AU2002253219B2

AU2002253219B2 - Quinolyl propyl piperidine derivatives, the preparation thereof and compositions containing same

Info

Publication number: AU2002253219B2
Application number: AU2002253219A
Authority: AU
Inventors: Eric Bacque; Christophe Daubie; Youssef El-Ahmad; Michel Evers; Jean-Luc Malleron; Serge Mignani; Stephane Mutti; Michel Tabart; Fabrice Viviani
Original assignee: Novexel SA
Current assignee: Novexel SA
Priority date: 2001-03-13
Filing date: 2002-03-11
Publication date: 2007-12-20
Anticipated expiration: 2022-03-11
Also published as: CA2440067A1; IL157850A0; JP2004523573A; CY1106710T1; CA2440067C; AU2002253219B8; FR2822154A1; MXPA03007848A; DK1370550T3; FR2822154B1; DE60220258T2; CL2004001085A1; IL157850A; DE60220258D1; EP1370550B1; ES2284856T3; EP1370550A1; WO2002072572A1; JP4262481B2; PT1370550E

Description

IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/FR02/00851 RWS Group plc, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and French languages, is a true and correct translation of the PCT Application incorporating amended sheets filed under No. PCT/FR02/00851.

Date: 30 July 2003 S. ANTHONY Director For and on behalf of RWS Group plc WO 02/072572 PCT/FR02/00851 1 QUINOLYL PROPYL PIPERIDINE DERIVATIVES, THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING SAME The present invention relates to quinolylpropylpiperidine derivatives of general formula: Ri

N--R

3 R2 which are active as antimicrobials. The invention also relates to their preparation and to compositions containing them.

In Patent Applications WO 99/37635 and WO 00/43383, there have been described antimicrobial quinolylpropylpiperidine derivatives of general formula:

A-B-(CH

2 )n N-R, A-B-(CH 2

N-R,

S33 2

<R

1 )m R 2

R

3 or N r~f- in which the radical RI is in particular (Cl-6)alkoxy,

R

2 is hydrogen, R 3 is at the 2- or 3-position and represents (C1-6)alkyl which may be optionally substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted with alkyl, and the like, R 4 is a group -CH 2

-R

5 for which R II is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl which is optionally substituted, phenylalkenyl which is optionally substituted, heteroarylalkyl which is optionally substituted, heteroaryl which is optionally substituted, and the like, n is 0 to 2, m is 1 or 2 and A and B are in particular oxygen, sulfur, sulfinyl, sulfonyl, NR 11

CR

6

R

7 for which R 6 and R7 represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amino, and Z 1 to Z 5 are N or CRia, and the like.

In European Patent Application EP30044, there have been described quinoline derivatives which are useful as cardiovascular agents and which correspond to the general formula:

H

A-B-CH

2

N-C-R

3

SR

2

N

in which R 1 is in particular alkyloxy, A-B is -CH 2

-CH

2

-CHOH-CH

2

-CH

2 -CHOH-, -CH 2 -CO- or -CO-CH 2

R

1 is H, OH or alkyloxy, R 2 is ethyl or vinyl, R 3 is in particular alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, diphenylalkyl which is optionally substituted, phenylalkenyl which is optionally substituted, benzoyl or benzoylalkyl which is optionally substituted, heteroaryl or heteroarylalkyl which is optionally substituted and Z is H or alkyl or forms with R 3 a cycloalkyl radical.

It has now been found, and this is what constitutes the subject of the present invention, that the products of general formula for which: RI is a hydrogen or halogen atom or a hydroxyl, amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino or alkylalkyloxyamino radical,

R

2 represents a carboxyl, carboxymethyl or hydroxymethyl radical,

R

3 represents an alkyl (1 to 6 carbon atoms) radical substituted with a phenylthio radical which may itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], with a cycloalkylthio radical in which the cyclic portion contains 3 to 7 members, or with a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and itself optionally substituted [with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino] or R 3 represents a propargyl radical substituted with a phenyl radical which may itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], or substituted with a 3- to 7-membered cycloalkyl radical or substituted with a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and itself optionally substituted [with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], and

R

4 represents an alkyl (containing 1 to 6 carbon atoms), alkenyl-CH 2 or alkynyl-CH 2 (in which the alkenyl or alkynyl portions contain 2 to 6 carbon atoms), cycloalkyl or cycloalkylalkyl (in which the cycloalkyl portion contains 3 to 8 carbon atoms) radical, in their diastereoisomeric forms or their mixtures and/or in their cis or trans forms, as well as their salts, are potent antibacterial agents.

It is understood that the alkyl radicals and portions are in the form of a straight or branched chain and contain (unless otherwise stated) 1 to 4 carbon atoms, and that in the alternative case where Ri represents a halogen atom or when R 3 carries a halogen substituent, the latter may be chosen from fluorine, chlorine, bromine or iodine. Preferably fluorine.

In the above general formula, when R 3 carries an aromatic heterocyclyl substituent, the latter may be chosen (without limitation) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidinyl.

According to the invention, the products of general formula may be obtained by condensing the R 3 chain with the quinolylpropylpiperidine derivative of general formula:

R'

NH

R,4- F

R'

N

in which R 4 is as defined above, R'i represents a hydrogen atom or a hydroxyl radical and R' 2 represents a protected carboxyl or carboxymethyl radical, to obtain a quinolylpropylpiperidine derivative of general formula: N-R3 R-0 F R'2, for which R' 1

R'

2 and R 4 are as defined above and R 3 is as defined above, then, where appropriate, halogenation of the derivative for which R'i is a hydroxyl radical, if it is desired to obtain a quinolylpropylpiperidine derivative for which

R

1 is a halogen atom, or conversion of the hydroxyl radical represented by R' 1 to an oxo radical, and then to a hydroxyimino or II I alkyloxyimino radical, according to known methods which do not adversely affect the rest of the molecule, to obtain a quinolylpropylpiperidine derivative of general formula:

R

5 0N

N-R

3 R R (IV)

N

for which R' 2

R

3 and R 4 are as defined above, and R 5 is a hydrogen atom or an alkyl radical, and by the reduction of the derivative of general formula (IV) for which R 5 is a hydrogen atom to an amine, and optionally by the conversion to a monoalkylated or dialkylated amine, or optionally by the reduction of the derivative of general formula (IV) for which R 5 is a hydrogen atom to a hydroxylamine or of the derivative of general formula (IV) for which R 5 is an alkyl radical to an alkyloxyamine, and then, where appropriate, to obtain the derivative for which RI is alkylalkyloxy-amino, the derivative obtained for which RI is alkyl-oxyamino is converted by alkylation, and/or, where appropriate, reduction of the protected carboxyl radical R' 2 to a hydroxymethyl radical according to known methods which do not adversely affect the rest of the molecule, and then optionally separation of the diastereoisomers, separation of the cis and trans forms, removal, where appropriate, of the -I acid-protecting radical, and/or conversion of the product obtained to a salt.

The condensation of the chain R 3 with piperidine is advantageously carried out by the action of a derivative of general formula:

R

3 -X (V) in which R 3 is as defined above and X represents a halogen atom, a methylsulfonyloxy radical, a trifluoromethylsulfonyloxy or p-toluenesulfonyloxy radical, the procedure being carried out in an anhydrous, preferably inert (nitrogen or argon for example) 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 nitrogen-containing organic base (for example triethylamine) or an inorganic base (alkali metal carbonate:potassium carbonate for example) at a temperature of between 20 0 C and the reflux temperature of the solvent.

Preferably, a derivative for which X is a bromine or iodine atom is caused to react.

When R 3 represents propargyl substituted with phenyl, cycloalkyl or heterocyclyl, it may also be preferable to condense a propargyl halide, and then to substitute the chain with a phenyl, cycloalkyl or heterocyclyl radical. In this alternative case, the addition of the propargyl chain is carried out by means of propargyl bromide, under the conditions set out above for R 3 in the presence or in the absence of an alkali metal iodide such as for example potassium or sodium iodide.

When substitution with a phenyl or heterocyclyl radical is involved, the reaction is carried out by the action of a halide derived from the cyclic radical to be substituted, in the presence of triethylamine, in anhydrous medium, optionally with no solvent or in a solvent such as an amide (dimethylformamide for example) or a nitrile (acetonitrile for example) and in the presence of a palladium salt such as for example tetrakis(triphenylphosphine)palladium and copper(I) iodide, at a temperature of between 20 0

C

and the reflux temperature of the solvent.

When substitution with a cycloalkyl group is involved, the reaction is carried out by the action of an organolithium compound such as n-butyllithium or tert-butyllithium on the propargyl derivative obtained above, in anhydrous medium in an ether such as for example tetrahydrofuran at a temperature of between -78 and 0°C, followed by the action of a cycloalkanone followed by the deoxygenation of the intermediate alcohol according to conventional methods.

It is understood that when the alkyl radicals represented by R 3 carry carboxyl or amino substituents, the latter are protected beforehand and then released after the reaction. The procedure is carried out according to customary methods which do not adversely affect the rest of the molecule, in particular according to the methods described by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd A. Wiley Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

The protected carboxyl or carboxymethyl radical represented by R' 2 may be chosen from the easily hydrolyzable esters. By way of example, there may be mentioned methyl, benzyl or tert-butyl esters, or allyl or phenylpropyl esters. Optionally, the carboxyl radical is protected simultaneously with the reaction.

In this case, the product of general formula (II) used carries a radical R' 2 carboxyl or carboxymethyl.

The halogenation intended to obtain a quinolylpropylpiperidine derivative for which RI is a halogen atom, from the derivative for which R'i is hydroxyl, may be carried out in the presence of an aminosulfur trifluoride (diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®), morpholinosulfur trifluoride for example) or alternatively in the presence of sulfo tetrafluoride. The fluorination reaction may also be carried out by the action of a fluorinating agent such as a sulfur fluoride [for example morpholinosulfur trifluoride, sulfur tetrafluoride Org. Chem., 3808 (1975)), diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988)), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®). Alternatively, the fluorination reaction may also be carried out by means of a fluorinating agent such as hexafluoropropyldiethylamine (JP 2 039 546) or N-(2-chloro-l,1,2trifluoroethyl)diethylamine. The halogenation reaction may also be carried out using a reagent such as a tetraalkylammonium, trialkylbenzyl-ammonium or trialkylphenylammonium halide or using an alkali metal halide optionally substituted with a crown ether.

When a tetraalkylammonium halide is used, the latter may be chosen, by way of example, from tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium (tetra-n-butylammonium for example), tetrapentylammonium, tetracyclohexylammonium, triethylmethylammonium, tributylmethylammonium or trimethylpropylammonium halides.

The procedure is carried out in an organic solvent such as a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform) or in an ether (tetrahydrofuran or dioxane for example) at a temperature of between -78 and 40 0 C (preferably between 0 and 30 0 It is advantageous to carry out the procedure in an inert medium (argon or nitrogen in particular).

It is also possible to carry out the procedure by treatment with a halogenating agent such as thionyl chloride or phosphorus trichloride in an organic solvent such as a chlorinated solvent (dichloromethane or chloroform for example), at a temperature of between 0°C and the reflux temperature of the reaction mixture.

The conversion of the hydroxyl radical to an oxo radical is carried out using conventional oxidation methods described in the literature, for example by D. Swern oxidation, 44, 41-48 (1979) in particular in the presence of oxalyl chloride and of dimethyl sulfoxide, optionally in a solvent such as dichloromethane, or without solvent, at a temperature of between -60 and 200C, followed by the conversion of the oxo radical to a hydroxyimino or alkyloxyimino radical.

The conversion of the oxo radical to a hydroxyimino or alkyloxyimino radical is carried out by the action of hydroxylamine (hydroxylamine hydrochloride for example) or of alkyloxyamine, optionally in hydrochloride form, in a solvent such as pyridine or an alcohol (such as methanol or ethanol for example) and in the presence of a nitrogen base such as triethylamine or pyridine at a temperature of between 0 and 60 0

C.

I

The reduction of the derivative of general formula for which R 5 is hydrogen, to an amine is carried out according to the customary methods which do not adversely affect the rest of the molecule, in particular by the action of a reducing agent such as for example a hydride (alkali metal borohydride: sodium or potassium borohydride for example or aluminum and lithium hydride) in the presence or in the absence of molybdenum oxide, the procedure being preferably carried out under an inert atmosphere (nitrogen or argon for example), in an organic solvent such as an alcohol (methanol, ethanol or isopropanol for example) or a chlorinated solvent (for example dichloromethane) at a temperature of between -10 and 40 0

C.

The reduction of the derivative of general formula (IV) to a hydroxylamine or to an alkyloxyamine is carried out in particular in the presence of an organic acid (carboxylic acid such as for example acetic acid), by the action of a reducing agent such as for example a hydride chosen from sodium triacetoxyborohydride (optionally prepared in situ) or sodium cyanoborohydride, preferably under an inert atmosphere (nitrogen or argon for example), in an organic solvent such as an alcohol (methanol, ethanol or isopropanol for example) or a chlorinated solvent (for example dichloromethane) at a temperature of between -30 and 0

C.

The conversion of the amino radical represented by RI to an alkylamino or dialkylamino radical is carried out according to the customary methods, in particular by the action of an alkyl halide, optionally in a basic medium in the presence of a nitrogen base such as a trialkylamine (triethylamine, diisopropylethylamine, and the like), pyridine, or in the presence of an alkali metal hydride (sodium hydride), in an inert solvent such as an amide (dimethylformamide for example) or an oxide (dimethyl sulfoxide for example), at a temperature of between 0 C and the reflux temperature of the reaction medium.

The conversion of the alkyloxyamino radical represented by RI to an alkylalkyloxyamino radical is carried out according to the method described above for the alkylation of the amine.

The removal, where appropriate, of the acidprotecting radical to obtain a quinolylpropylpiperdine derivative for which R 2 is a carboxyl or carboxymethyl radical is carried out according to the usual methods, in particular by acid hydrolysis or saponification of the ester R' 2 In particular, sodium hydroxide is caused to act in an aqueous-organic medium, for example in an alcohol such as methanol or an ether such as dioxane, at a temperature of between 200C and the reflux temperature of the reaction mixture. It is also -I possible to use hydrolysis in aqueous hydrochloric medium at a temperature of between 20 and 100 0

C.

Where appropriate, the derivative of general formula for which R 2 is hydroxymethyl may be prepared from the derivative for which R' 2 is protected carboxyl. In particular, the procedure is carried out by reducing the product protected in the form of an ester R' 2 according to the customary methods which do not adversely affect the rest of the molecule, in particular by the action of a hydride (aluminum and lithium hydride or diisobutylaluminum hydride for example) in a solvent such as an ether (tetrahydrofuran for example) at a temperature of between 20 and 60 0

C.

The quinolylpropylpiperidine derivative of general formula (II) for which R' 2 represents a protected carboxymethyl radical, and R'i is a hydrogen atom, may be prepared by selective hydrogenation of the quinolylpropylpiperidine derivative of general formula:

NH

R (VI) S JR"2

N

in which R 4 is as defined above and R" 2 is the protected carboxyl radical corresponding to R' 2 and in which the amine functional group of the piperidine is protected beforehand, at a pressure of 1 to 100 bar and at a temperature of between 20 and 80 0 C, in a solvent such as in particular an alcohol (ethanol for example) or an amide (dimethylformamide for example) in the presence of a catalyst, for example palladium on carbon or palladium on barium sulfate.

The protection of the amino of the piperidine is carried out according to the customary methods which do not adversely affect the rest of the molecule and which are compatible with the reaction, in particular according to the references cited above. The protective radical is more particularly the benzyloxycarbonyl radical. In this case, the hydrogenation reaction leads directly to the deprotection of the amine.

The quinolylpropylpiperidine derivative of general formula (VI) may be prepared by condensing a quinoline derivative of general formula: Hal

R

4 -O F R4"O (VII)

N

in which R 4 is as defined above and Hal represents an iodine or bromine atom, with a piperidine derivative of general formula: N-Rz (Vill) in which R" 2 is as defined above and Rz represents an amino-protecting radical.

The reaction is carried out by the successive action of an organoborane (9-borabicyclo[3.3.1]nonane for example) in a solvent such as an ether (tetrahydrofuran, dioxane for example) at a temperature of between and 20 0 C, followed by the addition of the quinoline derivative of general formula (VII), by analogy with the methods described by Suzuki et al., Pure and Appl.

Chem., 57, 1749 (1985). The reaction is generally carried out in the presence of a palladium salt (palladiumdiphenylphosphinoferrocene chloride for example) and of a base such as potassium phosphate, at a temperature of between 20 0 C and the reflux temperature of the solvent.

The piperidine derivative of general formula (VIII) may be prepared by the Wittig reaction, by condensing a phosphorus ylide with a piperidine derivative of general formula: N-Rz 0

(IX)

in which Rz is as defined above.

The procedure is advantageously carried out using methyl (triphenylphosphoranylidene)acetate, in a solvent such as for example toluene, at a temperature of between 20 and 110 0

C.

The 3-oxopiperidine derivative of general formula (IX) may be prepared according to or by analogy with the method described by Y. Takeuchi et al., Synthesis, 10, 1814 (1999).

The quinolylpropylpiperidine derivative of general formula for which R' 2 is a carboxyl radical and R'i is a hydrogen atom, may be prepared from the corresponding derivative for which R' 2 is protected carboxymethyl, by reducing this radical to an alcohol, converting to a p-toluenesulfonyloxy derivative, and then converting this derivative to a vinyl derivative by an elimination reaction followed by the oxidation of the derivative obtained.

According to another alternative, the quinolylpropylpiperidine derivative of general formula for which R' 2 is a carboxyl radical and R'i is a hydrogen atom may be prepared by condensing a quinoline derivative of general formula (VIII) as defined above, with a piperidine derivative of general formula: -N-Rz

R'

2 (X) in which Rz is as defined above and R' 2 represents a protected carboxyl radical as defined above, followed by removal of the amino-protecting radical Rz.

The reaction is carried out under conditions similar to the conditions described for the reaction of the quinoline derivative of general formula (VII) and of the piperidine derivative of general formula (VIII).

The elimination of the radical Rz is carried out according to the known methods cited above, cited in examples, or described by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wiley Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

The product of general formula may be prepared according to or by analogy with the method described below in the examples.

The reduction, in alcohol, of the acid protected in the form of a radical R' 2 at the 3-position of the piperidine, to a hydroxyethyl radical is carried out according to the customary methods which do not adversely affect the rest of the molecule, in particular the procedure is carried out by the action of a hydride (lithium and aluminum hydride or diisobutylaluminum hydride for example) in a solvent such as an ether (tetrahydrofuran for example) at a temperature of between 20 and 60 0

C.

The conversion of the quinolylpropylpiperidine derivative for which R' 2 is hydroxyethyl to a p-toluenesulfonyloxyethyl derivative is carried out in particular according to the method described by L.F. Fieser and M. Fieser, Reagents for Organic Synthesis, vol. 1, 1179 (1967), starting with ptoluenesulfonyl chloride in the presence of a base such as a tertiary amine (for example triethylamine) or an aromatic amine (for example pyridine), in a halogenated solvent (for example dichloromethane) or without solvent, at a temperature of between 0 and 50 0

C.

The conversion of the p-toluenesulfonyloxyethyl derivative to a vinyl derivative is carried out by an elimination reaction, in particular according to the method described by A. Sharma et al., Org. Prep Proced. Int., 25(3), 330-333 (1993), in the presence of a base such as for example potassium t-butoxide in a solvent such as dimethylsulfoxide for example, at a temperature of between 20 and 1000C.

The conversion of the vinyl derivative to a derivative for which R' 2 is carboxyl is carried out by the oxidation methods described in the literature, in particular using sodium metaperiodate in the presence of ruthenium trichloride hydrate, in a mixture of solvents such as for example the water/acetonitrile mixture, at a temperature of between 20 and 600C.

The quinolylpropylpiperidine derivative of general formula (II) for which R'i is a hydroxyl radical may be prepared by oxidizing, in a basic medium, the corresponding derivative for which R'i is a hydrogen atom. The 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 1000C.

The quinoline derivatives of general formula (VII) for which Hal is an iodine atom may be prepared by analogy with the work by E. Arzel et al., Tetrahedron, 55, 12149-12156 (1999) from 3-fluoro-6methoxyquinoline, by the successive action of a base and then of iodine. Lithium diisopropylamide is for example used in a solvent such as an ether (tetrahydrofuran) at a temperature of between -80 and 200C. The 3-fluoro-3-methoxyquinoline may be obtained by pyrolysis of 6-methoxyquinoline diazonium 3-tetrafluoroborate or 3-hexafluorophosphate according to the Balz-Schieman reaction, Org. Synth., Coll 5, 133 (1973), at a temperature of between 100 and 240 0 C. The 6-methoxyquinoline diazonium 3-tetrafluoroborate or 6-methoxyquinoline diazonium 3-hexafluorophosphate may be obtained from 3-amino-6-methoxyquinoline by the action of an alkali metal nitrite (sodium nitrite for example) in an acid medium (tetrafluoroboric acid or hexafluorophosphoric acid) in a solvent such as water, at a temperature of between -10 and +20 0 C, by analogy with the work by A. Roe et al., J. Am. Chem. Soc., 71, 1785-86 (1949) or by the action of an alkyl nitrite (such as for example isoamyl nitrite) and of the complex of diethyl ether trifluoroborate in a solvent such as an ether (tetrahydrofuran for example) at a temperature of between -10 and +100C. The 3-amino- 6-methoxyquinoline is prepared as described by N. Heindel, J. Med. Chem., 13, 760 (1970). The quinoline derivative of general formula (VII) for which Hal is a bromine atom may also be prepared by analogy with this method.

The intermediates of the quinolylpropylpiperidine derivatives for which R 4 represents alkenyl-CH 2 alkynyl-CH 2 cycloalkyl or cycloalkylalkyl may be obtained by analogy with the preparation of the intermediates for which R 4 is alkyl, by the action of the corresponding halogenated derivative on the quinoline derivative hydroxylated at the 6-position.

It is understood that the derivatives of general formula (III), (IV) or their starting intermediates may exist in the cis or trans form at the level of the substituents at the 3- and 4-position of piperidine. The derivatives of the trans configuration may be obtained from the derivatives of the cis configuration according to or by analogy with the method described in International Application WO 99/37635.

The quinolylpropylpiperdine derivatives of general formula may be purified, where appropriate by physical methods such as crystallization or chromatography.

Moreover, it is understood that when Ri is other than the hydrogen atom, diastereoisomeric forms exist and that the diastereoisomeric forms and mixtures thereof also fall within the scope of the present invention. The latter may be in particular separated by chromatography on silica or by High-Performance Liquid Chromatography (HPLC). Likewise, the cis and trans derivatives may be separated by chromatography on silica or by High-Performance Liquid Chromatography

(HPLC).

The quinolylpropylpiperidine derivatives of general formula may be converted to addition salts with acids, by known methods. It is understood that these salts also fall within the scope of the present invention.

As examples of addition salts with pharmaceutically acceptable acids, there may be mentioned the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates, or with the substitution derivatives of these compounds).

Some of the quinolylpropylpiperidine derivatives of general formula carrying a carboxyl radical may be converted to the form of metal salts or to addition salts with the nitrogen bases according to methods known per se. These salts also fall within the scope of the present invention. The salts may be obtained by the action of a metal (for example an alkali or alkaline-earth metal) base, of ammonia or of an amine, on a product according to the invention, in an appropriate solvent such as an alcohol, an ether or water, or by an exchange reaction with a salt of an organic acid. The salt formed precipitates after optional concentration of the solution, it is separated by filtration, decantation or freeze-drying. As examples of pharmaceutically acceptable salts, there may be mentioned the salts with alkali metals (sodium, potassium, lithium) or with alkaline-earth metals (magnesium, calcium), the ammonium salt, the salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-pphenethylamine, N,N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, chloline, arginine, lysine, leucine, dibenzylamine).

The quinolylpropylpiperidine derivatives according to the invention are particularly advantageous antibacterial agents.

In vitro, on gram-positive microbes, the quinolylpropylpiperidine derivatives according to the invention have proved active at concentrations of between 0.03 and 4 gg/ml on meticillin-resistant Staphylococcus aureus AS5155, also at concentrations of between 0.06 and 8 pg/ml on Streptococcus pneumoniae 6254-01 and at concentrations of between 0.06 and 64 pg/ml on Enterococcus faecium H983401, and on gramnegative microbes they have proved active at concentrations of between 0.12 and 32 gg/ml on Moraxella catharrhalis IPA152; in vivo, they have proved active on experimental infections of mice with Straphylococcus aureus IP8203 at doses of between 12 and 150 mg/kg by the subcutaneous route (CD 50 and for some of them at doses of between 26 and 150 mg/kg by the oral route.

Finally, the products according to the invention are particularly advantageous because of their low toxicity. None of the products exhibited toxicity at the dose of 100 mg/kg by the subcutaneous route in mice (2 administrations).

Among the products according to the invention, there may be mentioned in particular the quinolyipropyiquinoline derivatives described hereinafter: (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6rethoxyquinolin-4-yl )propyl] phenylthioethyl)piperidine-3carboxyl 1 ic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propylll[ 2 3 fluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4--yl)propyl] -l-12- difluoropheriylthio) ethyllpiperidine-3-carboxYlic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-]-P1 2 3 5 difluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro--6methoxyquinoin-4-yl)propyJ- (2,3,5trifluorophenylthio) ethyllpiperidine-3-carboxYlic acid (3RS,4RS) or (3SR,4RS)-4-[3--(3-fluoro-6methoxyquinolin-4-yl)propyl]---[3-(npropylthio)propyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyll (nbutylthio) ethyl]piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] (cyclopropylthio) ethyl]piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl [2- (cyclobutylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolii-4--yl)propyl [2- (cyclopefltylthio) ethyllpiperidine-3-carboxy-ic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquiriolin-4-yl) propyl] (cyclohexylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] (thien-2yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl 2-yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-l-[2-(thien-3yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol- 2-yl) thioethylllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6rethoxyquinolin-4-yl)propyl] (pyridin-2yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] -1-12- (3-fluoropyridin- 2-yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl (3-f luorophenyl)prop- 2-ynyl] piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolifl-4-yl)propYl] difluorophenyl)prop-2-yfll]piPeridife-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyll difluorophenyl)prop-2-ynyl] -piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5trifluorophenyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] -1-[3-(thien-2-yl)prop- 2-ynyllpiperidine--3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] -1-[3-(thien-3-yl)prop-2ynyl] piperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-rnethoxyquinolin-4-y1)propyl]-1- (2phenylthioethyl) piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l- (3fluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquir'olif-4-yl)propylli>1[ 2 2 5 difluorophenylthio) ethyllpiperidine-3-carboxylic acid 3RS,4RS) or (3SR,4RS)-4-[3--(R,S)-hydroxy-3-(3fluoro-6-methoxycxuinolin-4-yl)propyl]-l-[ 2 difluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolil-4-yl)propyl] (2,3,5trifluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl] (npropylthio) ethyllpiperidine-3-carboxylic acid 3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-rnethoxyquinolin-4-yl)propyl (nbutylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)--hydroxy-3-(3fluoro-6-methoxyquinoliri-4-yl)propyl]-l- [2- (cyclopropylthio) ethyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyll-l-[2- (cyclobutylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl] (cyclopentylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4--[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-y-)propYl]-l- [2- (cyclohexylthio) ethylllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolil-4-yl)propyl] fluorothien-2-yl) thioethyllpiperidirie-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquirolifl-4-yl)propyl] (thien-3yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl-lK> thiazol-2-yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquiflolif-4-yl)propYlll1> fluoropyridin-2-y1) thioethyllpiperidine-3-carboxYlic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-y1)propyll l[2- (pyridin-2yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-rnethoxyquinolin-4-yl)propyl (3fluoropheriyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl] difluorophenyl)prop-2-ynyl] -piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)--hydroxy-3-(3fluoro-6--methoxyquinolifl-4-yl)propyl]-l-[3 difluoropheny1)prop-2-yny1]piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-( 2 3 5 trifluorophenyl)prop-2-ynyllpiperidifle-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-rnethoxyquinolin-4-yl)propyl]-l-[3- (thien-2yl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyguinolin-4-yl)propyl]-l-[ 3 (thien-3yl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2-( 2 difluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyguinolin-4-yl)propyl difluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2- (cyclopentylthio) ethyllpiperidine-3-carboxylic acid 3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl [2- (cyclohexylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fIluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propylllK 2 -(thien-2yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyuinolifl-4y)propy1]121,3thiazol>2 yl) thioethyllpiperidifle-3-carboxyliC acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-~methoxyquinoif-4-yl)propylli> [(pyridin-2yl) thioethyllpiperidine-3-Carboxylic acid (3RS,4RS) or (3SR.4RS)-4-[3-(R,S)-fluoro-3-(3-flUOro- 6-methoxyquinolin-4-yl)propyl]-l-[ 3 phenyl)prop-2-ynyllpiperidife3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-rethoxyquinolin-4-Yl)propyl] (2,3,5trifluorophenyl)prop-2-yfl1piperidife3carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinoli±-4--y1)propyl] -1-[>(thien-2-yl)prop-2ynyllpiperidine-3--carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-anmino-3-(3-fluoro- 6-methoxyquinolifl-4-yl)propyl] phenylthioethyl )piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] -1-12- (3fluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] 2- difluorophenylthio) ethyllpiperidirie-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll-1-[2- difluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-anino--3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-rethoxyquinolin-4-yl)propyl] -1-13- (npropylthio)propyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propylL]-1-12- (nbutylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] (cyclopropylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-113-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl--2- (cyclobutylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] -1-12- (cyclopentylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2- (cyclohexylthio) ethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll-1- (thien-2yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1- (5-fluorothien-2yl) thioethyJl]piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyguinolin-4-yl)propyll-1- (thien-3yl) thioethyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxycpainolin-4-yl)propyl] (1,3-thiazol-2yl) thioethyllpiperidirae-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1- (pyridin-2yl) thioethyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amirio-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl (pyridin-3yl) thioethyllpiperidine-3-carboxylic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[3-(3fluorophenyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amno-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] difluorophenyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl difluorophenyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] (2,3,5trifluorophenyl)prop-2-ynyllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll-1-[3- (thien-2-yl)prop-2ynyl]piperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[13- (thien-3-yl) -prop- 2-yryllpiperidine-3-carboxylic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl (2phenylthioethyl )piperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yIl)propyl]-1-[2-(3fluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl difluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl difluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6rethoxyquinoliri-4-yl)propyl] -1-12- (2,3,5trifluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1- (npropylthio)propyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yJl)propyl]-1- (nbutylthio) ethylblpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl [2- (cyclopropylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] (cyclobutylthio) ethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] (cyclopentylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4--[3-(3-fluoro-6methoxyquinolin-4-yl)propyl [2- (cyclohexylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3--(3-fluoro-6methoxyquinolin-4-yl)propyl]-1- (5-fluoro-thien-2yl) thioethyllpiperidine-3-acetic acid 3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6iethoxyquinolin-4-yl)propyl]-1- (thien-3yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl 3-thiazol-2yl) thioethylllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-ylJpropyll1-1- (pyridin-2yl) thioethyllpiperidifle-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6rethoxyquino2-in- 4 -yl)propyl] (3-f luoropyridin-2yl) thioethyllpiperidifle-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquirlolin-4-yl)propyl] (3-f luorophenyl)prop- 2-ynyllpiperidine-3-acetiC acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyqtiinolin-4-yJl)propyl] difluoropheny1)prop-2-ynl1piperidinfe3acetic acid (3RS,4RS) or (3SR,4RS)-4-I3-(3-fI1uoro-6rethoxyquinolin-4-yl)propylJ-]--[3- difluorophenyl)prop-2-ynyllpiperidie3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6rethoxyquinolin-4-yl)propyl] (2,3,5trifluorophenylL)prop-2-yfylpiperidie3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fJluoro-6methoxyquinolin-4-y)propy--[3(thief 2 yl)prop- 2 ynyl] piperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl] 3-(thien-3-yl)prop-2ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-rnethoxyquiflolif-4-yl)propyll l(2phenylthioethyl) piperidine-3 -acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)--hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl (3fluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolil-4-yl)propyJ-]-l-[ 2 difluorophelylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquiiolifl-4-yl)propy1] (2,3,5trifluorophenyithia) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3- (npropylthio) propyl] piperidine- 3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl] (nbutylthio) ethyllpiperidine-3-acetic acid 3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolirl-4-yl)propyl]-l-[2- (cyclopropylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl--1 2 (cyclobutylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyqiainolin-4-yl)propyll (cyclohexylthio) ethyl]piperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl] fluorothien-2-yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or C3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-y-)propyl]-l (thien-3yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquifolif-4-y)propylll[ 2 3 thiazol-2-yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-m~ethoxyqu-ifolOJif-4-y]l)propyl]lK> (pyridin-2yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l- (3fluoropyridin-2-yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3--(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propy---[3- (3fluorophenyl)prop-2-ynyllpiperidile-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propy---[3- difluorophenyl)prop-2-ynyllpiperidile-3-acetic acid (3RS.RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 3 2 5 difluorophenyl)prop-2-ynyl]piperidile-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyguinolin-4-yl)propyl]-l-[ 3 (thien-2yl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl---[ 3 (thien-3yl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] difluoropheriylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2- difluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-f1uor0 6-methoxyquinlJi-4yl)propylJ-lK2- (cyclopentylthio) ethylLpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll]-1- [2- (cyclohexylthio) ethyllpiperidine-3-acetic acid 3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yIl)propyl]-1-[2- (thien-2yl) thioethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] 3-thiazol-2yl) thioethyl]piperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquiriolin-4-yl)propyl]-1-[2- (pyridin-2yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll phenyl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenyl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3--(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[3- (thien-2-yl) -prop- 2-ynyl]piperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1- (2phenylthioethyl)piperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl] (3fluorophenylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl difluorophenylthio) ethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl (2,3,5trifluorophenylthio)ethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-rethoxyquinolin-4-yl)propyl (npropyithia) propyl] piperidine-3 -acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amrino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2-(nbutylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyll [2- (cyclopropylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinoliri-4-y1)propyl] (cyclobutylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amiflo-3-(3-fluoro- 6-methoxyquinolil-4-y1)propyl] 12- (cyclopentylthio) ethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,.4RS)-4-[3-(R,S)-arino-3-(3-fluoro- 6-methoxyquinolin-4-yl1)propylli>[2 (cyclohexylthio) ethyllpiperidifle-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amJ-no-3-(3-fluoro- 6-ehxqioi--lpoyl--2(-lootin2 yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-rethoxyquinolin-4-yl)propyl]-l [2-(thien-3yl) thioethyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amno-3-(3-fJluoro- 6-methoxyquiloli-4-y1)PropyI- (1,3-thiazol-2yl) thioethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-amfilo-3(3-fluoro 6-methoxyquinolin-4-yl)propyll l[2-(pyridin-2yl) thioethyllpiperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-am-no-3-(3-fJluoro- 6-methoxyquinolin-4-yl)propylli> 12-(3-fluoropyridin-2yl) thioethyl]piperidine-3-acetic acid (3RSRS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-i3-fluoro- 6-methoxyquinolin-4-yl)propyl] (3fluorophenyl)prop-2-yfyllpiperidife3acetic acid (3RS,4RS) or (3SR,4RS)-4-13-(R,S)-amilo-3-(3-fl~uoro- 6-methoxyquinolifl-4-y1)propyll difluorophenyl)prop-2-yylpiperidie3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl difluorophenyl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-arnino-3-(3-fluoro- 6-methoxyquinolin-4--yl)propyl]-1-[3-(2,3,5trifluorophenyl)prop-2-ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-l-[3- (thien-2-yl)prop-2ynyllpiperidine-3-acetic acid (3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-l- (thien-3-yl)prop-2ynyllpiperidine-3-acetic acid as well as their salts.

The following examples illustrate the present invention.

Example 1 (3RS, 4RS) (3-Fluoro-6-methoxyquinolin-4yl)propyl (thien-2-yl)thioethyl]piperidine-3acetic acid dihydrochioride A solution of 480 mg of methyl (3RS,4RS)-4- 13- (3-fluoro-6-methoxyquinolin-4-yl)propyl [2- (thien-2-yl) thioethyllpiperidine-3-acetate, 5 cm 3 of dioxane and 2.25 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring, at a temperature in the region of 60 0 C for 1 hour 30 minutes. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 0 C, the residue obtained is taken up in 50 cm 3 of water and 20 cm 3 of ether. The aqueous phase is separated after settling out and then washed with twice cm 3 of ether. It is then acidified by pouring 2.25 cm 3 of 1 N hydrochloric acid. The precipitate formed is dissolved by adding 75 cm 3 of dichloromethane.

The organic phase is separated after settling out, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The product obtained is then stirred in 30 cm 3 of acetone. 4 cm 3 of 4 N hydrochloric acid in dioxane are then poured over this solution. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C and then 15 cm 3 of acetone are added. This operation is repeated 5 times until a yellow solid is obtained, which solid is drained and then dried in a desiccator under reduced pressure (10 Pa) at a temperature of about 450C. 395 mg of (3RS,4RS)-4-[3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 2 -(thien-2yl)thioethyl]piperidine-3-acetic acid dihydrochloride are obtained in the form of a solid which is off-white in color.

H NMR spectrum (400 MHz, (CD 3 2 SO d6 at a temperature of 393K, 6 in ppm): from 1.40 to 1.90 (mt 7H); 2.29 (dd, J 16 and Hz 1H); 2.46 (unresolved complex 1H); from 2.65 to 3.45 (mt 5H); 3.09 (broad t, J 7.5 Hz 2H); 3.23 (broad s 4H); 3.99 (s 3H); 7.09 (dd, J and 3.5 Hz 1H); 7.27 (dd, J 3.5 and 1.5 Hz 1H); 7.38 J 3 Hz 1H); 7.40 (dd, J 9 and 3 Hz 1H); 7.62 (dd, J 5.5 and 1.5 Hz 1H); 7.98 (d, J 9 Hz 1H); 8.64 (broad s 1H).

Methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3acetate A suspension composed of 0.95 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, 0.7 g of potassium carbonate, 0.68 g of 2-(2-bromoethylthio)thiophene in 40 cm 3 of dimethylformamide is stirred for 16 hours at a temperature in the region of 600C under an inert atmosphere. After cooling to about 20 0 C, the reaction mixture is poured over 200 cm 3 of water and 200 cm 3 of ethyl acetate. The organic phase is separated after settling out and then washed with 5 times 100 cm 3 of water and then with 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure kPa) at a temperature in the region of 40 0 C The evaporation residue obtained is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 p; diameter 2 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate (68/32 by volume) mixture and collecting 15-cm 3 fractions. Fractions 15 to 21 are concentrated. 480 mg of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3acetate are obtained in the form of an orange-colored oil.

H NMR spectrum (300 MHz, (CD 3 2 SO d6, 8 in ppm: from 1.15 to 1.70 (mt 7H); from 1.90 to 2.05 (mt 2H); 2.08 (unresolved complex 1H); 2.17 (broad dd, J 16 and 4 Hz 1H); from 2.35 to 2.80 (mt 5H); 2.90 (mt 2H); 3.07 (broad t, J 7.5 Hz 2H); 3.57 (s 3H); 3.97 (s 3H); 7.06 (dd, J 5.5 and 4 Hz 1H); 7.17 (dd, J 4 and 1.5 Hz 1H); 7.38 J 3 Hz 1H); 7.40 (dd, J 9 and 3 Hz 1H); 7.62 (dd, J and 1.5 Hz 1H); 7.97 J 9 Hz 1H); 8.70 (broad s 1H).

Methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propylJpiperidine-3-acetate 2.65 g of methyl (4RS)-l-benzyloxycarbonyl-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine- 3-ylideneacetate, Z isomer, 45 cm 3 of absolute ethanol and 265 mg of 10% palladium on carbon are introduced into an autoclave. The reaction mixture is stirred under 5 bar of hydrogen at 220C for 24 hours and then filtered on supercel, and rinsed with 5 times 20 cm 3 of absolute ethanol. The combined filtrates are concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. 1.85 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate are obtained in the form of a colorless oil.

1H NMR spectrum (300 MHz, (CD 3 2 SO d6, 6 in ppm): from 1.10 to 1.80 (mt 7H); from 1.90 to 2.30 (mt 2H); from 2.35 to 2.60 (mt 3H); from 2.65 to 2.95 (mt 3.06 (mt 2H); 3.55 and 3.56 (2s 3H in total); 3.95 and 3.96 (2s 3H in total); from 7.30 to 7.45 (mt 2H); 7.96 J 9 Hz 1H); 8.70 (broad s 1H).

Methyl (4RS)-l-benzyloxycarbonyl-4-[3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-3-ylidenacetate, Z isomer.

A solution of 5.8 g of methyl (4RS)-4-allyll-benzyloxycarbonylpiperidin-3-ylideneacetate (Z isomer) in 15 cm 3 of tetrahydrofuran is slowly added, at a temperature in the region of 0°C, with stirring and under an inert atmosphere, to 45 cm 3 of a 0.5 M 9-borabicyclo[3.3.1]nonane solution in tetrahydrofuran.

The mixture is then brought to a temperature in the region of 20 0 C while the stirring is continued for a further 4 hours. 5.5 g of 4-iodo-3-fluoro- 6-methoxyquinoline in solution in 100 cm 3 of tetrahydrofuran are added, followed by 11.2 g of tribasic potassium phosphate, and finally 386 mg of palladiumdiphenylphosphinoferrocene chloride. The reaction mixture is heated for 2 hours under reflux and then stirred for 48 hours at room temperature. The suspension obtained is filtered. The filtrate is concentrated and then taken up in 200 cm 3 of ethyl acetate. The solution obtained is washed with twice 200 cm 3 of water and then with twice 200 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. 15 g of an oil are obtained, which oil is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 L; diameter 6 cm; height 38 cm), eluting with a cyclohexane-ethyl acetate mixture (85/15 by volume, making a gradient up to 70/30 by volume) and collecting 200-cm 3 fractions. Fractions 31 to 34 are combined and then concentrated. 4.7 g of methyl (4RS)-l-benzyloxycarbonyl-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-ylidenacetate (Z isomer) are obtained in the form of a colorless oil.

Infrared spectrum (CC1 4 3091; 3068; 3034; 1705; 1655; 1622; 1507; 1468; 1434; 1361; 1263; 1231; 1207; 1173; 1141; 1034; 909; 832 and 696 cm 1 Methyl (4RS)-4-allyl-l-benzyloxycarbonylpiperidin- 3-ylidenacetate, Z isomer A solution containing 16.3 g of (4RS)- 4-allyl-l-benzyloxycarbonylpiperidin-3-one in 200 cm 3 of toluene is stirred under reflux with methyl (triphenylphosphoranylidene)acetate, under an inert atmosphere, for 16 hours. After cooling to about 20 0

C,

the reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 0 C, the residue obtained, solubilized in 50 cm 3 of dichloromethane in the hot state, is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 p; diameter cm; height 45 cm), eluting with a cyclohexane-ethyl acetate (80/20 by volume) mixture and collecting 250-cm 3 fractions. Fractions 13 to 15 are combined and then concentrated as above. 5.8 g of methyl (4RS)-4-allyll-benzyloxycarbonylpiperidin-3-ylidenacetate (Z isomer) are obtained in the form of a colorless oil.

Infrared spectrum (CC1 4 3068; 3034; 2949; 2853; 1722; 1705; 1655; 1643; 1434; 1260; 1200; 1174; 1144; 993; 918 and 696 cm 1 (4RS)-4-allyl-l-benzyloxycarbonylpiperidin- 3-one may be prepared according to Takeuchi Y et al.

described in Synthesis 1999, 10, 1814.

Example 2 (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxy quinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl] piperidine-3-acetic acid dihydrochloride A solution of 70 mg of ethyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3acetate, 1 cm 3 of dioxane and 0.3 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring, at a temperature in the region of 60 0 C for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 0 C, the residue obtained is taken up in 25 cm 3 of water and 10 cm 3 of dichloromethane. The aqueous phase is separated after settling out and then acidified by pouring 0.3 cm 3 of 1 N hydrochloric acid. The precipitate formed is dissolved by adding 25 cm 3 of dichloromethane. The organic phase is washed with 10 cm 3 of a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The residue obtained is then dissolved in the hot state in 2 cm 3 of acetone. 0.07 cm 3 of 4 N hydrochloric acid in dioxane is poured over this solution which is obtained. The resulting mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. 72 mg of (3RS,4RS)- 4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxy quinolin-4yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3acetic acid dihydrochloride are obtained in the form of a powder which is white in color.

H NMR spectrum (400 MHz, (CD 3 2 SO d6 with a few drops of CD3COOD d4 at a temperature of 373K, 6 in ppm): from 1.20 to 2.00 (mt 7H); from 2.00 to 2.60 (mt from 2.75 to 3.20 (mt 6H); 3.94 (s 3H); 4.89 (broad t, J 7 Hz 1H); 7.07 (mt 1H); 7.24 (mt 1H); 7.37 (dd, J 9 and 2.5 Hz 1H); 7.60 (broad d, J 5 Hz 1H); from 7.90 to 8.00 (mt 2H); 8.62 (broad s 1H).

Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyguinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate A solution composed of 0.92 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride, 0.85 cm 3 of triethylamine, 535 mg of 2-(2-bromoethylthio)thiophene in 30 cm 3 of anhydrous dimethylformamide is stirred for 4 hours 30 minutes at a temperature in the region of 600C under an inert atmosphere. 0.3 cm 3 of triethylamine is then added and the mixture is again heated at 600C under an inert atmosphere for 15 hours. After cooling to about 200C, the reaction mixture is poured over 100 cm 3 of water and 100 cm 3 of ethyl acetate. The organic phase is separated after settling out, washed with 4 times 15 cm 3 of water and then with twice 50 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 A; diameter 1 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate (50/50 by volume) mixture and collecting 20-cm 3 fractions.

Fractions 13 to 15 are concentrated. 70 mg of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro- .6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]- 1-[2-(2-thienylthio)ethyl]piperidine-3-acetate are obtained in the form of an oil which is yellow in color.

Infrared spectrum (CC1 4 3617; 2934; 2799; 2764; 1737; 1623; 1508; 1467; 1231; 1033; 1011; 834 and 698 cmi Methyl (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine- 3-acetate dihydrochloride A solution of 940 mg of (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid in 20 cm 3 of methanol is cooled to a temperature in the region of -25 0 C, with stirring and under an inert atmosphere. 0.43 cm 3 of thionyl chloride is added to this solution over 5 minutes. The mixture is brought to a temperature in the region of 0 C while the stirring is continued for a further 1 hour 30 minutes. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C and then 30 cm 3 of methanol are added.

This series of operations is repeated 3 times. 920 mg of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine- 3-acetate dihydrochloride are obtained in the form of a yellow foam.

Infrared spectrum (KBr): 3249; 1949; 2503; 2020; 1731; 1622; 1604; 1555; 1497; 1457; 1420; 1308; 1242; 1200; 1175; 1080; 1014; 872; 832 and 795 cm (3RS,4RS) and (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid A solution of 1.16 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)- 3-propyl]-1-(tert-butyloxycarbonyl)piperidine- 3-acetate, 100 cm 3 of anhydrous dimethyl sulfoxide and 25 cm 3 of anhydrous tert-butanol is stirred under an inert atmosphere free of water at 20 0 C. This colorless solution is purged with pure oxygen until the reaction mixture becomes saturated. A solution containing 685 mg of potassium tert-butoxide in 8 cm 3 of anhydrous tertbutanol is then added. Oxygen is again introduced by bubbling for a further 3 hours and 30 minutes with vigorous stirring. The yellow solution obtained is purged with nitrogen and then cooled to 0°C. 0.5 cm 3 of pure acetic acid in 20 cm 3 of water is then added followed by 200 cm 3 of ether. The organic phase is separated after settling out, washed with 7 times 20 cm 3 of water and with 3 times 20 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. A gum is obtained which is taken up in 20 cm 3 of ether. The medium is again concentrated under the same conditions as above. 945 mg of (3RS,4RS) and (3SR,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine- 3-acetic acid are obtained in the form of a white foam.

I

Infrared spectrum (KBr): 2973; 2932; 2864; 1693; 1668; 1623; 1510; 1468; 1429; 1366; 1232; 1166; 1030 and 831 cm- 1 Infrared spectrum (CH 2 C1 2 3600; 2982; 2939; 2867; 1710; 1682; 1623; 1509; 1468; 1429; 1367; 1231; 1162; 1030; 909; 896 and 834 cm 1 Methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro- 6-methoxyquinolin-4-yl)-3-propyl]-1-(tertbutyloxycarbonyl)piperidine-3-acetate A solution of 1.85 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-3-acetate, 0.7 cm 3 of triethylamine and 40 cm 3 of dichloromethane is cooled, to a temperature in the region of 0°C, with stirring and under an argon atmosphere. A solution of 1.16 g of ditert-butyldicarbonate dissolved in 40 cm 3 of dichloromethane is added to this colorless solution over 20 minutes. The mixture is brought to a temperature in the region of 20 0 C while the stirring is continued for a further 10 hours. 200 cm 3 of water are then added to the reaction mixture. The organic phase is separated after settling out, washed with 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. An oil is obtained which is purified by chromatography, under a nitrogen pressure of 50 kPa, on I I a column of silica gel (particle size 20-45 I; diameter 2 cm; height 20 cm), eluting with a cyclohexane-ethyl acetate (70/30 by volume) mixture and collecting 40-cm 3 fractions. Fractions 8 to 12 are combined and then concentrated as above. 2.16 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin- 4 -yl)- 3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetate are obtained in the form of a colorless oil.

Infrared spectrum (CC1 4 3006; 1740; 1695; 1622; 1507; 1468; 1428; 1366; 1231; 1166; 1034; 909 and 832 cm' Example 3 (3SR,4RS)-4-[33-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid hydrochloride A solution of 195 mg of methyl (3SR,4RS)- 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]- 1-[2-(2-thienylthio)ethyl]piperidine-3-acetate, 2 cm 3 of dioxane and 0.9 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring, at a temperature in the region of 60 0 C for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 20 cm 3 of water and 10 cm 3 of ether. The aqueous phase is separated after settling out and then acidified by adding 0.9 cm 3 of 1 N hydrochloric acid.

The precipitate formed is dissolved with 20 cm 3 of dichloromethane. The organic phase is washed with twice cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The product obtained is then stirred in cm 3 of acetone. A solution of 2 cm 3 of 4 N hydrochloric acid in dioxane is poured over this solution. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C and then 5 cm 3 of acetone are added. This operation is repeated 4 times. 155 mg of (3SR,4RS)- 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]l-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid hydrochloride are obtained in the form of a solid which is off-white in color.

1H NMR spectrum (300 MHz, (CD 3 2 SO d6, 6 in ppm): from 1.15 to 2.10 (mt 8H); 2.10 (dd, J 15 and 7.5 Hz 1H); 2.47 (dd, J 15 and 4 Hz 1H); from 2.70 to 2.95 (mt 2H); 3.07 (broad t, J 7 Hz 2H); 3.20 (mt 4H); 3.44 (mt 2H); 3.96 (s 3H); 7.11 (dd, J and 4 Hz 1H); 7.32 (dd, J 4 and 1.5 Hz 1H); 7.40 (mt 1H); 7.41 (dd, J 9 and 2.5 Hz 1H); 7.72 (dd, J 5.5 and 1.5 Hz 1H); 7.97 J 9 Hz 1H); 8.71 (broad s 1H); from 9.85 to 10.05 (unresolved complex 1H).

Methyl (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine- 3-acetate A solution composed of 0.95 g of methyl (3RS,4RS) and (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate, 0.7 g of potassium carbonate, 0.68 g of 2-(2-bromoethylthio)thiophene in 40 cm 3 of dimethylformamide is stirred for 16 hours at a temperature in the region of 60 0 C under an inert atmosphere. After cooling to about 20 0 C, the reaction mixture is supplemented with 200 cm 3 of water and 200 cm 3 of ethyl acetate. The organic phase is separated after settling out and then washed with times 100 cm 3 of water and then with 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The evaporation residue obtained is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 diameter 2 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate (68/32 by volume) mixture and collecting 15-cm 3 fractions. Fractions 33 to 36 are concentrated. 195 mg of methyl (3SR,4RS)-4-[3-(3fluoro-6-methoxyquinolin-4-yl)propyl]- 1-[2-(2-thienylthio)ethyl]piperidine-3-acetate are obtained in the form of an orange-colored oil.

1H NMR spectrum (300 MHz, (CD 3 2 SO d6, 5 in ppm) from 1.00 to 1.80 (mt 9H); 1.89 (very broad t, J 10.5 Hz 1H); 2.07 (dd, J 15 and 7.5 Hz 1H); from 2.35 to 2.55 (mt 3H); from 2.65 to 2.80 (mt 2H); 2.90 J 7 Hz 2H); 3.05 (broad t, J 6.5 Hz 2H); 3.56 (s 3H); 3.95 (s 3H); 7.04 (dd, J 5 and 3.5 Hz 1H); 7.17 (dd, J 3.5 and 1.5 Hz 1H); 7.37 (mt 1H); 7.40 (dd, J 9 and 2.5 Hz 1H); 7.60 (dd, J and 1.5 Hz 1H); 7.96 J 9 Hz 1H); 8.69 (broad s 1H).

Example 4 (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2thienylthio)ethyl]piperidine-3-acetic acid A mixture of 0.355 g of methyl (3RS,4RS)-4- [3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-l-[2-(2-thienylthio)ethyl]piperidine-3acetate in 1.66 cm 3 of a 1 N aqueous sodium hydroxide solution and 5 cm 3 of dioxane is heated at a temperature in the region of 600C, with stirring, for 2 hours.

After cooling to about 20 0 C, the reaction mixture is concentrated to dryness to dryness under reduced pressure (2 kPa) at a temperature in the region of 0 C. The evaporation residue obtained is taken up in 30 cm 3 of water and 30 cm 3 of diethyl ether, the aqueous phase is separated after settling out and neutralized with 1.66 cm 3 of a 1 N aqueous hydrochloric acid solution and is then extracted with twice 100 cm 3 of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness according to the same conditions above. 0.238 g of (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2thienylthio)ethyl]piperidine-3-acetic acid is obtained in the form of a white solid.

1H NMR spectrum: (300 MHz, (CD 3 2 SO d6, 6 in ppm): from 0.95 to 2.80 (mts: 16H); 2.87 (mt 2H); 3.93 (s 3H); 4.65 (broad t, J 7 Hz 1H); 7.04 (broad dd, J and 3.5 Hz 1H); 7.16 (broad d, J 3.5 Hz 1H); 7.37 (very broad d, J 9.5 Hz 1H); 7.60 (broad d, J Hz 1H); 7.85 (mt 1H); 7.94 J 9.5 Hz 1H); 8.66 (mt 1H).

Methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2thienylthio)ethyl]piperidine-3-acetate 0.695 g of sodium borohydride is added in several portions to a mixture of 0.98 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 50 cm 3 of methanol cooled to the region of -50C, with stirring and under inert atmosphere. The reaction is very exothermic and in the vicinity of 0°C, 0.365 g of molybdenum trioxide is added all at once. The reaction mixture is stirred in the region of 20 0 C for 20 hours and then it is cooled to the vicinity of -60C and 0.695 g of sodium borohydride and 0.365 g of molybdenum trioxide are again added. The reaction mass is stirred for 5 hours in the region of 20 0 C and is then filtered on celite and the insoluble matter is washed with twice 50 cm 3 of methanol. The filtrate is concentrated to dryness to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatography under an argon pressure of kPa, on a column of silica gel (particle size 60 m; diameter 3 cm; height 25 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (50/50 by volume), ethyl acetate and then dichloromethanemethanol (90/10 by volume) and collecting 50-cm 3 fractions. Fractions 17 to 20 are combined and then concentrated to dryness according to the conditions described above. 0.355 g of methyl (3RS,4RS)-4-[3- (R,S)amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]- 1-[2-(2-thienylthio)ethyl]piperidine-3-acetate is obtained in the form of a colorless oil.

Infrared spectrum: (CC1 4 2932; 2765; 1736; 1623; 1508; 1230; 1167; 1033; 833 and 699 cm 1 Methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl)-1-[2-(2thienylthio)ethyl]piperidine-3-acetate 0.363 g of hydroxylamine hydrochloride is added in several portions to a mixture of 0.99 g of methyl (3RS,RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin- 4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3acetate in 10 cm 3 of pyridine, with stirring and under an inert atmosphere, and the whole is heated in the region of 60 0 C for 16 hours. After cooling in the region of 200C, the reaction mass is concentrated to dryness to dryness under reduced pressure (8 kPa) at a temperature in the region of 55 0 C. The evaporation residue is taken up in 75 cm 3 of ethyl acetate and cm 3 of distilled water. The organic phase is washed with three times 40 cm 3 of distilled water at 40 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate for 30 minutes, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 0.98 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(fluoro-6methoxyquinolin-4-yl)propyl)-1-[2-(2thienylthio)ethyl]piperidine-3-acetate is obtained in the form of a yellow gum.

Mass spectrum: El m/z=528 [M-OH] m/z=514 [M-OCH3] m/z=416 [M-C 5 HsS2] base peak m/z=115 [C 4

H

3

S

2 DCI m/z=546 MH Methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6methoxyquinolin-4-yl)propyl)-1-[2-(2thienylthio)ethyl]piperidine-3-acetate 4.7 cm 3 of dimethyl sulfoxide in 15 cm 3 of dichloromethane are poured, over 10 minutes, into a solution of 3.3 cm 3 of oxalyl dichloride Ln 40 m 3 of dichloromethane cooled to -700C, with stirring and under an inert atmosphere. After 10 minutes, a solution of 4 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 2 thienylthio)ethyl]piperidine-3-acetate in 25 cm 3 of dichloromethane is poured in over 10 minutes. After 20 minutes, in the region of -70 0 C, 21 cm 3 of triethylamine in 20 cm 3 of dichloromethane are added dropwise over 15 minutes and the reaction mixture is stirred for 15 minutes in the region of -700C and then for 2 hours in the region of 20 0 C. 100 cm of distilled water are poured over the reaction mass, the organic phase is separated after settling out, washed with 100 cm 3 of a saturated aqueous sodium hydrogen carbonate solution, with twice 75 cm 3 of water and 75 cm 3 of a saturated aqueous sodium chloride solution. The organic extract is dried over magnesium sulfate for 30 minutes, filtered and concentated to dryness to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 g; diameter 3 cm; height 40 cm), eluting with a cyclohexane-ethyl acetate (60/40 by volume) mixture and collecting 50-cm 3 fractions. Fractions 11 to 16 are combine concentrated to dryness according to the described above. 3.16 g of methyl (3RS,4R (fluoro-6-methoxyquinolin-4-yl)propyl)-1thienylthio)ethyl]piperidine-3-acetate ar the form of a yellow oil.

Infrared spectrum: (CC1 4 2930 1621; 1505; 1231; 1198; 1154; 1028; 834; Example (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoromethoxyquinolin-4-yl)propyl]-1-(2,5difluorophenylthio)ethyl]piperidine-3-ace hydrochloride A mixture of 0.2 g of methyl (3 (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinol propyl]-1-(2,5-difluorophenylthio)ethyl]p acetate in 3 cm 3 of methanol, 3 cm 3 of dic cm 3 of a. 10 N aqueous sodium hydroxide so] heated at a temperature in the region of stirring, for 22 hours. After cooling in of 20 0 C, the reaction mixture is concentr dryness under reduced pressure (2 kPa) at in the region of 500C. The evaporation re is taken up in 10 cm 3 of distilled water with a sufficient volume of a concentrate solution in order to obtain a pH in the r The mixture is extracted with 20 cm 3 of e d and then conditions S)-4-[3-oxo-3e obtained in :1738; 1699; 699 cm 1 6tic acid RS,4RS)-4-[3in-4-yl)iperidine-3ixane and 1.77 ution is 65 0 C, with the vicinity ated to a temperature sidue obtained ind acidified d acetic acid egion of 5-6.

:hyl acetate, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness according to the conditions described above. The oil obtained is taken up in 10 cm 3 of acetone and 10 cm 3 of a hydrochloric dioxane solution and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue is again taken up in 10 cm 3 of acetone and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0

C

and then dried in a desiccator for 18 hours. 0.181 g of (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2,5-difluorophenylthio)ethyl]piperidine-3-acetic acid hydrochloride is obtained in the form of an orange-colored pourer solid melting in the vicinity of 124 0

C.

1 H NMR spectrum (300 MHz, (CD 3 2 SO d6, 8 in ppm). A mixture of two stereoisomers in approximate proportions 60/40 is observed.

from 1.00 to 3.85 (mts 18H); 3.89 and 4.07 (2 broad s 3H in total); 5.34 and 5.49 (2 mts 1H in total); from 7.05 to 7.55 (mts 4H); from 7.90 to 8.20 (mt 2H); 8.68 and 8.85 (2 broad s 1H in total); from 9.65 to 10.70 (unresolved complexes 2H in total).

Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate A mixture of 6.5 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate dihydrochloride, 3.9 g of 2-(2-bromoethylthio)-1,4-difluorobenzene dissolved in 10 cm 3 of dimethylformamide, 2.32 g of potassium iodide, 5.8 g of potassium carbonate and 3.93 cm 3 of trietylamine in 200 cm 3 of acetonitrile is heated, with stirring and under an inert atmosphere, for 22 hours at a temperature in the region of 70 0 C. After cooling to a temperature in the region of 200C, the reaction mixture is filtered and the insoluble matter is washed with twice 30 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The evaporation residue is taken up in 100 cm 3 of distilled water and 150 cm 3 of ethyl acetate. The organic phase is washed with 3 times 100 cm 3 of distilled water twice 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness according to the conditions described above. The oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 pun; diameter 4 cm), eluting with a cyclohexane-ethyl acetate (50/50 by volume) mixture and collecting 60-cm 3 fractions. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. 1.7 g of methyl (3RS, 4RS) S) -hydroxy-3- (3-fluoro-6methoxyquinolin-4-yl)propyl] difluorophenylthio) ethyllpiperidine-3-acetate are obtained in the form of an orange-colored pourer viscous oil.

1H NMR spectrum (300 MHz, (CD 3 2 S0 d6, 8 in ppm) The mixture of two stereoisomers in the proportions 50/50 is observed.

from 0.90 to 2.60 (mt :14H); from 2.60 to 2.80 (mt 2H); 3.08 (broad t, J 7 Hz 2H); 3.47 and 3.55 (2 s :3H in total); 3.89 (s 3H); 5.33 (very broad t, J =7 Hz: 5.3(broad s H);7.05rlt :lH); from 7.15 to 7.35 (mt 7.38 (d mt, J 9 Hz: 1H); from 7.90 to 8.00 (mt 8.68 (broad s H).

Example 6 (3RS,4RS) S) -amino-3- (3-fluoro-6methoxyquinolin-4-yl)propyl difluorophenylthio) ethyl] piperidine-3-acetic acid hydrochloride A mixture of 0.09 g of methyl (3RS,4RS)-4-[3- (R,S)-amino-3- (3-f luoro-6-methoxyquinolin-4-yl)propyll- 1- 5-difluorophenylthio) ethyllpiperidine-3-acetate in 0.36 cm 3 of a 1 N aqueous sodium hydroxide solution and 3 cm 3 of dioxane is heated at a temperature in the region of 55 0 C, with stirring and under an inert atmosphere, for 4 hours. After cooling in the vicinity of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 500C. The evaporation residue obtained is taken up in 5 cm 3 of distilled water and is acidified with a normal aqueous hydrochloric acid solution and is concentrated N. The aqueous phase is washed with 8 cm 3 of dichloromethane and then concentrated according to the conditions described above. The residue obtained is taken up in 10 cm 3 of acetone and then it is filtered on sintered glass. 0.081 g of (3RS,4RS)-4-[3-(R,S)-amino- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetic acid hydrochloride is obtained in the form of a white solid.

NMR spectrum 1 H NMR spectrum (400 MHz,

(CD

3 2 SO d6 with addition of a few drops of CD3COOD d4, at a temperature of 383K, 6 in ppm). A mixture of stereoisomers is observed.

from 1.20 to 2.55 (mt 12H); from 2.80 to 3.60 (mt 6H); 4.03 (s 3H); 5.16 (mt 1H); 7.12 (mt 1H); 7.25 (mt 1H); 7.42 (mt 1H); 7.49 (broad d, J 9 Hz 1H); 7.54 (mt 1H); 8.06 J 9 Hz 1H); 8.76 (broad s 1H).

Methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate 0.261 g of sodium borohydride is added, in several portions, to a mixture of 0.4 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 25 cm 3 of methanol cooled in the region of -2 0 C, with stirring and under an inert atmosphere. The reaction mass is stirred in the region of 0°C for 20 minutes and then 0.14 g of molybdenum trioxide is added. The reaction mixture is stirred in the region of 20 0 C for 24 hours and then it is cooled in the vicinity of -20C and 0.261 g of sodium borohydride and 0.14 g of molybdenum trioxide are again added. The reaction mixture is stirred for 18 hours in the region of 200C and is then filtered on celite. The filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C. The evaporation residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 um; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (50/50 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm 3 fractions. Fractions 26 to 41 are combined and then concentrated to dryness according to the conditions described above. 0.202 g of methyl (3RS,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate is obtained in the form of a colorless oil.

Infrared spectrum: (CC1 4 2938; 1736; 1623; 1507; 1484; 1230; 1189; 1168; 1033; 909 and 833 cm i Methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate 0.347 g of hydroxylamine hydrochloride is added, in several portions, to a mixture of 1 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6methoxyquinolin-4-yl)propyl)-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate in 10 cm 3 of pyridine, with stirring and under an inert atmosphere, and the whole is stirred in the region of 0 C for 24 hours and then for 20 hours in the region of 500C and for 1.25 hours in the region of 62 0 C. After cooling in the region of 200C, the reaction mass is concentrated to dryness to dryness under reduced pressure (1.5 kPa) at a temperature in the region of 500C. The evaporation residue is taken up in 70 cm 3 of ethyl acetate and 40 cm 3 of distilled water. The organic phase is separated after settling out, washed with 3 times 40 cm 3 of distilled water and 40 cm 3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The evaporation residue is purified by chromatrography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 Jm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm 3 fractions. Fractions 1 to 21 are combined and then concentrated to dryness according to the conditions described above. 0.813 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate is obtained in the form of a whitish viscous oil.

Infrared spectrum: (CC1 4 3585; 3174; 2930; 1738; 1621; 1506; 1484; 1229; 1189; 1167; 1029; 909 and 833 cm 1 Methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate 1.88 cm 3 of dimethyl sulfoxide in 6 cm 3 of dichloromethane are poured, over 10 minutes, into a solution of 1.32 cm 3 of oxalyl dichloride in 30 cm 3 of dichloromethane cooled to -700C, with stirring and under an inert atmosphere. After 10 minutes, a solution of 1.7 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5difluorophenylthio)ethyl]piperidine-3-acetate in 15 cm 3 of dichloromethane is poured in over 10 minutes. After minutes, 8.4 cm 3 of triethylamine in 10 cm 3 of dichloromethane are added dropwise over 15 minutes and the reaction mixture is stirred for 45 minutes in the region of -70 0 C and then for 20 hours in the region of 0 C. 50 cm 3 of distilled water are poured over the reaction mass, the organic phase is separated after settling out, washed with 50 cm 3 of a saturated aqueous sodium hydrogen carbonate solution, with twice 30 cm 3 of distilled water and 30 cm 3 of a saturated aqueous sodium chloride solution. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particule size 40-60 pm; diameter 3 cm), eluting with a cyclohexane-ethyl acetate (60/40 by volume) mixture and collecting 10-cm 3 fractions. The fractions containing the expected product are combined and then concentrated to dryness according to the conditions described above. 1.37 g of methyl (3RS,4RS)- 4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l- [2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate are obtained.

Infrared spectrum: (CC14) 2930; 1737; 1701; 1621; 1506; 1484; 1468; 1232; 1189; 1166; 1028; 905 and 834 cml Example 7 (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(2,5cyclopentanethio)ethylpiperidine-3-acetic acid hydrochloride A mixture of 0.12 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-(2,5-cyclopentanethio)-ethyl-pip6ridine-3acetate in 2 cm 3 of dioxane and 0.6 cm 3 of a 1 N aqueous sodium hydroxide solution is heated at a temperature in the region of 550C, with stirring, for 18 hours. After cooling in the vicinity of 20 0 C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The evaporation residue is taken up in 5 cm 3 of distilled water, acidified with a sufficient volume of a 1 N aqueous hydrochloric acid solution in order to obtain a pH in the region of 6. The mixture is extracted with 8 cm 3 of dichloromethane and the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness according to the same conditions described above. The residue is taken up in 5 cm 3 of acetone and 1 cm 3 of a 4 N hydrochloric acid solution in dioxane and then concentrated to dryness under reduced pressure (1 kPa) at a temperature in the region of 500C. The residue is again taken up in 5 cm 3 of acetone and concentrated to dryness according to the conditions described above. 0.078 g of (3RS,4RS)-4-[3-(R,S)hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1- (2,5-cyclopentanethio)ethyl]piperidine-3-acetic acid hydrochloride is obtained in the form of an orangecolored pourer powder melting in the vinicinity of 125 0

C.

NMR spectrum 1H NMR spectrum (400 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3 COOD d4, at a temperature of 383K, 6 in ppm): from 1.20 to 2.55 (mt 18H); 2.89 (mt 2H); from 3.00 to 3.35 (mt 7H); 3.94 (s 3H); 5.39 (mt 1H); 7.39 (dd, J 9 and 2 Hz 1H); 7.97 (d, J 9 Hz 1H); 7.99 (mt 1H); 8.63 (broad s 1H).

Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(2,5-cyclopentanethio)ethylpiperidine-3-acetate A mixture of 1 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-pip4ridine-3-acetate hydrochloride, 0.424 g of (2-chloroethylthio)cyclopentane, 0.388 g of potassium iodide, 0.97 g of potassium carbonate and 0.656 cm 3 of trietylamine in 30 cm 3 of acetonitrile is heated, with stirring, for 18 hours at a temperature in the region of 65 0 C. After cooling to a temperature in the region of 20 0 C, the reaction mixture is filtered and the insoluble matter is washed with twice 20 cm 3 of acetonitrile. The filtrate is concentrated to dryness under reduced temperature (1 kPa) at a temperature in the region of 50 0 C. The evaporation residue is taken up in 20 cm 3 of distilled water and 30 cm 3 of ethyl acetate. The organic phase is washed with twice 20 cm 3 of distilled water and with twice 20 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness according to the conditions described above. The oil obtained is purified by chromatography under an argon pressure of kPa, on a column of silica gel (particle size 40-60 pjn; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume) and then dichloromethane-methanol (90/10 by volume) and collected 6-cm 3 fractions. Fractions 6 to 25 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 0 C. 0.42 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2- (cyclopentanethio)ethyl]piperidine-3-acetate is obtained in the form of a yellow oil.

Infrared spectrum: (CC1 4 3616; 2928; 2853; 1737; 1623; 1508; 1231; 1165; 1032; 907 and 834 cm The preparation of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)]propylpiperidine-3-acetate hydrochloride was described above.

Example 8 Synthesis of stereoisomers of 4-[3-hydroxy-3-(3-fluoro- 6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid The absolute stereochemistry of each stereoisomer called hereinafter I, II, III, IV, V, VI, VII is not known.

Stereoisomer I A solution of 0.625 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer I) in 10 cm 3 of dioxane and 3 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring, at a temperature in the region of 60 0 C for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 10 cm 3 of water, acidified with a 1 N aqueous hydrochloric acid solution. The precipitate formed is filtered, dried in an oven under a reduced pressure (10 Pa) at a temperature in the region of 20 0 C for 18 hours. The product obtained is then stirred in 30 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is then poured in. The reaction mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C and then the product is taken up with acetone 3 times by evaporating according to the conditions described above, at each stage. 0.42 g of 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 2 2 thienylthio)ethyl]piperidine-3-acetic acid dihydrochloride (stereoisomer I) is obtained in the form of a white solid. (aD 20 +56.90+/-1.0 in methanol at 1 H NMR spectrum (400 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3 COOD d4, at a temperature of 373K, 8 in ppm): from 1.25 to 2.65 (mt 9H); 2.33 (dd, J 15 and 5 Hz 1H); from 3.05 to 3.40 (mt 8H); 3.94 (s 3H); 5.40 (broad t, J 7 Hz 1H); 7.09 (mt 1H); 7.28 (broad d, J 3 Hz 1H); 7.37 (very broad d, J 9 Hz 1H); 7.62 (broad d, J 5 Hz 1H); from 7.90 to 8.00 (mt 2H); 8.61 (broad s 1H).

Stereoisomer II A solution of 0.545 g methyl 4-[3-hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 2 2 (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer II) in 10 cm 3 of dioxane and 2.6 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring, at a temperature in the region of 60 0 C, for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 400C, the residue obtained is taken up in 10 cm 3 of water, acidified with a 1 N aqueous hydrochloric acid solution in order to obtain a pH equal to 6. The suspension is taken up in 20 cm 3 of dichloromethane and

I

then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution is poured into dioxane. The precipitate formed is filtered, dried in an oven under reduced pressure Pa) at a temperature in the region of 20 0 C for 18 hours. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage. 0.43 g of 4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid dihydrochloride (stereoisomer II) is obtained in the form of a white solid. (0D 20 +55.90+/-0.9 in methanol at 1H NMR spectrum (400 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3 COOD d4, at a temperature of 373K, 6 in ppm): from 1.25 to 2.60 (mt 10H); from 3.00 to 3.40 (mt 8H); 3.94 (s 3H); 5.39 (dd, J 7 and 5 Hz 1H); 7.09 (dd, J 5 and 3 Hz 1H); 7.28 (broad d, J 3 Hz 1H); 7.38 (dd, J 9 and 2.5 Hz 1H); 7.63 (broad d, J 5 Hz 1H); from 7.90 to 8.05 (mt 2H); 8.63 (broad s 1H).

Stereoisomer III A solution of 0.458 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer III) in 10 cm 3 of dioxane and 2.2 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 60 0 C, for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 10 cm 3 of water, acidified with an aqueous acetic acid solution in order to obtain a pH equal to 6. The suspension is taken up in 20 cm 3 of dichloromethane and then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is poured in. The precipitate formed is filtered, dried in an oven under reduced pressure Pa) at a temperature in the region of 20 0 C for 18 hours. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage. 0.42 g of 4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid (stereoisomer III) in the form of a white solid.

(aD 2 0 -46.90+/-0.9 in methanol at 1H NMR spectrum (400 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3 COOD d4, at a temperature of 373K, 6 in ppm): from 1.25 to 2.60 (mt 10H); from 3.00 to 3.40 (mt 8H); 3.94 (s 3H); 5.39 (broad t, J 7 Hz 1H); 7.09 (mt 1H); 7.28 (broad d, J 3 Hz 1H); 7.38 (very broad d, J 9 Hz 1H); 7.63 (broad d, J 5 Hz 1H); from 7.90 to 8.05 (mt 2H); 8.62 (broad s 1H).

Stereoisomer IV A solution of 0.454 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer IV) in 10 cm 3 of dioxane and 2.2 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 600C, for 1 hour. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 10 cm 3 of water, acidified with an aqueous acetic acid solution in order to obtain a pH equal to 6. The suspension is taken up in 20 cm 3 of dichloromethane and then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is poured in. The precipitate formed is filtered, dried in an oven under a reduced pressure Pa) at a temperature in the region of 20 0 C for 18 hours. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage. 0.35 g of 4-[3-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2-thienylthio)ethyl]piperidine-3-acetic acid dihydrochloride (stereoisomer IV) is obtained in the form of a white solid. (aD 20 -54.80+/-1.1 in methanol at 1H NMR spectrum (400 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3 COOD d4, at a temperature of 373K, 8 in ppm): from 1.25 to 2.60 (mt 9H); 2.22 (broad dd, J 15 and 5 Hz 1H); from 3.00 to 3.40 (mt 8H); 3.94 (s 3H); 5.40 (mt 1H); 7.10 (mt 1H); 7.29 (broad d, J 3 Hz 1H); 7.38 (very broad d, J 9 Hz 1H); 7.64 (broad d, J 5 Hz 1H); from 7.90 to 8.05 (mt 2H); 8.62 (broad s 1H).

Stereoisomer V A solution of 0.560 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer V) in 10 cm 3 of dioxane and 2.2 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 60 0 C, for 2 hours. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 10 cm 3 of water, acidified with an aqueous acetic acid solution in order to obtain a pH equal to 6. The suspension is taken up in 20 cm 3 of dichloromethane and then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is poured in. The precipitate formed is concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage, and then dried in an oven under a reduced pressure (10 Pa) at a temperature in the region of 20 0 C for 120 hours. 0.4 g of 4-[3-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2thienylthio)ethyl]piperidine-3-acetic acid is obtained (stereoisomer V) in the form of a white solid.

(aD 20 +83.40+/-1.3 in methanol at 1 H NMR spectrum (400 MHz, (CD 3 2 SO d6, 8 in ppm): 0.95 (mt 1H); 1.41 (mt 2H); from 1.65 to 2.15 (mt 6H); 2.36 (dd, J 16.5 and 3.5 Hz 1H); from 2.70 to 2.90 (mt 2H); 3.13 (mt 2H); 3.20 (mt 2H); from 3.35 to 3.55 (mt 2H); 3.91 (s 3H); 5.32 (broad t, J 7.5 Hz 1H); 7.10 (dd, J 5.5 and 3.5 Hz 1H); 7.28 (dd, J 3.5 and 1 Hz 1H); 7.38 (dd, J 9 and 3 Hz 1H); 7.68 (dd, J 5.5 and 1 Hz 1H); 7.94 (mt 1H); 7.96 J 9 Hz 1H); 8.70 J 1.5 Hz 1H); 10.15 (unresolved complex 1H).

Stereoisomer VI A solution of 0.36 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate stereoisomer VI) in 10 cm 3 of dioxane and 1.7 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 60 0 C, for 2 hours. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 10 cm 3 of water, acidified with an aqueous acetic acid solution in order to obtain a pH equal to 6. The suspension is taken up in twice 10 cm 3 of dichloromethane and then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is poured in. The precipitate formed is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage, and then dried in an oven under a reduced pressure (10 Pa) at a temperature in the region of 20 0 C for 48 hours. 0.325 g of 4-[3-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-l-[ 2 thienylthio)ethyl]piperidine-3-acetic acid dihydrochloride (stereoisomer VI) is obtained in the form of a white solid. (CD 2 0 in methanol at 1 H NMR spectrum (300 MHz, (CD 3 2 SO d6, 8 in ppm) from 1.30 to 2.20 (mt 9H); 2.46 (mt 1H); from 2.70 to 2.95 (mt 2H); from 3.10 to 3.30 (mt 4H); from 3.35 to 3.65 (mt 2H); 3.91 (s 3H); 5.32 (dd, J 8 and 6 Hz 1H); 7.12 (dd, J 5.5 and 3.5 Hz 1H); 7.31 (dd, J 3.5 and 1Hz 1H); 7.40 (dd, J 9 and 3 Hz 1H); 7.72 (dd, J 5.5 and 1Hz 1H); 7.96 (d, J 9 Hz 1H); 7.98 (mt 1H); 8.70 J 1.5 Hz 1H); 9.93 (unresolved complex 1H).

Stereoisomer VII A solution of 0.39 g of methyl 4-[3-hydroxy- 3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate (stereoisomer VII) in 10 cm 3 of dioxane and 1.8 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 60 0 C, for 2 hours. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 400C, the residue obtained is taken up in 10 cm 3 of water, acidified with an aqueous acetic acid solution in order to obtain a pH equal to 6. The suspension is taken up in 20 cm 3 of dichloromethane and then the organic phase is separated after settling out, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The product obtained is then stirred in 20 cm 3 of acetone and a 4 N hydrochloric acid solution in dioxane is poured in. The precipitate formed is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue obtained is then taken up in acetone several times while evaporating according to the conditions described above, at each stage, and then dried in an oven under a reduced pressure (10 Pa) at a temperature in the region of 20 0 C for 48 hours. 0.4 g of 4-[3-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2thienylthio)ethyl]piperidine-3-acetic acid dihydrochloride (stereoisomer VII) is obtained in the form of a white solid (aD 20 -27.10+/-0.7 in methanol at 1 H NMR spectrum (300 MHz, (CD 3 2 SO d6, 8 in ppm): from 1.30 to 2.20 (mt 9H); 2.45 (mt 1H); from 2.70 to 2.95 (mt 2H); from 3.10 to 3.30 (mt 4H); from 3.35 to 3.70 (mt 2H); 3.91 (s 3H); 5.32 (dd, J 8 and 6 Hz 1H); 7.10 (dd, J 5.5 and 3.5 Hz 1H); 7.30 (dd, J 3.5 and 1Hz 1H); 7.39 (dd, J 9 and 3 Hz 1H); 7.71 (dd, J 5.5 and 1Hz 1H); 7.95 J 9 Hz 1H); 7.97 (mt 1H); 8.68 J 1.5 Hz 1H); 9.96 (unresolved complex 1H).

Synthesis of stereoisomers of methyl 4-[3-hydroxy-3-(3fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2- (thienylthio)ethyl)]piperidine-3-acetate A mixture of 11.9 g of methyl 4-[3-hydroxy-3- (3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3acetate hydrochloride, 4.5 g of 2-(2-bromoethylthio)thiophene, 3 g of potassium iodide, 7.5 g of potassium carbonate and 5 cm 3 of trietylamine in 200 cm 3 of acetonitrile and 100 cm 3 of dimethylformamide is heated, with stirring, for 16 hours at a temperature in the region of 65 0 C. The reaction mixture is filtered, the filtrate is concentrated to dryness under reduced pressure (1 kPa) at a temperature in the region of 0 C. The evaporation residue is purified by chromatography under an argon pressure of 40 kPa, on a column of silica gel (particle size 40-60 pm; diameter 8 cm, height 40 cm), eluting with a cyclohexane-ethyl acetate (50/50 by volume) mixture, collecting 200-cm 3 fractions after the passage of 3 dm 3 of a cyclohexaneethyl acetate (50/50 by volume) mixture. Fractions to 40 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C in order to obtain 3.1 g of a mixture of stereoisomers I, II, III, IV, in the form of a yellow oil and fractions 48 to 90 are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C in order to obtain 3.8 g of a mixture of stereoisomers V, VI, VII, VIII, in the form of a yellow oil.

The absolute stereochemistry of each stereoisomer (esters) called hereinafter I, II, III, IV V, VI, VII, VIII is not known Starting with the mixture of stereoisomers I, II, III, IV obtained above, the separation of each stereoisomer is carried out by HPLC: The separation of 2 pairs of stereoisomers (I+II) and (III+IV) is carried out on a stationary chiral phase starting with 22.7 g of the I, II, III, IV mixture described above in example 2, (type of phase: chiracel OD; particle size 20 gmm; diameter 80 mm; mass of the stationary phase 1.2 kg), under a pressure of 600 kPa, the mobile phase is composed of a mixture of heptane-2-propanol (90/10 by volume) having a flow rate of 160 cm 3 per minute and the UV detector wavelength is set at 265 nm. The fractions containing a first pair of diastereoismers noted (I+II) are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and 1.3 g are obtained in the form of an oil with a recovery rate equal to 96%. The fractions containing the second pair of diastereoismers noted (III+IV) are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and 1.03 g thereof are obtained in the form of an oil with a recovery rate equal to 76%. Next, the products of each pair of stereoisomers (I-II and III-IV) are separated on a chiralpak AD column (particle size 20 gmm; diameter 80 mm; mass of the stationary phase 1.2 kg) under a pressure of 800 kPa, the mobile phase is composed of a mixture of heptane-ethanol (90/10 by volume) having a flow rate of 200 cm 3 per minute and the UV detector wavelength is set at 280 nm. The fractions containing each product are isolated and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 0 C; 0.632 g of the stereoisomer I, 0.553 g of the stereoisomer II, 0.463 g of the stereoisomer III, 0.46 g of the stereoisomer IV are thus obtained.

NMR spectrum of stereoisomer I: 1 H (300 MHz, (CD 3 2

SO

d6, 8 in ppm): from 0.85 to 1.55 (mt 6H); from 1.75 to 2.10 (mt 6H); from 2.35 to 2.55 (mt 2H); from 2.55 to 2.80 (mt 2H); 2.87 J 7 Hz 2H); 3.50 (s 3H); 3.89 (s 3H); 5.33 (broad t, J 7 Hz 1H); 5.82 (broad s 1H); 7.04 (dd, J 5.5 and 3.5 Hz 1H); 7.15 (dd, J 3.5 and 1.5 Hz 1H); 7.38 (dd, J 9 and 3 Hz 1H); 7.60 (dd, J 5.5 and 1.5 Hz 1H); from 7.90 to 8.00 (mt 2H); 8.68 J 2 Hz 1H).

HPLC condition: Chiralpack® column, flow rate 1 cm 3 /min, elution condition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to 28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35 min (in a gradient) ethanol-heptane (7/93 by volume) Retention time: 24.13 min NMR spectrum of stereoisomer II: 1 H (300 MHz, (CD 3 2

SO

d6, 8 in ppm): from 1.00 to 1.55 (mt 6H); from 1.70 to 2.15 (mt 5H); 2.21 (dd, J 16 and 3 Hz 1H); from 2.30 to 2.60 (mt 2H); 2.67 (mt 2H); 2.89 (t, J 7 Hz 2H); 3.59 (s 3H); 3.90 (s 3H); 5.34 (mt 1H); 5.83 (very broad d, J 3 Hz 1H); 7.05 (dd, J 5.5 and 3.5 Hz 1H); 7.17 (broad dd, J and 1.5 Hz 1H); 7.39 (dd, J 9 and 3 Hz 1H); 7.61 (dd, J 5.5 and 1.5 Hz 1H); 7.96 J 9 Hz 1H); 7.99 (mt 1H); 8.69 (broad s 1H).

HPLC condition: Chiralpack® column, flow rate 1 cm 3 /min, elution condition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to 28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35 min (in a gradient) ethanol-heptane (7/93 by volume) Retention time: 29.04 min NMR spectrum of stereoisomer III: 1 H (300 MHz, (CD 3 2

SO

d6, 8 in ppm) from 1.00 to 1.55 (mt 6H); from 1.70 to 2.15 (mt 5H); 2.21 (dd, J 16 and 3.5 Hz 1H); from 2.30 to 2.60 (mt 2H); 2.67 (mt 2H); 2.88 (t, J 7 Hz 2H); 3.58 (s 3H); 3.90 (s 3H); 5.33 (mt 1H); 5.82 (broad s 1H); 7.04 (dd, J 5.5 and Hz 1H); 7.16 (dd, J 3.5 and 1.5 Hz 1H); 7.38 (dd, J 9 and 3 Hz 1H); 7.59 (dd, J 5.5 and Hz 1H); 7.96 J 9 Hz 1H); 7.97 (mt 1H); 8.68 (broad d, J 1.5 Hz 1H).

HPLC condition: Chiralpack® column, flow rate 1 cm 3 /min, elution condition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to 28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35 min (in a gradient) ethanol-heptane (7/93 by volume) Retention time: 23 min NMR spectrum of stereoisomer IV: 1 H (300 MHz, (CD 3 2

SO

d6, 8 in ppm) from 0.90 to 1.55 (mt 6H); from 1.75 to 2.10 (mt 6H); from 2.35 to 2.55 (mt 2H); from 2.55 to 2.80 (mt 2H); 2.87 J 7 Hz 2H); 3.50 (s 3H); 3.90 (s 3H); 5.35 (mt 1H); 5.83 (d, J 3 Hz 1H); 7.04 (dd, J 5.5 and 3.5 Hz 1H); 7.15 (broad dd, J 3.5 and 1.5 Hz 1H); 7.38 (dd, J 9 and 3 Hz 1H); 7.60 (broad dd, J 5.5 and Hz 1H); from 7.90 to 8.00 (mt 2H); 8.69 (broad s 1H).

HPLC condition: Chiralpack® column, flow rate 1 cm 3 /min, elution condition from 0 to 13 mim: ethanol-heptane (7/93 by volume) from 13 to 28 min (in a gradient) ethanol-heptane (15/93 by volume) from 28 to 35 min (in a gradient) ethanol-heptane (7/93 by volume) Retention time: 25.38 min Starting with the mixture of stereoisomers V, VI, VII, VIII obtained above, the separation of each stereoisomer is carried out by HPLC: The separation of the 2 pairs of stereoisomers is carried out on a C18 stationary phase starting with 3.5 g of the V, VI, VII, VIII mixture described above (type of phase: KROMACIL® C18; particle size 7 gm; diameter 4.6 mm; mass of the stationary phase 1 kg), under a pressure of 5 000 kPa, the mobile phase is composed of a mixture of water-acetonitrilemethanol-trifluoroacetic acid (60/15/25/0.05 by volume) having a flow rate of 140 cm 3 per minute and the UV detector wavelength is set at 254 nm. The fractions containing the first pair of stereoisomers noted (V+VIII) are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and 1.84 g thereof are obtained in the form of an oil. The fractions containing the second pair of stereoisomers noted (VI+VII) are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40 0 C and 1.42 g thereof are obtained in the form of an oil. Next, the enantiomers of the pair of stereoisomers (V+VIII) are separated on a CHIRALPAK® AS column (particle size 20 Am; diameter 80 mm; mass of the stationary phase 1.2 kg) under a pressure of 290 kPa, the mobile phase is composed of a mixture of isopropanol-heptanetriethylamine (10/90/0.1 by volume) having a flow rate of 110 cm 3 per minute and the UV detector wavelength is set at 265 nm. The fractions containing each enantiomer are isolated and then concentrated under a reduced pressure (2 kPa) at a temperature in the region of 0 C; 0.5 g of stereoisomer V is thus obtained, the enantiomers of the pair of stereoisomers VI VII are separated on an OC type CHIRALCEL® column (particle size Am; diameter 60 mm; mass of the stationary phase 600 g) under a pressure of 230 kPa, the mobile phase is composed of an ethanol-heptane-triethylamine (10/90/0.1 by volume) mixture having a flow rate of 90 cm 3 per minute and the UV detector wavelength is set at 265 nm.

The fractions containing each enantiomer are isolated and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40 0 C; 0.36 g of stereoisomer VI and 0.68 g of stereoisomer VII are thus obtained.

1H NMR spectrum stereoisomer V: (300 MHz, (CD 3 2 SO d6, 8 in ppm) from 0.80 to 2.00 (mt 8H); 2.08 (broad dd, J 16.5 and 8 Hz 1H); 2.35 (dd, J 16.5 and 4 Hz 1H); from 2.20 to 3.30 (mt 8H); 3.55 (s 3H); 3.92 (s 3H); 5.33 (mt 1H); 5.88 J 4 Hz 1H); 7.08 (dd, J 5.5 and 3.5 Hz 1H); 7.25 (broad d, J 3.5 Hz 1H); 7.42 (dd, J 9 and 3 Hz 1H); 7.68 (dd, J 5.5 and 1 Hz 1H); 7.95 (mt 1H); 7.97 (d, J 9 Hz 1H); 8.69 (broad d, J 1.5 Hz 1H); from 8.90 to 10.00 (unresolved complexes 1H).

HPLC condition: separation on Chiralpak AS 20 Am phase.

Elution condition: heptane, ethanol, trethylamine (85/15/0.1% volume); 1 ml/min UV 254 nm Retention time: 9.37 min 1H NMR spectrum stereoisomer VI: (300 MHz, (CD 3 2 SO d6, 6 in ppm): from 1.00 to 2.65 (mt 12H); 2.06 (dd, J 15.5 and 7.5 Hz 1H); 2.40 (dd, J 15.5 and 4 Hz 1H); from 2.65 to 2.90 (mt 2H); 2.91 (broad t, J 7 Hz 2H); 3.54 (s 3H); 3.90 (s 3H); 5.32 (mt 1H); 5.84 J 4 Hz 1H); 7.05 (dd, J and 3.5 Hz 1H); 7.16 (dd, J 3.5 and 1.5 Hz 1H); 7.39 (dd, J 9 and 3 Hz 1H); 7.61 (dd, J 5.5 and Hz 1H); 7.96 J 9 Hz 1H); 7.99 (mt 1H); 8.68 (broad d, J 1.5 Hz 1H).

HPLC condition: separation on Chiracel OC 10 gmn type phase Elution condition: heptane, ethanol, triethylamine (90/10/0.1% by volume); 1 mi/mmn; UV 254 rim Retention time: 17.5 min 1 H NNR spectrum stereoisomer VII: (300 MHz, (CD 3 2 S0 d6, 8 in ppm) from 1.00 to 2.65 (int 12H); 2.05 (dd, J 15 and 7.5 Hz 1H); 2.40 (dd, J =15 and 4 Hz 1H); 2.79 (int 2H); 2.93 (broad t, J =7 Hz 2H); 3.56 (s 3.90 (s 3H); 5.31 (int 1 5.84 (d, J =4 Hz H);7.05 (dd,J =5.5 and3.5 Hz 7.19 (broad d, J 3.5 Hz 1H); 7.40 (dd, J 9 and 3 Hz 1H); 7.62 (dd, J =5.5 and 1 Hz 1H); 7.96 (d, J 9 Hz 1H); 7.99 (mt 1 8.68 (broad d, J 1.5 Hz 1H).

HPLC condition: separation on Chiracel OC 10 gin type phase Elution condition: heptane, ethanol, triethylamine (90/10/0.1% by volume); 1 mi/mmn; UV 254 rim.

Retention time: 23.76 min Exam~ple 9 (3RS,4RS)-4- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenlyl)prop- 2-ynyl] piperidin-3-yl)acetic acid dihydrochioride A mixture of 0.97 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxy-quinoline-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl]piperidin-3-yl-acetate in 30 cm 3 of dioxane and 4 cm 3 of a 1 N aqueous sodium hydroxide solution is heated at a temperature in the region of 50 0 C, with stirring, for 18 hours. After cooling in the vicinity of 20 0

C,

the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 50 0 C. The evaporation residue is taken up in 10 cm 3 of distilled water, acidified with a sufficient volume of a 1 N aqueous hydrochloric acid solution in order to obtain a pH in the region of 4. The mixture is extracted with twice 15 cm 3 of dichloromethane and the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness according to the same conditions described above. The residue is taken up in cm 3 of acetone and 1 cm 3 of a hydrochloric acid solution in dioxane and then concentrated to dryness under reduced pressure (1 kPa) at a temperature in the region of 50 0 C. The residue is again taken up in 5 cm 3 of acetone and concentrated to dryness according to the same conditions described above. 0.69 g of (3RS,4RS)-4- [3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2ynyl]piperidin-3-yl-acetic acid dihydrochloride is obtained in the form of a solid melting in the vicinity of 1350C.

Infrared spectrum: (KBr tablet): 3126; 2938; 2541; 2022; 1720; 1628; 1604; 1555; 1498; 1448; 1421; 1308; 1243; 1180; 1141; 1097; 1000; 870 and 780 cm-1 Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro- 6 methoxyquinolin-4-yl)propyl]-l-[3-(2,3,5trifluorophenyl)prop-2-ynyl]piperidin-3-yl-acetate A mixture of 1.7 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin- 4 yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate, 0.077 g of copper iodide, 1.2 g of 1-bromo-2,3,5-trifluorobenzene, 0.23 g of 2-tetrakis(triphenylphosphine)palladium(0) in 17 cm 3 of triethylamine is heated at a temperature in the region of 800C, with stirring, for 8 hours. After cooling in the region of 200C, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 500C. The evaporation residue is taken up in 20 cm 3 of ethyl acetate, washed with 3 times 15 cm 3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness according to the same conditions described above. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 pm; diameter 3 cm), eluting with a mixture of cyclohexane-ethyl acetate (80/20 by volume) and collecting 15-cm 3 fractions. Fractions 48 to 78 are combined and then concentrated to dryness according to the same conditions described above. 0.97 g of methyl (3RS,4RS)- 4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin- 4 yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop- 2 ynyl]piperidin-3-yl}acetate is obtained in the form of an oil.

Infrared spectrum (CC1 4 3618; 3089; 2935; 2804; 2766; 2223; 1737; 1623; 1508; 1496; 1232; 1166; 1132; 1075; 999; 861 and 834 cm-1 Example (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio) ethyl]piperidine-3-carboxylic acid dihydrochloride A solution of 630 mg of methyl (3RS,4RS)-4- [3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3carboxylate, 6 cm 3 of dioxane and 3 cm 3 of a 1 N aqueous sodium hydroxide solution is heated, with stirring at a temperature in the region of 60 0 C, for 2 hours. 3 cm 3 of a 1 N aqueous sodium hydroxide solution are added and the solution is heated for 1 hour at 60 0 C. After concentrating the reaction mixture under reduced pressure (5 kPa) at a temperature in the region of 40 0 C, the residue obtained is taken up in 20 cm 3 of water and 20 cm 3 of diethyl ether. The aqueous phase is separated after settling out and is then acidified with a pouring in of 6 cm 3 of 1 N hydrochloric acid. The white precipitate formed is extracted with 150 cm 3 of ethyl acetate. The organic phase is washed with twice cm 3 of a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. 499 mg of (3RS,4RS)- 4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3carboxylic acid are obtained in the form of a white pourer solid.

1 H NMR spectrum (300 MHz, (CD 3 2 SO d6 with, 6 in ppm). A mixture of stereoisomers in the proportions 50/50 is observed.

from 0.90 to 2.25 (mt 10H); from 2.45 to 2.65 (mt 2H); from 2.70 to 3.05 (mt 4H); 3.92 (s 3H); 5.31 (mt 1H); from 5.50 to 6.20 (broad unresolved complex 1H); 7.04 (mt 1H); 7.18 (mt 1H); 7.38 (mt 1H); 7.59 (mt 1H); from 7.90 to 8.05 (mt 2H); 8.67 (mt 1H); from 11.50 to 13.50 (very broad unresolved complex).

Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3-carboxylate 0.74 cm 3 of triethylamine is added to a solution composed of 1.17 g of methyl (3RS, 4RS) (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]piperidine-3-carboxylate dihydrochloride in cm 3 of acetonitrile and 10 cm 3 of DMF, followed by 638 mg of 2-(2-bromoethylthio)thiophene in 10 cm 3 of acetonitrile, 1 g of potassium carbonate and 431 mg of potassium iodide. The mixture is stirred for 15 hours at a temperature in the region of 65 0 C under an inert atmosphere. After cooling to about 200C, the reaction mixture is filtered on sintered glass. The filtrate is taken up in 100 cm 3 of acetonitrile and concentrated under reduced pressure (5 kPa). The residue is taken up in 200 cm 3 of ethyl acetate and 100 cm 3 of water. The organic phase is separated after settling out, washed with twice 75 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, concentrated under reduced pressure (5 kPa) at a temperature in the region of 400C. The residue obtained is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 diameter 2 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (25/75 by volume) and collecting 50-cm 3 fractions. Fractions 6 to 8 are concentrated. 630 mg of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-[2-(2-thienylthio)ethyl]piperidine-3carboxylate are obtained in the form of a colorless oil.

Infrared spectrum (CC1 4 3616; 2950; 2811; 2770; 1739; 1623; 1508; 1497; 1354; 1232; 1158; 1133; 1034; 907; 834 and 700 cm-1 Methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate dihydrochloride A solution of 1.26 g of (3RS,4RS)-4-[3-(R,S)hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1- (tert-butyloxycarbonyl)piperidine-3-carboxylic acid in 50 cm 3 of methanol is cooled to a temperature in the region of -250C, with stirring and under an inert atmosphere. 1.6 cm 3 of thionyl chloride are added to this solution over 25 minutes. The mixture is brought to a temperature in the region of 20 0 C, while the stirring is continued for a further 48 hours. The reaction mixture is concentrated under reduced pressure kPa) at a temperature in the region of 400C, taken up in 100 cm 3 of toluene and the mixture is again concentrated under reduced pressure (5 kPa). The residue is taken up in 50 cm 3 of diisopropyl ether, triturated and concentrated to dryness under reduced pressure (5 kPa). 1.17 g of methyl (3RS,4RS)-4-[3- (R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate dihydrochloride are obtained in the form of a yellow powder.

100 Infrared spectrum (KBr tablet):3415; 3129; 2949; 2772; 2473; 2022; 1733; 1622; 1603; 1555; 1496; 1420; 1307; 1242; 1172; 1019; 871 and 795 cm-1 (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid A solution of 1.77 g of methyl (3RS,4RS)-4- [3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tertbutyloxycarbonyl)piperidine-3-carboxylate, 140 cm 3 of anhydrous dimethyl sulfoxide and 30 cm 3 of anhydrous tert-butanol is stirred under an inert atmosphere free of water at 20 0 C. This solution is purged with pure oxygen until the reaction mixture becomes saturated. A solution containing 1.75 g of potassium tert-butoxide in 10 cm 3 of anhydrous tert-butanol is then added.

Oxygen is again introduced by bubbling for a further 1 hour and 10 minutes with vigorous stirring. The solution obtained is purged with nitrogen and then cooled to 0°C. 1 cm 3 of pure acetic acid in 100 cm 3 of water is then added followed by 100 cm 3 of water and 500 cm 3 of ether. The organic phase is separated after settling out, washed with 7 times 100 cm 3 of water and with 3 times 100 cm 3 of a saturated aqueous sodium chloride solution. The aqueous phase is extracted with 400 cm 3 of ethyl acetate, washed with 7 times 75 cm 3 of water and 3 times 75 cm 3 of a saturated aqueous sodium chloride solution. The 2 organic phases are combined, 101 dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 1.26 g of (3RS,4RS)- 4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3carboxylic acid are obtained in the form of a white foam.

1 H NMR spectrum (400 MHz, (CD 3 2 SO d6 with, at a temperature of 383 K, 8 in ppm). A mixture of stereoisomers is observed.

from 0.85 to 2.30 (mt 16H); from 2.60 to 3.25 (mt 3.88 (mt 1H); 3.94 (s 3H); 4.00 (broad dd, J 14 and 3 Hz 1H); 5.35 (mt 1H); 7.38 (mt 1H); from 7.90 to 8.00 (mt 2H); 8.63 (broad s 1H).

Methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3carboxylate A solution of 1.45 g of methyl (3RS,4RS)-1- (tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate in 20 cm 3 of tetrahydrofuran is slowly added, at a temperature in the region of 0°C, with stirring and under an inert atmosphere, to 16 cm 3 of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran. The mixture is then brought to a temperature in the region of 20 0 C while the stirring is continued for a further 4 hours. 1.52 g of 4-iodo-3-fluoro-6-methoxyquinoline in solution in 40 cm 3 of tetrahydrofuran are added, 102 followed by 100 mg of palladiumdiphenylphosphinoferrocene chloride and finally 3.18 g of tribasic potassium phosphate. The reaction mixture is heated for hours under reflux and then filtered in the hot state on sintered glass. The filtrate is taken up in cm 3 of ethyl acetate and concentrated to dryness under reduced pressure (5 kPa). The residue is taken up in cm 3 of ethyl acetate and 40 cm 3 of water. The organic phase is separated after settling out, washed with twice 40 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. The residue is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 JL; diameter 2.5 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (75/25 by volume) and collecting 50-cm 3 fractions. Fractions 16 to 22 are combined and then concentrated. 1,77 g of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3propyl]-1-(tert-butyloxycarbonyl)piperidine-3carboxylate are obtained in the form of a colorless oil.

1H NMR spectrum (300 MHz, (CD 3 2 SO d6 with, 8 in ppm): from 1.25 to 1.90 (mt 16H); 2.61 (mt 1H); from 2.65 to 3.25 (mt 4H); 3.47 (broad s 3H); from 3.60 to 4.05 (mt 2H); 3.96 (s 3H); 7.36 J 3 Hz 1H); 103 7.40 (dd, J 9 and 3 Hz 1H); 7.97 J 9 Hz 1H); 8.70 (broad s 1H).

Methyl (3RS,4RS)-1-(tert-butyloxycarbonyl)-4allylpiperidine-3-carboxylate 11.34 g of tributyltin hydride are added to a solution of 10.1 g of methyl 1-(tert-butyloxycarbonyl)- 4-allyl-4-(methoxallyl)hydroxypiperidine-3-carboxylate in 250 cm 3 of toluene under an inert atmosphere and at a temperature close to 20 0 C. 25 mg of AIBN are then added and the reaction mixture is heated at the reflux temperature of the solvent for 1 hour. The mixture is cooled to a temperature close to 20 0 C, concentrated to dryness under reduced pressure (5 kPa). The residue is taken up in 50 cm 3 of dichloromethane and then purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 p; diameter 7 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (75/25 by volume) and collecting 200-cm 3 fractions. Fractions 6 to 8 are combined, and then concentrated. 1.4 g of methyl (3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine- 3-carboxylate are obtained in the form of a colorless oil.

1H NMR spectrum (400 MHz, (CD 3 2 SO d6 with, at a temperature of 353 K, 8 in ppm): from 1.35 to 1.50 (mt 1H); 1.40 (s 9H); from 1.65 to 1.80 (mt 1H); 1.89 (mt 1H); from 1.95 to 2.20 (mt 2H); 2.62 (mt 104 1H); 2.97 (mt 1H); 3.22 (dd, J 14 and 4 Hz 1H); 3.60 (s 3H); from 3.65 to 3.80 (mt 1H); 3.91 (broad dd, J 14 and 5 Hz 1H); 5.02 (mt 2H); from 5.65 to 5.85 (mt 1H).

Methyl 1-(tert-butyloxycarbonyl)-4-allyl-4- (methoxallyl)hydroxypiperidine-3-carboxylate 7.57 g of dimethylaminopyridine are added, under an inert atmosphere, to a solution of 9.4 g of methyl 1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine-3-carboxylate in 120 cm 3 of acetonitrile and then 5.7 cm 3 of oxalyl chloride are poured in over minutes. After stirring for 15 hours at a temperature close to 20 0 C, 1.22 g of dimethylaminopyridine are added followed by 0.92 cm 3 of oxalyl chloride. The stirring is maintained for 15 hours at the same temperature. This addition procedure is repeated once again and the stirring is continued for 6 hours. The reaction mixture is taken up in 200 cm 3 of ethyl acetate and 200 cm 3 of a saturated aqueous sodium bicarbonate solution. The organic phase is separated after settling out, washed with twice 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered on sintered glass. The filtrate is stirred for one hour with 11 g of silica, filtered on sintered glass, taken up in 20 g of silica and 300 cm 3 of ethyl acetate, and then concentrated under reduced pressure (5 kPa) at a temperature in the 105 region of 40 0 C. 12.15 g of methyl 1-(tert-butyloxycarbonyl)-4-allyl-4-(methoxallyl)hydroxypiperidine-3carboxylate are obtained in the form of a beige oil.

Infrared spectrum (CC1 4 3082; 2980; 2954; 1775; 1748; 1699; 1641; 1424; 1392; 1367; 1245; 1202; 1162; 1142; 993 and 925 cm-1 Methyl 1-(tert-butyloxycarbonyl)-4-allyl-4hydroxypiperidine-3-carboxylate 101.66 g of methyl l-(tert-butyloxycarbonyl)- 4-oxopiperidine-3-carboxylate are added, under an inert atmosphere and at a temperature close to 20 0 C, to 2.156 liters of a saturated aqueous solution of ammonium chloride and of THF (10/1 by volume) of THF.

34.73 cm 3 of allyl bromide are then added, followed by 77.51 g of zinc while maintaining the temperature below 300C. A solution of 69.47 cm 3 of allyl bromide in 50 cm 3 of THF is then poured in dropwise. After stirring for 3 hours at a temperature close to 200C, the reaction is incomplete. 77.51 g of zinc are again added and then 104 cm 3 of allyl bromide are poured in dropwise while the temperature is maintained below 300C. The stirring is maintained at a temperature close to 20 0 C for hours. The reaction is incomplete. 35 g of zinc are again added and then 55 cm 3 of allyl bromide are poured in dropwise while the temperature is maintained below 300C. The stirring is maintained at a temperature close to 20 0 C for 4 hours. The reaction is incomplete. 10 g 106 of zinc are again added and then 25 cm 3 of allyl bromide are poured in dropwise while the temperature is maintained below 30 0 C. The stirring is maintained at a temperature close to 20 0 C for 2 hours. The reaction mixture is taken up in 900 cm 3 of a 1 N HC1 solution and 2 liters of ethyl ether and filtered on sintered glass.

The filtrate is washed with 3 times 500 cm 3 of etyl ether. The organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (5 kPa). A yellow oil is obtained which is purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 t; diameter 12 cm; height 60 cm), eluting with a mixture of cyclohexane-ethyl acetate (80/20 by volume) and collecting 200-cm 3 fractions. Fractions 51 to 75 are combined and then concentrated. 63.5 g of methyl 1-(tert-butyloxycarbonyl)-4-allyl-4-hydroxypiperidine- 3-carboxylate are obtained in the form of a light yellow oil.

Infrared spectrum (CC1 4 3513; 3078; 2980; 2954; 1697; 1641; 1423; 1392; 1366; 1200; 1163; 962 and 919 cm-1 Methyl 1-(tert-butyloxycarbonyl)-4-oxopiperidine-3carboxylate 65.27-cm 3 of trietylamine are added, with stirring, to a suspension of 89.93 g of 107 3-methoxycarbonyl-4-piperidone hydrochloride (at 98% purity) in 900-cm 3 of dichloromethane, cooled to a temperature in the region of 0°C, followed by 91.12 g of di-tert-butyl dicarbonate solubilized beforehand in 400-cm 3 of dichloromethane. The mixture is stirred for 12 hours at a temperature close to 20 0 C. The trietylamine hydrochloride is filtered, and then the filtrate is washed with 3 times 500-cm 3 of water and then with twice 500-cm 3 of a saturated aqueous sodium chloride solution. The organic phase is filtered on sintered material containing fine silica, dried over sodium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40 0 C. 101.66 g of methyl l-(tert-butyloxycarbonyl)- 4-oxopiperidine-3-carboxylate are obtained in the form of a light yellow oil.

Infrared spectrum (CH 2 C1 2 2982; 2932; 2872; 1740; 1691; 1664; 1622; 1477; 1468; 1423; 1367; 1338; 1309; 1235; 1200; 1167; 1123; 1064 cm The present invention also relates to the pharmaceutical compositions containing at least one quinolylpropylpiperidine derivative according to the invention, where appropriate in the form of a salt, in the pure state or in the form of a combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.

108 The compositions according to the invention may be used orally, parenterally, topically, rectally or as aerosols.

As solid compositions for oral administration, tablets, pills, gelatin capsules, powders or granules may be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents or adjuvants such as sucrose, lactose or starch. These compositions may comprise substances other than the diluents, for example a lubricant such as magnesium stearate or a coating intended for a controlled release.

As liquid compositions for oral administration, solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents such as water or paraffin oil may be used. These compositions may also comprise substances other than the diluents, for example wetting products, sweeteners or flavorings.

The compositions for parenteral administration may be solutions which are sterile or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, may be used. These compositions may also contain adjuvants, in particular wetting, 109 isotonizing, emulsifying, dispersing and stabilizing agents.

The sterilization may be carried out in several ways, for example with the aid of a bacteriological filter, by irradiation or by heating.

They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.

The compositions for topical administration may be, for example, creams, ointments, lotions or aerosols.

The compositions for rectal administration are suppositories or rectal capsules, which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in pyrogen-free sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active ingredient is finely divided and combined with a water-soluble solid diluent or vehicle having a particle size of to 80 pm, for example dextran, mannitol or lactose.

110 O In human therapy, the novel quinolylpropylpiperidine derivatives according 1 to the invention are particularly useful in the treatment of infections of bacterial Z origin. The doses depend on the desired effect and on the duration of the treatment. The doctor will determine the dosage which they judge to be most appropriate according to the treatment, according to the age, weight and degree o of the infection and other factors specific to the subject to be treated. Generally, C the doses are between 750 mg and 3 g of active product in 2 or 3 doses per day p by the oral route or between 400 mg and 1.2 g by the intravenous route for an N adult.

C 10 The following example illustrates a composition according to the invention.

(N

Example 11 Starting with the mixture of stereoisomers A, B, C and D, the separation of each stereoisomer is carried out by HPLC: The separation of the 2 pairs of stereoisomers and obtained in example 10 is carried out on a C18 stationary phase starting with 2,97 g of the A, B, C, D mixture (type of phase: SIMMETRY® C18; particle size 7 pm; diameter 80 mm; mass of the stationary phase 1 kg), under a pressure of 3 600 kPa, the mobile phase is composed of a mixture of acetonitrile methanolammonium acetate pH 5.5 (35/20/45 by volume) having a flow rate of 130 cm 3 per minute and the UV detector wavelength is set at 280 nm. The fractions containing the first pair of stereoisomers noted are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40°C and 1.1 g thereof are obtained in the form of an oil. The fractions containing the second pair of stereoisomers noted are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 400C and 0.78 g thereof are obtained in the form of an oil. Next, the enantiomers of the pair of stereoisomers are separated on a CHIRALPAK® AD column (particle size 20 pm; diameter 80 mm; mass of the stationary phase 1.2 kg) under a pressure of 1 200 kPa, the mobile phase is composed of a mixture of heptane-ethanol(80/20 by volume) having a flow rate of 140 cm 3 per minute and the UV detector wavelength is set at 280 nm. The enantiomers of the pair of stereoisomers C+D are separated on an OF type CHIRALCEL® column 111 O (particle size 20 pm; diameter 60 mm; mass of the stationary phase 700 g) under cl a pressure of 550 kPa, the mobile phase is composed of an heptane-isopropanol- Sdiisopropylamine (75/25/0.2 by volume) mixture having a flow rate of 120 cm 3 per minute and the UV detector wavelength is set at 280 nm. The fractions containing each enantiomer are isolated and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40°C; 0.624 g of stereoisomer A, 0.618 g c of stereoisomer B, 0.325 g of stereoisomer C and 0.485 g of stereoisomer D are In thus obtained.

C 10 Example 12 Example of saponification (3R. 4R)-4-[3S-hvdroxy-3-(3-fluoro-6-methoxyquinolin-4-vl)propvl1-1-[2-(2thienylthio) ethl]l-piperidine-3-carboxvlic acid.

OH 0- S F HO O A solution of 620 mg of methyl (3R,4R)-4-[3S-hydroxy-3-(3-fluoro-6methoxyquinolin-4-yl)propyl]-1-[2-(2-thienylthio)ethyl]-piperidine-3-carboxylate (stereoisomer 10 cm 3 of dioxane and 4.8 cm 3 of an aqueous solution of 1N sodium hydroxide was heated with stirring to a temperature of about 60°C for 3 hours. After concentrating the reaction medium under reduced pressure (5 kpA) at a temperature of about 40°C, the residue obtained was taken up in 100 cm 3 water and 100 cm 3 diethyl ether. The aqueous phase was decanted then acidified by running in 4.7 cm 3 of 1N hydrochloric acid. The white precipitate formed was extracted using 100 cm 3 ethyl acetate and then twice using 50 cm 3 ethyl acetate.

The organic phases were combined, dried on magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature of about 111a 2000. 575 mg of (3R,4R)-4-[3S-hyd roxy-3-(3-fluoro-6-methoxyquinolin-4- C1 yI)propyl]-l -[2-(2-thienylthio)ethyl]-piperid ine-3-carboxylic acid were obtained in the form of a white powder.

EXAMPLE A A liquid composition intended for parenteral use is prepared according to the customary technique which comprises: *(3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yI)propyI]-l N ie n-2-yI)th ioethyll p ipe rid in e-3-acetic acid 125 mg *glucose qs *sodium hydroxide qs pH 4-4.5 water for qs 50 ml EXAMPLE B A liquid composition intended for parenteral use is prepared according to the customary technique which comprises: (3RS ,4RS R,S)-hyd roxy-3-(3-fluoro- 6-methoxyquinolin-4-yl )propyl]- 1 -[2-(2-thienylthio)ethyl]piperid ine-3-acetic acid 125 mg glucose qs sodium hydroxide qs pH 4-4.5 water for qs 50 ml

Claims

1. Quinolylpropylpiperidine derivative, characterized in that it corresponds to the general formula R N-R 3 ,i -F (I) N for which: RI is a hydrogen or halogen atom or a hydroxyl, amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino or alkylalkyloxyamino radical, R 2 represents a carboxyl, carboxymethyl or hydroxymethyl radical, R 3 represents an alkyl (1 to 6 carbon atoms) radical substituted with a phenylthio radical which may itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro- methoxy, carboxyl, alkyloxycarbonyl, cyano or amino], with a cycloalkylthio radical in which the cyclic portion contains 3 to 7 members, or with a 5- to

6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and itself optionally substituted [with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro- 113 methoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino] or R 3 represents a propargyl radical substituted with a phenyl radical which may itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], or substituted with a 3- to 7-membered cycloalkyl radical or substituted with a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and itself optionally substituted [with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], and R 4 represents an alkyl (containing 1 to 6 carbon atoms), alkenyl-CH 2 or alkynyl-CH 2 (in which the alkenyl or alkynyl portions contain 2 to 6 carbon atoms), cycloalkyl or cycloalkylalkyl (in which the cycloalkyl portion contains 3 to 8 carbon atoms) radical, it being understood that the alkyl radicals and portions are in the form of a straight or branched chain and contain (unless otherwise stated) 1 to 4 carbon atoms in its diastereoisomeric forms or mixtures thereof and/or in its cis or trans forms, as well as its salts. 2. (3RS, 4RS)-4-[3-(R,S)-Hydroxy-3-(3- fluoro-6-methoxyquinolin-4-yl)propyl]-l-[2- AMENDED SHEET 114 (2-thienylthio) ethyl] piperidine-3-carboxylic acid, as well as its salts. 3. (3R,4R)-4-[3-(S)-Hydroxy-3-(3-fluoro-6- methoxyquinolin-4-yl)propyl]-1-[2-(2- thienylthio)ethyl]piperidine-3-carboxylic acid, as well as its salts. 4. Process for preparing the quinolylpropylpiperidine derivative according to Claim 1, characterized in that the chain R 3 defined in Claim 1 is condensed with the quinolylpropylpiperidine derivative of general formula: R' NH R04-0 F R- N in which R 4 is as defined in Claim 1, R'I represents a hydrogen atom or a hydroxyl radical and R' 2 represents a protected carboxyl or carboxymethyl radical, to obtain a quinolylpropylpiperidine derivative of general formula: AMENDED SHEET 115 R' N-R3 R4-O F R'2 N for which R'i, R' 2 and R 4 are as defined above and R 3 is as defined in Claim 1, and then, where appropriate, the derivative for which R'I is a hydroxyl radical is halogenated so as to obtain a quinolylpropylpiperidine derivative for which R 1 is a halogen atom, or, the hydroxyl radical is converted to an oxo radical, and then to a hydroxyimino or alkyloxyimino radical, according to known methods, to obtain a quinolylpropylpiperidine derivative of general formula: F R' 2 (IV) N for which R' 2 is as defined above, R 3 and R 4 are as defined in Claim 1, and R 5 is a hydrogen atom or an alkyl radical, and the derivative of general formula (IV) for which R 5 is a hydrogen atom is reduced to an amine, and optionally converted to a monoalkylated or dialkylated amine, or optionally by the reduces the AMENDED SHEET 116 derivative of general formula (IV) for which Rs is a hydrogen atom to a hydroxylamine, or the derivative of general formula (IV) for which R 5 is an alkyl radical to an alkyloxyamine, and then, where appropriate, to obtain the derivative for which RI is alkylalkyloxyamino, the derivative obtained for which RI is alkyloxyamino is converted by alkylation, and/or, where appropriate, the protected carboxyl radical R' 2 is reduced to a hydroxymethyl radical according to known methods, and then optionally the diastereoisomers are separated, the cis and trans forms are separated, the acid-protecting radical is eliminated, where appropriate, and/or the product obtained is converted to a salt. Process according to Claim 4, characterized in that the condensation of the chain R 3 with the piperidine is carried out by the action of a derivative of general formula: R 3 -X in which R 3 is as defined in Claim 1 and X represents a halogen atom, a methylsulfonyloxy radical, a trifluoromethylsulfonyloxy or p-toluenesulfonyloxy radical. 6. Process according to either of Claims 4 and 5, characterized in that when R 3 represents propargyl substituted with phenyl, cycloalkyl or AMENDED SHEET 117 r- O heterocyclyl, the reaction is preferably carried out by condensation of a propargyl N halide, and then substitution of the chain with a phenyl, cycloalkyl or heterocyclyl Z radical.

7. Quinolylpropylpiperidine derivative of general formula: N-R/, N-R 3 R4- IIF (IV) in which R' 2 is as defined in Claim 4, R 3 and R 4 are as defined in claim 1, and R is a hydrogen atom or an alkyl radical.

8. A compound of formula (II) R 4 -O wherein represents a hydrogen atom or a hydroxyl radical; R' 2 represents a protected carboxyl or carboxymethyl radical; and R 4 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl-CH 2 alkynyl-CH 2 cycloalkyl, or cycloalkylalkyl radical, wherein the alkenyl and alkynyl portions contain 2 to 6 carbon atoms and the cycloalkyl portions contain 3 to 8 carbon atoms, 118 or a diastereolsomeric form, a cis form, or a trans form of a compound of formula or a salt of any of the foregoing.

9. The compound of formula (II) as set forth in claim 8, wherein R'i represents a hydroxyl radical. The compound of formula (II) as set forth in claim 8, wherein R' 2 represents a hydrolyzable ester of the carboxyl or carboxymethyl radical.

11. The compound of formula (II) as set forth in claim 8, wherein R 4 represents methyl.

12. A compound of the formula (III) wherein R'i represents a hydrogen atom or a hydroxyl radical; R' 2 represents a protected carboxyl or carboxymethyl radical; R 3 represents an alkyl radical having 1 to 6 carbon atoms, which is substituted with: a phenylthio radical, which is optionally substituted with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, a cycloalkylthio radical in which the cyclic portion contains 3 to 7 members, or a 5- to 6-membered aromatic heterocyclylthio radical with 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur, and wherein the 5- to 6- 119 O membered aromatic heterocyclylthio radical is optionally substituted with at least c one radical chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, O trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, and amino; or Z R 3 represents a propargyl radical substituted with: C 5 a phenyl radical, which is optionally substituted with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, n a 3- to 7-membered cycloalkyl radical, or cN a 5- to 6-membered aromatic heterocyclyl radical with 1 to 4 heteroatoms 0 10 chosen from nitrogen, oxygen, and sulfur, and wherein the 5- to 6-membered cN aromatic heterocyclyl radical is optionally substituted with at least one radical chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, and amino; and R 4 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl-CH 2 alkynyl-CH 2 cycloalkyl, or cycloalkylalkyl radical, wherein the alkenyl and alkynyl portions contain 2 to 6 carbon atoms and the cycloalkyl portions contain 3 to 8 carbon atoms, or a diasterecisomeric form, a cis form, or a trans form of a compound of formula (III), or a salt of any of the foregoing.

13. The compound of formula (111) as claimed in claim 12, wherein R'i represents a hydroxyl radical.

14. The compound of formula (III) as claimed in claim 12, wherein R' 2 represents a hydrolyzable ester of the carboxyl or carboxymethyl radical. The compound of formula (III) as claimed in claim 12, wherein R 3 represents an alkyl radical substituted with the optionally substituted phenylthio radical, the cycloalkylthio radical, or the optionally substituted heterocyclylthio radical. O 16. The compound of formula (111) as claimed in claim 12, wherein R 3 represents a propargyl radical substituted with the optionally substituted phenyl O radical, the cycloalkyl radical, or the optionally substituted heterocyclyl radical. (N

17. The compound of formula (III) as claimed in claim 12, wherein R 4 ON 5 represents methyl. n18. 11Quinolylpropylpiperidine derivative substantially as hereinbefore Ci described with reference to any one of Examples 1 to

19. A liquid composition substantially as hereinbefore described with reference to Example A or Example B.

20. Pharmaceutical composition, characterized in that it contains at least one derivative according to claim 1, in the pure state or in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.

21. A method of treating infections of bacterial origin, the method including administering to a patient a therapeutically effective amount of derivative according to claim 1 or of a composition according to claim 19 or claim

22. Use of a derivative according to claim 1 or of a composition according to claim 19 or claim 20 in the manufacture of a medicament. NOVEXEL WATERMARK PATENT TRADEMARK ATTORNEYS P23131AU00