ZA200202073B - Quinolyl propyl piperidine derivatives and their use as antibacterial agents. - Google Patents

Quinolyl propyl piperidine derivatives and their use as antibacterial agents. Download PDF

Info

Publication number
ZA200202073B
ZA200202073B ZA200202073A ZA200202073A ZA200202073B ZA 200202073 B ZA200202073 B ZA 200202073B ZA 200202073 A ZA200202073 A ZA 200202073A ZA 200202073 A ZA200202073 A ZA 200202073A ZA 200202073 B ZA200202073 B ZA 200202073B
Authority
ZA
South Africa
Prior art keywords
radical
substituted
halogen
alkyl
alkyloxycarbonyl
Prior art date
Application number
ZA200202073A
Inventor
Jean-Luc Malleron
Michel Tabart
Jean-Christophe Carry
Michel Evers
Youssef El Ahmad
Serge Mignani
Fabrice Viviani
Michel Cheve
Original Assignee
Aventis Pharma Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharma Sa filed Critical Aventis Pharma Sa
Publication of ZA200202073B publication Critical patent/ZA200202073B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Description

A
. i . h 20
L - BD02s 2075
WO 01/25227 1 PCT/FRQ0/02541
QUINOLYLPROPYLPIPERIDINE DERIVATIVES, THEIR PREPARATION
AND THE COMPOSITIONS WHICH COMPRISE THEM
The present invention relates to quinolylpropylpiperidine derivatives of general : oo we formula: | | Co ve : Re : ’ R }
Ce : rR’, . LC
R, ST
R,-O SN .
R,
Mm
ZF
N which are active as antimicrobials. The invention also ) relates to their preparation and to the compositions ’ 10 comprising them. :
Patent Application WO 99/37635 has disclosed antimicrobial quinolylpropylpiperidine derivatives of general formula: pres § 0) Ry Ry # : N in which the R; radical is in particular (Cl-6)alkoxy, - | R; is hydrogen, Rj; is in the 2- or 3-position and represents (Cl-6)alkyl which can optionally be substituted by 1 to 3 substituents chosen from thiol, halogen, alkylthio, .trifluoromethyl, alkyloxycarbonyl, alkylcéarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, .
o hydroxyl optionally substituted by alkyl, and the like, ) Ry is a -CH;-Rs group in which Rs is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, optionally substituted : heteroarylalkyl, optionally substituted heteroaroyl, - and the like, n is 0 to 2, m is 1 or 2 and A and B are SE in particular oxygen, sulfur, sulfinyl, sulfonyl or E } : CR¢R; in which R¢ and R; represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, amine, and the like.
European Patent Application EP30044 has disclosed quinoline derivatives, of use as cardiovasculars, corresponding to the general formula: : re b z/
S00 R,
NZ in which R; is in particular alkyloxy, A-B is -CH;-CH;-, -CHOH-CH;-, -CH;-CHOH-~, -CH,CO- or -CO~-CH;-, Ri; is H, OH or alkyloxy, R; is ethyl or vinyl, Ry; is in particular alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, : alkynyl, tetrahydrofuryl, phenylalkyl, optionally _ substituted diphenylalkyl, optionally substituted oo phenylalkenyl, optionally substituted benzoyl or benzoylalkyl, or optionally substituted heteroaryl or hetercarylalkyl, and Z is H or alkyl or forms, with Rs, a cycloalkyl radical.
PS
®
It has now been found, and it is this which forms the subject matter of the present invention, that the products of general formula (I) in which:
R; is a hydrogen or halogen atom or a hydroxyl radical,
R’; is a hydrogen atom or can represent halogen when R; oo is also a halogen atom, and oo a * R° is a hydrogen atom, or else oo
R; and R° together form a bond and | :
R’; is a hydrogen atom,
R; represents a carboxyl, carboxymethyl or 3 -carboxy- ethyl radical, and
Ry represents an alkyl radical (1 to 6 carbon atoms) substituted by 1 to 3 substituents chosen from hydroxyl, halogen, oxo, carboxyl, alkyloxycarbonyl, alkyloxy or alkylthio or from a phenyl, phenylthio or phenylalkylthio radical, which can themselves carry 1 to 4 substituents [chosen from halogen, hydroxyl, : alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido (1 to 4C) or amino], or from a cycloalkyl or cycloalkylthio oo cl | radical, the cyclic part of which comprises 3 to 7 oo members, or from a 5- to 6-membered aromatic heterocyclyl or heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally themselves substituted [by halogen,
® oo So ] Co ee ee me me
J hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, : cyano or amino], or R; represents a propargyl radical substituted by a phenyl radical which can itself carry 1 to 3 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, E oo carboxyl. alkyloxycarbonyl, cyano or amino] or | oo _ substituted by a cycloalkyl radical comprising 3 to 7° members or substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], or Rj; represents cinnamyl or 4-phenylbuten-3-yl, or else
R, represents a hydroxymethyl, alkyloxycarbonyl, oo : alkyloxycarbonylmethyl or 2-(alkyloxycarbonyl) ethyl radical (the alkyl portions of which comprise 1 to 6 carbon atoms) and - R; represents an alkyl radical (1 to 6 carbon atoms) substituted by a phenylthio radical which can itself : carry 1 to 3 substituents [chosen from halogen, _ hydroxyl, alkyl, alkyloxy, trifluoromethyl, tri fluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], by a cycloalkylthio radical, the cyclic part of "which comprises 3 to 7 members, or by a 5- to 6-membered aromatic heterocyclylthio radical comprising
® ®
1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, 5 cyano or amino] or Rj; represents a propargyl radical - _ substituted by a phenyl radical which can itself carry . : 1 to 3 substituents [chosen from halogen, hydroxyl, - a : : alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino] or substituted by a cycloalkyl radical comprising 3 to 7 members or substituted by a 5- to 6-membered aromatic : heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], ‘and Rs represents an alkyl radical (comprising 1 to 6 carbon atoms), an alkenyl-CH,- radical or an alkynyl-CH,- radical. the alkenyl or alkynyl parts of : : which comprise 2 to 6 carbon atoms, ie being understood that the alkyl radicals and - nN oo portions are straight-chain or branched-chain radicals and portions, in their diastereoisomeric forms or their mixtures, as well as their salts, are powerful antibacterial agents.
®
It is understood that the alkyl radicals and portions are straight- or branched-chain radicals and portions and comprise (except when specifically mentioned) 1 to 3 carbon atoms and that, in the alternative where R; or R’; represent a halogen atom or ‘when R; carries a halogen substituent, the latter can be = = chosen from fluorine, chlorine, bromine or iodine, N preferably fluorine.
In the above general formula, when Rs carries an aromatic heterocyclyl substituent, the latter can be chosen (without implied limitation) from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, : pyridazinyl, pyrazinyl or pyrimidinyl. It is also understood that, in the definition of Rj, the substituted alkyl radical only simultaneously carries a : single cyclic radical.
According to the invention, the products of general formula (I) can be obtained by condensation of the R; chain onto the quinolylpropylpiperidine derivative of general formula: . | R™ .
SE R", NH - : RO ~ o 5 on
NT in which Ry; is defined as previously, R’’; and R'’", represent hydrogen atoms or together form an oxo
® radical and R’; represents a protected carboxyl, carboxymethyl or 2-carboxyethyl radical, or an alkyloxycarbonyl, alkyloxycarbonylmethyl or 2- (alkyloxycarbonyl)ethyl radical, in order to obtain a quinolylpropylpiperidine derivative of general formula:
Rr", oo
R N-R, : iy : oo . “1 NK - : 2 (1)
Co NT oo : in which R*';, R*"'1, R’3 and Ry are defined as above and
Ry; is defined as previously, followed, if appropriate, by the removal of the acid- protecting radical, then, if appropriate, followed by the reduction of the oxo radical represented by R’’; and R’’’; to an alcohol in which R; represents hydroxyl, then, optionally, by halogenation, if it is desired to obtain a quinolylpropylpiperidine derivative in which R; is a : ~ halogen atom, and, optionally, by dehydrohalogenation EE of the corresponding halogenated derivative, in order ~~. 20 to obtain a quinolylpropylpiperidine derivative in | y ‘which R; and R° together form a bond, or else by B dihalogenation of the product of general formula (III) in which R’’; and R’’’; together form an oxo radical, in
_ @ order to obtain a quinolylpropylpiperidine derivative in which R; and R’; are halogen atoms, and/or, if appropriate, followed by the reduction of the acid, protected in the form of an R’; radical, in : the 3-position of the piperidine to a hydroxymethyl EE radical and optionally by the conversion to a . carboxymethyl or 2-carboxyethyl radical according to = the usual methods, then, optionally, followed by the removal of the acid- protecting radical and optionally by the conversion of the product obtained to a salt. ’
The condensation of the Ri; chain onto the piperidine is advantageously carried out by the action of a derivative of general formula:
Ry-X (IV) in which R; is defined as previously and X represents a halogen atom, a methylsulfonyl radical, a trifluoro- methylsulfonyl radical or a p-toluenesulfonyl radical, ~ the reaction being carried out in an anhydrous environment, preferably an inert environment (nitrogen : - or argon, for example), 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 : nitrogenous organic base (for example, triethylamine) : . or an inorganic base (alkali metal carbonate: potassium
@ carbonate, for example), at a temperature of between oo 20°C and the reflux temperature of the solvent. Co - Preferably, the reaction is carried out with a derivative in which X is a bromine or iodine atom.
When R; represents propargyl substituted by : : phenyl, cycloalkyl or heterocyclyl, it is often _ ) : : oo preferable to condense a propargyl halide and then to SE a oo substitute the chain with a phenyl, cycloalkyl or : heterocyclyl radical. oo
In this alternative, the addition of the propargyl chain is carried out by means of propargyl bromide, under the conditions set out above for R;, in the : presence or absence of an alkali metal iodide, such as, for example, potassium iodide or sodium iodide.
When it is a matter of the substitution by a phenyl or heterocyclyl radical, 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 an anhydrous environment 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, = oo tetrakis (triphenylphosphine)palladium, and of cuprous | : oo | iodide, at a temperature of between 20°C and the reflux temperature of the solvent. : When it is a matter of the substitution by a cycloalkyl _ group, 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 an anhydrous environment in an ether, such as, for example, tetrahydrofuran, at a temperature of between -78 and 0°C, and then the action of a cycloalkanone, followed by the deoxygenation of the intermediate alcohol according to conventional methods. SE
It is understood that, when the alkyl 0 radicals represented by R; carry carboxyl or amino CL substituents, the latter are protected beforehand and then released after the reaction. These operations are - carried out according to the usual methods which do not
Ce detrimentally affect the remainder 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 ed.), A. Wiley - Interscience oo
Publication (1991), or by McOmie, Protective Groups in
Organic Chemistry, Plenum Press (1973).
The protected carboxyl radical represented by - R’; can be chosen from easily hydrolyzable esters.
Mention may be made, by way of example, of methyl, benzyl or tert-butyl esters or alternatively phenylpropyl or propargyl esters. The protecting of the . carboxyl radical is optionally carried out
Co simultaneously with the reaction. In this case, the | oo . 25 product of general formula (II) employed carries an R’;, radical which is the carboxyl radical.
The reduction of the oxo radical to an
E alcohol is carried out according to the usual methods
® ® which do not detrimentally affect the remainder of the molecule, in particular by the action of a reduction agent, such as, for example, a hydride (alkaline borohydride: sodium borohydride, potassium borohydride, : 5 sodium triacetoxyborohydride or sodium cyanoboro- hydride, for example, lithium aluminum hydride or diisobutylaluminum hydride), the reaction preferably : being carried out in under an inert atmosphere, in an N organic solvent, such as an alcohol (methanol, ethanol or isopropanol, for example) or an ether (for example, tetrahydrofuran) or a chlorinated solvent (for example, dichoromethane), at a temperature of between 20°C and : the reflux temperature of the solvent.
The halogenation intended to produce a quinolylpropylquinoline derivative in which R’; is a halogen atom from the derivative in which R‘; is hydroxyl can be carried out, in the presence of an aminosulfur trifluoride (diethylaminosulfur © trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®) or morpholinosulfur trifluoride, for example) or alternatively in the presence of sulfur » tetrafluoride, by means of a reagent, such as a : ~~ tetraalkylammonium, trialkylbenzylammonium or Co : : oo | trialkylphenylammonium halide, or by means of an alkali : metal halide, optionally with a crown ether added. The fluorination reaction can also be carried out by the : action of a fluorinating agent such as a sulfur fluoride [for example, morpholinosulfur trifluoride,
® _ sulfur tetrafluoride (J. Org. Chem., 40, 3808 (1975)), : diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 : (1988) ) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®) . Alternatively, the fluorination reaction can also be carried out by means of a fluorinating ~ agent such as hexafluoropropyldiethylamine (JP 2 039 : a 546). or N- (2-chloro-1,1,2-trifluoroethyl)diethylamine. ~ When a tetraalkylammonium halide is employed, the - latter can be chosen, by way of example, from tetramethylammonium, tetraethylammonium, tetrapropyl- ammonium, tetrabutylammonium (tetra (n-butyl) ammonium, for example), tetrapentylammonium, tetracyclohexyl- ammonium, triethylmethylammonium, tributylmethyl- ammonium or trimethylpropylammonium halides.
The reaction 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°C (preferably between 0 and 30°C). It is advantageous to carry out the reaction in an inert environment (argon or nitrogen, in particular) .
It is also possible to carry out the reaction by treatment with a halogenating agent, such as thionyl oo ] 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 dihalogenation of the product of general formula (III) in which R’’; and R’’’; together form an oxo radical, in order to produce a quinolylpropylpiperidine derivative in which R; and R’; : are halogen atoms, can be carried out under conditions analogous to those of the above halogenation.
The dehydrohalogenation of the halogenated : derivative obtained from the derivative in which R; is hydroxyl can be carried out in particular by treatment with diazabicyclo([5,4,0]undec-7-ene in an aromatic organic solvent (toluene, for example) at a temperature of between 20°C and the reflux temperature of the reaction mixture. : :
The reduction of the acid, protected in the . form of an R’; radical, in the 3-position of the piperidine to a hydroxymethyl radical is carried out according to the usual methods which do not : detrimentally affect the remainder of the molecule, in particular, the reduction is carried out by the action of a hydride (lithium aluminum hydride or diisobutyl- oo aluminum hydride, for example) in a solvent, such as an oe ether (tetrahydrofuran, for example), at a temperature of between 20 and 60°C.
The conversion of the hydroxymethyl radical in the 3-position of the piperidine to a carboxymethyl radical is carried out according to the usual methods
® ® which do not detrimentally affect the remainder of the ~ molecule, in particular, it can be carried out by the : action of a halogenating agent, such as, for example, thionyl chloride or phosphorus trichloride or : phosphorus tribromide, and then of an alkaline cyanide (potassium cyanide or sodium cyanide, for example), in N oo ‘order to prepare the corresponding cyanomethyl derivative, followed by the hydrolysis of the nitrile.
The halogenation can be carried out in a chlorinated | | } solvent (dichloromethane or chloroform, for example) at a temperature of between 0°C and the reflux temperature oo of the solvent.
The reaction of the alkaline cyanide can be carried out in a solvent, such as dimethyl sulfoxide, an amide : (dimethylformamide, for example), a ketone (acetone, for example), an ether, such as, for example, tetrahydrofuran, or an alcohol, such as, for example, methanol or ethanol, at a temperature of between 20°C and the reflux temperature of the reaction mixture.
The hydrolysis of the nitrile is carried out according to conventional methods which do not detrimentally affect the remainder of the molecule, in particular by
Co the action of hydrochloric acid in methanolic medium, oo at a temperature of between 20 and 70°C, followed by oo oo the saponification of the ester obtained (for example, . by sodium hydroxide in a mixture of dioxane and water), . or else directly by the action of aqueous sulfuric acid at a temperature of between 50 and 80°C.
® _
The conversion of the hydroxymethyl radical in the 3-position of the piperidine to a 2-carboxyethyl Co : radical is carried out, for example, from the halogenated derivative prepared as described above by condensation of the sodium salt of diethyl malonate, : followed by acid hydrolysis in aqueous medium of the : : product obtained. ] Co
The removal, if appropriate, of the acid- protecting radical, in order to obtain a quinolyl- propylpiperidine derivative in which R; is a carboxyl radical, is carried out according to the usual methods, in particular by acid hydrolysis or saponification of the R’; ester. In particular, sodium hydroxide is reacted in aqueous/organic medium, for example in an alcohol, such as methanol, or an ether, such as dioxane, at a temperature of between 20°C and the reflux temperature of the reaction mixture. The hydrolysis can also be carried out in aqueous hydrochloric medium at a temperature of between 20 and 100°c. : | The quinolylpropylpiperidine derivative of : general formula (II) or the corresponding acid in which
R', represents a carboxyl radical can be prepared : ) according to or by analogy with the methods described hereinbelow in the examples or according to or by analogy with the methods disclosed in European Patent
Application EP 30044 or in International Application
WO 99/37635. The intermediates of the quinolylpropyl-
_ ® : piperidine derivatives in which Rs represents alkenyl-
CH,0- or alkynyl-CH;O- can be obtained, by analogy with the preparation of the intermediates in which Rs is alkyloxy, by the action of the corresponding halogenated derivative on the quinoline derivative hydroxylated in the 6-position.
The protected 2-carboxyethyl derivative of ] general formula (II) can be obtained according to or by analogy with the method disclosed in International oo
Application WO 99/37635, followed by the hydrolysis of the nitrile and by the esterification of the acid thus : obtained, or can be prepared according to or by analogy with the methods described hereinbelow in the examples.
It is understood that the derivatives of general formula (I), (II) or (III) or their starting intermediates can exist in the cis or trans form with regard to the substituents in the 3- and 4-position of the piperidine. The derivatives with the trans configuration can be obtained from the derivatives with the cis configuration according to or by analogy with the method disclosed in International Application
WO 99/37635. g The quinolylpropylpiperidine derivatives of general formula (I) can be purified, if appropriate, by physical methods, such as crystallization or chromatography. . : Furthermore, it is understood that, when R’; } is a hydrogen atom and R; is hydroxyl or halogen,
® ® diastereoisomeric forms exist and that the diastereoisomeric forms and their mixtures also come within the scope of the present invention. The latter can be separated in particular by silica chromatography or by High Performance Liquid Chromatography (HPLC). "The quinolylpropylpiperidine derivatives of . Co general formula (I) can be converted to addition salts with acids by known methods. It is understood that these salts also come within the scope of the present invention.
Mention may be made, as examples of addition salts with pharmaceutically acceptable acids, of the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulfates, nitrates or phosphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methane- sulfonates, ethanesulfonates, phenylsulfonates, p-toluenesulfonates, isethionates, naphthylsulfonates or camphorsulfonates, or with substituted derivatives of these compounds).
Some of the quinolylpropylpiperidine derivatives of general formula (I) carrying a carboxyl - radical can be converted to the form of metal salts or
So to addition salts with nitrogenous bases according to oo methods known per se. These salts also come within the scope of the present invention. The salts can be obtained by the action of a metal base (for example, an : alkali metal or alkaline earth metal base), of ammonia
® @ or 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, and it is
I separated by filtration, settling or lyophilization.
Mention may be made, as examples of pharmaceutically acceptable salts, of the salts with alkali metals . (sodium, potassium or lithium) or with alkaline earth metals (magnesium or calcium), the ammonium salt or the salts of nitrogenous bases (ethanolamine, diethanol- amine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, NN-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-B-phenethyl- amine, NN'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine or dibenzylamine) . . The quinolylpropylpiperidine derivatives according to the invention are particularly advantageous antibacterial agents. : : In vitro, with regard to gram-positive microorganisms, the quinolylpropylpiperidine derivatives according to the invention have proved to
Le active at concentrations of between 0.015 and | oo 4 ug/ml with regard to meticillin-resistant
Staphylococcus aureus AS5155, and most of them at concentrations of between 0.06 and 8 pg/ml with regard to. Streptococcus pneumoniae IP53146 and at
®
J concentrations of between 0.12 and 64 ug/ml with regard oo to Enterococcus faecium ATCC19434 or HS83401 and, with regard to gram-negative microorganisms, they have proved to be active at concentrations of between 0.12 and 32 ug/ml with regard to Moraxella catharrhalis
IPA152; in vivo, they have proved to be active with regard to experimental infections of mice with
Staphylococcus aureus IP8203 at doses of between 10 and 150 mg/kg subcutaneously (CDsgq) and, for some of them, at doses of between 20 and 150 mg/kg orally.
Finally, the products according to the invention are particularly advantageous because of their low toxicity. None of the products displayed toxicity at a dose of 100 mg/kg subcutaneously in mice (2 administrations).
More particularly advantageous, among the products according to the invention, are the quinolylpropylquinoline derivatives of general formula (I) in which:
R; is a hydrogen or halogen atom or a hydroxyl radical, -
R’; is a hydrogen atom, and
R° is a hydrogen atom, or else
R; and R° together form a bond and
R’; 1s a hydrogen atom, :
® ®
R, represents a carboxyl or carboxymethyl radical, and
Ry; represents an alkyl radical (1 to 6 carbon atoms) substituted by 1 to 3 substituents chosen from halogen, oxo, alkyloxy or alkylthio or from a phenyl or 'phenylthio radical, which can themselves carry 1 to oo 4 halogen atoms, or from a cycloalkyl or cycloalkylthio ~~ radical, the cyclic part of which comprises 3 to 7 members, or from a 5- to 6-membered aromatic heterocyclyl or heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally themselves substituted by halogen, or R; represents a propargyl radical substituted by a phenyl radical which can itself carry 1 to 3 halogen substituents or a propargyl radical substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur, or Ra represents cinnamyl, or else
R, represents a hydroxymethyl, alkyloxycarbonyl or oo alkyloxycarbonylmethyl radical (the alkyl portions of : : which comprise 1 to 6 carbon atoms) and
Ry; represents an alkyl radical (1 to 6 carbon atoms) oo ) ~~ substituted by a 5- to 6-membered aromatic | oo heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur, or R; represents a propargyl radical substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur, and Ry represents an alkyl radical (comprising 1 to 6 carbon atoms), : the alkyl radicals and portions being straight- or branched-chain radicals and portions, as well as the diastereoisomeric forms or their mixtures, as well as their salts, and more especially preferred, among these products, are the following products: e (3R,4R)-4-[3-Hydroxy-3-(6-methoxyquinolin-4- vl)propyll-1-(2-(2-thienylthio)ethyllpiperidine-3- acetic acid; . (3R, 4R) -4- [3-(6-Methoxyquinolin-4-yl)propyl]-1-[2-(2- thienylthio)ethyllpiperidine-3-acetic acid; e (3R,4R)-4-[3-Fluoro-3-(6-methoxygquinolin-4-
Co y1)propyll-1-[2-(2-thienylsulfanyl)ethyllpiperidine- -
J-acetic acid; 25. e (3R,4R)-1-[2-(3-Fluorophenylthio)ethyl]-4-[3-hydroxy- 3- (6-methoxyquinolin-4-yl)propyllpiperidine-3-acetic acid;
®
PA
* (3R,4R)-4-[3-Hydroxy-3- (6-methoxyquinolin-~-4- - v1l)propyl]-1-(3-(2,3,5-trifluorophenyl)prop-2-ynyl]- pPiperidine-3-carboxylic acid. 5 .
The products cited in the examples are . particularly preferred; the quinolylpropylpiperidine derivatives hereinbelow are also advantageous products: (3R,4R) -4-[3-(6~-Methoxyquinolin-4-yl)propyl]- 1-(4-phenylbutyl]piperidine-3-carboxylic acid {3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-[4~(2-fluorophenyl)butyllpiperidine-3-carboxylic acid (3R,4R) -4-[3~- (6-Methoxyquinolin-4-yl)propyl]- : 1-[{4-(3-fluorophenyl)butyl]lpiperidine~3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- : 1-(3-(4-fluorophenyl)propyllpiperidine-3-carboxylic acid (3R, 4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] - 1-[4-(4-fluorophenyl)butyl]lpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[{3-(2,3-difluorophenyl) propyl]piperidine~-3-carboxylic acid Co (3R, 4R) ~4- [3 (6-Methoxyquinolin-4-y1) propyl] - | oo a 1-[4-(2,3-di fluorophenyl) butyl]piperidine-3-carboxylic oo acids . (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl)propyll- 1-(3- (2, 6-di fluorophenyl) propyl]piperidine-3-carboxylic acid
® ®
(3R, 4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- : 1- [4- (2, 6-difluorophenyl) butyl] piperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2-chlorophenyl)propyl]lpiperidine-3-carboxylic acid ' (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[4-(2-chlorophenyl)butyl]piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1-[3-(3-chlorophenyl)propyllpiperidine-3-carboxylic acid (3R,4R) -4-[3~-(6-Methoxyquinolin-4-yl)propyll]- 1-[4-(3-chlorophenyl)butyl]piperidine-3-carboxylic acid (3R,4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[3-(4-chlorophenyl)propyllpiperidine-3-carboxylic : acid (3R,4R) -4~-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[4-(4-chlorophenyl)butyllpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2,3-dichlorophenyl)propyllpiperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[4-(2,3-dichlorophenyl)butyl]piperidine-3-carboxylic acid | : oo oo ~ (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-(3-(2,6-dichlorophenyl)propyllpiperidine-3-carboxylic acid : (3R, 4R) ~4- [3- (6-Methoxyquinolin-4-y1) propyl] -
® ® 1-(4-(2,6-dichlorophenyl)butyl]piperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-[{3-(2-methylphenyl)propyl]lpiperidine-3-carboxylic acid . (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- IE 1-[4-(2-methylphenyl)butyl]piperidine-3-carboxylic acid (3R,4R) -4-(3-(6-Methoxyquinolin~-4-yl)propyl]- : 1-({5-(2-methylphenyl)pentyl]lpiperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-{(3-methylphenyl)propyll]lpiperidine-3-carboxylic acid (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] - 1-[4-(3-methylphenyl)butyl]piperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1 [3- (4-methylphenyl)propyl]piperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyll]- 1-(4-(4-methylphenyl)butyl]piperidine-3-carboxylic acid
So (3R, 4R) —4- [3- (§-Methoxyquinolin-4-y1) propyl] - 1-[3-(2-methoxyphenyl)propyllpiperidine-3-carboxylic acid = : (3R, 4R) —4- [3 (6-Methoxyquinolin-4-yl) propyl] - : 1-[4-(2-methoxyphenyl)butyl]lpiperidine-3-carboxylic acid : (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - 1-[3-(3-methoxyphenyl)propyllpiperidine-3-carboxylic
® @® acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[{4-(3-methoxyphenyl)butyllpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-{4-methoxyphenyl)propyl]piperidine-3-carboxylic acid EE ES (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)propyl]- ~ : 1-[4- (4-methoxyphenyl)butyl]piperidine-3-carboxylic acid : (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2-trifluoromethylphenyl)propyl]lpiperidine- 3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[4-(2-trifluocromethylphenyl)butyl]piperidine- 3-carboxylic acid (3R, 4R) -4-(3- (6-Methoxyquinolin-4-yl)propyl]- 1-[3-(3-trifluoromethylphenyl)propyl]piperidine- 3-carboxylic acid | : (3R,4R)-4-[3~(6-Methoxyquinolin-4-yl)propyll- 1-[4-(3-trifluoromethylphenyl)butyl]piperidine- - 3-carboxylic acid (3R, 4R) -4-[3- (6-Methoxyquinolin-4-yl)propyl]- oo oo . 1-[3-(4-trifluoromethylphenyl)propyllpiperidine- : : 25 3-carboxylic acid (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl)propyll]- 1-[4-(4-trifluoromethylphenyl)butyl]lpiperidine- 3-carboxylic acid
® ®
(3R,4R) ~-4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-[3-phenylthiopropyllpiperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1l) propyl] - 1-[3-(2-fluorophenylthio)propyllpiperidine-3-carboxylic acid (38, 4R) ~4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[3- (3-fluorophenylthio)propyl]piperidine-3-carboxylic © acid | | | So © (3R,4R)-4-[3- (6-Methoxyquinolin-4-yl)propyl]- 1-[2-(4-fluorophenylthio)ethyl]lpiperidine-3-carboxylic : acid (3R, 4R) -4-[3- (6-Methoxyguinolin-4-yl) propyl] - 1-[3- (4-fluorophenylthio)propyl]lpiperidine-3-carboxylic acid (3R,4R)-4-([3-(6-Methoxyquinolin-4-yl)propyl]- 1-[2-(2,3-difluorophenylthio)ethyl]piperidine- 3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2,3-difluorophenylthio)propyl]piperidine- 3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl)propyl]- 1-[2-(2,6-difluorophenylthio)ethyl]lpiperidine- ~ 3-carboxylic acid oo : | EE ~~ (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl)propyll- 1-[3-(2,6-difluorophenylthio) propyl]lpiperidine- 3-carboxylic acid | : (3R,4R) -4-[3- (6-Methoxyqguinolin-4-yl)propyl]- : 1-(2- (2-chlorophenylthio) ethyl]piperidine-3-carboxylic .
PS
® acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2-chlorophenylthio)propyllpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- ~ 1-[2-(3-chlorophenylthio)ethyl]piperidine-3-carboxylic | Co oo acid (3R, 4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] - 1-[3-(3-chlorophenylthio)propyl]piperidine-3-carboxylic acid (3R, 4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-[{2-(4-chlorophenylthio)ethyl]piperidine-3-carboxylic oo acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-{3-(4-chlorophenylthio)propyllpiperidine-3-carboxylic acid (3R, 4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-{2-(2,3-dichlorophenylthio)ethyllpiperidine- 3-carboxylic acid (3R,4R)-4-(3-(6-Methoxyquinolin-4-yl)propyl]- : 1-[3-(2,3-dichlorophenylthio)propyllpiperidine- : 3-carboxylic acid © (3R,4R)-4- [3- (6-Methoxyquinolin-4-yl) propyl]- oo © 1-[2-(2,6-dichlorophenylthio)ethyllpiperidine- ~ = | - 3-carboxylic acid | : (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-([3-(2,6-dichlorophenylthio)propyl]lpiperidine- 3-carboxylic acid
® @®
(3R,4R)-4-[3-(6-Methoxyquinolin-4-yl) propyl] - 1-{2-(2-methylphenylthio)ethyl]lpiperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(2-methylphenylthio)propyllpiperidine-3-carboxylic acid : (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] - : - 1-[2-(3-methylphenylthio)ethyl]piperidine-3-carboxylic n acid .
+ 10 (3R,4R)-4-[3-(6-Methoxyqguinolin-4-vyl)propyl]- 1-[{3-(3-methylphenylthio)propyllpiperidine-3-carboxylic acid (3R,4R) -4-[3~- (6-Methoxyquinolin-4-yl)propyl]l- 1-[2-(4-methylphenylthio)ethyllpiperidine-3-carboxylic acid (3R, 4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] - 1-[3~(4-methylphenylthio)propyllpiperidine-3-carboxylic acid : (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] -
1-[2-(2-trifluoromethylphenylthio)ethyllpiperidine- 3-carboxylic acid : : (3R, 4R) -4— [3 (6-Methoxyquinolin-4-yl) propyl] -
. . 1- (3- (2-trifluoromethylphenylthio) propyllpiperidine- - oo . 3-carboxylic acid oo IE oo oo
(3R,4R) -4-[3- (6-Methoxyquinolin-4-yl) propyl] -
. 1-[2-(3-trifluoromethylphenylthio)ethyllpiperidine-
. 3-carboxylic acid j (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]-
® ®
1-[(3-(3-trifluoromethylphenylthio)propyllpiperidine- 3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[2- (4-trifluoromethylphenylthio)ethyl]piperidine- 3-carboxylic acid (3R, 4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- . 1-[3- (4-trifluoromethylphenylthio) propyl] piperidine- 3-carboxylic acid (3R, 4R) -4- [3 ~ (6-Methoxyquinolin-4-y1) propyl] - oo 1-([2-(2-methoxyphenylthio)ethyllpiperidine-3-carboxylic oo acid : (3R, 4R)-4-[3-{6-Methoxygquinolin-4-yl)propyl]- 1-[3-(2-methoxyphenylthio)propyl]piperidine- ’ 3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyll]- 1-[2-(3-methoxyphenylthio)ethyl]lpiperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl} - 1-[3-(3-methoxyphenylthio)propyllpiperidine- 3-carboxylic acid | . : (3R, 4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[2- (4-methoxyphenylthio)ethyl]piperidine-3-carboxylic acid : _ © (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyll- oo 1-(3- (4-methoxyphenylthio)propyl]piperidine- 3-carboxylic acid (3R, 4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl] - 1- [cyclopropylmethyl]lpiperidine~3-carboxylic acid
®
LC) (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-{2-(cyclopropyl)ethyllpiperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - l-[{cyclobutylmethyllpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- a 1-[2-(cyclobutyl)ethyl]piperidine-3-carboxylic acid oo (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - R l1-{cyclopentylmethyl]piperidine-3-carboxylic acid (3R,4R)-4~[3-(6-Methoxyquinolin-4-yl)propyl]- | oo 1-[2-{cyclopentyl)ethyllpiperidine-3-carboxylic acid (3R,4R)-4-[3~-(6-Methoxyquinolin-4-yl)propyl]- 1-[cyclohexylmethyl]piperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- : 1-[2- (cyclohexyl) ethyl]piperidine-3-carboxylic acid (3R,4R)-4-[3~-(6-Methoxyquinolin-4-yl)propyl]l- 1-[2-(cyclopropylthio)ethyllpiperidine-3-carboxylic acid (3R,4R) -4-[3- (6-Methoxyquinolin-4-yl)propyll]- 1-[3-(cyclopropylthio)propyl]piperidine-3-carboxylic - 20 acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyll- 1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylic acid - - (3R, 4R) -4- [3- (6-Methoxyquinolin-d-y1) propyl] - © 1-[3-(cyclobutylthio)propyl]piperidine-3-carboxylic Co ‘acid . (3R,4R)-4-[3-(6-Methoxyguinolin-4-yl)propyl]- ; 1-[2- (cyclopentylthio)ethyl]piperidine-3-carboxylic : acid
@® ® {3R,4R) -4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(cyclopentylthio)propyl]piperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-{3-(cyclohexylthio)propyllpiperidine-3-carboxylic acid oo (3R, 4R) -4- [3 (6-Methoxyquinolin-4-yl) propyl] - oo 1-[2-methylthioethyl]piperidine-3-carboxylic acid (3R, 4R) -4- [3- (6-Methoxyquinolin-4-y1) propyl] - 1-[3-methylthiopropyllpiperidine-3-carboxylic acid (3R,4R) -4-[3-(6-Methoxyquinolin-4-yl) propyl] - l-[2-ethylthicethyl]lpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3~-ethylthiopropyllpiperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxygquinolin-4-yl)propyl]- 1-[2-(n-propylthio)ethyl]piperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-[3-(n-propylthio)propyl]piperidine-3-carboxylic acid (3R,4R)-4-[3-(6-Methoxyquinolin-4-yl)propyl]- 1-{2-(n-butylthio)ethyl]piperidine-3-carboxylic acid
N (3R,4R)-4-[3- (6-Methoxyquinolin-4-yl)propyl]- : 1-[3-(n-butylthio)propyl]piperidine-3-carboxylic acid © (3R, 4R) ~4- [3- (6-Methoxyquinolin-4-y1) propyl] - oo 1-[4- (thien-2-y1)butyl]piperidine-3-carboxylic acid (3R,4R)-4-[3- (6-Methoxyquinolin-4-yl)propyl]- 1-[3-(thien-2-yl)thiopropyllpiperidine-3-carboxylic acid So (3R, 4R) -4- [3- (6-Methoxyquinolin-4-yl) propyl] -

Claims (16)

® ® 534 CLAIMS
1. A quinolylpropylpiperidine derivative of general formula: R, hl R, N=R, Mm N in which: : R; is a hydrogen or halogen atom or a hydroxyl radical, R’; is a hydrogen atom or can represent halogen when R; : is also a halogen atom, and R° is a hydrogen atom, or else R; and R° together form a bond and R’: is a hydrogen atom, and either R; represents a carboxyl, carboxymethyl or 2-carboxy- ethyl radical, Ri; represents an alkyl radical (1 to 6 carbon atoms) substituted by 1 to 3 substituents chosen from hydroxyl, halogen, oxo, carboxyl, alkyloxycarbonyl, alkyloxy or alkylthio or from a phenyl, phenylthio or phenylalkylthio radical, which can themselves carry 1 to 4 substituents [chosen from halogen, hydroxyl, AMENDED SHEET
®
® 535 alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido (1 to 4C) or amino], or from a cycloalkyl or cycloalkylthio radical, the cyclic part of which comprises 3 to 7 members, or from a 5- to 6-membered aromatic heterocyclyl or heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally themselves substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl,
trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], or Riz represents a propargyl radical substituted by a phenyl radical which can itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy,
carboxyl, alkyloxycarbonyl, cyano or amino] or substituted by a cycloalkyl radical comprising 3 to 7 members or substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], or Rj represents cinnamyl or 4-phenylbuten-3-vyl, and R; represents an alkenyl-CH,- or alkynyl-CH,_
radical, the alkenyl or alkynyl parts of which comprise 2 to 6 carbon atoms, or
AMENDED SHEET
®
® 536 R; represents a carboxyl, carboxymethyl or 2- carboxyethyl radical, and
Rs represents an alkyl radical (1 to 6 carbon atoms)
substituted by 1 to 3 substituents chosen from halogen, oxo, carboxyl, alkyloxycarbonyl or alkylthio or from a phenylthio or phenylalkylthio radical, which can themselves carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, acetamido (1 to 4C) or amino), or from a cycloalkylthio ‘radical, the cyclic part of which comprises 3 to 7 members, or from a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur and optionally themselves substituted [by halogen, hydroxyl, alkyl,
alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], or Rs represents a propargyl radical substituted by a phenyl radical which can itself carry 1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino] or substituted by a cycloalkyl radical comprising 3 to 7 members or substituted by 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulphur and optionally itself
AMENDED SHEET
® @® 537 substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], and Ry represents an alkyl radical (comprising 1 to 6 carbon atoms), or else R; represents a hydroxymethyl, alkyloxycarbonyl, alkyloxycarbonylmethyl or 2-(alkyloxycarbonyl)ethyl radical (the alkyl parts of which comprise 1 to 6C) and R; represents. an alkyl radical (1 to 6 carbon atoms) substituted by a phenylthio radical which can itself carry 1 to 4 substituents [chosen from halogen, : hydroxyl, alkyl, alkyloxy, trifluoromethyl,
trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino], by a cycloalkylthio radical, the cyclic part of which comprises 3 to 7 members, or by a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino] or R; represents a propargyl radical substituted by a phenyl radical which can itself carry
1 to 4 substituents [chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano or amino] or substituted by a cycloalkyl radical comprising 3 to 7
AMENDED SHEET members or substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur and optionally itself substituted [by halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano or amino], and Rs represents an alkyl radical (comprising 1 to 6 carbon atoms), an alkenyl-CH,- radical or an alkynyl- CH;- radical, the alkenyl or alkynyl parts of which comprise 2 to 6 carbon atoms, it being understood that the alkyl radicals and portions are straight- or branched-chain radicals and protions and comprise, except when specifically mentioned, 1 to 4 carbon atoms, i in its diastereoisomeric forms or their mixtures, as : well as its salts.
2. A quinolylpropylpiperidine derivative according to claim 1, characterized in that R; is a hydrogen or halogen atom or a hydroxyl radical, R’; is a hydrogen atom, and R° is a hydrogen atom, or else R; and R° together form a bond and R’; is a hydrogen atom, AMENDED SHEET
® ® 539 R; represents a carboxyl or carboxymethyl radical, and R3 represents an alkyl radical (1 to 6 carbon atoms) substituted by 1 to 3 substituents chosen from halogen, oxo or alkylthio or from a phenylthio radical, which can themselves carry 1 to 4 halogen atoms, or from a cycloalkylthio radical, the cyclic part of which comprises 3 to 7 members, or from a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 ' heteroatoms chosen from nitrogen, oxygen or sulfur and optionally themselves substituted by halogen, or R; represents a propargyl radical substituted by a phenyl radical which can itself carry 1 to 3 halogen : substituents or a propargyl radical substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur, or else Rz represents a hydroxymethyl, alkyloxycarbonyl or alkyloxycarbonylmethyl radical (the alkyl portions of which comprise 1 to 6 carbon atoms) and R:; represents an alkyl radical (1 to 6 carbon atoms) substituted by a 5- to 6-membered aromatic : heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen or sulfur, or Rs; represents a propargyl radical substituted by a 5- to 6-membered aromatic heterocyclyl radical comprising 1 - to 4 heteroatoms chosen from nitrogen, oxygen or AMENDED SHEET
® ® 540 sulfur, and Ry represents an alkyl radical (comprising 1 to 6 carbon atoms), the alkyl radicals and portions being straight- or branched-chain radicals and portions, in its diastereoisomeric forms or their mixtures, as well as its salts.
3. A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterized in that it is (3R,4R)-4-[3-hydroxy-3- (6-methoxyquinolin-4- yl)propyll-1-[2-(2-thienylthio)ethyl]piperidine-3- acetic acid, in its diastereoisomeric forms or their mixtures, as well as its salts.
4. A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterized in that it is (3R,4R)-4-[3-(6-methoxyquinolin-4- vl)propyl]l-1-[2-(2-thienylthio)ethyl]lpiperidine-3- acetic acid, as well as its salts.
5, A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterized in : that it is (3R,4R)-4-[3-fluoro-3-(6-methoxyquinolin-4- yl)propyl]-1-[2-(2-thienylsulfanyl)ethyllpiperidine-3- acetic acid, in its diastereoisomeric forms or their mixtures, as well as its salts.
6. A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterized in AMENDED SHEET
LJ ® 541 that it is (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4- [3-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine- 3-acetic acid, in its diastereoisomeric forms or their mixtures, as well as its salts.
7. A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterized in that it is (3R,4R)-4-[3-hydroxy-3-(6-methoxyquinolin-4- yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2- ynyllpiperidine-3-carboxylic acid, in its diastereoisomeric forms or their mixtures, as well as its salts.
8. A process for the preparation of quinolylpropylpiperidine derivative according to claim 1, characterized in that the R; chain defined in claim 1 is condensed onto the quinolylpropylpiperidine derivative of general formula: R™y al NH RO KR, an
N . in which R; is defined as in claim 1, R’’; and R’' represent hydrogen atoms or together form an oxo radical and R’; represents a protected carboxyl, : carboxymethyl or 2-carboxyethyl radical, or an alkyloxycarbonyl, alkyloxycarbonylmethyl or 2- : (alkyloxycarbonyl) ethyl radical, in order to obtain a quinolylpropylpiperidine derivative of general formula: AMENDED SHEET
® ® 542
: i. R", NR, ne o Re {I NZ in which R’’;, R’’'’1, R’; and Ry, are defined as above and R; is defined as in claim 1, then, if appropriate, the acid-protecting radical is removed, or else, if appropriate, the oxo radical represented by R’’; and R’’’; is reduced to an alcohol in which R; represents hydroxyl, then, optionally, halogenation is carried out, if it is desired to obtain a quinolylpropylpiperidine derivative in which R; is a halogen atom, and, optionally, dehydrohalogenation of the corresponding halogenated derivative is carried out, in order to obtain a quinolylpropylpiperidine : derivative in which R; and R° together form a bond, or else dihalogenation of the product of general formula : (III) in which R’’; and R’’'’; together form an oxo radical is carried out, in order to obtain a quinolylpropylpiperidine derivative in which R; and R’;are halogen atoms, and/or, if appropriate, the acid, protected in the form of an R’; radical, in the 3-position of the piperidine is reduced to a hydroxymethyl radical and optionally AMENDED SHEET
> ¢ : h 543 converted to a carboxymethyl or 2-carboxyethyl radical according to the usual methods, then, optionally, the acid-protecting radical is removed and/or, if appropriate, the diastereoisomers are separated and the product obtained is optionally converted to a salt.
9. A process according to claim 2, characterized in that the condensation of the Ri; chain onto the piperidine is carried out by the action of a derivative of general formula: : : R3-X in which R; is defined as previously and X represents a halogen atom, a methylsulfonyl radical, a trifluoro- methylsulfonyl radical or a p-toluenesulfonyl radical.
10. A process according to either of claims 2 and 3, characterized in that, when Rj3 represents propargyl substituted by phenyl, cycloalkyl . or heterocyclyl, the reaction is preferably carried out . by condensation of a propargyl halide and then substitution of the chain with a phenyl, cycloalkyl or heterocyclyl radical.
11. Pharmaceutical composition, characterized in that it comprises 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. AMENDED SHEET
PCTIFR00/02547 a 12. A quinolylpropylpiperidine derivative according to either of claims 1 and 2, characterised in that it is (3R,4R) -4- [3-hydroxy-3- (6-methoxyquinolin-4- y1)propyl]-1-[2-(2-thienylthio) ethyl] piperidine-3- carboxylic acid, in its diastereomeric forms or their ] : BE mixtures, or a salt thereof.
13. A derivative according to claim 1, substantially as herein described and illustrated.
14. A process according to claim 8, - 10° substantially as herein described and illustrated. :
15. A composition according to claim 11, substantially as herein described and illustrated. ;
16. A new derivative, a new brocess for preparing a derivative, or a new composition, substantially as herein described. : | a AMENDED SHEET
ZA200202073A 1999-09-17 2002-03-13 Quinolyl propyl piperidine derivatives and their use as antibacterial agents. ZA200202073B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9911679A FR2798656B1 (en) 1999-09-17 1999-09-17 DERIVATIVES OF QUINOLYL PROPYL PIPERIDINE, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM

Publications (1)

Publication Number Publication Date
ZA200202073B true ZA200202073B (en) 2003-08-27

Family

ID=9549990

Family Applications (1)

Application Number Title Priority Date Filing Date
ZA200202073A ZA200202073B (en) 1999-09-17 2002-03-13 Quinolyl propyl piperidine derivatives and their use as antibacterial agents.

Country Status (30)

Country Link
EP (2) EP1218370B1 (en)
JP (1) JP2004527448A (en)
KR (1) KR20020038757A (en)
CN (1) CN1374959A (en)
AP (1) AP2002002459A0 (en)
AT (1) ATE284399T1 (en)
AU (1) AU7429500A (en)
BG (1) BG106524A (en)
BR (1) BR0014060A (en)
CA (1) CA2383836A1 (en)
CZ (1) CZ2002940A3 (en)
DE (2) DE60016611T2 (en)
DZ (1) DZ3195A1 (en)
EA (1) EA005183B1 (en)
EE (1) EE200200138A (en)
FR (1) FR2798656B1 (en)
GE (1) GEP20043223B (en)
HR (1) HRP20020214A2 (en)
HU (1) HUP0204283A3 (en)
IL (1) IL148720A0 (en)
MA (1) MA26820A1 (en)
MX (1) MXPA02001979A (en)
NO (1) NO20021253L (en)
OA (1) OA12022A (en)
PL (1) PL354809A1 (en)
SK (1) SK3632002A3 (en)
TN (1) TNSN00184A1 (en)
WO (1) WO2001025227A2 (en)
YU (1) YU19002A (en)
ZA (1) ZA200202073B (en)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9822440D0 (en) 1998-10-14 1998-12-09 Smithkline Beecham Plc Medicaments
GB9917408D0 (en) 1999-07-23 1999-09-22 Smithkline Beecham Plc Compounds
GB9917406D0 (en) 1999-07-23 1999-09-22 Smithkline Beecham Plc Compounds
CZ2003243A3 (en) 2000-07-26 2003-09-17 Smithkline Beecham P. L. C. Aminopiperidine quinolines and their azaisosteric analogs exhibiting antibacterial activity
GB0031086D0 (en) * 2000-12-20 2001-01-31 Smithkline Beecham Plc Medicaments
GB0101577D0 (en) 2001-01-22 2001-03-07 Smithkline Beecham Plc Compounds
GB0112836D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
GB0112834D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
JP4445753B2 (en) 2002-01-29 2010-04-07 グラクソ グループ リミテッド Aminopiperidine derivatives
WO2003064431A2 (en) 2002-01-29 2003-08-07 Glaxo Group Limited Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
AR040336A1 (en) 2002-06-26 2005-03-30 Glaxo Group Ltd PIPERIDINE COMPOUND, USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND PROCEDURE TO PREPARE SUCH COMPOUND
TW200406413A (en) 2002-06-26 2004-05-01 Glaxo Group Ltd Compounds
FR2842807A1 (en) * 2002-07-23 2004-01-30 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, PROCESS AND PREPARATION INTERMEDIATES AND COMPOSITIONS COMPRISING THE SAME
FR2844270B1 (en) 2002-09-11 2006-05-19 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, THEIR PROCESS AND PREPARATION INTERMEDIATES AND THE COMPOSITIONS CONTAINING THEM
FR2844268B1 (en) * 2002-09-11 2004-10-22 Aventis Pharma Sa QUINOLYL PROPYL PIPERIDINE DERIVATIVES, PROCESSES AND INTERMEDIATES FOR THEIR PREPARATION, AND COMPOSITIONS CONTAINING THEM
AU2003301414B8 (en) * 2002-10-10 2010-06-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Novel compounds with antibacterial activity
AU2003291227A1 (en) 2002-11-05 2004-06-07 Smithkline Beecham Corporation Antibacterial agents
US7232832B2 (en) 2002-11-05 2007-06-19 Smithkline Beecham Corporation Antibacterial agents
AU2003294565A1 (en) 2002-12-04 2004-06-23 Glaxo Group Limited Quinolines and nitrogenated derivatives thereof and their use as antibacterial agents
CA2581057A1 (en) * 2004-10-05 2006-04-13 Actelion Pharmaceuticals Ltd New piperidine antibiotics
EP1799674B1 (en) * 2004-10-05 2010-05-05 Actelion Pharmaceuticals Ltd. New piperidine antibiotics
JP2008528587A (en) 2005-01-25 2008-07-31 グラクソ グループ リミテッド Antibacterial agent
US7605169B2 (en) 2005-01-25 2009-10-20 Glaxo Group Limited Antibacterial agents
US7592334B2 (en) 2005-01-25 2009-09-22 Glaxo Group Limited Antibacterial agents
EP1846416A4 (en) 2005-01-25 2009-07-01 Glaxo Group Ltd Antibacterial agents
ES2376488T3 (en) 2006-01-26 2012-03-14 Actelion Pharmaceuticals Ltd. TETRAHYDROPIRAN ANTIBIOTICS.
US7709483B2 (en) 2006-04-06 2010-05-04 Glaxo Group Limited Pyrrolo-quinoxalinone derivatives as antibacterials
GB0613208D0 (en) 2006-07-03 2006-08-09 Glaxo Group Ltd Compounds
EP1992628A1 (en) 2007-05-18 2008-11-19 Glaxo Group Limited Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones
KR20120011093A (en) * 2007-05-09 2012-02-06 화이자 인코포레이티드 Substituted heterocyclic derivatives and compositions and their pharmaceutical use as antibacterials
EP2080761A1 (en) 2008-01-18 2009-07-22 Glaxo Group Limited Compounds
EP2352734A1 (en) 2008-10-17 2011-08-10 Glaxo Group Limited Tricyclic nitrogen compounds used as antibacterials
US8318940B2 (en) 2009-01-15 2012-11-27 Glaxo Group Limited Naphthyridin-2 (1 H)-one compounds useful as antibacterials
EP3057948B1 (en) * 2013-10-14 2018-03-14 Eisai R&D Management Co., Ltd. Selectively substituted quinoline derivatives
CR20170069A (en) 2014-08-22 2017-04-28 Glaxosmithkline Intelectual Property Dev Ltd TRICYCLIC COMPOUNDS CONTAINING NITROGEN FOR THE TREATMENT OF INFECTION BY NEISSERIA GONORRHOEAE
UY36851A (en) 2015-08-16 2017-03-31 Glaxosmithkline Ip Dev Ltd COMPOUNDS FOR USE IN ANTIBACTERIAL APPLICATIONS
CN113603675A (en) 2015-12-17 2021-11-05 默克专利有限公司 Polycyclic TLR7/8 antagonists and their use in the treatment of immune disorders
JP7125385B2 (en) 2016-08-08 2022-08-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング TLR7/8 antagonists and their uses

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69908555T2 (en) * 1998-01-26 2004-05-06 Smithkline Beecham P.L.C., Brentford CHINOLINE DERIVATIVES AS AN ANTIBACTERIAL MEDICINAL PRODUCT
AU2437900A (en) * 1999-01-20 2000-08-07 Smithkline Beecham Plc Piperidinylquinolines as protein tyrosine kinase inhibitors

Also Published As

Publication number Publication date
DE60016611D1 (en) 2005-01-13
GEP20043223B (en) 2004-04-26
ATE284399T1 (en) 2004-12-15
SK3632002A3 (en) 2003-04-01
HRP20020214A2 (en) 2005-04-30
BR0014060A (en) 2002-05-21
MA26820A1 (en) 2004-12-20
BG106524A (en) 2003-01-31
CZ2002940A3 (en) 2002-07-17
DZ3195A1 (en) 2001-04-12
NO20021253D0 (en) 2002-03-13
EP1484328A1 (en) 2004-12-08
DE60034713D1 (en) 2007-06-14
AU7429500A (en) 2001-05-10
DE60034713T2 (en) 2008-01-17
KR20020038757A (en) 2002-05-23
FR2798656A1 (en) 2001-03-23
CA2383836A1 (en) 2001-04-12
DE60016611T2 (en) 2005-12-22
IL148720A0 (en) 2002-09-12
EE200200138A (en) 2003-06-16
OA12022A (en) 2006-04-19
AP2002002459A0 (en) 2002-06-30
EA200200374A1 (en) 2002-10-31
JP2004527448A (en) 2004-09-09
YU19002A (en) 2005-06-10
EP1218370B1 (en) 2004-12-08
WO2001025227A3 (en) 2001-11-22
HUP0204283A3 (en) 2004-07-28
EA005183B1 (en) 2004-12-30
FR2798656B1 (en) 2004-12-17
HUP0204283A2 (en) 2003-04-28
MXPA02001979A (en) 2002-08-20
PL354809A1 (en) 2004-02-23
NO20021253L (en) 2002-04-24
EP1484328B1 (en) 2007-05-02
EP1218370A2 (en) 2002-07-03
CN1374959A (en) 2002-10-16
WO2001025227A2 (en) 2001-04-12
TNSN00184A1 (en) 2005-11-10

Similar Documents

Publication Publication Date Title
ZA200202073B (en) Quinolyl propyl piperidine derivatives and their use as antibacterial agents.
US6403610B1 (en) Quinolylpropylpiperidine derivatives, their preparation and the compositions which comprise them
US6603005B2 (en) Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them
US6841562B2 (en) Quinolylpropylpiperidine derivatives, intermediates and compositions containing them, and preparation therefor
US6602884B2 (en) Quinolylpropylpiperidine derivatives, their preparation, and compositions containing them
US7232834B2 (en) Quinolylpropylpiperidine derivatives, intermediates and compositions containing them, and preparation therefor
KR100849608B1 (en) Heterocyclylalkyl piperidine derivatives, their preparation and compositions containing same
JPWO2006126676A1 (en) Cyclic amine derivatives having substituted alkyl groups
JP4262481B2 (en) Quinolylpropylpiperidine derivatives, their preparation and compositions containing them
EP1943242A1 (en) Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists
MXPA06006035A (en) Cyclic amine derivative having heteroaryl ring.
WO2001019827A1 (en) A novel process for the synthesis of sildenafil citrate
JP4917022B2 (en) Diastereoselective synthesis method using 6-bromo-4- (3-chlorophenyl) -2-methoxy-quinoline
US6806277B2 (en) Quinolylpropylpiperidine derivatives, preparation process and intermediates, and compositions including them