FR2941955A1 - NOVEL VANCOMYCIN-AMINOQUINOLEIN HYBRID MOLECULES DENOMMEES "VANCOMYQUINES", THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The present invention relates to new vancomycin-aminoquinoline hybrid molecules called "vancomycin®", their preparation and their therapeutic application. The present invention particularly relates to novel hybrid molecules covalently connecting vancomycin to substituted 4-aminoquinolines. The present invention describes the preparation of these hybrid molecules called "vancomyquines" corresponding to formula (I) as well as their therapeutic use as an antibacterial agent.

Description

The present invention relates to novel hybrid molecules covalently connecting vancomycin or one of its derivatives to substituted 4-aminoquinolines. The present invention describes the preparation of these hybrid molecules called vancomyquines` corresponding to formula (I) as well as their therapeutic use as antibacterial agent.

STATE OF THE ART

The development of mufti-resistant bacterial strains has become a major public health problem (Talbot GH et al., Bad Bugs Need Drugs: An Update on the Development of the Antimicrobial Availability Task Force on the Infectious Disease of America. ; 42: 657). Among the most dangerous bacteria, methicillin-resistant Staphylococcal aureus strains (MRSA) were responsible for nearly 100,000 bacterial infections in the United States in 2007, killing nearly 19,000 people. This figure exceeds that of AIDS-related deaths (Taubes, G. The Bacters fight back, Science 2008, 321: 356). Until now the antibiotic of choice for treating infections due to these strains of MRSA, nosocomial infections for the vast majority, was vancomycin. Unfortunately, since the appearance of strains of staphylococci but also enterococci of decreased sensitivity to vancomycin and following several therapeutic failures, the use of vancomycin is now very controversial (Deresinski S, Counterpoint: Vancomycin and Staphylococcal aureus an antibiotic infers obsolescence Clin Infect Dis 2007; 44: 1543). It is therefore urgent to find an alternative to the use of vancomycin for the treatment of bacterial infections caused by MRSA strains. Hybrid molecules covalently linking an aminoquinoline moiety to an antibiotic residue have already been described in the FR Patents. 20040008441., US 20070060558 and in the international application VVO 2006024741. Various classes of antibiotics have thus been linked to aminoquinolines with a marked improvement in antibacterial activity. In these patents, aminoquinoline units have also been grafted onto vancomycin. The resulting hybrid molecules have been found to be very active with minimal inhibitory Cc values, which are similar to those of the base subfructure: Id vanc: on, ycine ,.

In patent FR 20040008441 and the international application WO 2006024741, the exemplified vancomyquins covalently connect vancomycin to a 4-aminoquinoline substituted at the 7-position with a chlorine atom, the link connecting them being either an alkyl chain or an aromatic group of ethoxybenzyl type: PA1157 PA1158 PA1159 = Vancomycin In the examples of the application US 20070060558, the 4-aminoquinolines connected to vancomycin are substituted in position 2 or 7 by a methyl or trifluoromethyl group and the bond which links them is an aromatic group of type Ethoxybenzyl: HNNH 2HCl PA 1276 HNF ~~ NH HN 2HC1 CH3 N CF3 PAl274 PAl275 F3C OBJECTS OF THE INVENTION The phenomena of vancomycin resistance and its lack of bactericidal activity are at the origin of numerous therapeutic failures. The main purpose of the present invention is to provide novel molecules with antibacterial activity as an alternative to vancomycin. The object of the invention is also to solve this technical problem by providing molecules having lower inhibitory concentrations lower than those of vancomycin, greater bactericide, at lower concentrations and better efficacy in vivo, especially in comparison to the vanconiyquines already described. The present invention also aims to provide new molecules with antibacterial activity whose manufacture is relatively easy. 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, particularly on a pharmaceutical scale. X represents an oxygen molecule, ofen / e or a group selected from 2941955. The novelty of the present invention relates to the discovery of new hybrid molecules. Anl / nOqu / nolein-vancornyne replicates the formula: wherein: n represents 0, 1, 2, 3 or 4 - Y represents a group chosen from: p - (Cr + Cn) @ kvle - substituted or not by one or more substituents chosen independently from a group Z, ~ - / [- C / (a) optionally substituted with one or more of the substituents independently selected from a group Z, non-aromatic heterocycle when Y forms a cyclic structure with R1, whether or not substituted with one or more of the substituents selected independently from a group Z,, ° [[) a / ky! X-X is a nitrogen atom, wherein X is substituted or unsubstituted by one or more substituents independently selected from a group consisting of: connected to the otome d'aroie etooL! part ([r [/) n! ky! e | 4 R3 j 3 Il 1 He Il -`v-- `--u - C--, - m - C-- '- m -` -' C --- - Z represents a a hakmenc atom or a group chosen from: CF3, OCF3, OR3, COOH, PDH NHR3, N (R3) 2, [O has COOR3, CONHR3, CON (R3) 2, SO3H. SO2NHc3, and R5 represents a hydrogen atom or a preferably unsubstituted group; -R ~ represents a group selected from -OR3 or _N (R5a) (Rsb); ~ So - ~~ and R may be the same or different and re- ntent a hydrogen atom or a group (CI-Cs) alkyl substituted or not by one or more substituents independently selected from a group Z; and - Ria, R2 are organic chemical groups. According to one variant: R 1 represents a (CrCu) alkyl group, preferably an unsubstituted group, or a Z group; or a preferably unsubstituted phenyl group; R represents one or more identical or different substituents, occupying any positions and representing a substituent chosen from: a group Z, * - (CrCu) a / kv! e substituted or not by one or more of the chosen substituents 20 independently from a group Z, w -X- / CrCu> a] kv / e substituted or not by one or more substituents independently selected from a group Z, o - (CrCr) alkyl-X- (Cr-C) alkyl substituted or unsubstituted with one or more substituents independently selected from a Z group; R represents a hydrogen atom or a group selected from: non-aromatic hetero / ocide when A forms a ring structure with Y, substituted or unsubstituted by one or more of the substituents chosen independently from a group 1; represents an item ir3yuserie e sulfur or a group uhoi ru mi: K` [} K 'D ~~ O, 0u0 0 Y represents a group selected from: • - (C1-C11) alkyl- substituted or not by one or more of substituents independently selected from a carbocycle-non-aromatic Z, • - (C 3 -C 12) group optionally substituted with one or more of the substituents independently selected from a group Z, • non-aromatic heterocycle when Y forms a cyclic structure with NR 2, substituted or not by one or more of the substituents independently selected from a group Z, • - (C1-C12) alkyl-X-, X not being bonded to the nitrogen atom, 10 * - (C1-C12) alkyl -X- (C1-C5) alkyl-substituted or unsubstituted with one or more substituents independently selected from a group Z, the part connected to the nitrogen atom being the part - (C1-C12) alkyl; Z represents a halogen atom or a group chosen from: CF3, OCF3, OR3, COOH, P03H2, NHR3, N (R3) 2, COR3, COOR3, CONHR3, CON (R3) 2, SO3H, SO2NHR3, and SO2N (R3) 2; - R3 represents a hydrogen atom or a (C1-C12) alkyl group, preferably unsubstituted; R4 represents a group chosen from -OR3 or -N (Rsa) (R5b); R5a and Rsb may be identical or different and represent a hydrogen atom or a (C1-C6) alkyl group optionally substituted with one or more substituents chosen independently from a Z group. The present invention provides a preparation method compounds of formula (I) according to the invention as well as reaction intermediates. The compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful for purifying or isolating the compounds of formula (I) are also part of the invention. The compounds of formula (I) may exist in the form of hydrates or solvates, namely in the form of condensation or combination with one or more water molecules or with a solvent. Such hydrates and solvans are also part of the invention. The compounds of formula (I) may exist as racemic, including unsaturated, dry, or pure. In the fornuli molecule (I), the group Y (C 1 -C 4) alkyl, and preferably (C 2 -C) alkyl group in the molecule of formula (I), the R 1a group may represent a methyl, methoxy, CF 3 or OCF 3 group. , COOH, or a phenyl group, preferably unsubstituted and the group Ru), optionally present, may represent, preferably in position 7 or 8, a halogen atom, preferably chlorine or fluorine, a methyl or methoxy group, optionally substituted with a halogen atom, and preferably a fluorine atom, such as for example the CF3 group, or OCF3. The compounds of formula (I) may be combined in a pharmaceutical composition with excipients. Pharmaceutical compositions containing a therapeutically active amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient also form part of the present invention. The compounds of formula (I) may also be combined in a pharmaceutical composition with one or more other active ingredients, such as, for example, another antibiotic. Pharmaceutical compositions containing one or more other active ingredients are also the subject of the present invention. According to the invention, it has been unexpectedly and non-obviously found that the molecules of formula (I) lead to a clear amplification of the antibacterial activity. The bactericidal hybrid molecules according to the invention is particularly unexpected. The compounds of formula (I) are thus capable of reducing by 4 log the bacterial load of a strain of methicillin-resistant Staphylococcus aureus. In addition, the surprising antibacterial activity of these hybrid molecules was confirmed by demonstrating their efficacy in a murine MRSA sepsis model. Knowing the terrible incidence of MRSA on nosocomial infections, the skilled person can therefore measure the major advantage of the present invention.

The compounds of formula (1) are thus very effective as antibacterial agents. Another aspect of the present invention is therefore the use of the compounds of formula (I) as an antibacterial agent. The invention also provides a method of preventing or treating a bacterial infection in a mammal. DETAILED DESCRIPTION OF THE INVENTION

The subject of the present invention is novel olefininvanconnycin hybrid molecules having the formula (1) as well as their therapeutic use as an antibacterial agent. In the definition of the compounds of formula (I), halogen is understood to mean a fluorine, chlorine, bromine or iodine atom. (C1-C5) alkyl, or respectively (C1-C6) alkyl, or respectively (C1-Cn) alkyl, or respectively (CrCu) akvie, Onentendungpoupea! Kv! Ee linear or branched from one to five or 10 respectively from one to six carbon atoms or from one to eleven carbon atoms or from one to twelve carbon atoms, such as the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl groups, b-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, dodecyl and dodecyl. The term "non-aromatic carbocyclic" (C3-Cza) means a mono or polycyclic fused, bridged or spiro group. By monocyclic group is meant in particular a monocyclic alkyl group of three to seven carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. By polycyclic group, fused, bridged or spiranic is meant, in particular, groups of five to twelve carbon atoms, di- or tricyclic fused, bridged or spiranic, including for example norbornyl, bornyl, isobornyl, noradamantyl, spiro [5.5] undecyl, bicyclo [2.2.1] heptyl, biqc / O [3.1.1] heptyl, bioc [o] [3.2.1] octyl. Heterocycle is understood to mean in particular a monocyclic group of three to seven atoms comprising one, two or three heteroatoms chosen from O, S or N, such as the heterocycle azeridine, azet / dine, pyrrolidine, oxazolidine, thiazolidine, piperidine, piperazine, morpholine 25 outhiomorphVUnc. By addition set to pharmaceutically acceptable acids is meant a salt acceptable for administration to a mammal, non-toxic, non-toxic dosage administered, regardless of the mode of administration. By way of nonlimiting example, the pharmaceutically acceptable acid salts include the salts of acetic acid, ascorbic acid, benzenesulfonylbenzoate, cyclohexylhydroxyphosphate, hydrochloric acid, citric acid and ethylphosphonic acid. gutonic, guturonic, glutamic, acochic, obonic, maleic, globular, methanesulphonic, nitric, oxalic, phosphoric, succinic, so-called. o! ueoeso! honiqoe. Preferred compounds of formula (I) in which: represents a fluorine or chlorine atom or a group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH 4, dimethylamino or unsubstituted phenyl; preferably at position 7 or 8, represents a fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or n-hexyl atom, fluorine group, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n- hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH2, dimethylamino, CONHCH2CH2NH2r CONHCH2CH2NMe2, CONHCH2PO3H2, CONHCH2CH2PO3H2, NHCH2COOH, NHCH2CH2COOH, NHCH2PO3H2, NHCH2CH2PO3H2 or NHCH2CH2SO3H; R2 represents a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl or octyl group; nonyl, decyl, undecyl, dodecyl, CH2COOH, CH2CH2COOH, CH2PO3H2, CH2CH2PO3H2 or CH2CH2SO3H; R4 is OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2P03H2r NHCH2CH2PO3H2 or -NHCH2CH2NMe2; Y is chosen such that the group R2N (Q) -Y-NHV represents a group chosen from: 9. I, Q R2N, R1, R2, R2N, R2N, R2N, R2N, R2N, R2N, R2N, R2N, R2N, R2N, R2NR, R2N, R2N, R2N, R2N, R2N, R2N, R2N, R2N, ## STR1 ## wherein R 1 is R 1, R 2, R 1, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, and R 2 R2N Q 1 R2N? R2N R2N R2N R2N R2N R2N R2R R2N QQQ R2N QQQ R2E R2N QQQ R2N QQ R2N QS R2Q R2R O2 R2N R1 NH2 NHR2 NR2 NHR2NR Methylene Y bound covalently to vancomycin. According to a variant of the invention, in the molecule of formula (I), the group Y is chosen from an unsubstituted (C 1 -C n) alkyl group, and preferably an ethyl, propyl, butyl or pentyl group, for example linearly , and / or branched, and / or cyclic; optionally interrupted by one or more oxygen atoms, one or more sulfur atoms, or one or more amine, amide, ester, and / or sulfonamide groups. The invention in particular according to a second variant covers the compounds of formula (I) in which Rab represents, preferably in position 7 or 8, a halogen atom, preferably chlorine or fluorine, a methyl or methoxy group, optionally substituted by one or more halogen atoms, and preferably a fluorine atom, such as for example the group CF3, or OCF3. The invention covers, in a third variant, the compounds of formula (I) in which R '3 represents a halogen atom, a methyl, methoxy, CF 3, OCF 3 or COOH group or a phenyl group, preferably an unsubstituted group. The invention covers, in a fourth variant, the compounds of formula (I) in which R 2 represents a hydrogen atom or a substituted (C 1 -C 6) alkyl group, and for example represents a methyl, ethyl or propyl group, butyl pentyl, or hexyl, preferably linear. The invention covers, in a fifth variant, the compounds of formula (I) in which R4 represents a hydroxyl group. The invention covers in particular according to a sixth variant the compounds of formula (I) in which n represents 0 or 1.

The invention covers in the above variants all the possible combinations, in particular those in which the compounds of formula (I) are differently defined, including the particular embodiments According to the present invention, the compounds of the formula are further preferred. wherein: n represents 0 or I; R represents a halogenated atony, a methyl, methoxy, CF, OCF, COOH group or a phenyl group, preferably unsubstituted; , Iin halogen, chlorine or fluorine atom, a methyl or methoxy group, optionally substituted with one or more halogen atoms, and preferably one or more fluorine atoms, such as, for example, the group CFa or OCFs ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

R4 represents an OH group;

Y represents an unsubstituted (CHCl) alkyl group, and preferably an unsubstituted (2-yn) group. Among the compounds of formula (1) which are subjects of the invention, mention may be made especially of the following compounds:

N-4- [4- (7-chloro-2-trifluoromethyl) -N-4-ylamino) -butyl] -vinyl);

N-4- [4- [8-Oero-2-trifluoromethyl] quinol-4-yl] amino] butybdione; N-4- [4- (2-phenylsulfonyl-4-ylmanyl) butyl] -vancom [a] n-4- [4- (2-methylethyl) -4-yl] amino) - butyl] -vancornycin-N-4- [4- (2-methyl-quinyl-4-yl) amino) -butyl] -vancoonycin;

N-4- {4- [ethyl-2- (2-methyl-quinolin-4-yl) amino] -butyl-vanoalkycin;

In the basic state or addition salts with acids, as well as with hydrates or solvates. It has been discovered very unexpectedly that when vancomycin is substituted as illustrated in formula (1), then the resulting vancomycin is very active. The bactericide of these vanconlyquinps is in particular very surprising vis-à-vis

20 MRSA with a reduction of 4 log of 19noculum in 24 h. This totally unexpected property of these new vanconnyquines was not evident from the previous patent applications. The increase in activity is obtained by 2-substituted-4-aminoquinolines in which the group connecting Vancomycin and aminoquinoline does not contain an aromatic group. The present invention therefore relates to these new ~ 25 ~ vanmomnyqu! Nem,! Eurpréponation, and utfflsation as antibacterial agent. The compounds of the formula (II) according to the invention can be prepared according to the procedures described hereinafter (the typical or preferred conditions of the examples given by way of example), such as temperature, time, number of equivalences, etc.) It is obvious that other conditions can be used to modulate and optimize the method of p / epzyUon according to optimization procedures known to those skilled in the art. The various methods described in patent applications FR 2004 0008441, WO 2006/024741, and US 2007/0060558 are applicable. According to the invention, the compounds of the present invention can be prepared according to the invention. Formula (1) according to a two-step reductive amination process carried out in the same vessel This process comprises the following steps: a) a glycopeptide of the formula: ## STR2 ## wherein R 4 is as defined for a form compound ule (I) including in their different variants, or one of its salts, with a compound of formula: (III) in which n, e, Rie, R2 and Y are as defined for a compound of formula (I) ) including in their different variants. The coupling reaction is in the presence of a base and leads to a non-isolated reaction intermediate (presumed mixture of imine and / or hemiaminal); B) the activated intermediate is treated with a reducing agent in the presence of an acid. The compounds of formula (I) thus obtained after steps a) and b) can then, after purification, be converted into the acid addition salt. Step a) is carried out with one or more equivalents of aldehyde of formula (III; [reference 1 to 3 equivalents of aldehyde are used in this cape, This step is typically carried out in an inert solvent, preferably the Inert solvent is selected from N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone or a mixture of two or more solvents, and the reaction is typically conducted between 0.degree. C. and 80 ° C., preferably at room temperature (ie 20-25 ° C.) for 1 to 24 hours, preferably from 1 to 6 hours, Any base capable of neutralizing the salt of a compound of formula (II) and to facilitate the formation of the reaction intermediate (imine and / or hemiaminal) can be used in this step including organic bases such as amines, alkaline carboxylate salts (ie sodium acetate) and inorganic bases such as that alkaline carbonates (ie carbonate of lithi um, potassium carbonate, sodium carbonate). Preferably, the base used in this step is a tertiary amine, for example triethylamine, N, N-diisopropylethylamine or N-methylmorpholine. A preferred base is N, N-diisopropylethylamine. The base is typically used in excess relative to the glycopeptide of formula (II). Preferably, from 1.5 to 30 equivalents of base are used and more preferably 3 or 30 equivalents of base. Step b) of reducing the intermediate compound (imine and / or hemiaminal) is carried out in the same container. Any reducing agent capable of reducing the intermediate compound (imine and / or hemiaminal) and compatible with the organic functions of a glycopeptide of formula (II) may be used in this step. For example, the reducing agents that may be used are: sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, or a borane complex such as: BH 3 pyridine, BH 3 tert-butylamine, BH 3 'N methylmorpholine, BH3. morpholine, BH3.dimethylphosphine, BH3 • triphenylphosphine, BH3 • tetrahydrofuran, BH3 • trimethylamine, BH3.dimethylamine, BH3.dimethylsulfide, BH3 • isoamylsulfide, BH3 • triethylamine, BH3 • N, N-diisopropylethylamine, BH3.N, N-diethylaniline, BH3ammoniac. Preferably, the reducing agent used is sodium cyanoborohydride. From 1 to 6 equivalents of reducing agent are typically used for this step, and more preferably from 3 to 4.5 equivalents. The reduction step is typically carried out at a temperature between 0 ° C and 80 ° C, preferably at 50 ° C, for a period of 1 to 24 hours, preferably 20 to 24 hours. A protic solvent is typically added in this step, including, for example, methanol, propanol, isopropanol or r-butanol, methanol is preferably used as a protic solvent, and the reduction step is typically carried out in an acidic medium. The acid used may, for example, denote a carboxylic acid, ie acetic acid, trifluoroacetic acid, citric acid, formic acid or methanesulphonic acid, for example, or a mineral acid. hydrochloric acid, uric acid, phosphoric acid, for example). Preferably the acid used is trifluoroacetic acid. The acid is typically used in excess with respect to the compound of formula (L1 and with respect to the base, preferably from 1.5 to 45 equivalents of acid are used relative to the compound of formula (II) and more preferably 4.5 or 45 equivalents of acid To prepare the compounds of formula (I) in the form of acid addition salts, all pharmaceutically acceptable acids may be used, including acetic, ascorbic, benzenesulphonic, benzoic acids, hydrobromic bromide, camphorsulfonic, hydrochloric, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, lactic, lactobionic, maleic, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic. acetic, hydrochloric, citric, fumaric, gluconic, glucuronic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric and tartaric acid. They are typically prepared using from 1 to 5 equivalents of acid, preferably 1 to 2 equivalents, at a temperature between 0 ° C and 25 ° C, preferably 0 to 5 ° C. The compounds of formula (I) may be purified by any of the conventional methods, such as by precipitation, filtration, washing or by means of high pressure liquid chromatography. The glycopeptides of formula (II) are known or commercially available or are prepared by conventional methods known to those skilled in the art. A compound of formula (II) is vancomycin. The aldehydes of formula (III) used in the process of the present invention can be prepared by reacting a compound of the formula: Hal (IV) wherein n, and R1 are as defined for a compound of formula (I) and Hal is a halogen atom, with a derivative having an amine function and an acetal function, such as the derivatives of formula 25 in which R 'Fit Y are as defined for a comfi formula (I) and Alk (in alkyl group to give a compound of formula rR wherein n, R'3, Rit ', R2 and Y are as defined for a compound of formula (I). formula (IV) with a derivative of formula (V), the reaction is typically carried out either without a solvent, or in a chlorinated organic solvent such as dichloromethane, an ethereal solvent such as tetrahydrofuran or 2-methyltetrahydrofuran, or an amide solvent such as N, N-dimethylformamide. the reaction is carried out without solvent Typically from 1 to 5 equivalents of the formula (V) derivative are used, preferably from 2 to 3.5 equivalents. The reaction can be carried out in the presence or absence of a base. The bases that can be used are organic bases such as amines, alkali metal carboxylate salts (ie sodium acetate) and inorganic bases such as alkaline carbonates (ie lithium carbonate, potassium carbonate, sodium carbonate) . Preferably, the reaction is conducted without a base. Typically the reaction is carried out at a temperature between 20 ° C and 150 ° C, preferably 80 to 100 ° C, for 2 to 24 hours, preferably 15 to 24 hours. The derivatives of formula (VI) can then be converted into aldehyde of formula (III) in an acidic medium. Any acid capable of hydrolyzing the acetal function of the derivatives of formula (VI) to the aldehyde may be used. By way of nonlimiting example, the acids that can be used are hydrochloric, nitric, sulfuric, phosphoric, acetic, trifluoroethylene acids or any mixture of two of them. Preferably a mixture of acetic acid and trifluoroacetic acid is used.

A variant for the preparation of the aldehydes of formula (III) consists of reacting a derivative of formula (IV) with an aminoalcohol of formula: ## STR2 ## in which R 2 and Y are as defined for a compound of formula (I) including in their different variants, to give a compound of formula: (VII) OH (VIII) (R '-') NR v, in which n. and Y are as defined for a compound of formula (1) including in their different variants. When a compound of formula (IV) is reacted with a derivative of formula (VII), the lion is typically carried out either without a solvent or in an organic chlorine solvent such as clichloromethane, an ethereal solvent such as -al-ydrofuran or methyltetrahydrofuran, or an amide solvent such as N, N-dimethylformamide. Preferably, the reaction is conducted without solvent. Typically, from 1 to 5 equivalents of derivative of formula (VII) are used, preferably from 2 to 3.5 equivalents. The reaction can be carried out in the presence or absence of a base. The bases which can be used are organic bases such as amines, alkali metal carboxylate salts (sodium acetate) and inorganic bases such as alkaline carbonates (lithium carbonate, potassium carbonate, sodium). Preferably, the reaction is conducted without a base. Typically the reaction is carried out at a temperature between 20 ° C and 150 ° C, preferably 80 to 150 ° C, for 2 to 24 hours, preferably 2 to 6 hours. The derivatives of formula (VIII) can then be converted into aldehyde of formula (III) by a conventional oxidation reaction, well known to those skilled in the art (see for example March's, Advanced Organic Chemistry, 5th edition, John Wiley & Sons, New York, 2001). Preferably, the oxidation reaction is carried out according to a Swern type oxidation in the presence of dimethylsulfoxide (from 2 to 4 equivalents, preferably 2.2 equivalents) and oxalyl chloride (from 1 to 2 equivalents, preferably 1 to 2 equivalents, preferably , 1 equivalent).

Typically the reaction is carried out in a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform) at a temperature of between -80 ° C. and 20 ° C., preferably from -80 ° to -40 ° C., for 10 minutes to 2 hours. preferably from 20 minutes to 1 hour. The quinolines of formula (IV) are known or commercially available or are prepared by conventional halogenation methods from the corresponding alcohol of formula: ## STR2 ## in which n, Ris and e are as defined for a compound of formula (I) including in their different variants. Typically, for. preparing a derivative of formula (N), a compound of formula (IX) is treated with a halogenating agent such as PCI, PCI, POCI, PBri, HBr, BBr, or SOLI.

The reaction is typically carried out without a solvent or in an inert solvent such as a chlorinated organic solvent (for example dichloromethane, dichloroethane, chloroform), tetrahydrofuran, methyltetrahydrofuran, ethyl acetate or toluene. The quinolines of formula (IX) are known or commercially available. by conventional methods known to those skilled in the art. The acetals and alcohols respectively of formula V) and (VII) are known or commercially available by conventional methods.

The process for preparing the compounds of formula (I) of the present invention is simple, conventional and can be used on an industrial scale, in particular pharmaceutical.

PHARMACEUTICAL USES The vancomycin-aminoquinoline hybrid molecules of formula (I) according to the invention can be used as an antibacterial agent. Thus, according to another of its aspects, the subject of the invention is medicaments for human or veterinary medicine which comprise at least one compound of formula (I), or a salt of addition of this compound to a pharmaceutically acceptable acid, or else a solvate or a hydrate of the compound of formula (I). Thus the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, goats, sheep, cattle, swine, poultry, rabbits, etc.) in the treatment or prevention of bacterial infections. For example and without limitation, the compounds of formula (I) are useful for the prevention or the treatment of bacterial infections with gram + or anaerobic germs such as staphylococci (Staphylococcus spp.), Streptococci (Streptococcus spp.), Enterococci (Enterococcus spp.) Or Clostridium spp. By way of non-limiting example, the bacterial species effectively treated with the compounds according to the invention are: methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) ), Vancomycin Intermediate Susceptibility Staphylococcus aureus (VISA), Vancomycin Resistant Staphylococcus Aureus (VRSA), Methicillin-Resistant Coagulase-Negative Staphylococci (SCNMS), Methicillin-Resistant Coagulase-Negative Staphylococci (SCNMR), Streptococci group A, group B streptococci, group C streptococci, group G streptococci, enterococcus faeca vancomycin (VSE), vancomycin-resistant Enter-aux-sus / cefc / s (VRF VanA or VanB), vancomycin-sensitive enzyme (VSE), vancomycin resistant rctetococcus laec'LJm (VRE VanA or VanB ), Clostridiur diffici / e.

Bacterial infections for which the compounds of formula (I) are useful are those infections susceptible to the compounds according to the invention, including for example and without limitation: bacteremia, endocarditis, peritonitis, mediastinitis, skin and tissue infections. osteomal infection: iculals, meningitis, ventriculitis on bypass vulva, catheter infections, implantable chamber, pulmonary infections, infections, pseudomembranous colitis., As can be seen from Tables 1 to 3, the vancomyquins of the invention are very As an antibacterial agent, the MICs of the methionine-resistant Staphylococcus autos (MRSA) according to the invention are much lower than those currently available on the market, such as vancomycin, for anti-Gram + antibiotics. teicoplanin, daptomycin or linezolid (Table 1, Example 6) These values allow them to be effective at co-efficients. ncentrations lower as demonstrated by bactericidal kinetics values for a 1 μg / mL MRSA strain (Table 1, Example 6). The results obtained show that the presence of the substituent RIS at the 2-position on the quinoline nucleus is important to reach the bactericidal threshold corresponding to 3 log of reduction of the initial bacterial load. Finally, with a Y-type bond, not containing an aromatic nucleus, the vancomyquines according to the invention are capable of reducing by more than 4 log this bacterial load in 24 hours. Moreover, the bactericidal experiments were carried out in the presence of 50% of human serum in order to better mimic the physiological conditions. Under these conditions, vancomycines are able to eradicate a strain of MRSA at only 1 pg / mL while none of the comparators currently on the market are active at this concentration, any more than telavancin. The vancomyquins according to the invention retain their potent antibacterial activity in vivo (Example 7). In fact, in a model of murine sepsis induced by MRSA, by way of example, vancomycin PA1409 according to the invention is capable of curing 100% of infected mice at a dose of only 5 mg / kg. At this dose, vancomycin is bactericidal (Alog> 3) unlike vancomycin which is not bactericidal and can cure only 50% of mice. In addition, the compounds according to the invention are active on Gram + bacteria other than MRSA as demonstrated for example by the values of the MICs of vancomycin PAI4O9 with respect to a panel of bacteria (Table 3, example 8). Indeed, all values of the MICs of vancomycin PA1409 are lower than those of all comparators. The vancomyquins according to the invention may therefore be used for the prevention or the treatment of various infections involving seed seeds susceptible to the hybrid molecules according to the invention.

According to one of its aspects, the present invention relates to the use of a compound of formula (I; or one of its addition salts with a pharmaceutically acceptable acid or one of its solvates or hydrates For the treatment or prevention of renal immune disorders, a further aspect of this invention is its pharmaceutical compositions comprising, as an active ingredient, a compound according to the invention. contain an effective dose of at least one compound according to the invention, or one of its addition salts with a pharmaceutically acceptable acid or a solvate or a hydrate of said compound, whether or not an excipient or a phasic vehicle The said excipients or carriers are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art In the present description, the term "excipient" or "carrier" is intended to mean "excipients" or "excipients". pharmaceutically acceptable container or vehicle, a compound or a combination of compounds entering into a pharmaceutical composition not causing side reactions and which allows for example the facilitation of the administration of the active compound (s), the increase of its duration of vet or its effectiveness in the body, the increase of its solubility in solution or the improvement of its conservation. These well-known pharmaceutically acceptable vehicles will be adapted by those skilled in the art depending on the nature and the mode of administration of the compound. The modes of administration, dosage forms and optimal dosages may be determined according to the criteria generally taken into account in the establishment of a treatment adapted to a patient such as age or body weight of the patient, the severity of his general condition, tolerance to treatment and side effects noted. Compounds of formula 0 may be administered systemically, particularly intravenously, intramuscularly, intradermally, intraperitoneally, intraspinally, subcutaneously, or topically, or orally. Pharmaceutical compositions comprising, as an active ingredient, a compound according to the invention may take a variety of dosage forms, for example the form of solid compositions, formulations or emulsions, gels, ointments or creams. As solid compositions for oral administration, tablets, pills, powders (gum capsules, cachets) or granules can be used In these compositions, the principle of the invention is mixed with one or more Inert diluents such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compounds also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (diagees) or a varnish

soils of the mucins, syrups and elixirs Vha / maccohement -, palceps pal contain examples of diluents) such as water, 1 ethanol, gly i ol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers. As solid compositions for topical use, creams, ointments or gels can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents or adjuvants, such as lactose, cellulose derivatives, or talc for example. These compositions may also comprise substances other than diluents, for example fatty acids and their derivatives or fats of animal, plant or synthetic origin. As liquid compositions, pharmaceutically acceptable emulsions may be used for local use. solutions, suspensions containing inert diluents such as water, oils (paraffin oil, petroleum jelly, olive oil), organic esters. These compositions may, in addition, contain substances other than diluents, for example wetting, emulsifying, dispersing or stabilizing substances. Sterile compositions for parenteral administration may be aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or vehicle, water, glycerine, sorbitol, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate can be used. or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting agents, complexing agents (such as cyclodextrin), isotonic agents (such as glucose), emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can then be dissolved at the time of use in sterile water or any other sterile injectable medium, such as an aqueous glucose solution. Examples of pharmaceutical compositions for parenteral administration, containing a compound of formula (I) or a pharmaceutically acceptable salt thereof or one of its solvates or hydrates according to the invention, are given in Example 9. S dosas. Compounds of formula (i) in the compositions of this invention may be adjusted to provide an amount of active substance which is effective in providing a therapeutic response for a particular corpuscle of the method of the present invention. The chosen level of dosage therefore depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors, and these doses are generally in the range of about 0.01 to about 0.01. at 100 mg of active ingredient per kg of body weight and per day, in one or more doses, Preferably the compounds according to the invention or one of their addition salts with a pharmaceutically acceptable acid or a salt thereof. hydrates are administered intravenously at a dosage of between 0.1 and 20 mg per kg of body weight per day, once daily, there may be special cases where higher or lower dosages are appropriate; such dosages do not come out of this of the invention. The pharmaceutical compositions according to the invention may comprise at least one molecule of formula (1) as described above in combination with at least one other pharmaceutically active molecule. The pharmaceutical compositions according to the present invention may further contain compound of the formula one (or more) other active ingredient useful in the treatment or prevention of bacterial infections. This other active ingredient may be another antibiotic tal that, by way of non-limiting example, an antibiotic of the family of: penicillins (eg penicillin G, ampicillin, amoxicillin, tioicillin, piperacillin), cephakepnrinæs (egceftriaxone, cefotaxima, cefixoxime, cefebamet, cehepirne, cefixme), penems and carbapenems (eg imipenem, meropenem, doripenem, faropenem), monobactams (eg aztreonam, carumonam, tigemonam), fosfomycin, aminoglycosides (eg streptomycin, gentamicin, amikacin, dibekacin), polypeptides ( eg polymyxin, colistin, bacillin), macrolides (eg erythromycin A, clarithromycin, azythromycin, spiramycin, josamycin), streptogramin-synergistins (eg pristinamycin, quinupristin, daprofen), lincosamides (eg lincomycin, clindamycin), tetracyclines (eg tetracycline, doxycycline, minocycline), cyclins (bo 'A), chloramphenicol (eg chloramphenicol, 25 thiannphenico) / quino! ones (eg.dpr ooxadne, hevooxacin, moxifloxacin, gemifloxacime, garenoxacin), / ifamycins (c. rifampicin), nitroimidazoles and nitrofurans (metron / daro! e, hnidazo! ~, oiiro [u / nnioine), oxazn! idmones (Unëzohde) or! ipodepsmephdes (dapkzmycin) According to another I! 'invenbon, the compound It is also possible to formulate one or more of its adducts with a pharmaceutically acceptable acid or one of its solvates or hydrates and another associated active ingredient / peptide. spread over time

The composition according to the invention is in a neutral and provided phannaoruhque form. By separate use is meant the administration, at the same time, of the two compounds of the composition according to the invention, each included in a separate pharmaceutical form. By use spread over time, the successive but time-shifted administration of the compound of formula (I) according to the invention, or of one or more other active ingredients, respectively, in a first pharmaceutical form, then one or more other active ingredients, or respectively of the compound of formula (I) according to the invention, under the same pharmaceutical formulation or in a different pharmaceutical formulation, the administration of the other (other) active principle (s) ( s) generally not later than 24 hours after administration of the first compound. EXAMPLES

The following EXAMPLES describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and only illustrate the present invention. In the preparations and in the Examples, the following abbreviations are used: DMSO: dimethylsulfoxide DMF: N, N-dimethylformamide SM: DCI mass spectrometry Desorption Chemical Ionization ES: Electrospray PF: melting point Dec .: HPLC decomposition: high pressure liquid chromatography Theor: theoretical Experimental experiment CMI minimal concentration Inhibitory CFU: colony-forming unit log: logarithm decimal \ log decimal logarithms difference SASf1 Stap / vrococ sensitive to methicillin MRSA: Staphylococcus aureus resistant to methicillin h-VISA. Heteroecine / heterochemical susceptibility to SCNSM: Staphylococcus coagulase negative methicillin-sensitive SCNRM: Staphylococcus coi-nu `.,. meticillin resistant Vanco: vancomycin Teico: teicoplanin Linear: linezolid Dapto: daptornycin Tel: telavancin DC5_: curative dose 50% (dose to cure 50% of animals) Proton nuclear magnetic resonance spectra (1H NMR) are recorded in DMSO-d6 or CDCl3. The chemical shifts S are expressed in parts per million (ppm). For the interpretation of spectra, the following abbreviations are used: s: singlet, d: doublet, t: triplet, q: quadruplet, quint: quintuplet, m: multiplet, dd: doublet split, td: triplet split. The compounds of formula (I) according to the invention can be purified by high-pressure preparative liquid chromatography. A 50 x 400 mm Interchim STRATEGY C18-2 column, 10 m, flow rate: 80 to 100 mL, was used under isocratic conditions using an eluent of water, acetonitrile and trifluoroacetic acid (0.5%). ).

Example 1: PA1409 N-4- [4- (7-Chloro-2-trifluoromethylquinolin-4-ylamino) butyl] -vancomycin dihydrochloride 1.1. 4,7-Dichloro-2-trifluoromethylquinoline An argon suspension of 7-chloro-4-hydroxy-2-trifluoromethylquinoline (30 g, 0.12 mol) in 44 mL of POCI3 (0.48 mol) is heated at 110 ° C. for 2 hours. . After returning to ambient temperature, the POCl3 is removed by distillation. The dried product under vacuum is then neutralized in aqueous ammonia solution at 0 ° C. 200 ml of ethyl acetate are then added. The organic phase is separated and the aqueous phase is reextracted with 100 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The product is obtained in the form of a brown solid (27.6 g, 86%). 1 H NMR (300MHz, DMSO) δ ppm: 7.20 (1H, dd, 7U 90 11z, 112H7.82 tr (82H), 9.0H n,:% 5 (1H, s) Embedded image A 1-chloro-trifluoromethyl-4-yl-ethoxybutylamine suspension An argon suspension of 4,7-dichloro-2-trifluoromethylquinoline (Example 1.1) (11.6 g, 0.04 mol ) in 22.6 ml of 4-aminobutyraldehyde diethylacetal (0.13 mol) is heated at 100 ° C. for 18 hrs After returning to ambient temperature, the reaction medium is diluted with 150 ml of dichloromethane and 150 ml of 5% carbonated water solution.

The organic phase is separated and the aqueous phase is reextracted with 50 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The product is obtained after precipitation in a dichloromethane / hexane mixture at 6 ° C., in the form of a white powder (13 g, 76%). Melting point: 85.1 ° C. 1 H NMR (300 MHz, CDCl 3) δ ppm: 1.25 (6H, t, J = 6.9 Hz), 1.90 (4H, m), 3.41 (2H, q, J = 6.3 Hz. ), 3.58 (2H, m), 3.73 (2H, m), 4.61 (1H, t, J = 5.1 Hz), 5.78 (1H, m), 6.69 (1H, m.p. , s), 7.43 (1H, dd, 1 = 9.0 Hz, J = 2.1 Hz), 7.72 (1H, d, 1 = 9.0 Hz), 8.06 (1H, d , J = 2.1 Hz). Mp 85 ° C. MS (ES> 0) m / z: 391.3 (M + H +).

1.3. 4- (7-Chloro-2-trifluoromethyl-quinolin-4-ylamino) -butyraldehyde To a solution of (7-chloro-2-trifluoromethylquinolin-4-yl) - (4,4-diethoxy-butyl) amine (Example 1.2) (8.0 g, 0.02 mol) in 110 ml of an aqueous solution of 80% acetic acid are added 21.3 ml of trifluoroacetic acid (0.29 mol). The mixture is stirred at room temperature for 1 h 30. The mixture is cooled to 0 ° C. and diluted with distilled water. The pH of the solution is then brought back to pH 6 by the addition of a 5% solution of carbonated water. The product is then filtered. The white precipitate is washed with milliQ water and then twice with heptane. The dried solid under vacuum is obtained in the form of a yellow powder (5.3 g, 82%). 1 H NMR (300 MHz, DMSO) δ ppm: 1.91 (2H, m), 2.62 (2H, t, J = 7 Hz), 3.38 (2H, q, 1 = 6.9 Hz), 6.83 (1H, s), 7.61 (1H, d, 1 = 9.0 Hz), 7.94 (1H, s), 8.37 (1H, d, J = 9.0 Hz), 9.72 (1H, s), MS (DC1 / CH4> O) m / z: 317 (M + H +). Mp 134 ° C. MS (DC1 / CH4> O) m / z: 317.1 (M + H.

1.4. (4- (7-2-trifluoromethylquinolin-4-ylaniino) -butyl-vancomycin dihydrochloride To a solution under argon of vancomycin monohydrochloride 9.9 q, 6.7 mmol) and t 47-chloro 2-trifluoromethyl-quinolin-4-ylamino) -butyraldehyde (Example 1.3) 8.7 mmol) in 550 mL of anhydrous dimethylformamide are injected 33 mL of N, N-diisopropylethylamine (201 mmol). After stirring for 1 hour at room temperature, 550 ml of methanol are dissolved in the medium. Then, 1.7 ml of sodium azanoborohydride (27.0 mmol) and 22 ml are added successively to the mixture. trifluoroacetic acid (302 mmol). The mixture is stirred for 20 h at 50 ° C. After HPLC control of the reaction, the reaction mixture is concentrated by rotary evaporation to approximately 300-400 ml. The remaining solution is precipitated by slow addition to 1.5 L of diethyl ether. The suspension obtained is filtered and the precipitate is washed with diethyl ether. The precipitate is taken up and washed 4 times with an aqueous solution at pH 8.5 before being dried under vacuum. The product is then purified by preparative HPLC. Fractions of purity> 96% are pooled and lyophilized. The lyophilizate is resolubilized in 400 mL of water and desalted by passage over PL-HCO3 ion exchange resin. The desalted product is then re-acidified at 0 ° C. with 2 equivalents of 0.1N hydrochloric acid. After lyophilization, PA1409 is obtained in the form of a white lyophilizate (0.8 g, 6%, purity: 98%). 1H NMR (500 MHz, 298 K, DMF), ppm: 0.93 (3H, d, J = 6.0Hz), 1.01 (3H, d, J = 5.9Hz), 1.21 ( 3H, d, J = 6.3 Hz), 1.71 (3H, s), 1.78-1.76 (3H, m), 1.90-2.10 (5H, m), 2.12. -2.21 (2H, m), 3.05 (1H, brs), 3.23 (1H, brs), 3.67-3.76 (4H, m), 3.82 (1H, m). ) 4.13 (1H, brs), 4.20 (2H, broad t, J = 5.8Hz), 4.53 (1H, d, 1 = 12.3Hz), 4.74 (1H, d, J = 5.6Hz), 4.77 (1H, d, _1 = 5.8Hz), 4.84 (1H, q, J = 6.5Hz), 4.96 (1H, broad s. ), 5.33 (2H, s), 5.46 (3H, m), 5.60 (2H, m), 5.81 (1H, brs), 5.90 (1H, s), 6, 02 (1H, d, 1 = 7.4 Hz), 6.39 (1H, brs), 6.49 (1H, d, 1 = 2.1 Hz), 6.52 (1H, d, 1 = 5.6 Hz), 6.63 (1H, m), 6.66 (1H, d, J = 2.1 Hz), 6.84 (1H, d, J = 8.5 Hz), 6.87. (1H, s), 6.91 (1H, d, J = 9.5Hz), 7.17 (1H, brs), 7.23 (1H, s), 7.46 (1H, d, J). = 8.5 Hz), 7.48 (1H, d, J = 8.5 Hz), 7.62 (1H, dd, J = 2.2 Hz, J = 9.1 Hz), 7.66 ( 2H, t, J = 8.2 Hz), 7.74 (1H, brs), 7.96 (1H, d, J = 2.2 Hz), 8.02 (1H, d, J = 1, 5 Hz), 8.29 (1H, broad t), 8.45 (1H, brs), 8.57 (1H, d, J = 5.7Hz), 8.76 (1H, d, J = 9.1 Hz), 8.86 (1H, brs), 9.18-9.35 (4H, m), 9.74 (1H, s). Mp: 186 ° C (dec) MS (ES> 0) m / z: 1750.5 (M + H +), 875.8 (M + 2H +). Elemental analysis: for C80H87Cl3F3N11O24 2HCl.11.6H2O:% theor. C 47.27, H 5.57, N 7.58; % experiment C 47.27, H 5.56, N 7.60. .Exempted _2: PA1389 N-4-; 4- (8-Fluoro-2-trifluoromethylquinolin-4-ylamino) butyl] vencomycin dihydrochloride 2.1. 4-Chloro-8-fluoro-2-trifluoromethylquinoline This compound is prepared according to the procedure described in Example 1.1 from 9.6 g of S-fluoro-1-hydroxy-trifluoromethylquinoline (0.04 mol (in 39 ml of POCI). (0.42 mol) The product is obtained in the form of a white powder after recrystallization in methenol water 9.0 q, CLIN H (300 NlHc DM90 e ppm: 7.95 (2H, m; 8, 15 ' 2.2, 4- (8-Fluoro-2-trifluoromethyl-quinolin-4-ylamino) -butans-1-ol An argon suspension of 4-chloro-8-fluoro-2-trifluoromethylquinoline ( Example 2.1) (9.0 g, 0.04 mol) in 10 ml of 4-aminobutan-1-ol (0.11 mol) is heated at 150 ° C. for 2 h 30. After cooling to room temperature, the reaction medium is triturated with 100 ml of a 10% aqueous solution of sodium hydroxide The pasty yellow solid obtained is filtered and washed with water The product is obtained after recrystallization in ethanol / water in the form of a yellow powder (8 8 g, 80%) 1H NMR (300 MHz, DMSO) δ ppm: 1.55 (2H NMR (CDCl3)? H, m), 1.72 (2H, m), 3.35-3.49 (4H, m), 4.73 (1H, t, J = 5.1Hz), 6.82 (1H, s). ), 7.52-7.59 (2H, m), 7.87 (1H, broad t), 8.15 (1H, d, J-7.5 Hz). MS (DC1 / NH3> 0) m / z: 303.1 (M + H +).

2.3. 4- (8-Fluoro-2-trifluoromethylquinolin-4-ylamino) butyraldehyde. To a solution under argon of oxalyl chloride (1.3 mL, 14.5 mmol) in 33 mL of anhydrous dichloromethane cooled to -60 ° C is slowly added a solution of dimethylsulfoxide (2.1 mL, 29.0 mmol ) in 7 mL of anhydrous dichloromethane. The mixture is stirred for 10 minutes at -60 ° C. On this mixture cooled to -70 ° C is added 4- (8-fluoro-2-trifluoromethylquinolin-4-ylamino) -butan-1-ol (Example 2.2) (4.0 g, 13.2 mmol). The suspension obtained is stirred for 30 min at -60 ° C. before the addition of 9.2 ml of triethylamine (66.0 mmol). The resulting solution is stirred for 10 min at -10 ° C. The reaction is then quenched by the addition of 160 ml of water followed by 160 ml of chloroform. The separated aqueous phase is re-extracted twice with dichloromethane. The combined organic phases are washed with a saturated aqueous solution of NaCl and then dried over magnesium sulfate before being concentrated to dryness under vacuum. The product is obtained as a yellow-orange powder (3.8 g, 96%). 1H NMR (300MHz, DMSO) cS ppm: 1.92 (2H, quint, J = 7.2Hz), 2.62 (2H, t, J - 6.9H7), 3.40 (2H, m). ), 6.89 (1H, s), 7.50-7.62 (2H, m), 7.92 (1H, t, -7- 5.4 Hz), 8.15 (1H, dd, J- 7.5Hz >> = 1.2Hz), 9.72 (1H, s). MS C DC1 / NH, O) 301.2 (M H +.

2.4. N-4 [4e: 7-Chloro-2-trifluoromethylquinoline-4. ylamino) -butyl vancomycin dihydrochloride. PA1389 is prepared according to the procedure described in Example 1.4 from 12.5 g of vancomycin monohydrochloride (8.4 mmol), 3.8 g of 4 (8-fluoro-2-trifluoromethylquinolin-4-lzimino) -hutyraldehyde (Example 12.6 ~~ ol, 4.4 ml of diisopropylethylamine (25.2 mmol), 2.4 g of sodium cyanoborohydride (38.8 mmol) and 2.9 ml of trifluoroacetic acid (37.8 mmol The product is purified by preparative HPLC The fractions of purity> 96% are combined and freeze-dried before being desalted by passage over PL-HCO3 ion exchange resin, the desalted product is then re-acidified to 0 ° C. C with 2 equivalents of 0.1 N hydrochloric acid After lyophilization, PA1389 is obtained in the form of a white lyophilisate (0.8 g, 5%, purity:> 97%) MS (ES> 0) m / z: 1732.9 (M + H +), 888.0 (M + 2H +), Elemental analysis: for C 80 H 87 Cl 2 F 4 N 11 O 2 O 2HCl • 7.8H 70:% theory C 49.36, H 5.42, N 7.91; 3% experiment C 49.36, H 5.55, N 7.85.

Example 3 PA1402 N-4- [4- (2-Phenylquinolin-4-ylamino) butyl] -vancomycin dihydrochloride 3.1. 4- (2-Phenylquinolin-4-ylamino) -butan-1-ol This product is prepared according to the procedure described in Example 2.2 from 10.2 g of 4-chloro-2-phenylquinoline (0.04 mol ), in 11.9 mL of 4-aminobutan-1-ol (0.13 mol). The product is obtained after recrystallization from ethanol / water as a white powder (10.9 g, 87%). 1 H NMR (300 MHz, DMSO) δ ppm: 1.59 (2H, quint, J = 6.9 Hz), 1.76 (2H, quint, J = 7.2 Hz), 3.41-3.50. (4H, m), 4.49 (1H, t, J = 5.1Hz), 6.97 (1H, s), 7.19 (1H, t, 1 = 5.4Hz), 7.38; -7.53 (4H, m), 7.62 (1H, td, J = 8.4Hz, 1 = 1.2Hz), 7.85 (1H, dd, J = 8.4Hz, J = 0); , 9Hz), 8.19 (2H, dd, J = 8.4Hz, J = 1.2Hz), 8.23 (1H, d, 1 = 7.8Hz). MS (DC1 / NH3> 0) m / z: 293.3 (M + H +). 3.2. 4- (2-phenylquinolin-4-ylamino) -butyraldehyde. This product is prepared according to the procedure described in Example 2.3 from 4.0 g of 4- (2-phenylquinolin-4-ylamino) -butan-1-ol (Example 3.1) (13.0 mmol), 1 25 mL of oxalyl chloride (14.4 mmol), 2.0 mL of dimethylsulfoxide (28.8 mmol) and 9.0 mL of triethylamine (65.0 mmol). The product is obtained in the form of a yellow powder (3.9 g, 1001 (1H NMR (300 MHz, DM 50) ppm: 1.98 (2H, quint, J = 6.9 Hz), 2, 65.2H, t, 6.9Hz), 3.42m), 7.03 (s), 1.22H, r11), 7.38-7.00 (4H, m), 7.63. (1H, m), 7.85 (1H, 9.75 (1 N-4- [4- (2-Phenylquinolin-4-ylamino) butyl vancomycin hydrochloride, PA1402 is prepared according to the procedure described in Example 1.4. from 13.3 g of vancomycin monohydrochloride (8.9 mmol), 3.9 g of 4- (2-phenylquinolin-4-ylamino) butyraldeh, Example X13.4 mmol), of 1, N diisopropylethylamine (27.0 mmol), 2% sodium cyanoborohydride (40.0 mmol) and 3.1 ml trifluoroacetic acid (40.0 mmol) were purified by preparative HPLC. purity> 96% are collected and lyophilized before being desalted by passage over PL-HCO ion exchange resin The desalted product is then re-acidified at 0 ° C. with 2 equivalents of 0.1N hydrochloric acid After lyophilization PA1402 is obtained under the form of a white lyophilisate (0.5 g, 3%, purity:> 99%). MS (ES> 0) m / z: 1723.1 (M + H +), 863.0 (M + 2H +). Elemental analysis: for C 50 H 9, H 6.00, N 7.59, Experiment C 50.30, H 5.81, N 7.45.

Example 4: PA1418 N-4- [4- (2-Methylquinolin-4-ylamino) butyl] -vancomycin dihydrochloride 4.1. (4,4-Diethoxybutyl) - (2-methylquinolin-4-yl) amine. This product is prepared according to the procedure described in Example 1.2 from 13.6 ml of 4-chloroquinaldine (0.07 mol) in 35.0 ml of 4-aminobutyraldehyde diethylacetal (0.20 mol). The product is obtained after precipitation in dichloromethane / pentane in the form of a light beige powder (22.5 g, 100%). 1H NMR (300 MHz, DMSO) ppm: 1.10 (6H, t, J = 6.9Hz), 1.68 (4H, m), 2.46 (3H, s), 3.26 (2H, m.p. m), 3.42 (2H, m), 3.55 (2H, m), 4.52 (1H, t, J = 5.1Hz), 6.34 (1H, $), 7.01 (1H, m.p. , t, J = 5.1Hz), 7.32 (1H, td, J = 6.9Hz, J = 1.2Hz), 7.53 (1H, td, J = 6.9Hz, J = 1.2Hz ), 7.68 (1H, dd, J = 8.4Hz, J = 0.9Hz), 8.15 (1H, d, J = 8.1 Hz). MS (DC1 / NH3> 0) m / z: 303.5 (M + H +). 4.2. 4- (2-Methylquinolin-4-ylamino) butyraldehyde. This product is prepared according to the procedure described in Example 1.3 from 12.0 g of (4,4-diethoxybutyl) - (2-methylquinolin-4-yl) amine (Example 4.1) (0.04 mol), 218 mL of 80% aqueous acetic acid solution and 42.8 mL of trifluoroacetic acid (0.55 mol). The product is obtained as a yellow oil (10 g, 100%). 1 H NMR (300 MHz, DMSO) (δ ppm: 1.93 (2H, quint, -7.5 Hz), 2.61-2.66 (5H, m), 3.49 (2H, 6, 6 Hz), 6.80 (1H, s), 63 H, m, 43 (1H, d, 8.4 H), 9.10 1 H, t, J 5.4 Hz), 9.72 (1H, t, J = 0.9 Hz).

4.3. N-4- (4- (2-Methylquinolin-4-ylamino) butyl] -vancomycin dihydrochloride PA141.8 is prepared according to the procedure described in Example 1.4 from 16.0 g of vancomycin monohydrochloride (10, 8 mmol), 6.2 g of 4- (2-methanylquinolin-4-ylamino) butyraldehyde (Example 4.2) (27.0 mmol), 56.4 ml of N, N-diisopropylethylamine (324.0 mmol), 3.0 g of sodium cyclohexylol (mmol) and 7.5 ml of trifluoroacetic acid (486.0 mmol). The product is purified by preparative HPLC. Fractions of> 96% purity are pooled and lyophilized before being desalted by passage through PL-HCO 2 ion exchange resin. The desalted product is then re-acidified to 0 ° C. with 2 equivalents of 0.1N hydrochloric acid. After freeze-drying, PA1418 is obtained as a white phyllite (0.7 g, 4%, purity:> 97%). SNI (ES> O) m / z: 1661.1 (M + H +), 831.5 (y4 + 2H +). Elemental analysis: for C85H91Cl2NI1O2 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • C

Example 5: K41398 inol 5.1. 4- [Ethyl- (2-methylquinolin-4-yl) amino] -butan-1-ol This product is prepared according to the procedure described in Example 2.2 from 11 ml of 4-chloroquinaldine (0.05 mol) in 14.0 mL of minobutan-1id (0.11 mol). The product is obtained in the form of a brown oil (21.9 g, 100%). 1H NMR (300MHz, WHO)) δpln1: 1.08 (3H, t = 6.9Hz), 1.49 (2H, m), 1.55 (2H, m), 2.56 (3H, m.p. s), 3.23-3.40 (6H, m), 4.38 (1H, t, J = 5.1 Hz), 6.88 (1H, s), 7.43 (1H, td, 1), = 6.9 Hz, J = 1.5 Hz), 7.60 (1H / td'1 = 6.9 Hz, _1 = 1.5 Hz), 7.82 (1H, dd, J = 8.4 Hz, 1 = 1.2 Hz), 7.95 (1H, dd,} = 8.4 Hz, _1 = 1.2 Hz). MS (DCI NH?> O) m / z: 259.2 / M + H +.

5.2. 4- [Ethyl- (2-methylquinolin-4-yl) amino] butyraldehyde.

This product was prepared according to the procedure described in Example 2.3 from 6.0 g of 4- [eth- (2-methylthio [IV-4-yl] arnino] -bubsn-1-n! (Example 5.1) (2), 0 mmol), 2.2 mmol of oxalyl chloride (25.0 mmol), 2.2 mL of dimethylsulfoxide (51.0 mmol) and 16.0 mL of triethylamine (115.0 mmol). The product is obtained in the form of a brown oil (6.2 g, 100%). 1 H NMR (300 MHz, DMSO) δ ppm ~ 1.07 (3H, t, J = 6.9Hz), 1.78 (2H, qu (N ~ .7 = 6.9Hz), 2.48 (2H). , m), 2.57 (3H, s), 3.28 / 4H, m), 6.93 (1H, s), 7.44 (1H, td / J = 6.9Hz, J = 1, 5 Hz), 7.61 (1H, td, J-6.0 H /, J = 1.5 Hz), 7.83 (1H, dd, 8.4 Hz,} = 0.9 Hz). , 7.94 (1M,

5.3. K? 4-? -Ethyl; (1-yl) quinolin-4-yl) aminolbutylsocomycin dichlorohydroxy;

PA1398 is prepared according to the procedure described in Example 1.4, starting from 23.8 g of vancomycin monohydrochloride (16.1 mmol), 6.2 g of 4- [ethyl] (2'meihy / qoino! In (5.2) (24.2 mmol), 52.0 mL of N, N-diisopropylamine (480.0 mmol, 4 μg), m.p. sodium cyanobonohydride (64.0 mmol), 5% trihydroacetic acid (720.0 mmol), the product is purified by filtration and purified fractions of purity> 96%. and lyophilized before desalting by passage over PL-HCO3 ion exchange resin The desalted product is then re-acidified at 0 ° C. with 2 equivalents of 0.1N hydrochloric acid After lyophilization, PA1398 is obtained under the white lyophilizate (0.2 g, 1%, purity: 97%) MS (ES> 0) m / z: 1689.1 (M + H +), 845.5 (M + 2H) Elemental analysis for C 82 H 95 Cl 2 N 2 O 24 · 2HCl · 10.8H 2 O:% theory C 50.52, H 6.11, N 7.87,% experiment C 50.50, H 5.65, N 7.73.

EXAMPLE 6 Bactericide to Staphylococcus aureus MRSA (mR isolate) at 1 μg / mL in the presence of 50% human serum (Alog CFU) MICs were determined in a Muller Hinton (Difco) liquid medium after 24 h with shaking at 37 ° C. ° C. In the case of daptomycin, 50 mg / L CaCl2 was added. For bactericides, the concentrations of test products were obtained in Muller Hinton liquid medium (10 mL) in the presence of 50% of human AB + serum. 50 me CaCl 2 was added in the case of daptomycin. The different test tubes and a tube without product-test were inoculated with a bacterial suspension adjusted to 107 bacteria / mL (1% in final concentration). After homogenization, a count was made (TO). The tubes were incubated at 370C with shaking. Samples were taken at T7h and T24h for enumeration of residual viable bacteria. Enumeration was done by inclusion (Trypcase-soy agar) of 1 mL serial dilutions of Reason 10. CFUs were counted after 24 h at 48 h incubation at 36 1 ° C.

Table 1: Bactericide to Staphyloaxcus aureus MRSA (mR isolate) at 1 gg / ml in the presence of 50% human serum Compose Ria Rn) Y CH2 CMI Bactericidal ... rio [ft T 7h-. 2: Monitoring. Vancormycire. 0.8,: 0.01% Teolin opanine, 0.7 Ltolene. 2 5 3 4 Teavancine 0.5: 1: 20.6 F PA-1246 CH2 CH2 CH1 0.1 PAl276 F CH-CH%. H 0 s 33.% H. CH PAl2I 2 Cf (H CH.% OH ...-O-CHCH 0.19 1. 2 -1 3.1 o .... Ä ..._.% Like vancomycin described in patents FR 20040008441, WO 2006024741 and US 20070060558, the vancomyquines of formula (I) according to the invention have very low MICs with respect to methicillin-resistant Staphylococcus aureus, the values of these MICs are all The bactericidal properties of the compounds of formula (I) are remarkable: at only 1 μg / ml and in the presence of 50% of human serum, the vancomyquines according to the invention are capable of decreasing more than 4 log the bacterial population of a strain of Staphylococcus aureus MRSA in 24 hours The presence of a substituent RI 'in position 2 on the quinoline is essential to reach the bactericidal (- 3 log) e 24 hr (PAl274 and PAl275 compared to PAl246 and PAl276). The presence of another substituent Rn) does not decrease the activity of vancomycin (PA1385). Finally, the reduction of 4 log is reached with a Y-type linkage containing no aromatic ring between vancomycin and aminoquinoline ( see PA1409, PA1389, PA1402, PA1418, and PA1398).

Example 7: In vivo efficacy The in vivo efficacy of a vancomycin according to the invention: vancomycin PA1409 was tested in a murine sepsis model due to a methicillin-resistant strain of Staph / ococcus aureus (ATCC33592) The 6-7 week old Swiss mice were inoculated intraperitoneally with 200 μl of a 57 μl bacterial suspension in gastric mucin (inoculum 7 × 10 cfu mouse) (70 μg vancomycin PA 1409 was then administered by intravenously 1 h and 4 h post-infection at the following doses: 1 to 5 to 10 mg kg / day in solution in 50 glucose (ie 2x0.5 to 2x2.5 to 2x5 ng, U. mice survival ( The dose was monitored up to 74 for the determination of the ability to cure 50% of the mice (DC). An additional group of 5 PA1385 2-CF 8-C PAl274 2-CH PA1418 2-CH PA1398 PA1402 2-PhH CH2-CH2-O-C6H4-CH2 0.25 5.5 -3.4 -3.5H CH2-CH2-CH2-CH2 0.25 5.2 -2, 7 -4,2 CH2-CH2-CH CHI 0.5 2.6 -4.3 CH-CH2-CHS-CH2 0.25 2.6 -4.3 CH, CH = CH2-CH2 0.125 -4.3 PA1389 * log CFU * -, log CFU CH-CH2-CH2-CH2 0.5 mice per dose was used for enumeration of bacteria present in the blood. This sample was taken 5 h post-infection and sown in trypcase-soya agar for counting at 24 h.

Table 2: In vivo efficacy in a model of murine sepsis due to Staphy / ocaccus aureus SARM Compound Vancomycin PA1409 Dose (mglkg / d) 1 5 10 1 5 10 Survival (%) 0% 50% 91.6% 66.7% 100% 100% (alive / treated) (0/12) (6/12) (11/12) (4/6) (6/6) (6/6) Reduction of bacteremia - - 2,0 - 2 , 7 - 1.9 - 3.5 - 5 (Alog CFU) DC50 (mg / kg / day) 5.0 0.9 The vancomyquines according to the invention are also very effective in vivo. Indeed, in a model of murine sepsis due to Staphylococcus aureus MRSA, vancomycin PA1409 is able to cure 100% of mice at only 5 mg / kg whereas at 10 mg / kg the 100% of healing is still not achieved with vancomycin. The healing dose to achieve 50% healing is more than 5 times lower for vancomycin PA1409 than for vancomycin. In addition, at 5 mg / kg, the compound according to the invention makes it possible to reduce bacteremia by more than 3 log (bactericide to AUFC-3 log) whereas vancomycin is still not bactericidal at 10 mg / kg,

Example 3: MICs Versus Panel of Gram Bacteria The MICs were determined by the agar dilution method (CLSI / CA-SFM method). The inocula were adjusted to a turbidity of 0.5 McFarland and diluted 1/100 (except for streptococci diluted 1: 10). Seeding was done at the Steers apparatus, which emits UFC per spot. The medium was an agar medium of Muller Dalton (BioMerieuxa In the case of daptomycin, the media were supplemented with calcium chloride (30 M g, The: iannn es were $ 0.00, rte, rsrL, ept for the The vancomycin or higher concentration tested was 32 ml.The incubations were done at 3 ° C. and the CM reading was made at 24 h.

Bacterial strains: Staphylococcus aureus SASM (clinical isolate VA010), Staphylococcus aureus MRSA CCUG 31966 (VA064), Staphylococcus aureus h-VISA MU3 ATGC 700698 (VA033). Staphylococcus CNSMS (VA016 clinical isolate). Staphylococcus CNSMR (VA018 clinical isolate), Streptococcus A (VA154), Streptococcus B (VA169), Streptococcus C (VA160). Streptococcus G (VA162), Enterococcus faecalis VSE JH2-2 (VA107), Enterococcus faecium VSE BM4107 (VA106). Table 3: MICs (pg / mL) against a panel of Gram + bacteria Vanco Teico Bacteria Dapto Teta PA1409 Staphylococcus aureus SASM 0.5 1 2 0.25 0.5 0.25 Staphylococcus aureus MRSA 0, 5 1 2 0.25 0.5 0.25 Staphylococcus aureus h-VISA 2 32 2 1 1 0.5 Staphylococcus CNSMS 1 2 1 0.25 0.25 0.5 Staphylococcal CNSMR 2 8 1 0.5 0.25 0.25 Streptococcus A 0.25 0.12 1 0.25 0.06 0.016 Streptococcus B 0.25 0.5 1 0.25 0.06 0.03 Streptococcus C 0.25 0.25 1 0.06 0 , 12 0.03 Streptococcus G 0.25 0.25 1 0.12 0.06 0.008 Enterococcus faecalis 1 0.5 2 1 0.5 0.12 Enterococcus faecium 0.5 1 2 2 0.25 0.06 L The antibacterial activity of vancomycin according to the invention is not limited to MRSA. Indeed, as shown in Table 3, vancomycin PA1409 has very low MICs against a panel of Gram + bacteria,

Example 9 iii: Examples of pharmaceutical compositions exerr.N. The following are examples of pharmaceutical compositions containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof according to the invention, for example, for a pharmaceutical administration. 9.1 Pharmaceutical composition example A: liquid formulation An injectable preparation containing the following components may be prepared: Ingredients Amount Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g Sterile 5% aqueous glucose solution qs 10 to 100 ml The compound of formula (I) or one of its pharmaceutically acceptable salts or one of its solvates or hydrates, in the form of a powder or lyophilizate, is solubilized in a sterile 5% aqueous glucose solution. kept cold (eg 4 to 6 ° C).

9.2. Example of pharmaceutical composition B: liquid formulation Another example of an injectable preparation contains the following components: Ingredients Amount Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g Hydroxypropyl-3-cyclodextrin 0.1 to 25 g Sterile 5% aqueous glucose solution qs 10 to 100 ml Hydroxypropyl-3-cyclodextrin is solubilized in the sterile 5% aqueous glucose solution. The compound according to the invention is then solubilized in this preparation. The formulation is kept cold (eg 4 to 6 ° C). 9.3. Example of a pharmaceutical composition C: solid formulation Another example of a pharmaceutical composition for a solid formulation consists of a sterile lyophilizate of a compound of formula (I) according to the invention or one of its addition salts with a pharmaceutically acid acceptable or a solvate or hydrate. For parenteral administration, just before use, a solution of the compound of formula III is reconstituted by the addition of 20 ml of sterile water or sterile aqueous glucose solution, 250-500 mg of the compound. according to the invention in the form of sterile lyophilisate. This solution is then diluted in 100 to 200 ml of a vehicle compatible with an irtraveir injection. and an aqueous glucose solution at 5% sterile.25 9.4. Example of pharmaceutical composition D: solid formulation Another pharmaceutical composition-free for parenteral administration is illustrated by the following composition: Ingredients Amount Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g Hydroxypropyl-r3-cyclodextrin 0.1 to 25 g Sterile water qs 10 to 100 ml Hydroxypropyl-3-cyclodextrin is solubilized in water. The compound according to the invention is then dissolved in this preparation. The solution obtained is sterilized by filtration at 0.22 mm and is then placed in sterile vials for intravenous injection and freeze-dried. The vials are capped, labeled and stored at room temperature or cold (eg 4 to 6 ° C).

Claims (7)

REVENDICATIONS1. An aminoquinoline-vancomycin type molecule of the general formula wherein: n is 0, 1, 2, 3 or 4; Y represents a group chosen from: ~ (CI-Cu) a] kvle-substituted or not by one or more of the substituents chosen independently from a group Z, ~ - (C ~ -Czx) carbocyclic non-aromatic substituted or by one or more of the substituents independently selected from a non-aromatic heterocyclic group Z when Y forms a cyclic structure with NR 2, substituted or unsubstituted by one or more of the substituents independently selected from a group Z, ° - (C, -C) ./-> * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * '' '' '' '' '' '' '' '' '' '' ''. In one or more of the substituents selected independently from a group 2, it is possible for the nitrogen atom to be free of the following: - ([r] - alkyl; X represents a hydrogen atom; , sulfur or a group choxf by m OK` [) K {l! ! ~! Z represents a halogen atom or a group chosen from: CF3, OCF3, OR3, COOH; , PO Hz NHR3,, COR3, COOR3, CONHR3, CON (R3) 2, SO3H SO2NHc3, and Suzm (v). R3 represents a hydrogen atom or a (C1-C) alkyl group, preferably unsubstituted; R4 represents a group chosen from -OR3 or N (ps5) (Rs5) / -Rsm ~ and R u may be identical or different and represent a hydrogen atom or a group (CI-C.6) alkyl substituted or not by one or more of the substituents chosen independently from a gn] upernentZ; and R 1, R 1 and R 2 are organic chemical groups. 2. Molecule according to claim 1, characterized in that in the molecule of formula (1): - Ria represents a group _vle, preferably unsubstituted, or a group Z, or a phenyl group preferably nOnyubstKuté; Rm represents one or more identical or different substituents, occupying any positions and representing a substituent chosen from: a group Z, p - (CrCu), which may or may not be substituted by one or more substituents chosen independently from a group Z, ~ -X- (CI-Cm) a! kv! substituted or unsubstituted by one or more of the substituents independently selected from a group Z, * '([I- [a) a / kv! f (- (Cz-Cu) æ! kv (e) substituted or not by one or more of substituents independently selected from a group Z - R2 represents a hydrogen atom or a group selected from: non-aromatic heterocycly when R / forms a ring structure with Y, optionally substituted with one or more of the substituents independently selected from a group Z - X repulses a sulfur oxygen atom or a group chosen from 0 R` DK` DO 3 | ki "m 30 3. Mo! Ecx! C according to claim 1 or 2, char. According to the formula (1) - n represents 0 or 1 - Ria represents a fluorine or chlorine atom or a group, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, tert butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH2, dimethylamino or unsubstituted phenyl; R 1, preferably in position 7 or 8, represents a fluorine, chlorine, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl atom, fluorine group, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH2, dimethylamino, CONHCH2CH2NH2, CONHCH2CH2NMe2, CONHCH2PO3H2, CONHCH2CH2PO3H2, NHCH2COOH, NHCH2CH2COOH, NHCH2PO3H2, NHCH2CH2PO3H2 or NHCH2CH2SO3H; R2 represents a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl or heptyl group; octyl, nonyl, decyl, undecyl, dodecyl, CH2COOH, CH2CH2COOH, CH2PO3H2r CH2CH2PO3H2 or CH2CH2SO3H; R4 represents an OH, -NHCH2COOH, -NHCH2CH2COOH, -NHCH2PO3H2r -NHCH2CH2PO3H2 or -NHCH2CH2NMe2 group; Y is chosen such that the group R2N (Q) -Y-NHV represents a group chosen from: Q NH NMR R2N? R2N? 2N Q Q R2N .., ä - w ≠ i R2N s? R2N? R2N Q R2N? R2N R2N-N3 -, -, Q 1 Q R21tiwo Q? ReN R2N Q Q R2N Q R2N Q? R2NN-2i ---- sr! H Q R2N 1 0 R2N Q 1 o? R2NN H R2N Sss H Q 4. Molecule according to any one of claims 1 to 3, characterized in that in the molecule of formula (I): - n represents 0 or 1; - Ria represents a halogen atom, a methyl group, methoxy, CF3, OCF3, COOH, or a phenyl group, preferably unsubstituted; RItD represents, preferably in position 7 or 8, a halogen atom, preferably chlorine or fluorine, a methyl or methoxy group, optionally substituted by one or more halogen atoms, and preferably one or more fluorine atoms, as for example the group CF3, or OCF3; R2 represents a hydrogen atom or a (C1-C6) alkyl group; - R4 represents a group H; Y represents an unsubstituted (C1-CII) alkyl group. 5. Molecule according to any one of claims 1 to 4, characterized in that in the molecule of formula (I) the group Y is chosen from an unsubstituted (CICII) alkyl group, and preferably an ethyl, propyl group, butyl or pentyl, for example linear, and / or branched, and / or cyclic; optionally interrupted by one or more oxygen atoms, one or more sulfur atoms, or one or more amine, amide, ester, and / or sulfonamide groups. 6. Molecule according to any one of claims 1 to 5, characterized in that R4 represents a hydroxyl group. 7. Molecule according to claim 1, characterized in that in the molecule of formula (I) is chosen from the compounds: N-4-14- (7-chloro-2-fluorifluoromethylquinolin-4-ylamino) butyl-J-vancomycin, N-4- 4- (8-fluoro-2-trifluoromethylquinolin-4-ylamino) butyl] vancomycin, -N-4-phenylquinol-4-ylamino-butyl-vancomycin, -N-4 [4- (2-methylquinolin-4-ylamino) ) -butyl-vancomycin, 4-ethyl-2-methylquinolin-4-yl) aminol butyl-vancomycin. Molecuie according to what a vendications! It is understood that in the formic acid molecule I) is in a basic state or aridition salts with acids, and in the state of hydrates or solvates. 9. The molecule according to any of claims 1 to 8 as an antibacterial agent, especially for the prevention or treatment of a bacterial infection of a mammal. The molecule according to claim 9 for the prevention or treatment of bacterial infection with Gram + or anaerobic germs such as Staphylococci (Staphylococcus spp.), Streptococci (Streptacoccus 8pp.), Enterococci (Enterococcus spp. CIstndiVn7 Spp., Such as, for example, methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus with intermediate viancomycin sensitivity (VISA), Staphylococcus avxreYu / vancomycin-resistant (VRSA). ), methicillin-sensitive coagulase-negative staphylococci (SCNMS), methicillin-resistant coagulase-negative staphylococci (SCNMR), group A streptococci, group B streptococci, group C streptococci, group G streptococci, enterococcus faecaYs susceptible to vancomycin (VSE), vancomycin-resistant Enterococcus fæyza8s (VREVanA0uVanB) / G7berccczugfaeuixn vancomycin-sensitive (VSE), orEnd Vancomycin-resistant tissue (VRE VanAuVan8l, CXogtndium / difficile. 11. The molecule according to any one of claims 9 to 10, characterized in that the infection concerns a human being, or a mammal, such as for example a dog, a cat, an equine, a sheep, a bovine, a goat, a pig, a poultry or a rabbit, and preferably the human being. 12. Pharmaceutical composition, characterized in that it comprises at least one molecule according to any one of claims 1 to 13. Pharmaceutical composition according to claim 1, characterized in that it comprises at least one molecule according to any one of claims in combination with the Mo: S pharmaceohquemont another active molecule. 1.4. Pharmuceub composition. , andicaUoos 12 or 1.3, characterized in that it is intended for the prevenUon or treatment of a bacterial infection of a mammal.