FR2874922A1 - New aminoquinoline-antibiotic hybrids, useful as antibacterials in human and veterinary medicine, disinfectants and in agriculture - Google Patents

Abstract

Aminoquinoline-antibiotic hybrid compounds (I) are new. Aminoquinoline-antibiotic hybrid compounds of formula Q-(Y1)p-(U)p'-(Y2)p''-A (I) are new Q : aminoquinoline residue; p, p', p'' : 0 or 1 Y1, Y2, U : bond or linking group; and A : residue of an antibiotic. The full definitions are given in the DEFINITIONS - Full Definitions field. An independent claim is also included for a method of preparing (I) by fixing the -(Y1)p-(U)p'-(Y2)p''- group to one of Q and A, and reacting the product with the other of A and Q; or by attaching a group amino--(Y1)p-(U)p'-(Y2)p''- to Q and reacting the product with A. ACTIVITY : Antibacterial. The compound (2S,5R,6R)-6-{[1-(7-chloroquinolin-4-yl)piperidine-4-carbonyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3,2,0]heptane-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester (Ia) had MIC and minimum bactericidal concentration against Staphylococcus aureus MSSA CIP 4.83 of 0.012 and 0.49 mu g/ml, respectively. MECHANISM OF ACTION : None given.

Description

The invention relates to hybrid QA molecules containing an aminoquinoleic unit (Q) covalently linked to an antibiotic residue (A). The invention also relates to their synthesis and their uses as an antibacterial agent.

STATE OF THE ART
Over the last 50 years, the introduction of penicillin followed by many other antimicrobial agents has been one of the greatest successes of modern medicine in the treatment of bacterial infections (Greenwood, D. et al in Antimicrobial Chemotherapy, Greenwood, D., Oxford University Press: New York, United States, 2000). The emergence and spread of bacterial strains resistant to virtually all currently available antimicrobial agents is becoming a serious public health problem (World Health Organization, Antimicrobial Resistance: A Threat to the World.) Essential Drugs: The Point, 2000, 28 and 29, 1-35, available at www.who.int).
The problem of bacterial resistance is also analyzed by Coates, A .; et al. in Nature Rev. Drug Discov. 2002, 1, 895-910 entitled The Future Challenges Facing the Development of New Antimicrobial Drugs.
Aminoquinolines (Q) are known molecules.
Furthermore, it has been shown in the literature by Mallea et al., That in admixture with various classes of antibiotics, aminoquinolines (Q) inhibited active efflux of antibiotics (see Mallea, M .; et al., Alkylaminoquinolines inhibits bacterial efflux pump in multidrug-resistant clinical isolates Biochem J. 2003, 376, 801-805). This publication is considered by the inventors to be the closest document to the invention. Various documents teach that particular antibiotics may be coupled by particular covalent bonds to aromatic compounds defined by a general formula to improve antibiotic properties. However, these documents very generally disclose the aromatic portion which is coupled to the antibiotic and teach no particular activity of an aminoquinoline substituent.

GOALS OF THE INVENTION
The main object of the present invention is to solve the new technical problem of providing a solution which makes it possible to find new antibiotic molecules that are less prone to the resistance of the bacteria.
The main purpose of the invention is to find new antibiotic molecules that are even more effective than current antibiotics.
The invention also aims to find new antibiotic molecules that can be active on strains of bacteria resistant to certain current antibiotics.
The main purpose of the present invention is also to solve these new technical problems by providing new antibiotic molecules, the manufacture of which is relatively easy, according to an inexpensive manufacturing process and providing good industrial yields.
The present invention solves for the first time all of these technical problems in a satisfactory, safe and reliable manner, usable on an industrial scale, in particular on a pharmaceutical scale.
SUMMARY OF THE INVENTION The novelty of the present invention relates to the preparation and evaluation of hybrid QA molecules. According to the invention, the aminoquinoline part (Q) of these new molecules has been covalently attached to an antibiotic residue (A).
These hybrid QA molecules may be named, for example, in a general manner against antibiotics or in particular penicillins, cephaloquines, quinoloquines, nitroimidaquines, streptogramicins, diaminopyrimiquines, vancomyquines, oxazoquines, when the unit A is an antibiotic residue, or a penicillin or cephalosporin unit, respectively. quinolone, nitroimidazole, pristinamycin, diaminopyrimidine, vancomycin or oxazolidinone.
According to the invention, it has unexpectedly been found that the covalent attachment of an aminoquinoline to an antibiotic does not lead to a loss of antibiotic activity, but rather to an amplification effect of the antibiotic. antibiotic activity, which forms the basis of the present invention. None of the disclosures of the prior art known to the inventors teach or clearly suggest that aminoquinoline-type compounds provide an amplifying effect of antibiotic activity when covalently coupled with an antibiotic. Those skilled in the art would rather expect a risk of loss of activity by covalently linking an antibiotic residue to an aminoquinoline.
In particular, aminoquinolines make it possible to combine an inhibitory effect of the efflux pumps of certain resistant bacteria and the antibacterial effect of the antibiotic.
The AQ hybrid molecule has an antibacterial activity that is unexpectedly superior to any of its A or Q components taken separately.
Another particularly unexpected effect of the invention is that it has surprisingly been found that antibiotic activity is maintained in the case of a covalent bond with an aminoquinoline for different classes of antibiotics. Thus, this unexpected improvement in activity is not limited to a particular type of antibiotic.
This constitutes a particularly important technical improvement of the invention insofar as the current trend for antibiotic treatment is no longer with the use of broad-spectrum antibiotics. Indeed, currently, broad-spectrum antibiotics are strongly involved in the selection of resistant organisms and more carry with them the inherent danger of profound changes in the flora with development of secondary complications sometimes formidable. Therefore, the use of antibiotics should aim at the use of an antibiotic as selective as possible on the germ in question, for a period as short as possible.
Due to the fact that the invention is not limited to a particular class of antibiotic, it may thus be possible to modify the different families of antibiotics without reducing their effectiveness, on the contrary.
The invention will therefore provide a panel of active molecules resistant strains and may be used according to their specific activity.

DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will therefore be able to measure the major advantage of the present invention, which covalently fixes an aminoquinoline-type unit (Q) to a residue (A) representing an antibiotic residue, linked together by a covalent bond which can be direct or indirect by the use of a spacer arm represented by - (Yi) p (U) p'- (U2) p "-The invention relates essentially to new hybrid antibiotic molecules represented by the general formula (I) :

in which - Q represents a molecule of the aminoquinoline type; - A represents an antibiotic residue; interconnected by a covalent bond represented by - (Y1) p - (U) p '- (y2) p "-, a covalent bond which can be direct or indirect by the use of a spacer arm.
The antibiotic residue A is covalently bonded either directly to the aminoquinoline or to the spacer arm and may be connected in particular to Q, Y1, U, or Y2, especially as defined below, at any fixation site, especially by reaction with one of the reactive functions of the compounds A.
The present invention also relates to their manufacturing process, their various uses, pharmaceutical compositions containing them, and a method of therapeutic treatment. These new molecules can in particular be used as an antibacterial agent.
According to a first aspect, the present invention provides a hybrid aminoquinoline-antibiotic compound characterized in that it has the following general formula (I):

in which: Q represents an aminoquinoline of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (Illd) below:

in the above formulas: the sign indicates the site of attachment of the other fragment, for example either Y1, or U, or Y2, or A; n and n 'independently represent 0, 1, 2 or 3; - R1a and Rib (generally R1) represent one or more identical or different substituents, occupying any positions and representing a radical selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, sulfate, sulfonate, phosphate , phosphonate, nitro, cyano, aryl or heteroaryl as defined below or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonylamino, said alkyl groups preferably comprising 1 , 2, 3, 4, 5, or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl radicals , hydroxyimine, ether or thioether and may themselves bear 1 to 4 substituents, identical or different, c among halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, carbonyl, amine, nitro, urea, aryl or heteroaryl as defined below, - R2a and R2b (generally R2) being identical or different substituents, as the case may be. optionally form a ring structure together or with Y1, Y2, U or A and representing a hydrogen atom or an alkyl radical preferably C1, C2, C3, C4, C5, or C6, linear, branched or cyclic, containing the where appropriate, one or more amine, amide, thioamide, sulphonyl, urea, thiourea, carbamate, oxime, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether radicals and capable of carrying 1 to 4 substituents, identical or different, chosen from halogen; , hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl as defined below, - p, p ', p "are independently of each other 0 or 1, - Y 1 and Y 2, identical or di different from Q, U or A, and represent a linear, branched or cyclic, saturated or unsaturated C 1, C 2, C 3, C 4, C 5, or C 6 alkyl chain, containing optionally one or more amine, amide, thioamide, sulfonyl, sulfonamide, oxo, carboxy, thiocarboxy, carbonyl, thiocarbonyl, urea, thiourea, carbamate, oxime, ether or thioether, aryl or heteroaryl radical as defined below, the alkyl chain may also carry 1 to 4 substituents, identical or different, preferably selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, carbonyl, amine, nitro, oxime, aryl or heteroaryl as defined herein -after, or selected from alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfamoyl, alkylureido, alkylcarbamoyloxy, alkoxycarbonylamino, alkylcarbamoy groups; 1-dialkylcarbamoyl, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxyimine, said alkyl groups comprising from 1 to 6 linear, branched or cyclic carbon atoms which may themselves contain one or more amine, amide, thioamide, sulfonyl, sulfonamide, carboxy or thiocarboxy radicals; , carbonyl, thiocarbonyl, oxime, ether, thioether, aryl or heteroaryl as defined below, the chain in Cl, C2, C3, C4, C5, or C6 optionally forming a ring structure with R2 including N of the aminoquinoline part Q and / or the function U and Y1 and Y2 can be connected together or to Q, U or A by a single or multiple connection, - U, which can be linked by a single or multiple connection to Q, Y1 Y2 or A is a function amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, urea, thiourea, carbamate, ether, thioether, thiocarbonyl, sulfonate, oxime, oxyamine, alkoxyimine (C = N-OR) or alkoxyiminocarbonyl (C (O) - C = N-OR) with R representing a hydrogen atom or a linear, branched or cyclic C 1, C 2, C 3, C 4, C 5 or C 6 alkyl radical, optionally containing one or more amine or amide radicals; , thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether, A represents an antibiotic residue.
It is understood that the aryl or heteroaryl radical is preferably a 5- to 6-membered aromatic ring comprising 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur and oxygen and that the aryl or heteroaryl radicals may they themselves carry one or more substituents selected from the group halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, oxo, nitro or cyano.
Heterocycle is preferably a 5- to 6-membered saturated or unsaturated ring comprising 1, 2, 3, or 4 heteroatoms chosen from nitrogen, sulfur and oxygen, which can itself carry one or more substituents chosen from halogen, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, oxo, nitro or cyano.
In the definition of the compounds of formula (I) above and in what follows, halogen is understood to mean a fluorine, chlorine, bromine or iodine atom.
In the definition of the compounds of formula (I) above and in what follows, the term antibiotic residue, consisting of the part A of the hybrid molecules, a chemical entity derived from an antibiotic, an antibiotic modification or an antibiotic precursor.
Some compounds are accidentally described in the prior art, therefore the invention does not cover:
1) When A is 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 1-cyclopropyl-6,8-difluoro-4-oxo-1,4-acid dihydro-quinoline-3-

Q is different from 7-chloro-4-aminoquinoline; either the compounds of formula:

2) When A is (4S, 5R, 6S) -6 - [(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene 2-carboxylic acid and when the link - (Y1) p- (U) p- (Y2) p- between A and Q is 3-thioazetidine, then the quinoline part of the substituent Q can not be attached to the link by the position 2, for example the compound of formula:

3) When A is a 5-lactam of formula 3-chloro-azetidin-2-one substituted in

a direct covalent bond between the N1 nitrogen of A and the extracyclic nitrogen of a 2 aminoquinoline, then Q is different from 2-amino-4-methylquinoline, for example the compounds of formula:

4) When A is a cephalosporin, and when the link - (Y1) P- (U) p- (Y2) P'- is located in position 3 of the cephalosporin and this link contains an amide function, then Q is different a 6,7-dihydroxy-4-dimethylaminoquinolin-3-yl, for example the compound of formula:

amide function, and when Q is a 4-aminoquinoline bonded by the 3-position, then the amine function of 4-aminoquinoline can not be free, for example the compounds of formula:

6) When A is a penicillin or a cephalosporin substituted at position 3

amide, thioamide, urea or thiourea, then Q is different from a 3-aminoquinoline or a 6-aminoquinoline, for example the compounds of the following formula:

amide function, then Q is different from 4-hydroxy-6-acetylamino-quinolin-3-yl, for example the compound of formula:

8) When A is (6R, 7R) -7- [2- (2-amino-thiazol-4-yl) -2 (Z) -methoxyiminoacetylamino] -8-oxo-5-thia-1-aza acid -bicyclo [4.2.0] oct-2-ene carboxylic acid, and that the link -

either the compound of formula:

9) When A is (5S) -4- {5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl} -2-

N of the aminoquinoline then Q is different from the quinolin-4-yl, the compound of formula:

a methylene bond, then Q is different from the following quinolines: 2-morpholino-4-methyl-quinolin-7-yl, 4-methyl-8-aminoquinolin-6-yl, 4-methyl-5-aminoquinolin-6Yl, 2-dimethylamino 4-methyl-quinolin-6-yl, 2-dimethylamino-4,8-dimethylquinolin-6-yl, 2-morpholino-4,8-dimethyl-quinolin-6-yl, 2-methyl-4-dimethylamino-8-methoxy- quinolin-6-yl, for example the compounds of formula:

11) When A is 2-methyl-5-nitro-imidazol-1-yl, directly attached to the extracyclic nitrogen atom of aminoquinoline Q (p = p '= p "= 0) then Q is different the following quinolines: 7-chloro-quinolin-4-ylamino, 2-methyl-8-hydroxy-quinolin-4-

hydroxy-quinolin-4-ylamino, ie the compounds of formula:

12) When A is 2-methyl-5-nitro-imidazol-1-yl, and the link - (Y1) p- (U) p (Y2) p'- is a 2-ethyl- (1- cyclohexan-4-yl) -amine then Q is different from 7-chloroquinolin-4-ylamino, ie the compound of formula:

According to preferred compounds of the invention, the Q part of the hybrid molecules of formula (I) represents either an aminoquinoline of formula (IIa) or (IIb) in which the antibiotic residue is attached to the amine function, or an aminoquinoline of formula (IIIa), (IIIb), (IIIc) or (Illd) where the antibiotic residue is directly attached to the quinoline ring.
According to one embodiment, the hybrid molecules containing an aminoquinoline of formula (IIa) or (IIb) have been prepared from halogenoquinolines and amino derivatives also containing a reactive function to fix the antibiotic residue or from the reactive function. amine of an aminoquinoline.
According to another embodiment, quinoline precursors of the hybrid molecules containing an aminoquinoline of type (IIIa), (IIIb), (IIIc) or (Illd) are aminoquinolines also having a reactive function such as halogen, haloalkyl, hydroxy, amine, hydroxyalkyl, aminoalkyl, sulfonamide or carboxy.
According to the invention which relates to the compounds of formula (I), A represents an antibiotic residue. This residue may advantageously be chosen from the large families of antibiotics known to those skilled in the art such as, for example, β-lactams, quinolones, oxazolidinones, fosfomycin derivatives, nitroimidazoles, nitrofurans, sulphonamides streptogramins or synergistins, lincosamides, tetracyclines, phenicolates, fusidic acid derivatives, diaminopyrimidines, aminoglycosides, macrolides, polypeptides, glycopeptides, rifamycins, or lipodepsipeptides. following compounds of formula (I) covered by the invention, some examples of formulas of the antibiotic residue A are given by way of non-limiting examples.
Hybrid aminoquinoline-β-lactam molecules According to an advantageous embodiment of the compounds of formula (I) according to the invention, A may be chosen from the family of β-lactams containing, inter alia: penams (or penicillins) of formula (IV), oxapenames of formula (V), penems of formula (VI), carbapenemics of formula (VII), cephems (or cephalosporins) of formula (Villa), (VIIIb), (IXa) or (IXb), cephamycins of formula (City) or (VIIId), oxacephemers of formula (Xa) or (Xb), carbachephems of formula (XIa) or (XIb) and monobactams of formula (XII) below:

in which - R 1 is as defined above, - R3a and R3b (generally R3) represent identical or different substituents, selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, aldehyde, amine, sulfate , sulfonate, phosphate, phosphonate, nitro, cyano, aryl or heteroaryl as defined above or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfamoyl, alkylureido, alkylcarbamoyloxy, alkoxycarbonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy , alkoxycarbonyl, alkoxyimine, said alkyl groups preferably comprising 1, 2,3, 4, 5, or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide or thioamide radicals; , sulfonyl, sulfonamide, oxo, carboxy, thiocarboxy, carbonyl, thiocarbonyl, urea, thiourea, carbamate, oxim e, ether or thioether and may themselves carry 1 to 4 substituents, identical or different, selected from halogen, hydroxy, trifluoromethyl, methyl, trifluoromethoxy, methoxy, carboxy, carbonyl, amine, nitro, urea, aryl or heteroaryl or heterocycle such as defined above, R4a and R4b (in a general manner R4) which are identical or different, which may optionally form a cyclic structure together or a multiple bond, represent a hydrogen atom or a linear or branched C1 to C6 alkyl radical; or cyclic, saturated or unsaturated, containing optionally one or more radicals amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, oxime, urea, carbamate, ether or thioether and may carry 1 to 4 substituents, identical or different, selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl as defined pre R5 is a hydrogen atom or an alkyl radical, preferably C 1, C 2, C 3, C 4, C 5, or C 6, linear or branched or cyclic, saturated or unsaturated, - V represents a methoxy group or a hydrogen atom. hydrogen, - HetAr represents a heteroaryl as defined above.
The (3-lactams of formulas (IV), (V), (VIb), (Villa), (City), (Xa), (XIa) and (XII) may for example be coupled to a quinoline unit by using their amine function.
The coupling reaction with carbapenems of formula (VIIb) a can be carried out for example from a carbonyl or hydroxy group.
A reactive functional group of the hydroxy, halogen, or alkene type can be advantageously used for the attachment of cephalosporins, cephamycins, oxacephems and carbachephems of the respective formulas (VIIIb), (VIIId), (IXa), (IXb), (Xb) and ( XIb).
In another family of compounds according to the invention, A represents a quinolone unit such as those described by the following formula (XIIIa) or (XIIIb),

in which - R3 and R4 are as defined above, - R6 and R7 are identical or different substituents, which may optionally form a cyclic structure together and representing a hydrogen atom or a substituent selected from the group consisting of halogen, hydroxy, heterocycle, aryl or heteroaryl as defined above, or an alkyl, alkoxy or alkylamino radical, said alkyl groups comprising 1, 2, 3, 4, 5 or 6 carbon atoms, linear, branched or cyclic saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether radicals and capable of carrying 1 to 4 identical or different substituents chosen from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, nitro, aryl, or heteroaryl as defined above, - Z is a nitrogen or carbon atom.
An amine or halogen type reactive function of the quinolones known to those skilled in the art may advantageously be used for the coupling reaction with a quinoline derivative.
Aminoquinoline-Oxazolidinone Hybrid Molecules In another embodiment of the compounds according to the invention, A represents an oxazolidinone residue such as those described by the following formulas (XIVa), (XIVb) or (XIVc),

in which R3, R6 and R7 are as defined above.
Such hybrid molecules can be advantageously prepared either by using an amine, hydroxy, or halogen reactive function of an oxazolidinone or by synthesis of the oxazolidinone ring from an aminoquinoline having a protected amine function and (R) -glycidyl butyrate according to the methods known to those skilled in the art.
Aminoquinoline-Fosfomycin Hybrid Molecules In another embodiment of the compounds according to the invention, A represents a derivative of fosfomycin such as that described by the following formula (XV),

wherein R4a and R4b, identical or different, may optionally form a ring structure together are as defined above.
The synthesis of hybrid molecules derived from fosfomycin may for example be carried out by epoxidation of an alkene precursor before or after binding to the aminoquinoline.
Hybrid aminoquinoline-nitroimidazole or aminoquinoline-nitrofuran molecules In another family of compounds according to the invention, A represents a nitroimidazole residue such as those described by formulas (XVIa) or (XVIb) or a nitrofuran residue such as that described by formula (XVII ) following,

in which R3 is as defined above.
A reactive functional group of the hydroxy, epoxy, amine or halogen type can for example be used in the coupling reaction of the nitroimidazole or nitrofuran derivatives of formula (XVI) or (XVII) with a quinoline unit.
Hybrid aminoquinoline sulfonamide molecules In another embodiment of the compounds according to the invention, A represents a sulphonamide residue such as that described by the following formula (XVIII),

This residue may, for example, be attached to a quinoline unit from a sulphonamide or sulphonic acid reactive functional group.
Hybrid aminoquinoline-streptogramin or synergistin molecules In another family of compounds according to the invention, A represents a streptogramin or synergistin residue such as those described by the following formulas (XIXa), (XIXb) or (XX),

wherein R3, R4a, R4b, Rs and m are as defined above.
The synthesis of hybrid molecules incorporating a streptogramin or synergistin derivative can be carried out, for example, from precursors of the pristinamycin or virginiamycin type.
Hybrid aminoquinoline-lincosamide molecules In another embodiment of the compounds according to the invention, A represents a lincosamide residue such as that described by the following formula (XXI),

The lincosamides have a hydroxy function or a halogen atom which for example can be used to graft them on an aminoquinoline.
Aminoquinoline-tetracycline Hybrid Molecules In another embodiment of the compounds according to the invention, A represents a tetracycline residue such as those described by the following formulas (XXIIa), (XXIIb) and (XXIIc),

in which - R3, R4 and R6 are as defined above, - R8 and R9a, R9b identical or different, represent a hydrogen atom or a radical selected from the group hydroxy or methyl.
The coupling reaction with the tetracyclines of formula (XXIIa), (XXIIb) or (XXIIc) can be carried out for example from their amide function or by modification of an aromatic CH group.
Aminoquinoline-Chloramphenicol Hybrid Molecules In another family of compounds according to the invention, A represents a chloramphenicol derivative such as those described by the following formulas (XXIIIa) or (XXIIIb),

in which - R3 is as defined above, - W represents a radical NO2 or SO2R5, Rs being as defined above.
A reactive function of the hydroxy or halogen type may for example be used for fixing the chloramphenicol derivatives according to the modes (XXIIIa) and (XXIIIb).
Aminoquinoline-Fusidic Acid Hybrid Molecules In another embodiment of the compounds according to the invention, A represents a fusidic acid derivative such as those described by the following formulas (XXIVa), (XXIVb) or (XXIVc),

The fusidic acid derivatives of formula (XXIV) as defined above may be grafted to an aminoquinoline for example from a hydroxy function.
Aminoquinoline-diaminopyrimidine hybrid molecules In another family of compounds according to the invention, A represents a diaminopyrimidine residue such as those described by the following formula (XXV),

in which Rs is as defined above.
Hybrid molecules incorporating a diaminopyrimidine residue may be prepared in particular by using a reactive functional group of hydroxy or halogen type of a known diaminopyrimidine or by cyclization with guanidine of an acrylonitrile precursor.
In another family of compounds according to the invention, A represents an aminoglycoside residue formed by the union of a genin unit of the aminocyclitol group with one or more monosaccharides, at least one of which is an aminosocercin and linked between they by glycosidic bridges. There are many aminoglycosides with various chemical structures that can be coupled to an aminoquinoline using one of their reactive functions of amino or hydroxy type.
In another embodiment of the compounds according to the invention, A represents a macrolide residue: at 14 atoms such as those described by the formulas (XXVIa),

to 15 atoms such as those described in formulas (XXVIIa), (XXVIIb), (XXVIIc) and (XXVIId) below,

- or to 16 atoms such as those described by formulas (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId) and (XXVIIIe) following,

in which - R3, R4, R6, and R7 are as defined above, - R10 is an oxygen atom linked by a carbonyl-type double bond to the macrocycle or a hydroxyl group or a glycosidic bridge-linked glycosidic derivative macrocycle and may carry 1 to 6 substituents, identical or different, selected from hydroxy, alkyl, alkylamino, dialkylamino or alkoxy, said alkyl groups comprising 1, 2, 3, 4, 5 or 6 linear or branched carbon atoms, saturated or unsaturated and may carry a carboxy substituent.
Advantageously, the reactive functions of the hydroxy, amino or carbonyl macrolides can be used for the coupling reaction with the aminoquinolines.
Hybrid aminoquinoline-polypeptide molecules In another family of compounds according to the invention, A represents a polypeptide residue such as derivatives of polymyxins or bacitracin linking various peptide structures. These residues have been grafted to an aminoquinoline, in particular by one of their free amino functions.
Hybrid aminoquinoline-glycopeptide molecules In another embodiment of the compounds according to the invention, A represents a glycopeptide residue such as: the vancomycin derivatives described by formulas (XXIXa), (XXIXb), (XXIXc), (XXIXd) ), (XXIXe) and (XXIXf) following,

or derivatives of teicoplanin described by the following formulas (XXXa) or (XXXb),

wherein R3, R4, and R6 are as defined above.
The derivatives of vancomycin and teicoplanin may for example be attached to a quinoline unit from one of their reactive functions of amino, carboxy, amide or hydroxy type or by modification of an aromatic CH group.
In another family of compounds according to the invention, A represents a rifamycin residue such as those described by the following formulas (XXXIa) and (XXXIb),

in which R6 occupies any position and can form a ring structure with Y1, Y2 or U is as defined above.
The preparation of an aminoquinoline-rifamycin hybrid molecule can be carried out, for example, from a reactive function of rifamycin of the amino, halogen, hydroxy or aldehyde type.
Hybrid aminoquinoline-lipodepsipeptide molecules In another embodiment of the compounds according to the invention, A represents a lipodepsipeptide residue such as the daptomycin derivatives described by the following formula (XXXII),

The lipodepsipeptides can be grafted on a quinoline for example from one of their reactive functions of amino, hydroxy or carboxy type.
Formulas (IV) to (XXXII) give examples of binding sites of an aminoquinoline on a residue A but other binding sites have been envisaged on the compounds A. It is understood that the invention is directed to hybrid molecules aminoquinoline A connected by any site of attachment.
The invention also relates to any hybrid molecule of formula (I) covalently linking an aminoquinoline to an antibiotic residue A other than those described by formulas (IV) to (XXXII).
When the bond - (Y 1) P - (U) p '- (Y 2) p - contains one or more asymmetric centers, the invention relates to mixtures in all proportions of stereoisomers as well as pure stereoisomers.
The compounds of the invention may be in the form of acid addition salts, base addition salts or zwitterions as well as prodrugs or prodrug salts. The invention also relates to these different forms and their mixtures.
Advantageously, the compounds of formula (I) are those having the group Q representing a group of formula (IIa) or (IIIa) defined above.
Advantageously, the compounds of formula (I) are those having the group Q representing a group of formula (IIb) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (IV) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (Villa), (IXa) or (IXb) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XIIIa) or (XIIIb) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XIVa) or (XIVb) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XVIa) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XIXb) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XXV) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XXVIb), (XXVIc) or (XXVId) defined above.
Advantageously, the compounds of formula (I) are those having the group A representing a group of formula (XXIXa) defined above.
According to another preferred mode of preparation, the aminoquinolines are of the 4-aminoquinoline, 2-aminoquinoline or 8-aminoquinoline type. Their synthesis can be made from commercially available synthons, which provides a very interesting advantage of these compounds in addition to their activity.
In the hybrid molecules of formula (I) according to the invention, the aminoquinolines of formula (IIa) and (IIIa) in which the amino group is in position 4 with respect to the endocyclic nitrogen atom are more particularly preferred ( it is then 4-aminoquinolines) or in position 2 with respect to the endocyclic nitrogen atom (it is then 2-aminoquinolines) or the aminoquinolines of formula (IIb) in which the amino group is at position 8 (8-aminoquinolines).
These 4-aminoquinolines, 2-aminoquinolines and 8-aminoquinolines have the following formulas (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIIId) and (XXXIIIe),

wherein R1a, R1b (generally R1), R2, n and n 'are as defined above. According to a preferred arrangement of the invention, R 1 advantageously represents a single substituent, this substituent being a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro group occupying any position. . According to another preferred arrangement, in the formulas (XXXIIIa), (XXXIIIb) and (XXXIIIe) R2 is advantageously a hydrogen atom or a methyl group or forms a ring structure with Y1 including N of aminoquinoline (such as Piperidine or piperazine). In formulas (XXXIIIb) and (XXXIIId), R2a and R2b are advantageously identical or different substituents which can form a ring structure together, these substituents preferably being a hydrogen atom or a group methyl, cyclopropyl or 2- (diethylamino) ethyl, or a heterocycle when R2a and R2b form a ring structure together (such as aziridin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, or 4-methylpiperazin-1-yl).
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) P "- representing a group in which p = p '= p" = 0, the link between Q and A being direct.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) P - (U) p '- (y 2) p "- representing a group in which p' = 1 and p = p" = 0, U being as defined above and advantageously representing a carbonyl group.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) p "- representing a group in which p' = 1 and p = p" = 0, U being as defined above and advantageously representing a thioether group.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) p''- representing a group in which p' = 1 and p = p "= 0, U being as defined above and advantageously representing an alkoxyiminocarbonyl group (preferably hydroxyiminocarbonyl or methoxyiminocarbonyl).
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) p "- representing a group in which p = 1 and p' = p" = 0, Y 1 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain capable of forming a ring structure with A or R 2 including N of aminoquinoline.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) P "- representing a group in which p = 1 and p '= p" = 0, Y 1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain substituted by fluorine atoms.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (y 2) p - representing a group in which p = 1 and p '= p "= 0, Y 1 being as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain containing an amine or ether radical.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) P "- representing a group in which p = p '= 1 and p" = 0, U being as defined above and advantageously representing a carbonyl group and Y1 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which can form a ring structure with R 2 including N aminoquinoline.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (y 2) p "- representing a group in which p = p '= 1 and p" = 0, U being as defined above and advantageously representing an amine group and Y 1 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain, which may contain an amine, ether or amide radical; or urea and may form a ring structure with U and / or R2 including N of aminoquinoline.
Advantageously, the compounds of formula (I) are those having the

p "= 0, U being as defined above and advantageously representing a thioether function and Y1 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain, which may be substituted by fluorine atoms.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) P '' - representing a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing an ether function and Y 1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain.
Advantageously, the compounds of formula (I) are those having the groups - (Yl) p - (U) p '- (Y 2) p "- representing a group in which p = p' = 1 and p" = 0, U being as defined above and advantageously representing a carbamate function and Y1 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain, which is saturated or unsaturated and may contain an ether radical and / or aryl.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) P "- representing a group in which p '= p" = 1 and p = 0, U being as defined above and advantageously representing an amide function and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an amine or thioether radical.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) p "- representing a group in which p = p' = p" = 1, U being such as defined above and advantageously representing an amine function and Y 1 and Y 2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain, which may be substituted with fluorine atoms or a hydroxy group and capable of forming a ring structure with U and / or R2 including N of aminoquinoline.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) P "- representing a group in which p = p' = p" = 1, U being such as defined above and advantageously representing an ether function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an aryl radical.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) P - (U) p '- (y 2) p''- representing a group in which p = p' = p "= 1, U being as defined above and advantageously representing a thioether function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (Y 2) p "- representing a group in which p = p' = p" = 1, U being such as defined above and advantageously representing an amide function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may be substituted by fluorine atoms.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p '- (y 2) p "- representing a group in which p = p' = p" = 1, U being such as defined above and advantageously representing a carbamate function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may be substituted by fluorine atoms.
Advantageously, the compounds of formula (I) are those having the groups - (Y 1) p - (U) p - (Y 2) p "- representing a group in which p = p '= p" = 1, U being such as defined above and advantageously representing a urea function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may be substituted by fluorine atoms.
Advantageously, according to the invention, A represents a cephalosporin, a penicillin, a quinolone, a nitroimidazole, a streptogramin, a diaminopyrimidine, a macrolide, a glycopeptide or an oxazolidinone.
Preferred aminoquinolines Q are covalently linked to an antibiotic residue A to form hybrid molecules, including the following hybrid molecules.
The invention particularly relates to hybrid molecules comprising a 4-aminoquinoline of formula (XXXIIIa) or an 8-aminoquinoline of formula (XXXIIIe) and a residue A of the family of penicillins of formula (IV). Such molecules respond to

Y 2, U, p, p ', p ", m, n and n' are as defined above.

Similarly, other preferred hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or (XXXIIIb), or an 8-aminoquinoline of formula (XXXIIIe) and a residue A of the cephalosporin family of formula (Villa). These hybrid molecules of great interest correspond to the structure (XXXVa), (XXXVb) or (XXXVc) in which R1, R2, R3, R4, Y1, Y2, U, p, p ', p ", m, n and n are as defined above.

Other types of preferred hybrid molecules of the family of aminoquinoline-cephalosporin hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or (XXXIIIb) and of cephalosporins of formula (IXa) or (IXb). These hybrid molecules correspond to the structure (XXXVd), (XXXVe), (XXXVf), (XXXVg) or (XXXVh) in which R1, R2, R3, R4, Y1, Y2, U, p, p ', p ", m, n and n 'are as defined above.

According to a preferred arrangement, in the aminoquinoline-penicillin or aminoquinoline-cephalosporin hybrid molecules of formulas (XXXIVa), (XXXIVb), (XXXIVc), (XXXVa), (XXXVb), (XXXVc), (XXXVd), (XXXVe ), (XXXVf), (XXXVg) or (XXXVh), R 1 and R 2 are advantageously the preferred aminoquinoline substituents (XXXIIIa), (XXXIIIb) and (XXXIIIe) defined above and R4 is a hydrogen atom or an easily hydrolysable group in vivo in the context of prodrug molecules (such as 2,2-dimethyl-propionyloxymethyl).
In the aminoquinoline-penicillin hybrid molecules of formulas (XXXIVa) or (XXXIVb), according to a preferred arrangement, R3a and R3b advantageously represent two identical substituents of alkyl type (such as two methyl substituents).
In the aminoquinoline-cephalosporin hybrid molecules of formulas (XXXVa), (XXXVb), (XXXVc), (XXXVd) or (XXXVe), R3 is advantageously a halogen or a C1, C2, C3, C4, C5 alkyl chain. or saturated or unsaturated C6 optionally containing a carboxy or ether radical (such as a methyl, vinyl, acetoxymethyl or methoxymethyl group) and which may carry a heteroaryl substituent or

hydroxy-2-methyl-5-oxo-2,5-dihydro- [1,2,4] triazin-3-ylsulfanylmethyl).
In the aminoquinoline-cephalosporin hybrid molecules of formulas (XXXVf), (XXXVg) or (XXXVh), R preferably represents a hydrogen atom or a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl radical (from preferably methyl) and Ar, as defined above, advantageously represents a heteroaryl of 2-aminothiazol-4-yl, 2-amino-5-chloro-thiazol-4-yl or 5-amino- [1,2,4] - type. thiadiazol-3-yl.
In the aminoquinoline-penicillin or aminoquinoline-cephalosporin hybrid molecules of formulas (XXXIVa), (XXXIVb), (XXXIVc), (XXXVa), (XXXVb), (XXXVc), (XXXVd), (XXXVe), (XXXVf) (XXXVg) or (XXXVh) it is preferred, as a group (Y1) p- (U) p- (Y2) p, a group in which p, p 'and p "are independently of one another 0 or 1, U being as defined above and advantageously representing a carbonyl, amide, thioether or alkoxyiminocarbonyl function and Y1 and Y2 being as defined above and advantageously representing a C1, C2, C3, C4 and C5 alkyl chain, or linear or branched, cyclic or acyclic C6, which may optionally contain an amine or thioether radical and may be substituted by fluorine atoms.
Particularly preferred are: compounds of formula (XXXIVa), (XXXIVb), (XXXIVc), (XXXVa), (XXXVb), (XXXVc) according to the invention which comprise as a group (Y1) p- ( U) p '- (Y2) p "a carbonyl group (p' = 1, p = p" = 0), alkoxyiminocarbonyl (p '= 1, p = p "= 0) (preferably hydroxyiminocarbonyl or methoxyiminocarbonyl), or C 1, C 2, C 3, C 4, C 5, or C 6 alkylcarbonyl (p = p '= 1, p "= 0) (preferably acetyl, 3-propionyl, 2-propionyl, 2-methyl-2-propionyl, 4-butyryl, 3-methyl-3-butyryl or piperidine-4-carbonyl (including R2 and N of aminoquinoline)), - the compounds of formula (XXXVd) according to the invention which comprise as a group (Y1) p- (U) p- (Y 2) p "a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl group (p = 1, p '= p" = O) (preferably 2-ethyl, 3-propyl, 2-propyl, 2-methyl-2-propyl, 2,2-difluoro-3-propyl, or 4-piperidin-1-yl), the compounds of formula (XXXVe) according to the invention which comprise as a group ( Y1) p- (U) p- (Y2) p "a gro alkylcarbamoyl uptake (p = 0, p '= p "= 1) (preferably 2-ethylcarbamoyl, 3-propylcarbamoyl, 2-propylcarbamoyl, 1carbonylpiperidin-4-yl), the compounds of formula (XXXVf) according to the invention which comprise as a group (Y1) P- (U) P, - (Y2) p "an alkylamine group (p = p '= 1, p" = 0) (preferably methylamino, 2-ethylamino, 3-propylamino , 2-propylamino, 2,2-difluoro-3-propylamino, 4-piperidin-1-yl, 4-piperazin-1-yl or piperidin-4-ylamino (including R2 and N of aminoquinoline)), dialkylamine (p = p '= p "= 1) (preferably methylamino-2-ethyl, methylamino-3-propyl, methylamino-2-propyl, methylamino-2,2-difluoro-3-propyl, 4piperidin-1-ylmethyl, 4-methylpiperazin-1-yl or 4-methylaminopiperidin-1-yl (including R2 and N of aminoquinoline)), alkylsulfanyl (p = p '= 1, p "= 0) (preferably methylsulfanyl, 2-ethylsulfanyl , 3-propylsulfanyl, 2-propylsulfanyl, 2,2-difluoro-3-propylsulfanyl, or piperidin-4-ylsulfanyl (including R2 and N from am). inoquinoline)) or dialkylsulfanyl (p = p '= p "= 1) (preferably methylsulfanyl-2-ethyl, methylsulfanyl3-propyl, methylsulfanyl-2-propyl, methylsulfanyl-2,2-difluoro-3-propyl, 4-methylsulfanylpiperidin-1 -yl (including R2 and N of aminoquinoline)), - compounds of formula (XXXVg) according to the invention which comprise as

p "= 1, p = 0) (preferably methylsulfanyl), alkylaminoalkylcarbamoyl (p = 0, p '= p" 1) (preferably methylamino-2-ethylcarbamoyl, methylamino-3-propylcarbamoyl, methylamino-2-propylcarbamoyl, 4 methylpiperazine-1-carbonyl, 4-methylaminopiperidin-1-carbonyl, 1-methylpiperidin-4-ylcarbamoyl) or alkylsulfanylalkylcarbamoyl (p = 0, p '= p "= 1) (preferably methylsulfanyl-2ethylcarbamoyl, methylsulfanyl-3-propylcarbamoyl, methylsulfanyl 2-propylcarbamoyl, 4-methylsulfanylpiperidine-1-carbonyl), the compounds of formula (XXXVh), according to the invention, which comprise, as a group (Y1) P- (U) P (Y2) P "a C1-C6 alkyl group; , C2, C3, C4, C5, or C6 (p = 1, p '= p "= 0) (preferably methyl).
Another type of preferred compounds is characterized in that it relates to the aminoquinoline-quinolone hybrid molecules corresponding to the formula (XXXVIa) or (XXXVIb) in which R1, R2, R3, R4, R6, R7, Y1, Y2, U, Z, p, p ', p ", n and n' are as defined above.

In the aminoquinoline-quinolone hybrid molecules of the formulas (XXXVIa) and (XXXVIb), in a preferred embodiment, Z is a carbon atom, and R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines of formula (XXXIIIa) defined above, R 3 is a hydrogen or fluorine atom and R4 is a hydrogen atom.
In the aminoquinoline-quinolone hybrid molecules of formulas (XXXVIa), in a preferred embodiment, R6 is a linear, branched or cyclic C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain (preferably a radical ethyl or cyclopropyl) or forms a ring structure with R7 and R7 is a hydrogen or halogen atom, a methoxy group or forms a cyclic structure with R6 such as a 3-methyl-3,4-

a group in which p = p '= p "= 0 is preferred as the group (Y1) p- (U) p' - (Y2) p", where Q is directly linked to A, or a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing an amine function and Y 1 being as defined above and advantageously representing a C 1, C 2, C 3 and C 4 alkyl chain; C5, or C6 may form a ring structure with U or R2 (including N of aminoquinoline) and optionally containing an amine radical.The compounds of formula (XXXVIa) according to the invention are particularly preferred, especially those whose link (Y 1) P- (U) p- (Y 2) p "is absent or which include a 2-ethylamino, 4-ethylpiperazin-1-yl or 4-piperazin-1-yl group (including R 2 and N) aminoquinoline) as a group (Y1) p- (U) P- (y2) p "In the aminoquinoline-quinolone hybrid molecules of formulas (XXXVIb), - in a preferred arrangement, R6 is a heterocycle preferably containing 1 or 2 heteroatoms (such as piperazin-1-yl, N-methylpiperazin-1-yl, 3-methylpiperazin-1-yl or 3-amino-pyrrolidin-1-yl), it is preferred, as a group (Y 1) p - (U) P- (Y2) p '"a group in which p = p' = p" = 0, Q being directly bonded to A and the exocyclic nitrogen atom of aminoquinoline corresponding to the atom d endocyclic nitrogen of quinolone, or a group in which p = 1 and p '= p "= 0, Y1 being as defined above and preferably representing a C1, C2, C3, C4, C5 alkyl chain, or C6 which can form a cyclic structure with R2. In particular, the compounds of formula (XXXVIb) according to the invention are particularly preferred, in particular those whose (Y1) p- (U) p- (Y 2) P "bond is absent or which include a 2-ethyl, or 4-piperidin-1-yl group (including R2 and N of aminoquinoline) as

Aminoquinoline-Nitroimidazole Hybrid Molecules In the aminoquinoline-nitroimidazole hybrid molecules, the compounds of formula (XXXVII) in which R1, R2, R3, Y1, Y2, U, p, p ', p ", n and n' are more particularly preferred. are as defined above.

According to a preferred arrangement, in the aminoquinolinenitroimidazole hybrid molecules of formula (XXXVII), R1 and R2 advantageously represent the preferred aminoquinoline substituents (XXXIIIa), R3 is a methyl group and as a group (y1) p- (U) p ' - (y2) p ", a group in which p = 1 and p '= p" = 0 is preferred, Yi being as defined above and advantageously representing a C1, C2, C3, C4, C5 alkyl chain, or C6 or a group in which p = p '= p "= 1, U being as defined above and advantageously representing an amine function, Y1 being as defined above and advantageously representing a C1, C2 alkyl chain , C3, C4, C5 or C6 being able to form a ring structure with R2 including N of aminoquinoline and Y2 being as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain. In particular, the compounds of the formula (XXXVII) are particularly preferred. the invention, especially those which comprise

propylamino) -propan-2-ol, 1- (2-propylamino) -propan-2-ol, or 1- (4-piperazin-1-yl) propan-2-ol as a group (Y1) p- ( U) p- (Y2) p '' Hybrid aminoquinoline-streptogramin molecules Another type of preferred compounds is characterized in that it relates to the aminoquinoline-streptogramin hybrid molecules corresponding to the formula (XXXVIII) in which R1, R2, R4a, R4b, R5, Y1, Y2, U, p, p ', p ", n and n' are as defined above.

In the aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII), in a preferred embodiment, R1 and R2 advantageously represent the preferred aminoquinoline substituents (XXXIIIa) defined above, R4 and Rs are C1, C2, C3 alkyl chains. C4, C5, or C6 (preferably R4 is methyl and R5 is ethyl); as a group (Y1) P- (U) P (Y2) p '', a group is preferred in which p = p '= p "= 1, U being as defined above and advantageously representing a thioether function and Y1 and Y2 being as defined above and preferably representing a C1, C2, C3, C4, C5 or C6 alkyl chain. In particular, the compounds of formula (XXXVIII) according to the invention which comprise a 1- (2-ethylamino) methylsulfanyl, 1- (2-propylamino) methylsulfanyl, 1- (3-propylamino) methylsulfanyl group, or

Aminoquinoline-diaminopyrimidine hybrid molecules In the aminoquinoline-diaminopyrimidine hybrid molecules, compounds of formula (XXXIX) in which R1, R2, R4, Rs, Y1, Y2, U, p, p ', p ", n are especially preferred. and n 'are as defined above.

According to a preferred arrangement, in the aminoquinoleinediaminopyrimidine hybrid molecules of formula (XXXIX), R1 and R2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa) defined above, R5 is a hydrogen atom and as a group (Y1) p- ( U) p- (Y2) p '', a group is preferred in which p = p '= p "= 1, U being as defined above and advantageously representing an ether function, Y1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 alkyl chain, or C 6 and Y 2 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain containing a radical aryl as defined above which can itself carry 1 to 4 identical or different substituents. In particular, the compounds of formula (XXXIX) according to the invention which comprise a 4- (2-ethoxy) -benzyl, 4- ( 2-ethoxy) -3-methoxy-benzyl, 4- (2-ethoxy) - 3,5-dimethoxy-benzyl or 3- (2-ethoxy) -4,5-dimethoxybenzyl as a group (y1) p- (U) p '- (y2) p Hybrid aminoquinoline-macrolide molecules Another type of compounds Preferred is characterized in that it relates to the aminoquinoline-macrolide hybrid molecules having the formula (XLa) (XLb) or (XLc) wherein R1, R2, R5, R6, R7, R10, Y1, Y2, U, p , p ', p ", n and n' are as defined above.

In the aminoquinoline-macrolide hybrid molecules of formula (XLa), (XLb) and (XLc), in a preferred embodiment, R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa), R 3 is a hydroxyl or methoxy group, R4 is a hydrogen atom, R6 and R7 are hydroxy groups, R10 is an oxygen atom linked by a carbonyl-type double bond to the macrocycle or a glycosidic bond linked to a glycosidic derivative at the macrocycle and capable of carrying 1 to 6 substituents (preferably an L-cladinose derivative).
In the aminoquinoline-macrolide hybrid molecules of formula (XLa), a group in which p = p '= 1 and p is preferred as the group (Y1) P- (U) P (Y2) P " = 0, U being as defined above and advantageously representing an oxyamine function linked by a double bond to A (thus forming an oxime function) and Yi being as defined above and advantageously representing a C1, C2 alkyl chain; C3, C4, C5, or C6 may contain an ether radical. Particularly preferred are the compounds of formula (XLa) according to the invention, which comprise an O 2 -ethyl-

oxime as a group (Y1) p- (U) p- (Y2) p '' In the aminoquinoline-macrolide hybrid molecules of formula (XLb), it is preferred, as a group (Y1) p- (U) p '- (Y2) p ", a group in which p = 1 and p' = p" = 0, Y1 being as defined above and advantageously representing a C1, C2, C3, C4, C5 alkyl chain; or C6 may contain an ether radical. Particularly preferred are the compounds of formula (XLb) according to the invention which comprise a 2-ethyl, 3-propyl, 2-propyl, 4-butyl or 2- (2-ethoxy) -ethyl group as a group (Yi ) p- (U) p (Y2) p.
In the aminoquinoline-macrolide hybrid molecules of formula (XLc), the group (Y1) p- (U) p- (Y2) p '' is preferably a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing an ether or carbamate function and Y 1 being as defined above and advantageously representing a saturated C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain; or unsaturated, which may contain an ether radical and / or an aryl radical.The compounds of formula (XLc) according to the invention which comprise a 2-ethoxy, 3-propoxy, 2-propoxy and 2-ethoxy-group are particularly preferred. 2-ethoxy, 3-allyloxy, 2-ethylcarbamoyloxy, 3-propylcarbamoyloxy, 4-butylcarbamoyloxy, 4- (2-ethoxy) -benzylcarbamoyloxy as (Y1) p- (U) p (Y2) p-.
Aminoquinoline-glycopeptide hybrid molecules In the aminoquinoline-glycopeptide hybrid molecules, compounds of formula (XLIa) or (XLIb) in which R1, R2, Y1, Y2, U, p, p ', p ", n and are as defined above.

In the aminoquinoline-glycopeptide hybrid molecules of formulas (XLIa) or (XLIb), according to a preferred arrangement, R1 and R2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa) and (XXXIIIb), R4 is a hydrogen atom and R3 is a hydroxy group.
In the aminoquinoline-glycopeptide hybrid molecules of formula (XLIa),

Y 1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may form a ring structure with the nitrogen atom of residue A and R 2 (including N of the aminoquinoline) and which may be substituted with fluorine atoms or a group in which p = p '= p "= 1, where U is as defined above and advantageously represents an ether or amine function, Yi being as defined above and preferably representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may form a ring structure with U and R 2 (including N of aminoquinoline) and Y 2 being as defined above and advantageously representing an alkyl chain C1, C2, C3, C4, C5, or C6 may contain an aryl radical as defined above which can itself bear 1 to 4 identical or different substituents.The compounds of formula (XLIa) according to the invention are particularly preferred. which comprise a 2-ethyl group, 3-propyl, 4-butyl, 2,2-difluoropropyl, 4-piperazin-1-yl, 4-piperazin-1-ylmethyl or 4- (2-ethoxy) -benzyl as a group (Y1) p- (U ) p (Y2) p ".
In the aminoquinoline-glycopeptide hybrid molecules of formula (XLIb), a group in which p = 1 and p '= p "= is preferred as the group (Y1) P- (U) P- (Y2) p". O, Y 1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain or a group in which p = 0 and p '= p "= 1, U being such that defined above and advantageously representing an amide function, Y2 being as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain. The compounds of formula (XLIb) are particularly preferred. according to the invention, which comprise a methyl, ethylcarbamoyl, propylcarbamoyl or butylcarbamoyl group as (Y1) p- (U) p '- (y2) p group. Hybrid aminoquinoline-oxazolidinone molecules Other types of preferred hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or a 2-aminoquinoline of formula (XXXIIIc) and an oxazolidinone of formula (XIVa or (XIVb) These aminoquinoline-oxazolidinone hybrid molecules have the formula (XLIIa) (XLIIb) or (XLIIc) wherein R1, R2, R6, R7, Y1, Y2, U, p, p ', p ", n and n 'are as defined above.

In the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa), (XLIIb), or (XLIIc), in a preferred embodiment, R 1 and R 2 are advantageously the preferred aminoquinoline substituents (XXXIIIa) and (XXXIIIc), R 6 is a hydrogen atom. hydrogen or fluorine, R7 is a 5- to 6-membered heterocycle comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (preferably morpholin-4-yl or piperazin-1-yl) and R3 is advantageously a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an amide radical (such as an acetylaminomethyl chain), carbamate (such as a methoxycarbonylaminomethyl chain) or ether and which may be substituted with a heterocycle ( such as a [1,2,3] -triazollylmethyl or isoxazol-3-ylmethyl chain.
In the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa), a group in which p = p '= p "= 1, is preferred as the group (Y1) p- (U) p- (Y2) p". being as defined above and advantageously representing an amide or carbamate function and Y1 and Y2 being as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain which can form a cyclic structure with U and / or R2 including N of aminoquinoline.The compounds of formula (XLIIa) according to the invention, which comprise a grouping, are particularly preferred.

methyl) -1- (methylcarbamoyl) ethyl, 3- (methylcarbamoyl) propyl, 2- (methylcarbamoyl) propyl, 2- (2-methyl) -2- (methylcarbamoyl) propyl, 4- (methylcarbamoyl) piperidine, 1Y or 2-ethylcarbamoyloxymethyl, 2- (1-methyl) ethylcarbamoyloxymethyl, 3propylcarbamoyloxymethyl, 2-propylcarbamoyloxymethyl, 4-piperazine-1carbonyloxymethyl as (Y1) p- (U) p '- (Y2) p ".
In the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIb), the group (Y1) p- (U) p- (Y2) p '' is preferably a group in which p = p '= p "= 1, U being as defined above and advantageously representing a carbamate function and Y1 and Y2 being as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain which can form a cyclic structure with U and / or R2 including N of aminoquinoline The compounds of formula (XLIIb) according to the invention, which comprise a 2-ethylcarbamoyloxymethyl, 2 (1-methyl) ethylcarbamoyloxymethyl, 3-propylcarbamoyloxymethyl, 2propylcarbamoyloxymethyl group, are particularly preferred. , 4-piperazine-1-carbonyloxymethyl as a group (Y1) p (U) p- (Y2) p-.
In the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIc), a group in which p = p '= p "= 0 is preferred as the group (Y1) p- (U) p- (Y2) p''. the link being direct between Q and A or a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing an amine function and Y 1 being as defined above and representing advantageously a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which can form a ring structure with U and / or R 2, including N of aminoquinoline and optionally containing an amine, amide, urea or carbamate radical. especially the compounds of formula (XLIIc) according to the invention, which comprise either a direct bond between Q and A or a 2-ethylamino, 2- (1-methyl) ethylamino, 3-propylamino, 2-propylamino, 3- (2-ethylamino) group. -methyl) -propylamino, 2,2-difluoro-3-propylamino, 4-piperazin-1-yl, 4-ethylpiperazin-1-yl, or 4- (2-acetyl) -piperazin-1-yl, 4- (3-propionyl) piperazin-1-yl 1- (2-propionyl) -piperazin-1-yl, 4- (2-methyl-3-propionyl) -piperazin-1-yl or 4- (2-ethylcarbamoyl) -piperazin-1-yl, 4- ( 3-propylcarbamoyl) -piperazin-1-yl, 4- (2-propylcarbamoyl) -piperazin-1-yl, 4- [3- (2-methyl) -

(2-Ethoxycarbonyl) -piperazin-1-yl, 4- (3-propoxycarbonyl) -piperazin-1-yl, 4- [2- (2-methyl) propoxycarbonyl) -piperazin-1-yl as a Group (Y1 ) p- (U) p '- (Y2) p ".
The invention also provides methods for synthesizing the molecules of formula (I) defined above.
These methods include the reaction of reactive derivatives or precursors of aminoquinolines Q and reactive derivatives or antibiotic residue precursors A,

defined in relation to formula (I).
Various synthetic routes will be easily accessible to those skilled in the art by operating according to conventional techniques.
Advantageously, the process for producing a compound Q - (Y 1) p - (U) p - (Y 2) P "- A, as defined above, comprises: a) the binding of the group (Y 1) p - (U) ) p '- (Y2) p "on an aminoquinoline Q, then the reaction of this intermediate compound with A, in particular an antibiotic residue; b) fixing the (Y1) p - (U) p '- (Y2) p "- group with A, in particular an antibiotic residue, and then attaching this intermediate to an aminoquinoline Q; an amino- (Y 1) p - (U) p '- (Y 2) P - group on a corresponding quinoline which makes it possible to obtain an intermediate compound Q - (Y 1) p - (U) p' - (y 2) p ", then fixing this intermediate compound on A, in particular on an antibiotic residue A.

It is advantageous to prepare hybrid molecules containing, as derivative Q, a 4-aminoquinoline of formula (XXXIIIa) and as residue A a penicillin of formula (IV) as follows:
a-1) a compound of formula (XLIII) can be reacted:

in which Ria, Rib, n and n 'are as defined above and hal represents a halogen atom, with a derivative of formula (XLIV):

where R2, Y1, p and p 'are as defined above and U represents a carboxy or carboxyalkyl group (preferably U = COOH) which leads to the production of a 4-aminoquinoline of formula (XLV):

in which R 1a, R 1b, R 2, Y 1, n, n ', p and p' are as defined above, b-1). The 4-aminoquinoline of formula (XLV) is then coupled in the presence of an activator of the function U, with an antibiotic precursor A of formula (XLVI), where appropriate in the form of an addition salt with an acid (such as ptoluene sulphonic acid) in which R3a, R3b, R4 , and m are as defined above,

which leads to hybrid molecules of formula (XXXIVa) in which p "= 0.
Step a-1) is advantageously carried out in molten phenol, at a temperature of 120 [deg.] C to 150 [deg] C. After returning to ambient temperature, the product is obtained after various washes and / or extractions and optionally recrystallization by dissolution in the carbonated water and precipitation by addition of hydrochloric acid.
Step b-1) is advantageously carried out in a solvent such as an amide (preferably dimethylformamide) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxy-benzotriazole system for example) at room temperature.
Similarly, it is advantageous for the preparation of the hybrid molecules containing as derivative Q an 8-aminoquinoline of formula (XXXIIIe) and as residue A a penicillin of formula (IV) to proceed as follows:
b-2) the coupling reaction is carried out between a reactive derivative of 8-aminoquinoline of formula (XLVII) wherein R1a, R1b, R2, Y1, n, n ', p and p' are as defined above and U represents a carboxy or carboxyalkyl group (preferably U = COOH):

and an antibiotic precursor A of formula (XLVI). This coupling reaction leads to hybrid molecules of formula (XXXIVc) in which p "= 0.
Step b-2) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP or the icyclohexylcarbodimid / hydoxybenzotriazole system, for example).
In another process, for preparing hybrid molecules containing, as residue A, a cephalosporin of formula (Villa) and as derivative Q, an aminoquinoline of formula (XXXIIIa):
b-3) the coupling of the aminoquinoline reactive derivative of formula (XLV), in the presence of an activator of the function U, with a cephalosporin of formula (XLVIII), where appropriate in the form of an addition salt with an acid (such as toluenesulfonic acid) in which R3 and R4 are as defined above and m = 0,

which leads to obtaining a mixture of isomers and cephems of formula (XLIX):

wherein R 1 R 1b, R 2, R 3, R 4, Y 1, U, n, n ', p and p' are as defined above, c-3) is then carried out an oxidation of the mixture of A / A isomers of formula (XLIX) which leads to oxidized cephalosporins of configuration only, of formula (L):

wherein R1a, R1b, R2, R3, R4, Y1, U, m, n, n ', p and p' are as defined above. This oxidation is followed, if appropriate, by acid hydrolysis of the COOR4 ester function for the synthesis of hybrid molecules of formula (XXXVa) in which R4 = H and m = 1. These latter can then be obtained in salt form by reaction. with a pharmacologically acceptable acid, d-3) the compounds of formula (L) are reduced to obtain the aminoquinoline-cephalosporin hybrid molecules of formula (XXXVa) in which R1a, R1b, R2, R3, R4, Y1, U, n, n ', p - and p' are as defined above and p "= m = 0. In the case where R4 is a protective group, the deprotection can be carried out by acid hydrolysis. This step is followed, if necessary, by protonation with a pharmacologically acceptable acid, to obtain the product in salt form.
Step b-3) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxybenzotriazole system for example).
Step c-3) is advantageously carried out in a halogenated solvent (dichloromethane for example) at 0 ° C. by slow addition of a solution of the oxidizing agent (for example 3-chloroperoxybenzoic acid).
Step d-3) is advantageously carried out at low temperature (-20 ° C.) in an amide solvent (dimethylformamide for example) under an inert atmosphere and in the presence of a reducing agent such as trichlorophosphine.
When a deprotection step is necessary, it is advantageously carried out in a halogenated solvent, under an inert atmosphere, in the presence of a compound used to trap the liberated carbocation (anisole, for example). The hydrolysis can be carried out by addition of an acid (such as trifluoroacetic acid) at 0 ° C. prolonged from stirring at room temperature.
In another process, for preparing hybrid molecules containing as residue A a cephalosporin of formula (Villa) and as derivative Q an aminoquinoline of formula (XXXIIIb):
a-4) halogen a hydroxyquinoline of formula (XLVIII) wherein R1a, R1b, n, n 'and p' are as defined above and U represents a carboxylic ester:

to obtain a halogenated quinoline of formula (XLIX):

in which hal represents a halogen atom, a'-4) the halogenated quinoline of formula (XLIX) is coupled wherein R1a, R1b, n, n 'and p' are as defined above and U represents a carboxylic ester with an amine of formula (L) where R2a, and R2b are as defined above:

which leads to obtaining an aminoquinoline of formula (LI):

a "-4) is saponified aminoquinoline of formula (LI) wherein R1a, Rlb, n, n 'and p' are as defined above and U represents a carboxylic ester to obtain the aminoquinoline of formula (LI where U is a carboxylic acid, b-4) the coupling of the aminoquinoline reactive derivative of formula (LI), in the presence of an activator of the function U, with a cephalosporin of formula (XLVIII), the case optionally in the form of an addition salt with an acid (such as p-toluenesulphonic acid) in which R 3 and R 4 are as defined above and m = 0, which leads to the production of a mixture of isomers of and Cephems of Formula (LII):

wherein R 1a, R 1, R 2, R 3, R 4, Y 1, U, n, n ', p and p' are as defined above, c-4), then the isomer / formula mixture is oxidized ( LII) which leads to oxidized cephalosporins of configuration only, of formula (II):

wherein Ria, Rib, Rz, R3, R4, Y1, U, m, n, n ', p and p' are as defined above, d-4) the compounds of formula (III) are reduced to obtain the aminoquinoline-cephalosporin hybrid molecules of formula (XXXVb) in which Ria, R1b, Rz, R3, R4, Yi, U, n, n ', p and p' are as defined above and p = p "= m In the case where R 4 is a protecting group, the deprotection can be carried out by acid hydrolysis This step is followed, if necessary, by protonation with a pharmacologically acceptable acid to obtain the product in salt form.
Step a-4) is advantageously carried out with a chlorinating agent (such as trichlorooxyphosphine) at reflux.
Step a'-4) is advantageously carried out under reflux in an excess of amine of formula (L).
Step a-4) is advantageously carried out in a mixture of alcoholic solvent (ethanol for example) and a mineral base in aqueous solution (such as an aqueous sodium hydroxide solution).
Step b-4) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP for example).
Step c-4) is advantageously carried out according to the conditions described for step c-3). Step d-4) is advantageously carried out according to the conditions described for step d-3). In another method, for preparing aminoquinoline cephalosporin hybrid molecules of formula (XXXVf) wherein U represents a thioether function:
a-5) a 4-aminoquinoline of formula (XLV) is coupled in which R1a, R1b, R2, Y1, n, n ', p and p' are as defined above and U represents a thiol group with a residual cephalosporin of formula (LIV) in which R4, Y2, m and p "are as defined above, hal represents a halogen atom and the protective group of the amine is for example a tert-butyloxycarbonyl group:

which leads to obtaining cephalosporins of formula (LV):

wherein Ria, Rib, Rz, R3, R4, Y1, Y2, U, m, n, n ', p, p' and p "are as defined above and U represents a thioether function, a'-5) deprotects the amine by an acid treatment which leads to obtaining cephalosporins of formula (LVI):

wherein R 1a, R 1b, R 2, R 3, R 4, Y 1, Y 2, U, m, n, n ', p, p' and p "are as defined above, at -5) the cephalosporin of formula ( LVI) with an activated 2-heteroaryl-2alkoxyiminoacetic acid of formula (LVII):

wherein R and heteroaryl HetAr are as defined above and the activating group of the acid is for example a sulfanylbenzothiazole group.
Step a-5) is advantageously carried out in an amide solvent (such as dimethylformamide) at room temperature, in the presence of a base (such as N, Ndiisopropylethylamine) and sodium iodide.
Step a'-5) is advantageously carried out in an acidic medium (a formic acid / hydrochloric acid mixture for example) at room temperature.
Step a -5) is advantageously carried out in a halogenated solvent (dichloromethane for example) between -10 [deg] C and 25 [deg] C in the presence of a base (such as triethylamine).
When a deprotection step is necessary, it is advantageously carried out in a halogenated solvent, under an inert atmosphere, in the presence of a compound used to trap the liberated carbocation (anisole, for example). The hydrolysis can be carried out by addition of an acid (such as trifluoroacetic acid) at 0 ° C. prolonged from stirring at room temperature.
Aminoquinoline-Quinolone Hybrid Molecules In another preferred method, for preparing aminoquinoline-quinolone hybrid molecules of formula (XXXVIa) in which p "= 0, U representing an amine function and Y1 being a C1, C2, C3, C4 alkyl chain , C5 or C6 containing an amino radical, the coupling of an aminoquinoline of formula (LIV) is carried out:

in which R1a, R1b, R2, n and n 'are as defined above and hal represents a halogen atom with a quinolone of formula (LIX):

wherein R3, R4, R6, R7, Z and p 'are as defined above. The coupling reaction is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (potassium carbonate for example) and at a temperature of 140 [deg] C.
In another process, for the preparation of the aminoquinoline-nitroimidazole hybrid molecules of formula (XXXVII) in which p '= p "= 0, it is advantageous to couple an aminoquinoline of formula (LX):

wherein R 1a, R 1b, R 2, Y 1, n, n 'and p are as defined above and hal represents a halogen atom, with 2-methyl-5-nitroimidazole.
The coupling reaction is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (potassium carbonate or triethylamine for example) and at a temperature of between 70 and 140 ° C.
Similarly, for the preparation of the aminoquinolinenitroimidazole hybrid molecules of formula (XXXVII) in which p = p '= p "= 1, Y2 being a C1, C2, C3, C4, C5 or C6 alkyl chain carrying a hydroxy and a U substituent representing an amine function, it is advantageous to carry out a coupling reaction between an aminoquinoline of formula (XLV) in which R 1a, R 1b, R 2, Y 1, n, n ', p and p' are as defined above and U represents an amine function, with a nitroimidazole residue of formula (LXI):

wherein R3 and p "are as defined above and Y2 contains a cyclic ether function.
This coupling reaction is advantageously carried out in an alcoholic solvent (such as ethanol) in the presence of a base (triethylamine for example) and at the reflux temperature of the alcoholic solvent.
Hybrid aminoquinoline-streptogramin molecules In another process, for the preparation of the aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII) in which p = p '= p "= 1, U representing a thioether function and Y2 being a methylene, it is advantageous to coupling an aminoquinoline of formula (XLV) wherein Ria, Rib, R2, Y1, n, n ', p and p' are as defined above and U represents a thiol function, with a streptogramin residue of formula (LXII ):

wherein R4a, R4b and Rs are as defined above.
This coupling reaction is advantageously carried out in an organic solvent (such as acetone) and at low temperature (-20 ° C. for example).
Hybrid Aminoquinoline-Diaminopyrimidine Molecules It is advantageous to prepare hybrid molecules containing, as derivative Q, a 4-aminoquinoline of formula (XXXIIIa) and as residue A a diaminopyrimidine of formula (XXV) in which R5 is as defined above in the manner described above. following: a) an aminoquinoline of formula (LX) is coupled in which R1a, R1b, R2, Y1, n, n 'and p are as defined above and hal represents a halogen atom, with a derivative of formula (LXIII) wherein Y2, p 'and p "are as defined above, Y2 containing an oxy function on a terminal carbon thus forming an aldehyde function and U representing an alcohol function:

which leads to the production of a 4-aminoquinoline of formula (LXIV):

in which R1a, Rib, R2, Y1, n, n ', p, p' and p "are as defined above and U represents an ether function, b) aminoquinoline of formula (LXIV) containing an aldehyde function can then be condensed on a nitrile derivative of formula (LXV) in which R5 is as defined previously:

which leads to obtaining an acrylonitrile intermediate of formula (LXVI) in which R1a, R1b, R2, Rs, Y1, n, n ', p, p' and p "are as defined above and U represents an ether function:

The acrylonitrile intermediate (LXVI) is obtained in the form of a mixture of Zet E isomers, c) the cyclization of the Zet E isomer mixture of the acrylonitrile intermediate (LXVI) with guanidine leads to the aminoquinoline-hybrid molecules. diaminopyrimidine of formula (XXXIX) in which p = p '= p "= 1 and U represents an ether function, step a) is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (carbonate of potassium) and at a temperature of 60.C.
Step b) is advantageously carried out in an organic solvent (dimethylsulfoxide for example) in the presence of a base (such as potassium tert-butoxide) added in small portions at low temperature (10 ° C. for example) followed by stirring at room temperature.
Step c) is advantageously carried out in 2 steps: the guanidine is placed in the presence of a base (such as potassium tert-butoxide) in an alcoholic solvent (for example ethanol) at room temperature. The suspension obtained is advantageously filtered on an inert support (celite for example), the filtrate is then brought into contact with the mixture of isomers Z and E of the acrylonitrile intermediate (LXVI) in an alcoholic solvent (ethanol by Example) at room temperature followed by a reflux of 7 h.
In another process, for the preparation of the aminoquinoline-macrolide hybrid molecules of formula (XLa) in which p "= 0, U representing an oxyimine function, it is advantageous to couple an aminoquinoline of formula (LVI) in wherein R1a, R1b, R2, Y1, n, n 'and p are as defined above and hal represents a halogen atom, with a macrolide residue of formula (LXVII) wherein R3, R6, R7, R10 and p 'are as defined above and U is an oxime function:

This coupling reaction is advantageously carried out in an amide solvent (such as dimethylformamide) in the presence of a base (crushed sodium hydroxide, for example) at room temperature.
Aminoquinoline-glycopeptide hybrid molecules In another process, for the preparation of the aminoquinoline-glycopeptide hybrid molecules of formula (XLIa) in which p = p '= p "= 1, U representing an ether function, it is advantageous to proceed in the same manner. next: a-1) one couples an aminoquinoline of formula (LXIV) in which Ria, R1b, Rz, Yi, n, n ', p, p' and p "are as defined above, Y2 containing an oxy function on a terminal carbon thus forming an aldehyde function, with a glycopeptide residue of formula (LXVIII) in which R3 and R4 are as defined above:

The coupling reaction a-1) is advantageously carried out by first bringing together the glycopeptide residue with a base (diisopropylethylamine, for example) in an amide solvent (such as dimethylformamide or dimethylacetamide) at ambient temperature. stirring at 70 [deg.] C for 2 hours. On this mixture is then added a solution of a reducing agent (such as sodium cyanoborohydride) in an alcoholic solvent (methanol for example) at 70.degree. The mixture is advantageously stirred for 2 h 30 at 70 [deg] C then 20 h at room temperature.
Similarly, for the preparation of the aminoquinoline glycopeptide hybrid molecules of formula (XLIa) in which p '= p "= 0, it is advantageous to proceed as follows: b) a compound of formula (XLIII) in which R1a, R1b, n and n 'are as defined above and hal represents a halogen atom, with a derivative of formula (LXIX) where R2, Y1 and p are as defined above:

which leads to the production of a 4-aminoquinoline of formula (LXX):

in which R 1a, R 1b, R 2, Y 1, n, n 'and p are as defined above, c) the acetal of the compound of formula (LXX) is hydrolyzed in acidic medium, which leads to 4-aminoquinolines of formula (XLV) in which R1a, R1b, R2, Y1, n, n ', p and p' are as defined above and U is an aldehyde function, a-2) a 4-aminoquinoline of formula (XLV) with a glycopeptide residue of formula (LXVIII) wherein R3 and R4 are as defined above.
Step b) is advantageously carried out without a solvent at a temperature of 110.degree. The acid hydrolysis c) is advantageously carried out in an aqueous solution of acetic acid in the presence of trifluoroacetic acid at 70 ° C.
The coupling reaction a-2) is advantageously carried out under the conditions described for the coupling reaction a-1).
In another process, for the preparation of the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa) in which p = p '= p "= 1, where U represents a carbamate function, it is advantageous to couple an aminoquinoline of Formula (XLV) wherein R1a, R1b, R2, Y1, n, n ', p and p' are as defined above and U represents an amine function, with an oxazolidinone residue of formula (LXXI):

in which R 6, R 7, Y 2 and p "are as defined above This coupling reaction is advantageously carried out in a chlorinated solvent (such as dichloromethane) in the presence of triphosgene and a base (for example triethylamine). ), at room temperature.

Similarly, for the preparation of the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIb) in which p = p '= p "= 1, where U represents a carbamate function, it is advantageous to couple an oxazolidinone residue of formula (LXXI) in which R6, R7, Y2 and p "are as defined above with a 2-aminoquinoline of formula (LXXII):

wherein R1a, R1b, R2, Y1, n, n ', p and p' are as defined above and U represents an amine function. This coupling reaction is advantageously carried out in a chlorinated solvent (such as dichloromethane) in the presence of triphosgene and a base (for example triethylamine) at room temperature.
Similarly, for the preparation of the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa) in which p = p '= p "= 1, where U represents an amide function, it is advantageous to couple an aminoquinoline of formula (XLV) in which R1a R1b, R2, Y1, n, n ', p and p' are as defined above and U represents a carboxy function, with an oxazolidinone residue of formula (LXXIII):

in which R6, R7, Y2 and p "are as defined above This coupling reaction is advantageously carried out in an amide solvent (such as dimethylformamide) in the presence of an activator of the U function (PyBOP for example) and a base (such as N-methylmorpholine) at room temperature.
To obtain the hybrid molecules in the acid addition salt form, protonation of the basic nitrogens is carried out by adding a pharmacologically acceptable acid. By way of examples of addition salts with pharmacologically acceptable acids, mention may be made of the salts formed with the mineral acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or with the organic acids (citrates, tartrates, fumarates, lactates). ). The reaction can be carried out with 2 equivalents of acid added at 0 ° C.
The compounds of formula (I) may also be converted into the form of metal salts or of addition salts with the nitrogenous bases according to the methods known per se. Examples of pharmacologically acceptable salts are salts with alkali metals (sodium, potassium, lithium), alkaline earth metals (magnesium, calcium), ammonium salt or nitrogenous base salts ( triethylamine, diisopropylamine, ethanolamine, procaine, N-benzyl-2-phenylethylamine, tris (hydroxymethyl) aminomethane, N, N'-dibenzylethylenediamine).
The invention also covers the prodrugs of hybrid molecules of formula (I) which are hydrolysed in vivo releasing the active molecule. These prodrugs were prepared by conventional techniques known to those skilled in the art.
Advantageously, the invention covers the use of a compound Q as defined above for covalently fixing, for example by a bond - (Yl) p (U) p '- (Y 2) p "- as defined above an antibiotic residue A defined above.

PHARMACEUTICAL USES
In this part: the invention covers the pharmaceutical use of a compound according to the present invention as defined by formula I. The invention also covers the pharmaceutical use of compounds excluded 2) to 12). The invention also covers the pharmaceutical use of the compounds excluded 1) except for the disinfection or treatment of infections caused by Mycoplasma sp.
The invention covers the use of a compound as defined above for the manufacture of a pharmaceutical composition intended in particular for the treatment of a bacterial infection of an animal or a human being or a treatment of medical equipment contaminated with bacteria, including infection or bacterial contamination due to Staphylococcus aureus, for example Staphylococcus aureus MSSA (methicillin-sensitive), Staphylococcus aureus MRSA (methicillin-resistant), Staphylococcus aureus NorA (quinolone-resistant) efflux), Staphylococcus aureus MsrA (efflux-resistant macrolide) or Staphylococcus aureus VISA (or GISA) (resistant to vancomycin), Staphylococcus epidermidis eg Staphylococcus epidermidis MSCNS (Methicillin-sensitive negative coagulase) or Staphylococcus epidermidis MRCNS (coagulase) Methicillin-Resistant Negative), Streptococcus pneumoniae, eg Streptococcus pneumoniae PSSP (penicillin-sensitive) or Streptococcus pneumoniae PRSP (penicillin-resistant), Streptococcus pneumoniae mefE (efflux-resistant macrolide), Streptococcus pyogenes, Enterococcus faecalis, eg Enterococcus faecalis ERV (vancomycin-resistant), Haemophilus influenzae, Moraxella catarrhalis , Escherichia coli, Bacillus subtilis, Bacillus thuringiensis or Bacteroides fragilis.
The hybrid molecules of the invention as defined in this part can be very advantageously used for the treatment of bacterial infections due to the germs on which they are active.
Thus, the hybrid molecules of the invention active on Streptococcus pneumoniae can be very advantageously used for the treatment of infections such as pneumonia, meningitis, otitis, or acute sinusitis.
Likewise, the hybrid molecules of the invention that are active on Staphylococcus aureus can be used for the treatment of infections such as skin and / or mucosal infections, nosocomial infections, or osteomyelitis.
Similarly, the hybrid molecules of the invention that are active on Staphylococcus epidermidis can be used for the treatment of infections such as nosocomial and iatrogenic infections due to this bacterium.
Nosocomial, urinary, cutaneous, genital, biliary, dental, and otitis-sinusitis infections or endocarditis due to Enterococcus faecalis can be advantageously treated by the active hybrid molecules on this bacterium.
Similarly, the hybrid molecules of the invention active on Streptococcus pyogenes can be used for the treatment of infections such as bacterial angina, other ENT diseases, skin infections, scarlet fever, erysipelas, impetigo or gangrene. skin.
Similarly, the hybrid molecules of the invention which are active on Haemophilus influenzae can be used for the treatment of ENT diseases, complications of influenza or meningitis.
Similarly, the hybrid molecules of the invention that are active on Moraxella catarrhalis can be used for the treatment of ENT diseases caused by this bacterium.
Escherichia coli infections such as urinary tract infections, abdominal infections or infantile diarrhea can be advantageously treated by the active hybrid molecules on this bacterium.
Likewise, the hybrid molecules of the invention which are active on Bacillus sp. may be used for the treatment of food poisoning caused by this bacterium.
Infections due to Bacteroides fragilis such as bacteremia, abscess and lesions, peritonitis, endocarditis or wound infections can be advantageously treated by the hybrid molecules active on this bacterium.
The invention therefore also relates to the application of these hybrid molecules of high interest defined above, to develop drugs for the food industry and in human and veterinary medicine for the treatment of a bacterial infection or as a bactericide for industrial applications.
In particular, it is advantageous to deliver an effective amount of the compound of the present invention for the aforementioned treatments and cited below.
The invention also covers a method of therapeutic treatment of an animal or of a human being in need, characterized in that it comprises administering thereto a therapeutically effective amount of a hybrid compound according to the invention of formula (I) above.
Particular embodiments of this treatment are clearly apparent to those skilled in the art of the antibiotic activity concerned and to the description of the invention as a whole including the examples which form an integral part thereof. The study of the pharmacological properties of hybrid molecules of formula (XXXIVa), (XXXIVc), (XXXVa), (XXXVb), (XXXVIa), (XXXVII), (XXXVIII), (XXXIX), (XLa), (XLIa) and (XLIIa) exemplary data have shown that these hybrid molecules are particularly interesting antimicrobial agents, their antibacterial activity being very important and perfectly unexpected for a person skilled in the art.

(XXXIVc), (XXXVa) and (XXXVb) have a very strong antibacterial activity, especially on Gram + germs.
For example, the hybrid aminoquinoline-penicillin PA 1007 molecule (example 1), called penicillin, has antibacterial activity of the same level as that of penicillin G. Since PA 1007 is a prodrug, this result suggests excellent activity. in vivo after hydrolysis of the ester function by the enzymes of the host.
The aminoquinoline-cephalosporin hybrid molecules, called cephaloquines, are highly active in vitro on Staphylococcus aureus, Streptococcus pneumoniae sensitive to penicillin and Streptococcus pyogenes at minimal inhibitory concentrations (MICs) of between 0.0015 and 0.78 μg / mL. More interesting is the activity of some of them on two strains of Streptococcus pneumoniae PRSP resistant to penicillin (CIP 104471 and a clinical isolate) at concentrations of between 0.006 and 6.25 pg / mL for the MIC and between 0.025 and 12.5 μg / mL for CMB (minimal bactericidal concentration). The most active molecule (MIC: 0.006 pg / mL) was even 8 times more effective than ceftriaxone (MIC: 0.05 pg / mL), tested on the same strains. Ceftriaxone is one of the antibiotics currently used. to treat pneumonia cases due to penicillin-resistant P. pneumoniae. Hybrid molecules with interesting activity on S. pneumoniae PRSP (MIC from 0.006 to 0.39 pg / mL) were also active on Haemophilus influenzae, another causative agent of pneumonia, with MICs of 0.78 to 3, 12 μg / mL (see Example 39, Tables III and IV).
The amplification effect of the antibiotic activity of the hybrid molecules is clearly demonstrated by a study of the activity of the constitutive structures Q and A

1/1 association of these substructures. The results are remarkable and perfectly exemplify this amplification: only the hybrid molecule has an interesting antibacterial activity. The covalent bond between the two parts therefore brings an important and completely unexpected effect for those skilled in the art (Example 39, Table V).
Moreover, it has been shown that, in the presence of human serum, the aminoquinoline-cephalosporin hybrid molecules such as those tested as examples, remained active in vitro not only on 5. aureus but also on 5. pneumoniae PRSP. Under the same conditions ceftriaxone totally loses its antibacterial activity due to a strong serum protein binding well known to those skilled in the art (Example 39, Table VI).
In addition, a stability study in solution of these hybrid molecules showed that they were stable not only at physiological pH 7 pH in solution at 37 [deg] C but also in acid pH 1 (equivalent to the pH of the stomach ). For example, the 1/2 life of the most active molecule on S. pneumoniae resistant to penicillin is 15 h at pH 1 in solution at 37 [deg] C while ceftriaxone is almost completely degraded in same conditions in less than 6 h with a 1/2 life less than 2 h (Example 38, Tables 1 and II).
Hybrid aminoquinoline-quinolone molecules The superiority of QA hybrid molecules is not limited to the beta lactam family. Indeed, examples of aminoquinoline-quinolone hybrid molecules of formula (XXXVIa) have shown remarkable results in terms of antibacterial activity, whether on sensitive strains or on resistant strains. Thus quinoloquine PA 1126 (Example 21) is very active on sensitive strains such as 5. aureus MSSA (susceptible to black B. subtilis but also on resistant strains such as S, pneumoniae PRSP, E. faecalis VRE or S. aureus NorA The activity of PA 1126 on this last strain is particularly interesting since it is a quinolone-resistant strain (MIC of ciprofloxacin> 50 microg / mL) with a MIC of 0.18 microg / ml. mL on this same strain, PA 1126 is 280-fold more active than the substructure from which it is derived (Example 39, Table VII).
The spectrum of activity of fluoroquinolones is broad, such as that of PA 1126. These antibiotics, despite their tendency to favor the phenomena of resistance are essential in emergency cases or pre- and post-operative treatments. Quinoloquine PA 1127 (Example 22) remains an interesting molecule because it has a narrow spectrum of activity centered on Gram - bacteria.
Aminoquinoline-Nitroimidazole Hybrid Molecules The activity of the aminoquinoline-nitroimidazole hybrid molecules of formula (XXXVII), such as, for example, nitroimidaquin PA 1129 (Example 23) () is of the same level as that of the reference molecule in the nitroimidazole family : metronidazole (Example 39, Table VIII).
Aminoquinoline-Streptogramin Hybrid Molecules The family of aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII) is interesting in view of its narrow activity spectrum centered on susceptible or resistant Gram + bacteria. Thus the activity of the aminoquinolestreptogramin hybrid molecule PA 1182 (Example 26), called a general term streptogramiquine or more specifically pristinaquine, is 4 to 8 times better on Gram + bacteria than that of the antibiotic A of which it is compound (Example 39, Table IX).
Aminoquinoline-Macrolide Hybrid Molecules In this family of hybrid molecules of formula (XLa) called macroliquines, exemplified by erythromycin PA 1169 (Example 30), the addition of an aminoquinoline to an antibiotic residue of the macrolide family leads to a 8-fold increase in activity on Streptococcus pneumoniae PSSP. In addition, erythromycin PA 1169 is active on an efflux-resistant Macrolide Streptococcus pneumoniae strain (MIC of Erithromycin: Microg / mL, MIC of PA 1169: 1.25 Microg / mL) (Example 39, Table 1). X).
Aminoquinoline-Glycopeptide Hybrid Molecules The contribution of the covalent bond between an aminoquinoline and an antibiotic residue is most remarkable and unexpected on the aminoquinoline glycopeptide hybrid molecules of formula (XLIa). Indeed, on all strains tested (sensitive or resistant), the antibacterial activity of vancomyquins is much higher than that of their constitutive substructure A: vancomycin. For these hybrid molecules, the activity gain provided by the covalent bond with an aminoquinoline ranges from 4 to 260 (Example 39, Table XI).
Aminoquinoline-Oxazolidinone Hybrid Molecules The examples of aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa) demonstrate an antibacterial activity equivalent to that of linezolid (the only molecule of the class on the market). It is known to those skilled in the art that the in vivo activity will be very influenced by the pharmacokinetic properties which could be in the case of the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa) better than the reference product (Example 39 , Table XII).
All of these properties enable said products of the invention, as well as their salts, hydrates, prodrugs and prodrug salts, to be used as a medicament.
The invention covers compositions, in particular by making use of the properties of these hybrid molecules for the preparation of pharmaceutical compositions.
The pharmaceutical composition comprises, as active principle, at least one previously defined AQ compound in a pharmaceutically acceptable excipient.
The pharmaceutical compositions of the invention contain an effective amount of at least one hybrid molecule of formula (I) as defined above, as well as a pharmaceutically acceptable vehicle. As is known to those skilled in the art, various forms of excipients may be used adapted to the mode of administration and some of which may promote the effectiveness of the active molecule, for example by promoting a release profile making this molecule active overall more effective for the intended treatment.
The pharmaceutical compositions of the invention can thus be administered in different forms, more especially for example in injectable, sprayable or unmanageable form, for example intramuscularly, intravenously, subcutaneously, intradermally, orally, topically, rectally, vaginally, ophthalmically, nasally. , transdermal or parenteral. The present invention covers in particular the use of a compound according to the present invention, for the manufacture of a composition, in particular a pharmaceutical composition.
The compounds according to the invention can advantageously be used in an effective amount. These amounts are generally between 10 mg and 2 g of active ingredient per day.
The pharmaceutical compositions of the invention containing an effective amount of at least one hybrid molecule of formula (I) as defined above, may also contain other pharmacologically active substances. In particular, in the pharmaceutical compositions of the invention, it is possible to combine a hybrid AQ molecule of formula (I) with a resistance enzyme inhibitor such as

can be cited: clavulanic acid (3- (2-hydroxyethylidene) -7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid), sodium sulbactam ([2S- (2 alpha, 5 alpha)] -

sodium).
The compositions of the invention are particularly suitable for the treatment of a bacterial infection in humans or animals or for the disinfection of equipment, in particular medical equipment.
The invention is now illustrated by examples representing the presently preferred embodiments forming part of the invention but which can in no way be used to limit the scope thereof, the invention being a pioneer in the creation of a new family of active compounds covalently combining at least one antibiotic and at least one aminoquinoline.
In the examples all percentages are given by weight (unless otherwise indicated), the temperature is in degrees Celsius, the pressure is the atmospheric pressure unless otherwise indicated. The chemicals used are commercial especially at Aldrich or Acros unless otherwise indicated.

EXAMPLES
Examples 1 to 4 below exemplify preparations of hybrid molecules of the quinoline penicillin family.
Example 1 Preparation of a quinoline penicillin, ref PA 1007

oxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.

1.1. 1- (7-Chloro-quinolin-4-yl) -piperidine-4-carboxylic acid.
A mixture of 4,7-dichloroquinoline (17.4 g, 0.09 mol), isonipecotic acid (23.8 g, 0.18 mol) and phenol (46.3 g, 0.49 mol) is heated at 120 ° C. with magnetic stirring for 24 h. After returning to ambient temperature, the reaction medium is diluted with 400 ml of ethyl acetate, filtered on sintered and the precipitate is washed with water. This precipitate is then recrystallized by hot dissolution (100 ° C.) in 300 ml of 10% (w / v) carbonated water and precipitation at 0 ° C. by addition of an aqueous HCl solution. M to pH 5. The precipitate formed is filtered and then washed successively with water, acetone and diethyl ether before being dried under vacuum. The product is obtained in the form of a white powder (18.4 g, 72%).
1 H NMR (300 MHz, CD 3 COOD) ppm: 2.11 (2H, dd, J = 10.6 Hz, J = 13.9 Hz), 2.27 (2H, d, J = 13.9 Hz), 2 , 92 (1H, m), 3.60 (2H, dd, J = 10.6 Hz, J = 13.4 Hz), 4.20 (2H, d, J =

= 9.2 Hz), 8.18 (1H, d, J = 2.0 Hz), 8.72 (1H, d, J = 7.0 Hz). MS (IS> 0) m / z: 291.0 (M + H +).

dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethylpropionyl-oxymethyl ester.
3.6 ml of N-methylmorpholine (32.7 mmol) are added to a mixture of 1- (7-chloroquinolin-4-yl) -piperidine-4-carboxylic acid (Example 1.1) (3.0 g, 10, 3 mmol) and 6aminopenicillanic acid pivaloyloxymethyl ester tosylate salt POM-APA-Ts (prepared according to the method described by R.-de-Vains et al., Tetrahedron Lett. 2001, 42, 7033-7036) (5.2 g, 10.3 mmol) in 75 mL of DMF. The suspension is stirred magnetically for 15 min before the addition of PyBOP activator (5.4 g, 10.3 mmol). Magnetic stirring is continued for 24 hours at room temperature. The reaction medium is then diluted with 100 ml of dichloromethane and then washed successively with 100 ml of carbonated water at 10% (w / v), twice 100 ml of water and 100 ml of water saturated with NaCl. The organic phase is dried over magnesium sulphate, filtered and then evaporated. The oil obtained is purified by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: ethyl acetate). The cleanest fractions in TLC revealed under UV are evaporated. PA 1007 is obtained after recrystallization chloroform / n-hexane as a white powder (1.4 g, 23%).
IR (KBr) cm-1: (C = O) 1786, 1757, 1681. 1H NMR (300 MHz, CDCl3) δ ppm: 1.22 (9H, s), 1.53 (3H, s), 1, 65 (3H, s), 2.13 (4H, m), 2.43 (1H, m), 2.84 (2H, dd, J = 11.4Hz, J = 12.3Hz), 3, 60 (2H, d, J = 12.3 Hz), 4.44 (1H, s), 5.58 (1H, d, J = 4.0 Hz), 5.75 (1H, dd, J = 4 , 0 Hz, J = 8.7 Hz), 5.77 (1H, d, J = 5.7 Hz), 5.88 (1H, d, J = 5.7 Hz), 6.57 (1H, d, J = 8.7 Hz), 6.80 (1H, d, J = 5.1 Hz), 7.41 (1H, dd, J = 2.0 Hz, J = 9.0 Hz), 7 , 89 (1H, d, J = 9.0 Hz), 8.02 (1H, d, J = 2.0 Hz), 8.69 (1H, d, J = 5.1 Hz). MS (IS> 0) m / z: 603.2

9.15; % experiment C 56.80, N 8.83.
EXAMPLE 2 Preparation of a quinoline-penicillin, ref PA 1008 (2S, 5R, 6R) -3,3-Dimethyl-7-oxo-6- [3- (quinolin-8-ylamino) -propionylamino] -4 thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester.

PA 1008 is prepared according to the procedure described in Example 1.2 from 4.3 g of 3- (quinolin-8-ylamino) -propionic acid (19.9 mmol) (prepared according to the method described by ZJ Beresnevicius et al. Heterocycl Chem., 2000, 36, 432-438), 10.0 g of POM-APA-Ts (19.9 mmol), 6.5 ml of N-methylmorpholine (59.1 mmol) and 3 g of PyBOP (19.9 mmol). PA 1008 is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 6-35 Microm, eluent: n-hexane / ethyl acetate 55/45 v / v) and recrystallization diethyl ether / n-hexane in the form a yellow powder (2.3 g, 22%).
IR (KBr) cm-1: (C = O) 1784, 1755, 1667.RNH (300 MHz, 298K, CDCl3), ppm: 1.16 (9H, s), 1.37 (6H, s), 2.64 (2H, t, J = 6.6Hz), 3.61 (2H, m), 4.34 (1H, s), 5.45 (1H, d, J = 4.2Hz), 5.67 (1H, dd, J = 4.2 Hz, J = 8.7 Hz), 5.70 (1H, d, J = 5.4 Hz), 5.80 (1H, d, J = 5. , 4 Hz), 6.34 (1H, brs), 6.67 (1H, d, J = 7.5 Hz), 7.03 (1H, d, J = 8.4 Hz), 7.09

8.4 Hz), 7.99 (1H, dd, J = 1.5 Hz, J = 8.1 Hz) 8.66 (1H, dd, J = 1.5 Hz, J = 4.2 Hz) . MS (IS> 0) m / z: 529.2 (M + H +). Elemental analysis: for C26H32N4O6S:% theor. C 59.07, N, 10.60; % experiment C 59.19, N 10.50.
Example 3 Preparation of a quinoline penicillin, ref PA 1012 (2S, 5R, 6R) -6- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -3,3-dimethyl-7- oxo-4-thia1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.

3.1. (7-Chloro-quinolin-4-ylamino) -acetic acid, ref PA 1117.
This compound is prepared by modification of the method described by E. O. Titus et al. (J. Org Chem 1948, 13, 61). A mixture of 4,7-dichloroquinoline (30.0 g, 0.15 mol), glycine (25.0 g, 0.33 mol) and phenol (80.0 g, 0.85 mol) is heated to 120 [ deg] C with magnetic stirring for 24 h. After returning to ambient temperature, the reaction medium is diluted with 1 L of diethyl ether and extracted with 1 L of 10% (w / v) carbonated water. The aqueous phase is passed over Norit A charcoal hot (100 [deg] C), filtered and then brought to pH 5 at 0 [deg] C with an aqueous solution of 2M HCl. The precipitate formed is filtered and washed successively with water, acetone and diethyl ether before being dried under vacuum. PA 1117 is obtained as a white powder (27.0 g, 75%).
1 H NMR (300 MHz, CF 3 COOD) ppm: 4.51 (2H, s), 6.72 (1H, d, J = 6.9Hz), 7.68 (1H, d, J = 9.0Hz) , 7.87 (1H, s), 8.10 (1H, d, J = 9.0Hz), 8.30 (1H, d, J = 6.9Hz).
3.2. (2S, 5R, 6R) -6- [2- (7-Chloro-quinolin-4-ylamino) -acetylamino] -3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.
PA 1012 is prepared according to the procedure described in Example 1.2 from 1.3 g of (7-chloro-quinolin-4-ylamino) -acetic acid (Example 3.1) (5.6 mmol), 2.8 g of POMAPA-Ts (5.6 mmol), 1.8 mL of N-methylmorpholine (16.4 mmol) and 2.9 g of PyBOP (5.6 mmol). PA 1012 is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: ethyl acetate / chloroform 8/2 v / v) and recrystallization chloroform / n-hexane in the form of a white powder (0.3 g, 11%). IR (KBr) cm-1: (C = O) 1784, 1759, 1669. NMR H (300 MHz, CDCl3) ppm: 1.20 (9H, s), 1.39 (3H, s), 1.44 (3H, s), 4.04 (2H, brs), 4.39 (1H, s), 5.57 (1H, d, J = 4.2Hz), 5.74 (1H, dd, J = 4.2 Hz, J = 9.0 Hz), 5.75 (1H, d, J = 5.4 Hz), 5.85 (1H, d, J = 5.4 Hz), 6.21 ( 1H, brs), 6.29 (1H, d, J = 6.0 Hz), 7.36 (1H, dd, J = 1.8 Hz, J = 9.0 Hz), 7.53 (1H , d, J = 9.0 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.95 (1H, d, J = 1.8 Hz), 8.51 (1H, d , J = 6.0

% theor. C 52.12, N 9.72; % experiment C 52.41, N 9.39.
EXAMPLE 4 Preparation of a quinoline-penicillin, ref PA 1013 (2S, 5R, 6R) -6- [3- (7-chloro-quinolin-4-ylamino) -propionylamino] -3,3-dimethyl-7- oxo-4thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.

4.1. 3- (7-Chloro-quinolin-4-ylamino) -propionic acid.
This compound is prepared by modification of the method described by WJ Humphlett et al. (J. Am Chem Soc 1951, 73, 61), according to the procedure described in Example 3.2 and from 25.1 g of 4,7-dichloroquinoline (0.13 mol), 23.6 g of 3-alanine (0.26 mol) and 66.5 g of phenol (0.71 mol) The product is obtained in the form of a white powder (19.5 g, 62%).
1 H NMR (300 MHz, CF 3 COOD) δ ppm: 2.90 (2H, t, J = 6.0 Hz), 3.86 (2H, t, J = 6.0 Hz), 6.73 (1H, d). , J = 7.2 Hz), 7.53 (1H, dd, J = 1.5 Hz, J = 9.0 Hz), 7.72 (1H, d, J = 1.5 Hz), 7, 96 (1H, d, J = 9.0 Hz), 8.14 (1H, d, J = 7.2 Hz).
4.2. (2S, 5R, 6R) -6- [3- (7-Chloro-quinolin-4-ylamino) -propionylamino] -3,3-dimethyl-7oxo-4-thia-1-aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester.
PA 1013 is prepared according to the procedure described in Example 1.2 from 2.2 g of 3- (7-chloro-quinolin-4-ylamino) -propionic acid (Example 4.1) (8.0 mmol), 4, 1 g of POM-APA-Ts (8.0 mmol), 2.6 ml of N-methylmorpholine (23.6 mmol) and 4.1 g of PyBOP (8.0 mmol). PA 1013 is obtained after several chloroform / n-hexane recrystallizations in the form of a white powder (1.2 g, 27%).
IR (KBr) cm-1: (C = O) 1787, 1760, 1662. NMR H (300 MHz, CDCl3) δ ppm: 1.23 (9H, s), 1.48 (3H, s), 1, 53 (3H, s), 2.73 (2H, m), 3.69 (2H, m), 4.42 (1H, s), 5.55 (1H, d, J = 4.2Hz), 5.71 (1H, dd, J = 4.2 Hz, J = 8.7 Hz), 5.77 (1H, d, J = 5.7 Hz), 5.87 (1H, d, J = 5. , 7 Hz), 6.37 (1H, d, J = 5.4 Hz), 6.75 (1H, brs), 7.37 (1H, dd, J = 1.8 Hz, J = 9, 0 Hz), 7.76 (1H, d, J = 9.0 Hz), 7.93 (1H, d, J = 1.8 Hz), 8.46 (1H, d, J = 5.4 Hz ). SM (IS> 0)

54.58, N 9.79; % experiment C 54.41, N 9.84.
Examples 5 to 19 exemplify preparations of hybrid molecules of the aminoquinoline-cephalosporin family.
EXAMPLE 5 Preparation of an Aminoquinoline-Cephalosporin Ref PA 1046 (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloroquinolin-4-ylamino) acetylamino] -8-oxo-5- thia1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

5.1. Mixture of (6R, 7R) -3-acetoxymethyl-7- [2- (7-chloroquinolin-4-ylamino) acetylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct -2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester: 2/3.
To a suspension of (7-chloro-quinolin-4-ylamino) -acetic acid (Example 3.1, PA 1117) (2.9 g, 10.0 mmol) in 80 ml of DMF are successively added 1-hydroxybenzotriazole HOBT (1, 4 g, 10.4 mmol) and N, N'-dicyclohexylcarbodiimide DCC (2.1 g, 10.4 mmol). The mixture is left stirring for 30 minutes before the addition of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene 2-carboxylic acid benzhydryl ester p-toluenesulphonic acid (prepared according to the procedure described by RG Micetichet coll., Synthesis 1985, 6-7, 693-695) (6.1 g, 10.0 mmol) followed by triethylamine (2 7 mL, 20.0 mmol). Magnetic stirring is continued for 24 hours at room temperature. The reaction medium is then diluted with 400 ml of ethyl acetate and then filtered. The filtrate is washed successively with 400 ml of carbonated water at 10% (w / v), twice 400 ml of water and 400 ml of water. water saturated with NaCl. The organic phase is dried over magnesium sulfate, filtered and evaporated. The oil obtained is purified by liquid chromatography on silica gel (SiO 2 60A CC 6-35 Microm, eluent: dichloromethane / ethanol 90/10 v / v). The cleanest fractions in TLC revealed under UV are evaporated. The coupling product is obtained in the form of an orange powder (3.2 g, 48%) in a mixture / 37/63, used as such in the next step.
5.2. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -5,8-

To a 0.degree. C. solution of the mixture / example 5.1 (5.1 g, 7.8 mmol) in 200 ml of dichloromethane is added dropwise, over a period of 3 hours, a solution of 3-chloroperoxybenzoic acid (2.6 g, 15.1 mmol) in 250 mL of dichloromethane. The reaction medium is then washed with a mixture of 400 ml of 5% (w / v) carbonated water and 250 ml of a 6% (w / v) aqueous sodium sulphite solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The powder obtained is washed with ethyl acetate with magnetic stirring for 30 min, filtered, washed with diethyl ether and dried under vacuum. The oxidation product is obtained as a yellow powder (4.0 g, 76%).
IR (KBr) cm-1: (C = O) 1788, 1738, 1663. NMR H (300 MHz, DMSO) ppm: 1.95 (3H, s), 3.60 (1H, d, J = 18, 9 Hz), 3.93 (1H, d, J = 18.9 Hz), 4.11 (2H, m), 4.58 (1H, d, J = 13.2 Hz), 4.95 (1H). , d, J = 4.5 Hz), 5.02 (1H, d, J = 13.2 Hz), 6.03 (1H, dd, J = 4.5 Hz, J = 8.1 Hz), 6.39 (1H, d, J = 5.4 Hz), 6.94 (1H, s), 7.28-7.52 (11H, m), 7.83 (2H, brs), 8, 23 (1H, d, J = 9.0 Hz), 8.34 (1H, d, J = 8.1 Hz), 8.44 (1H, d, J = 5.4 Hz). MS (IS> 0) m / z: 673.1 (M + H +).
5.3. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -8-oxo-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester.
To a solution at -20 [deg] C under argon of (6R, 7R) -3-acetoxymethyl-7- [2- (7-chloro)

carboxylic acid benzhydryl ester (Example 5.2) (3.8 g, 5.6 mmol) in 40 mL of dry DMF is added dropwise 1.1 mL of trichlorophosphine (12.6 mmol). The reaction is stirred magnetically for 1 h at -20 [deg.] C. The reaction medium is then diluted with 150 ml of dichloromethane and then washed successively with twice 150 ml of water and 150 ml of water saturated with NaCl. The organic phase is dried over magnesium sulfate, filtered and evaporated. The product is obtained after recrystallization dichloromethane / diethyl ether in the form of a beige powder (1.7 g, 46%).
IR (KBr) cm-1: (C = O) 1785, 1735, 1689. 1H NMR (300 MHz, DMSO) δ ppm: 1.96 (3H, s), 3.56 (1H, d, J = 18) , 3 Hz), 3.69 (1H, d, J = 18.3 Hz), 4.37 (2H, m), 4.64 (1H, d, J = 13.2 Hz), 4.86 ( 1H, d, J = 13.2 Hz), 5.16 (1H, d, J = 5.1 Hz), 5.83 (1H, dd, J = 5.1 Hz, J = 8.4 Hz) , 6.71 (1H, d, J = 7.2 Hz), 6.93 (1H, s), 7.27-7.49 (10H, m), 7.82 (1H, dd, J = 1), , 8 Hz, J = 9.0 Hz), 8.08 (1H, d, J = 1.8 Hz), 8.57 (1H, d, J = 9.0 Hz), 8.61 (1H, d, J = 7.2 Hz), 9.38 (1H, d, J = 8.4 Hz), 9.74 (1H, brs). MS (IS> 0) m / z: 657.2 (M + H +).
5.4. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -8-oxo-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid.
To a solution at 0 ° C under argon of (6R, 7R) -3-acetoxymethyl-7- [2- (7-chloroquinolin-4-ylamino) -acetylamino] -8-oxo-5-thia-1 aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (1.3 g, 1.9 mmol) (Example 5.3) in 15 ml of dry dichloromethane is added 0.8 ml of anisole (7.5 mmol) followed by 1.4 ml of trifluoroacetic acid injected dropwise (19.0 mmol). The reaction is stirred magnetically for 1 h 30 at room temperature. The product in the form of triflate salt is precipitated by addition of diethyl ether and filtered. The powder obtained is washed with water, ethanol and diethyl ether before being dried under vacuum. PA 1046 is obtained in the form of a light beige powder (0.5 g, 54%).
IR (KBr) cm-1: (C = O) 1760, 1664. 1H NMR (400MHz, DMSO) δ ppm: 2.01 (3H, s), 3.22 (1H, d, J = 17.6); Hz), 3.47 (1H, d, J = 17.6 Hz), 4.05 (2H, d, J = 6.0 Hz), 4.76 (1H, d, J = 12.0 Hz) , 4.97 (1H, d, J = 4.8 Hz), 4.99 (1H, d, J = 12.0 Hz), 5.51 (1H, dd, J = 4.8 Hz, J = 8.4 Hz), 6.33 (1H, d, J = 5.6 Hz), 7.49 (1H, dd, J = 2.4 Hz, J = 9.2 Hz), 7.80 (1H , d, J = 6.0 Hz), 7.82 (1H, d, J = 2.4 Hz), 8.25 (1H, d, J = 9.2 Hz), 8.40 (1H, d , J = 5.6 Hz), 9.11 (1H, d, J = 8.4 Hz). MS (IS> 0) m / z: 491.2 (M + H +). Elemental analysis: for

Example 6 Preparation of an aminoquinoline-cephalosporin, ref PA 1089 (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloroquinolin-4-ylamino) acetylamino] -8-oxo-5- thia1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride.

To a solution at 0 [deg] C PA 1046 (Example 5.4) (0.5 g, 1.0 mmol) in 40 mL of chloroform / ethanol 1/1 v / v, is added dropwise 0 8 mL of a solution of 5M HCl in 2-propanol (4.0 mmol). After 30 minutes of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether. The precipitate is filtered, washed with cold ethanol then with diethyl ether and dried under vacuum. PA 1089 is obtained in the form of a light beige powder (0.4 g, 76%).
1 H NMR (300 MHz, DMSO) δ ppm: 2.03 (3H, s), 3.50 (1H, d, J = 18.3 Hz), 3.65 (1H, d, J = 18.3 Hz) , 4.36 (2H, m), 4.70 (1H, d, J = 12.9 Hz), 5.00 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J = 4.8 Hz), 5.74 (1H, dd, J = 4.8 Hz, J = 7.8 Hz), 6.71 (1H, d, J = 6.6 Hz), 7.81. (1H, d, J = 9.0Hz), 8.02 (1H, s), 8.52 (1H, d, J = 9.0Hz), 8.60 (1H, d, J = 6, 6 Hz), 9.33 (1H, d, J = 7.8 Hz), 9.58 (1H, brs) 13.80 (1H, brs). Elemental analysis: for

10.05.
Example 7 Preparation of an aminoquinoline-cephalosporin, ref PA 1088

thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride.

To a solution at 0 [deg] C under argon of (6R, 7R) -3-acetoxymethyl-7- [2- (7-chloro-quinolin)

acid benzhydryl ester (Example 5.2) (1.8 g, 2.7 mmol) in 20 ml of dry dichloromethane is added 1.2 ml of anisole (10.7 mmol) followed by 2.0 ml of trifluoroacetic acid injected dropwise (27.0 mmol). The reaction is stirred magnetically for 1 h 30 at room temperature. The product in the form of triflate salt is precipitated by addition of diethyl ether, filtered and washed with dichloromethane. The powder obtained is suspended in 20 ml of a 1/1 v / v chloroform / ethanol mixture and cooled to 0 ° C. This suspension is successively added 1.4 ml of a 2 M solution of NH 3 in the 2-ol. propanol (2.7 mmol) stirred for 15 min then 1.1 mL of a solution of 5 N HCl in 2-propanol (4.0 mmol) stirred for 30 min. The product is then precipitated with diethyl ether. The precipitate is filtered, washed with chloroform, ethanol and then with diethyl ether and dried under vacuum. PA 1088 is obtained as a slightly yellow powder (0.5 g, 24%).
1 H NMR (400 MHz, DMSO) ppm: 2.03 (3H, s), 3.62 (1H, d, J = 18.4Hz), 3.89 (1H, d, J = 18.4Hz); , 4.41 (2H, m), 4.61 (1H, d, J = 12.9Hz), 4.92 (1H, d, J = 4.0Hz), 5.20 (1H, d, J = 12.9 Hz), 5.89 (1H, dd, J = 4.0 Hz, J = 8.2 Hz), 6.73 (1H, d, J = 6.5 Hz), 7.79. (1H, d, J = 9.0 Hz), 8.08 (1H, s), 8.55 (1H, d, J = 9.0 Hz), 8.60 (1H, d, J = 6, 5 Hz), 8.65 (1H, d, J = 8.2 Hz), 9.56 (1H, brs), 13.76 (brs). MS (IS> 0) m / z: 507.2 (M-Cl) +.

exper. C 43.51, N 9.59.
Example 8 Preparation of an aminoquinoline-cephalosporin, ref PA 1092

thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

A suspension of PA 1088 (Example 7) (0.5 g, 0.8 mmol) is deprotonated with magnetic stirring for 30 min in 40 ml of water at room temperature. The product is filtered, washed with ethanol and then with diethyl ether and dried under vacuum. PA 1092 is obtained in the form of a slightly yellow powder (0.2 g, 31%).
1 H NMR (250 MHz, DMSO) ppm: 2.00 (3H, s), 3.55 (1H, d, J = 18.2Hz), 3.85 (1H, d, J = 18.2Hz) , 4.20 (2H, m), 4.57 (1H, d, J = 12.5Hz), 4.88 (1H, brs), 5.18 (1H, d, J = 12.5Hz). ), 5.89 (1H, brs), 6.51 (1H, brs), 7.60 (1H, d, J = 9.0Hz), 7.88 (1H, s),

44.25, N 9.83; % experiment C 44.21, N 9.57.
Example 9 Preparation of an aminoquinoline-cephalosporin, ref PA 1037 (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloro-quinolin-4-ylamino) -propionylamino] -8-oxo-5thia 1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

9.1. Mixture of (6R, 7R) -3-acetoxymethyl-7- [3- (7-chloro-quinolin-4-ylamino) propionyl-amino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0 ] oct-2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloro-quinolin-4-ylamino) -propionyl-amino] -8oxo-5- thia-1-aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester:
The coupling product is prepared according to the procedure described in Example 5.1 from 5.7 g of 3- (7-chloroquinolin-4-ylamino) -propionic acid (Example 4.1) (19.8 mmol), 2.8 g of HOBT (20.7 mmol), 4.3 g of DCC (20.7 mmol), 8.7 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia -1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p-toluene sulfonic acid (19.8 mmol) and 2.8 mL of triethylamine (19.8 mmol). The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: ethyl acetate / ethanol 90/10 v / v to remove the impurities and then ethyl acetate / ethanol / triethylamine 90/5/5 v / v / v) in the form of an orange powder (6.1 g, 46%) in a mixture / 20/80, used as it is in the next step.
9.2. (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -5,8-

The oxidation reaction is carried out according to the procedure described in Example 5.2 from 6.4 g of the mixture A / A of Example 9.1 (9.5 mmol) and 3.3 g of 3chloroperoxybenzoic acid (19 0 mmol). The product is obtained in the form of a yellow powder (4.9 g, 75%).
IR (KBr) cm-1: (C = O) 1788, 1733, 1647. 1 H NMR (400 MHz, DMSO) ppm: 1.98 (3H, s), 2.71 (2H, t, J = 6, 9 Hz), 3.53 (2H, q, J = 6.9 Hz), 3.65 (1H, d, J = 18.7 Hz), 3.96 (1H, d, J = 18.7 Hz). ), 4.62 (1H, d, J = 13.4 Hz), 4.97 (1H, d, J = 4.8 Hz), 5.08 (1H, d, J = 13.4 Hz), 5.98 (1H, dd, J = 4.8 Hz, J = 8.2 Hz), 6.55 (1H, d, J = 5.5 Hz), 6.96 (1H, s), 7.267, 46 (9H, m), 7.47 (1H, dd, J = 2.2 Hz, J = 9.0 Hz), 7.53 (2H, d, J = 7.3 Hz), 1H, d, J = 2.2 Hz), 8.25 (1H, d, J = 9.0 Hz), 8.43 (1H, d, J = 5.5 Hz), 8.50 (1H, d, J = 8.2 Hz). MS (IS> 0) m / z: 687.3 (M + H +).
9.3. (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester.
The reduction reaction is carried out according to the procedure described in Example 5.3 from 5.6 g of (6R, 7R) -3-acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -

benzhydryl ester (Example 9.2) (8.2 mmol) and 1.6 mL of trichlorophosphine (18.3 mmol). The product is obtained after recrystallization dichloromethane / diethyl ether as a beige powder (5.0 g, 91%).
IR (KBr) cm-1: (C = O) 1783, 1738, 1679. 1H NMR (400MHz, DMSO) δ ppm: 1.96 (3H, s), 2.72 (2H, t, J = 6); , 8 Hz), 3.48 (1H, d, J = 18.3 Hz), 3.64 (1H, d, J = 18.3 Hz), 3.78 (2H, q, J = 6.8 Hz), 4.62 (1H, d, J = 13.0 Hz), 4.85 (1H, d, J = 13.0 Hz), 5.15 (1H, d, J = 4.9 Hz) , 5.81 (1H, dd, J = 4.9 Hz, J = 8.3 Hz), 6.92 (1H, d, J = 7.2 Hz), 6.92 (1H, s), 7.297 , 49 (10H, m), 7.79 (1H, dd, J = 2.1Hz, J = 9.1Hz), 8.07 (1H, d, J = 2.1 Hz), 8.58 (1H,

Hz). MS (IS> 0) m / z: 671.2 (M + H +).
9.4. (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -8-

The deprotection reaction is carried out according to the procedure described in Example 5.4 from 3.0 g of (6R, 7R) -3-acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) propionyl) amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (Example 9.3) (4.5 mmol), 2.0 mL of anisole (18.4 mmol) and 3.3 mL of trifluoroacetic acid (45.0 mmol). PA 1037 is obtained in the form of an unbleached powder after recrystallization by dissolution in 5% (w / v) bicarbonate water and precipitation at 0 ° C. with an aqueous solution of 2M HCl to pH 6 (0.6 g, 27%).
IR (KBr) cm-1: (C = O) 1773, 1753, 1653. NMR H (400 MHz, DMSO) ppm: 2.02 (3H, s), 2.68 (2H, t, J = 6, 7 Hz), 3.39 (1H, d, J = 18.0 Hz), 3.58 (1H, d, J = 18.0 Hz), 3.71 (2H, m), 4.68 (1H). , d, J = 12.7 Hz), 5.00 (1H, d, J = 12.7 Hz), 5.07 (1H, d, J = 4.9 Hz), 5.70

9.1 Hz), 7.96 (1H, d, J = 2.1 Hz), 8.46 (1H, d, J = 9.1 Hz), 8.54 (1H, d, J = 6, 8 Hz), 8.94 (1H, brs), 9.06 (1H, d, J = 8.2 Hz). MS (IS> 0) m / z: 505.0 (M + H +) Analysis

47.34, N 9.93 Example 10: Preparation of an aminoquinoline cephalosporin, ref PA 1063 (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) propionylamino ] -5,8-dioxo

PA 1063 is obtained by deprotection of (6R, 7R) -3-acetoxymethyl-7- [3- (7-chloro)

carboxylic acid benzhydryl ester (Example 9.2) (1.1 g, 1.6 mmol) according to the procedure described in Example 5.4 with 0.7 mL of anisole (6.2 mmol) and 1.2 mL of acid trifluoroacetic acid (15.5 mmol). PA 1063 is obtained in the form of an unbleached powder (0.6 g, 27%).
IR (KBr) cm-1: (C = O) 1774, 1732, 1647. 1 H NMR (250 MHz, DMSO) δ ppm: 2.01 (3H, s), 2.71 (2H, brs), 3 , 55 (1H, d, J = 18.6 Hz), 3.59 (2H, brs), 3.78 (1H, d, J = 18.6 Hz), 4.59 (1H, d, J) = 12.9 Hz), 4.85 (1H, brs), 5.21 (1H, d, J = 12.9 Hz), 5.79 (1H, brs), 6.67 (1H, s). broad), 7.58 (1H, d, J = 9.0Hz), 7.87 (1H, s), 8.11 (1H, brs), 8.338.46 (3H, m). MS (IS> 0) m / z: 521.1 (M + H +).
Example 11 Preparation of an aminoquinoline-cephalosporin, ref PA 1082 (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) propionylamino] -5,8-dioxo

PA 1082 is prepared according to the procedure described in Example 6 starting from 0.7 g of PA 1063 (Example 10) (1.4 mmol) and 0.5 ml of a solution of HCl 5 M in the 2 propanol (4.0 mmol). PA 1082 is obtained in the form of an unbleached powder (0.4 g, 55%).
1 H NMR (250 MHz, DMSO) ppm: 2.02 (3H, s), 2.76 (2H, m) 3.60 (1H, d, J = 18.6Hz), 3.76 (2H, m). ), 3.85 (1H, d, J = 18.6 Hz), 4.58 (1H, d, J = 13.1 Hz), 4.89 (1H, d, J = 4.2 Hz), 5.20 (1H, d, J = 13.1Hz), 5.83 (1H, dd, J = 4.2Hz, J = 7.7Hz), 6.91 (1H, d, J = 7); , 1 Hz), 7.80 (1H, d, J = 8.8 Hz), 8.04 (1H, s), 8.55 (3H, m), 9.43 (1H, brs), 14 , 04 (s large). MS (IS> 0) m / z: 521.1 (M-Cl) +. Elemental analysis: for

9.25.
Example 12: Preparation of aminoquinoline cephalosporin, ref PA 1053 (6R, 7R) -3-Acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8-oxo-5-thia1 aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

12.1. 4- (7-Chloroquinolin-4-yl) butyric acid.
This compound is prepared according to the procedure described in Example 1.1 from 30.0 g of 4,7-dichloroquinoline (0.15 mol), 32.8 g of 4-aminobutyric acid (0.32 mol) and 77.0 g of phenol (0.82 mol). The product is obtained in the form of a white powder (32.7 g, 82%).
1 H NMR (300 MHz, CF 3 COOD) ppm: 2.23 (2H, quint, J = 6.9 Hz), 2.71 (2H, t, J = 6.9 Hz), 3.71 (2H, t, J = 6.9 Hz), 6.81 (1H, d, J = 7.5 Hz), 7.64 (1H, dd, J = 1.8 Hz, J = 9.0 Hz), 7.82. (1H, d, J = 1.8 Hz), 8.08 (1H, d, J = 9.0 Hz), 8.22 (1H, d, J = 7.5 Hz).
12.2. Mixture of (6R, 7R) -3-acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct -2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8oxo-5-thia-1- aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester: /.
The coupling product is prepared according to the procedure described in Example 5.1 from 7.8 g of 4- (7-chloroquinolin-4-yl) butyric acid (Example 12.1) (24.5 mmol), 3.5 g of HOBT (25.7 mmol), 5.3 g of DCC (25.7 mmol), 15.1 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia -1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p-toluene sulfonic acid (24.5 mmol) and 6.9 mL of triethylamine (49.5 mmol). The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: ethyl acetate / ethanol / triethylamine 90/9/1 v / v / v) in the form of an orange powder (3.3 g, 20%) in a mixture / 22/78, used as it is in the next step.
12.3. (6R, 7R) -3-Acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -5,8-

The oxidation reaction is carried out according to the procedure described in Example 5.2 from 3.3 g of the mixture / Example 12.2 (4.8 mmol) and 1.7 g of 3chloroperoxybenzoic acid (9.6 g). mmol). The product is obtained in the form of an orange-yellow powder (2.5 g, 74%).
IR (KBr) cm-1: (C = O) 1791, 1735, 1655. 1 H NMR (300 MHz, DMSO) ppm: 1.92 (2H, quint, J = 7.2 Hz), 2.01 (3H); , s), 2.43 (2H, t, J = 7.2 Hz), 3.33 (2H, m), 3.65 (1H, d, J = 18.9 Hz), 3.96 (1H , d, J = 18.9 Hz), 4.61 (1H, d, J = 13.2 Hz), 4.96 (1H, d, J = 4.2 Hz), 5.07 (1H, d , J = 13.2 Hz), 5.95 (1H, dd, J = 4.2 Hz, J = 7.8 Hz), 6.57 (1H, d, J = 5.7 Hz), 6, 95 (1H, s), 7.27-7.54 (11H, m), 7.66 (1H, brs), 7.80 (1H, d, J = 2.1Hz), 1H, d, J = 9.0 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.43 (1H, d, J = 5.7 Hz). MS (IS> 0) m / z: 701.3 (M + H +).
12.4. (6R, 7R) -3-Acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester.
The reduction reaction is carried out according to the procedure described in Example 5.3 from 2.9 g of (6R, 7R) -3-acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) -

benzhydryl ester (Example 12.3) (4.1 mmol) and 0.8 mL of trichlorophosphine (9.1 mmol). The product is obtained after recrystallization dichloromethane / diethyl ether in the form of a beige powder (2.5 g, 89%).
IR (KBr) cm-1: (C = O) 1784, 1730, 1661. 1 H NMR (300 MHz, DMSO) ppm: 1.92 (2H, quint, J = 7.2 Hz), 1.96 (3H); , s), 2.38 (2H, t, J = 7.2 Hz), 3.53 (2H, m), 3.53 (1H, d, J = 18.6 Hz), 3.67 (1H , d, J = 18.6 Hz), 4.62 (1H, d, J = 12.9 Hz), 4.86 (1H, d, J = 12.9 Hz), 5.16 (1H, d , J = 4.8 Hz), 5.79 (1H, dd, J = 4.8 Hz, J = 8.1 Hz), 6.91 (1H, d, J = 6.9 Hz), 6, 92 (1H, s), 7.28-7.49 (10H, m), 7.78 (1H, dd, J = 1.8Hz, J = 9.0Hz), 8.04 (1H, d); , J = 1.8 Hz), 8.56 (1H, d, J = 6.9 Hz), 8.63 (1H, d, J = 9.0 Hz), 8.97 (1H, d, J = 8.1 Hz), 9.56 (1H, brs). MS (IS> 0) m / z: 685.2 (M + H +).
12.5. (6R, 7R) -3-Acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid.
The deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.8 g of (6R, 7R) -3-acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino). ] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (Example 12.4) (1.2 mmol), 0.5 mL of anisole (4.8 mmol) and 0.9 mL of trifluoroacetic acid (12.1 mmol). PA 1053 is obtained in the form of a white powder after recrystallization by dissolution in 5% (w / v) bicarbonate water and precipitation at 0 ° C. with an aqueous 2 M HCl solution. pH 6 (0.3 g, 35%).
IR (KBr) cm-1: (C = O) 1769, 1737, 1653. NMR H (300 MHz, DMSO) ppm: 1.91 (2H, m), 2.02 (3H, s), 2.37 (2H, t, J = 7.2 Hz), 3.41 (2H, m), 3.44 (1H, d, J = 18.3 Hz), 3.61 (1H, d, J = 18, 3 Hz), 4.69 (1H, d, J = 12.9 Hz), 5.00 (1H, d, J = 12.9 Hz), 5.09 (1H, d, J = 4.8 Hz ), 5.68 (1H, dd, J = 4.8 Hz, J = 8.1 Hz), 6.73 (1H, d, J = 6.0 Hz), 7.64 (1H, d, J) = 9.0 Hz), 7.89 (1H, s), 8.41 (1H, d, J = 9.0 Hz), 8.52 (2H, broad m), 8.90 (1H, d, J = 6.0

theor. C, 49.77, N, 10.10; % experiment C, 49.79, N, 9.74.
Example 13 Preparation of an aminoquinoline-cephalosporin, ref PA 1054

oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

13.1. Mixture of (6R, 7R) -3-acetoxymethyl-7- [1- (7-chloroquinolin-4-yl) -piperidine-

ester: /.
2.1 ml of N-methylmorpholine (19.4 mmol) are added to a mixture of 1- (7-chloroquinolin-4-yl) -piperidine-4-carboxylic acid (Example 1.1) (1.2 g, 3, 9 mmol) and (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p -toluene sulfonic acid (2.4 g, 3.9 mmol) in 40 mL of DMF. The suspension is stirred magnetically for 15 min before the addition of PyBOP activator (2.0 g, 3.9 mmol). Magnetic stirring is continued for 24 hours at room temperature. The reaction medium is then diluted with 50 ml of dichloromethane and then washed successively with 50 ml of 5% (w / v) carbonated water, twice 50 ml of water and 50 ml of water saturated with NaCl. The organic phase is dried over magnesium sulphate, filtered and then evaporated. The coupling product is obtained in the form of an orange powder (2.5 g, 90%) in a A / A 32/68 mixture, used as such in the next step.

ester.
To a solution at 0 [deg] C of the mixture / 12 // 1 of Example 13.1 (10.1 g, 14.2 mmol) in 100 ml of dichloromethane is added dropwise over a period of 3 hours, a solution of 3-chloroperoxybenzoic acid (4.9 g, 28.4 mmol) in 100 mL of dichloromethane. The reaction medium is then washed with a mixture of 100 ml of 5% (w / v) bicarbonate water and 100 ml of a 5% (w / v) aqueous solution of sodium sulphite. The organic phase is dried over magnesium sulfate, filtered and evaporated. The product is then purified by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: dichloromethane / ethanol 90/10 v / v). The cleanest fractions in TLC revealed under UV are evaporated. The product is obtained in the form of an unbleached powder (4.0 g, 38%).
IR (KBr) cm-1: (C = O) 1787, 1733, 1653. NMR H (400 MHz, CDCl3) δ ppm: 2.05 (3H, s), 2.10 (4H, m), 2, 50 (1H, m), 2.87 (2H, m), 3.28 (1H, d, J = 19.2Hz), 3.88 (1H, d, J = 19.2Hz), 3, 63 (2H, d, J = 12.0Hz), 4.56 (1H, d, J = 4.8Hz), 4.78 (1H, d, J = 14.4Hz), 5.32 ( 1H, d, J = 14.4 Hz), 6.18 (1H, dd, J = 4.8 Hz, J = 9.6 Hz), 6.83 (1H, d, J = 5.2 Hz) , 6.97 (1H, s), 6.97 (1H, d, J = 9.6 Hz), 7.27-7.49 (11H, m), 7.92 (1H, d, J = 9 , 2 Hz), 8.05 (1H, d, J = 2.0 Hz), 8.71 (1H, d, J = 5.2 Hz). MS (IS> 0) m / z: 727.3 (M + H +).
13.3. (6R, 7R) -3-Acetoxymethyl-7- [1- (7-chloro-quinolin-4-yl) -piperidine-4-carbonyl] -

ene-2-carboxylic acid benzhydryl ester (Example 13.2) (0.6 g, 0.9 mmol) in 6 mL of dry DMF is added dropwise 0.2 mL of trichlorophosphine (1.9 mmol). The reaction is left under magnetic stirring for 1 h at -20 [deg] C. The reaction medium is then diluted with 20 ml of dichloromethane and then washed successively with twice 20 ml of water and 20 ml of water saturated with NaCl. The organic phase is dried over magnesium sulfate, filtered and evaporated. The product is obtained after recrystallization dichloromethane / diethyl ether in the form of an unbleached powder (0.5 g, 83%).
IR (KBr) cm-: (C = O) 1783, 1732, 1672. NMR H (400 MHz, CDCl3) δ ppm: 2.02 (3H, s), 2.11-2.23 (4H, m) , 3.07 (1H, m), 3.20 (1H, d, J = 18.8 Hz), 3.45 (2H, m), 3.50 (1H, d, J = 18.8 Hz) , 4.02 (2H, m), 4.48 (1H, d, J = 14.1Hz), 4.95 (1H, d, J = 14.1Hz), 4.99 (1H, d, J = 4.9 Hz), 5.94 (1H, dd, J = 4.9 Hz, J = 8.5 Hz), 6.48 (1H, d, J = 6.7 Hz), 6.82 (1H, s), 7.30-7.55 (12H, m), 7.91 (1H, d, J = 9.2 Hz), 8.29 (1H, d, J = 8.5 Hz) , 8.33 (1H, d, J = 6.7 Hz), 8.48 (1H, d, J = 1.8 Hz). MS (IS> 0) m / z: 711.2 (M + H +).

carboxylic acid benzhydryl ester (0.5 g, 0.6 mmol) (Example 13.3) in 10 ml of dry dichloromethane is added 0.3 ml of anisole (2.5 mmol) followed by 0.5 ml of trifluoroacetic acid injected dropwise (6.3 mmol). The reaction is stirred magnetically for 1 h 30 at room temperature. The product, in the form of triflate salt, is precipitated by addition of diethyl ether and filtered. The powder obtained is washed with water, acetone, diethyl ether before being dried under vacuum. PA 1054 is obtained in the form of an unbleached powder (0.2 g, 44%).
IR (KBr) cm-1: (C = O) 1763, 1737, 1648. 1H NMR (400MHz, DMSO) ppm: 1.86-1.98 (4H, m), 2.02 (3H, s); , 2.58 (1H, m), 2.85 (2H, m), 3.30 (1H, d, J = 17.2Hz), 3.53 (1H, d, J = 17.2Hz) , 3.56 (2H, m), 4.75 (1H, d, J = 12.4Hz), 5.01 (1H, d, J = 12.4Hz), 5.03 (1H, d, J = 4.4 Hz), 6.03 (1H, dd, J = 4.4 Hz, J = 8.0 Hz), 7.02 (1H, d, J = 5.0 Hz), 7.56.

(1H, d, J = 5.0 Hz), 8.89 (1H, d, J = 8.0 Hz). MS (IS> 0) m / z: 545.2 (M + H +).
Example 14 Preparation of an aminoquinoline-cephalosporin, ref PA 1074

oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride.

To a solution at 0 [deg] C of PA 1054 (Example 13.4) (0.5 g, 0.8 mmol) in 40 ml of a 1/1 v / v chloroform / ethanol mixture is added dropwise. 2 mL of a solution of 5M HCl in 2-propanol (1.0 mmol). After 20 minutes of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether. The precipitate is filtered, washed with cold acetone and then with diethyl ether and dried under vacuum. PA 1074 is obtained in the form of an unbleached powder (0.3 g, 54%).
IR (KBr) cm-1: (C = O) 1779, 1736, 1668. 1 H NMR (300 MHz, DMSO) δ ppm: 1.79-1.99 (4H, m), 2.03 (3H, s). 2.74 (1H, m), 3.43 (2H, m), 3.55 (1H, d, J = 18.3Hz), 3.64 (1H, d, J = 18.3Hz); ), 4.24 (1H, d, J = 12.9 Hz), 5.00 (1H, d, J = 12.9 Hz), 5.12 (1H, d, J = 4.5Hz), 5.69 (1H, dd, J = 4.5Hz, J = 8.1Hz), 7.20 (1H, d, J = 7). , 2 Hz), 7.68 (1H, dd, J = 1.5 Hz, J = 9.0 Hz), 8.11 (1H, d, J = 1.5 Hz), 8.15 (1H, d, J = 9.0 Hz), 8.65 (1H, d, J = 7.2 Hz), 8.98 (1H, d, J = 8.1 Hz). MS (IS> 0) m / z: 545.2 (M-

8.94; % experiment C, 47.89, N, 8.92.
Example 15 Preparation of an aminoquinoline-cephalosporin, ref PA 1100 (6R, 7R) -3-Acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) -acetylamino] -8oxo-5-thia- 1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

15.1. (7-Trifluoromethyl-quinolin-4-ylamino) -acetic acid.
This compound is prepared according to the procedure described in Example 1.1 from a mixture of 2.5 g of 4-chloro-7- (trifluoromethyl) quinoline (10.8 mmol), 1.8 g of glycine (23 g). 7 mmol) and 5.7 g of phenol (60.4 mmol) heated for 24 h at 150 ° C. The product is obtained in the form of a white powder (1.8 g, 62%).
1 H NMR (300 MHz, DMSO) ppm: 4.10 (2H, d, J = 6.0 Hz), 6.48 (1H, d, J = 5.4 Hz),

8.43 (1H, d, J = 9.0 Hz), 8.52 (1H, d, J = 5.4 Hz).
15.2. (6R, 7R) -3-acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) -acetylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] -octin 2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) acetylamino] -8-oxo-5-thia-1 aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester: /.
The coupling product is prepared according to the procedure described in Example 13.1 from 0.7 g of (7-trifluoromethyl-quinolin-4-ylamino) -acetic acid (Example 15.1) (2.6 mmol), 1, 6 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p-toluene sulfonic acid (2.6 mmol), 1.4 mL of N-methylmorpholine (13.0 mmol) and 1.3 g of PyBOP (2.6 mmol). The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 6-35 Microm, eluent: ethyl acetate / triethylamine / ethanol 96/3/1 v / v / v) in the form of a light beige powder (0.6 g, 32%) in a mixture / 31/69, used as it is in the next step.
15.3. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-trifluoromethylquinolin-4-ylamino)]

benzhydryl ester.
The oxidation reaction is carried out according to the procedure described in Example 5.2 from 0.6 g of the A / A mixture of Example 15.2 (0.8 mmol) and 0.3 g of 3chloroperoxybenzoic acid (1 g). 7 mmol). The product is obtained in the form of a yellow powder (0.5 g, 91%).
IR (KBr) cm-1: (C = O) 1786, 1734, 1668. 1 H NMR (300 MHz, DMSO) ppm: 1.95 (3H, s), 3.60 (1H, d, J = 18, 6 Hz), 3.93 (1H, d, J = 18.6 Hz), 4.15 (2H, m), 4.57 (1H, d, J = 13.5 Hz), 4.95 (1H). , d, J = 4.8 Hz), 5.02 (1H, d, J = 13.5 Hz), 6.04 (1H, dd, J = 4.8 Hz, J = 9.0 Hz), 6.51 (1H, d, J = 5.4 Hz), 6.94 (1H, s), 7.26-7.52 (10H, m), 7.75 (1H, dd, J = 1, 5 Hz, J = 8.7 Hz), 8.01 (1H, brs), 8.13 (1H, d, J = 1.5 Hz), 8.38 (1H, d, J = 9.0). Hz), 8.40 (1H, d, J = 8.7 Hz), 8.56 (1H, d, J = 5.4 Hz). MS (IS> 0) m / z: 707.2 (M + H +).
15.4. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) acetylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid benzhydryl ester.
The reduction reaction is carried out according to the procedure described in Example 5.3 from 0.4 g of (6R, 7R) -3-acetoxymethyl-7- [2- (7-trifluoromethyl) quinolin-4-

benzhydryl ester (Example 15.3) (0.6 mmol) and 0.1 mL of trichlorophosphine (1.3 mmol). The product is obtained after recrystallization dichloromethane / diethyl ether in the form of a beige powder (0.2 g, 54%).
1 H NMR (300 MHz, DMSO) ppm: 1.96 (3H, s), 3.35 (2H, m), 4.37 (2H, m), 4.64 (1H, d, J = 12.9). Hz), 4.93 (1H, brs), 4.96 (1H d, J = 12.9Hz), 5.78 (1H, brs), 6.55 (1H, brs), 6, 87 (1H, s), 7.25-7.43 (10H, m), 7.62 (1H, brs), 8.29 (1H, brs), 8.39 (1H, brs), 8.56 (1H, brs), 8.93 (1H, brs), 9.32 (1H, brs).
15.5. (6R, 7R) -3-Acetoxymethyl-7- [2- (7-trifluoromethylquinolin-4-ylamino)]

The deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.2 g of (6R, 7R) -3-acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) -acetylamino] 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (Example 15.4) (0.3 mmol), 0.1 mL of anisole ( 1.3 mmol) and 0.2 mL of trifluoroacetic acid (3.2 mmol). PA 1100 is obtained in the form of a yellow powder after successive washings with water, acetonitrile and diethyl ether (0.1 g, 54%). IR (KBr) cm-1: (C = O) 1772, 1734, 1674.RMN H (300 MHz, DMSO) ppm: 2.03 (3H, s), 3.49 (1H, d, J = 18, 0 Hz), 3.63 (1H, d, J = 18.0 Hz), 4.17 (2H, d, J = 5.7 Hz), 4.69 (1H, d, J = 12.8 Hz). ), 5.00 (1H, d, J = 12.8 Hz), 5.11 (1H, d, J = 4.8 Hz), 5.73 (1H, dd, J = 4.8 Hz, = 8.4 Hz), 6.54 (1H, d, J = 5.4 Hz), 7.83 (1H, d, J = 9.0 Hz), 8.16 (1H, s), 8, 43 (1H, brs), 8.51 (1H, d, J = 9.0Hz), 8.58 (1H, brs), 9.25 (1H, d, J = 8.4Hz). SM

C, 44.97, N, 9.54; % experiment C 44.94, N 9.15.
EXAMPLE 16 Preparation of an aminoquinoline-cephalosporin, ref. PA 1101 (6R, 7R) -3-Acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -8-oxo-5- thia1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

16.1. (2-Methyl-quinolin-4-ylamino) -acetic acid.
This compound is prepared according to the procedure described in Example 1.1 from a mixture of 4.8 g of 4-chloro-quinaldine (27.3 mmol), 4.5 g of glycine (60.0 mmol) and 14.6 g of phenol (155.0 mmol) heated 24 h at 150 [deg.] C. The product is obtained in the form of a white powder (3.8 g, 64%).
1 H NMR (300 MHz, CF 3 COOD) ppm: 2.60 (3H, s), 4.37 (2H, s), 6.42 (1H, s), 7.59 (1H, t, J = 7.2; Hz), 7.66 (1H, d, J = 8.4 Hz), 7.80 (1H, t, J = 7.5 Hz), 7.95 (1H, d, J = 8.7 Hz) .
16.2. Mixture of (6R, 7R) -3-acetoxymethyl-7- [2- (2-methylquinolin-4-ylamino) -

ester and (6R, 7R) -3-acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct- 3-ene-2-carboxylic acid benzhydryl ester:
The coupling product is prepared according to the procedure described in Example 13.1 starting from 0.7 g of (2-methyl-quinolin-4-ylamino) -acetic acid (Example 16.1) (3.5 mmol), 2, 2 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydroxy ester p-toluene sulfonic acid (3.5 mmol), 1.9 mL of N-methylmorpholine (17.5 mmol) and 1.8 g of PyBOP (3.5 mmol). The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 6-35 Microm, eluent: ethyl acetate / triethylamine / ethanol 95/3/2 v / v / v) in the form of an orange powder (1.3 g, 58%) in a mixture / 21/79, used as it is in the next step.
16.3. (6R, 7R) -3-Acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -5,8-

The oxidation reaction is carried out according to the procedure described in Example 5.2 from 1.3 g of the A / A mixture of Example 16.2 (2.0 mmol) and 0.7 g of 3chloroperoxybenzoic acid (4 g). 0 mmol). The product is obtained in the form of an orange powder (1.1 g, 83%).
IR (KBr) cm-1: (C = O) 1792, 1734, 1652. NMR H (300 MHz, DMSO) δ ppm: 1.95 (3H, s), 2.52 (3H, s), 3, 62 (1H, d, J = 18.9 Hz), 3.95 (1H, d, J = 18.9 Hz), 4.13 (2H, m), 4.58 (1H, d, J = 13). , 5 Hz), 4.96 (1H, d, J = 4.2 Hz), 5.03 (1H, d, J = 13.5 Hz), 6.04 (1H, dd, J = 4.2 Hz, J = 8.7 Hz), 6.34 (1H, s), 6.94 (1H, s), 7.26-7.54 (11H, m), 7.64 (1H, t, J). = 7.5 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.89 (1H, m), 8.17 (1H, d, J = 8.7 Hz), 8, 42 (1H, d, J = 8.7 Hz). MS (IS> 0) m / z: 653.2 (M + H +).
16.4. (6R, 7R) -3-Acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester.
The reduction reaction is carried out according to the procedure described in Example 5.3 from 2.3 g of (6R, 7R) -3-acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -

benzhydryl ester (Example 16.3) (3.5 mmol) and 0.7 mL of trichlorophosphine (7.8 mmol). The product is obtained after recrystallization dichloromethane / diethyl ether in the form of a beige powder (1.8 g, 82%).
IR (KBr) cm-1: (C = O) 1784, 1733, 1639. 1 H NMR (300 MHz, DMSO) ppm: 1.96 (3H, s), 2.73 (3H, s), 3.58. (1H, d, J = 18.3 Hz), 3.70 (1H, d, J = 18.3 Hz), 4.33 (2H, m), 4.63 (1H, d, J = 12, 9 Hz), 4.87 (1H, d, J = 12.9 Hz), 5.19 (1H, d, J = 5.1 Hz), 5.85 (1H, dd, J = 5.1 Hz). , J = 8.1 Hz), 6.61 (1H, s), 6.93 (1H, s), 7.28-7.50 (10H, m), 7.70 (1H, m), 7. , 94 (2H, m), 8.46 (1H, d, J = 8.7 Hz), 9.37 (1H, d, J = 8.1 Hz), 9.42 (1H, t, d, J = 6.0 Hz). MS (IS> 0) m / z: 637.2 (M + H +).
16.5. (6R, 7R) -3-Acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid.
The deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.8 g of (6R, 7R) -3-acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) acetylamino). ] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (Example 16.4) (1.2 mmol), 0.5 mL of anisole (4.9 mmol) and 0.9 mL of trifluoroacetic acid (12.4 mmol). PA 1101 is obtained in the form of a yellow powder after successive washings with water, acetone and diethyl ether (0.2 g, 27%).
IR (KBr) cm-1: (C = O) 1772, 1736, 1652. 1H NMR (400MHz, DMSO) ppm: 2.01 (3H, s), 2.59 (3H, s), 3.38 (1H, d, J = 17.6Hz), 3.58 (1H, d, J = 17.6Hz), 4.21 (2H, m), 4.74 (1H, d, J = 12, 4 Hz), 5.01 (1H, d, J = 12.4 Hz), 5.06 (1H, d, J = 4.8 Hz), 5.64 (1H, dd, J = 4.8 Hz). , J = 8.0 Hz), 6.46 (1H, s), 7.58 (1H, t, J = 7.4 Hz), 7.80 (1H, t, J = 7.5 Hz), 7.89 (1H, broad, J = 7.8 Hz), 8.33 (1H, d, J = 8.6 Hz), 8.77 (1H, brs), 9.26 (1H, d). , J 8.0 Hz). MS (IS> 0) m / z: 471.2 (M + H +). Elemental analysis: for

EXAMPLE 17 Preparation of an aminoquinoline-cephalosporin, ref. PA 1191 (6R, 7R) -3-Acetoxymethyl-7- [4-morpholin-4-yl-quinolinecarbonyl) -amino] -8-oxo-5-thia1 -aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

17.1 4-Chloroquinoline-2-carboxylic acid ethylester.
A mixture of 4-hydroxy-quinoline-2-carboxylic acid ethyl ester (10.0 g, 46.0 mmol) and phosphorus oxychloride (43 mL, 460.0 mmol) was refluxed for 2.5 hours. After returning to ambient temperature, the mixture is concentrated to dryness by a tube tube before the slow addition of 26 ml of water and then 44 ml of 28% ammonia. The product is then extracted with 500 mL of boiling ethyl acetate. The organic phase is evaporated to dryness. The product is obtained in the form of a white powder after recrystallization from a methanol / water mixture (9.3 g, 86%).
1 H NMR (250 MHz, DMSO) δ ppm: 1.48 (3H, t, J = 7.0Hz), 4.55 (2H, q, J = 7.0Hz), 7.74 (1H, dt). , J = 1.1 Hz, J = 6.3 Hz), 7.84 (1H, dt, J = 1.4 Hz, J = 7.0 Hz), 8.25 (1H, s), 8, (1H, m), 8.34 (1H, m). MS (IS> 0) m / z: 235.9 (M + H +).
17.2. Morpholin-4-yl- (4-morpholin-4-yl-quinolin-2-yl) -methanone.
A mixture of 4-chloro-quinoline-2-carboxylic acid ethyl ester (Example 17.1) (4.5 g, 19 mmol) and morpholine (16 mL, 190.0 mmol) was refluxed under argon for 16 h. The reaction medium is then diluted with 200 ml of dichloromethane and washed successively 3 times with 200 ml of water and then 200 ml of a saturated aqueous solution of NaCl. The organic phase is dried over magnesium sulfate, filtered and dried under vacuum. The product is obtained in the form of a white powder (5.5 g, 88%).
1 H NMR (250 MHz, CDCl 3) δ ppm: 3.30 (4H, s), 3.74 (4H, d, J = 2.9 Hz), 3.86 (4H, s), 3.99 (4H). , t, J = 4.3 Hz), 7.20 (1H, s), 7.57 (1H, t, J = 7.5 Hz), 7.71 (1H, t, J = 7.1) , 8.00 (1H, m), 8.04 (1H, m). MS (IS> 0) m / z: 328.0 (M + H +).
17.3. 4-Morpholin-4-yl-quinoline-2-carboxylic acid.
To a solution of morpholin-4-yl- (4-morpholin-4-yl-quinolin-2-yl) -methanone (Example 17.2) (5.2 g, 16.0 mmol) in 60 mL of ethanol is added an aqueous solution of 2.7 M sodium hydroxide (160.0 mmol). The medium is left stirring for 15 hours. The white precipitate is filtered and dried under vacuum (3.1 g, 75%).
1 H NMR (250 MHz, DMSO) δ ppm: 3.15 (4H, t, J = 4.1 Hz), 3.88 (4H, t, J = 4.5 Hz), 7.51 (1H, t). , J = 7.1 Hz), 7.65 (1H, t, J = 7.16 Hz), 7.66 (1H, s), 8.00 (1H, d, J = 8.0 Hz), 8.24 (1H, d, J = 8.4 Hz).
17.4. Mixture of (6R, 7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinolin-2-carbonyl) amino] -8-oxo-5-thia-1-aza-bicylo [4.2.0] oct -2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinolin-2-carbonyl) -amino] -8-oxo-5-thia1 -aza-bicylo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester: The coupling product is prepared according to the procedure described in Example 13.1 from 3.2 g of 4-morpholine. 4-yl-quinoline-2-carboxylic acid (Example 17.3) (12.4 mmol), 7.5 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1 azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydroxy ester p-toluene sulfonic acid (12.4 mmol), 4.0 mL of N-methylmorpholine (37.2 mmol) and 6.4 g of PyBOP (12.4 mmol) .The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: dichloromethane / ethyl acetate 80/20 v / v) under the form of an orange powder (3.7 g, 45%) in a mixture / 23/77, used as what in the next step.
17.5. (6R, 7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinoline-2-carbonyl) -amino] -5,8

The oxidation reaction is carried out according to the procedure described in Example 5.2 from 3.2 g of the mixture / Example 17.4 (4.8 mmol) and 2.2 g of 3chloroperoxybenzoic acid (13.0 g). mmol). The product is purified by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: dichloromethane / ethyl acetate 80/20 (v / v) in the form of a yellow powder (1.1 g, 33%).
1 H NMR (300 MHz, CDCl 3) δ ppm: 2.00 (3H, s), 3.25 (1H, d, J = 18.9 Hz), 3.33 (4H, t, J = 4.8 Hz. ), 3.90 (1H, d, J = 18.9 Hz), 4.00 (4H, t, J = 4.5 Hz), 4.64 (1H, d, J = 4.8 Hz), 4.82 (1H, d, J = 14.1Hz), 5.35 (1H, d, J = 14.1Hz), 6.35 (1H, dd, J = 10.2Hz, J = 4; , 8 Hz), 7.00 (1H, s), 7.30-7.37 (10H, m), 7.51 (1H, s), 7.52 (1H, m), 7.75 (1H, m.p. , m), 8.03 (1H, d, J = 8.4 Hz), 8.12 (1H, d, J = 8.4 Hz), 9.37 (1H, d, J = 10.5 Hz) ).
17.6. (6R, 7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinoline-2-carbonyl) -amino] -8-oxo5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid benzhydryl ester.
The reduction reaction is carried out according to the procedure described in Example 5.3 from 0.8 g of (6R-7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinoline-2-carbonyl) ) -

ester (Example 17.5) (1.1 mmol) and 0.2 mL of trichlorophosphine (2.4 mmol). The product is obtained after solubilization in dichloromethane and addition of diethyl ether until the product falls into the form of a brown oil. The supernatant is removed and the oil is dried under vacuum (0.7 g, 91%). 1 H NMR (300 MHz, CDCl 3) δ ppm: 2.04 (3H, s), 3.32 (4H, t, J = 4.1 Hz), 3.42 (1H, d, J = 15.9 Hz). ), 3.65 (1H, d, J = 15.9 Hz), 3.98 (4H, t, J = 4.7 Hz), 4.82 (1H, d, J = 13.5 Hz), 5.05 (1H, d, J = 13.5Hz), 5.12 (1H, d, J = 4.9Hz), 6.07 (1H, m), 6.98 (1H, s), 7.27-7.33 (10H, m), 7.59 (1H, t, J = 8.1 Hz), 7.71 (1H, m), 7.73 (1H, s), 8.02 (1H, d, J = 8.4 Hz), 8.20 (1H, m).
17.7. (6R, 7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl-quinoline-2-carbonyl) -amino] -8-oxo5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid.
The deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.7 g of (6R-7R) -3-acetoxymethyl-7 - [(4-morpholin-4-yl) quinolin-2-carbonyl) amino ] -8-oxo-5-thia-1-aza-bicylo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (Example 17.6) (1.0 mmol), 0.4 mL of anisole (4.0 mmol) and 0.7 mL of trifluoroacetic acid (10.0 mmol). The addition of hexane to the reaction medium leads to the formation of an oil. The supernatant is removed and the oil is triturated with cold water until a yellow precipitate is obtained which is filtered, washed with hexane and then with ether and dried under vacuum. PA 1191 is obtained as a yellow powder (10 mg, 2%) .1H NMR (300 MHz, DMSO) ppm: 2.04 (3H, s), 3.30 (4H, m), 3, (1H, d, J = 18.2Hz), 3.69 (1H, d, J = 18.1Hz), 3.90 (4H, s), 4.70 (1H, d, J = 12); , 8 Hz), 5.03 (1H, d, J = 12.8 Hz), 5.27 (1H, d, J = 4.9 Hz), 5.95 (1H, m), 7.59 (b.p. 1H, s), 7.67 (1H, t, J = 7.4 Hz), 7.82 (1H, t, J = 8.0 Hz), 8.11 (2H, d, J = 8.2 Hz), 9.23 (1H, d, J = 9.2 Hz). SM (IS> 0) m / z:

54.69, N, 10.21; % experiment C, 54.64, N, 10.17.
Example 18: Preparation of an aminoquinoline-cephalosporin, ref PA 1192 (6R-7R) -3-Acetoxy-7 - {[(4- (2-diethylaminoethylamino) -quinoline-2-carbonyl] -amino} -8oxo 5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

18.1. 4- (2-Diethylamino-ethylamino) -quinoline-2-carboxylic acid (2-diethylamino-ethyl) amide.
This compound is prepared according to the procedure described in Example 17.2 from 1.5 g of 4-chloroquinoline-2-carboxylic acid ethyl ester (Example 17.1) (6.4 mmol) and 9 ml of N, N diethylethylenediamine (64.0 mmol). The product is obtained in the form of a brown oil (2.6 g, 100%).
1 H NMR (250 MHz, CDCl 3) δ ppm: 1.06 (12H, m), 2.61 (8H, m), 2.70 (2H, t, J = 6.6Hz), 2.80 (2H; , t, J = 6.0 Hz), 3, 34 (2H, dd, J = 10.3 Hz, J = 4.7 Hz), 3.52 (2H, dd, J = 13.0 Hz, = 6.5 Hz), 6.21 (1H, s), 7.31 (1H, s), 7.44 (1H, t, J = 6.9 Hz), 7.62 (1H, t, J). = 7.0 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 8.4 Hz), 8.60 (1H, s).
18.2. 4- (2-Diethylaminoethylamino) -quinoline-2-carboxylic acid.
This compound is prepared according to the procedure described in Example 17.3 from 3.3 g of 4- (2-diethylaminoethylamino) -quinoline-2-carboxylic acid (2-diethylamino-ethyl) amide (Example 18.1) ( 8.6 mmol) and 34 mL of 2.5 M aqueous sodium hydroxide solution (86 mmol). Reflux heating is maintained for 10 days. After returning to ambient temperature, the reaction medium is diluted with 100 ml of ethanol and 100 ml of water and then it is washed with 200 ml of dichloromethane. The pH of the aqueous phase is then brought back to 7, at 0 ° C., with an aqueous solution of 1N HCl. The aqueous phase is evaporated to dryness and the product is extracted with 40 mL of DMF with stirring. The suspension is filtered and the filtrate is evaporated to dryness in vacuo. The product is obtained in the form of an orange oil (2.5 g, 100%).
1 H NMR (250 MHz, DMSO) ppm: 1.24 (6H, t, J = 7.0Hz), 3.22 (4H, q, J = 6.6Hz), 3.49 (2H, m). , 4.02 (2H, m), 7.29 (1H, s), 7.65 (1H, m), 7.92 (1H, t, J = 10.6Hz), 8.31 (1H, d, J = 8.5 Hz), 8.82 (1H, d, J = 8.5 Hz), 9.63 (1H, s).
18.3. (6R, 7R) -3-acetoxymethyl-7- [4- (2-diethylamino-ethylamino) -quinoline-2-carbonyl] -amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] mixture oct-2-ene-2-carboxylic acid benzhydryl ester and (6R, 7R) -3-acetoxymethyl-7 - {[4- (2-diethylaminoethylamino) -

benzhydryl ester acid: A / A.
The coupling product is prepared according to the procedure described in Example 13.1 starting from 1.6 g of 4- (2-diethylaminoethylamino) -quinoline-2-carboxylic acid (Example 18.2) (3.2 mmol), 2.0 g of (6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p-toluene sulfonic acid (3.2 mmol), 1 mL of N-methylmorpholine (10.0 mmol) and 1.7 g of PyBOP (3.2 mmol). The coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 Microm, eluent: dichloromethane / ethanol 90/10 (v / v) in the form of an orange oil (1.1 g , 52%) in a 45/55 A / A mixture, used as it is in the next step.
18.4. (6R, 7R) -3-acetoxymethyl-7 - {[4- (2-diethylamino-ethylamino) -quinoline-2-carbonly] -

ester.
The oxidation reaction is carried out according to the procedure described in Example 5.2 from 1.1 g of the mixture / Example 18.3 (1.6 mmol) and 0.7 g of 3chloroperoxybenzoic acid (4.1 mmol). The oxidation product is obtained after recrystallization dichloromethane / ether in the form of an orange powder (0.5 g, 39%). 1 H NMR (300 MHz, CDCl 3) δ ppm: 1.37 (6H, q, J = 3.3 Hz), 2.07 (3H, s), 3.26 (1H, d, J = 18.3 Hz. ), 3.45 (4H, t, J = 6.3 Hz), 3.57 (1H, d, J = 16.8 Hz), 3.70 (2H, m), 3.88 (2H, m). ), 4.62 (1H, d, J = 3.6 Hz), 4.78 (1H, d, J = 13.8 Hz), 5.35 (1H, d, J = 14.1 Hz), 6.34 (1H, dd, J = 10.2 Hz, J = 5.1Hz), 7.01 (1H, s), 7.15-7.43 (12H, m), 7.61 (1H); , t, J = 7.8 Hz), 7.96 (2H, m), 9.47 (2H, d, J = 10.8 Hz).
18.5. (6R, 7R) -3-acetoxymethyl-7 - {[4- (2-diethylamino-ethylamino) -quinoline-2-carbonyl] -

The reduction reaction is carried out according to the procedure described in Example 5.3 from 0.5 g of (6R, 7R) -3-acetoxymethyl-7 - [(4-diethylamino-quinoline-2-carbonyl) -

ester (Example 18.4) (0.6 mmol) and 0.1 mL of trichlorophosphine (1.4 mmol). The reduction product is obtained after recrystallization dichloromethane / diethyl ether as an orange oil (0.2 g, 51%).
1 H NMR (300 MHz, DMSO) δ ppm: 1.24 (6H, s), 1.98 (3H, s), 3.24 (4H, s), 3.42 (2H, d, J = 1); , 2 Hz), 3.63 (1H, d, J = 18.3 Hz), 3.73 (1H, d, J = 16.5 Hz), 3.84 (1H, s), 4.68 ( 1H, d, J = 13.5Hz), 4.90 (1H, d, J = 12.9Hz), 5.33 (1H, d, J = 4.2Hz), 6.04 (1H, m), 6.92 (1H, s), 7.19-7.50 (11H, m), 7.60 (1H, m), 7.78 (1H, m), 7.98 (1H, m). ), 8.46 (1H, m).
18.6. (6R-7R) -3-acetoxy-7 - [(4- (2-diethylaminoethylamino) -quinolin-2-carbonyl] amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
The deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.2 g of (6R, 7R) -3-acetoxymethyl-7 - {[4- (2-diethylaminoethylamino)]

acid benzhydryl ester (Example 18.5) (0.3 mmol), 0.1 ml of anisole (1.3 mmol) and 0.2 ml of trifluoroacetic acid (3.2 mmol). After returning to ambient temperature, the reaction mixture is filtered. The filtrate is precipitated with ether and the new filtered precipitate is washed with dichloromethane. The latter is solubilized in water and brought to pH 5 with a 5% (w / v) aqueous solution of NaHCO3. The aqueous phase is evaporated to dryness and the product is extracted with 40 mL of DMF with stirring. The suspension is filtered and the filtrate is evaporated to dryness in vacuo. The product is obtained in the form of an orange powder (50 mg, 29%).
1 H NMR (300 MHz, DMSO) ppm: 1.16 (6H, s), 2.03 (3H, s), 3.03 (4H, m), 3.33 - 3.49 (3H, m), 3.65 (2H, d, J = 19.2Hz), 4.75 (1H, d, J = 11.7Hz), 5.03 (1H, d, J = 13.2Hz), 5, 24 (1H, m), 5.96 (1H, m), 7.20 (1H, s), 7.56 (1H, m), 7.81 (2H, m), 7.93 (1H, m), , J = 7.2 Hz), 8.30 (1H, d, J = 7.8 Hz), 9.03 (1H, d, J = 9.3 Hz). Elemental analysis: for

EXAMPLE 19 Preparation of an aminoquinoline-cephalosporin, ref PA 1199 (6R-7R) -7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetylamino] -3- [2- ( 7-chloroquinolin-4-ylamino) -ethylsulfanylmethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

benzhydrylester.
To a solution under argon of 7-tert-butoxycarbonylamino-3-chloromethyl-8-oxo-5-thia-1aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (prepared according to the method described by HA Albrecht et al., J. Med Chem., 1994, 37, 400-407) (0.8 g, 1.5 mmol) in 10 mL of dimethylformamide is added sodium iodide (0.2 g, 1.5 mmol). After stirring for 30 minutes, 0.4 g of 2- (7-chloroquinolin-4-ylamino) ethanethiol (prepared according to the method described by J. Lhomme et al., Tetrahedron 1989, 45, 6455-6466). (1.5 mmol) are added to the mixture followed by 0.2 ml of N, N-diisopropylethylamine (1.5 mmol). Stirring is continued for 17 hours at room temperature. The reaction medium is then diluted with 50 ml of chloroform and then washed successively with twice 50 ml of water and 50 ml of water saturated with NaCl. The organic phase is dried over magnesium sulphate, filtered and then evaporated. The product is obtained after purification by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 μm, eluent: ethyl acetate / dichloromethane 90/10 v / v) in the form of a white powder (0.1 g , 12%). 1 H NMR (250 MHz, CDCl3) ppm: 1.48 (9H, s), 2.84 (2H, m), 3.08 (1H, d, J = 13.7Hz), 3.37-3, 71 (4H, m), 4.06 (1H, d, J = 13.7Hz), 5.67 (2H, m), 6.32 (1H, d, J = 5.9Hz), 6, 90 (1H, s), 7.28-7.41 (12H, m), 7.78 (1H, d, J = 8.9Hz), 8.07 (1H, d, J = 2.0Hz) ), 8.36 (1H, d, J = 5.7 Hz). MS (DCI / NH3> 0) m / z: 717 (M + H +).
19.2. (6R-7R) -7-Amino-3-chloromethyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

ylamino) -ethylsulfanylmethyl] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester (0.1 g, 0.2 mmol) (Example 19.1) in 0.5 ml of formic acid is injected at room temperature 0.05 ml of 12M hydrochloric acid. After stirring for 1 h, the medium is precipitated by adding 10 mL of a 2/1 v / v ethyl acetate / acetone mixture. The precipitate formed is filtered, washed with dichloromethane and then with diethyl ether before being dried under vacuum. The product is obtained in the form of a white powder (0.1 g, 82%).
1 H NMR (250 MHz, DMSO) ppm: 2.89 (2H, m), 3.75 (6H, m), 5.11 (1H, d, J = 4.9Hz), 5.23 (1H, m.p. m), 6.89 (1H, d, J = 7.0 Hz), 7.79 (1H, d, J = 9.0 Hz), 8.12 (1H, d, J = 1.7 Hz) , 8.55 (1H, d, J = 7.0Hz) 8.74 (1H, d, J = 9.0Hz), 9.77 (1H, brs). MS (IS> 0) m / z: 451.15 (M + H +).
19.3. (6R-7R) -7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetylamino] -3- [2- (7-chloroquinolin-4-ylamino) -ethylsulfanylmethyl] -8- oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid.
To a suspension of (6R-7R) -7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (62 mg, 0, 1 mmol) (Example 19.2) at -5 [deg] C / -10 [deg] C in 5 ml of dichloromethane are successively added 40 μl of triethylamine (0.3 mmol) and then 50 mg of (2-amino-thiazol 4-yl) -methoxyiminothethioacetic acid 5-benzothiazol-2-yl ester (0.1 mmol). After stirring for 1 hour at room temperature, the medium is diluted with 10 ml of distilled water. The emulsion is filtered and the precipitate is washed successively with cold water (6 ° C.), with cold ethanol (6 ° C.), with dichloromethane and then with diethyl ether before being dried. under vacuum. PA 1199 is obtained as white powder (38 mg, 47%).
1 H NMR (250 MHz, DMSO) δ ppm: 2.80 (2H, m), 3.08 (2H, m), 3.50 (4H, m), 3.83 (3H, s), 5.12. (1H, d, J = 4.5Hz), 5.70 (1H, m), 6.61 (1H, d, J = 4.5Hz), 6.75 (1H, s), 7.22 (1H, d, J = 4.5Hz). (2H, s), 7.50 (1H, d, J = 9.2 Hz), 7.81 (1H, s), 8.36 (2H, m) 9.59 (1H, d, J = 7). , 6 Hz). MS (IS> 0) m / z: 634.05 (M + H +).
Examples 20 to 22 below exemplify the manufacture of hybrid molecules of the aminoquinoline-quinolone family. Example 20: Hybrid aminoquinoline-quinolone molecule, ref. PA 1123

quinoline-3-carboxylic acid.

An argon suspension of 4,7-dichloroquinoline (0.6 g, 2.9 mmol), ciprofloxacin (0.6 g, 2.0 mmol) and potassium carbonate (0.1 g, 9.8 mmol) ) in 13 mL of dimethylacetamide is heated at 140 [deg.] C for 24 h. After returning to ambient temperature, the suspension is filtered. The filtrate is precipitated with diethyl ether and the precipitate formed is filtered off and washed with water. It is then stirred again with 100 mL of chloroform for 1 hour before being filtered again and then dried under vacuum. PA 1123 is obtained in the form of an unbleached powder (0.3 g, 35%).
1 H NMR (300 MHz, DMSO) δ ppm: 1.23 (2H, m), 1.33 (2H, m), 3.72 (4H, m), 3.85 (1H, m), 4.04. (4H, m), 7.25 (1H, d, J = 6.9Hz), 7.59 (1H, d, J = 7.5Hz), 7.73 (1H, dd, J = 2, 1 Hz, J = 9.3 Hz), 7.98 (1H, d, J = 13.2 Hz), 8.11 (1H, d, J = 2.1 Hz), 8.30 (1H, d , J = 9.3 Hz), 8.69 (1H, s), 8.76 (1H, d, J = 6.9 Hz). MS (IS> 0) m / z: 493.2 (M + H +). Analysis

62.30, N 11.26.
EXAMPLE 21 Hybrid Aminoquinoline-Quinolone Molecule, Ref PA 1126 7- [4- (7-Chloro-quinolin-4-yl) -piperazin-1-yl] -1-cyclopropyl-6-fluoro-4-oxo-1 4-dihydroquinoline-3-carboxylic acid hydrochloride.

To a 0.degree. C. solution of PA 1123 (Example 19) (0.1 g, 0.2 mmol) in 10 ml of chloroform is added dropwise 0.4 ml of a 5 M HCl solution. in 2-propanol (2.0 mmol). After 1 hour of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether and filtered. The solid is then stirred again with 100 mL of chloroform for 3 h, then it is filtered, washed with ethanol and with diethyl ether before being dried under vacuum. PA 1126 is obtained in the form of a yellow powder (0.1 g, 77%).
1 H NMR (300 MHz, DMSO) δ ppm: 1.22 (2H, m), 1.32 (2H, m), 3.73 (4H, m), 3.83 (1H, m), 4.08. (4H, m), 7.26 (1H, d, J = 6.6Hz), 7.58 (1H, d, J = 7.5Hz), 7.74 (1H, J = 8.7 Hz). ), 7.93 (1H, d, J = 13.5 Hz), 8.15 (1H, s), 8.31 (1H, d, J = 8.7 Hz), 8.69 (1H, s), ), 8.75 (1H, d, J = 6.6 Hz). MS (IS> 0) m / z: 493.2 (M-Cl) +. Elemental analysis: for

1,4-dihydroquinoline-3-carboxylic acid hydrochloride.

An argon suspension of (2-bromoethyl) - (7-chloroquinolin-4-yl) -amine (0.5 g, 1.8 mmol), ciprofloxacin (0.4 g, 1.2 mmol ) and potassium carbonate (0.8 g, 5.9 mmol) in 10 mL dimethylformamide is heated at 140 [deg.] C with magnetic stirring for 24 h. After returning to ambient temperature, the suspension is filtered. The solid is solubilized in 20 ml of water and the solution is brought to neutral pH with an aqueous solution of 1 M HCl. The precipitate formed is filtered and washed successively with water, ethanol and then with ether. diethyl. The product obtained is then resuspended in a 1/1 v / v chloroform / ethanol mixture, cooled to 0.degree. C. and 1.2 ml of a 5M HCl solution added dropwise in the 2 -propanol (5.9 mmol). After 1 hour of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether and filtered. The solid is then stirred again with 50 ml of dichloromethane for 17 h and then it is filtered, washed with dichloromethane and with diethyl ether before being dried under vacuum. PA 1127 is obtained in the form of an unbleached powder (0.1 g, 9%).
1 H NMR (300 MHz, DMSO) δ ppm: 1.21 (2H, m), 1.31 (2H, m), 3.42-4.09 (13H, m), 7.10 (1H, d, J = 7.2 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.82 (1H, dd, J = 1.8 Hz, J = 9.0 Hz), 7.98; (1H, d, J = 12.9 Hz), 8.10 (1H, d, J = 1.8 Hz), 8.69 (1H, s), 8.70 (1H, d, J = 7, 2 Hz), 8.83 (1H, d, J = 9.0 Hz), 9.80 (1H, s), 11.80 (1H, s), 14.50 (1H, s). SM (IS> 0) m / z:

N, 9.77; % experiment C, 47.22, N, 9.63.
Examples 23 to 25 below exemplify the manufacture of hybrid molecules of the aminoquinoline-nitroimidazole family. EXAMPLE 23 Hybrid Aminoquinoline-Nitroimidazole Molecule, Ref PA 1129 (7-Chloro-quinolin-4-yl) - [2- (2) -methyl-5-nitro-imidazol-1-yl) -ethyl] -amine.

To a solution under argon of (2-bromo-ethyl) - (7-chloro-quinolin-4-yl) -amine (prepared according to the method described by B. Meunier et al., Patent application FR 2862304) (0, 7 g, 2.5 mmol), and 2-methyl-5-nitroimidazole (0.3 g, 2.5 mmol) in 10 ml of dimethylformamide is injected with 0.8 ml of triethylamine (5.5 mmol). . The mixture is heated at 140 ° C. for 24 hours. After returning to ambient temperature, the reaction medium is diluted with 200 ml of dichloromethane and washed successively with twice 200 ml of water and then 200 ml of water saturated with NaCl. The organic phase is dried over magnesium sulphate, filtered and then concentrated on a rotary evaporator until the product begins to precipitate. The precipitation is continued at 6 ° C. for 24 h and the filtered product is washed with dichloromethane. cold (6 ° C.) and then with diethyl ether before being dried under vacuum. PA 1129 is obtained in the form of a white powder (0.1 g, 7%).
1 H NMR (300 MHz, DMSO) δ ppm: 2.21 (3H, s), 3.73 (2H, q, J = 5.7 Hz), 4.25 (2H, t, J = 5.7 Hz). ), 6.64 (1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 5.7 Hz), 7.49 (1H, dd, J = 2.1 Hz, = 9.0 Hz), 7.81 (1H, d, J = 2.1 Hz), 8.13 (1H, d, J = 9.0 Hz), 8.37 (1H, s), 8, 43 (1H, d, J = 5.4 Hz). MS (DCI / NH3> 0) m / z: 332 (M + H +). Elemental analysis: for C15H14ClN5O2:% theor. C, 54.30, N, 21.11; % experiment C 54.07, N 21.41.
EXAMPLE 24 Aminoquinoline-Nitroimidazole Hybrid Molecule, Ref PA 1130

An argon suspension of (2-bromo-ethyl) - (7-trifluoromethylquinolin-4-yl) amine (prepared according to the method described by B. Meunier et al., Patent application FR 2862304) (0.5 g 1.7 mmol), 2-methyl-5-nitroimidazole (0.2 g, 1.8 mmol) and potassium carbonate (1.2 g, 8.8 mmol) in 20 ml of dimethylformamide are added. heated at 70 [deg.] C for 24 hours. The treatment is then identical to that described for PA 1129 (Example 20). PA 1130 is obtained in the form of a white powder (0.1 g, 24%).
1 H NMR (300 MHz, DMSO) ppm: 2.21 (3H, s), 3.76 (2H, q, J = 5.4 Hz), 4.27 (2H, t, J = 5.4 Hz) , 6.75 (1H, d, J = 5.4 Hz), 7.58 (1H, t, J = 5.4 Hz), 7.73 (1H, d, J = 8.7 Hz), , 10 (1H, s), 8.34 (1H, d, J = 8.7 Hz), 8.38 (1H, s), 8.54 (1H, d, J = 5.4 Hz). SM

theor. C, 51.34, N, 18.71; % experiment C, 51.13, N, 18.73.
EXAMPLE 25 Hybrid Aminoquinoline-Nitroimidazole Molecule, Ref PA 1173 1- [2- (7-Chloro-quinolin-4-ylamino) -ethylamino] -3- (2-methyl-5-nitro-imidazol-1-yl) propan -2-ol.

method described by E. Grunberg et al., J. Med. Chem. 1974, 17, 1019-1020) (0.6 g, 3.2 mmol) in 10 mL of absolute ethanol is injected with 0.2 mL of triethylamine (1.3 mmol). The mixture is refluxed for 5 hours. After returning to ambient temperature, the reaction medium is concentrated to dryness on a rotary evaporator and purified by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 Microm, eluent: dichloromethane / methanol / ammonia 30% 88/10/2 v / v / v). PA 1173 is obtained after recrystallization from ethanol / water at 6 ° C. in the form of a white powder (0.2 g, 16%).
1 H NMR (300 MHz, DMSO) δ ppm: 2.02 (1H, brs), 2.44 (3H, s), 2.66 (1H, dd, J = 12.1Hz, J = 6.2. Hz), 2.67 (1H, dd, J = 12.1 Hz, J = 5.1Hz), 2.86 (2H, t, J = 6.4Hz), 3.38 (2H, q, J = 6.4 Hz), 3.83 (1H, m), 4.15 (1H, dd, J = 14.2 Hz, J = 9.2 Hz), 4.49 (1H, dd, J = 14.2 Hz, J = 3.1 Hz), 5.15 (1H, d, J = 5.3 Hz), 6.53 (1H, d, J = 5.4 Hz), 7.25 (1H , t wide, J = 6.4 Hz), 7.45 (1H, dd, J = 9.0 Hz, J = 2.3 Hz), 7.78 (1H, d, J = 2.3 Hz) , 8.02 (1H, s), 8.26 (1H, d, J = 9.0 Hz), 8.40 (1H, d, J = 5.4 Hz). MS (DCI / NH3> 0) m / z:

52.01, N 20.00; % experiment C, 51.98, N, 19.94.
Example 26 below exemplifies the manufacture of hybrid molecules of the aminoquinoline-streptogramin family. Example 26: Hybrid aminoquinoline-streptogramin molecule, ref. PA 1182

according to the method described by J.-P. Bastart et al., patent EP 0432029A1) (0.6 g, 0.7 mmol) in 20 ml of acetone is added in small portions over 1 h 30 a suspension of 2- (7-chloro-quinolin-4-ylamino) -ethanethiol (prepared according to the method described by J. Lhomme et al., Tetrahedron 1989, 45, 6455-6466) (0.2 g, 0.8 mmol) in 5 mL of acetone. The mixture is maintained at -20 ° C. with stirring for 5 h 30. The suspension obtained is filtered and the precipitate is washed with acetone. After concentration on a rotary evaporator, the filtrate is purified by liquid gel chromatography. silica (SiO2 60 ° C, 635 Microm, eluent: dichloromethane / methanol / ammonia 30% 92/6/2 v / v / v). PA 1182 is obtained as a pale yellow powder (0.3 g, 44%).
H NMR (250 MHz, CDCl3) ppm: 0.58 (1H, dd, J = 5.9 Hz, J = 14.8 Hz), 0.90 (3H, t, J = 7.4 Hz), 1 , 09-1.36 (5H, m), 1.50-1.72 (3H, m), 2.00-2.43 (5H, m), 2.62-2.73 (2H, m) , 2.83-3.03 (9H, m), 3.20-3.28 (5H, m), 3.53-3.61 (2H, m), 4.56 (1H, dd, J = 6.4 Hz, J = 8.2 Hz), 4.81-4.92 (3H, m), 5.20-5.31 (2H, m), 5.83 (1H, d, J = 9 , 1 Hz), 5.90 (1H, dd, J = 1.5 Hz, J = 6.4 Hz), 6.20 (1H, brs), 6.45 (1H, d, J = 5, 7 Hz), 6.50 (1H, d, J = 9.8 Hz), 6.58 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 8.6 Hz). ), 7.16 (2H, m), 7.28 (3H, m), 7.35 (1H, dd, J = 2.1Hz, J = 9.0Hz), 7.47 (2H, m). ), 7.86 (1H, dd, J = 2.1Hz, J = 3.6Hz), 7.91 (1H, d, J = 9.0Hz), 8.02 (1H, d, J) = 2.1 Hz), 8.43 (1H, d, J = 9.9 Hz), 8.50 (1H, d, J = 5.7 Hz), 8.80 (1H, d, J = 9). , 1 Hz), 11.65 (1H, brs). MS (IS> 0) m / z: 1117.6

59.65, N 12.12; % experiment C 59.71, N 12.13.
Examples 27 to 29 below exemplify the manufacture of hybrid molecules of the aminoquinoline diaminopyrimidine family. EXAMPLE 27 Hybrid Aminoquinoline-Diaminopyrimidine Molecule, Ref PA 1154

27.1. 4- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -benzaldehyde.
An argon suspension of (2-bromo-ethyl) - (7-chloroquinolin-4-yl) -amine (5.0 g, 17.5 mmol), 4-hydroxybenzaldehyde (3.0 g, 24, 5 mmol) and potassium carbonate (7.3 g, 52.5 mmol) in 60 mL dimethylformamide is heated at 60 [deg.] C for 24 h. After returning to ambient temperature, the reaction medium is diluted with 200 mL of dichloromethane and washed with 3 times 200 mL of water. The organic phase is dried over magnesium sulphate, filtered and then concentrated on a rotary evaporator. The oil obtained is purified by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 μm, eluent: ethyl acetate / ethanol / triethylamine 90/5/5 v / v / v). The product is obtained as a slightly yellow powder (2.8 g, 49%).
1 H NMR (300 MHz, CDCl 3) ppm: 3.83 (2H, q, J = 5.1Hz), 4.41 (2H, t, J = 5.1Hz), 5.38 (1H, broad t. ), 6.54 (1H, d, J = 5.4 Hz), 7.08 (1H, broad d, J = 8.7 Hz), 7.42 (1H, dd, J = 2.1 Hz, J = 9.0Hz), 7.72 (1H, d, J = 9.0Hz), 7.89 (1H, broad d, J = 8.7Hz), 8.01 (1H, d, J). = 2.1 Hz), 8.62 (1H, d, J = 5.4 Hz), 9.93 (1H, s). MS (DCI / NH3> 0) m / z: 327 (M + H +).

phenylamino-acrylonitrile.
To a solution under argon and at 10 [deg.] C of 4- [2- (7-chloroquinolin-4-ylamino) -ethoxy] benzaldehyde (Example 27.1) (1.1 g, 3.3 mmol), and of anilinopropionitrile (0.5 g, 3.6 mmol) in 10 ml of dry dimethylsulfoxide are added in small portions over 5 min 0.4 g of potassium tert-butoxide (3.7 mmol). Stirring is maintained at a temperature of 10 [deg.] C for 1 h and then the cold bath is removed and stirring is continued at room temperature for 20 h. 200 ml of cold water are added to the crude reaction product and the product is extracted with 3 times 200 ml of ethyl acetate. The combined organic phases are washed again with 3 times 200 ml of water before being concentrated on a rotary evaporator. The product is obtained after recrystallization in ethanol at -18 ° C. in a Z mixture and in the form of a white powder (0.6 g, 40%).
1 H NMR (300 MHz, CDCl3) ppm: 3.42 and 3.55 (2H, 2s), 3.69 (2H, q, J = 5.4 Hz), 4.23 (2H, t, J = 5). , 4 Hz), 6.60 (1H, d, J = 5.7 Hz), 6.89-7.07 (3H, m), 7.17-7.30 (6H, m), 7.46 (1H, dd, J = 2.4 Hz, J = 9.0 Hz), 7.50 (1H, broad t, J = 5.4 Hz), 7.64 (1H, d, J = 12.9 Hz), 7.79 (1H, d, J = 2.4 Hz), 8.29 (1H, d, J = 9.0 Hz), 8.42 (1H, d, J = 5.4 Hz) , 9.12 (1H, d, J = 12.9 Hz). MS (DCI / NH3> 0) m / z: 455 (M + H +).

To an argon solution of guanidine hydrochloride (0.3 g, 3.3 mmol) in 5 ml of absolute ethanol are added 0.4 g of potassium tert-butoxide (3.3 mmol). The suspension is stirred for 1 h before being filtered on celite. The filtrate is injected into a suspension under argon of the mixture Zet Ede 2- 4- [2- (7-chloroquinolin-4-ylamino) -ethoxy] -benzyl} -3-phenylamino-acrylonitrile (Example 27.2) (0.5 g 1.1 mmol) in 3 mL absolute ethanol and this mixture is refluxed for 7 h. After cooling to room temperature, the suspension is filtered and the precipitate is washed successively with water, ethanol and then with diethyl ether. PA 1154 is obtained in the form of a white powder (0.1 g, 26%).
1 H NMR (500 MHz, DMSO) δ ppm: 3.52 (2H, s), 3.68 (2H, q, J = 5.4 Hz), 4.20 (2H, t, J = 5.4 Hz. ), 5.66 (2H, s), 6.02 (2H, s), 6.59 (1H, d, J = 5.4 Hz), 6.87 (2H, d, J = 8.4 Hz). ), 7.12 (2H, d, J = 8.4 Hz), 7.47 (3H, m), 7.79 (1H, d, J = 2.1 Hz), 8.29 (1H, d), , J = 9.0 Hz), 8.41 (1H, d, J = 5.4 Hz). MS (DCI / NH3> 0) m / z: 421 (M + H +). Elemental analysis:

EXAMPLE 28 Aminoquinoline-diaminopyrimidine Hybrid Molecule, Ref PA 1161 5- {4- [2- (7-Chloroquinolin-4-ylamino) -ethoxy] -3-methoxy-benzyl} -pyrimidine-2,4-diamine

28.1. 4- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -3-methoxy-benzaldehyde.
This compound is prepared according to the procedure described in Example 27.1 starting from 1.2 g of (2-bromo-ethyl) - (7-chloro-quinolin-4-yl) -amine (4.3 mmol). 9 g of vaniline (6.0 mmol) and 1.8 g of potassium carbonate (12.8 mmol) in 20 ml of dimethylformamide. The product is obtained in the form of a white powder without purification by liquid chromatography on silica gel but after washing the solid with ethanol (1.0 g, 69%).

1 H NMR (300 MHz, DMSO) δ ppm: 3.73 (2H, q, J = 5.1 Hz), 3.81 (3H, s), 4.37 (2H, m), 6.54 (1H). , d, J = 5.4 Hz), 7.23 (1H, d, J = 8.1 Hz), 7.40 (1H, d, J = 1.8 Hz), 7.47 (1H, dd , J = 2.1 Hz, J = 9.0 Hz), 7.51-7.56 (2H, m), 7.80 (1H, d, J = 2.1 Hz), 8.28 (1H , d, J = 9.0 Hz), 8.44 (1H, d, J = 5.4 Hz), 9.84 (1H, s). MS (DCI / NH3> 0) m / z: 357 (M + H +).
28.2. Mixture Z and E of 2- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -3-methoxybenzyl} -3-phenylamino-acrylonitrile.
This compound is prepared according to the procedure described in Example 27.2 from 0.5 g of 4- [2- (7-chloroquinolin-4-ylamino) -ethoxy] -3-methoxy-benzaldehyde (Example 28.1). (1.3 mmol), 0.2 g of anilinopropionitrile (1.5 mmol) and 0.2 g of potassium tert-butoxide (1.5 mmol) in 5 ml of dry dimethylsulfoxide. The product is obtained in a Z and E mixture, in the form of a white powder, after recrystallization at 6 ° C. in ethanol to which a few drops of water have been added (0.3 g, 46%).
1 H NMR (300 MHz, DMSO) ppm: 3.42 and 3.56 (2H, 2s), 3.70 (5H, m), 4.21 and 4.35 (2H, 2t, J = 5.4 Hz ), 6.61 (1H, d, J = 5.4 Hz), 6.78 (1H, d, J = 8.1 Hz), 6.89-6.98 (3H, m), 7.17. -7.30 (4H, m), 7.45-7.53 (2H, m), 7.64 and 7.62 (1H, 2d, J = 12.9Hz), 7.80 (1H, d); , J = 2.1 Hz), 8.28 (1H, d, J = 9.3 Hz), 8.42 (1H, d, J = 5.4 Hz), 9.08 and 9.10 (1H , 2d, J = 12.9 Hz). MS (DCI / NH3> 0) m / z: 485 (M + H +).
28.3. 5- {4- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -3-methoxy-benzyl} -pyrimidine-2,4diamine.
PA 1161 is prepared according to the procedure described in Example 27.3 from 0.3 g of guanidine hydrochloride (3.1 mmol), 0.4 g of potassium tert-butoxide (3.1 mmol), and 0.5 g. 2- {4- [2- (7-Chloroquinolin-4-ylamino) -ethoxy] -3-methoxy-benzyl} -3-phenylamino-acrylonitrile (Example 28.2) (1.0 mmol) in 3 mL of ethanol absolute. After reflux in ethanol, the product is filtered hot and washed with methanol. PA 1161 is obtained in the form of a white powder (0.1 g, 21%).
1 H NMR (500 MHz, DMSO) δ ppm: 3.52 (2H, s), 3.66 (2H, q, J = 5.5 Hz), 3.70 (3H, s), 4.19 (2H). , t, J = 5.5 Hz), 5.67 (2H, s), 6.04 (2H, s), 6.60 (1H, d, J = 5.4 Hz), 6.70 (1H , dd, J = 1.7 Hz, J = 8.1 Hz), 6.88 (1H, d, J = 1.7 Hz), 6.90 (1H, d, J 8.1 Hz), , 47 (3H, m), 7.80 (1H, d, J = 2.2Hz), 8.28 (1H, d, J = 9.1Hz), 8.42 (1H, d, J = 5.4 Hz). MS (DCI / NH3> 0) m / z: 451 (M + H +). Elemental analysis: for

16.46.
Example 29: Aminoquinoline-diaminopyrimidine hybrid molecule, ref PA 1187 5- {3- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzyl} -pyrimidine-2,4-diamine

29.1. 3- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzaldehyde.
This compound is prepared according to the procedure described in Example 27.1 from 2.6 g of (2-bromo-ethyl) - (7-chloro-quinolin-4-yl) -amine (9.1 mmol), 2 0 g of 5-hydroxyvertraldehyde (11.0 mmol) and 3.8 g of potassium carbonate (27.4 mmol) in 30 ml of dimethylformamide. The product is obtained in the form of a white powder after purification by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 Microm, eluent: dichloromethane / methanol / ammonia 30% 88/10/2 v / v / v) (1.5 g, 43%).
1 H NMR (250 MHz, DMSO) ppm: 3.71 (3H, s), 3.75 (2H, m), 3.84 (3H, s), 4.35 (2H, m), 6.64 (b.p. 1H, d, J = 5.2Hz), 7.24 (1H, s), 7.30 (1H, s), 7.46 (1H, d, J = 8.9Hz), 7.51 (b.p. 1H, m), 7.79 (1H, s), 8.27 (1H, d, J = 8.9Hz), 8.42 (1H, d, J = 5.2Hz), 9.85 ( 1H, s). MS (FAB> 0) m / z: 387 (M + H +).
29.2. Zet mixture of 2- [2- (7-chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxybenzyl} -3-phenylamino-acrylonitrile.
This compound is prepared according to the procedure described in Example 27.2 from 1.5 g of 3- [2- (7-chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzaldehyde (example 29.1) (3.9 mmol), 0.6 g of anilinopropionitrile (4.2 mmol) and 0.5 g of potassium tert-butoxide (4.4 mmol) in 5 ml of dry dimethylsulfoxide. The product is obtained in a mixture of Z and E, in the form of a white powder, after recrystallization at 6 ° C. in ethanol with the addition of a few drops of water (1.1 g, 53%).
1 H NMR (250 MHz, DMSO) ppm: 3.41 and 3.55 (2H, 2s), 3.58 (3H, s), 3.72 (5H, m), 4.22 and 4.36 (2H); , 2m), 6.60 (3H, m), 6.93 (1H, m), 7.19-7.30 (4H, m), 7.42-7.52 (2H, m), 7, 65 and 7.66 (1H, 2d, J = 12.9 Hz), 7.79 (1H, d, J = 2.1 Hz), 8.27 (1H, d, J = 9.1 Hz), 8.40 (1H, d, J = 5.3 Hz), 9.10 and 9.12 (1H, 2d, J = 12.9 Hz). MS (DCI / NH3> 0) m / z: 515 (M + H +).

2,4-diamine.
PA 1187 is prepared according to the procedure described in Example 27.3 from 0.3 g of guanidine hydrochloride (3.1 mmol), 0.3 g of potassium tert-butoxide (3.1 mmol), and 0.5 g. 2- [3- (2- (7-Chloroquinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzyl-3-phenylamino-acrylonitrile (Example 29.2) (1.0 mmol) in 6 mL of ethanol absolute. The reflux in ethanol is prolonged until 20 h and after return to ambient temperature, the product is extracted with chloroform in biphasic medium chloroform / water. Concentration of the organic phase under vacuum afforded PA 1187 as a white powder (0.3 g, 65%).
1 H NMR (250 MHz, DMSO) δ ppm: 3.50 (2H, s), 3.55 (3H, s), 3.69 (5H, m), 4.19 (2H, t, J = 5, 2 Hz), 5.69 (2H, s), 6.08 (2H, s), 6.58 (2H, s), 6.60 (1H, d, J = 5.4 Hz), 7.47. (3H, m), 7.79 (1H, d, J = 2.1 Hz), 8.26 (1H, d, J = 9.1Hz), 8.41 (1H, d, J = 5, 4 Hz). SM

theor. C, 56.34, N, 16.43; % experiment C 56.41, N 16.03.
Example 30 below exemplifies the manufacture of hybrid molecules of the aminoquinoline-macrolide family. Example 30: Hybrid aminoquinoline-macrolide molecule, ref. PA 1169

An argon suspension of erythromycin A 10-oxime (prepared according to the method described by U. Takehiro Amano et al., US Patent 5274085) (1.0 g, 1.3 mmol), (2bromo-ethyl) - ( 7-chloro-quinolin-4-yl) -amine (0.4 g, 1.5 mmol), and crushed sodium hydroxide (0.1 g, 1.5 mmol) in 10 mL of dry dimethylformamide is stirred at room temperature. room temperature for 3 hours. The reaction medium is then diluted with 50 ml of chloroform and washed with 3 times 100 ml of water. The organic phase is dried over sodium sulfate, filtered and then concentrated on a rotary evaporator. The product is then purified by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 Microm, eluent: dichloromethane / methanol / aqueous ammonia 30%. / 5/2 v / v / v). PA 1169 is obtained after recrystallization from propan-2-ol / water 1/1 v / v at 6 [deg] C, in the form of a white powder (0.3 g, 22%).
1 H NMR (250 MHz, CDCl3) ppm: 0.85 (3H, m), 0.90-1.39 (24H, m), 1.40-1.79 (8H, m), 1.80-2. , 50 (16H, m), 2.71 (1H, q, J = 6.9Hz), 2.80-3.10 (3H, m), 3.22 (1H, m), 3.30 ( 3H, s), 3.40-3.80 (6H, m), 3.99 (2H, m), 4.20 (2H, m), 4.40 (2H, m), 4.85 (1H; , d, J = 4.5 Hz), 5.07 (1H, d, J = 9.0 Hz), 5.67 (1H, brs), 6.43 (1H, d, J = 5.5 Hz), 7.35 (1H, dd, J = 2.1Hz, J = 9.0Hz), 7.81 (1H, d, J = 9.0Hz), 7.97 (1H, d, J = 2.1 Hz), 8.51 (1H, d, J = 5.5 Hz). MS (DCI / NH3> 0) m / z: 967 (M + H +). Elemental analysis: for C 49 H 79 ClN 4 O 13 H 2 O:% theor. C 59.71, N 5.68; % experiment C 59.85, N 5.46.
Examples 31 to 33 below exemplify the manufacture of hybrid molecules of the aminoquinoline-glycopeptide family. EXAMPLE 31 Hybrid Aminoquinoline-Glycopeptide Molecule, Ref PA 1157 N-4- {4- [2- (7-Chloro-quinolin) 4-ylamino) -ethoxy] -benzyl} -vancomycine

To a solution under argon and at 70 ° C. of vancomycin hydrochloride (0.8 g, 0.5 mmol) and 4- [2- (7-chloroquinolin-4-ylamino) -ethoxy] -benzaldehyde ( Example 26.1) (0.2 g, 0.7 mmol) in 24 ml of dimethylacetamide are injected with 0.2 ml of diisopropylethylamine (1.1 mmol). After stirring for 2 h of this mixture at 70 ° C., a solution of sodium cyanoborohydride (0.1 g, 2.1 mmol) in 2 ml of methanol is added. The mixture is stirred for 2 h 30 at 70 [deg.] C. and then 20 h at room temperature. The suspension obtained is centrifuged and the supernatant is precipitated with acetonitrile. This new precipitate is centrifuged and washed successively with acetonitrile and then with diethyl ether. It is then purified by semi-preparative HPLC: 10 micron C18 column (21.2 x 150 mm), isocratic gradient at 19% of eluent B for 45 min (eluent A: water 0.1% trifluoroacetic acid, eluent B: acetonitrile / water 0.1% trifluoroacetic acid 9/1 v / v), flow rate 15 mL / min, double detection at 280 and 330 nm. The trifluoroacetic acid salt of PA 1157 is obtained after lyophilization of the fractions collected, in the form of a white powder (25 mg, 3%).
NMR H (500 MHz, DMSO d6) δ ppm: 0.86 (3H, d, J = 6.0 Hz), 0.91 (3H, d, J = 6.0 Hz), 1.13 (3H, d, J = 6.2 Hz), 1.47 (3H, s), 1.56-1.69 (3H, m), 1.81 (1H, broad d, J = 12.8 Hz), 2 , 0.9-2.18 (2H, m), 2.57 (1H, m), 2.65 (3H, s), 3.30 (2H, m), 3.45-3.60 (4H, m), ), 3.70 (1H, broad, J = 9.1 Hz), 3.94 (5H, m), 4.12 (1H, brs), 4.21 (1H, d, J = 11, 7 Hz), 4.31 (3H, m), 4.43 (1H, d, J = 5.6 Hz), 4.46 (1H, m), 4.68 (1H, m), 4.96 (1H, brs), 5.12 (1H, d, J = 6.0Hz), 5.15 (1H, brs), 5.18 (1H, s), 5.21 (1H, brs) ), 5.28 (1H, brs), 5.35 (1H, d, J = 7.6Hz), 5.38 (1H, broad d, J = 4.2Hz), 5.61 (1H); , s), 5.77 (1H, d, J = 7.7 Hz), 5.84 (1H, brs), 6.00 (1H, d, J = 6.0 Hz), 1H, brs), 6.25 (1H, d, J = 1.7 Hz), 6.41 (1H, d, J = 1.7 Hz), 6.57 (1H, brs), 6, 72 (2H, m), 6.78 (1H, d, J = 8.8 Hz), 6.97-7.25 (8H, m), 7.34 (1H, d, J = 8.3 Hz). ), 7.38 (2H, d, J = 8.6 Hz), 7.47 (2H, m), 7.57 (1H, d, J = 8.4 Hz), 7.75 (1H, dd); , J = 9.1 Hz, J = 1.8 Hz), 7.86 (1H, s), 7.98 (1H, s), 8.08 (1H, ss) arge), 8.53-8.67 (6H, m), 9.13 (1H, s), 9.20 (1H, s), 9.25 (1H, brs), 9.48 (1H, m.p. s). MS (IS> 0) m / z: 1761.0 (M + H +), 881.1 (M + 2H +).
EXAMPLE 32 Hybrid Aminoquinoline-Glycopeptide Molecule, Ref PA 1158 N-4- [4- (7-Chloroquinolin-4-ylamino) -butyl] -vancomycin

An argon suspension of 4,7-dichloroquinoline (2.0 g, 10.0 mmol) in 5.2 mL of 4-aminobutyraldehyde diethylacetal (30.0 mmol) was heated at 110 [deg.] C for 29 h. After returning to ambient temperature, the reaction medium is diluted with 50 ml of dichloromethane and 100 ml of a 5% solution of carbonated water. The organic phase is separated and the aqueous phase is reextracted with 3 times 50 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and then concentrated under vacuum. The product is obtained after recrystallization from hexane at 18.degree. C. in the form of a white powder (2.2 g, 69%).
1 H NMR (300 MHz, DMSO) δ ppm: 1.10 (6H, t, J = 6.9 Hz), 1.65 (4H, m), 3.27 (2H, m), 3.52 (2H). , m), 3.56 (2H, m), 4.15 (1H, t, J = 5.1Hz), 6.47 (1H, d, J = 5.4Hz), 7.32 (1H , t, J = 5.1 Hz), 7.44 (1H, dd, J = 1.5 Hz, J = 9.0 Hz), 7.77 (1H, d, J = 1.5 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.4 Hz). MS (DCI / NH3> 0) m / z: 323 (M + H +).
32.2. 4- (7-Chloro-quinolin-4-ylamino) -butyraldehyde.
To a solution under argon of (7-chloro-quinolin-4-yl) - (4,4-diethoxy-butyl) -amine (Example 32.1) (0.3 g, 0.9 mmol) in 5 mL of a 80% aqueous acetic acid solution is added 1 ml of trifluoroacetic acid (13.0 mmol). The mixture is heated at 70.degree. C. for 1 h 30. After returning to ambient temperature, the mixture is evaporated to dryness. The product is obtained in the form of a yellow powder (0.3 g, 100%).
1 H NMR (300 MHz, DMSO) ppm: 1.92 (2H, m), 2.64 (2H, t, J = 6.9Hz), 3.53 (2H, q, J = 6.9Hz) , 6.93 (1H, d, J = 7.2 Hz), 7.80 (1H, dd, J = 1.8 Hz, J = 9.3 Hz), 7.96 (1H, d, J = 1.8 Hz), 8.53 (1H, d, J = 9.3 Hz), 8.58 (1H, d, J = 7.2 Hz), 9.40 (1H, broad t), 9, 71 (1H, s). MS (IS> 0) m / z: 249.1 (M + H +).
32.3. N-4- [4- (7-Chloro-quinolin-4-ylamino) -butyl] -vancomycine.
PA 1158 is prepared according to the procedure described in Example 31 starting from 100 mg of vancomycin hydrochloride (0.1 mmol), 32 mg of 4- (7-chloro-quinolin-4-ylamino) butyraldehyde (Example 32.2) ( 0.1 mmol), 0.04 mL of diisopropylethylamine (0.2 mmol) and 17 mg of sodium cyanoborohydride (0.3 mmol) in 3 mL of dry dimethylformamide. The product is purified by semi-preparative HPLC with an isocratic gradient at 17% eluent B for 45 min and a flow rate of 17 ml / min. The trifluoroacetic acid salt of PA 1158 is obtained after lyophilization of the collected fractions, in the form of a white powder (10 mg, 9%).
NMR H (500 MHz, DMSO d6) δ ppm: 0.86 (3H, d, J = 6.0 Hz), 0.92 (3H, d, J = 6.0 Hz), 1.10 (3H, d, J = 6.1Hz), 1.36 (3H, s), 1.58-1.76 (7H, m), 1.82 (1H, broad d, J = 12.6Hz), 1 99 (1H, m), 2.17 (1H, m), 2.56 (1H, m), 2.65 (3H, s), 2.82 (2H, m), 3.28 (2H, m.p. m), 3.31 (1H, brs), 3.47 (1H, m), 3.53-3.59 (4H, m), 3.70 (1H, broad d, J = 10.5 Hz). ), 3.96 (1H, brs), 4.10 (1H, brs), 4.20 (1H, broad d, J = 10.8Hz), 4.27 (1H, brs), 4 , 44 (2H, m), 4.65 (1H, m), 4.95 (1H, brs), 5.11-5.20 (4H, m), 5.29-5.32 (2H, m.p. m), 5.36 (1H, brs), 5.61 (1H, s), 5.76 (2H, m), 5.98 (1H, brs), 6.02 (1H, brs). , 6.25 (1H, d, J = 1.6 Hz), 6.41 (1H, d, J = 1.6 Hz), 6.57 (1H, brs), 6.71 (2H, m.p. ), 6.78 (1H, d, J = 8.7 Hz), 6.92 (1H, d, J = 7.2 Hz), 7.04-7.33 (5H, m), 7.46 -7.49 (3H, m), 7.57 (1H, d, J = 8.2 Hz), 7.80 (1H, dd, J = 9.1 Hz,, J = 1.7 Hz), 7.85 (1H, s), 8.01 (2H, m), 8.32 (1H, brs), 8.53-8.58 (4H, m), 8.68 (1H, brs) , 9.01 (1H, brs), 9.11 (1H, s), 9.19 (1H, s), 9.31 (1H, ss), arge), 9.42 (1H, brs), 9.48 (1H, brs). MS (IS> 0) m / z: 842.0 (M + 2H +).
EXAMPLE 33 Hybrid Aminoquinoline-Glycopeptide Molecule, Ref PA 1159 N-4- [4- (7-Chloroquinolin-4-ylamino) -ethyl] -vancomycin

33.1. (7-Chloro-quinolin-4-yl) - (2,2-dimethoxy-ethyl) -amine.
This compound is prepared according to the procedure described in Example 32.1 from 2.0 g of 4,7-dichloroquinoline (10.0 mmol), and 3.3 ml of aminoacetaldehyde dimethylacetal (30.0 mmol). The product is obtained after recrystallization from a dichloromethane / hexane mixture, in the form of a beige powder (2.3 g, 87%).
1 H NMR (300 MHz, DMSO) δ ppm: 3.33 (6H, s), 3.41 (2H, t, J = 5.7 Hz), 4.63 (1H, t, J = 5.7 Hz. ), 6.56 (1H, d, J = 5.4 Hz), 7.34 (1H, t, J = 5.7 Hz), 7.46 (1H, dd, J = 2.1 Hz, J); = 9.0 Hz), 7.79 (1H, d, J = 2.1 Hz), 8.27 (1H, d, J = 9.0 Hz), 8.41 (1H, d, J = 5 , 4 Hz). MS (DCI / NH3> 0) m / z: 267 (M + H +).
33.2. (7-Chloro-quinolin-4-ylamino) acetaldehyde.
This compound is prepared according to the procedure described in Example 32.2 from 0.3 g of (7-chloro-quinolin-4-yl) - (2,2-dimethoxyethyl) amine (Example 33.1) (1). 1 mmol) in 5 mL of 80% aqueous acetic acid and 1 mL of trifluoroacetic acid (13.0 mmol). The product is obtained after dry evaporation of the reaction mixture in the form of a red powder (0.4 g, 100%).
1 H NMR (300 MHz, DMSO) ppm: 4.67 (2H, d, J = 5.7 Hz), 6.81 (1H, d, J = 7.2 Hz), 7.83 (1H, dd, J = 2.1 Hz, J = 9.0 Hz), 8.01 (1H, d, J = 2.1 Hz), 8.52 (1H, d, J = 9.0 Hz), 8.59. (1H, d, J = 7.2 Hz), 9.56 (1H, broad t), 9.65 (1H, s). MS (IS> 0) m / z: 221.1 (M + H +).
33.3. N-4- [4- (7-Chloroquinolin-4-ylamino) -ethyl] -vancomycin, PA 1159 is prepared according to the procedure described in Example 31 starting from 100 mg of vancomycin hydrochloride (0.1 mmol ), 24 mg of (7-chloro-quinolin-4-ylamino) acetaldehyde (Example 33.2) (0.1 mmol), 0.05 mL of diisopropylethylamine (0.3 mmol) and 13 mg of sodium cyanoborohydride (0, 2 mmol) in 3 mL of dry dimethylformamide. The product is purified by semi-preparative HPLC with an isocratic gradient of 16% eluent B for 45 min and a flow rate of 17 ml / min. The trifluoroacetic acid salt of PA 1159 is obtained after lyophilization of the fractions collected, in the form of a white powder (9 mg, 8%).
1 H NMR (500 MHz, DMSO d6) ppm: 0.86 (3H, broad d, J = 4.6 Hz), 0.91 (3H, broad d, J = 4.6 Hz), 1.11 (3H) , d, J = 5.0 Hz), 1.38 (3H, s), 1.60-1.76 (3H, m), 1.89 (1H, m), 2.01 (1H, m) , 2.17 (1H, m), 2.55 (1H, m), 2.65 (3H, s), 3.13 (2H, m), 3.25-3.50 (4H, m), 3.50-3.62 (2H, m), 3.69 (1H, broad, J = 10.1Hz), 3.83 (2H, brs), 3.96 (1H, brs), 4.08 (1H, brs), 4.21 (1H, broad, J = 10.8Hz), 4.27 (1H, brs), 4.44 (2H, m), 1H, d, J = 5.6 Hz), 4.96 (1H, brs), 5.11-5.20 (4H, m), 5.31 (2H, brs), 5.37 (1H). broad s), 5.60 (1H, s), 5.76 (1H, d, J = 6.6Hz), 5.87 (1H, brs), 5.99 (1H, brs), 6.03 (1H, brs), 6.26 (1H, s), 6.41 (1H, s), 6.57 (1H s brs), 6.71-6.77 (3H, m), 6.90 (1H, d, J = 6.1Hz), 7.03-7.57 (8H, m), 7.79 (1H, d, J = 8.6Hz), 7.84 (1H , s), 8.02 (1H, s), 8.39-8.78 (7H, m), 9.10 (1H, brs), 9.12 (1H, s), 9.20 (1H, s), , s), 9.49 (1H, s). MS (IS> 0) m / z: 827.0 (M + 2H +).
Examples 34 to 37 below exemplify the manufacture of hybrid molecules of the aminoquinoline-oxazolidinone family. EXAMPLE 34 Hybrid Aminoquinoline-Oxazolidinone Molecule, Ref PA 1183 (5S) - [2- (7-Chloroquinolin-4-ylamino ) -ethyl] -carbamic acid 3- (3-fluoro-4-morpholin-4-ylphenyl) -2-oxo-oxazolidin-5-ylmethylester

To an argon solution of 3- (3-fluoro-4-morpholin-4-yl-phenyl) -5-hydroxymethyloxazolidin-2-one (prepared according to the method described by SJ Brickner et al., J. Med Chem. 1996, 39, 673-679) (0.6 g, 2.0 mmol) in 10 mL of dichloromethane are injected with 0.3 mL of triethylamine (2.0 mmol). After stirring for 5 minutes, a solution of triphosgene (0.2 g, 0.8 mmol) in 5 ml of dichloromethane is added. The reaction mixture is stirred for 7 h at room temperature before addition of a

method described by B. Meunier et al., ChemBioChem 2000, 1, 281-283) (0.5 g, 2.0 mmol) and triethylamine (0.3 mL, 2.0 mmol) in 15 mL of dichloromethane. Stirring is continued for 17 hours at room temperature. The reaction medium is then diluted with 20 ml of dichloromethane and washed successively with 10 ml of a 1 M aqueous sodium hydroxide solution and then 2 times with 50 ml of water. The organic phase is dried over sodium sulphate, filtered and then concentrated on a rotary evaporator. The product is then purified by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 pm, eluent: dichloromethane / methanol 9/1). PA 1183 is obtained after recrystallization from a dichloromethane / n-hexane mixture, in the form of a light beige powder (0.5 g, 49%).
1 H NMR (250 MHz, CDCl3) δ ppm: 3.00 (4H, m), 3.41 (2H, m), 3.59 (2H, m), 3.78 (1H, m), 3.85 (4H, m), 4.01 (1H, t, J = 9.0 Hz), 4.40 (2H, m), 4.82 (1H, m), 5.71 (1H, t, J = 6.0 Hz), 6.20 (1H, brs), 6.30 (1H, d, J = 5.3 Hz), 6.78 (1H, t, J = 8.8 Hz), 6, 92 (1H, dd, J = 2.3 Hz, J = 8.8 Hz), 7.32 (1H, dd, J = 2.0 Hz, J = 8.9 Hz), 7.42 (1H, dd, J = 2.3 Hz, J = 14.2 Hz), 7.72 (1H, d, J = 8.9 Hz), 7.90 (1H, d, J = 2.9 Hz), , 47 (1H, d, J = 5.3 Hz). MS (DCI / NH3> 0) m / z: 544 (M + H +). Elemental analysis: for

N, 11.86.
EXAMPLE 35 Hybrid Aminoquinoline-Oxazolidinone Molecule, Ref PA 1185

oxazolidin-5-ylmethyl] -propionamide

To an argon solution of 5-aminomethyl-3- (3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one (prepared according to the method described by SJ Brickner et al., J. Med. 1996, 39, 673-679) (0.7 g, 2.4 mmol) in 20 ml of DMF are successively added 0.7 g of 3- (7-chloro-quinolin-4-ylamino) -propionic acid ( Example 4.1) (2.4 mmol), 1.3 g of PyBOP (2.4 mmol) and 1.3 ml of γ-methylmorpholine (12.2 mmol). After stirring for 24 h at room temperature, the reaction medium is diluted with 100 mL of chloroform and washed with 3 times 100 mL of a saturated solution of bicarbonate water. The organic phase is dried over sodium sulfate, filtered and then concentrated on a rotary evaporator. The product is then purified by liquid chromatography on silica gel (SiO 2 60 ° C 6-35 Microm, eluent: dichloromethane / methanol 85/15). PA 1185 is obtained after recrystallization from chloroform / n-hexane as a white powder (0.3 g, 24%).
1 H NMR (250 MHz, DMSO) δ ppm: 2.52 (2H, m), 2.93 (4H, m), 3.46 (4H, m), 3.68 (1H, m), 3.70 (4H, m), 4.01 (1H, t, J = 9.0Hz), 4.71 (1H, m), 6.48 (1H, d, J = 5.6Hz), 7.00. (1H, t, J = 9.0 Hz), 7.08 (1H, dd, J = 2.0 Hz, J = 9.0 Hz), 7.44 (2H, m), 7.53 (1H , broad), 7.77 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 9.0 Hz), 8.39 (1H, m), 1H, d, J = 5.6 Hz). MS (IS> 0) m / z: 528.50 (M + H +). Elemental analysis: for C26H27ClFN5O4H2O:% theor. C, 57.19, N, 12.83; % experiment C, 57.02, N, 12.66.
EXAMPLE 36 Aminoquinoline-Oxazolidinone Hybrid Molecule, Ref PA 1193

oxazolidin-5-ylmethyl] -acetamide

This compound is prepared according to the procedure described in Example 35 from 0.7 g of 5-aminomethyl-3- (3-fluoro-4-morpholin-4-yl-phenyl) -oxazolidin-2-one (2). 2 mmol), 0.5 g of (7-chloro-quinolin-4-ylamino) -acetic acid (2.2 mmol), 1.2 g of PyBOP (2.2 mmol) and 1.2 ml of V-methylmorpholine (11.2 mmol) in 20 mL of dimethylformamide. PA 1193 is obtained in the form of a white powder after purification by liquid chromatography on silica gel (SiO 2 60? CC 6-35 Microm, eluent: chloroform / methanol 92/8 v / v) followed by recrystallization from a mixture chloroform / n-hexane (0.5 g, 48%).
1 H NMR (250 MHz, DMSO) δ ppm: 3.08 (4H, m), 3.57 (2H, m), 3.79 (1H, m), 3.86 (4H, m.p.

Hz), 7.15 (1H, t, J = 9.0 Hz), 7.24 (1H, dd, J = 2.4 Hz, J = 9.0 Hz), 7.59 (2H, m) , 7.85 (1H, t, J = 5.9 Hz), 7.91 (1H, d, J = 2.2 Hz), 8.34 (2H, m), 8.39 (1H, t, J = 5.3 Hz). MS (IS> 0) m / z: 514.30 (M + H +). Elemental analysis: for C25H25ClFN5O4 0.7H2O:% theor. C, 57.02, N 13.30; % experiment C, 57.02, N 13.07.
EXAMPLE 37 Hybrid Aminoquinoline-Oxazolidinone Molecule, Ref PA 1196 (5S) - [2- (6-Chloro-quinolin-2-ylamino) -ethyl] -carbamic acid 3- (3-Fluoro-4-morpholin-4-ylphenyl) ) -2-oxo-oxazolidin-5-ylmethyl ester

This compound is prepared according to the procedure described in Example 34 starting from 0.6 g of 3- (3-fluoro-4-morpholin-4-yl-phenyl) -5-hydroxymethyl-oxazolidin-2-one (2 , 1 mmol), 0.3 mL of triethylamine (2.1 mmol), 0.2 g of triphosgene (0.8 mmol), 0.5 g of N- (6-chloroquinolin-2-yl) -ethane- 1,2-diamine (2.1 mmol) (prepared according to the method described by TJ Egan et al., J. Med Chem 2000, 43, 283-291) and 0.3 ml of triethylamine (2.1 mmol ) in 10 ml of dichloromethane.PA 1196 is obtained in the form of a white powder after purification by liquid chromatography on silica gel (SiO 2 60 ° C 635 Microm, eluent: chloroform / methanol 91.5 / 8.5 v / v followed by recrystallization from chloroform / n-hexane (0.5 g, 48%).
1 H NMR (250 MHz, DMSO) ppm: 2.74 (4H, m), 3.23 (2H, m), 3.42 (2H, m), 3.72 (4H, m), 3.79 ( 1H, m), 4.16 (1H, t, J = 9.1 Hz), 4.23 (2H, m), 4.88 (1H, m), 6.77 (1H, d, J = 9. , 0 Hz), 7.04 (1H, t, J = 9.1 Hz), 7.17 (1H, dd, J = 2.2 Hz, J = 9.1 Hz), 7.23 (1H, t, J = 5.4 Hz), 7.39-7.59 (4H, m), 7.70 (1H, d, J = 1.9 Hz), 7.82 (1H, d, J = 9; , 0 Hz). MS (DCI / NH3> 0) m / z: 544 (M + H +).
Example 38: Stability Tests of the Aminoalinolein Cephalosporin Hybrid Molecules at Physiological pH and Acid pH

determined in solution at 37 [deg.] C at physiological pH (pH 7, 75/25 v / v phosphate / acetonitrile buffer) and at acidic pH (pH 1, 0.1 M HCl / 70/30 v / v ethanol) by high pressure liquid chromatography coupled to a UV-visible detector (Beckman Coulter ODS C18 column, 5.5 microm, 4.6 x 250 mm; eluents: A: 0.1% TFA, B: CH3CN / H20 90/10 0.1 % TFA, gradient: from 10% to 100% of B in 30 min, then 100% of B for 10 min, flow rate 1 ml / min, = 254 nm, volume injected: MicroL).
The stability results at pH 7 and pH 1 obtained with the various aminoquinoline-cephalosporin hybrid molecules of Examples 6, 7 and 14 are listed in Tables 1 and II below.
TABLE 1: Stability at pH 7 Purity of hybrid molecules (in percent) versus time (hours)

TABLE II: Stability at pH 1 Purity of hybrid molecules (as a percentage) versus time (hours)

The results in Tables 1 and II demonstrate excellent stability of the hybrid molecules obtained at the tested pH, in particular at pH 1 (pH of the stomach).
EXAMPLE 39 Antibacterial Activity of the Hybrid Molecules The antibacterial activity of the exemplary hybrid molecules was evaluated by determining the minimum inhibitory concentrations (MIC) in μg / mL per micromethod in a liquid medium and minimum bactericidal concentrations (CMB) in μg / mL. by transplanting on agar medium, on various Gram + and Gram-, aerobic and anaerobic bacterial species: Staphylococcus aureus MSSA (methicillin sensitive) CIP 4.83, Staphylococcus aureus MRSA (methicillin-resistant clinical isolate), Staphylococcus aureus NorA (quinolone-resistant) efflux) 1199B, Staphylococcus aureus MsrA (efflux macrolide resistant) PUL5054 (pMS97), Staphylococcus aureusVISA (intermediate vancomycin sensitivity) CIP 106757, Staphylococcus epidermidis MSCNS (methicillin-sensitive Staphylococcus coagulase) E93, Staphylococcus epidermidis MRCNS (Staphylococcus coagulase negative methicillin-resistant) D10, Streptococcus pneumoniae PSSP (penicillin-sensitive) CQI 201 and CIP 69.2, Streptococcus pneumoniae PRSP (penicillin-resistant G) CQR 162, a clinical isolate and CIP 104471, Streptococcus pneumoniae mefE (macrolide-resistant efflux) (clinical isolate), Streptococcus pyogenes CIP 56.41T, Enterococcus faecalis ERV (vancomycin-resistant) CIP 104 676, Enterococcus faecalis VRE VanA (vancomycin-resistant) CIP 106996, Enterococcus faecalis VRE VanB (vancomycin-resistant) CIP 106998, Haemophilus influenzae (beta-lactamase producer) CIP 102514, Moraxella catarrhalis CIP 7321T, Escherichia coli CIP 54127, Bacillus subtilis CIP 5262, Bacillus thuringiensis CIP 104676, Bacteroides fragilis AIP 7716 (inoculation suspensions: 108 bacteria / mL, incubation at 37 [deg] C, 5% CO2 for Streptococcus, Haemophilus, and Enterococcus).
The results of the hybrid molecules according to the invention obtained on the various bacterial species indicated above are listed in Tables III to XIII below.
Aminoquinoline-β-Lactam Hybrid Molecules TABLE III: Antibacterial Activity of an Example of an Aminoquinoline-Penicillin Hybrid Molecule on Staphylococcus aureus MSSA CIP 4.83 (MIC and CMB in Microg / mL)

It is clear from Tables III and IV above that the antibacterial activity of

perfectly unexpected for a person skilled in the art, in particular on Gram + bacteria such as 5. pneumoniae and 5. pyogenes.
TABLE V Antibacterial activity of the constitutive structures of an example of a hybrid aminoquinoline-cephalosporin molecule, tested separately and in a 1/1 (mole / mole) combination (MIC in microg / ml).

7-ACA: 7-aminocephalosporanic acid; PA 1117: (7-chloro-quinolin-4-ylamino) acetic acid; PA 1046: Coupling product between 7-ACA and PA 1117.
The results in Table V clearly demonstrate the amplifying effect of antibiotic activity when Q and A are joined by a covalent bond.
TABLE VI: Antibacterial activity of an example of a hybrid aminoquinoline-cephalosporin molecule in the presence of human serum (MIC in Microg / mL).

This table shows that the example of hybrid aminoquinoline-cephalosporin molecule remains active in vitro in the presence of human serum, unlike the reference molecule. Hybrid aminoquinoline-quinolone molecules TABLE VII: Antibacterial activity of examples of aminoquinoline-quinolone hybrid molecules (CMI in microg / mL).

These results show a very strong increase in antibacterial activity provided by the aminoquinoline when it is attached to an antibiotic of the quinolone family.
Hybrid aminoquinoline-nitroimidazole molecules TABLE VIII: Antibacterial activity of examples of aminoquinoline-nitroimidazole hybrid molecules (MIC in g / mL).

The aminoquinoline-nitroimidazole hybrid molecules are active on an anaerobic bacteria strain.
Aminoquinoline-Streptogramin Hybrid Molecules TABLE IX: Antibacterial Activity of Examples of Aminoquinoline-Streptogramin Hybrid Molecules (MIC in g / mL).

Aminoquinoline significantly improves the activity of streptogramins as shown in the example of the table above.
Aminoquinoline-Macrolide Hybrid Molecules TABLE X: Antibacterial activity of an example of aminoquinoline-macrolide hybrid molecules (MIC in .g / ml).

In the example of an aminoquinoline-macrolide hybrid molecule, aminoquinlein provides an interesting gain of activity on penicillin-sensitive S. pneumoniae but also on an efflux-resistant macrolide strain.
Hybrid aminoquinoline-glycopeptide molecules TABLE XI: Antibacterial activity of examples of hybrid aminoquinoline-glycopeptide molecules (MIC in g / mL).

The effect of the covalent attachment of an aminoquinoline on an antibiotic residue of the glycopeptide family is particularly remarkable with significantly improved bacterial activity on sensitive strains but also on resistant strains.
Aminoquinoline-Oxazolidinone Hybrid Molecules TABLE XII: Antibacterial Activity of an Example of Aminoquinoline-Oxazolidinone Hybrid Molecules (MIC in Microg / mL).

The aminoquinoline-oxazolidinone hybrid molecule tested as an example demonstrates antibacterial activity equivalent to the reference molecule.

Claims (32)

1. An aminoquinoline-antibiotic hybrid compound, characterized in that it is represented by the general formula (I):  in which : Q represents an aminoquinoline of formula (IIa), (IIb), (IIIa), (IIIb), (IIIc) or (Illd) below:  in the formulas above: the sign indicates the site of attachment of the other fragment, for example either Y1, or U, or Y2, or A; n and n 'independently represent 0, 1, 2 or 3; - Ria and Rlb (generally Ri) represent one or more identical or different substituents, occupying any positions and representing a radical selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, sulfate, sulfonate, phosphate , phosphonate, nitro, cyano, aryl or heteroaryl or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonylamino, said alkyl groups preferably comprising 1, 2, 3, 4 Linear or branched or cyclic, saturated or unsaturated, 5, or 6 carbon atoms, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, hydroxyimine, ether or thioether radicals and may themselves carry 1 to 4 substituents, identical or different, chosen from halogen, hyd roxy, trifluoromethyl, trifluoromethoxy, carboxy, carbonyl, amine, nitro, urea, aryl or heteroaryl, R2a and R2b (generally R2) being identical or different substituents, which can optionally form a ring structure together or with Y1, Y2, U or A and representing a hydrogen atom or an alkyl radical, preferably C1 C 1, C 2, C 3, C 4, C 5, or C 6, linear, branched or cyclic, optionally containing one or more amine, amide, thioamide, sulfonyl, urea, thiourea, carbamate, oxime, sulfonamide, carboxy, thiocarboxy, carbonyl radicals, thiocarbonyl, ether or thioether and may carry 1 to 4 substituents, identical or different, selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl, p, p ', p "are independently of one another 0 or 1, Y1 and Y 2, which may be identical or different, which may be linked by a single or multiple bond to Q, U or A, and represent an alkyl chain, preferably of C 1, C 2, C 3, C 4, C 5, or C 6, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, oxo, carboxy, thiocarboxy, carbonyl, thiocarbonyl, urea, thiourea, carbamate, oxime, ether or thioether, aryl or heteroaryl radicals the alkyl chain may also carry 1 to 4 substituents, which may be identical or different, preferably chosen from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, carbonyl, amine, nitro, oxime, aryl or heteroaryl, such as defined below, or selected from alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfamoyl, alkylureido, alkylcarbamoyloxy, alkoxycarbonylamino, alkylcarbam groups; oyl, dialkylcarbamoyl, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxyimine, said alkyl groups comprising from 1 to 6 linear, branched or cyclic carbon atoms which may themselves contain one or more amine, amide, thioamide, sulfonyl, sulfonamide or carboxy radicals , thiocarboxy, carbonyl, thiocarbonyl, oxime, ether, thioether, aryl or heteroaryl as defined below, the C1, C2, C3, C4, C5 or C6 chain possibly forming a ring structure with R2 including N of the aminoquinoline part Q and / or the function U and Y1 and Y2 can be connected together or to Q, U or A by a single or multiple link, U, which can be bound by a single or multiple bond to Q, Y1, Y2 or A is an amine, amide, thioamide, sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, urea, thiourea, carbamate, ether, thioether or thiocarbonyl function; , sulfonate, oxime, oxyamine, alkoxyimine (C = N-OR) or alkoxyiminocarbonyl (C (O) -C = N-OR) with R representing a hydrogen atom or an alkyl radical preferably of C1, C2, C3, C4, C5, or C6, linear, branched or cyclic, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether radicals, - A represents an antibiotic residue, with the exception of the compounds: 1) When A is 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 1-cyclopropyl acid -6,8-difluoro-4-oxo-1,4-dihydro-quinolin-3-carboxylic acid, and when the - (Y 1) p- (U) p- (Y 2) p - link between A and Q is a piperazine, then Q is different from 7-chloro-4-aminoquinoline, ie the compounds of formula:  2) When A is (4S, 5R, 6S) -6 - [(R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene 2-carboxylic acid and when the link - (Y1) p- (U) p- (Y2) p "- between A and Q is 3-thioazetidine, then the quinoline part of the substituent Q can not be attached to the link by the position 2, for example the compound of formula:  3) when A is a (3-lactam of formula 3-chloro-azetidin-2-one substituted at 4, and when in the - (Y1) p- (U) p- (Y2) p "-, p link, p ', and p "are 0, thereby forming a direct covalent bond between the nitrogen N1 of A and the extracyclic nitrogen of a 2 aminoquinoline, then Q is different from 2-amino-4-methylquinoline, either by for example, the compounds of formula:  4) when A is a cephalosporin, and when the link - (Yi) p- (U) p- (Y2) p "- is located in position 3 of the cephalosporin and this link contains an amide function, then Q is different a 6,7-dihydroxy-4-dimethylaminoquinolin-3-yl, for example the compound of formula:  5) when A is a penicillin, and the link - (Y1) p- (U) p- (Y2) p "- contains an amide function, and when Q is a 4-aminoquinoline linked by the 3-position, then the amine function of 4-aminoquinoline can not be free, for example the compounds of formula:  6) when A is a penicillin or a cephalosporin substituted in position 3  amide function, then Q is different from 4-hydroxy-6-acetylamino-quinolin-3-yl, for example the compound of formula:  8) when A is (6R, 7R) -7- [2- (2-amino-thiazol-4-yl) -2 (Z) -methoxyiminoacetylamino] -8-oxo-5-thia-1-aza acid; -bicyclo [4.2.0] oct-2-ene carboxylic acid, and that the link (Yi) p- (U) p- (Y2) p "- is a methylene bond, then Q is different from 5-aminoquinolin-1 yl, or the compound of formula:  Fluoro-phenyl, and that the link - (Y1) p- (U) p- (Y2) p "- is a 4-piperazin-1-yl linkage including R2 and N of aminoquinoline, whereas Q is different from quinolin -4-yl, the compound of formula: 10) when A is a diaminopyrimidine, and the bond - (Y1) p (U) p '- (Y2) p "- is a methylene bond, then Q is different from the following quinolines: 2-morpholino-4-methyl-quinolin 7-yl, 4-methyl-8-aminoquinolin-6-yl, 4-methyl-5-aminoquinolin-6-yl, 2-dimethylamino-4-methyl-quinolin-6-yl, 2-dimethylamino-4,8-dimethylquinolin 6-yl, 2-morpholino-4,8-dimethyl-quinolin-6-yl, 2-methyl-4-dimethylamino-8-methoxy-quinolin-6-yl, for example compounds of the formula: 11) when A is 2-methyl-5-nitroimidazol-1-yl, directly attached to the extracyclic nitrogen atom of aminoquinoline Q (p = p '= p "= 0) then Q is different the following quinolines: 7-chloro-quinolin-4-ylamino, 2-methyl-8-hydroxy-quinolin-4-  hydroxy-quinolin-4-ylamino, ie the compounds of formula: 12) when A is 2-methyl-5-nitro-imidazol-1-yl, and that the - (Y1) p- (U) p '(Y2) p - bond is a 2-ethyl- (1) bond; -cyclohexan-4-yl) -amine then Q is different from 7-chloroquinolin-4-ylamino, ie the compound of formula: 2. Compound according to claim 1, characterized in that the group A represents an antibiotic, one of its derivatives or precursors, chosen from the group consisting of a (3-lactam, a quinolone, an oxazolidinone, a derivative of fosfomycin, nitroimidazole, nitro-furan, sulfonamide, streptogramin, synergistin, lincosamide, tetracycline, chloramphenicol, fusidic acid derivative, diaminopyrimidine, aminoglycoside, macrolide, polypeptide , a glycopeptide, a rifamycin, a lipodepsipeptide. 3. Compound according to claim 1, characterized in that the antibiotic residue A is chosen from the family of beta-lactams containing: penames (or penicillins) of formula (IV), oxapenames of formula (V), penems of formula ( VI), carbapenems of formula (VII), cephems (or cephalosporins) of formula (Villa), (VIIIb), (IXa) or (IXb), cephamycins of formula (City) or (VIIId), oxacephems of formula (Xa) or (Xb), carbachephems of formula (XIa) or (XIb) and monobactams of formula (XII) below:  in which R 1 is as defined in claim 1, - R3a and R3b (generally R3) represent identical or different substituents, selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, aldehyde, amine, sulfate, sulfonate, phosphate, phosphonate, nitro, cyano, aryl or heteroaryl or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfamoyl, alkylureido, alkylcarbamoyloxy, alkoxycarbonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxyimine, said alkyl groups preferably comprising 1, 2,3 , 4, 5 or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, oxo, carboxy, thiocarboxy, carbonyl, thiocarbonyl, urea radicals , thiourea, carbamate, oxime, ether or thioether and may themselves carry 1 to 4 identical substituents or different, chosen from halogen, hydroxy, trifluoromethyl, methyl, trifluoromethoxy, methoxy, carboxy, carbonyl, amine, nitro, urea, aryl or heteroaryl or heterocycle, - R4a and R4b (generally R4) identical or different, which may optionally form a ring structure together or a multiple bond, represent a hydrogen atom or a linear, branched or cyclic, saturated C 1 to C 6 alkyl radical or unsaturated, optionally containing one or more amine, amide, thioamide, sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, oxime, urea, carbamate, ether or thioether radicals and capable of carrying 1 to 4 identical or different substituents, selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl, - R5 is a hydrogen atom or an alkyl radical preferably C1, C2, C3, C4, C5, or C6, linear or branched or cyclic, saturated or unsaturated, V represents a methoxy group or a hydrogen atom, - HetAr represents a heteroaryl. 4. Compound according to claim 1, characterized in that the antibiotic residue A represents a quinolone unit represented by the following formula (XIIIa) or (XIIIb),  in which R3 and R4 are as defined previously, R 6 and R 7 are identical or different substituents, which may optionally form a cyclic structure together and representing a hydrogen atom or a substituent chosen from the group consisting of halogen, hydroxy, heterocycle, aryl or heteroaryl, or an alkyl radical; alkyl, alkoxy or alkylamino, said alkyl groups comprising 1, 2, 3, 4, 5, or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide or thioamide radicals; , sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether and which may carry 1 to 4 substituents, identical or different, chosen from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, nitro, aryl, or heteroaryl, Z is a nitrogen or carbon atom. 5. Compound according to claim 1, characterized in that the antibiotic residue A represents an oxazolidinone residue represented by the following formulas (XIVa), (XIVb) or (XIVc),  in which R3, R6 and R7 are as defined above. 6. Compound according to claim 1, characterized in that the antibiotic residue A represents a derivative of fosfomycin of formula (XV) below,   wherein R4, and R4b, identical or different, can optionally form a cyclic structure together are as defined above. 7. Compound according to claim 1, characterized in that the antibiotic residue A represents a nitroimidazole residue of formulas (XVIa) or (XVIb) or a nitrofuran residue of formula (XVII) below,  in which R3 is as previously defined 8. Compound according to claim 1, characterized in that the antibiotic residue A represents a sulphonamide residue of formula (XVIII) below, 9. Compound according to claim 1, characterized in that the antibiotic residue A represents a streptogramine or synergistine residue of formulas (XIXa), (XIXb) or (XX) below,  in which R3, R4a, R4b, Rs and m are as defined above. 10. Compound according to claim 1, characterized in that the antibiotic residue A represents a lincosamide residue of formula (XXI) below, 11. Compound according to claim 1, characterized in that the antibiotic residue A represents a tetracycline residue of formulas (XXIIa), (XXIIb) and (XXIIc) below,  in which R3, R4 and R6 are as defined above, - R8 and R9a, R9b identical or different, represent a hydrogen atom or a radical selected from hydroxy or methyl group. 12. Compound according to claim 1, characterized in that the antibiotic residue A represents a chloramphenicol derivative of formulas (XXIIIa) or (XXIIIb) below,  in which R3 is as defined above, W represents an N02 or SO2R5 radical, R5 being as defined above. 13. Compound according to claim 1, characterized in that the antibiotic residue A represents a fusidic acid derivative of the following formulas (XXIVa), (XXIVb) or (XXIVc), 14. Compound according to claim 1, characterized in that the antibiotic residue A represents a diaminopyrimidine residue of the following formula (XXV),  in which Rs is as defined above. 15. Compound according to claim 1, characterized in that the antibiotic residue A represents an aminoglycoside residue formed by the union of a genin unit of the aminocyclitol group with one or more monosaccharides, at least one of which is an aminosecre and interconnected. by glycosidic bridges. 16. Compound according to claim 1, characterized in that the antibiotic residue A represents a macrolide residue: at 14 atoms of formulas (XXVIa), (XXVIb), (XXVIc) and (XXVId), at 15 atoms of formulas (XXVIIa), (XXVIIb), (XXVIIc) and (XXVIId) following, - or to 16 atoms of formulas (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId) and (XXVIIIe) following,  in which R3, R4, R6 and R7 are as defined above, - R10 is an oxygen atom bonded by a carbonyl-type double bond to the macrocycle or a hydroxyl group or a glycoside-linked glycoside derivative linked to the macrocycle and capable of carrying 1 to 6 substituents, identical or different, chosen from hydroxy, alkyl , alkylamino, dialkylamino or alkoxy, said alkyl groups comprising 1, 2, 3, 4, 5, or 6 linear or branched carbon atoms, saturated or unsaturated and may carry a carboxy substituent. 17. Compound according to claim 1, characterized in that the antibiotic residue A represents a polypeptide residue such as polymyxin derivatives or bacitracin connecting various peptide structures. 18. Compound according to claim 1, characterized in that the antibiotic residue A represents a glycopeptide residue chosen from: vancomycin derivatives of the following formulas (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe) and (XXIXf), - or derivatives of teicoplanin of formulas (XXXa) or (XXXb) following,  wherein R3, R4, and R6 are as previously defined. 19. Compound according to claim 1, characterized in that the antibiotic residue A represents a rifamycin residue of formulas (XXXIa) and (XXXIb) below,  in which R6 occupies any position and can form a ring structure with Y1, Y2 or U is as defined above. 20. Compound according to claim 1, characterized in that the antibiotic residue A represents a lipodepsipeptide residue of formula (XXXII) below, 21. A compound according to any one of claims 1 to 20, characterized in that Q is chosen from a 4-aminoquinoline, a 2-aminoquinolines, and an 8-aminoquinolines of formulas (XXXIIIa), (XXXIIIb), (XXXIIIc), ( XXXIIId) and (XXXIIIe) following,  in which Ria, Rlb (generally R1), R2, n and n 'are as in the above. 22. A compound according to any one of claim 23, characterized in that R 1 represents a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro group occupying any position, in the formulas (XXXIIIa), (XXXIIIb) and (XXXIIIe) R2 represents a hydrogen atom or a methyl group or forms a ring structure with Y1 including N of aminoquinoline, in formulas (XXXIIIb) and (XXXIIId) R2, and R2b represent a hydrogen atom or a methyl, cyclopropyl or 2- (diethylamino) ethyl group, or a heterocycle when RZa and R2b form a ring structure together. 23. A compound according to any one of claims 1 to 22, characterized in that the compounds of formula (I) are those having the groups - (Yl) p - (U) p '- (Y 2) p "chosen from in which p = p '= p "= 0, the link between Q and A being direct, a group in which p' = 1 and p = p" = 0, U being as defined above and advantageously representing a carbonyl group a group in which p '= 1 and p = p "= 0, U being as defined above and advantageously representing a thioether group, a group in which p' = 1 and p = p" = 0, U being such that defined above and advantageously representing an alkoxyiminocarbonyl group (preferably hydroxyiminocarbonyl or methoxyiminocarbonyl), a group in which p 1 and p '= p "= 0, Y 1 being as defined above and advantageously representing a C 1, C 2, C 3 alkyl chain, C4, C5, or C6 linear or branched and can form a cyclic structure with A or R2 included N is aminoquinoline, a group in which p = 1 and p '= p "= 0, Y 1 being as previously defined and preferably representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain substituted by fluorine atoms, a group in which p = 1 and p '= p "= 0, Y 1 being as defined above and advantageously representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain containing an amine radical; or ether, a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing a carbonyl group and Y1 being as defined above and advantageously representing a C1, C2, C3 alkyl chain; C4, C5, or C6 linear or branched and can form a ring structure with R2 including N of aminoquinoline, a group in which p = p '= 1 and p "= 0, U being as defined above and representing advantageously an amine group and Y1 being as defined above and representing antiagulously a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an amine, ether, amide or urea radical and may form a ring structure with U and / or R 2 including N of aminoquinoline a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing a thioether function and Y1 being as defined above and advantageously representing a C1, C2, C3, C4 alkyl chain; C5, linear or branched C6, which may be substituted by fluorine atoms, a group in which p = p '= 1 and p "= 0, U being as defined above and advantageously representing an ether function and Y1 being such as defined above and advantageously representing a C1, C2, C3, C4, C5 or C6 alkyl chain, a group in which p = p '= 1 and p "= 0, U being as defined previously and advantageously representing a functional group. carbamate and Y1 being such that defined above and advantageously representing a linear or branched, saturated or unsaturated C 1, C 2, C 3, C 4, C 5, or C 6 alkyl chain which may contain an ether and / or aryl radical, a group in which p '= p "= 1 and p = 0, U being as defined above and advantageously representing an amide function and Yz being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain a radical amine or thioether, a group in which p = p '= p "= 1, U being as defined above and advantageously representing an amine function and Y 1 and Y 2 being as defined above and advantageously representing a C 1, C 2 alkyl chain, C3, C4, C5, or linear or branched C6, which may be substituted by fluorine atoms or a hydroxy group and which may form a ring structure with U and / or R2, including N of aminoquinoline, a group of in which p = p '= p "= 1, U being as defined above and advantageously representing an ether function and Y1 and Y2 being as defined above and advantageously representing a C1, C2, C3, C4, C5 alkyl chain, or linear or branched C6 may contain an aryl radical, a group wherein p = p '= p "= 1, U being as defined above and advantageously representing a thioether function and Yi and Yz being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 alkyl chain, a group in which p = p '= p "= 1, U being as defined above and advantageously representing an amide function and Y 1 and Y 2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may be substituted by fluorine atoms, a group in which p = p '= p "= 1, U being such that e defined above and advantageously representing a carbamate function and Y1 and Y2 being as defined above and advantageously representing a linear or branched C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may be substituted by fluorine atoms, a group in which p = p '= p "= 1, U being as defined above and advantageously representing a urea function and Y 1 and Y 2 being as defined above and advantageously representing a C 1, C 2, C 3 and C 4 alkyl chain, C5, or C6 linear or branched and may be substituted by fluorine atoms. 24. Compound according to claim 1, characterized in that it is represented by the structure (XXXIVa), (XXXIVb) or (XXXIVc) in which R1a, R1b, R2, R3a, R3b, R4, Y1, Y2, U, p, p ', p ", m, n and n' are as previously defined.  of structure (XXXVa), (XXXVb) or (XXXVc) wherein R1, R2, R3, R4, Y1, Y2, U, p, p ', p ", m, n and n' are as previously defined  of structure (XXXVd), (XXXVe), (XXXVf), (XXXVg) or (XXXVh) wherein R1, R2, R3, R4, Y1, Yz, U, p, p ', p ", m, n and n 'are as previously defined 25. Compound according to claim 1, characterized in that it is represented by the formula (XXXVIa) or (XXXVIb) in which R1, R2, R3, R4, R6, R7, Y1, Y2, U, Z, p, p ', p ", n and n' are as defined above. 26. Compound according to claim 25, characterized in that in the aminoquinoline-quinolone hybrid molecules of formulas (XXXVIa), R 6 is a linear, branched or cyclic C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain or forms a ring structure with R 7 and R 7 is a hydrogen or halogen atom, a methoxy group or a form a ring structure with R6 such as 3-methyl-3,4dihydro-2H- [1,4] oxazine; the group (Y1) p- (U) p, - (Y2) p ", is a group in which p = p '= p" = 0, Q being directly linked to A, or a group in which p = p = = 1 and p "= 0, U being as defined above and advantageously representing an amine function and representing a C1, C2, C3, C4, C5 or C6 alkyl chain which can form a cyclic structure with U or R2 (including N of aminoquinoline) and optionally containing an amine radical. 27. Compound according to claim 25, characterized in that in the aminoquinoline-quinolone hybrid molecules of formulas (XXXVIb), - R6 is a heterocycle containing 1 or 2 heteroatoms; the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = p" = 0, Q being directly bonded to A and the exocyclic nitrogen atom of aminoquinoline corresponding to the endocyclic nitrogen atom of quinolone, or a group in which p = 1 and p '= p "= 0, Y1 being as defined above and advantageously representing a C1-alkyl chain, C2, C3, C4, C5, or C6 can form a ring structure with R2. 28. Compound according to claim 1, characterized in that it is represented by the formula (XXXVII) in which R1, R2, R3, Y1, Y2, U, p, p ', p ", n and n' are such as previously defined 29. A compound according to claim 28, characterized in that in the aminoquinoline-nitroimidazole type hybrid molecules of formula (XXXVII), R1 represents a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy or cyano group. , amine or nitro occupying any position and R2 represents a hydrogen atom or a methyl group or forms a ring structure with Y1 including N of aminoquinoline, R3 is a methyl group and as the group (Y1) p- (U) p '- (Y2) p "is a group in which p = 1 and p' = p" = 0, where Y1 represents a C1, C2, C3, C4, C5 alkyl chain, or C6 or a group in which p = p '= p "= 1, where U represents an amine function, Y1 represents a C1, C2, C3, C4, C5 or C6 alkyl chain which may form a ring structure with R2 including N aminoquinoline and Y2 represents a C1, C2, C3, C4, C5 or C6 alkyl chain bearing a hydroxy substituent. 30. Compound according to claim 1, characterized in that it is represented by the formula (XXXVIII) in which R1, R2, R4a, R4b, R5, Y1, Y2, U, p, p ', p ", n and are as defined previously 31. Compound according to claim 30, characterized in that in the aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII), R1 represents a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro group occupying any position and R2 represents a hydrogen atom or a methyl group or forms a cyclic structure with Y1 including N of aminoquinoline, R4 and R5 are C1, C2, C3, C4, C5, or C6 alkyl chains; the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = p" = 1, U representing a thioether function and Y1 and Yz representing a C1-alkyl chain; , C2, C3, C4, C5, or C6. 32. Compound according to claim 1, characterized in that it is represented by the formula (XXXIX)) in which R1, R2, R4, R5, Y1, Y2, U, p, p ', p ", n and n 'are as previously defined 33. A compound according to claim 32, characterized in that in the aminoquinoline-diaminopyrimidine hybrid molecules of formula (XXXIX), R1 represents a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy or cyano group. wherein R 2 is a hydrogen atom or a methyl group or a cyclic structure with Y 1 including N of aminoquinoline, R 5 is a hydrogen atom and the group (Y 1) p (U) p '- (Y2) p "is a group in which p = p' = p" = 1, U preferably represents an ether function, Y1 represents a C1, C2, C3, C4, C5, or C6 alkyl chain; Y 2 represents a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain containing an aryl radical which can itself bear 1 to 4 identical or different substituents. 34. A compound according to claim 1, characterized in that it is represented by the formulas (XLa) (XLb) or (XLc) in which R1, R2, R5, R6, R7, R10, Y1, Y2, U, p , p ', p ", n and n' are as previously defined 35. Compound according to claim 34, characterized in that in the aminoquinoline-macrolide hybrid molecules of formula (XLa), (XLb) and (XLc), R1 represents a halogen atom or a hydroxyl, methyl or methoxy group. trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro occupying any position and R2 represents a hydrogen atom or a methyl group or forms a ring structure with Y1 including N of aminoquinoline, R3 is a hydroxy or methoxy group, R4 is a hydrogen atom, R6 and R7 are hydroxy groups, R10 is an oxygen atom linked by a carbonyl-type double bond to the macrocycle or a glycosidic bond linked to a glycosidic derivative at the macrocycle and capable of carrying 1 to 6 substituents, in the aminoquinoline-macrolide hybrid molecules of the formula (XLa), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = 1 and p" = 0, U representing an oxyamine function linked by a double bond to A (thus forming an oxime function) and Y 1 representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an ether radical, in the aminoquinoline-macrorolide hybrid molecules of formula (XLb), the group (Y 1 p- (U) p '- (Y2) p "is a group in which p = 1 and p' = p" = 0, representing a C1, C2, C3, C4, C5 or C6 alkyl chain which may contain an ether radical, in the aminoquinoline-macrolide hybrid molecules of formula (XLc), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = 1 and p "= 0, U representing an ether or carbamate function and Y1 representing a saturated or unsaturated C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain, which may contain an ether radical and / or an aryl radical. 36. A compound according to claim 1, characterized in that it is represented by the formulas (XLIa) or (XLIb) in which R1, R2, Y1, Y2, U, p, p ', p ", n and n' are as defined previously 37. A compound according to claim 36, characterized in that in the aminoquinoline-glycopeptide hybrid molecules of formulas (XLIa) or (XLIb), R1 represents a halogen atom or a hydroxyl, methyl, methoxy, trifluoromethyl or trifluoromethoxy group. , carboxy, cyano, amine or nitro occupying any position and R2 represents a hydrogen atom, a methyl, cyclopropyl, or 2- (diethylamino) ethyl group, or forms a ring structure with Y1 including N of aminoquinoline, or a heterocycle when R2a, and R2b form a ring structure together, R4 is a hydrogen atom and R3 is a hydroxy group, in the aminoquinoline-glycopeptide hybrid molecules of formula (XLIa), the group (Yi) p (U) p - (Y2) p "is a group in which p = 1 and p '= p" = 0, Y1 representing a C1, C2, C3, C4, C5 or C6 alkyl chain which can form a cyclic structure with the atom nitrogen of residue A and R2 (including N of aminoquinoline) and be substituted by fluorine atoms or a group in which p = p '= p "= 1, where U represents an ether or amine function, Y1 represents a C1, C2, C3, C4, C5 or C6 alkyl chain which can form a cyclic structure with U and R 2 (including N of aminoquinoline) and Y 2 and representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an aryl radical as defined above which may itself carry 1 with 4 identical or different substituents, in the aminoquinoline-glycopeptide hybrid molecules of formula (XLIb), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = 1 and p' = p "= 0, where Y1 represents a C1, C2, C3, C4, C5 or C6 alkyl chain or a group in which p = 0 and p '= p" = 1, U representing an amide function, Y2 representing a chain C1, C2, C3, C4, C5, or C6 alkyl. 38. A compound according to claim 1, characterized in that it is represented by the formula (XLIIa), (XLIIb), or (XLIIc) in which R1, R2, R6, R7, Y1, Y2, U, p, p ', p ", n and n' are as previously defined 39. A compound according to claim 38, characterized in that in the aminoquinoline-oxazolidinone type hybrid molecules of formula (XLIIa), (XLIIb), or (XLIIc), according to a preferred arrangement, R1 represents a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro occupying any position and R2 represents a hydrogen atom or a methyl, cyclopropyl or 2- (diethylamino) ethyl group, or forms a cyclic structure with Y1 including N of aminoquinoline, or a heterocycle when R2a and R2b form a ring structure, R6 is a hydrogen or fluorine atom, R7 is a 5- to 6-membered heterocycle having 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen (preferably morpholin-4-yl or piperazin-1-yl) and R3 is a C1, C2, C3, C4, C5 or C6 alkyl chain which may contain an amide, carbamate or ether radical and may be substituted by a heterocycle in the aminoquinolineoxazolidinone hybrid molecules of formula (XLIIa), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = p" = 1, U representing an amide function or carbamate and Y1 and Y2 representing a C1, C2, C3, C4, C5 or C6 alkyl chain capable of forming a ring structure with U and / or R2 including N of aminoquinoline, in the aminoquinoline-oxazolidinone hybrid molecules of the formula (XLIIb), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = p" = 1, U representing a carbamate function and Y1 and Y2 representing an alkyl chain C1, C2, C3, C4, C5, or C6 being able to form a ring structure with U and / or R2 including N of aminoquinoline, in the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIc), the group (Y1) p- (U) p '- (Y2) p "is a group in which p = p' = p" = 0, the link being direct between Q and A or a group in which p = p '= 1 and p "= 0, where U represents an amine function and Y1 represents a C1, C2, C3, C4, C5 or C6 alkyl chain that can form a ring structure with U and / or R2 including N aminoquinoline and optionally containing an amine, amide, urea or carbamate radical. 40. Compound according to claim 1, characterized in that it is chosen from: - (2S, 5R, 6R) -6 - {[1- (7-Chloro-quinolin-4-yl) -piperidin-4-carbonyl] -amino} -3,3-dimethyl-7-oxo-4-thia-1 -aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester;  aza-bicyclo [3.2.0] heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester; - (2S, 5R, 6R) -6- [2- (7-Chloro-quinolin-4-ylamino) -acetylamino] -3,3-dimethyl-7-oxo-4-yia-1-aza-bicyclo [3.2.0 heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester; - (2S, 5R, 6R) -6- [3- (7-Chloro-quinolin-4-ylamino) -propionylamino] -3,3-dimethyl-7-oxo-4-yl-1-aza-bicyclo [3.2.0 heptane-2-carboxylic acid 2,2-dimethyl-propionyloxymethyl ester; - (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid; - (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid hydrochloride; - (6R, 7R) -3-Acetoxymethyl-7- [2- (7-chloro-quinolin-4-ylamino) -acetylamino] -5,8-dioxo - (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid; - (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -5,8- - (6R, 7R) -3-Acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionylamino] -5,8- - (6R, 7R) -3-Acetoxymethyl-7- [4- (7-chloroquinolin-4-ylamino) butyrylamino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid;  8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride; - (6R, 7R) -3-Acetoxymethyl-7- [2- (7-trifluoromethyl-quinolin-4-ylamino) -acetylamino] -8oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid; - (6R, 7R) -3-Acetoxymethyl-7- [2- (2-methyl-quinolin-4-ylamino) -acetylamino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2 -ene-2-carboxylic acid; - (6R, 7R) -3-Acetoxymethyl-7- [4-morpholin-4-yl-quinolinecarbonyl) amino] -8-oxo-5-yl-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid; - (6R-7R) -3-Acetoxy-7 - {[(4- (2-diethylamino-ethylamino) -quinolin-2-carbonyl] -amino} -8oxo-5-thia-1-aza-bicyclo [4.2. 0] oct-2-ene-2-carboxylic acid; - (6R-7R) -7- [2- (2-Amino-thiazol-4-yl) -2-methoxyiminoacetylamino] -3- [2- (7-chloroquinolin-4-ylamino) -ethylsulfanylmethyl] -8 -oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid; - [2- (2-Methyl-5-nitroimidazol-1-yl) -ethyl] - (7-trifluoromethyl-quinolin-4-yl) -amine; 1- [2- (7-Chloro-quinolin-4-ylamino) -ethylamino] -3- (2-methyl-5-nitro-imidazol-1-yl) propan-2-ol; 5- {4- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -benzyl} -pyrimidine-2,4-diamine; 5- {4- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -3-methoxy-benzyl} -pyrimidine-2,4-diamine; 5- {3- [2- (7-Chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzyl} -pyrimidine-2,4-diamine; N-4- [4- (7-chloro-quinolin-4-ylamino) -butyl] -vancomycin; N-4- [4- (7-chloro-quinolin-4-ylamino) -ethyl] -vancomycin; - (5S) - [2- (7-Chloroquinolin-4-ylamino) -ethyl] -carbamic acid 3- (3-fluoro-4-morpholin-4-ylphenyl) -2-oxo-oxazolidin-5-ylmethylester ; (5S) -3- (7-Chloro-quinolin-4-ylamino) - N - [(3-fluoro-4-morpholin-4-yl-phenyl) -2-oxooxazolidin-5-ylmethyl] - propionamide; (5S) -2- (7-Chloro-quinolin-4-ylamino) - N - [(3-fluoro-4-morpholin-4-yl-phenyl) -2-oxooxazolidin-5-ylmethyl] - acetamide; - (5S) - [2- (6-Chloro-quinolin-2-ylamino) -ethyl] -carbamic acid 3- (3-fluoro-4-morpholin-4-ylphenyl) -2-oxo-oxazolidin-5-ylmethyl ester. 41. A compound according to any one of claims 1 to 40, characterized in that it is in salt form, for example as alkali metal salts, or alkaline earth metal salts, ammonium salt or nitrogenous base salts. . 42. A compound according to any one of claims 1 to 40, characterized in that it is used as an antibacterial agent. 43. Pharmaceutical composition characterized in that it comprises as active ingredient at least one compound according to any one of claims 1 to 42, in admixture with a pharmaceutically acceptable excipient. 44. Pharmaceutical composition according to claim 43, characterized in that it is in a form capable of being administered in injectable, sprayable or unmanageable form, intramuscularly, intravenously, subcutaneously, intradermally, orally, topically, rectally, vaginally, ophthalmic. , nasal, transdermal or parenteral. 45. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for carrying out a disinfection treatment of medical equipment. 46. Use of a compound as defined in any one of claims 1 to 42 for the manufacture of a composition comprising said compound in an amount effective to treat a bacterial infection of an animal or a human being . 47. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of an infection or a bacterial contamination due to Staphylococcus aureus, Staphylococcus aureus MSSA (susceptible with methicillin), Staphylococcus aureus MRSA (methicillin-resistant), Staphylococcus aureus NorA (efflux-resistant quinolone), Staphylococcus aureus MsrA (efflux-resistant macrolide) or Staphylococcus aureus VISA (or GISA) (resistant to vancomycin), Staphylococcus epidermidis, Staphylococcus epidermidis MSCNS ( methicillin-sensitive coagulase-negative) or Staphylococcus epidermidis MRCNS (methicillin-resistant coagulase negative), Streptococcus pneumoniae, Streptococcus pneumoniae PSSP (penicillin-sensitive), Streptococcus pneumoniae PRSP (penicillin-resistant) or Streptococcus pneumoniae mefE (macrolide-resistant) efflux), Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecalis vancomycin-resistant, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Bacillus subtilis or Bacteroides fragilis. 48. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of pneumonia, meningitis, otitis, or acute sinusitis, due to Streptococcus pneumoniae, said compound being selected from compounds active on Streptococcus pneumoniae. 49. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for treating an infection of the skin and / or mucous membranes, a nosocomial infection , or osteomyelitis, due to Staphylococcus aureus said compound being selected from the compounds active on this bacterium. 50. Use of a compound as defined in any one of claims 1 to 42 for the manufacture of a pharmaceutical composition for the treatment nosocomial and iatrogenic infections due to Staphylococcus epidermidis, said compound being selected from the compounds active on this bacteria. 51. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of an infection selected from nosocomial, urinary, cutaneous, genital, biliary dental infections and otitis-sinusitis or endocarditis due to Enterococcus faecalis, said compound being selected from compounds active on this bacterium. 52. Use of a compound as defined in any one of claims 1 to 42 for the manufacture of a pharmaceutical composition for the treatment of infections due to Streptococcus pyogenes selected from: bacterial angina, ENT disease, infections cutaneous, scarlet fever, erysipelas, impetigo or subcutaneous gangrene, said compound being selected from the compounds active on Streptococcus pyogenes. 53. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of ENT diseases, complication of influenza or meningitis, due to Haemophilus influenzae, said compound being selected from compounds active on this bacterium. 54. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of ENT diseases due to Moraxella catarrhalis, said compound being selected from the compounds active on this bacteria. 55. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of a urinary tract infection, abdominal, or infantile diarrhea, due to Escherichia coli, said compound being selected from compounds active on this bacterium. 56. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment of food poisoning due to Bacillus sp., Said compound being chosen from active compounds on this bacteria. 57. Use of a compound as defined in any one of claims 1 to 42, for the manufacture of a pharmaceutical composition for the treatment bacteremia, abscess and lesions, peritonitis, endocarditis or wound infections due to Bacteroides fragilis, said compound being selected from compounds active on this bacterium. 58. Use according to any one of claims 48 to 57, characterized in that  formula (XXXIVa), (XXXIVc), (XXXVa) and (XXXVb), the aminoquinoline-cephalosporin hybrid molecules of formula (XXXVd), (XXXVe), (XXXVf), (XXXVg), (XXXVh), the aminoquinoline-quinolone hybrid molecules of formula (XXXVIa) the aminoquinoline-nitroimidazole hybrid molecules of formula (XXXVII)), the aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII), the aminoquinoline-diaminopyrimidine hybrid molecules of formula (XXXIX) ), the hybrid molecules of formula (XLa) called macroliquines, the aminoquinoline glycopeptide hybrid molecules of formula (XLIa), and the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa). 59. Use according to any one of claims 48 to 57, characterized in that the compound is chosen from hybrid molecules, and the following compounds of formula (I): where A is 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolin-3-carboxylic acid or 1-cyclopropyl-6,8-difluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid, the - (Y 1) p- (U) p '- (Y 2) p - link between A and Q is piperazine, and Q is 7-chloro-4-aminoquinoline, where A is 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or 1-cyclopropyl-6,8-difluoro-4-oxo-1,4-acid dihydroquinoline-3-carboxylic acid, the - (Y 1) p- (U) p- (Y 2) p '' link - between A and Q is a piperazine, and Q is 7-chloro-4-aminoquinoline;  bicyclo [3.2.0] hept-2-ene-2-carboxylic acid, the link - (Y1) p- (U) p '- (Y2) p "- between A and Q is 3thioazetidine, and the quinoline part of the substituent Q attached to the link by position 2 where A is a (3-lactam of formula 3-chloro-azetidin-2-one substituted at 4, the - (Y1) p- (U) p '- (Y2) p' '-, p, p' link and p "are 0, thereby forming a direct covalent bond between the nitrogen N1 of A and the extracyclic nitrogen of a 2-aminoquinoline, and Q is 2-amino-4-methylquinoline where A is a cephalosporin, the link - (Y1) p- (U) p '- (Y2) p' '- is located in position 3 of the cephalosporin, this link containing an amide function, and Q is a 6, 7-dihydroxy4-diméthylaminoquinolin-3-yl where A is a penicillin, the - (Y1) p- (U) p '- (Y2) p "- bond contains an amide function, and Q is a 4-aminoquinoline bonded by the 3-position, with the amine function of 4 free aminoquinoline; where A is a penicillin or a cephalosporin substituted in position 3 by the  thioamide, urea or thiourea, and Q is 3-aminoquinoline or 6-aminoquinoline;  and Q is 4-hydroxy-6-acetylamino-quinolin-3 where A is (6R, 7R) -7- [2- (2-amino-thiazol-4-yl) -2 (Z)) - methoxyiminoacetylamino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene carboxylic acid, and the bond - (Yi) p (U) p- (Y 2) p'- is a link methylene, and where Q is 5-aminoquinolin-1-yl where A is (5S) -4- {5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl} -2-fluorophenyl, the - (Y1) p- (U) p '- linkage ( Y2) p "- is a 4-piperazin-1-yl linkage including R2 and N of aminoquinoline, and Q is quinolin-4-yl, where A is a diaminopyrimidine, the - (Y1) p- (U) p '- (Y2) p "- bond is a methylene bond, and Q is one of the following quinolines: 2-morpholino-4-methyl-quinolin 7yl, 4-methyl-8-aminoquinolin-6-yl, 4-methyl-5-aminoquinolin-6-yl, 2-dimethylamino-4-methyl-quinolin-6-yl, 2-dimethylamino-4,8-dimethyl-quinolin 6-yl, 2-morpholino-4,8-dimethyl-quinolin-6-yl, 2-methyl-4-dimethylamino-8-methoxyquinolin-6-yl where A is 2-methyl-5-nitroimidazol-1-yl, directly attached to the extracyclic nitrogen atom of aminoquinoline Q (p = p '= p "= 0) and Q is one of following quinolines: 7-chloro-quinolin-4-ylamino, 2-methyl-8-hydroxy-quinolin-4-ylamino,  quinolin-4-ylamino; where A is 2-methyl-5-nitroimidazol-1-yl, the - (Y1) p- (U) p '- (Y2) p - bond is a 2-ethyl- (1-cyclohexan) linkage -4-yl) -amine, and Q is 7-chloro-quinolin-4-ylamino. 60. Pharmaceutical compositions of the invention comprising an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 42, in combination with other pharmacologically active substances. 61. Pharmaceutical compositions according to claim 59, characterized in that at least one compound of formula (I) defined in any one of claims 1 to 42 is combined with a resistance enzyme inhibitor. 62. Pharmaceutical compositions according to claim 60, characterized in that the resistance enzyme inhibitor is a beta-lactamase inhibitor, preferably chosen from clavulanic acid (3- (2-hydroxyethylidene) -7-oxo acid). 4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid), sodium sulbactam ([2S- (2 alpha, 5 alpha)] -  sodium). 63. Use of a compound as defined in any one of claims 1 to 42 for the manufacture of a composition for the food industry. 64. Use of a compound according to claim 1, characterized in that A is (Y2) p "- between A and Q is piperazine, and Q is 7-chloro-4-aminoquinoline for the manufacture of a pharmaceutical composition comprising said compound in an amount effective to treat a bacterial infection of an animal or of a human being other than an infection due to mycoplasma sp., in admixture with a pharmaceutically acceptable excipient. 65. Use of at least one compound of formula (I) in which A is 2-methyl-5-nitroimidazol-1-yl, directly attached to the extracyclic nitrogen atom of aminoquinoline Q (p = p p = 0), where Q is selected from 7-chloro-quinolin-4-ylamino, 2-methyl-8-hydroxyquinolin-4-ylamino, 2-methyl-3-n-propyl-8- hydroxy-quinolin-4-ylamino, and 2-methyl-5-nitro-8-hydroxy-quinolin-4-ylamino, or at least one compound of formula (I) wherein A is 2-methyl-5-nitroimidazol -1-yl, the - (Y1) p- (U) p '- (Y2) p "- bond is a 2-ethyl- (1-cyclohexan-4-yl) -amine linkage, and Q is the 7- chloroquinolin-4-ylamino, for the manufacture of a pharmaceutical composition comprising said compound in an amount effective to treat a bacterial infection of an animal or a human being, in admixture with a pharmaceutically acceptable excipient. 66. A process for producing a compound Q - (Y 1) p - (U) p - (Y 2) p "- A, as defined in any one of claims 1 to 42, characterized in that comprises: a) either fixing the (Yi) p - (U) p '- (Y2) p - group on an aminoquinoline Q, then reacting this intermediate compound with A; b) the binding of the (Y1) p - (U) p '- (Y2) p "group with A, then the attachment of this intermediate to an aminoquinoline Q; c) the attachment of an amino- (Yi) group; ) p - (U) p '- (Y2) p "on a corresponding quinoline to obtain an intermediate compound Q - (Yl) p - (U) p' - (Y2) p", then the fixation of this compound intermediate on A.