WO2010089341A1 - Nouvelles molécules hybrides de vancomycine-aminoquinoléine, leur préparation et leur application dans des produits thérapeutiques - Google Patents

Nouvelles molécules hybrides de vancomycine-aminoquinoléine, leur préparation et leur application dans des produits thérapeutiques Download PDF

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Publication number
WO2010089341A1
WO2010089341A1 PCT/EP2010/051342 EP2010051342W WO2010089341A1 WO 2010089341 A1 WO2010089341 A1 WO 2010089341A1 EP 2010051342 W EP2010051342 W EP 2010051342W WO 2010089341 A1 WO2010089341 A1 WO 2010089341A1
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group
unsubstituted
vancomycin
molecule
butyl
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PCT/EP2010/051342
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English (en)
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Muriel Sanchez
Bernard Meunier
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Palumed S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Novel vancomycin-aminoquinoline hybrid molecules their preparation and their application in therapeutics
  • 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.
  • 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:
  • 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.
  • - n 0, 1, 2, 3 or 4
  • - Y represents a group selected from:
  • 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.
  • R la represents a (Q-C ⁇ Jalkyl 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:
  • - 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,
  • 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-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.
  • 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.
  • group Y can be a (Q-C ⁇ Jalkyl group, and preferably
  • 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 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.
  • 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.
  • the compounds of formula (I) are capable of reducing by 4-log the bacterial load of a strain of methicillin-resistant Staphylococcus aureus.
  • the surprising antibacterial activity of these hybrid molecules was confirmed by demonstrating their efficacy in a murine model of MRSA septicemia. Knowing the serious 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.
  • 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,
  • (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.
  • the pharmaceutically acceptable acid salts include the salts of acetic, ascorbic, benzenesulfonic, benzoic, hydrobromic, camphosulfonic, hydrochloric, citric, ethanesulfonic, fumar ⁇ c, gluconic, glucuronic, glutamic, lactic, lactobionic, rnale ⁇ c, mandelic, methanesulfonic, nitric, oxalic, phosphoric, succinic, sulfuric, tartaric, and p- toluenesulfonic acid.
  • the compounds of formula (I) are preferred in which;
  • 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, tr ⁇ flu ⁇ r ⁇ methoxy, methoxy, ethoxy, n- propoxy, isopropoxy, /?-butoxy, Isobutoxy, sec-but ⁇ xy, te/t-butoxy, /?-pentyloxy, isopentyloxy, /hhexyloxy, isohexyloxy, heptyloxy, octyloxy, n ⁇ nyloxy, dec
  • R lb preferably in position 6, 7 or 8, represents an atom or group: fluorine, chlorine, methyl, ethyl, ⁇ propyl, isopropyl, /?-butyl, isobutyl, sec-butyl, t ⁇ rf-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, decyl,
  • 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;
  • R 2 N(Q)-Y-(CH 2 ) P -NHV represents a group selected from:
  • 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.
  • Q-CnJalkyl group 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 .
  • 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.
  • R la represents a halogen atom, a methyl, methoxy, CF 3 , OCF 3 , COOH group or a phenyl group, preferably unsubstituted.
  • 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 la represents a hal
  • 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.
  • - n 0 or 1
  • - 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.
  • 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 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:
  • 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:
  • 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.
  • 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 ⁇ 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).
  • 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.
  • 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 - ⁇ _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 -dimethylsulf ⁇ de, BH 3 isoamylsulf ⁇ de, BH 3 "triethylamine, BH 3 'N,N-diisopropylethylamine, BH 3 -N,N- diethylaniline, BHyammonia.
  • a borane complex such as: BH 3 -pyridine, BH
  • 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).
  • 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.
  • 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.
  • 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.
  • aldehydes of formula (III) used in the method of the present invention can be prepared by reaction of a compound of formula:
  • 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,
  • 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.
  • 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.
  • a chlorinated organic solvent such as dichloromethane
  • an ethereal solvent such as tetrahydrofuran or 2- methyltetrahydrofuran
  • an amide solvent such as N,N-dimethylformamide.
  • the reaction is carried out without solvent.
  • 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.
  • the reaction is carried out without a base.
  • 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.
  • 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:
  • 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.
  • a chlorinated organic solvent such as dichloromethane
  • an ethereal solvent such as tetrahydrofuran or 2- methyltetrahydrofuran
  • an amide solvent such as N,N-dimethyIformamide.
  • the reaction is carried out without solvent.
  • 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.
  • the reaction is carried out without a base.
  • 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).
  • 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).
  • 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.
  • a chlorinated solvent for example dichloromethane, dichloroethane, chloroform
  • n, R la and R lb are as defined for a compound of formula (I) including in their different variants.
  • 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 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.
  • the vancomycin-aminoquinoline hybrid molecules of formula (I) according to the invention can be used as an antibacterial agent.
  • 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).
  • 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.
  • 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.
  • the bacterial species that can be treated effectively with the compounds according to the invention are: methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-res ⁇ stant
  • Staphylococcus aureus MRSA
  • Staphylococcus aureus with intermediate resistance to vancomycin VSA
  • vancomycin-resistant Staphylococcus aureus VRSA
  • coagulase- negative methicillln-sensitive staphylococci CMSS
  • coagulase-negative methicillin- resistant staphylococci CMRS
  • group A streptococci group B streptococci
  • group C streptococci group G streptococci
  • vancomycin-sens ⁇ tive Enterococcus faecalis VSE
  • vancomycin-resistant Enterococcus faecalis VRE VanA or VanB
  • vancomycin-sensitive vancomycin VRE VanA or VanB
  • 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.
  • 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 l ⁇ nezolid (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 ⁇ g/mL (table 1, example 10).
  • 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.
  • 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 ⁇ g/mL whereas none of the comparators currently on the market is active at this concentration, no more than telavancin.
  • 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 ( ⁇ log >3), in contrast to vancomycin, which is not bactericidal and only makes it possible to cure 50% of the mice.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • solid compositions for oral administration it is possible to use tablets, pills, powders (gelatin capsules, tablets) or granules.
  • 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.
  • 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.
  • 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.
  • compositions for topical use it is possible to use creams, ointments or gels.
  • 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.
  • inert diluents or additives such as lactose, cellulose derivatives, or talc for example.
  • compositions can also comprise substances other than diluents, for example fatty acids and their derivatives or fats of animal, vegetable or synthetic origin.
  • liquid compositions it is possible to use pharmaceutically acceptable emulsions for local usage, solutions, suspensions containing inert diluents such as water, oils
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, ampic ⁇ l ⁇ n, amoxicillin, ticarcillin, piperacillin), cephalosporins (e.g. ceftriaxone, cefotaxime, cefpodoxlme, cefetamet, cefepime, ceflxime), penems and carbapenems (e.g. imipenem, meropenem, doripenem, faropenem), monobactams (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
  • metalronidazole tinidazole
  • nitrofurantoin oxazolidinones
  • lipodepsipeptides daptomycin
  • 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 describe the preparation of some compounds according to the invention. These examples are nonlimiting and are only for illustrating the present invention.
  • 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
  • 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-d ⁇ or CDCI 3 .
  • the chemical shifts ⁇ 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 ⁇ m, flow: 80 to 100 mL, in isocratic conditions using an eluent composed of water, acetonitrile and trifluoroacetic acid (0.5%).
  • 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%).
  • 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%).
  • 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.
  • 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%).
  • PA1402 is prepared according to the procedure described in example 1.4 from
  • 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 >9 ⁇ % 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.
  • 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%).
  • 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.
  • 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%).
  • 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-d ⁇ ethy!aniline borane complex (44.0 mmol) and 3.7 mL of trifluoroacetic acid (50.0 mmol). The product is purified by preparative HPLC.
  • 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%).
  • 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),
  • Example 10 Bactericidal action against Staphylococcus aureus MRSA (isolate mR) at 1 ⁇ g/mL in the presence of 50% of human serum ( ⁇ log 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.
  • 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 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 ⁇ g/mL in the presence of 50% of human serum
  • 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.
  • 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
  • vancomyquine PA1409 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 methic ⁇ llin- resistant Staphylococcus aureus (ATCC33592), The mice (Swiss), 6 to 7 weeks old, were inoculated intraperitoneally with 200 ⁇ L 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.
  • mice/dose 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
  • vancomyquines® according to the invention are also very effective in vivo.
  • 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
  • the compound according to the invention makes it possible to reduce bacteremia by more than 3 log (bactericidal action at ⁇ CFU > -3log) whereas vancomycin is not bactericidal at 10 mg/kg.
  • 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 ⁇ g/mL, except for vancomyquine PA1409 for which the upper concentration tested was 32 ⁇ g/mL.
  • the incubations were carried out at 37 0 C and the MICs were read at 24 h.
  • Staphylococcus aureus MSSA clinical isolate VA010
  • Staphylococcus aureus MRSA CCUG 31966 VA064
  • 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 ( ⁇ g/mL) with respect to a panel of Gram+ bacteria
  • the antibacterial activity of the vartcomyquines® according to the invention is not limited to MRSA.
  • vancomyquine PA1409 gives very low MICs with respect to a panel of Gram+ bacteria.
  • Vancomyquines ® can be prepared in the form of bases or of salts of addition to acids 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 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 ⁇ g/mL in the presence of 50% of human serum ( ⁇ log CFU) were determined as in example 10. ⁇ log CFU were determined at T24h.
  • this example shows that soluble compounds can be prepared at least to test the bactericidal activity and to the administration in v ⁇ y ⁇ , if needed. Furthermore, this example shows that the bactericidal activity remains constant for different salts of a compound.
  • Example 14 Examples of pharmaceutical compositions
  • 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.
  • An injectable preparation containing the following components can be prepared: Ingredients Quantity
  • 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).
  • Another example of an injectable preparation contains the following components: Ingredients Quantity
  • the hydroxypropyl- ⁇ -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).
  • 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.
  • 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,
  • composition for parenteral administration is illustrated by the following composition:

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Abstract

La présente invention concerne de nouvelles molécules hybrides de vancomycine-aminoquinoléine désignées « vancomyquines® », leur préparation et leur application dans des produits thérapeutiques. La présente invention concerne notamment de nouvelles molécules hybrides dans lesquelles la vancomycine est liée de manière covalente à des 4-aminoquinoléines substituées. La présente invention concerne la préparation de ces molécules hybrides désignées « vancomyquines® » correspondant à la formule (I) ainsi que leur utilisation thérapeutique en tant qu'agent antibactérien.
PCT/EP2010/051342 2009-02-06 2010-02-04 Nouvelles molécules hybrides de vancomycine-aminoquinoléine, leur préparation et leur application dans des produits thérapeutiques WO2010089341A1 (fr)

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FR0950753A FR2941955A1 (fr) 2009-02-06 2009-02-06 Nouvelles molecules hybrides vancomycine-aminoquinoleine denommees " vancomyquines", leur preparation et leur application en therapeutique
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US15507009P 2009-02-24 2009-02-24
US61/155,070 2009-02-24
FR0952912 2009-04-30
FR0952912A FR2941956A1 (fr) 2009-02-06 2009-04-30 NOUVELLES MOLECULES HYBRIDES VANCOMYCINE-AMINOQUINOLEINE DENOMMEES "VANCOMYQUINESr", LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
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FR2874922A1 (fr) 2004-07-30 2006-03-10 Palumed Sa Molecules hybrides qa ou q est une aminoquinoleine et a est un residu antibiotique, leur synthese et leurs utilisations en tant qu'agent antibacterien

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FR2874922A1 (fr) 2004-07-30 2006-03-10 Palumed Sa Molecules hybrides qa ou q est une aminoquinoleine et a est un residu antibiotique, leur synthese et leurs utilisations en tant qu'agent antibacterien
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FR2941956A1 (fr) 2010-08-13
AR075690A1 (es) 2011-04-20
FR2941955A1 (fr) 2010-08-13
UY32418A (es) 2010-03-26

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