The present invention relates to novel hybrid molecules in which vancomycin or one of its derivatives is bound covalently to substituted 4-aminoquinolines, The present invention describes the preparation of these hybrid molecules designated "vancomyquines® ^" corresponding to formula (I) as well as their therapeutic use as an antibacterial agent.

PRIOR ART

The development of multiresistant bacterial strains has become a major public health problem (Talbot GH et at. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Disease of America. Clin Infect Dis 2006; 42: 657). Among the bacteria that are the most dangerous, the methicillin-resistant strains of Staphylococcus aureus (MRSA) were responsible in the United States in 2007 for close to 100 000 bacterial infections, thus causing the death of nearly 19 000 persons. This figure exceeds that for AIDS-related deaths (Taubes G. The bacteria fight back. Science 2008; 321: 356). Until now the antibiotic of choice for treating the infections due to these MRSA strains, which for the most part are nosocomial infections, was vancomycin. Unfortunately, since the appearance of strains of staphylococci but also of enterococci with reduced sensitivity to vancomycin and following several therapeutic failures, the use of vancomycin is now very controversial (Deresinski S. Counterpoint: Vancomycin and Staphylococcus aureus - an antibiotic enters obsolescence. Clin Infect Dis 2007; 44: 1543). It is therefore urgent to find an alternative to the use of vancomycin for treating the bacterial infections caused by the MRSA strains.

Hybrid molecules linking an aminoquinoline unit covalently to an antibiotic residue have already been described in patents FR 2874922, US 20070060558 and in international application WO 2006024741, Various classes of antibiotics have been attached to aminoquinolines in this way, giving a marked improvement in antibacterial activity. In these patents, aminoquinoline units were also grafted onto vancomycin. The resultant hybrid molecules proved to be very active, with values of minimum inhibitory concentrations well below those of the basic substructure; vancomycin. In patent FR 2874922 and international application WO 2006024741, the vancomyqulnes® in the examples covalently link vancomycin to a 4-aminoquinoline substituted in position 7 with a chlorine atom, the bond joining them being either an alkyl chain or an aromatic group of the ethoxybenzyl type:

In the examples of application US 20070060558, 4-aminoquino!ines grafted to vancomycin are substituted in position 2 or 7 with a methyl or trifluoromethyl group and the bond that joins them is an aromatic group of the ethoxybenzyl type:

AIMS OF THE INVENTION

The phenomena of resistance to vancomycin as well as its lack of bactericidal action account for numerous therapeutic failures.

The main aim of the present invention is to provide novel molecules with antibacterial activity as an alternative to vancomycin.

The invention also aims to solve this technical problem by providing molecules displaying minimum inhibitory concentrations lower than those of vancomycin, greater bactericidal action, at lower concentrations and better efficacy in vivo, notably in comparison with the vancomyquines* already described.

The present invention also aims to provide novel 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, certain and reliable manner, usable on an industrial scale, notably on a pharmaceutical scale. SUMMARY OF THE INVENTION

The innovative character of the present invention relates to the discovery of novel aminoquinoline-vancomycin hybrid molecules corresponding to the formula:

in which:

- n represents 0, 1, 2, 3 or 4

- p represents 0, 1, 2, 3, 4, 5 or 6

- Y represents a group selected from:

• -(Ci-Cu)alkyl-, unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p represents 1,

• -(CrC ₁₂ )alkyl-X-, unsubstituted or substituted with one or more of the substituents selected independently from a group Z, the portion joined to the nitrogen atom of NR ² being the -(CrC ₁₂ )alkyl portion, and p does not represent 0;

• Nonaromatic -(C ₃ -Ci ₂ )carbocycle-, the carbocycle being unsubstituted or substituted with one or more of the substituents selected independently from a group Z;

• Nonaromatic -(C ₃ -C ₁₂ )QrDOCyCIe-X-, X not being bound to the nitrogen atom of NR ² , and said carbocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p does not represent 0;

• Nonaromatic heterocycle when Y forms a cyclic structure with NR ² , and said heterocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z,

• Nonaromatic heterccycIe-X-, X not being bound to the nitrogen atom of NR ² _# and said heterocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p does not represent 0,

- X represents an oxygen atom, a sulfur atom or a group selected from:

- Z represents a halogen atom or a group selected from: CF ₃ , OCF ₃ , OR ³ , PO ₃ H ₂ , NHR ³ , N(R ³ J ₂ , COR ³ , COOR ³ , CONHR ³ , CON(R ³ J ₂ , SO ₃ H, SO ₂ NHR ³ , and SO ₂ N(R ³ J ₂ ;

- R ³ represents a hydrogen atom or a (C _r C ₁₂ )alkyl group, preferably unsubstituted;

- R ⁴ represents a group selected from -OR ³ or -N(R ^5a )(R ^5b );

- R ^Sa and R ^5b can be identical or different and represent a hydrogen atom or a (Q- QJalkyl group, unsubstituted or substituted with one or more of the substituents selected independently from a group Z; and

- R ^la , R ^lb , R ² are organic chemical groups.

According to one variant:

- R ^la represents a (Q-CπJalkyl group, preferably unsubstituted, or a group Z; or a phenyl group, preferably unsubstituted;

- R ^lb represents one or more substituents which may be identical or different, occupying any positions and representing a substituent selected from:

• a group Z,

• -(Q-C ₁₂ )alkyl, unsubstituted or substituted with one or more of the substituents selected independently from a group Z,

• -X-(CrCi ₂ )alkyI, unsubstituted or substituted with one or more of the substituents selected independently from a group Z,

• -(C ₁ -C ₆ )alkyl-X-(CrC ₁₂ )aIkyl, unsubstituted or substituted with one or more of the substituents selected independently from a group Z; - R ² represents a hydrogen atom or a group selected from:

• -(Ci-Ci ₂ )alkyl, unsubstituted or substituted with one or more of the substituents selected independently from a group Z,

• -(C ₁ -C ₆ )alkyI-X-(C ₁ -Ci ₂ )alkyt, unsubstituted or substituted with one or more of the substituents selected independently from a group Z, • Nonaromatic heterocycle when R ² forms a cyclic structure with Y, unsubstituted or substituted with one or more of the substituents selected independently from a group Z;

- π represents 0, 1, 2, 3 or 4 - p represents 0, 1, 2, 3, 4, 5 or 6

- X represents an oxygen atom, a sulfur atom or a group selected from:

- Y represents a group selected from: • -(CrCii)alkyl-, unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p represents 1,

• -(CrC ₁₂ )alkyl-X-, unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p does not represent 0, the portion joined to the nitrogen atom of NR ² being the -(CrCi ₂ )alkyl portion; • Nonaromatic -(C ₃ -C ₁₂ )carbocycle-, said carbocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z;

• Nonaromatic -(C ₃ -C ₁₂ )carbocycle-X-, X not being bound to the nitrogen atom of NR ² , and said carbocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p does not represent 0; • Nonaromatic heterocycle when Y forms a cyclic structure with NR ² , said heterocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z;

• Nonaromatic heterocycle-X-, X not being bound to the nitrogen atom of NR ² , and said heterocycle can be unsubstituted or substituted with one or more of the substituents selected independently from a group Z, and p does not represent 0;

- Z represents a halogen atom or a group selected from: CF ₃ , OCF ₃ , OR ³ , PO ₃ H ₂ , NHR ³ , N(R ³ ) ₂ , COR ³ , COOR ³ , CONHR ³ , CON(R ³ ) ₂ , SO ₃ H, SO ₂ NHR ³ , and SO ₂ N(R ³ J ₂ ;

- R ³ represents a hydrogen atom or a (Ci-C ₁₂ )alkyl group, preferably unsubstituted;

- R ⁴ represents a group selected from -OR ³ or -N(R ^5a )(R ^5b ); - R ^Sa and R ^5b can be identical or different and represent a hydrogen atom or a (C ₁ - QJalkyl group, unsubstituted or substituted with one or more of the substituents selected independently from a group Z,

The present invention provides a method of preparation of the compounds of formula (I) according to the invention as well as of the reaction intermediates, The compounds of formula (I) can be in the form of bases or of salts of addition to acids. Said salts of addition form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids but the salts of other acids that can be used for the purification or isolation of the compounds of formula (I) also form part of the invention.

The compounds of formula (I) can be in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Said hydrates and solvates also form part of the invention. The compounds of formula (I) can be in the form of racemates, including all of the degrees of mixing, or in the form of pure enantiomers.

In the molecule of formula (I), group Y can be a (Q-CπJalkyl group, and preferably

(CrQ)alkyl-

In the molecule of formula (I), group R ^la can represent a methyl, methoxy, CF ₃ , OCF ₃ , COOH group, or a phenyl group, preferably unsubstituted and group R ^lb , optionally present, can represent, preferably in position 6, 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, for example the group CF ₃ , or OCF ₃ .

The compounds of formula (I) can be combined in a pharmaceutical composition with excipients. The pharmaceutical compositions containing a therapeutically active amount of a compound of formula (I) or of a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable excipient, also form part of the present invention.

The compounds of formula (I) can also be combined in a pharmaceutical composition with one or more other active principles, for example another antibiotic. Pharmaceutical compositions containing one or more other active principles also constitute an object of the present invention.

According to the invention, it was discovered unexpectedly and non-obviously that the molecules of formula (I) led to a significant intensification of antibacterial activity. The bactericidal action of the hybrid molecules according to the invention is particularly unexpected. Thus, the compounds of formula (I) are capable of reducing by 4-log the bacterial load of a strain of methicillin-resistant Staphylococcus aureus. Moreover, the surprising antibacterial activity of these hybrid molecules was confirmed by demonstrating their efficacy in a murine model of MRSA septicemia. Knowing the terrible incidence of MRSA in nosocomial infections, a person skilled in the art will therefore be aware of the major benefits of the present invention.

The compounds of formula (I) 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 present invention relates to novel aminoquinoline-vancomycin hybrid molecules corresponding to formula (I) as well as their therapeutic use as an antibacterial agent.

In the definition of the compounds of formula (I), halogen means an atom of fluorine, of chlorine, of bromine or of iodine,

(CrQ)alkyl, or respectively (Q-CuJalkyl, or respectively (CrC ₁₂ )alkyl, means a linear or branched alkyl group with one to six carbon atoms or respectively with one to eleven carbon atoms or respectively with one to twelve carbon atoms, such as the methyl, ethyl,

^propyl, isopropyl, /?-butyI, isobutyl, sec-butyl, tetf-butyl, /?-pentyl, isopentyl, /?-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl group.

(C ₃ -Ci ₂ )carbocycle, nonaromatic, means a mono- or polycyclic, condensed, bridged or spiran group. Monocyclic group notably means a monocyclic alkyl group with three to seven carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyl, cydohexyl or cycloheptyl group. Polycyclic, condensed, bridged or spiran group notably means the groups with five to twelve carbon atoms, di- or tricyclic condensed, bridged or spiran, including for example the norbornyl, bornyl, isobornyl, adamantyl, noradamantyl, spiro[5.5]undecyl, bicyclo[2.2.1]heptyl, bicydo[3.1.1] heptyl, bicyclo[3.2.1]octyl groups.

Heterocycle notably means a monocyclic group with three to seven atoms comprising one, two or three heteroatoms selected from O, S or N, such as the azeridine, azetidine, pyrrolidine, oxazolidine, thiazolidine, piperidine, piperazine, morpholine or thiomorpholine heterocycle.

Salt of addition to pharmaceutically acceptable acids means a salt that is acceptable for administration to a mammal (e.g. salts that are nontoxic at the dosage administered) regardless of the method of administration. As nonlimiting examples, the pharmaceutically acceptable acid salts include the salts of acetic, ascorbic, benzenesulfonic, benzoic, hydrobromic, camphosulfonic, hydrochloric, citric, ethanesulfonic, fumarϊc, gluconic, glucuronic, glutamic, lactic, lactobionic, rnaleϊc, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, and p- toluenesulfonic acid. In particular, the compounds of formula (I) are preferred in which;

- n represents 0 or 1

- p represents 1 or 2

- R ^la represent a fluorine or chlorine atom or a methyl, ethyl, ^propyl, isopropyl, n- butyl, isobutyl, sec-butyl, ferf-butyl, /i-pentyl, isopentyl, /?-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trϊfluørαmethoxy, methoxy, ethoxy, n- propoxy, isopropoxy, /?-butoxy, Isobutoxy, sec-butøxy, te/t-butoxy, /?-pentyloxy, isopentyloxy, /hhexyloxy, isohexyloxy, heptyloxy, octyloxy, nαnyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH ₂ , dimethylamino or unsubstituted phenyl group;

- R ^lb , preferably in position 6, 7 or 8, represents an atom or group: fluorine, chlorine, methyl, ethyl, ^propyl, isopropyl, /?-butyl, isobutyl, sec-butyl, tørf-butyl, /?-pentyl, isopentyl, /?-hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, ^propoxy, isopropoxy, /?-butoxy, isobutoxy, sec- butoxy, te/t-butoxy, ^pentyloxy, isopentyloxy, ^hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, COOH, NH ₂ , dimethylamino, CONHCH ₂ CH ₂ NH ₂ , CONHCH ₂ CH ₂ NMe ₂ , CONHCH ₂ PO ₃ H ₂ , CONHCH ₂ CH ₂ PO ₃ H ₂ , NHCH ₂ CH ₂ NMe ₂ , NHCH ₂ COOH, NHCH ₂ CH ₂ COOH, NHCH ₂ PO ₃ H ₂ , NHCH ₂ CH ₂ PO ₃ H ₂ or NHCH ₂ CH ₂ SO ₃ H;

- R ² represents a hydrogen atom or a methyl, ethyl, ^propyl, isopropyl, /?-butyl, isobutyl, sec-butyl, te/f-butyl, /hpentyl, isopentyl, /hhexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, CH ₂ COOH, CH ₂ CH ₂ COOH, CH ₂ PO ₃ H ₂ , CH ₂ CH ₂ PO ₃ H ₂ , CH ₂ CH ₂ SO ₃ H, piperidine or piperazine group;

- R ⁴ represents an OH, -NHCH ₂ COOH, -NHCH ₂ CH ₂ COOH, -NHCH ₂ PO ₃ H ₂ , -NHCH ₂ CH ₂ PO ₃ H ₂ or -NHCH ₂ CH ₂ NMe ₂ group;

- Y is selected such that the group R ² N(Q)-Y-(CH ₂ ) _P -NHV represents a group selected from:

y. representing the covalent bond joining Y to the (CH ₂ ) _P group. According to a variant of the invention, in the molecule of formula (I), group Y is selected from an unsubstituted (Q-CnJalkyl group, and preferably a methyl, ethyl, propyl, butyl, pentyl or hexyl group, 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.

The invention notably covers, according to a second variant, the compounds of formula (I) in which R ^lb represents, preferably in position 6, 7 or 8, a halogen atom, preferably chlorine or fluorine, a methyl or methoxy group, optionally substituted with one or more halogen atoms, and preferably a fluorine atom, for example the group CF ₃ , or OCF ₃ .

The invention notably covers, according to a third variant, the compounds of formula (I) in which R ^la represents a halogen atom, a methyl, methoxy, CF ₃ , OCF ₃ , COOH group or a phenyl group, preferably unsubstituted. The invention notably covers, according to a fourth variant, the compounds of formula (I) in which R ² represents a hydrogen atom or a substituted or unsubstituted (Cr QJalkyl group, and for example represents a methyl, ethyl, propyl, butyl, pentyl, or hexyl group, preferably linear, or forms a cyclic structure with Y, for example a piperidine or piperazine structure. The invention notably covers, according to a fifth variant, the compounds of formula

(I) in which R ⁴ represents a hydroxy group.

The invention notably covers, according to a sixth variant, the compounds of formula (I) in which n represents 0 or 1.

The invention notably covers, according to a seventh variant, the compounds of formula (I) in which p represents 1 or 2.

The invention covers, in the aforementioned variants, all possible combinations, notably those in which the compounds of formula (I) are defined differently, including the particular embodiments.

According to the present invention, we further prefer the compounds of formula (I) in which:

- n represents 0 or 1;

- p represents 1 or 2;

- R ^la represents a halogen atom, a methyl, methoxy, CF ₃ , OCF ₃ , COOH group or a phenyl group, preferably unsubstituted; - R ^lb represents, preferably in position 6, 7 or 8, a halogen atom, preferably chlorine or fluorine, a methyl or methoxy group, optionally substituted with one or more halogen atoms, and preferably one or more fluorine atoms, for example the group CF ₃ , or OCF ₃ ;

- R ² represents a hydrogen atom or a (Q-QJalkyl group; - R ⁴ represents an OH group;

- Y represents an unsubstituted (Ci-Cu)alkyl group, and preferably an unsubstituted (Q- Q)alkyl group.

Among the compounds of formula (I) covered by the invention, we may notably mention the following compounds: - N-4-[4-(7-chloro-2-trifluoromethylquinolin-4-ylamino)-butyl] -vancomycin;

- N-4-[4-(8-fluoro-2-trifluoromethylquϊnolin-4-ylamino)-butyl ]-vancomycin;

- N-4-[4-(2-phenylquinolin-4-ylamino)-butyl]-vancomycin;

- N-4-[4-(2-methylquinolin-4-ylamino)-butyl]-vancomycin;

- N-4-{4-[ethyl-(2-methylquinolin-4-yl)amino]-butyl}-vancomyci n; - N-4-[6-(7-chloro-2-trifluoromethylquinolin-4-ylamino)-hexyl] -vancomycin;

- N-4-{2-[l-(7-chloro-2-trifluoromethylquinolin-4-ylamino)-pip eridin-4-yl]-ethyl}- vancomycin;

in the form of a base or of salts of addition to acids, as well as in the form of hydrates or of solvates.

It was discovered, very unexpectedly, that when vancomycin is substituted in the manner illustrated in formula (I), the resultant vancomyquines® are very active. The bactericidal action of these vancomyquines® is in particular very surprising with respect to MRSA with a reduction of 4-log of the inoculum in 24 h. This totally unexpected property of these novel vancomyquines* was not obvious from reading the previous patent applications. The gain in activity is obtained by 4-aminoquinolines substituted in position 2 whose group Y joining the vancomycin and the aminoquinoline does not contain an aromatic group. The present invention therefore relates to these novel vancomyquines®, their preparation, and their use as an antibacterial agent.

METHOD OF PREPARATION

The compounds of formula (I) according to the invention can be prepared according to the procedures described below. The typical or preferred process conditions are given as examples (solvent, temperature, time, number of equivalents, etc.). It is quite apparent that other conditions can be used, for modulating and optimizing the method of preparation according to optimization procedures that are known by a person skilled in the art. These method variants remain within the scope of the present invention.

The various methods described in patent applications FR 2874922, WO 2006024741, and US 20070060558 are applicable.

In accordance with the invention, the compounds of formula (I) can be prepared according to a method of reductive amination in 2 stages, carried out in the same vessel. This method comprises the following stages: a) a glycopeptide of formula:

in which R ⁴ is as defined for a compound of formula (I) including in their different variants, or a salt thereof, is coupled to a compound of formula:

in which n, R ^la , R ^lb , R ² and Y are as defined for a compound of formula (I) including in their different variants, and p represents 1, 2, 3, 4, 5 or 6. The coupling reaction takes place in the presence of a base and leads to a reaction intermediate that is not isolated (presumed to be a mixture of imine and/or of hemtaminal); b) the reaction intermediate is treated with a reducing agent in the presence of an acid.

The compounds of formula (I) thus obtained after stages a) and b) can then, after purification, be converted to a salt of acid addition

Stage a) is carried out with one or more equivalents of aldehyde of formula (III) Preferably 1 to 3 equivalents of aldehyde are used in this stage. This stage is typically carried out in an inert solvent, the inert solvent preferably being selected from N,N- dimethylformarnide, N,N-dimethylacetamide, N-methylpyrrolidinone or any mixture of at least two of these solvents. The reaction is typically carried out at a temperature between 0 ⁰ C and 80 ⁰ C, preferably at room temperature (i.e. 20-25 ⁰ C) for 1 to 24 h, preferably 1 to δ h.

Any base capable of neutralizing the salt of a compound of formula (II) and of facilitating the formation of the reaction intermediate (imine and/or hemiaminal) can be used in this stage including organic bases such as amines, alkali carboxylate salts (i.e. sodium acetate) and inorganic bases such as alkali carbonates (i.e. lithium carbonate, potassium carbonate, sodium carbonate). Preferably, the base used in this stage 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.

Stage b) of reduction of the intermediate (imine and/or hemiaminal) is carried out in the same vessel. Any reducing agent capable of reducing the intermediate (imine and/or hemiaminal) and compatible with the organic functions of a glycopeptide of formula (II) can be used in this stage. For example, reducing agents that can be used are: sodium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride, or a borane complex such as: BH ₃ -pyridine, BH ₃ -ή_y?-butylamine, BH ₃ -N- methylmorpholine, BH ₃ -morphoIine, BH^dimethylphosphine, BH ₃ "triphenylphosphine, BH ₃ -tetrahydrofuran, BH ₃ -trimethylamine, BH ₃ -dimethylamine, BH ₃ -dimethylsulfϊde, BH ₃ isoamylsulfϊde, BH ₃ "triethylamine, BH ₃ 'N,N-diisopropylethylamine, BH ₃ -N,N- diethylaniline, BHyammonia. Preferably, the reducing agent used is sodium cyanoborohydride or BH ₃ -N,N-diethyIaniline complex. From 1 to 6 equivalents of reducing agent are typically used for this stage, and more preferably from 3 to 4.5 equivalents. The reduction stage is typically carried out at a temperature between 0 ⁰ C and 80 ⁰ C, preferably at 50 ⁰ C, for a duration of 1 to 24 h, preferably 20 to 24 h. A protic solvent is typically added in the course of this stage, including for example methanol, /?-propanol, isopropanol or /?-butanol. Methanol is preferably used as the protic solvent.

The reduction stage is typically carried out in an acid medium. The acid used can for example be a carboxylic acid (i.e. acetic acid, trifluoroacetic acid, citric acid, formic acid, methanesulfonic acid for example) or an inorganic acid (i.e. hydrochloric acid, sulfuric acid, phosphoric acid for example). Preferably, the acid used is trifluoroacetic acid. The acid is typically used in excess relative to the compound of formula (II) and relative 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. For preparing the compounds of formula (I) in the form of salts of acid addition, all the pharmaceutically acceptable acids can be used, including acetic, ascorbic, benzenesulfonic, benzoic, hydrobromic, camphosulfonic, hydrochloric, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, lactic, lactobionic, maleic, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acids. The acetic, hydrochloric, citric, fumaric, gluconic, glucuronic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric and tartaric acids are preferably used. These salts are typically prepared using from 0.1 to 5 equivalents of acid, preferably from 0.5 to 3 equivalents, at a temperature between 0 ⁰ C and 25°C, preferably from 0 to 5°C. The compounds of formula (I) can be purified by all the classical methods, such as by precipitation, filtration, washing or by means of high-performance liquid chromatography.

The glycopeptides of formula (II) are known or are commercially available or are prepared by the classical methods known by a person skilled in the art. One compound of formula (II) is vancomycin.

The aldehydes of formula (III) used in the method of the present invention can be prepared by reaction of a compound of formula:

in which n, R ^la and R ^lb are as defined for a compound of formula (I) and "Hal" is a halogen atom, with a derivative bearing an amine function and an acetal function, such as the derivatives of formula: in which R ² and Y are as defined for a compound of formula (I), p represents 1, 2, 3,

4, 5, or 6, and "AIk" is an alkyl group with 1 to 4 carbon atoms, to obtain a compound of formula; in which n, R ^la , R ^lb , R ² and Y are as defined for a compound of formula (I), and p represents 1, 2, 3, 4, 5 or 6.

When a compound of formula (IV) Is reacted with a derivative of formula (V), the reaction is typically carried out either without 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. Preferably, the reaction is carried out without solvent. Typically, from 1 to 5 equivalents of derivative of formula (V) 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 the organic bases such as the amines, the alkali carboxylate salts (i.e. sodium acetate) and the inorganic bases such as the alkali carbonates (i.e. lithium carbonate, potassium carbonate, sodium carbonate). Preferably, the reaction is carried out without a base. Typically the reaction is carried out at a temperature between 20 ⁰ C and 150 ⁰ C, preferably from 80 to 100 ⁰ C, for 2 to 24 h, preferably 15 to 24 h.

The derivatives of formula (VI) can then be converted to aldehyde of formula (III) in an acidic medium. All the acids capable of hydrolyzing the acetal function of the derivatives of formula (VI) to aldehyde can be used. As nonlimiting examples, the acids that can be used are the hydrochloric, nitric, sulfuric, phosphoric, acetic, trifluoroacetic 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:

Ri "- ^Y Nur" ^0H p (VII) in which p, R ² and Y are as defined for a compound of formula (I) including in their different variants, to lead to a compound of formula:

(VIII) in which n, p, R ^la , R ^lb , R ² and Y are as defined for a compound of formula (I) including in their different variants.

When a compound of formula (IV) is reacted with a derivative of formula (VII), the reaction is typically carried out either without 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-dimethyIformamide. Preferably, the reaction is carried out 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 that can be used are the organic bases such as the amines, the alkali carboxylate salts (i.e. sodium acetate) and the inorganic bases such as the alkali carbonates (i.e. lithium carbonate, potassium carbonate, sodium carbonate). Preferably, the reaction is carried out without a base. Typically the reaction is carried out at a temperature between 20 ⁰ C and 150 ⁰ C, preferably from 80 to 150 ⁰ C, for 2 to 24 h, preferably 2 to 6 h. The derivatives of formula (VIII) can then be converted to aldehyde of formula (III) by a classical oxidation reaction, well known by a person 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 an oxidation of the Swern type in the presence of dimethylsulfoxide (from 2 to 4 equivalents, preferably 2.2 equivalents) and of oxalyl chloride (from 1 to 2 equivalents, preferably 1.1 equivalent). Typically the reaction is carried out in a chlorinated solvent (for example dichloromethane, dichloroethane, chloroform) at a temperature between -80 ⁰ C and 20 ⁰ C, preferably from -80 to -40 ⁰ C, for 10 min to 2 h, preferably from 20 min to 1 h.

The quinolines of formula (IV) are known or are commercially available or are prepared by the classical methods of halogenation from the corresponding alcohol of formula;

in which n, R ^la and R ^lb are as defined for a compound of formula (I) including in their different variants. Typically, to prepare a derivative of formula (IV), a compound of formula (IX) is treated with a halogenatlng agent such as PCI ₅ , PCI ₃ , POCI ₃ , PBr ₃ , HBr, BBr ₃ or SOCI ₂ . The reaction is typically carried out without solvent or in an inert solvent such as a chlorinated organic solvent (for example dichloromethane, dichloroethane, chloroform), tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or toluene.

The quirtolines of formula (IX) are known or are commercially available or are prepared by the classical methods known by a person skilled in the art. The acetals and alcohols respectively of formula (V) and (VII) are known or are commercially available or are prepared by the classical methods known by a person skilled in the art.

The method of preparation of the compounds of formula (I) of the present invention is simple, conventional and is usable on an industrial, notably pharmaceutical, scale.

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 invention relates to medicinal products for human or veterinary medicine that comprise at least one compound of formula (I), or a salt of addition of this compound to a pharmaceutically acceptable acid, or a solvate or a hydrate of the compound of formula (I).

Thus the compounds according to the invention can be used in humans or in animals (notably in mammals including, but not limited to the family of dogs, cats, equines, goats, ovines, bovines, pigs, rabbits, or in the poultry family) in the treatment or prevention of bacterial infections.

For example and nonlimitatively, the compounds of formula (I) can be used for the prevention or treatment of bacterial infections by Gram+ bacteria or anaerobes such as the staphylococci {Staphylococcus spp.), streptococci {Streptococcus spp.), enterococci {Enterococcus spp.) or Clostridium spp. As nonlimitϊng examples, the bacterial species that can be treated effectively with the compounds according to the invention are: methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resϊstant

Staphylococcus aureus (MRSA), Staphylococcus aureus with intermediate resistance to vancomycin (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), coagulase- negative methicillln-sensitive staphylococci (CNMSS), coagulase-negative methicillin- resistant staphylococci (CNMRS), group A streptococci, group B streptococci, group C streptococci, group G streptococci, vancomycin-sensϊtive Enterococcus faecalis (VSE), vancomycin-resistant Enterococcus faecalis (VRE VanA or VanB), vancomycin-sensitive

Enterococcus faecium (VSE), vancomycin-resistant Enterococcus faecium (VRE VanA or VanB), Clostridium difficile. The bacterial infections for which the compounds of formula (I) can be used are the infections by microorganisms that are sensitive to the compounds according to the invention, including for example and nonlimitatively: bacteremias, endocarditis, peritonitis, mediastinitis, infections of the skin and of the soft tissues, osteo-articular infection, meningitis, shunt valve ventriculitis, infections on catheter or implantable chamber, pulmonary infections, urinary infections, pseudomembranous colitis.

As shown in Tables 1 to 4, the vancomyquines® of the invention are very effective as antibacterial agents. The MICs of the vacomyquines® according to the invention with respect to methicillin-resistant Staphylococcus aureus (MRSA) are far lower than those of the antiGram+ antibiotics currently on the market such as vancomycin, teicoplanin, daptomycin or lϊnezolid (table 1, example 10). These values mean they can be effective at lower concentrations, as demonstrated by the values for the kinetics of bactericidal action versus a strain of MRSA at 1 μg/mL (table 1, example 10). The results obtained show that the presence of the substituent R ^la in position 2 on the quinoline nucleus is important for reaching the European threshold of bactericidal action corresponding to 3- log of reduction of the initial bacterial load. Finally, with a type Y bond, not containing an aromatic nucleus, the vancomyquines® according to the invention are capable of reducing this bacterial load by more than 4-log in 24 h which corresponds to the American threshold of bactericidal activity. This one-log difference in the reduction of the bacterial load (i.e. 10-fold) can have a crucial clinical impact. Furthermore, the experiments on bactericidal action were carried out in the presence of 50% of human serum in order to mimic physiological conditions as far as possible. In these conditions, the vancomyquines® are capable of eradicating a strain of MRSA at only 1 μg/mL whereas none of the comparators currently on the market is active at this concentration, no more than telavancin.

The vancomyquines® according to the invention maintain their powerful antibacterial activity in vivo (example 11). Indeed, in a murine model of septicemia induced by MRSA, for example vancomyquine PA1409 according to the invention is able to cure 100% of infected mice at a dose of only 5 mg/kg. At this dose, vancomyquine® is bactericidal (Δlog >3), in contrast to vancomycin, which is not bactericidal and only makes it possible to cure 50% of the mice.

Moreover, the compounds according to the invention are active against Gram+ bacteria other than MRSA, as demonstrated for example by the values of the MICs of vancomyquine PA1409 with respect to a panel of bacteria (table 3, example 12). In fact, all the values of the MICs of vancomyquine PA1409 are lower than those of all the comparators. The vancomyquines* according to the invention can therefore be used for the prevention or treatment of various infections involving Gram+ microorganisms that are sensitive to the hybrid molecules according to the invention.

The vancomyquines® according to the present invention can be prepared as acid addition salts to modulate their hydrosolubility. Salts of acetic, ascorbic, benzenesulfonic, benzoic, hydrobromic, camphosulfonic, hydrochloric, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, lactic, lactobionic, maleic, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acids can be easily produced with 0.1 to 5 equivalents of acid relative to the base form. For example, the salt of example 2 containing 0.7 equivalent of hydrochloric acid and the salt of example 3 with 2 equivalents of HCI are highly hydrosoluble when the base form of these salts

(example 1) is insoluble in water (table 4, example 13).

According to one of its aspects, the present invention relates to the use of a compound of formula (I), or a salt of addition thereof with a pharmaceutically acceptable acid or a solvate or hydrate thereof for the treatment or prevention of bacterial infections.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a salt of addition thereof with a pharmaceutically acceptable acid or a solvate or a hydrate of said compound, as well as optionally a pharmaceutically acceptable excipient or vehicle.

Said excipients or vehicles are selected according to the pharmaceutical form and the desired method of administration, from the usual excipients known by a person skilled in the art.

In the present description, pharmaceutically acceptable excipient or vehicle means a compound or a combination of compounds that are included in a pharmaceutical composition and do not cause side reactions and that for example facilitate administration of the active compound or compounds, increase its persistence and/or its efficacy in the organism, increase its solubility in solution or improve its storage. These pharmaceutically acceptable vehicles, which are well known, will be adapted by a person skilled in the art in relation to the nature and the method of administration of the selected compound.

The methods of administration, pharmaceutical forms and optimum posologies can be determined according to the criteria generally taken into account in the establishment of a treatment suitable for a patient, for example the patient's age or body weight, the seriousness of the patient's general condition, tolerance to the treatment and the side effects observed.

The compounds of formula (I) can be administered systemically, in particular by the intravenous, intramuscular, intradermal, intraperitoneal, intraspinal, subcutaneous, or topical route, or by the oral route.

The pharmaceutical compositions comprising, as active principle, a compound according to the invention can assume various pharmaceutical forms, for example solid or liquid compositions, or emulsions, gels, ointments or creams. As solid compositions for oral administration, it is possible to use tablets, pills, powders (gelatin capsules, tablets) or granules. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions can also comprise substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (coated tablets) or a varnish.

As liquid compositions for oral administration, it is possible to use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs, for example containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can include substances other than the diluents, for example wetting agents, sweeteners, thickeners, flavorings or stabilizers.

As solid compositions for topical use, it is possible to use creams, ointments or gels.

In these compositions, the active principle according to the invention is mixed with one or more inert diluents or additives, such as lactose, cellulose derivatives, or talc for example.

These compositions can also comprise substances other than diluents, for example fatty acids and their derivatives or fats of animal, vegetable or synthetic origin.

As liquid compositions, it is possible to use pharmaceutically acceptable emulsions for local usage, solutions, suspensions containing inert diluents such as water, oils

(paraffin oil, vaseline oil, olive oil), organic esters. These compositions can, moreover, contain substances other than diluents, for example wetting agents, emulsifiers, dispersants or stabilizers.

Sterile compositions for parenteral administration can be aqueous or nonaqueous solutions, suspensions or emulsions. As solvent or vehicle, it is possible to use water, glycerol, sorbitol, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions can also contain additives, in particular wetting agents, complexing agents (such as a cyclodextrin), isotonic agents (such as glucose), emulsifiers, dispersants and stabilizers. Sterilization can be carried out in various ways, for example by asepticizing filtration, by incorporating sterilizing agents in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can then be dissolved at the moment of use in sterile water or any other sterile injectable medium, such as an aqueous solution of glucose. Examples of pharmaceutical compositions for parenteral administration, containing a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof according to the invention, are given in example 14. The dosages of the compounds of formula (I) in the compositions of the invention can be adjusted in order to obtain an amount of active substance that is effective for obtaining the desired therapeutic response for a composition according to the method of administration. The dosage level selected therefore depends on the desired therapeutic effect, the route of administration, the desired duration of the treatment and other factors. Said doses are generally between 0.01 and 100 mg of active principle per kg of body weight per day, in one or more doses.

Preferably, the compounds according to the invention or one of their salts of addition with a pharmaceutically acceptable acid or a solvate or a hydrate are administered intravenously at a dosage between 0.1 and 20 mg per kg of body weight per day, in a single dose.

There may be particular cases where higher or lower dosages are appropriate; said dosages are still within the scope of the invention.

The pharmaceutical compositions according to the invention can comprise at least one molecule of formula (I) as described previously in combination with at least one other pharmaceutically active molecule.

The pharmaceutical compositions according to the present invention can contain, in addition to the compound of formula (I), one or more other active principles for use in the treatment or prevention of bacterial infections. This other active principle can be another antibiotic such as, as nonlimiting examples, an antibiotic from the family of: penicillins (e.g. penicillin G, ampicϋlϊn, amoxicillin, ticarcillin, piperacillin), cephalosporins (e.g. ceftriaxone, cefotaxime, cefpodoxlme, cefetamet, cefepime, ceflxime), penems and carbapenems (e.g. imipenem, meropenem, doripenem, faropenem), monobactams (e.g. aztreonam, carumonam, tϊgemønam), fosfømycin, aminosides (e.g. streptomycin, gβrttaπiϊcϊn, amikacin, dibekacin), polypeptides (e.g. polymyxin, colistin, bacitracin), macrolides (e.g. erythromycin A, clarithromycin, azithromycin, spiramycin, josamycin), streptøgramins-synergistins (e.g. pristinamycin, quinupristin, dalfopristin), Hncosamides (e.g. lincomycin, clindamycin), tetracyclines (e.g. tetracycline, doxycycline, minocycline), cyclines (tigecycline), chloramphenicols (e.g. chloramphenicol, thiamphenicol), quinolones (e.g. ciprofloxacin, levofloxacin, moxifloxacin, gemifloxacin, garenoxacin), rifamycins (e.g. rifampicin), nitro-imidazoles and nitrofurans (metronidazole, tinidazole, nitrofurantoin), oxazolidinones (linezolid) or lipodepsipeptides (daptomycin).

According to another aspect of the invention, the compound of formula (I), or one of its salts of addition with a pharmaceutically acceptable acid or one of its solvates or hydrates and the other combined active principle can be administered simultaneously, separately or spread over time.

"Simultaneous use" means the administration of the compounds of the composition according to the invention, comprised in one and the same pharmaceutical form.

"Separate use" means the administration, at the same time, of the two compounds of the composition according to the invention, each contained in a separate pharmaceutical form.

"Use spread over time" means the successive administration, with a time delay, of the compound of formula (I) according to the invention, or respectively of one or more other active principles, in a first pharmaceutical form, then of one or more other active principles, or respectively of the compound of formula (I) according to the invention, in the same pharmaceutical formulation or in a different pharmaceutical formulation, the administration of the other active principle(s) generally taking place not more than 24 h after administration of the first compound.

EXAMPLES The following EXAMPLES describe the preparation of some compounds according to the invention. These examples are nonlimiting and are only for illustrating the present invention.

The following abbreviations are used in the preparations and in the examples:

DMSO: dimethylsulfoxide DMF: N,N-dttnethytformamide

MS: mass spectrometry

DCI: Desorptlon Chemical Ionization

ES: Electrospray

MP: melting point Dec: decomposition HPLC: high-performance liquid chromatography

Theor: theoretical

Exp: experimental

MIC: minimum inhibitory concentration CFU: colony forming unit log: decimal logarithm

Δlog: difference of decimal logarithms

MSSA: methicillin-susceptible Staphylococcus aureus

MRSA: methidllin-resistant Staphylococcus aureus h-VISA: Staphylococcus aureus with hetero-intermediate sensitivity to vancomycin

SCNMS: Staphylococcus coagulase-negative methicillin-sensitive

SCNMR: Staphylococcus coagulase-negative methicillin-resistant

Vanco: vancomycin

Teico: teicoplanin Line: linezolid

Dapto: daptomycin

Tela: telavancin

CD ₅₀ : curative dose 50% (dose enabling 50% of the animals to be cured)

The proton nuclear magnetic resonance spectra ( ¹ H NMR) are recorded in DMSO-dβ or CDCI ₃ . The chemical shifts δ are expressed in parts per million (ppm). The following abbreviations are used for interpreting the spectra: s: singlet, d: doublet, t: triplet, q: quadruplet, quint: quintuplet, m: multiplet, dd: doublet of doublets, dt: doublet of triplets.

The compounds of formula (I) according to the invention can be purified by preparative high-performance liquid chromatography. The column used is Interchim STRATEGY C18-2 of 50 x 400 mm, 10 μm, flow: 80 to 100 mL, in isocratic conditions using an eluent composed of water, acetonitrile and trifluoroacetic acid (0.5%).

Example 1: PA1525 N-4-[4-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-butyl] -vancomycin

1.1. 4,7-Dichloro-2-trifluoromethylquinoline

A suspension under argon of 7-chloro-4-hydroxy-2-trifluoromethylquinoline (30 g,

0,12 mol) in 44 mL of POCI ₃ (0.48 mol) is heated at 110 ⁰ C for 2 hours. After cooling to room temperature, the POCI ₃ is removed by distillation. The product is dried under vacuum and then neutralized in ammonia solution at 0 ⁰ C. 200 mL of ethyl acetate is 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 under vacuum. The product is obtained in the form of a brown solid (27.6 g, 86%). ¹ H NMR (300 MHz, DMSO) δ ppm: 7.20 (IH, Uu ₁ J = 9.0 Hz, J = 2.1 Hz), 7.82 (IH, s), 8.24 (IH, d, J = 9.0 Hz), 8.25 (IH, s). MS (DCI/CH ₄ >0) m/z: 266 (M+H ⁺ ).

1.2. (7-Chloro-2-trifluoromethyIquinolin-4-yl)-(4,4-diethoxybutyl )amine

A suspension under argon 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 ⁰ C for 18 h. After cooling to room temperature, the reaction mixture is diluted with 150 mL of dichloromethane and 150 mL of a solution of 5% carbonated water. 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 under vacuum. 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, CDCI 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 (IH, t, J = 5.1 Hz),

5.78 (IH, m), 6.69 (IH, s), 7.43 (IH, dd, J = 9.0 Hz, J = 2.1 Hz), 7.72 (IH, d, J = 9.0 Hz), 8.06 (IH, d, J = 2.1 Hz). MP: 85°C. MS (ES>0) m/z: 391.3 (M+H ⁺ ).

1.3. 4-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-butyraldehy de

21.3 mL of trifluoroacetic acid (0.29 mol) is added to a solution of (7-chloro-2- trifluoromethylquinolin-4-yl)-(4,4-dϊethoxybutyl)amine (example 1.2) (8.0 g, 0.02 mol) in 110 mL of 80% aqueous solution of acetic acid. The mixture is stirred at room temperature for 1.5 h. The medium is cooled to 0 ⁰ C and diluted with distilled water. The pH of the solution is then adjusted to pH 6 by adding a solution of 5% carbonated water. The product is then filtered. The white precipitate is washed with millϊQ water, then twice with heptane. The solid, dried 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, J= 6.9 Hz), 6.83 (IH, s), 7.61 (IH, d, J= 9.0 Hz), 7.94 (IH, s), 8.37 (IH, d, J = 9.0 Hz), 9,72 (IH, s), MS (DCI/CH ₄ >0) m/z: 317 (M+H ⁺ ). MP: 134°C, MS (DQ/CH ₄ >0) m/z: 317,1 (M+H ⁺ ), 1,4. N^-^-^-Chloro^-trifluorσmethytquinolin^-ylaminoJ-butγO-van comycin; PA1525

33 mL of N,N-diisopropylethytamine (201 mmol) is injected into a solution under argon of vancomycin monohydrochloride (9.9 g, 6.7 mmol) and 4-(7-chloro-2- trifluoromethyl-quinoIin-4-ylamino)-butyraldehyde (example 1.3) (2.7 g, 8.7 mmol) in 550 mL of anhydrous dimethylformamide. After stirring for 1.5 h at room temperature, 550 mL of anhydrous methanol is added to the mixture. Then 1.7 g of sodium cyanoborohydride (27.0 mmol) and 22 mL of trifluoroacetic acid (302 mmol) are added successively to the mixture. The mixture is stirred for 20 h at 50 ⁰ C. After checking the reaction with HPLC, the reaction mixture is concentrated in a rotary evaporator to approx. 300-400 mL. The solution that remains is precipitated by slowly adding 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 again 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. The fractions of purity >96% are combined and lyophilized. The lyophilizate is redissolved in 400 mL of water and desalted by passage over PL-HCO ₃ ion-exchange resin. After freeze-drying, PA1525 is obtained in the form of a white lyophilizate (0.8 g, 6%, purity: 98%). ¹⁹ F NMR (300 MHz, 296 K, DMSO), ppm: -66.69 (3F, s), MP: 199°C (dec.) MS (ES>0) m/z: 1750.7 (M+H ⁺ ), 875.7 (M+2H ⁺ ). Elemental analysis: for C ₈₀ H ₈₇ CI ₃ F ₃ N ₁₁ O ₂₄ ^OH ₂ Oi ⁰ Zo theor. C 50.24, H 5.54, N 8.06; % exper. C 50.24, H 5.52, N 8.00.

Example 2: PA1525A

N-4-[4-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-but yl]-vancomycin x.hydrochloride (x = 0.7) The desalted product PA1525 (example 1.4) is suspended in water and the pH is adjusted to 4.5 by addition of HCI 0.1N at room temperature (final concentration of PA1525: 30 g/L). After 4 hours of stirring, the solution is lyophylized. PA1525A is obtained in the form of a white lyophilizate. ¹⁹ F NMR (300 MHz, DMSO) δ ppm: -66.66 (3F, s), MP: 210 ⁰ C (dec.) MS (ES>0) m/z: 1750.7 (M+H ⁺ ), 876.0 (M+2H ⁺ ). Elemental analysis: for C ₈₀ H ₈₇ CI ₃ F ₃ N ₁₁ O ₂₄ -ISJ H ₂ G'0.74 HCI: % theor. C 47.40, H 5.74, N 7.60; % exper. C 47.43, H 5.83, N 7.55.

Example 3: PA1409 N-4-[4-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-butyl] -vancomycin x.hydrochloride (x = 2)

The desalted product PA1525 (example 1.4) (0.8 g, 0.4 mmol) is acidified at 0 ⁰ C with 2 equivalents of 0.1N hydrochloric acid (7.8 mL, 0.8 mmol). After lyophilization,

PA1409 is obtained in the form of a white lyophilizate (0.8 g, 98%, purity; 98%). ¹ H NMR (500 MHz, 298 K, DMF), ppm: 0.93 (3H, d, J = 6.0 Hz), 1.01 (3H, d, J = 5.9 Hz), 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 (IH, s broad), 3.23 (IH, s broad), 3.67-3.76 (4H, m), 3.82 (IH, m) 4.13 (IH, s broad), 4.20 (2H, t large, J = 5.8 Hz), 4.53 (IH, d, J = 12.3 Hz), 4.74 (IH, d, J = 5.6

Hz), 4.77 (IH, d, J = 5.8 Hz), 4.84 (IH, q, J = 6.5 Hz), 4.96 (IH, s broad), 5.33 (2H, s), 5.46 (3H, m), 5.60 (2H, m), 5.81 (IH, s broad), 5.90 (IH, s), 6.02 (IH, d, J = 7.4 Hz),

6.39 (IH, s broad), 6.49 (IH, d, J= 2.1 Hz), 6.52 (IH, d, J= 5.6 Hz), 6.63 (IH, m), 6.66

(IH, ά, J = 2.1 Hz), 6.84 (IH, d, J = 8.5 Hz), 6.87 (IH, s), 6.91 (IH, d, J = 9.5 Hz), 7.17

(IH, s broad), 7.23 (IH, s), 7.46 (IH, d, J = 8.5 Hz), 7.48 (IH, d, J = 8.5 Hz), 7.62 (IH, dd, J = 2.2 Hz, J = 9.1 Hz), 7.66 (2H, t, J = 8.2 Hz), 7.74 (IH, s broad), 7.96 (IH, d, J = 2.2 Hz), 8.02 (IH, d, J = 1.5 Hz), 8.29 (IH, t broad), 8.45 (IH, s broad), 8.57 (IH, d, J =

5.7 Hz), 8.76 (IH, d, J = 9.1 Hz), 8.86 (IH, s broad), 9.18-9.35 (4H, m), 9.74 (IH, s).

MP: 186°C (dec.) MS (ES>0) m/z: 1750.5 (M+H ⁺ ), 875.8 (M+2H ⁺ ). Elemental analysis: for C ₈₀ H ₈₇ Cl ₃ F ₃ N _u O ₂₄ -2HCI-11.6H ₂ O:% theor. C 47.27, H 5.57, N 7.58; % exper. C 47.27,

H 5.56, N 7.60.

Example 4: PA1389

N-4-[4-(8-Fluoro-2-trifluoromethylquinolin-4-ylamino)-but yl]-vancomycin dihydrochloride

4.1. 4-ChIoro-8-fiuoro-2-trifluoromethylquinoline This compound is prepared according to the procedure described in example 1.1 from 9.6 g of 8-fluoro-4-hydroxy-2-trifiuoromethylquinoline (0.04 mol) in 39 mL of POCI ₃ (0.42 mol). The product is obtained in the form of a white powder after recrystallization from methanol/water (9.0 g, 88%), ¹ H NMR (300 MHz, DMSO) δ ppm: 7.93 (2H, m), 8.15 (IH, dd, J = 8.6 Hz, J = 1.0 Hz), 8.41 (IH, s). MS (DCI/NH ₃ >0) m/z: 250.1 (M+H ⁺ ).

4.2. 4-(8-Fluoro-2-trifluoromethylquinolin-4-ylamIno)-butan-l-ol

A suspension under argon of 4-chlørø-8-fluoro-2-trifIuoromethylquinoline (example 4,1) (9,0 g, 0,04 mol), In 10 mL of 4-aminobutan-l-ol (0.11 mol) is heated at 150 ⁰ C for 2.5 h. After cooling to room temperature, the reaction mixture is triturated with 100 mL of a 10% aqueous NaOH solution. The pasty yellow solid obtained is filtered and washed with water. The product is obtained after recrystallization from ethanol/water in the form of a yellow powder (8.8 g, 80%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.55 (2H, m), 1.72 (2H, m), 3.35-3.49 (4H, m), 4.73 (IH, t, J = 5.1 Hz), 6.82 (IH, s), 7.52-7.59 (2H, m), 7.87 (IH, t broad), 8.15 (IH, d, J = 7.5 Hz). MS (DCI/NH ₃ >0) m/z: 303.1 (M+H ⁺ ).

4.3. 4-(8-Fluoro-2-trifluoromethylquinoIin-4-ylamino)-butyraIdehy de

A solution of dimethylsulfoxide (2.1 mL, 29.0 mmol) in 7 mL of anhydrous dichloromethane is slowly added to a solution under argon of oxalyl chloride (1.3 mL, 14.5 mmol) in 33 mL of anhydrous dichloromethane cooled to -60°C. The mixture is stirred for 10 minutes at -60 ⁰ C. The 4-(8-fluoro-2-trifluoromethy!quinolin-4-y!amino)- butan-1-ol (example 4.2) (4.0 g, 13.2 mmol) is added to this mixture cooled to -70 ⁰ C. The suspension obtained is stirred for 30 min at -60 ⁰ C before adding 9.2 mL of triethylamine (66.0 mmol). The solution obtained is stirred for 10 min at -10 ⁰ C. The reaction is then quenched by adding 160 mL of water followed by 160 mL of chloroform. The aqueous phase is separated and reextracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous NaCI solution and then dried over magnesium sulfate before being concentrated to dryness under vacuum. The product is obtained in the form of a yellow-orange powder (3.8 g, 96%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.92 (2H, quint, J = 7.2 Hz), 2.62 (2H, t, J = 6.9 Hz), 3.40 (2H, m), 6.89 (IH, s), 7.50-7.62 (2H, m), 7.92 (IH, t, J = 5.4 Hz), 8.15 (lH.dd, J = 7.5 Hz, J = 1.2 Hz), 9.72 (IH, s). MS (DCI/NH ₃ >0) m/z: 301.2 (M+H ⁺ ).

4.4. N-4-[4-(8-Fluoro-2-trifluoromethylquinolin-4-ylamino)-butyl] -vancomycin dihydrochloride: PA1389

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-ylamino)-butyraldehyde (example 4.3) (12.6 mmol), 4.4 mL of diisopropylethylamine (25.2 mmol), 2.4 g of sodium cyanoborohydride (37.8 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 lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacfdified as described in example 3 with 2 equivalents of 0.1N hydrochloric acid at 0 ⁰ C, After lyophϊlization, PA1389 is obtained in the form of a white lyophϊlizate (0.8 g, 5%, purity: >97%). MS (ES>0) m/z: 1732.9 (M+H ⁺ ), 888.0 (M+2H ⁺ ). Elemental analysis: for C ₈ oH ₈₇ α ₂ F ₄ N ₁₁ θ ₂₄ -2HCl-7.8H ₂ 0;% theor. C 49.36, H 5.42, N 7.91;% exper. C 49.36, H 5.55, N 7.85.

Example 5: PA1402

N-4-[4-(2-PhenyIquinolin-4-yiamino)-butyl]-vancomydn dihydrochloride

5.1. 4-(2-Phenylquinolin-4-yIamino)-butan-l-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-l-ol (0.13 mol). The product is obtained after recrystallization from ethanol/water in the form of 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 (IH, t, J = 5.1 Hz), 6.97 (IH, s), 7.19 (IH, t, J = 5.4 Hz), 7.38-7.53 (4H, m), 7.62 (IH, dt, J = 8.4 Hz, J = 1.2 Hz), 7.85 (IH, dd, J = 8.4 Hz, J = 0.9 Hz), 8.19 (2H, dd, J = 8.4 Hz, J= 1.2 Hz), 8.23 (IH, d, J = 7.8 Hz). MS (DCI/NH ₃ >0) m/z; 293.3 (M+H ⁺ ).

5.2. 4-(2-PhenyIquinolin-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-l-ol (example 5.1) (13.0 mmol), 1.25 ml_ of oxalyl chloride (14.4 mmol), 2.0 rnL 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, 100%). ¹ H NMR (300 MHz, DMSO) δ ppm; 1.98 (2H, quint, J = 6.9 Hz), 2.65 (2H, t, J= 6.9 Hz), 3.42 (2H, m), 7.03 (IH, s), 7.22 (IH, m), 7.38-7.60 (4H, m), 7.63 (IH, m), 7.85 (IH, m), 8.22 (3H, m), 9.75 (IH, s).

5.3. N-4-[4-(2-Phenylquinolin-4-ylamino)-butyl]-vancomycin dihydrochloride: PA1402 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)-butyraldehyde (example 5.2) (13.4 mmol), 4.7 niL of N,N-diisopropylethylamine (27.0 mmol), 2.5 g of sodium cyanoborohydride (40.0 mmol) and 3.1 mL of trifluoroacetic acid (40.0 mmol). The product is purified by preparative HPLC, The fractions of purity >96% are combined and lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacidifled as described in example 3 with 2 equivalents of 0.1 N hydrochloric acid at 0 ⁰ C, After lyophllization, PA1402 is obtained In the form of a white lyophilizate (0,5 g, 3%, purity: >99%). MS (ES>0) m/z: 1723.1 (M+H ⁺ ), 863.0 (M+2H ⁺ ). Elemental analysis: for C ₈₅ H ₉₃ Cl ₂ N ₁₁ O ₂₄ ^HC)" 13H ₂ O:% theor. C 50.29, H 6.00, N 7.59;% exper. C 50.30, H 5.81, N 7.45.

Example 6: PA1418 N-4-[4-(2-Methylquinolin-4-ylamino)-butyl]-vancomydn dihydrochloride

6.1 (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 diethylaceta! (0.20 mol). The product is obtained after precipitation in dichloromethane/pentane in the form of a light beige powder (22.5 g, 100%). ¹ H NMR

(300 MHz, DMSO) 6 ppm: 1.10 (6H, t, J = 6.9 Hz), 1.68 (4H, m), 2.46 (3H, s), 3.26 (2H, m), 3.42 (2H, m), 3.55 (2H, m), 4.52 (IH, t, J = 5.1 Hz), 6.34 (IH, s), 7.01 (IH, t, J = 5.1 Hz), 7.32 (IH, dt, J = 6.9 Hz, J = 1.2 Hz), 7.53 (IH, dt, J = 6.9 Hz, J = 1.2 Hz), 7.68

(IH, dd, J = 8.4 Hz, J = 0.9 Hz), 8.15 (IH, d, J = 8.1 Hz). MS (DCI/NH ₃ >0) m/z: 303.5

(M+H ⁺ ).

6.2 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 6.1) (0.04 mol), 218 mL of a 80% aqueous solution of acetic acid and 42.8 mL of trifluoroacetic acid (0.55 mol). The product is obtained in the form of a yellow oil (10 g, 100%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.93 (2H, quint, J = 7.5 Hz), 2.61-2.66 (5H, m), 3.49 (2H, q, J = 6.6 Hz), 6.80 (IH, s), 7.63 (2H, m), 8.43 (IH, d, J = 8.4 Hz), 9.10 (IH, t, J = 5.4 Hz), 9.72 (IH, t, J = 0.9 Hz).

6.3 N-4-[4-(2-Methylquinolin-4-ylamino)-butyl]-vancomycin dihydrochloride: PA1418 PA1418 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-methnylquinoIin~4- ylamino)-butyraldehyde (example 6.2) (27.0 mmol), 56.4 mL of N,N- diisopropylethylamine (324.0 mmol), 3.0 g of sodium cyanoborohydride (48.5 mmol) and 37,5 mL of trifluoroacetic acid (486.0 mmol). The product is purified by preparative HPLC, The fractions of purity >9δ% are combined and lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacidified as described in example 3 with 2 equivalents of Q, IN hydrochloric acid at 0 ⁰ C. After lyophitization, PA1418 is obtained in the form of a white lyophilizate (0.7 g, 4%, purity: >97%). MS (ES>0) m/z: 1661.1 (M+H ⁺ ), 831.5 (M+2H ⁺ ). Elemental analysis: for C ₈₅ H _9I CI ₂ N ₁₁ O ₂₄ -ZHCI- 12H ₂ O:% theor. C 49,24, H 6.05, N 7.90;% exper. C 49.26, H 5.54, N 7.71.

Example 7: PA1398

N-4-{4-[Ethyl-(2-methylquinolin-4-yl)amino]-butyl}-vancom ycin dihydrochloride. 7.1 4-[Ethyl-(2-methylquinolin-4-yl)amino]-butan-l-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 4-ethylaminobutan-l-ol (0.11 mol). The product is obtained in the form of a brown oil (21.9 g, 100%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.08 (3H, t, J = 6.9 Hz), 1.49 (2H, m), 1.55 (2H, m), 2.56 (3H, s), 3.23- 3.40 (6H, m), 4.38 (IH, t, J = 5.1 Hz), 6.88 (IH, s), 7.43 (IH, dt, J= 6.9 Hz, J = 1.5 Hz), 7.60 (IH, dt, J= 6.9 Hz, J = 1.5 Hz), 7.82 (IH, dd, J = 8.4 Hz, J= 1.2 Hz), 7.95 (IH, dd, J= 8.4 Hz, J = 1.2 Hz). MS (DCI/NH ₃ >0) m/z: 259.2 (M+H ⁺ ).

7.2. 4-[Ethyl-(2-methylquinolin-4-yl)arnino]-butyraldehyde This product is prepared according to the procedure described in example 2.3 from

6.O g of 4-[ethyl-(2-methylquinolin-4-yl)amino]-butan-l-ol (example 7.1) (23.0 mmol), 2.2 mL 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) 6 ppm: 1.07 (3H, t, J = 6.9 Hz), 1.78 (2H, quint, J= 6.9 Hz), 2.48 (2H, m), 2.57 (3H, s), 3.28 (4H, m), 6.93 (IH, s), 7.44 (IH, dt, J = 6.9 Hz, J= 1.5 Hz), 7.61 (IH, dt, J = 6.9 Hz, J= 1.5 Hz), 7.83 (IH, dd, J= 8.4 Hz, J = 0.9 Hz), 7.94 (IH, dd, J = 8.4 Hz, J = 0.9 Hz), 9.61 (IH, t, J = 1.2 Hz). MS (DCI/NH ₃ >0) m/z: 257.2 (M+H ⁺ ).

7.3. N-4-{4-[Ethyl-(2-methylquinolin-4-yI)amino]-butyl}-vancomyci n dihydrochloride: PA1398

PA1398 is prepared according to the procedure described in example 1,4 from 23.8 g of vancomycin monohydrochloride (16.1 mmol), 6.2 g of 4-[ethyl-(2- methyIquinolin-4-yl)amino]-butyraldehyde (example 7.2) (24,2 mmol), 62,0 mL of N,N- diisopropyfethytamine (480.0 mmol), 4.1 g of sodium cyanoborohydride (64.0 mmol) and 53.5 mL of trifiuoroacetic acid (720.0 mmol). The product is purified by preparative HPLC. The fractions of purity >96% are combined and lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacidified as described in example 3 with 2 equivalents of 0.1N hydrochloric acid at O ⁰ C. After lyophilization, PA1398 is obtained in the form of a 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 CI ₂ N _u O ₂₄ -2HCI-10.8H ₂ O:% theor. C 50.52, H 6.11, N 7.87;% exper. C 50.50, H 5.65, N 7.73.

Example 8: PA1580

N-4-[6-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-hex yl]-vancomycin dihydrochloride.

8.1. 6-(7-Chloro-2-trifluoromethylquinolin-4-yl)amino]-hexan-l-ol This product is prepared according to the procedure described in example 2.2 from

5.0 g of 4,7-dichloro-2-trifluoromethylquinoline (example 1.1) (0.02 mol) and 6.6 g of 6- aminohexan-1-ol (0.06 mol). The product is obtained in the form of a beige powder (6.1 g, 92%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.41 (6H, m), 1.67 (2H, m), 3.36 (4H, m), 4.34 (IH, m), 6.74 (IH, s), 7.59 (IH, dd, J = 9.0 Hz, J = 2.1 Hz), 7.83 (IH, m), 7.92 (IH, d, J = 2.1 Hz), 8.38 (IH, d, J = 9.0 Hz). MS (DCI/NH ₃ >0) m/z: 347.1 (M+H ⁺ ).

8.2. 6-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)-hexanal

This product is prepared according to the procedure described in example 2.3 from 5.3 g of 6-(7-chloro-2-trifIuoromethylquinolin-4-yl)amino]-hexan-l-ol (example 8.1) (15,4 mmol), 1.5 mL of oxalyl chloride (17.0 mmol), 2.4 mL of dimethylsulfoxide (33,9 mmol) and 10.7 mL of triethylamine (77.0 mmol). The product is obtained in the form of a yellow powder (5.5 g, 100%). ¹ H NMR (300 MHz, DMSO) δ ppm: 1.41 (2H, m), 1.82 (4H, m), 2.54 (2H, td, J = 6.9 Hz, J = 1.5 Hz), 3,41 (2H, t, J = 6,9 Hz), 6.0 (IH, broad s), 6.71 (IH, s), 7,44 (IH, dd, J = 9.0 Hz, J = 2.1 Hz), 7.90 (IH, d, J = 2.1 Hz), 8.13 (IH, ά, J = 9.0 Hz), 9.82 (IH, t, J = 1.5 Hz). MS (DCI/NH ₃ >0) m/z: 345.0 (M+H ⁺ ).

8.3. N-4-[6-(7-Chloro-2-trifluoromethylquirtolin-4-ylamino)-hexyl ]-vancomycin dihydrochloride: PA1580,

PA1580 is prepared according to the procedure described in example 1.4 from 15.9 g of vancomycin monohydrochloride (11,0 mmol), 4.8 g of 6-(7-chloro-2- trifluoromethy!quinolin-4-ylamino)-hexyraldehyde (example 8.2) (14.0 mmol), 5.4 mL of N,N-diisopropylethylamine (33.0 mmol), 7.8 mL of N,N-dϊethy!aniline borane complex (44.0 mmol) and 3.7 mL of trifluoroacetic acid (50.0 mmol). The product is purified by preparative HPLC. The fractions of purity >96% are combined and lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacidified as described in example 3 with 2 equivalents of 0.1 N hydrochloric acid at 0 ⁰ C. After lyophilization, PA1580 is obtained in the form of a white lyophilizate (4.4 g, 21%, purity: 98%). MS (ES>0) m/z: 1779.3 (M+H ⁺ ), 889.8 (M+2H ⁺ ). Elemental analysis: for C ₈₂ H ₉₁ Cl ₃ F ₃ N ₁₁ O ₂₄ ^HCI- 14.4H ₂ O:% theor. C 46.67, H 5.82, N 7.30;% exper. C 46.94, H 6.25, N 7.09.

Example 9: PA1581

N-4-{2-[l-(7-Chloro-2-trifluoromethylquinolin-4-ylamino)- piperidin-4-yl]-ethyl}- vancomycin dihydrochloride.

9.1. 2-[l-(7-Chloro-2-trifluoromethylquinolin-4-yl)-piperidin-4-y l]-ethanol

This product is prepared according to the procedure described in example 2.2 from 6.9 g of 4,7-dichloro-2-trifluoromethylquinoline (example 1.1) (0.03 mol) and 4.0 g of 2- (piperidin-4-yl)-ethanol (0.04 mol). The product is obtained in the form of a white powder (7.1 g, 76%). ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm: 1.58 (2H, m), 1.70 (2H, q, J = 6.3 Hz), 1.79 (IH, m), 1.95 (2H, m), 2.00 (IH, broad s), 2.99 (2H, t, J = 12.0 Hz), 3.70 (2H, d, J = 12.0 Hz), 3.82 (2H, t, J = 6.3 Hz), 7.11 (IH, s), 7.50 (IH, dd, J = 9.0 Hz, J = 1.8 Hz), 7.93 (IH, U ₁ J= 9.0 Hz), 8.24 (IH, d, J= 1.8 Hz). MS (DCI/NH ₃ >0) m/z: 359.1 (M+H ⁺ ).

9.2. [l-(7-Chloro-2-trifluoromethylquinolin-4-yl)-piperidin-4-yl] -acetaldehyde

This product is prepared according to the procedure described in example 2.3 from

7.1 g of 2-[l-(7-chIoro-2-trifluoromethylquinolin-4-yI)-piperidin-4-y l]-ethanol (example 9.1) (19.7 mmol), 1.9 mL of oxalyl chloride (21.7 mmol), 3.1 mL of dϊmethylsutfoxide (43.4 mmol) and 13,5 mL of triethylamine. The product is obtained in the form of a light beige powder (6.3 g, 89%). ¹ H NMR (300 MHz, CDCI ₃ ) δ ppm: 1.68 (2H, m), 1.98 (2H, broad ύ, J = 12.9 Hz), 2.21 (IH, m), 2.55 (2H, m), 3.03 (2H, t, J = 12.3 Hz), 3.65 (2H, broad d, J = 12.3 Hz), 7.11 (IH, s), 7.50 (IH, dd, J = 9.0 Hz, J = 1.8 Hz), 7.93 (IH, d, J = 9.0 Hz), 8,24 (IH, ά, J= 1.8 Hz), 9.86 (IH, s). 9.3, N-4-{2-[i-(7-ChIoro-2-trifluoromethy!quinolin-4-ylamino)-pip erIdin-4-yl]-ethyl}- vancomycin dlhydrochloride: PA1581.

PA1581 is prepared according to the procedure described in example 1.4 from 8.0 g of vancomycin monohydrochloride (5.4 mmol), 2,1 g of [l-(7-chloro-2- tr!fIuoromethylquinoIin-4-yl)-piperidin-4-yI]-acetaIdehyde (example 9.2) (5.9 mmol),

2.7 mL of N,N-diisopropylethylamine (16.2 mmol), 3.8 mL of N,N-diethylaniline borane complex (21.5 mmol) and 1.8 mL of trifluoroacetic acid (24.2 mmol). The product is purified by preparative HPLC. The fractions of purity >96% are combined and lyophilized before being desalted by passing over PL-HCO ₃ ion-exchange resin. The desalted product is then reacidifled as described in example 3 with 2 equivalents of 0.1N hydrochloric acid at 0°C. After lyophilization, PA1581 is obtained in the form of a white lyophilizate (2.6 g,

22%, purity: 98%). MS (ES>0) m/z: 1789.2 (M+H ⁺ ), 895.8 (M+2H ⁺ ). Elemental analysis: for C ₈₃ H ₉₁ CI ₃ F ₃ N ₁₁ O ₂₄ ^HC)- 14.0H ₂ O:% theor. C 47.12, H 5.77, N 7.28;% exper. C 47.12,

H 5.75, N 7.19.

Example 10: Bactericidal action against Staphylococcus aureus MRSA (isolate mR) at 1 μg/mL in the presence of 50% of human serum (Δlog CFU)

The MICs were determined in Muller Hinton liquid medium (Difco) after 24 h with stirring at 37°C. In the case of daptomycin, 50 mg/L of CaCI ₂ was added.

For the bactericidal action, the concentrations of test products were obtained in Muller Hinton liquid medium (10 mL) in the presence of 50% of human serum AB+. 50 mg/L of CaCI ₂ was added in the case of daptomycin. The various test tubes, as well as a tube without test product, were inoculated with a bacterial suspension adjusted to 10 ⁷ bacteria/mL (1% in final concentration). After homogenization, a count was carried out (TO). The tubes were incubated at 37°C, with stirring. Samples were taken at T7h and T24h for counting the residual viable bacteria. The counts were performed by inclusion seeding (agar Trypcase-soya) of 1 mL of serial dilutions at a ratio of 10, The CFUs were counted after 24 h to 48 h of incubation at 36±1°C. Table 1: Bactericidal action on Staphylococcus aureus MRSA (isolate mR) at 1 μg/mL in the presence of 50% of human serum

Like the vancomyquines ^® described in patents FR 2874922, WO 2006024741 and US 20070060558, the vancomyquines® of formula (I) according to the invention display very low MICs with respect to methicillin-resistant Staphylococcus aureus. The values of these MICs are all lower than those of the comparators currently on the market.

The bactericidal action of the compounds of formula (I) is remarkable. At just 1 μg/mL and in the presence of 50% of human serum, the vancomyquines® according to the invention are capable of reducing, by more than 4 log, the bacterial population of a strain of Staphylococcus aureus MRSA in 24 h. The presence of a substituent R ^la in position 2 on the quinoline is indispensable for achieving the bactericidal action (-3log) in

24 h (PA1274 and PA1275 compared with PA1246 and PA1276). The presence of another substituent R ^lb does not diminish the activity of the vancomyquines® (PA1385). Finally the reduction of 4 log is achieved with a Y type bond not containing an aromatic nucleus between the vancomycin and the aminoquinoline (see PA1418, PA1398, PA1402, PA1389, PA1409, PA1580 and PA1581).

Example 11: Efficacy in vivo

The in vivo efficacy of a vancomyquine according to the invention: vancomyquine PA1409, was tested in a murine model of septicemia due to a strain of methicϊllin- resistant Staphylococcus aureus (ATCC33592), The mice (Swiss), 6 to 7 weeks old, were inoculated intraperitoneally with 200 μL of a bacterial suspension in 5% gastric mucin (inoculum 7xlO ⁷ CFU/mouse) (DO). Vancomyquine PA1409 was then administered intravenously 1 h and 4 h post-infection at the following doses: 1 - 5 - 10 mg/kg/d in solution in 5% glucose (i.e. 2x0.5 - 2x2,5 - 2x5 mg/kg/d). The survival of the mice (6 mice/dose) was monitored up to D4 to determine the dose enabling 50% of the mice to be cured (CD ₅₀ ). An additional group of 5 mice per dose was used for counting the bacteria present in the blood. This sample was taken 5 h post-infection and inoculated in agar trypcase-soya for counting at 24 h.

Table 2: In vivo efficacy in a murine model of septicemia due to Staphylococcus aureus MRSA

The vancomyquines® according to the invention are also very effective in vivo. In fact, in a murine model of septicemia due to Staphylococcus aureus MRSA, vancomyquine PA1409 is able to cure 100% of mice at only 5 mg/kg whereas at 10 mg/kg, 100% cure is not yet achieved with vancomycin. The curative dose to achieve 50% cure is more than

5 times lower for vancomyquine PA1409 than for vancomycin. Moreover, at 5 mg/kg the compound according to the invention makes it possible to reduce bacteremia by more than 3 log (bactericidal action at ΔCFU > -3log) whereas vancomycin is not bactericidal at 10 mg/kg.

Example 12:

MICs with respect to a panel of Gram+ bacteria

The MICs were determined by the method of dilution in agar (method CLSI/CA- SFM). The inocula were adjusted to a turbidity of 0.5 McFarland and diluted to 1/100 (except for the streptococci, diluted to 1/10), Inoculation was carried out with the Steers apparatus, supplying 10 ⁴ CFU per spot. The medium was an agar medium from Muller Hinton (BioMerieux). In the case of daptomycin, the media were supplemented with calcium chloride (30 mg/L). The ranges were from 0.008 to 256 μg/mL, except for vancomyquine PA1409 for which the upper concentration tested was 32 μg/mL. The incubations were carried out at 37 ⁰ C and the MICs were read at 24 h.

Bacterial strains: Staphylococcus aureus MSSA (clinical isolate VA010), Staphylococcus aureus MRSA CCUG 31966 (VA064), Staphylococcus aureus h-VISA

MU3 ATCC 700698 (VA033), Staphylococcus CNSMS (clinical isolate VA016),

Staphylococcus CNSMR (clinical isolate VA018), 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 (μg/mL) with respect to a panel of Gram+ bacteria

The antibacterial activity of the vartcomyquines® according to the invention is not limited to MRSA. In fact, as can be seen from table 3, vancomyquine PA1409 gives very low MICs with respect to a panel of Gram+ bacteria.

Example 13: Acid salts of vancomyquines®

Vancomyquines ^® can be prepared in the form of bases or of salts of addition to acids to modulate their hydrosolubility. For example, salts of acetic, ascorbic, benzenesulfonic, benzoic, hydrobromic, camphosulfonic, hydrochloric, citric, ethanesulfonic, fumaric, gluconic, glucuronic, glutamic, lactic, lactobionic, maleic, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acids can be easily produced without any intention to limit to a particular list of salts. Salts of acetic, hydrochloric, citric, fumaric, glucuronic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric acids were produced. From 0.1 to 5 equivalents of acid can be added to the vancomyquine base form. Two examples of acid addition salts are shown in table 4 with their corresponding pH values, hydrosolubility, MICs and bactericidal activity. The desalted product PA1525 (base form) and the hydrochloric acid salts PA1525A and PA1409 were prepared according to examples 1, 2 and 3 respectively. The pH values were determined in 30 mg/mL aqueous solutions. MICs were determined were determined in Muller Hinton liquid medium (Difco) after 24 h with stirring at 37°C. Bactericidal activities against a clinical strain of Staphylococcus aureus MRSA (isolate mR) at 1 μg/mL in the presence of 50% of human serum (Δlog CFU) were determined as in example 10. Δlog CFU were determined at T24h.

Table 4: Characteristics of acid addition salts of a vancomyquine

Two examples of acid addition salts are shown in table 4. While the base form of vancomyquine PA1525 is insoluble in water, addition of 0.7 or 2 equivalents of hydrochloric acid allows to achieve hydrosolubility and a good antibacterial activity.

Accordingly, this example shows that soluble compounds can be prepared at least to test the bactericidal activity and to the administration in vϊyø, if needed. Furthermore, this example shows that the bactericidal activity remains constant for different salts of a compound.

Example 14: Examples of pharmaceutical compositions

The following examples present nonlimiting examples of pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof or one of its solvates or hydrates according to the invention, for parenteral administration.

14.1 Example of pharmaceutical composition A: liquid formulation

An injectable preparation containing the following components can be prepared: Ingredients Quantity

Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g

Aqueous solution, 5% glucose, sterile q.s. 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 powder or of lyophilizate, is dissolved in a sterile 5% glucose aqueous solution. The formulation is stored cold (for example from 4 to 6°C).

14.2 Example of pharmaceutical composition B: liquid formulation

Another example of an injectable preparation contains the following components: Ingredients Quantity

Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g

Hydroxypropyl-β-cyclodextrin 0.1 to 25 g

Aqueous solution, 5% glucose, sterile q.s. 10 to 100 ml_ The hydroxypropyl-β-cyclodextrin is dissolved in the sterile 5% glucose aqueous solution. The compound according to the invention is then dissolved in this preparation. The formulation is stored cold (for example from 4 to 6°C).

14.3 Example of 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 salts of addition to a pharmaceutically acceptable add or a solvate or a hydrate. For parenteral administration, just before use, a solution of the compound of formula (I) is reconstituted by adding 20 mL of sterile water or of sterile 5% glucose aqueous solution, at 250 to 500 mg of the compound according to the invention in the form of sterile lyophilizate. This solution is then diluted in 100 to 200 mL of a vehicle compatible with intravenous injection such as sterile 5% aqueous solution of glucose,

14.4 Example of pharmaceutical composition D: solid formulation

Another example of a pharmaceutical composition for parenteral administration is illustrated by the following composition:

Ingredients Quantity

Compound of formula (I) or salt or solvate or hydrate 0.1 to 1 g

Hydroxypropyl-β-cyclodextrin 0.1 to 25 g

Sterile water q.s. 10 to 100 mL The hydroxypropyl-β-cyclodextrin is dissolved in the 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 put in sterile vials for intravenous injection and lyophilised. The bottles are stoppered, labeled and stored at room temperature or cold (for example from 4 to 6°C).