and then taken up with 75 cm of distilled water. The clear yellow solution was slightly acidified to pH 5 with 20 cm 2 N aqueous hydrochloric acid, then extracted with 75 cm<3>dichloromethane, and then twice with 50 cm<3>dichloromethane. The organic phase was separated by decantation, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.29 g of a residue which was treated with 5 cm<J>diisopropyl ether and then dried. This operation is repeated twice. 0.28g of enantiomer A l-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-

methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (undefined absolute configuration) as a crack colored solid.

EI mass spectrum: m/z=482 M+.; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2943; 1621; 1509; 1496; 1231; 1170; 1031; 830; 767 and 595 cm1.

[a]D20 = -37.5 +/-1 [dichloromethane, (c = 0.3), 589 nm].

Enantiomer A methyl 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained as follows: A solution of 1.68g methyl (±)-1-(2-propynyl)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate (racemic), 75 mg of copper diiodide, 0.67 g of 2,5-difluorobromobenzene and 0.24 g of tetrakistriphenylphosphine in 17 cm of triethylamine are heated at 80°C for one hour, then stirred at room temperature for 16 hours. The reaction mixture was diluted with 100 cm<3>ethyl acetate and then filtered, the organic phase was washed three times with 50 cm<3>distilled water, and then extracted with 100 cm 2 N hydrochloric acid solution. The aqueous phase is brought to pH 8-9 by adding potassium carbonate, and then extracted three times with 100 cm 3 of ethyl acetate each. The organic phases are combined, washed with 50 cm 3 of distilled water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) to give 1.83 g of a thick brown oil, which is purified by flash chromatography [eluent: cyclohexane / ethyl acetate (1 /l by volume)]. After concentrating the fractions under reduced pressure, 1.46 g of thick light yellow oil is obtained.

Separation on chiral HPLC of the two enantiomers A and B of methyl 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate takes place according to the method described in Examples 5 and 6.

For enantiomer A [a]D20 =-21.4 +/- 0.5 [methanol (c = 0.5), 589 nm]; EI mass spectrum m/z= 496 (M+).

For enantiomer B [ ]D20 =+ 19.2 +/- 0.7 [methanol (c = 0.5), 589 nm)]; EI mass spectrum m/z= 496 (M+).

Methyl (±)-1-(2-propynyl)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate (racemic) can be obtained as follows: 6.7 cm<3>triethylamine is added dropwise at room temperature to a solution of 6.23 g methyl (+)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate. of the dihydrochloride in 62 cm<3>dimethylformamide, followed dropwise by 2.4 cm<3>propargyl bromide. The solution was stirred at room temperature for 1 h, and then the reaction mixture was poured onto 180 g of crushed ice and 350 cm<3> of distilled water. The aqueous phase is extracted three times with 350 cm<3>ethyl ether each, the organic phases are combined, washed with 350 cm3 of distilled water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) to obtain 3.2 g of orange oil.

EI mass spectrum: m/z= 384 (M+).

Example 24

Enantiomer B of 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in example 23, starting from enantiomer B methyl 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+; m/z=151 C9H5F2+ basic peak (maximum).

Infrared spectrum KBr: 2943; 1621; 1509; 1496; 1231; 1170; 1031; 830; 767 and 595 cm"<1>.

[a]D<20>= +24.7 +/0.7 [methanol, (c = 0.3), 589 nm].

Example 25

Enantiomer A of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

Following the procedure described in Example 3, but with methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylate, enantiomer A 3- [3-(3-Chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid is obtained as a solid.

EI mass spectrum: m/z=500 M+. ; m/z=153 C9H7F2+ basic peak (maximum).

Infrared spectrum KBr: 2965; 2936; 1621; 1591; 1504; 1491; 1423; 1230; 1117; 831; 743 and 728 cm"1.

[a]D<2>° = -7.4 +/-0.6 [dichloromethane, (c = 0.5), 589 nm].

Methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylate was obtained by the procedure described in Example 1, starting from 4-bromo-3-chloro-6-methoxyquinoline.

EI mass spectrum: m/z=515 (M+).

Example 26

Enantiomer B 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylate, enantiomer B 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid is obtained as a solid.

EI mass spectrum: m/z=500 M+; m/z=153 C9H7F2+ base peak.

Infrared spectrum KBr: 2965; 2936; 1621: 1591; 1504; 1491; 1423; 1230; 1117; 831; 743 and 728 cm"1.

[a]D<20>= +5.5 +/-0.5 [dichloromethane, (c = 0.5), 589 nm]

Example27

Enantiomer A 1 -[3-(2,6-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,6-difluorobromobenzene, enantiomer A of 1-[3-(2,6-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2941; 1707; 1622: 1509; 1469; 1231; 1145; 1030; 1004; 830; 785 and 719 cm"1.

[a]D<2>° = -31 +/-0.7 [methanol, (c = 0.5), 589 nm].

Example28

Enantiomer B 1 -[3-(2,6-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,6-difluorobromobenzene, enantiomer B 1 -[3-(2,6-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2941; 1707; 1622; 1509; 1469; 1231; 1145; 1030; 1004; 830; 785 and 719 cm"1.

[a]D20 = +31.7 +/-0.9 [methanol, (c = 0.5), 589 nm].

Example 29

Enantiomer A (levorotatory) l-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (levorotatory) l-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate. acid (unknown absolute configuration) is obtained in the form of a white foam.

[a]D<20>= - 17.5 +/- 0.7 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm-1 2930; 1709; 1622; 1514; 1231; 1205; 1159; 1029; 832 and 793 cm"<1>.

CI mass spectrum m/z = 489 (MH)+ base peak.

Methyl (±)-1-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained by the procedure described in Example 2, starting from 2-(2-bromoethoxy)-1,4-difluorobenzene. A yellow oil is obtained.

EI mass spectrum: m/z 502 (M+).

2-(2-Bromoethoxy)-1,4-difluorobenzene can be obtained by the process described in patent WO200240474-A2.

Example30

Enantiomer B (dextrorotatory) 1-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl-3-pyrrolidinecarboxylate, enantiomer B (dextrorotatory) 1-[2-(2,5-difluorophenoxy)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 157°C.

[a]D<20>= + 22.6 +/- 0.7 [methanol (c = 0.5), 589 nml.

IR spectrum (KBr) cm"1 2930; 1709; 1622; 1514; 1231; 1205; 1159; 1029; 832 and 793 cm"'.

EI mass spectrum: m/z = 488 (M+); 345 (M - C7H52)+ base peak.

Example 31

Enantiomer A (dextrorotatory) sodium salt of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate, enantiomer A (dextrorotatory) sodium salt 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point between 265°C and 270°C.

[a]D<2>° = + 7.1 +/- 0.6 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"1 2952; 2815; 1621; 1558; 1506; 1412; 1229; 1125; 1028; 828; 744 and 705 cm"<1>.

ES mass spectrum: m/z = 491 (MH)+ main peak.

Methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate can be obtained by the procedure described in Example 2, starting from 3-chloro-4-bromo-6-methoxyquinoline and 2-[(2-bromoethyl)thio]thiophene. A colorless oil is obtained.

EI mass spectrum: m/z 504 (M+).

3-Chloro-4-bromo-6-methoxyquinoline can be obtained by the process described in patent WO200240474-A2.

Example 32

Enantiomer B (levorotatory) sodium salt of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate, enantiomer B of the (levorotatory) sodium salt of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-3-pyrrolidinecarboxylate. acid (unknown absolute configuration) is obtained as a white solid with a melting point between 269°C and 271°C.

[ct]D<2>° = - 3.3 +/- 0.5 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"' 2952; 2815; 1621; 1558; 1506; 1412; 1229; 1125; 1028; 828; 744 and 705 cm"<1.>

ES mass spectrum: m/z = 491 (MH)+ basic.

Example 33

Enantiomer A (dextrorotatory) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-3-[3-(34yloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylate, enantiomer A (dextrorotatory) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[24J2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid, melting point 146°C.

[a]D<20>= + 25.8 +/- 0.8 [methanol (c = 0.5), 589 nm].

IR spectrum (CH2C12) cm-1 2940; 1732; 1622; 1504; 1484; 1230; 1188; 1119 and 834 cm"'.

CI mass spectrum m/z = 521 (MH)+ base peak.

Methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylate can be obtained by the procedure described in Example 2, starting from 3-chloro-4-bromo-6-methoxyquinoline and 2-[(2-bromoethyl)thio]-1,4-difluoro-benzene. Ocher colored oil is obtained

EI mass spectrum: m/z 534 (M+).

Example 34

Enantiomer B (levorotatory) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylate, enantiomer B (levorotatory) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 146°C.

[a]D<20>= - 20.4 +/- 0.8 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"' 2953; 1707; 1620; 1504; 1483; 1231; 1188; 1118; 829 and 744 cm"'.

CI mass spectrum m/z = 521 (MH)+ base peak.

Example35

Enantiomer A 1-[(2E)-3-(2,5-dichlorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-1,4-dichlorobenzene, enantiomer A of 1-[(2E)-3-(2,5-dichlorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=516 M+.; m/z=481 (M- Cl)+ basic peak.

Infrared spectrum KBr: 2938; 1709; 1621; 1508; 1464; 1360; 1230; 1097; 1030; 969; 830; 811 and 785 cm"1

[a]D<2>° = -21.2 +/-0.6 [methanol, (c = 0.5), 589 nm].

Example36

Enantiomer B of 1-[(2E)-3-(2,5-dichlorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-1,4-dichlorobenzene, enantiomer B of 1-[(2E)-3-(2,5-dichlorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained as a solid at room temperature melting point 102°C.

EI mass spectrum: m/z=516 M+. ; m/z=481 (M -Cl)+ basic peak.

Infrared spectrum KBr: 2938; 1709; 1621; 1508; 1464; 1360; 1230; 1097; 1030; 969; 830; 811 and 785 cm"1.

[a]D<2>° = +22 [methanol, (c = 0.5), 589 nm].

Example37

Enantiomer A sodium salt of l-[(2E)-3-(3,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-3,5-difluorobenzene, enantiomer A of the sodium salt of 1-[(2E)-3-(3,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained as a solid condition.

EI mass spectrum: m/z=484 M+.; m/z=153 C9H7F2+ basic peak.

Infrared spectrum KBr: 2928; 1706; 1621; 1591; 1509; 1469; 1322; 1231; 1119; 1030; 984 and 831 cm"<1>.

[a]D<20>= -25.6 +/-0.8 [methanol, (c = 0.5), 589 nm]

Example 38

Enantiomer B 1 -[(2E)-3-(3,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-3,5-difluorobenzene, enantiomer B 1-[(2E)-3-(3,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=484 M+.; m/z=153 C9H7F2+ basic peak.

Infrared spectrum KBr: 2928; 1706; 1621; 1591; 1509; 1469; 1322; 1231; 1119; 1030; 984 and 831 cm"<1>.

[a]D<20>= +28.2<+>/-0.8 [methanol, (c = 0.5), 589 nm].

Example 39

Enantiomer A of 1-[3-(5-chloro-2-fluoro-phenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2-fluoro-5-chloro-bromobenzene, the enantiomer A of 1-[3-(5-chloro-2-fluoro-phenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum m/z=499 MH+ base peak.

Infrared spectrum CC14 : 2936; 1704; 1622; 1508; 1487; 1469; 1259; 1232; 1218 i

832 cm"'.

[a]D<2>° = -27.3 +/-0.9 [methanol, (c = 0.5), 589 nm].

Example 40

Enantiomer B of 1-[3-(5-chloro-2-fluoro-phenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2-fluoro-5-chloro-bromobenzene, enantiomer B of 1-[3-(5-chloro-2-fluoro-phenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum m/z=499 MH+ base peak.

Infrared spectrum KBr: 2942; 1707; 1621; 1509; 1486; 1469; 1260; 1231; 1145; 1085; 1030 and 830 cm"<1.>

[a]D<20>= +29.6<+/->1 [methanol, (c = 0.5), 589 nm].

Example 41

Enantiomer A of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,6-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid hydrochloride (absolute configuration unknown)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2,6-difluorobenzene, enantiomer A of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[(2E)-3-(2,6-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid hydrochloride (absolute configuration unknown) is obtained as solid substances with a melting temperature of 96°C.

EI mass spectrum: m/z=484 M+. ; m/z=153 C9H7F2+ basic peak

Infrared spectrum KBr: 2942; 2459; 1715; 1621; 1509; 1468; 1361; 1266; 1232; 990; 830 and 782 cm"1.

[a]D<20>= -22.3 +/-0.8 [methanol, (c = 0.5), 589 nm].

Example 42

Enantiomer B 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,6-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2,6-difluorobenzene, enantiomer B 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(2,6-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained as a solid melting temperature 88°C.

CI mass spectrum m/z=485 MH+ base peak.

Infrared spectrum KBr: 2941; 1710; 1621; 1508; 1467; 1360; 1266; 1231; 1144; 989; 830 and 782 cm"1.

[a]D<2>° = +23.7 +/-0.7 [methanol, (c = 0.5), 589 nm].

Example 43

Enantiomer A of 34L3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,4,5-trifluorenyl)-2-propynyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 3,4,5-trifluoro-bromobenzene, enantiomer A of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,4,5-trifluoronyl)-2-propynyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a solid.

EI mass spectrum: m/z=500 M+. ; m/z=169 C9H4F3+ basic peak.

Infrared spectrum KBr: 2944; 1709; 1621; 1612; 1528; 1429; 1232; 1048; 858 and 830 cm"<1>.

[a]D<2>° = -17.5 +/-0.5 [methanol, (c = 0.5), 589 nm].

Example 44

Enantiomer B 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,4,5-trifluorenyl)-2-propynyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 3,4,5-trifluorobromobenzene, enantiomer B of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,4,5-trifluorenyl)-2-propynyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a solid.

EI mass spectrum: m/z=500 M+.; m/z=169 C9H4F3+ basic peak.

Infrared spectrum KBr: 2944; 1709; 1621; 1612; 1528; 1429; 1232; 1048; 858 and 830 cm"<1>.

[a]D<20>= +16.8 +/-0.6 [methanol, (c = 0.5), 589 nm].

Example 45

Enantiomer A 1-[(2E)-3-(5-chloro-2-fluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2-fluoro-5-chlorobenzene, enantiomer A 14L(2E)-3-(5-chloro-2-fluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained. are in the solid state.

CI mass spectrum: m/z=501 MH+ base peak.

Infrared spectrum of KBrCCl4: 2936; 1707; 1621; 1508; 1482; 1231; 1033; 972; 832 i

649 cm"<1>.

[a]D20 = -17.4+/-0.6 [methanol, (c = 0.5), 589 nm].

Example 46

Enantiomer B 1-[(2E)3-(5-chloro-2-fluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2-fluoro-5-chloro-benzene, enantiomer B 1-[(2E)3-(5-chloro-2-fluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in solid state.

EI mass spectrum: m/z=500 M+.; m/z=169 C9H7CIF+ base peak.

Infrared spectrum CC14: 2936; 1707; 1621; 1508; 1482; 1231; 1033; 972; 832 and 649 cm"1.

[a]D<2>° = +18.3 +/-0.6 [methanol, (c = 0.5), 589 nm].

Example 47

Enantiomer A of 14L(2E)3-(2,3-difluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2,3-difluorobenzene, enantiomer A 1^(2E)3-(2,3-difluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum: m/z=485 MH+ base peak.

Infrared spectrum CC14: 2936; 1706; 1622; 1508; 1484; 1264; 1231; 1032; 973; 832 and 713 cm"<1>.

[a]D<2>° = -21.1 +/-0.6 [methanol, (c = 0.5), 589 nm].

Example 48

Enantiomer B 1-[(2E)3-(2,3-difluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-2,3-difluorobenzene, enantiomer B 1-[(2E)3-(2,3-difluoro-phenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=484 M+. basic spade ; m/z= 153 C9H7F2+

Infrared spectrum CC14: 2936; 1706; 1622; 1508; 1484; 1264; 1231; 1032; 973; 832 and 713 cm"<1>.

[a]D<2>° = +21.5 +/-0.7 [methanol, (c = 0.5), 589 nm].

Example 49

Enantiomer A of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(3,4,5-trifluoronyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-3,4,5-trifluorobenzene, enantiomer A 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(3,4,5-trifluoronyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained in as a solid substance with a melting temperature of 110°C.

EI mass spectrum: m/z=502 M+. ; m/z=171 C9H6F3+ basic peak.

Infrared spectrum KBr: 2940; 1620; 1529; 1509; 1442; 1359; 1232; 1042; 970; 831 and 790 cm"<1>.

[ct]D20 = +28.1 +/-0.8 [methanol, (c - 0.5), 589 nm].

Example 50

Enantiomer B of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-14L(2E)-3-(3,4,5-trifluorenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from 2-((2E)-3-chloro-2-propenyl)-3,4,5-trifluorobenzene, enantiomer B of 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[(2E)-3-(3,4,5-trifluoronyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained in as a solid substance with a melting temperature of 148°C.

EI mass spectrum: m/z=502 M+.; m/z=171 C9H6F3+ basic peak.

Infrared spectrum KBr: 2940; 1620; 1529; 1509; 1442; 1359; 1232; 1042; 970; 831 and 790 cm"1.

[a]D<20>= -19.4 +/-0.6 [methanol, (c = 0.5), 589 nm].

Example 51

Enantiomer A of 1-[3-(2,3-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,3-difluorobromobenzene, enantiomer A of 1-[3-(2,3-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum: m/z=483 MH+ basic peak.

Infrared spectrum KBr: 2941; 1706; 1621; 1584; 1509; 1489; 1473; 1231; 1146; 1030; 831; 784 and 716 cm"<1>.

[a]D<20>= -25.1 +/-0.8 [methanol, (c = 0.5), 589 nm].

Example52

Enantiomer B of 1-[3-(2,3-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,3-difluorobromobenzene, enantiomer B of 1-[3-(2,3-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+.; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2941; 1706; 1621; 1584; 1509; 1489; 1473; 1231; 1146; 1030; 831; 784 and 716 cm"1.

[a]D<20>= +27.2<+/->0.9 [methanol, (c = 0.5), 589 nm].

Example53

Enantiomer A of 1-[3-(3,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 3,5-difluorobromobenzene, enantiomer A of 1-[3-(3,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+.; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2937; 1708; 1619; 1586; 1509; 1470; 1430; 1231; 1122; 1030; 990; 857; 831 and 672 cm"1.

[a]D2U = -19.4+/-0.7 [methanol, (c = 0.5), 589 nm].

Example 54

Enantiomer B of 1-[3-(3,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 3,5-difluorobromobenzene, enantiomer B of 1-[3-(3,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

EI mass spectrum: m/z=482 M+; m/z=151 C9H5F2+ basic peak.

Infrared spectrum KBr: 2937; 1708; 1619; 1586; 1509; 1470; 1430; 1231; 1122; 1030; 990; 857; 831 and 672 cm"1.

[a]D<2>° = +27.7 +/-1 [methanol, (c = 0.5), 589 nm].

Example55

Enantiomer A of 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,5-dichlorobromobenzene, enantiomer A of 1-[3-(2,5-difluorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum: m/z=515 MH+ base peak.

Infrared spectrum KBr: 2928; 1709; 1621; 1509; 1468; 1231; 1096; 1031; 830; 786 and 600 cm"<1.>

[a]D<2>° = -22.5 +/-0.9 [methanol, (c = 0.5), 589 nm].

Example 56

Enantiomer B of 1-[3-(2,5-dichlorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 23, starting from 2,5-dichlorobromobenzene, enantiomer B of 1-[3-(2,5-dichlorophenyl)-2-propynyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained in the solid state.

CI mass spectrum: m/z=515 MH+; m/z=287 C17H20N2+ basic peak.

Infrared spectrum KBr: 2928; 1709; 1621; 1509; 1468; 1231; 1096; 1031; 830; 786 and 600 cm"1.

[a]D<2>° = +27.5 +/-0.9 [methanol, (c = 0.5), 589 nm]

Example57

Enantiomer A (dextrorotatory) l-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (dextrorotatory) 1-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 106°C.

[a]D<2>° = + 29.1 +/- 0.7 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm-1 2940; 1704; 1621; 1606; 1509; 1463; 1233; 1144; 990; 830 and 785 cm"1.

EI mass spectrum: m/z = 504 (M+); 345 (M- C7H5F2S)+ base peak.

Methyl (±)-1-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained by the procedure described in Example 2, starting from 2-[(2-bromoethyl)thio]-1,3-difluorobenzene. A light yellow oil is obtained.

EI mass spectrum: m/z 518 (M+).

2-[(2-Bromoethyl)thio]-1,3-difluoro-benzene can be synthesized by the process described in patent VVO200240474-A2.

Example58

Enantiomer B (levorotatory) l-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B (levorotatory) 1-[2-[(2,6-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 86°C.

[a]D<20>= - 29.3 +/- 0.8 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"<1>2940; 1704; 1621; 1606; 1509; 1463; 1233; 1144; 990; 830 and 785 cm"'.

CI mass spectrum m/z = 505 (MH+) major peak.

Example 59

Enantiomer A (dextrorotatory) l-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (dextrorotatory) 1-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 79°C.

[a]D<20>= + 22.3 +/- 0.7 [methanol (c = 0.5), 589 nm]].

IR spectrum (KBr) cm"1 2939; 1706; 1621; 1569; 1509; 1450; 1362; 1230; 1141; 1095; 1034; 830; 806 and 575 cm"1.

ES mass spectrum: m/z = 537 (MH+) main peak.

Methyl (±)-1-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be synthesized by the procedure described in Example 2, starting from 2-[(2-bromo-ethyl)thio]-1,4-dichlorobenzene. It yields a bright yellow oil.

EI mass spectrum: m/z 550 (M+).

2-[(2-Bromoethyl)thio]-1,4-dichlorobenzene can be synthesized by the process described in patent WO200240474-A2.

Example 60

Enantiomer B (levorotatory) l-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B (levorotatory) 1-[2-[(2,5-dichlorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point of 67°C.

[a]D<2>° = - 22.6 +/- 0.7 [methanol (c = 0.5), 589 nmJJ.

IR spectrum (KBr) cm"1 2939; 1706; 1621; 1569; 1509; 1450; 1362; 1230; 1141; 1095; 1034; 830; 806; and 575 cm"<1>.

CI mass spectrum: m/ z = 537 (MH+) main peak.

Examples 61 and 62

Diastereoisomers A (dextrorotatory) and C (levorotatory) sodium salt of l-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (of unknown absolute configuration) l-[(2E)-3-(2,5-Difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (mixture of two diastereoisomers A and C, unknown absolute configurations) (0.370 g) is injected into a column with a diameter of 6 cm and a length of 30 cm, in which there is 600 g of stationary chiral phase, which consists of particles of CHIROBIOTIC TM with a size of 10 µm. Elution is performed with a mobile phase [H2O / TF / TEA / acetic acid (ratio of volume parts 80 / 15 / 0.15 / 0.05)] with a flow rate of 100 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer A (dextrorotatory), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 0.150 g of white powder is obtained. This powder is then purified in the same column. Elution is performed with a mobile phase [ethanol/TEA/acetic acid (volume ratio 100/0.05/0.05)] at a flow rate of 100 ml/min. Diastereoisomer A (dextrorotatory), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 0.060 g of white foam is obtained.

[cx]d<20>= +54.5 +/- 1.2 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) 3428; 2959; 1622; 1591; 1509; 1491; 1429; 1355; 1231; 1148; 1029; 975; 830 and 728 cm"1.

ES mass spectrum: m/z = 501 (MH)+.

Diastereoisomer C (levorotatory), of unknown absolute configuration, which is the second eluted, is separated and concentrated under vacuum. 0.080 g of white foam is obtained.

[ct]D20 = -24.6 +/- 0.8 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) 3415; 2955; 1622; 1591; 1509; 1491; 1429; 1355; 1231; 1199; 1030; 975; 830 and 728 cm"1.

ES mass spectrum: m/z = 501 (MH)+. 1-[(2E)-3-(2,5-Difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) can be obtained by the procedures described in Examples 64 and 65, starting from enantiomers A 1-(1,1-dimethylethyl) and methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate (absolute configuration unknown), a yellow oil is obtained.

EI mass spectrum: m/z = 500 (M+).

Examples 63 and 64

Diastereoisomers B (levorotatory) and D (dextrorotatory) sodium salt of l-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (of unknown absolute configuration)

According to the procedure described in examples 62 and 63, starting from the sodium salt of 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers A and C of unknown absolute configuration): diastereoisomer B (levorotatory), of unknown absolute configuration, which is the first eluted, separated and concentrated under vacuum. 0.130 g of white foam is obtained.

[a]D<20>= -53.1 +/-1.0 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr): 3414; 2938; 1622; 1591; 1509; 1491; 1429; 1354; 1230; 1198; 1029; 974; 830 and 728 cm"1.

ES mass spectrum: m/z = 501 (MH)+.

Diastereoisomer D (dextrorotatory), of unknown absolute configuration, which is the second eluted, is separated and concentrated under vacuum. 0.100 g of white foam is obtained.

[ct]D20 = + 24.8 +/- 0.7 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) : 3397; 2958; 1622; 1591; 1509; 1491; 1429; 1355; 1230: 1199; 1029; 975; 831 and 728 cm"1.

ES mass spectrum: m/z = 501 (MH)+.

The sodium salt of l-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) can be obtained as follows: In 9.14 cm<3>5 N aqueous sodium hydroxide solution, it is added at a temperature of about 20°C, solution of 0.56 g (1.088 mmol) methyl 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylate (mixture of two diastereomers A and C, unknown absolute configuration) in 120 cm<3>dioxane. After stirring at reflux for 16 hours, the reaction mixture was cooled and then filtered under reduced pressure (2.7 kPa). A dry precipitate is obtained which is collected in 50 cm<3> of water. The pH is adjusted to a value of about 7 by the addition of 1 N aqueous solution of hydrochloric acid. The aqueous phase is filtered under reduced pressure (2.7 kPa). 7 g of dry precipitate is obtained, which is collected in 50 cm<3>methanol. NaCl is removed from the mixture by filtration. The filtrate was filtered to dryness under reduced pressure (2.7 kPa), and 1.2 g of a light yellow solid was obtained, which was purified by flash chromatography [eluent: dichloromethane / methanol (volume ratio 80 / 20) + 0.5% NH4OH]. After collecting the fractions under reduced pressure, 0.464 g of the sodium salt of 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (mixture of two diastereomers A and C, unknown absolute configurations) is obtained, in the form of a bright yellow foam.

EI mass spectrum: m/z = 522 (M+).

Methyl 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylate (a mixture of two diastereomers A and C of unknown absolute configuration) can be obtained by the procedure described in Examples 71 and 72, starting from enantiomer B 1-(1,1-dimethylethyl) and methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate (unknown absolute configuration); a yellow oil is obtained which hardens.

EI mass spectrum: m/z = 500 (M+).

Enantiomers A and B of 1-(1,1-dimethylethyl) and methyl 3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate (of unknown absolute configurations) can be obtained as follows: l-(1,1-Dimethylethyl) and methyl (±)-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidinedicarboxylate (2.55 g) is injected into a column with a diameter of 8 cm and a length of 30 cm, in which there is 1200 g of stationary chiral phase, which consists of VVHELK OI,SS TM particles with a size of 10\ xm. Elution is performed with a mobile phase [heptane / Mtbe / methanol / ethanol / TEA (ratio of volume parts 76/20/2/2/0.1)] with a flow rate of 140 ml/min, and UV detection by radiation of the wave length 254 nm.

Enantiomer A (right-handed), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 1.15 g of colorless oil is obtained.

[a]D<20>= + 23.6 +/- 0.9 [methanol, (c = 0.5), 589 nm)].

EI mass spectrum: m/z = 460 (M+), 359 (M - C5H9O2)+, 57 (C4H9+).

Enantiomer B (levogyric), of unknown absolute configuration, which is the second eluted, is separated and concentrated under vacuum. 1.25 g of colorless oil is obtained.

[a]D<20>= - 21.4 +/- 0.8 [methanol, (c = 0.5), 589 nm].

EI mass spectrum: m/z = 460 (M+), 359 (M - C5H9O2)+, 57 (C4H9+).

Example 65

Enantiomer A (levogyric) sodium salt of l-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown)

According to the procedure described in Example 3, starting from methyl (±)-1-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (levogyr) sodium salt 1-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-mcthoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point between 110°C and 113°C.

[a]D<20>= - 17.8 +/- 0.6 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"1 2955; 1620; 1509; 1483; 1230; 1188; 1032; 908; 825; 810; 785 and 757 cm"<1>.

CI mass spectrum: m/z = 519 (MH+) main peak.

Methyl (±)-1-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be synthesized by the procedure described in Example 2, starting from 2-[(3-bromopropyl)thio]-1,4-difluoro-benzene. An orange colored oil is obtained.

EI mass spectrum: m/z 532 (M+).

2-[(3-Bromopropyl)thio]-1,4-difluorobenzene can be synthesized by the process described in patent WO200240474-A2.

Example66

Enantiomer B (right-handed) sodium salt of l-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in Example 3, starting from methyl (±)-1-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B (right-handed) sodium salt 1-[3-[(2,5-difluorophenyl)thio]propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) is obtained as a white solid with a melting point between 121 °C and 123 °C.

[aJD<20>= + 18.8 +/- 0.8 [methanol (c = 0.5), 589 nm].

IR spectrum (KBr) cm"<1>2955; 1620; 1509; 1483; 1230; 1188; 1032; 908; 825; 810; 785 and 757 cm"1.

ES mass spectrum: m/z = 519 (MH+) main peak.

Example67

1- [2-[(2-Pyridinyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acids (unknown absolute configuration)

According to the procedure described in Examples 1 and 2, starting from 2-[(2-bromoethyl)thio]pyridine, an orange oil is obtained.

ES mass spectrum: m/z = 470 (MH+) main peak.

2-[(2-Bromoethyl)thio]pyridine can be synthesized by the process described in patent WO200240474-A2.

Example 68

Enantiomer A (right-handed) 1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in example 3, starting from methyl (±)-1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer A (right-handed) 1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained as a white solid.

[cc]D<20>= + 28.5<+/->0.7 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) cm"1 2929; 1635; 1621; 1531; 1510; 1231; 1187; 1030; 830 and 786 cm<1.>

ES mass spectrum: m/z = 488 (MH+) main peak.

Methyl (±)-l-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be synthesized as follows: To 1.65 cm<3>l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1.16 cm<3>mercaptoethanol is added and a solution 1.9 g (2.77 mmol) of methyl 1-[2-[(2,5-difluorophenyl)[(2-nitrenyl)sulfonyl]amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in 60 cm<3>dimethylformamide, at a temperature of about 20°C, in an argon atmosphere. After stirring for five hours, at a temperature of about 20°C, the reaction mixture is poured into 600 cm 3 of water, and then extracted 4 times with 200 cm 3 of dichloromethane each. The organic layers are combined, washed with 200 cm of water, dried with anhydrous magnesium sulfate, filtered and filtered to dryness under reduced pressure (2.7 kPa). 1.67 g of yellow oil is obtained, which is purified by flash chromatography [eluent: dichloromethane / methanol (volume ratio 95 / 5)]. After collection of the fractions under reduced pressure, 1.58 g of a yellow oil is obtained, which is purified again by flash chromatography [eluent: dichloromethane / ethyl acetate (v/v 911)]. After collecting the fractions under reduced pressure, 0.76 g of methyl (±)-1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate was obtained as a light yellow oil.

EI mass spectrum: m/z 501 (M+).

Methyl 1-[2-[(2,5-difluorophenyl)[(2-nitrenyl)sulfonyl]amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate can be obtained by the procedure described in example 2, starting from N-(2-bromoethyl)-N-(2,5-difluorophenyl)-2-nitrobenzenesulfonamide. A light yellow oil is obtained.

CI mass spectrum: m/z 687 (MH+).

N-(2-Bromoethyl)-N-(2,5-difluorophenyl)-2-nitrobenzenesulfonamide can be obtained by the process described in patent WO200240474-A2.

Example69

Enantiomer B (right-handed) 1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration)

According to the procedure described in example 3, starting from methyl (±)-1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate, enantiomer B (right-handed) 1-[2-[(2,5-difluorophenyl)amino]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration unknown) is obtained as a white solid.

[a]D<20>= - 40.5 +/- 0.9 [dichloromethane (c = 0.5), 589 nm].

IR spectrum (KBr) cm'1 2929; 1635; 1621; 1531; 1510; 1231; 1187; 1030; 830 and 786 cm"<1>.

ES mass spectrum: m/z = 488 (MH+) main peak.

Examples 70 and 71

Diastereoisomers A (dextrorotary) and C (levorotatory) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid

(of unknown absolute configurations)

3-[3-(3-Chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) (0.367 g) is injected into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of stationary chiral phase, which consists of CHIROBIOTIC TM particles with a diameter of 10 um. Elution is performed with a mobile phase [H2O / TF / TEA / acetic acid (ratio of volume parts 85/15/0.1/ 0.1)] with a flow rate of 90 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer A (right-handed), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 0.161g of colorless oil is obtained.

[a]D<2>° = + 63.7 +/- 1.7 [methanol, (c = 0.5), 589 nm].

IR spectrum (CH 2 Cl 2 ): 3593; 1718; 1621; 1503; 1491; 1421; 1355; 1231; 1185; 1117; 1068; 1036; 975 and 835 cm"1.

ES mass spectrum: m/z = 517 (MH)+.

Diastereoisomer C (levogyric), of unknown absolute configuration, which is the second eluted, is isolated and concentrated under vacuum. 0.0137 g of colorless oil is obtained.

[o,]d<20> has a negative sign in methanol [methanol, (c = 0.5), 589 nm].

IR spectrum (CH 2 Cl 2 ): 3587; 1723; 1621; 1503; 1491; 1421; 1355; 1231; 1117; 975; 897 and 836 cm-l.

ES mass spectrum: m/z = 517 (MH)+.

3-[3-(3-Chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers A and C of unknown absolute configurations) can be obtained as follows: 0.354 g of triethylamine, 0.74 g of sodium triacetoxyborohydride and a solution of 0.294 g (E)-3-(2,5-difluorophenyl)propenal, are added at a temperature of about 20°C, in an argon atmosphere, to a solution of 0.51 g (1.165 mmol) of dihydrochloride of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers A and C of unknown absolute configuration) in 25 cm<3>dichloromethane. After stirring for 2 hours at a temperature of about 20°C, the reaction mixture was filtered to dryness under reduced pressure (2.7 kPa). 1.82 g of precipitate is obtained, which is purified by flash chromatography [eluent: chloroform / methanol / 28% aqueous NH4OH (volume ratio 12 / 2.25 / 0.38)]. After collecting the fractions under reduced pressure, 0.42 g of 34L3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) was obtained as a yellow oil.

EI mass spectrum: m/z 516 (M+).

Dihydrochloride of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configuration) can be obtained as follows: In 16 cm<3>4 N hydrochloric acid is added at a temperature of about 20°C, a solution of 0.604 g (1.3 mmol) of 1,1-dimethylethyl 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinedicarboxylate (a mixture of two diastereoisomers A and C of unknown absolute configurations) in 20 cm<3>dioxane. After stirring for 48 hours, at a temperature of about 20°C, the reaction mixture was filtered to dryness under reduced pressure (2.7 kPa). 0.64 g of a yellow solid is obtained, which is powdered with 10 cm<3>diethyl ether. After filtration, the solid is washed with 10 cm of diethyl ether and then dried under reduced pressure (2.7 kPa). 0.6 g of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid dihydrochloride (a mixture of two diastereoisomers A and C of unknown absolute configurations) is obtained, in the form of a yellow solid.

EI mass spectrum: m/z 437 (M+).

1 -(1,1-Dimethylethyl) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyrrolidinedicarboxylate (a mixture of two diastereomers A and C of unknown absolute configuration) can be obtained as follows: Oxygen is blown through a solution of 2.3 g (5.12 mmol) of enantiomer A 1 -(1,1-dimethylethyl) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyrrolidinedicarboxylate (unknown absolute configuration) in 185 cm<3>dimethyl sulfoxide, at a temperature of about 20°C, for 20 minutes, until saturation occurs. After that, a solution of 1.32 g (11.78 mmol) of potassium tert-butoxide in 84 ml of tert-butanol is added. Then oxygen is blown again for 5 hours. After that, the reaction mixture is cooled to a temperature of about 0°C. Then 540 cm<3> of water is added to it, drop by drop, and the temperature is maintained at around 20°C. The pH is adjusted to a value between 5 and 6 by adding 1.5 cm of acetic acid. After that, 250 cm<3> of water is added to the reaction mixture. The reaction mixture is extracted 4 times with 250 cm<3>dichloromethane each. The organic layers are combined and washed with 250 cm<3> of water, dried with anhydrous magnesium sulfate, filtered and filtered to dryness under reduced pressure (2.7 kPa). 3.14 g of yellow oil is obtained, which is collected in 40 cm 3 of diethyl ether. The ether layer is washed twice with 20 cm 3 of water each, dried with anhydrous magnesium sulfate, filtered and filtered to dryness under reduced pressure (2.7 kPa). 1.27 g of 1-(1,1-dimethylethyl) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyrrolidine dicarboxylate (a mixture of two diastereomers A and C of unknown absolute configurations) are obtained, in the form of a light yellow foam.

EI mass spectrum: m/z 464 (M+).

Enantiomer A 1 -(1,1-dimethylethyl) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyrrolidine dicarboxylate (unknown absolute configuration) can be obtained as follows: In 50 cm<3> of a 5 N aqueous sodium hydroxide solution, a solution of 2.78 g (6 mmol) of enantiomer A is added at a temperature of about 20°C 1-(1,1-dimethylethyl) and 3-methyl 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyri'olidinedicarboxylate (absolute configuration unknown) in 230 cm<3>dioxane. After stirring at reflux for 18 hours, the reaction mixture was cooled and then filtered to dryness under reduced pressure (2.7 kPa). A precipitate is obtained which is collected in 700 cm<3> of water. The pH is adjusted to a value of about 4 by adding citric acid. After standing for 4 hours at a temperature of around 20°C, the suspension is filtered. The solid phase is washed 3 times with 50 cm<3> diisopropyl ether each, and then dried under reduced pressure (2.7 kPa), at a temperature of about 43°C. 2.3 g of enantiomer A 1-(1,1-dimethylethyl) 3-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-1,3-pyrrolidinedicarboxylate (unknown absolute configuration) are obtained, in the form of a white solid.

EI mass spectrum: m/z 448 (M+).

Enantiomers A and B of 1-(1,1-dimethylethyl) and 3-methyl 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidine dicarboxylate (of unknown absolute configuration) can be obtained as follows: 1-(1,1-Dimethylethyl) and 3-methyl (±)-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidine dicarboxylate (2.55 g) is injected into a column with a diameter of 6 cm and a length of 30 cm, in which there is 800 g of stationary chiral phase, which consists of VVHELK OI,SS TM particles of size 10 (im. Elution is performed with a mobile phase [heptane / MTBE / mctanol / isopropanol / TEA (ratio of volume parts74 / 20 / 1 /4 / 0.1)] with a flow rate of 120 ml/min, and detection by UV radiation with a wavelength of 254 nm.

Enantiomer A (right-handed), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 0.46 g of colorless oil is obtained.

EI mass spectrum: m/z = 462 (M+), 361 (M - C5H9O2)+, 57 (C4H9+).

[a]D<2>° = +18.8 +/- 0.6 [methanol, (c = 0.5), 589 nm].

Enantiomer B (levogyric), of unknown absolute configuration, which is the second eluted, is separated and concentrated under vacuum. 0.217 g of colorless oil is obtained.

[ot]D20 = -18.4 +/- 0.8 [methanol, (c = 0.5), 589 nm].

EI mass spectrum: m/z = 462 (M+), 361 (M - C5H9O2)+, 57 (C4H9+).

Examples 72 and 73

Diastereoisomers B (levorotatory) and D (dextrorotatory) of 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid

(of unknown absolute configurations)

According to the procedure described in examples 70 and 71, starting from 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers B and D of unknown absolute configuration): Diastereoisomer B (levogyric), of unknown absolute configuration, which is eluted first, is separated and concentrated under vacuum. 0.192 g of colorless oil is obtained.

[a]D<2>° = -68.3 +/- 0.9 [methanol, (c = 0.5), 589 nm]; [a]D<20>=-48.3 +/- 0.9 [DMSO, (c = 0.5), 589 nm].

IR spectrum (KBr): 3431; 1621; 1503; 1491; 1231; 1117; 977 and 728 cm"'.

ES mass spectrum: m/z = 517 (MH)+.

Diastereoisomer D (right-handed), of unknown absolute configuration, which was eluted second, was separated and concentrated under vacuum. 0.198 g of colorless oil is obtained.

[α]D<20>= +11.8 +/- 0.8 [DMSO, (c = 0.5), 589 nm)].

IR spectrum (KBr) : 3401; 1715; 1621; 1503; 1491; 1456; 1231; 1116; 973; 832 and 728 cm"1.

ES mass spectrum: m/z = 517 (MH)+.

3-[3-(3-Chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[(2E)-3-(2,5-diflupropenyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers B and D of unknown absolute configurations) can be obtained by the procedures described in examples 71 and 72, starting from enantiomers B of 1-(1,1-dimethylethyl) and 3-methyl 3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1,3-pyrrolidine dicarboxylate (unknown absolute configuration), a beige foam is obtained.

EI mass spectrum: m/z = 516 (M+).

Examples 74 and 75

Diastereoisomers A (dextrorotary) and C (levorotatory) 1-[3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid

(of unknown absolute configurations)

l-[3-(2,5-Difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configuration) (0.230 g) of particles is injected into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of stationary chiral phase consisting of CHTROBIOTIC TM diameter 10 um. Elution is performed with a mobile phase [H2O / TF / TEA / acetic acid (ratio of volume parts 80/ 20 / 0.1/ 0.1)] with a flow rate of 100 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer A (right-handed), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum. 0.072 g of white foam is obtained.

[a]D<2>° = +48.9 +/- 1.0 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr): 3414; 2927; 2856; 1715; 1622; 1598; 1497; 1427; 1355; 1263; 1231; 1198; 1142; 1030; 831; 813 and 789 cm"1.

EI mass spectrum: m/z = 502 (M+), 361 (M - C8H7F2)+, 343 (361 - H2O)+.

Diastereoisomer C (levogyric), of unknown absolute configuration, which eluted second, was isolated and concentrated under vacuum. 0.052 g of white foam is obtained.

[a]D<2>° = -24.0 +/- 0.8 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) : 3420; 2958; 1717; 1622; 1598; 1497; 1427; 1355; 1263; 1231; 1198; 1142; 1031; 831; 812 and 789 cm"'.

EI mass spectrum: m/z = 502 (M+), 361 (M - C8H7F2)+, 343 (361 - H2O)+. l-[3-(2,5-Difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) can be obtained as follows: 0.3 g (0.6 mmol) is added to 25 cm of methanol at room temperature under an argon atmosphere. 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl-3-pyrrolidinecarboxylic acid (mixture of two diastereomers A and C of unknown absolute configurations) and 0.03 g of 10% palladium on carbon. The reaction medium is purged with argon 5 times, and then hydrogenated at a pressure of 2 bar hydrogen, at room temperature for 24 hours. The catalyst is filtered on Celite®, the Celite® is washed three times with 25 cm<3>methanol each, and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). 0.26 g of 14L3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers A and C whose absolute configurations are unknown) is obtained in the form of a yellow varnish.

EI mass spectrum: m/z = 502 (M+).

Examples 76 and 77

Diastereoisomers B (levorotatory) and D (dextrorotatory) of 1-[3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid

(of unknown absolute configurations)

l-[3-(2,5-Difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (mixture of two diastereoisomers B and D of unknown absolute configurations) (0.600 g) of particles is injected into a column with a diameter of 6 cm and a length of 30 cm in which there is 600 g of a stationary chiral phase consisting of CHIROBIOTIC TM, with a diameter of 10 um. Elution is performed with a mobile phase [H20 / TF / TEA / acetic acid (ratio of volume parts 80 / 20 / 0.1/ 0.1)] with a flow rate of 100 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer B (levogyric), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum and then crystallized in the presence of water. 0.472 g of white powder is obtained.

[a]D<2>° negative sign in DMSO [DMSO, (c = 0.5), 589 nm].

IR spectrum (KBr) : 3431; 2950; 1622; 1510; 1497; 1459; 1427; 1355; 1266; 1242; 1230; 1187; 1144; 1080; 1031; 832 and 817 cm"1.

EI mass spectrum: m/z = 502 (M+), 361 (M - C8H7F2)+, 343 (361 - H2O)+.

Diastereoisomer D (right-handed), of unknown absolute configuration, which eluted second, was separated and concentrated under vacuum, then crystallized in the presence of water. 0.113 g of white powder is obtained.

[a]D<20>positive sign in DMSO [DMSO, (c = 0.5), 589 nm]].

IR spectrum (KBr) : 3418; 2953; 1622; 1593; 1509; 1497; 1467; 1427; 1384; 1355; 1266; 1231; 1197; 1142; 1069: 831 and 813 cm"1.

EI mass spectrum: m/z = 502 (M+), 361 (M - C8H7F2)+, 343 (361 - H2O)+. l-[3-(2,5-Difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers B and D of unknown absolute configuration) can be obtained as follows: 1.5 g (3 mmol) is added to 125 cm3 of methanol. 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers B and D of unknown absolute configurations), at room temperature, in an atmosphere of argon, and 0.15 g of 10% palladium on carbon. The reaction medium is purged with argon 5 times, and then hydrogenated at a pressure of 2 bar of hydrogen, at room temperature, for 24 hours. The catalyst is filtered on Celite®. Celite® is washed 3 times with 100 cm<3>methanol each, then filtered and filtered to dryness under reduced pressure (2.7 kPa). 1.31 g of 1-[3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (mixture of two diastereoisomers B and D of unknown absolute configurations) is obtained, in the form of a beige foam.

EI mass spectrum: m/z = 502 (M+).

Examples 78 and 79

Diastereoisomers A (levorotatory) and C (dextrorotatory) of 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (of unknown absolute configuration) l-[2-[(2,5-Difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C whose absolute configurations are unknown) (0.170 g) is injected into a column with a diameter of 6 cm and a length of 30 cm, in which there is 600 g of a stationary chiral phase consisting of particles CHIROBIOTIC TM with a diameter of 10 µm. Elution is performed with a mobile phase [EhO / TF / TEA / acetic acid (ratio of volume parts 80/20/0.1/0.1)] with a flow rate of 100 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer A (levogyric), of unknown absolute configuration, which eluted first, was separated and concentrated under vacuum and then crystallized in the presence of water. 0.057 g of white foam is obtained.

[ot]D<20>= - 45.6 +/- 0.9 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) : 3415; 1717; 1622; 1509; 1484; 1355; 1262; 1231; 1187; 1082; 1060; 1030; 908; 830; 804 and 757 cm"<1>.

CI mass spectrum m/z = 521 (MH) + , 503 (MH + - H 2 O).

Diastereoisomer C (right-handed), of unknown absolute configuration, which eluted second, was separated and concentrated under vacuum, then crystallized in the presence of water. 0.059 g of white foam is obtained.

[ct]D<20>= + 19.9 +/- 0.7 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr) : 3409; 1716; 1622; 1509; 1484: 1355; 1262; 1231; 1188; 1081; 1060; 1030; 908; 830; 805 and 757 cm"<1>.

CI mass spectrum m/z = 521 (MH) + , 503 (MH + - H 2 O). 1-[2-[(2,5-Difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-h pyrrolidinecarboxylic acid (a mixture of two diastereoisomers A and C of unknown absolute configurations) can be obtained by the procedures described in examples 70 and 71, starting from enantiomer B 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid. A beige solid is obtained.

EI mass spectrum: m/z = 520 (M+).

Examples 80 and 81

Diastereoisomers B (dextrorotary) and D (levorotatory) of l-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (unknown absolute configuration) l-[2-[(2,5-Difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (mixture of two diastereoisomers B and D of unknown absolute configurations) (0.100 g) is injected into a column with a diameter of 6 cm and a length of 30 cm containing 600 g of stationary chiral phase consisting of CHIROBIOTIC TM particles. with a diameter of 10 um. Elution is performed with a mobile phase [H20 / TF / TEA / acetic acid (ratio of volume parts 80 / 20 / 0.1/ 0.1)] with a flow rate of 100 ml/min, and detection with UV radiation at a wavelength of 254 nm.

Diastereoisomer B (right-handed), of unknown absolute configuration, which was eluted first, was separated and concentrated under vacuum, and then crystallized in the presence of water. 0.057 g of white foam is obtained.

[ot]D<2>° = + 42.3 +/- 0.9 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr): 3414; 1717; 1622; 1509; 1484; 1356; 1261; 1231; 1188; 1082; 1060; 1027; 908; 861; 805 and 757 cm"<1>.

EI mass spectrum: m/z = 520 (M)+, 361 (M - C7II5SF2)+. 343 (361 - H2O)+.

Diastereoisomer D (levogyric), of unknown absolute configuration, which eluted second, was separated and concentrated under vacuum and then crystallized in the presence of water. 0.059 g of white foam is obtained.

[a]D<20>= - 20.5 +/- 0.7 [methanol, (c = 0.5), 589 nm].

IR spectrum (KBr): 3414; 1717; 1622; 1509; 1484; 1355; 1261; 1231; 1188; 1082; 1028; 908; 804 and 757cm"<1>.

EI mass spectrum: m/z = 520 (M)+, 361 (M - C7H5SF2)+. 343 (361 - H2O)+. 1-[2-[(2,5-Difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid (a mixture of two diastereomers B and D of unknown absolute configurations) can be obtained by the procedures described in Examples 70 and 71, starting from enantiomer A 1-[24(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid. A beige solid is obtained.

EI mass spectrum: m/z = 520 (M<+>).

Claims (17)

1. 4-substituted quinoline derivatives, characterized by the fact that they correspond to the general formula: where: Xi, X2, X3, X4 and X5 represent >C-R'ido >C-R'5 respectively, or alternatively at least one of them represents a nitrogen atom, Ri, R'i, R'2, R3, R'4 and R'5 are the same or different and represent a hydrogen or halogen atom or one alkyl, cycloalkyl, phenyl, phenylthio, mono- or bicyclic heteroaryl or heteroarylthio, OH, SH, alkyloxy, difluoromethoxy, trifluoromethoxy, alkylthio, trifluoromethylthio, cycloalkyloxy, cycloalkylthio, acyl, acyloxy, acylthio, cyano, carboxy, alkyloxycarbonyl, cycloalkyloxycarbonyl, nitro, -NraRb or -CONRaRb radical (where Ra and Rb can be hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic heteroaryl or Ra and Rb form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle which may optionally contain another heteroatom selected from O, S or N and which carries, when appropriate, one alkyl, phenyl or mono- or bicyclic heteroaryl substituted on the nitrogen atom or when appropriate, when the sulfur atom is oxidized to the sulfinyl or sulfonyl state), or represents 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 above, or represent phenoxy, heterocyclyloxy, benzyloxy, heterocyclylmethyloxy, or alternatively may also represent difluoromethoxy or a radical having the structure -CmF2m+i, -SCmF2m+i or -OCmF2m+i for which m is an integer from 1 to 6 or alternatively R' 5 may also be trifluoroacetyl, m is equal to 1, 2 or 3; n equal to 0, 1 or 2; Y represents the group CHR, CO, CROH, CRNH2, CRF or CF2, R is a hydrogen atom or one alkyl (Ci-6) radical; Z represents a CH 2 group or alternatively Z represents an oxygen atom, a sulfur atom or an SO group or one SO 2 group and in that case, n equal to 2; R 2 represents the radical -CO 2 R, -CH 2 CO 2 R, -CH 2 -CH 2 CO 2 R, -CH 2 OH or -CH 2 -CH 2 OH, R as described above; R3 represents a phenyl radical, mono- or bicyclic heteroaryl, alk-R°3 for which alk is one alkylene radical and R°3 represents hydrogen, halogen, hydroxy, alkyloxy, alkylthio, alkylsulfinyl, 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, phenylalkylsulfinyl, phenylalkylsulfonyl, phenylalkylamino, N-alkyl-N-phenylaminoalkyl, N-cycloalkyl-N-phenylalkylamino, benzoyl, mono- or bicyclic heteroaryl, heteroaryloxy, heteroarylthio, heteroarylsulfonyl, heteroarylsulfonyl, heteroarylamino, N-alkyl-N-heteroarylamino, N-cycloalkyl-N-heteroarylamino, heteroarylcarbonyl, heteroarylalkyloxy, heteroarylalkylthio, heteroarylalkylsulfinyl, heteroarylalkylsulfonyl, heteroarylalkylamino, N-alkyl-N-heteroarylaminoalkyl, N-cycloalkyl-N-heteroarylaminoalkyl, (heteroaryl moieties mentioned above may be mono- or bicyclic), carboxy, alkyloxycarbonyl, -NRaRb or -CO-NRaRb for which Ra and Rb respectively represent hydrogen, alkyl, cycloalkyl, phenyl, mono- or bicyclic heteroaryl, or one of Ra or Rb is hydroxy, alkyloxy, cycloalkyloxy, or Ra and Rb form together with the nitrogen atom to which they are attached a 5- or 6-membered heterocycle which may optionally contain another heteroatom selected from O, S and N and carries when appropriate, one alkyl, alkyl, phenyl or mono- or bicyclic heteroaryl substituent on the nitrogen atom or when appropriate, when the sulfur atom oxidized to the sulfinyl or sulfonyl state, or alternatively R°3 represents -CR'b=CR'c-R'a for which R'a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl where the heteroaryl part is mono- or bicyclic, phenoxyalkyl, phenylthioalkyl, phenylsulfinylalkyl, phenylsulfonylalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, (heteroaryl moieties mentioned above may be mono- or bicyclic), phenylthio, phenylsulfinyl, phenylsulfonyl, and wherein R'b and R'c represent hydrogen hydrogen, alkyl or cycloalkyl, or alternatively R°3 represents the radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, (the heteroaryl moieties mentioned above are mono- or bicyclic aromatics), or alternatively R°3 represents the radical -CF2-phenyl or mono- or bicyclic -CF2-heteroaryl, where it is understood that phenyl, benzyl, benzoyl or the heteroaryl radicals or moieties mentioned above may be optionally substituted on the ring with 1 to 4 substituents selected from halogen, hydroxy, alkyl, alkyloxy, alkyloxyalkyl, haloalkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, carboxy, alkyloxycarbonyl, cyano, alkylamino, -NRaRb for which Ra and Rb are as defined above, phenyl, hydroxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, where it is understood that the alkyl or acyl radicals and moieties contain (unless otherwise indicated) 1 to 10 carbon atoms in the form of a straight or branched chain and that the cycloalkyl radicals contain 3 to 6 carbon atoms, in their enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or when appropriate the syn or anti forms or mixtures thereof, and their salt. 2. Derivatives of the general formula (I), as defined in claim 1, characterized in that: X], X2, X3, X4 and X5 are as defined in claim 1, Ri, R'i, R'2, R'3, R'4 and R'5, which are the same or different, represent a hydrogen or halogen atom, an alkyl or alkyloxy radical, or a methylene radical substituted with alkyloxy: Y represents a CH2 radical, CHOH, CHF, CHNH2 or C=0; mje equal to 1; as defined above; Z is a CH 2 group and n is equal to 0 or 1 or Z is an oxygen atom in which case n is equal to 2; R.2 is defined as above, i R3 represents the radical alk-R°3 for which alk is one 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, (where heteroaryl the moieties mentioned above may be mono- or bicyclic), -NRaRb or -CONRaRb for which Ra and Rb are as defined above, or alternatively 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-heteroarylaminoalkyl, heteroarylthio, (where the heteroaryl moieties mentioned above may be mono- or bicyclic), or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or alternatively R°3 represents the radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, (where the heteroaryl moieties mentioned above may be mono- or bicyclic), or alternatively R°3 represents -CF2-phenyl or mono- or bicyclic -CF2-heteroaryl radical, where it is understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or moieties mentioned above may be optionally substituted as described in claim 1, in its enantiomeric and diastereoisomeric form or a mixture of those forms and/or when appropriate in the syn or anti form or a mixture thereof, and their salts. 3. Derivatives of the general formula (I) as defined in claim 1, characterized in that: Xi, X2, X3, X4 and X5 represent >C-R'ido >C-R'5 respectively, Ri, R'i, R'2, R'3, R'4 and R's, which are the same or different, represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or a methylene radical substituted with alkyloxy; Y represents the radical CH2, CHOH, CHF, CHNH2 or C=0; mje equal to 1; her as defined in claim 1; Z is a CH 2 group and n is equal to 0 or 1 or Z is an oxygen atom in which case n is equal to 2; R2 is as defined in claim 1, and R3 represents the radical alk-R°3 for which alk is one alkylene radical and R°3 represents cycloalkyloxy, cycloalkylthio, phenoxy, phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryloxy, heteroarylthio, heteroarylalkyloxy, heteroarylalkylthio, or alternatively R3 represents - CR'b=CR'c-R'for which R' represents phenyl, phenylalkyl, phenylthioalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylthio or phenylthio, and for which R'b and R'c represent hydrogen, alkyl or cycloalkyl, or alternatively R°3 represents the radical -C=C-Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, where the heteroaryl parts mentioned above can be mono- or bicyclic, where it is understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above can be optionally substituted as described in claim 1, in their enantiomeric or diastereoisomeric form or their mixtures and/or in the corresponding syn or anti form or their mixtures and their salts. 4. Any of the derivatives of the general formula (I) according to claim 1, under the following names: • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[34-hydroxy-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenylsulfanyl)ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenyloxy)ethyl]-3-[3-(3-fluoro-6-mcthoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(thiophen-2-ylsulfanyl)ethyl-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-hydroxy-(3-fluoro-6-methoxyquinolin-4-yl)propyl]azetidine-3-carboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-hydroxy-(34,1oro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenylsulfanyl)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(2,5-difluorophenyloxy)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[2-(thiophen-2-ylsulfanyl)ethyl]-3-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid; • 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid; • 3-[3-(3-chloro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-pyrrolidinecarboxylic acid; • 1-[3-(2,5-difluorophenyl)propyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)]-3-hydroxypropyl]-3-pyrrolidinecarboxylic acid; • 1-[2-[(2,5-difluorophenyl)thio]ethyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3- hydroxypropyl]-3-pyrrolidinecarboxylic acid; in their enantiomeric or diastereoisomeric forms or their mixtures, and/or the corresponding syn or anti forms or their mixtures as well as their salts. 5. A process for obtaining a derivative of the general formula (I) as defined in claim 1, characterized in that the sequence R3 defined as in claim 1 is condensed with a 4-substituted quinoline derivative of the general formula: where X], X2, X3, X4_X5, Ri, R2, Y, Z, m and n are defined as in claim 1, R2 is protected when it bears a carboxy radical, followed when appropriate by removal of the group protecting the carboxy radical, optionally by separation of enantiomeric or diastereoisomeric forms and/or when appropriate syn and anti forms, and optionally by converting the resulting product into a salt. 6. The method according to claim 5, characterized in that the condensation of a series of R3 with a heterocyclic nitrogen most conveniently takes place by the action of a derivative of the general formula: R3-X (Ha) where R 3 is as defined above and X represents a halogen atom, methylsulfonyl radical, trifluoromethylsulfonyl or p-toluenesulfonyl radical. 7. The method according to one of claims 5 or 6, characterized in that when R°3 is the radical -alk-R°3 where alk is an alkyl radical and R°3 represents the radical -C=C-Rd, where Rd is defined as in claim 1, the reaction takes place via the condensation of an alkynyl halide of the formula HC=C-alk-X for which alk is as defined above and X is a halogen atom, and then with the substitution of a series with the corresponding Rd radical. 8. The method according to one of claims 5 or 6, characterized in that when R3 represents the radical -alk-R°3 for which alk is an alkyl radical and R°3 represents a phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino radical, the reaction takes place by constructing a series by first condensing a series of HO-alk-X for which X is a halogen atom, and then or by converting the obtained hydroxyalkyl series into haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl series and finally stimulate the reaction of an aromatic derivative having the structure R<0>3H or R°3H2 to act in a basic medium, or by causing the aromatic derivative to act directly under dehydrating conditions. 9. Method according to claim 5, characterized in that derivatives of the general formula (I) where R2 is hydroxymethyl or hydroxyethyl are obtained by the action of a suitable reducing agent on derivatives for which R2 is carboxy or carboxymethyl or protected carboxy or protected carboxymethyl. 10. The method according to claim 5, characterized in that derivatives of the general formula (II) for which Y is the group CHR are obtained by condensation of heteroaromatic derivatives of the general formula: where Ri, Xi, X2, X3, X4 and Xssu defined as in claim 1 and Hal represents a halogen atom, with a derivative of the general formula: where P is a protecting group and R, Z, m, n and R 2 are as defined in claim 1 or R 2 represents a protected radical if R 2 represents or carries a carboxylic acid functional group, followed by the removal of the protecting group and/or followed by the conversion, by successive operations, of the substituents of the aromatic cycle of the general formula (II) thus obtained, in order to obtain the expected derivatives bearing the radicals Ri, R'i, R'2, R'3, R'4, R'5, with appropriate removal of the protective radical(s) still present in the molecule. 11. The method according to claim 10, characterized in that derivatives of the general formula (IV) where R, Z, P, R2 and n are as defined in claim 10 and m is equal to 2 or 3, are obtained by condensation with derivatives of the general formula: where n, z and R 2 are as defined in claim 1 and P is as defined in claim 5 a product of the general formula wherein Hal represents a halogen atom and n and R are as defined in claim 1. 12. The method according to claim 10, characterized in that the derivatives of the general formula (IV) where R, Z, P, R2 and n are as defined in claim 10 and m is equal to 1, are obtained by condensation of the derivative of the general formula (V) as defined in claim 11 with a product of the dibromoethane type of the general formula: where R is as defined above, followed by removal of the hydrobromide from the resulting product. 13. Derivatives of general formula (II) as defined in claim 5. 14. Derivatives of general formula (IV) as defined in claim 10. 15. As drugs, derivatives of general formula (I) as defined in claim 1. 16. As medicaments, derivatives of general formula (I) as defined in any of claims 2 to 4. 17. Pharmaceutical form, characterized in that it consists of at least one derivative according to claim 1, in pure form or in combination with one or more pharmaceutically acceptable diluents and/or additives.