Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • 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

Definitions

• Hybrid molecules QA where O is an aminoquinoline and A is an antibiotic residue their synthesis and their uses as an antibacterial agent
• the subject of the invention is hybrid molecules "QA" containing an aminoquinoleic unit (Q) covalently linked to an antibiotic residue (A).
• the invention also relates to their synthesis and their uses as an antibacterial agent.
• the main object of the present invention is to solve the new technical problem of providing a solution which makes it possible to find new antibiotic molecules that are less prone to the resistance of the bacteria.
• the main purpose of the invention is to find new antibiotic molecules that are even more effective than current antibiotics.
• the invention also aims to find new antibiotic molecules that can be active on strains of bacteria resistant to certain current antibiotics.
• the main purpose of the present invention is also to solve these new technical problems by providing new antibiotic molecules, the manufacture of which is relatively easy, according to an inexpensive manufacturing process and providing good industrial yields.
• the present invention solves the first time all of these technical problems in a satisfactory, safe and reliable, usable on an industrial scale, particularly in the pharmaceutical scale.
• the novelty of the present invention relates to the preparation and evaluation of hybrid "QA" molecules.
• the aminoquinoline part (Q) of these new molecules has been covalently attached to an antibiotic residue (A).
• hybrid QA molecules can be named for example in general “antibiotic” or in particular “penicillins”, “cephaloquines”, “quinoloquines”, “nitroimidaquines”, “streptogramiquines”,
• Diaminopyrimiquines when the unit A is an antibiotic residue, penicillin, cephalosporin, quinolone, nitroimidazole, pristinamycin, diaminopyrimidine, vancomycin or oxazolidinone, respectively.
• aminoquinolines make it possible to combine an inhibitory effect of the efflux pumps of certain resistant bacteria and the antibacterial effect of the antibiotic.
• the AQ hybrid molecule has an antibacterial activity that is unexpectedly superior to any of its A or Q components taken separately.
• Another particularly unexpected effect of the invention is that it has surprisingly been found that antibiotic activity is maintained in the case of a covalent bond with an aminoquinoline for different classes of antibiotics.
• this unexpected improvement in activity is not limited to a particular type of antibiotic.
• the invention is not limited to a particular class of antibiotic, it may thus be possible to modify the different families of antibiotics without reducing their effectiveness, on the contrary.
• the invention will therefore provide a panel of active molecules resistant strains and may be used according to their specific activity.
• the invention essentially relates to novel hybrid antibiotic molecules represented by the general formula (I);
• Q represents a molecule of the aminoquinoline type
• - A represents an antibiotic residue
• the antibiotic residue A is covalently bonded either directly to the aminoquinoline or to the spacer arm and may be connected in particular to Q, Yi, U, or Y 2 , especially as defined below, at any fixation site. , especially by reaction with one of the reactive functions of the compounds A.
• the present invention also relates to their manufacturing process, their various uses, pharmaceutical compositions containing them, and a method of therapeutic treatment. These new molecules can in particular be used as an antibacterial agent.
• the present invention provides a hybrid aminoquinoline-antibiotic compound characterized in that it has the following general formula (I):
• Q represents an aminoquinoline of formula (IIa), (Hb), (HIa), (HIb), (HIc) or (HId) as follows: (IIa) (Hb)
• the sign " ⁇ indicates the site of attachment of the other fragment, for example either Y 1 , or U, or Y 2 , or A;
• n and n 'independently represent 0, 1, 2 or 3;
• Ri 3 and Rib (generally RO represent one or more identical or different substituents, occupying any positions and representing a radical selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, sulfate, sulfonate, phosphate , phosphonate, nitro, cyano, aryl or heteroaryl as defined below or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfamoyl, alkylsulfonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonyloxy, alkoxycarbonyl, alkylcarbonylamino, said alkyl groups preferably comprising 1 , 2, 3, 4, 5, or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more
• R 2a and R 2b - (generally R 2 ) being identical or different substituents, which may optionally form a ring structure together or with Y 1 , Y 2 , U or A and representing a hydrogen atom or a alkyl radical, preferably C 1, C 2, C 3, C 4, C 5, or C 6, linear, branched or cyclic, optionally containing one or more amine, amide, thioamide, sulphonyl, urea, thiourea, carbamate, oxime or sulphonamide radicals, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether and may carry 1 to 4 substituents, identical or different, selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl as defined below ,
• Y 1 and Y 2 which may be identical or different, which may be linked by a single or multiple bond to Q, U or A, and represent an alkyl chain preferably of C 1, C 2, C 3, C 4, C 5, or C 6, linear, branched or cyclic, saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulfonyl, sulfonamide, oxo, carboxy, thiocarboxy, carbonyl, thiocarbonyl, urea, thiourea, carbamate, oxime, ether or thioether, aryl or heteroaryl as defined below, the alkyl chain may also carry 1 to 4 substituents, identical or different, preferably selected from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, carbonyl, amine, nitro, oxime, aryl or heteroaryl as defined below, or selected from alkyl
• aryl or heteroaryl radical is preferably a 5- to 6-membered aromatic ring comprising 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur and oxygen and that the aryl or heteroaryl radicals may themselves carry one or more substituents selected from the group halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, oxo, nitro or cyano.
• Heterocycle is preferably a 5- to 6-membered saturated or unsaturated ring comprising 1, 2, 3, or 4 heteroatoms chosen from nitrogen, sulfur and oxygen, which can itself carry one or more substituents chosen from halogen, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, oxo, nitro or cyano.
• halogen is understood to mean a fluorine, chlorine, bromine or iodine atom.
• antibiotic residue consisting of the part A of the hybrid molecules, a chemical entity derived from an antibiotic, an antibiotic modification or an antibiotic precursor.
• the Q part of the hybrid molecules of formula (I) represents either an aminoquinoline of formula (IIa) or (Hb) in which the antibiotic residue is attached to the amine function, or an aminoquinoline of formula (IHa), (HIb), (IIIc) or (HId) where the antibiotic residue is directly attached to the quinoline ring.
• the hybrid molecules containing an aminoquinoline of formula (IIa) or (Hb) have been prepared from halogenoquinolines and amino derivatives also containing a reactive function for fixing the antibiotic residue or from the reactive function amine of an aminoquinoline.
• quinoline precursors of hybrid molecules containing an aminoquinoline of type (IHa), (HIb), (IIIc) or (HId) are aminoquinolines also having a reactive function such as halogen, haloalkyl, hydroxy, amine, hydroxyalkyl, aminoalkyl, sulfonamide or carboxy.
• A represents an antibiotic residue.
• This residue may advantageously be chosen from the large families of antibiotics known to those skilled in the art, such as, for example, ⁇ -lactams, quinolones, oxazolidinones, fosfomycin derivatives, nitroimidazoles, nitrofurans, sulphonamides, streptogramins or synergistins, lincosamides, tetracyclines, phenicolates, fusidic acid derivatives, diaminopyrimidines, aminoglycosides, macrolides, polypeptides, glycopeptides, rifamycins, or lipodepsipeptides.
• A may be chosen from the family of ⁇ -lactams containing inter alia: penames (or penicillins) of formula (IV), oxapenames of formula (V ), penems of formula (VI), carbapenems of formula (VII), cephems (or cephalosporins) of formula (VIIIa), (VIIIb), (IXa) or (IXb), cephamycins of formula (VIIIc) or (VIIId), oxacephems of formula (Xa) or (Xb), carbacephems of formula (XIa) or (XIb) and monobactams of formula (XII) below:
• R 1 is as defined above,
• R 3a and R 3b represent identical or different substituents chosen from the group consisting of halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, aldehyde, amine, sulphate, sulphonate, phosphate, phosphonate, nitro, cyano, aryl or heteroaryl as defined above or alkyl, alkylamino, dialkylamino, alkoxy, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfamoyl, alkylureido, alkylcarbamoyloxy, alkoxycarbonylamino, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxyimine, said alkyl groups comprising preferably 1, 2,
• R 43 and R 4b in general R 4 ) identical or different, which may optionally form a cyclic structure together or a multiple bond, represent a hydrogen atom or a linear, branched or linear C 1 to C 6 alkyl radical; cyclic, saturated or unsaturated, optionally containing one or more amine, amide, thioamide, sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, oxime, urea, carbamate, ether or thioether radicals and capable of carrying 1 to 4 identical substituents or different, chosen from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, amine, nitro, aryl or heteroaryl as defined above,
• R 5 is a hydrogen atom or an alkyl radical preferably C 1, C 2, C 3, C 4, C 5, or C 6, linear or branched or cyclic, saturated or unsaturated,
• V represents a methoxy group or a hydrogen atom
• HetAr represents a heteroaryl as defined above.
• the ⁇ -lactams of formulas (IV), (V), (VIb), (VIIIa), (VIIIc), (Xa), (XIa) and (XII) may for example be coupled to a quinoline unit using their function amine.
• the coupling reaction with carbapenems of formula (VIIb) a can be carried out for example from a carbonyl or hydroxy group.
• a reactive function of the hydroxy, halogen, or alkene type may be advantageously used for the attachment of cephalosporins, cephamycins, oxacepnems and carbachephems of the respective formulas (VIIIb), (VIIId), (IXa), (IXb), (Xb) and ( XIb).
• A represents a quinolone unit such as those described by the following formula (XIIIa) or (XIIIb),
• R 3 and R 4 are as defined above,
• R 5 and R 7 are identical or different substituents, which may optionally form a cyclic structure together and representing a hydrogen atom or a substituent selected from the group consisting of halogen, hydroxy, heterocycle, aryl or heteroaryl as defined previously, or an alkyl, alkoxy or alkylamino radical, said alkyl groups comprising 1, 2, 3, 4, 5, or 6 carbon atoms, linear, branched or cyclic, saturated or unsaturated, containing where appropriate one or more amino, amide, thioamide, sulphonyl, sulphonamide, carboxy, thiocarboxy, carbonyl, thiocarbonyl, ether or thioether radicals and capable of carrying 1 to 4 substituents, identical or different, chosen from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, amine, nitro, aryl, or heteroaryl as defined above,
• Z is a nitrogen or carbon atom.
• An amine or halogen type reactive function of the quinolones known to those skilled in the art may advantageously be used for the coupling reaction with a quinoline derivative.
• A represents an oxazolidinone residue such as those described by the following formulas (XIVa), (XIVb) or (XIVc), in which R 3 , R 6 and R 7 are as defined above.
• Such hybrid molecules can be advantageously prepared either by using an amine, hydroxy, or halogen reactive function of an oxazolidinone or by synthesis of the oxazolidinone ring from an aminoquinoline having a protected amine function and "(R) - glycidyl butyrate "according to methods known to those skilled in the art.
• A represents a derivative of fosfomycin such as that described by the following formula (XV),
• hybrid molecules derived from fosfomycin may for example be carried out by epoxidation of an alkene precursor before or after binding to the aminoquinoline.
• A represents a nitroimidazole residue such as those described by formulas (XVIa) or (XVIb) or a nitrofuran residue such as that described by the following formula (XVII),
• a reactive function of the hydroxy, epoxy, amine or halogen type may for example be used in the coupling reaction of the nitroimidazole or nitrofuran derivatives of formula (XVI) or (XVII) with a quinoline unit.
• A represents a sulphonamide residue such as that described by the following formula (XVIII),
• This residue may, for example, be attached to a quinoline unit from a sulphonamide or sulphonic acid reactive functional group.
• A represents a streptogramin or synergistin residue such as those described by the following formulas (XIXa), (XIXb) or (XX),
• hybrid molecules incorporating a streptogramin or synergistin derivative can be carried out, for example, from precursors of the pristinamycin or virginiamycin type.
• A represents a lincosamide residue such as that described by the following formula (XXI),
• the lincosamides have a hydroxy function or a halogen atom which for example can be used to graft them on an aminoquinoline.
• A represents a tetracycline residue such as those described by the following formulas (XXIIa), (XXIIb) and (XXIIc),
• R 3 , R 4 and R 6 are as defined above, - R 8 and R 9a , Rg b identical or different, represent a hydrogen atom or a radical selected from hydroxy or methyl group.
• the coupling reaction with the tetracyclines of formula (XXIIa), (XXIIb) or (XXIIc) can be carried out for example from their amide function or by modification of an aromatic CH group.
• A represents a chloramphenicol derivative such as those described by the following formulas (XXIIIa) or (XXIIIb),
• R 3 is as defined above
• - W represents a radical NO 2 or SO 2 Rs, R 5 being as defined above.
• a reactive function of the hydroxy or halogen type may for example be used for fixing the chloramphenicol derivatives according to the modes (XXIIIa) and (XXIIIb).
• A represents a fusidic acid derivative such as those described by the following formulas (XXIVa), (XXIVb) or (XXIVc),
• A represents a diaminopyrimidine residue such as those described by the following formula (XXV),
• Hybrid molecules incorporating a diaminopyrimidine residue may be prepared in particular by using a reactive functional group of hydroxy or halogen type of a known diaminopyrimidine or by cyclization with guanidine of an acrylonitrile precursor.
• A represents an aminoglycoside residue formed by the union of a genin unit of the aminocyclitol group with one or more monosaccharides, at least one of which is an aminoscre and linked together by glycosidic bridges.
• A represents a macrolide residue:
• R 3 , R 4 , R 6 and R 7 are as defined above,
• - Rio is an oxygen atom bonded by a carbonyl-type double bond to the macrocycle or a hydroxyl group or a glycoside-linked glycoside derivative linked to the macrocycle and may carry 1 to 6 substituents, identical or different, chosen from hydroxy, alkyl , alkylamino, dialkylamino or aikoxy, said alkyl groups comprising 1, 2, 3, 4, 5, or 6 linear or branched carbon atoms, saturated or unsaturated and may carry a carboxyl substituent.
• the reactive functions of the hydroxy, amino or carbonyl macrolides can be used for the coupling reaction with the aminoquinolines.
• A represents a polypeptide residue such as derivatives of polymyxins or bacitracin linking various peptide structures. These residues have been grafted to an aminoquinoline, in particular by one of their free amino functions.
• A represents a glycopeptide residue such as: the vancomycin derivatives described by the formulas (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe) and (XXIXf) following,
• the derivatives of vancomycin and teicoplanin may for example be attached to a quinoline unit from one of their reactive functions of amino, carboxy, amide or hydroxy type or by modification of an aromatic CH group.
• A represents a rifamycin residue such as those described by the following formulas (XXXIa) and (XXXIb),
• the preparation of an aminoquinoline-rifamycin hybrid molecule can be carried out, for example, from a reactive function of rifamycin of the amino, halogen, hydroxy or aldehyde type.
• A represents a lipodepsipeptide residue such as the daptomycin derivatives described by the following formula (XXXII),
• the lipodepsipeptides can be grafted on a quinoline for example from one of their reactive functions of amino, hydroxy or carboxy type.
• Formulas (IV) to (XXXII) give examples of binding sites of an aminoquinoline on a residue A but other binding sites have been envisaged on the compounds A. It is understood that the invention is directed to hybrid molecules aminoquinoline - A connected by any site of attachment.
• the invention also relates to any hybrid molecule of formula (I) covalently linking an aminoquinoline to an antibiotic residue A other than those described by formulas (IV) to (XXXII).
• the invention relates to mixtures in all proportions of stereoisomers as well as pure stereoisomers.
• the compounds of the invention may be in the form of acid addition salts, base addition salts or zwitterions as well as prodrugs or prodrug salts.
• the invention also relates to these different forms and their mixtures.
• the compounds of formula (I) are those having the group Q representing a group of formula (IIa) or (IHa) defined above.
• the compounds of formula (I) are those having the group Q representing a group of formula (Hb) defined above.
• the compounds of formula (I) are those having the group A representing a group of formula (IV) defined above.
• the compounds of formula (I) are those having the grouping
• the compounds of formula (I) are those having the group A representing a group of formula (XIIIa) or (XIIIb) defined above.
• the compounds of formula (I) are those having the group A representing a group of formula (XIVa) or (XIVb) defined above.
• the compounds of formula (I) are those having the grouping
• the compounds of formula (I) are those having the group A representing a group of formula (XIXb) defined above.
• the compounds of formula (I) are those having the group A representing a group of formula (XXV) defined above.
• the compounds of formula (I) are those having the group A representing a group of formula (XXVIb), (XXVIc) or (XXVId) defined above.
• the compounds of formula (I) are those having the group A representing a group of formula (XXIXa) defined above.
• the aminoquinolines are of the 4-aminoquinoline, 2-aminoquinoline or 8-aminoquinoline type. Their synthesis can be made from commercially available synthons, which provides a very interesting advantage of these compounds in addition to their activity.
• the aminoquinolines of formula (IIa) and (IIIa) in which the amino group is in position 4 with respect to the endocyclic nitrogen atom are more particularly preferred ( it is then 4-aminoquinolines) or in position 2 with respect to the endocyclic nitrogen atom (it is then 2-aminoquinolines) or the aminoquinolines of formula (Hb) in which the amino group is at position 8 (8-aminoquinolines).
• R 1 advantageously represents a single substituent, this substituent being a halogen atom or a hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, carboxy, cyano, amine or nitro group occupying any position .
• R 2 is advantageously a hydrogen atom or a methyl group or forms a cyclic structure with Yi including N of aminoquinoline (such as piperidine or piperazine).
• R 23 and R 2b advantageously represent identical or different substituents which can form a cyclic structure together, these substituents preferably being a hydrogen atom or a methyl, cyclopropyl or 2- (diethylamino) ethyl, or a heterocycle when R 2a and R 2b form a ring structure together (such as aziridin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, or 4-methylpiperazine -l-yl).
• A represents a cephalosporin, a penicillin, a quinolone, a nitroimidazole, a streptogramin, a diaminopyrimidine, a macrolide, a glycopeptide or an oxazolidinone.
• Preferred aminoquinolines Q are covalently linked to an antibiotic residue A to form hybrid molecules, including the following hybrid molecules.
• the invention particularly relates to hybrid molecules comprising a 4-aminoquinoline of formula (XXXIIIa) or an 8-aminoquinoline of formula (XXXIIIe) and a residue A of the family of penicillins of formula (IV).
• Such molecules correspond to the structure (XXXIVa), (XXXIVb) or (XXXIVc) in which R la , R lb , R 2 , R 3a , R 3b , Rt, Y 1 , Y 2 , U, p, p ', p ", m, n and n 'are as defined above.
• hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or (XXXIIIb), or an 8-aminoquinoline of formula (XXXIIIe) and a residue A of the cephalosporin family of formula (VIIIa).
• These hybrid molecules of great interest correspond to the structure (XXXVa), (XXXVb) or (XXXVc) in which R 1 , R 2 , R 3 , R 4 , Y 1 , Y 2 , U, p, p ', p ", m, n and n 'are as defined above.
• hybrid molecules of the family of aminoquinoline-cephalosporin hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or (XXXIIIb) and of cephalosporins of formula (IXa) or (IXb). These hybrid molecules respond to the structure (XXXVd), (XXXVe), (XXXVf), (XXXVg) or (XXXVh) in which R 1 , R 2 , R 3, R 4 , Y 1 / Y 2 , U, p, p ' , p ", m, n and n 'are as defined above.
• R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa), (XXXIIIb) and (XXXIIIe) defined above and R 4 is a hydrogen atom or a easily hydrolyzable group in vivo in the context of prodrug molecules (such as 2,2-dimethyl-propionyloxymethyl).
• R 3a and R 3b advantageously represent two identical substituents of alkyl type (such as two methyl substituents).
• R 3 advantageously represents a halogen or a C 1, C 2, C 3, C 4 alkyl chain, C5, or saturated or unsaturated C6 optionally containing a carboxy or ether radical (such as a methyl, vinyl, acetoxymethyl or methoxymethyl group) and capable of carrying a heteroaryl or heterocycle substituent (such as pyridinium-1-ylmethyl, 1-methyl-1); or 5-hydroxy-2-methyl-5-oxo-2,5-dihydro- [1,2,4] triazin-3-ylsulfanylmethyl).
• R preferably represents a hydrogen atom or a C1, C2, C3, C4, C5 or C6 alkyl radical (from preferably methyl) and "Ar", as defined above, advantageously represents a heteroaryl of 2-amino-thiazol-4-yl, 2-amino-5-chloro-thiazol-4-yl or 5-amino- [1,2 , 4] thiadiazole-3-yl.
• Another type of preferred compounds is characterized in that it relates to the aminoquinoline-quinolone hybrid molecules corresponding to the formula (XXXVIa) or (XXXVIb) in which R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , Y 1 , Y 2 , U, Z, p, p ', p ", n and n' are as defined above. above.
• Z is a carbon atom
• R 2 advantageously represent the substituents of the preferred aminoquinolines of formula (XXXIIIa) defined above, R 3 is a hydrogen or fluorine atom and R 4 is a hydrogen atom.
• R 6 is a linear, branched or cyclic C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain (preferably an ethyl or cyclopropyl radical) or forms a ring structure with R 7 and R 7 is a hydrogen or halogen atom, a methoxy group or forms a ring structure with R 6 such as 3-methyl-3,4-dihydro-2 / [1,4] oxazine;
• 1 or 2 heteroatoms such as piperazin-1-yl, N-methylpiperazin-1-yl, 3-methylpiperazin-1-yl or
• Particularly preferred compounds of formula (XXXVIb) according to the invention especially those whose link (Yi) p - (U) p ' - (Y 2 ) P " is absent or which comprise a 2-ethyl group, or 4-piperidin-1-yl (including R 2 and N of aminoquinoline) as (Y 1) p - (U) P KY 2) P ".
• R 1 and R 2 advantageously represent the preferred aminoquinoline substituents (XXXIIIa),
• Another type of preferred compounds is characterized in that it relates to the aminoquinoline-streptogramin hybrid molecules corresponding to the formula (XXXVIII) in which R 1 , R 2 , R 4a , R 4b / Rs / Yi; Y 2 ; U, p, p ', p ", n and n' are as defined above.
• the compounds of formula (XXXVIII) according to the invention which comprise a 1- (2-ethylamino) -methylsulfanyl, 1- (2-propylamino) -methylsulfanyl, 1- (3-propylamino) -methylsulfanyl group, or 1-piperidin-4-ylsulfanyimethyl as a group (Y 1) P - (U) P - (Y 2) P -
• Aminoquinoline-diaminopyrimidine hybrid molecules In the aminoquinoline-diaminopyrimidine hybrid molecules, the compounds of formula (XXXIX) in which R 1, R 2 , R 4 , R 5 , Y 1 , Y 2 , U, p, p ', p are more particularly preferred. ", n and n 'are as defined above.
• R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa) defined above
• Another type of preferred compounds is characterized in that it relates to the aminoquinolein-macrolide hybrid molecules corresponding to the formula (XLa) (XLb) or (XLc) in which R 1 , R 2 , R 5 , R 6 , R 7 , Rio / Y 1 , Y 2 , U, p, p ', p ", n and n' are as defined above.
• R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa), R 3 is a hydroxyl group or methoxy, R 4 is a hydrogen atom, R 6 and R 7 are hydroxy groups, R 10 is an oxygen atom bonded by a macrocycle-type carbonyl double bond or a glycosidically bonded glycosidic linkage derivative. macrocycle and can carry 1 to 6 substituents (preferably an L-cladinose derivative).
• the compounds of formula (XLa) according to the invention, which comprise an O-2-ethyl-oxime group, O-3, are particularly preferred.
• Particularly preferred are the compounds of formula (XLb) according to the invention which comprise a 2-ethyl, 3-propyl, 2-propyl, 4-butyl or 2- (2-ethoxy) -ethyl group as a group. .
• the compounds of formula (XLc) according to the invention which comprise a 2-ethoxy group are preferred, 3-propoxy, 2-propoxy, 2-ethoxy-2-ethoxy, 3-allyloxy, 2-ethylcarbamoyloxy, 3-propylcarbamoyloxy, 4-butylcarbamoyloxy, 4- (2-ethoxy) -benzylcarbamoyloxy as a group (Yi) p - (U) P -
• R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa) and (XXXIIIb), R 4 is a hydrogen atom and R 3 is a hydroxy group.
• the compounds of formula (XLIa) according to the invention which comprise a 2-ethyl, 3-propyl, 4-butyl, 2,2-difluor
• XLEb XLEb according to the invention, which comprise a methyl, ethylcarbamoyl, propylcarbamoyl or butylcarbamoyl group as (Yi) p - (U) p '- (Y 2 ) p "group.
• hybrid molecules are composed of a 4-aminoquinoline of formula (XXXIIIa) or a 2-aminoquinoline of formula (XXXIIIc) and an oxazolidinone of formula (XIVa) or (XIVb).
• These aminoquinoline-oxazolidinone hybrid molecules correspond to the formula (XLJIa) (XLJIb) or (XLIIc) in which R 1 , R 2 , R 6 , R 7 , Y 1 , Y 2 , U, p, p ', p ", n and n 'are as defined above.
• R 1 and R 2 advantageously represent the substituents of the preferred aminoquinolines (XXXIIIa) and (XXXIIIc),
• R 5 is a a hydrogen or fluorine atom
• R 7 is a 5- to 6-membered heterocycle comprising 1 to 4 heteroatoms chosen from nitrogen, sulfur and oxygen (preferably morpholin-4-yl or piperazin-1-yl)
• R 3 is advantageously a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may contain an amide radical (such as an acetylaminomethyl chain), carbamate (such as a methoxycarbonylaminomethyl chain) or ether and which may be substituted.
• a heterocycle such as a [1,2,3] -triazolylmethyl or isoxazol-3-ylmethyl chain).
• the compounds of formula (XLIIb) according to the invention which comprise a 2-ethylcarbamoyloxymethyl, 2- (1-methyl) ethylcarbamoyloxymethyl, 3-propylcarbamoyloxymethyl, 2-propylcarbamoyloxymethyl, 4-piperazin-1-carbonyloxymethyl group. as a group (Y 1 ) p - (UV (Y 2 V '.
• U being as defined above and advantageously representing an amine function
• Y 1 being as defined above and preferably representing a C 1, C 2, C 3, C 4, C 5 or C 6 alkyl chain which may form a ring structure with U and / or R 2 including N of aminoquinoline and optionally containing an amino, amide, urea or carbamate radical.
• the invention also provides methods for synthesizing the molecules of formula (I) defined above. These methods comprise the reaction of reactive derivatives or precursors of aminoquinolines Q and reactive derivatives or precursors of antibiotic residue A, so as to form between these derivatives, a coupling arm - (Yi) p - (U) P KY2 ) P "- W hat as defined in relation to formula (I) Various synthetic pathways will be readily accessible to the skilled working according to conventional techniques..
• the process for producing a compound Q - (Yi) p - (U) p ⁇ - (Y 2 V - A comprises: a) either the binding of the group (Yi) p - (U ) P ' - (Y 2 ) p "on an aminoquinoline Q, then the reaction of this intermediate compound with A, in particular an antibiotic residue; b) the attachment of the group (Yi) p - (U) P ' - (Y 2 V with A, in particular an antibiotic residue, then the attachment of this intermediate to an aminoquinoline Q; c) or the attachment of a group amino- (Yi) p - (U) P ' - (Y 2 V on a corresponding quinoline to obtain an intermediate compound Q - (Yi) p - (U) p- - (Y 2 V, then the binding of this intermediate compound on A, especially on an antibiotic residue A.
• hybrid molecules containing, as derivative Q, a 4-aminoquinoline of formula (XXXIIIa) and as residue A a penicillin of formula (IV) in the following manner: a-1) a compound of formula ( XLIII):
• Step a-1 is advantageously carried out in molten phenol, at a temperature of 120 ° C. to 150 ° C. After returning to ambient temperature the product is obtained after various washings and / or extractions and, if appropriate, recrystallization by dissolution in carbonated water and then precipitation by addition of hydrochloric acid.
• Step b-1) is advantageously carried out in a solvent such as an amide (preferably dimethylformamide) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxy-benzotriazole system for example) at room temperature.
• a solvent such as an amide (preferably dimethylformamide) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxy-benzotriazole system for example) at room temperature.
• Step b-2) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxybenzotriazole system for example).
• an activator of the U function PyBOP or the dicyclohexylcarbodiimide / hydroxybenzotriazole system for example.
• R a, Rib, R 2, R 3, R 4, Y, U, n, n ', p and p' are as defined above,
• Step b-3) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP or the dicyclohexylcarbodiimide / hydroxybenzotriazole system for example).
• an activator of the U function PyBOP or the dicyclohexylcarbodiimide / hydroxybenzotriazole system for example.
• Step c-3) is advantageously carried out in a halogenated solvent (dichloromethane for example) at 0 ° C. by slow addition of a solution of the oxidizing agent (for example 3-chloroperoxybenzoic acid).
• Step d-3) is advantageously carried out at low temperature (-20 ° C.) in an amide solvent (dimethylformamide for example) under an inert atmosphere and in the presence of a reducing agent such as trichlorophosphine.
• a deprotection step When a deprotection step is necessary, it is advantageously carried out in a halogenated solvent, under an inert atmosphere, in the presence of a compound used to trap the released carbocation (anisole, for example).
• the hydrolysis can be carried out by addition of an acid (such as trifluoroacetic acid) at 0 ° C., which is prolonged by stirring at room temperature.
• a-4) is a halogen hydroxyquinoline of formula (XLVIII) wherein R 3, R 3, n, n 'and p' are as defined above and U represents a carboxylic ester:
• R la, R ib, R 2, R 3, R 4, Y 1, U, n, n ', p and p' are as defined above,
• R 1 , R 3 , R 2 , R 3 , R 4 , Y 1, U, m, n, n ', p and p' are as defined above,
• Step a-4) is advantageously carried out with a chlorinating agent (such as trichlorooxyphosphine) at reflux.
• Step a'-4) is advantageously carried out under reflux in an excess of amine of formula
• Step a-4) is advantageously carried out in a mixture of alcoholic solvent
• Step b-4) is advantageously carried out according to the conditions described for step b-1) in the presence of an activator of the U function (PyBOP for example).
• Step c-4) is advantageously carried out according to the conditions described for step c-3).
• Step d-4) is advantageously carried out according to the conditions described for step d-3).
• R and heteroaryl HetAr are as defined above and the activating group of the acid is for example a sulfanylbenzothiazole group.
• Step a-5 is advantageously carried out in an amide solvent (such as dimethylformamide) at room temperature, in the presence of a base (such as N, N-diisopropylethylamine) and sodium iodide.
• Step a'-5) is advantageously carried out in an acidic medium (a formic acid / hydrochloric acid mixture for example) at room temperature.
• Step a -5) is advantageously carried out in a halogenated solvent (dichloromethane for example) between -10 ° C. and 25 ° C. in the presence of a base (such as triethylamine).
• a halogenated solvent diichloromethane for example
• a base such as triethylamine
• the coupling reaction is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (potassium carbonate for example) and at a temperature of 140 ° C.
• R la, R lb, R 2, Y, n, n 'and p are as defined above and "hal" represents a halogen atom, with 2-methyl-5-nitroimidazole.
• the coupling reaction is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (potassium carbonate or triethylamine for example) and at a temperature between 70 and 140 ° C.
• This coupling reaction is advantageously carried out in an alcoholic solvent (such as ethanol) in the presence of a base (triethylamine for example) and at the reflux temperature of the alcoholic solvent.
• an alcoholic solvent such as ethanol
• a base triethylamine for example
• This coupling reaction is advantageously carried out in an organic solvent (such as acetone) and at low temperature (-2O 0 C for example).
• organic solvent such as acetone
• the acrylonitrile intermediate (LXVI) is obtained in the form of a mixture of Zet E isomers 1
• the step a) is advantageously carried out in an amide solvent (dimethylformamide for example) in the presence of a base (potassium carbonate) and at a temperature of
• Step b) is advantageously carried out in an organic solvent (dimethylsulfoxide for example) in the presence of a base (such as potassium tert-butoxide) added in small portions at low temperature (for example 10 ° C.) followed by stirring at room temperature.
• a base such as potassium tert-butoxide
• Step c) is advantageously carried out in two steps:
• guanidine is placed in the presence of a base (such as potassium tert-butoxide) in an alcoholic solvent (for example ethanol) at room temperature.
• a base such as potassium tert-butoxide
• an alcoholic solvent for example ethanol
• the suspension obtained is advantageously filtered on an inert support (celite, for example), the filtrate is then brought into contact with the mixture of isomers Z and of the intermediate acrylonitrile (LXVI) in an alcoholic solvent (ethanol for example) at ambient temperature followed by a reflux of 7 h.
• This coupling reaction is advantageously carried out in an amide solvent (such as dimethylformamide) in the presence of a base (crushed sodium hydroxide, for example) at room temperature.
• amide solvent such as dimethylformamide
• base crushed sodium hydroxide, for example
• the coupling reaction a-1) is advantageously carried out by first bringing together the glycopeptide residue with a base (diisopropylethylamine, for example) in an amide solvent (such as dimethylformamide or dimethylacetamide) at ambient temperature. stirring at 70 0 C for 2 h. On this mixture is then added a solution of a reducing agent (such as sodium cyanoborohydride) in an alcoholic solvent (methanol for example) at 70 ° C. The mixture is advantageously stirred for 2 h 30 at 70 0 C and then 20 h at room temperature.
• a base diisopropylethylamine, for example
• an amide solvent such as dimethylformamide or dimethylacetamide
• Step b) is advantageously carried out without a solvent at a temperature of 110 ° C.
• the acid hydrolysis c) is advantageously carried out in an aqueous solution of acetic acid in the presence of trifluoroacetic acid at 70 ° C.
• the coupling reaction a-2) is advantageously carried out under the conditions described for the coupling reaction a-1).
• Y 1, n, n ', p and p' are as defined above and U represents a carboxy function, with an oxazolidinone residue of formula (LXXIII):
• addition salts with pharmacologically acceptable acids mention may be made of the salts formed with the mineral acids (hydrochlorides, hydrobromides, sulphates, nitrates, phosphates) or with the organic acids (citrates, tartrates, fumarates, lactates).
• the reaction can be carried out with 2 equivalents of acid added at 0 ° C.
• the compounds of formula (I) may also be converted into the form of metal salts or of addition salts with the nitrogenous bases according to the methods known per se.
• pharmacologically acceptable salts are salts with alkali metals (sodium, potassium, lithium), alkaline earth metals (magnesium, calcium), ammonium salt or nitrogenous base salts ( triethylamine, diisopropylamine, ethanolamine, procaine, N-benzyl-2-phenylethylamine, tris (hydroxymethyl) aminomethane, N, N'-dibenzylethylenediamine).
• the invention also covers prodrugs of hybrid molecules of formula
• the invention covers the use of a compound Q as defined above to set covalently, for example by a bond - (Yi) p - (U) p ' - (Y 2 ) p "- such that defined above, an antibiotic residue A defined above.
• the invention covers the pharmaceutical use of a compound according to the present invention as defined by formula I.
• the invention also covers the pharmaceutical use of compounds excluded 2) to 12).
• the invention also covers the pharmaceutical use of the compounds excluded 1) except for the disinfection or treatment of infections caused by Mycoplasma sp.
• the invention covers the use of a compound as defined above for the manufacture of a pharmaceutical composition intended in particular for the treatment of a bacterial infection of an animal or a human being or a treatment of medical equipment contaminated with bacteria, including infection or bacterial contamination due to Staphylococcus aureus, for example Staphylococcus aureus MSSA (methicillin-sensitive), Staphylococcus aureus MRSA (methicillin-resistant), Staphylococcus aureus NorA (quinolone-resistant) efflux), Staphylococcus aureus MsrA (efflux-resistant macrolide) or Staphylococcus aureus VISA (or GISA) (resistant to vancomycin), Staphylococcus epidermidis eg Staphylococcus epidermidis MSCNS (Methicillin-sensitive negative coagulase) or Staphylococcus epidermidis MRCNS (coagulase) negative methicillin-resistant), Streptococcus pneumoniae, for example
• hybrid molecules of the invention as defined in this part can be very advantageously used for the treatment of bacterial infections due to the germs on which they are active.
• the hybrid molecules of the invention active on Streptococcus pneumoniae can be very advantageously used for the treatment of infections such as pneumonia, meningitis, otitis, or acute sinusitis.
• hybrid molecules of the invention that are active on Staphylococcus aureus can be used for the treatment of infections such as skin and / or mucosal infections, nosocomial infections, or osteomyelitis.
• hybrid molecules of the invention that are active on Staphylococcus epidermidis can be used for the treatment of infections such as nosocomial and iatrogenic infections due to this bacterium.
• Nosocomial, urinary, cutaneous, genital, biliary, dental, and otitis-sinusitis infections or endocarditis due to Enterococcus faecalis can be advantageously treated by the active hybrid molecules on this bacterium.
• the hybrid molecules of the invention active on Streptococcus pyogenes can be used for the treatment of infections such as bacterial angina, other ENT diseases, skin infections, scarlet fever, erysipelas, impetigo or gangrene. skin.
• hybrid molecules of the invention which are active on Haemophilus influenzae can be used for the treatment of ENT diseases, complications of influenza or meningitis.
• hybrid molecules of the invention that are active on Moraxella catarrhalis can be used for the treatment of ENT diseases caused by this bacterium.
• Escherichia coli infections such as urinary tract infections, abdominal infections or infantile diarrhea can be advantageously treated by the active hybrid molecules on this bacterium.
• the hybrid molecules of the invention which are active on Bacillus sp. may be used for the treatment of food poisoning caused by this bacterium. Infections due to Bacteroides fragilis such as bacteremia, abscess and lesions, peritonitis, endocarditis or wound infections can be advantageously treated by the hybrid molecules active on this bacterium.
• the invention therefore also relates to the application of these hybrid molecules of high interest defined above, to develop drugs for the food industry and in human and veterinary medicine for the treatment of a bacterial infection or as a than bactericidal for industrial applications.
• the invention also covers a method of therapeutic treatment of an animal or of a human being in need, characterized in that it comprises administering thereto a therapeutically effective amount of a hybrid compound according to the invention of formula (I) above.
• aminoquinoline- ⁇ -lactam hybrid molecules of formula (XXXIVa), (XXXIVc), (XXXVa) and (XXXVb) have a very high antibacterial activity, in particular on Gram + seeds.
• penicillin has an antibacterial activity of the same level as that of penicillin G. Since PA 1007 is a prodrug, this result suggests an excellent activity in vivo after hydrolysis of the ester function by host enzymes.
• aminoquinoline-cephalosporin hybrid molecules called aminoquinoline-cephalosporin hybrid molecules
• Cephaloquines are very active in vitro on Staphylococcus aureus, Streptococcus pneumoniae sensitive to penicillin and Streptococcus pyogenes at minimal inhibitory concentrations (MIC) between 0.0015 and 0.78 ⁇ g / mL. More interesting still is the activity of some of them on two strains of Streptococcus pneumoniae PRSP resistant to penicillin (CIP 104471 and a clinical isolate) at concentrations between 0.006 and 6.25 ⁇ g / mL for the MIC and between 0.025 and 12.5 ⁇ g / mL for CMB (minimal bactericidal concentration).
• ceftriaxone is one of the antibiotics currently used to treat pneumonia caused by penicillin-resistant P. pneumoniae.
• Hybrid molecules with interesting activity on PRSP pneumoniae (MIC from 0.006 to 0.39 ⁇ g / mL) were also active against Haemophilus influenzae, another causative agent of pneumonia, with MICs of 0.78 to 3, 12 ⁇ g / mL (see Example 39, Tables III and IV).
• the life of the most active molecule on penicillin-resistant pneumoniae is 15 h at pH 1 in solution at 37 ° C whereas ceftriaxone is practically totally degraded under the same conditions and less than 6 hours with a life less than 2 hours (Example 38, Tables I and II).
• hybrid aminoquinoline-quinolone molecules of Formula (XXXVIa) showed remarkable results in terms of antibacterial activity, whether on sensitive strains or on resistant strains.
• the "quinoloquine" PA 1126 (Example 21) is very active on sensitive strains such as S. aureus MSSA (susceptible to black B. subtilis but also on resistant strains such as 5. pneumoniae PRSP, E. faeca / fs VRE or 5.
• PA 1126 is 280-fold more active than the substructure from which it originates (Example 39, Table VII).
• aminoquinoline-nitroimidazole hybrid molecules of formula (XXXVII), such as, for example, "nitroimidaquin" PA 1129 (Example 23) () is of the same level as that of the reference molecule in the family of nitroimidazoles: metronidazole (Example 39, Table VIII).
• the family of aminoquinoline-streptogramin hybrid molecules of formula (XXXVIII) is interesting in view of its narrow spectrum of activity centered on susceptible or resistant Gram + bacteria.
• the activity of the hybrid aminoquinoline-streptogramin PA 1182 molecule (example 26), called a general term “streptogramiquine” or more specifically "pristinaquine” is 4 to 8 times better on Gram + bacteria than that of antibiotic A of which it is composed (Example 39, Table IX).
• erythromycin PA 1169 In this family of hybrid molecules of formula (XLa) called “macroliquines”, exemplified by “erythromycin” PA 1169 (Example 30), the addition of an aminoquinoline to an antibiotic residue of the macrolide family leads to a gain of factor 8 activity on Streptococcus pneumoniae PSSP. In addition, erythromycin PA 1169 is active on an outbreak-efflux resistant Macrophage Streptococcus pneumoniae strain (Erithromycin MIC: 5 ⁇ g / mL, PA 1169 MIC: 1.25 ⁇ g / mL) (Example 39, Table X).
• aminoquinoline-Oxazolidinone hybrid molecules of formula (XLIIa) demonstrate an antibacterial activity equivalent to that of linezolid (the only molecule of the class on the market). It is known to those skilled in the art that the in vivo activity will be very influenced by the pharmacokinetic properties which could be in the case of the aminoquinoline-oxazolidinone hybrid molecules of formula (XLIIa) better than the reference product (Example 39 , Table XII).
• the invention covers compositions, in particular by making use of the properties of these hybrid molecules for the preparation of pharmaceutical compositions.
• the pharmaceutical composition comprises, as active principle, at least one previously defined AQ compound in a pharmaceutically acceptable excipient.
• the pharmaceutical compositions of the invention contain an effective amount of at least one hybrid molecule of formula (I) as defined above, as well as a pharmaceutically acceptable vehicle.
• various forms of excipients may be used adapted to the mode of administration and some of which may promote the effectiveness of the active molecule, for example in promoting a release profile making this active molecule globally more effective for the intended treatment.
• compositions of the invention can thus be administered in different forms, more especially for example in injectable, sprayable or unmanageable form, for example intramuscularly, intravenously, subcutaneously, intradermally, orally, topically, rectally, vaginally, ophthalmically, nasally. , transdermal or parenteral.
• the present invention covers in particular the use of a compound according to the present invention, for the manufacture of a composition, in particular a pharmaceutical composition.
• the compounds according to the invention can advantageously be used in an effective amount. These amounts are generally between 10 mg and 2 g of active ingredient per day.
• compositions of the invention containing an effective amount of at least one hybrid molecule of formula (I) as defined above may also contain other pharmacologically active substances.
• a hybrid AQ molecule of formula (I) may be combined with a resistance enzyme inhibitor such as ⁇ -lactamase inhibitors.
• ⁇ -lactamase inhibitors may be mentioned: clavulanic acid (3- (2-hydroxyethylidene) -7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane-2- acid carboxylic acid), sodium sulbactam ([2S- (2 alpha, 5 alpha)] - S ⁇ -dimethyl - ⁇ y-trioxo - ⁇ - thia-azabicycloCS ⁇ / Ojheptane ⁇ -carboxylate sodium 4,4 dioxide) and tazobactam sodium ([2S- (2 alpha, 3, beta, 5alpha)] - 3-methyl-4,4,7-trioxo-3- (1 / [1,2,3] -triazol-1 sodium ( 4- methyl-4-yl) -thiazol-1-azabicyclo [3.2.0] heptane-2-carboxylate).
• the compositions of the invention are particularly suitable for the treatment of a
• the suspension is stirred magnetically for 15 min before the addition of PyBOP activator (5.4 g, 10.3 mmol). Magnetic stirring is continued for 24 hours at room temperature.
• the reaction medium is then diluted with 100 ml of dichloromethane and then washed successively with 100 ml of carbonated water at 10% (w / v), twice 100 ml of water and 100 ml of water saturated with NaCl.
• the organic phase is dried over magnesium sulfate, filtered and evaporated.
• the oil obtained is purified by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: ethyl acetate). The cleanest fractions in TLC revealed under UV are evaporated.
• PA 1007 is obtained after recrystallization chloroform / n-hexane as a white powder (1.4 g, 23%).
• IR (KBr) cm- 1 : (C O) 1786, 1757, 1681.
• PA 1008 is prepared according to the procedure described in Example 1.2 from 4.3 g of "3- (quinolin-8-ylamino) -propionic acid" (19.9 mmol) (prepared according to the method described by ZJ Beresnevicius et al., Chem Heterocycl, Comp 2000, 36, 432-438), 10.0 g POM-APA-Ts (19.9 mmol), 6.5 ml IM-methylmorpholine (59.1 mmol). and 10.3 g of PyBOP (19.9 mmol).
• PA 1008 is obtained after purification by liquid chromatography on silica gel (SiO 2 6OA CC 6-35 ⁇ m, eluent: n-hexane / ethyl acetate 55/45 v / v) and recrystallization diethyl ether / n-hexane under the form of a yellow powder (2.3 g, 22%).
• aqueous phase is passed over charcoal Norit A hot (100 0 C), filtered and then brought to pH 5 at 0 ° C with an aqueous solution of HCl M.
• the precipitate formed is filtered and washed successively with water, acetone and diethyl ether before being dried under vacuum.
• PA 1117 is obtained as a white powder (27.0 g, 75%).
• PA 1012 is prepared according to the procedure described in Example 1.2 from 1.3 g of "(7-chloro-quinolin-4-ylamino) -acetic acid" (Example 3.1) (5.6 mmol), 2, 8 g of POM-APA-Ts (5.6 mmol), 1.8 ml of N-methylmorpholine (16.4 mmol) and 2.9 g of PyBOP (5.6 mmol).
• PA 1012 is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: ethyl acetate / chloroform 8/2 v / v) and recrystallization chloroform / n-hexane in the form of a white powder (0.3 g, 11%).
• IR (KBr) cm- 1 : (C O) 1784, 1759, 1669.
• This compound is prepared by modification of the method described by W.J. Humphlett et al. (J. Am Chem Soc 1951, 73, 61), according to the procedure described in Example 3.2 and from 25.1 g of 4,7-dichloroquinoline (0.13 mol), 23.6 g ⁇ -alanine (0.26 mol) and 66.5 g of phenol (0.71 mol). The product is obtained in the form of a white powder (19.5 g, 62%).
• PA 1013 is prepared according to the procedure described in Example 1.2 from 2.2 g of "3- (7-chloro-quinolin-4-ylamino) -propionic acid" (Example 4.1) (8.0 mmol), 4.1 g of POM-APA-Ts (8.0 mmol), 2.6 ml of N-methylmorpholine (23.6 mmol) and 4.1 g of PyBOP (8.0 mmol). PA 1013 is obtained after several chloroform / n-hexane recrystallizations in the form of a white powder (1.2 g, 27%).
• Examples 5 to 19 exemplify preparations of hybrid molecules of the aminoquinoline-cephalosporin family.
• Example 5 Preparation of an aminoquinoline-cephalosporin, ref PA 1046
• the filtrate is washed successively with 400 ml of carbonated water at 10% (w / v), twice 400 ml of water and 400 ml of water saturated with NaCl.
• the organic phase is dried over magnesium sulfate, filtered and evaporated.
• the oil obtained is purified by liquid chromatography on silica gel (SiO 2 6OA CC 6-35 ⁇ m, eluent: dichloromethane / ethanol 90/10 v / v).
• the cleanest fractions in TLC revealed under UV are evaporated.
• the coupling product is obtained in the form of an orange powder (3.2 g, 48%) mixed ⁇ 2 / ⁇ 3 37/63, used as such in the next step.
• the reaction medium is then diluted with 150 ml of dichloromethane and then washed successively with twice 150 ml of water and 150 ml of water saturated with NaCl.
• the organic phase is dried over magnesium sulfate, filtered and evaporated.
• the product is obtained after recrystallization dichloromethane / diethyl ether in the form of a beige powder (1.7 g, 46%).
• PA 1046 (Example 5.4) (0.5 g, 1.0 mmol) in 40 ml of a 1/1 v / v chloroform / ethanol mixture is added dropwise 0.8 mL of a solution of 5M HCl in 2-propanol (4.0 mmol). After 30 minutes of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether. The precipitate is filtered, washed with cold ethanol then with diethyl ether and dried under vacuum. PA 1089 is obtained in the form of a light beige powder (0.4 g, 76%).
• PA 1088 (Example 7) (0.5 g, 0.8 mmol) is deprotonated with magnetic stirring for 30 min in 40 ml of water at room temperature. The product is filtered, washed with ethanol and then with diethyl ether and dried under vacuum. PA 1092 is obtained in the form of a slightly yellow powder (0.2 g, 31%).
• the coupling product is prepared according to the procedure described in Example 5.1 from 5.7 g of "3- (7-chloro-quinolin-4-ylamino) -propionic acid” (Example 4.1) (19.8 mmol 2.8 g of HOBT (20.7 mmol), 4.3 g of DCC (20.7 mmol), 8.7 g of "(6R, 7R) -3-acetoxymethyl-7-amino-8- oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester / 7-toluene sulfonic acid »(19.8 mmol) and 2.8 ml of triethylamine (19 8 mmol).
• the coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: ethyl acetate / ethanol 90/10 v / v to remove the impurities and then ethyl acetate / ethanol / triethylamine 90/5/5 v / v / v) in the form of an orange powder (6.1 g, 46%) mixed ⁇ 2 / ⁇ 3 20/80, used as such in the next step.
• the oxidation reaction is carried out according to the procedure described in Example 5.2, starting from 6.4 g of the ⁇ 2 / ⁇ 3 mixture of Example 9.1 (9.5 mmol) and 3.3 g of acid 3. chloroperoxybenzoic acid (19.0 mmol).
• the product is obtained in the form of a yellow powder (4.9 g, 75%).
• PA 1037 is obtained in the form of an unbleached powder after recrystallization by dissolution in 5% (w / v) bicarbonate water and precipitation at 0 ° C. with an aqueous solution of 2M HCl to pH 6 (0.6 g, 27%).
• PA 1063 is obtained by deprotection of "(6R, 7R) -3-acetoxymethyl-7- [3- (7-chloroquinolin-4-ylamino) -propionyl-amino] -5,8-dioxo-5 ⁇ - 4- thiae 1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester "(Example 9.2) (1.1 g, 1.6 mmol) according to the procedure described in Example 5.4 with 0 7 ml of anisole (6.2 mmol) and 1.2 ml of trifluoroacetic acid (15.5 mmol). PA 1063 is obtained in the form of an unbleached powder (0.6 g, 27%).
• PA 1082 is prepared according to the procedure described in Example 6 starting from 0.7 g of PA 1063 (Example 10) (1.4 mmol) and 0.5 ml of a solution of HCl 5 M in the 2 propanol (4.0 mmol). PA 1082 is obtained in the form of an unbleached powder (0.4 g, 55%).
• This compound is prepared according to the procedure described in Example 1.1 from 30.0 g of 4,7-dichloroquinoline (0.15 mol), 32.8 g of 4-aminobutyric acid (0.32 mol) and 77.0 g of phenol (0.82 mol). The product is obtained in the form of a white powder (32.7 g, 82%).
• the coupling product is prepared according to the procedure described in Example 5.1 from 7.8 g of "4- (7-chloroquinolin-4-yl) butyric acid" (Example 12.1) (24.5 mmol). 3.5 g of HOBT (25.7 mmol), 5.3 g of DCC (25.7 mmol), 15.1 g of "(6 R, 7 R) -3-acetoxymethyl-7-amino-8- oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester p-toluenesulphonic acid (24.5 mmol) and 6.9 ml of triethylamine (49, 5 mmol).
• the coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: ethyl acetate / ethanol / triethylamine 90/9/1 v / v / v) in the form of an orange powder (3.3 g, 20%) mixed ⁇ 2 / ⁇ 3 22/78, used as such in the next step.
• PA 1053 is obtained in the form of a white powder after recrystallization by dissolution in 5% (w / v) bicarbonate water and precipitation at 0 ° C. with an aqueous solution of 2M HCl to pH 6 (0.3 g, 35%).
• IR (KBr) cm- 1 : (C O) 1769, 1737, 1653.
• the suspension is stirred magnetically for 15 min before the addition of PyBOP activator (2.0 g, 3.9 mmol). Magnetic stirring is continued for 24 hours at room temperature.
• the reaction medium is then diluted with 50 ml of dichloromethane and then washed successively with 50 ml of 5% (w / v) carbonated water, 2 times 50 ml of water and 50 ml of water saturated with IMaCl.
• the organic phase is dried over magnesium sulfate, filtered and evaporated.
• the coupling product is obtained in the form of an orange powder (2.5 g, 90%) mixed ⁇ 2 / ⁇ 3 32/68, used as such in the next step.
• the product is then purified by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: dichloromethane / ethanol 90/10 v / v).
• the cleanest fractions in TLC revealed under UV are evaporated.
• the product is obtained in the form of an unbleached powder (4.0 g, 38%).
• the reaction medium is then diluted with 20 ml of dichloromethane and then washed successively with twice 20 ml of water and 20 ml of water saturated with NaCl.
• the organic phase is dried over magnesium sulfate, filtered and evaporated.
• the product is obtained after recrystallization dichloromethane / diethyl ether in the form of an unbleached powder (0.5 g, 83%).
• IR (KBr) cm- 1 : (C O) 1783, 1732, 1672.
• the reaction is stirred magnetically for 1 h 30 at room temperature.
• the product in the form of triflate salt, is precipitated by addition of diethyl ether and filtered.
• the powder obtained is washed with water, acetone, diethyl ether before being dried under vacuum.
• PA 1054 is obtained in the form of an unbleached powder (0.2 g, 44%).
• PA 1054 (Example 13.4) (0.5 g, 0.8 mmol) in 40 ml of a 1/1 v / v chloroform / ethanol mixture is added dropwise 0.2 mL of a solution of 5M HCl in 2-propanol (1.0 mmol). After 20 minutes of magnetic stirring at 0 ° C., the product is precipitated with diethyl ether. The precipitate is filtered, washed with cold acetone and then with diethyl ether and dried under vacuum. PA 1074 is obtained in the form of an unbleached powder (0.3 g, 54%).
• This compound is prepared according to the procedure described in Example 1.1 from a mixture of 2.5 g of 4-chloro-7- (trifluoromethyl) quinoline (10.8 mmol), 1.8 g of glycine (23 g). 7 mmol) and 5.7 g of phenol (60.4 mmol) heated for 24 h at 150 ° C. The product is obtained in the form of a white powder (1.8 g, 62%).
• the coupling product is prepared according to the procedure described in Example 13.1 from 0.7 g of "(7-trifluoromethyl-quinolin-4-ylamino) -acetic acid” (Example 15.1) (2.6 mmol), 1.6 g of "(6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester toluene sulphonic acid (2.6 mmol), 1.4 ml of N-methylmorpholine (13.0 mmol) and 1.3 g of PyBOP (2.6 mmol).
• the coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 6OA CC 6-35 ⁇ m, eluent: ethyl acetate / triethylamine / ethanol 96/3/1 v / v / v) in the form of a light beige powder (0.6 g, 32%) mixed ⁇ 2 / ⁇ 3 31/69, used as such in the next step.
• PA 1100 is obtained in the form of a yellow powder after successive washings with water, acetonitrile and diethyl ether (0.1 g, 54%).
• IR (KBr) cm- 1 : (C O) 1772, 1734, 1674.
• This compound is prepared according to the procedure described in Example 1.1 from a mixture of 4.8 g of 4-chloro-quinaldine (27.3 mmol), 4.5 g of glycine (60.0 mmol) and 14.6 g of phenol (155.0 mmol) heated for 24 hours at 150 ° C. The product is obtained in the form of a white powder (3.8 g, 64%).
• the coupling product is prepared according to the procedure described in Example 13.1 starting from 0.7 g of "(2-methyl-quinolin-4-ylamino) -acetic acid” (Example 16.1) (3.5 mmol), 2.2 g of "(6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzene. toluene sulfonic acid hydryl ester "(3.5 mmol), 1.9 mL of N-methylmorpholine (17.5 mmol) and 1.8 g of PyBOP (3.5 mmol).
• the coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 6OA CC 6-35 ⁇ m, eluent: ethyl acetate / triethylamine / ethanol 95/3/2 v / v / v) in the form of an orange powder (1.3 g, 58%) mixed ⁇ 2 / ⁇ 3 21/79, used as such in the next step.
• the oxidation reaction is carried out according to the procedure described in Example 5.2 from 1.3 g of the ⁇ 2 / ⁇ 3 mixture of Example 16.2 (2.0 mmol) and 0.7 g of acid 3 chloroperoxybenzoic acid (4.0 mmol).
• the product is obtained in the form of an orange powder (1.1 g, 83%).
• the coupling product is prepared according to the procedure described in Example 13.1 starting from 3.2 g of "4-morpholin-4-yl-quinoline-2-carboxylic acid” (Example 17.3) (12.4 mmol), 7.5 g of "(6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzene.
• p-toluenesulfonic acid hydryl ester (12.4 mmol
• 4.0 ml N-methylmorpholine (37.2 mmol)
• 6.4 g PyBOP (12.4 mmol).
• the coupling product is obtained after purification by liquid chromatography on silica gel (SiO 2 60A CC 70-200 ⁇ m, eluent: dichloromethane / ethyl acetate 80/20 v / v) in the form of an orange powder (3, 7 g, 45%) in a mixture ⁇ 2 / ⁇ 3 23/77, used as such in the next step.
• the oxidation reaction is carried out according to the procedure described in Example 5.2 from 3.2 g of the mixture ⁇ 2 / ⁇ 3 of Example 17.4 (4.8 mmol) and 2.2 g of acid 3 chloroperoxybenzoic acid (13.0 mmol).
• the product is purified by liquid chromatography on silica gel (SiO 2 6OA CC 70-200 ⁇ m, eluent: dichloromethane / ethyl acetate 80/20 (v / v) in the form of a yellow powder (1.1 g , 33%).
• This compound is prepared according to the procedure described in Example 17.3 from 3.3 g of "4- (2-diethylaminoethylamino) -quinoline-2-carboxylic acid (2-diethylamino-ethyl) amide" (example 18.1) (8.6 mmol) and 34 mL of 2.5 M aqueous sodium hydroxide solution (86 mmol). Reflux heating is maintained for 10 days. After returning to ambient temperature, the reaction medium is diluted with 100 ml of ethanol and 100 ml of water and then it is washed with 200 ml of dichloromethane.
• the pH of the aqueous phase is then brought back to 7, at 0 ° C., with an aqueous solution of 1N HCl.
• the aqueous phase is evaporated to dryness and the product is extracted with 40 mL of DMF with stirring.
• the suspension is filtered and the filtrate is evaporated to dryness in vacuo.
• the product is obtained in the form of an orange oil (2.5 g, 100%).
• the coupling product is prepared according to the procedure described in Example 13.1 from 1.6 g of "4- (2-diethylaminoethylamino) -quinoline-2-carboxylic acid (Example 18.2) (3.2 mmol) 2.0 g of "(6R, 7R) -3-acetoxymethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester / ⁇ -toluenesulphonic acid "(3.2 mmol), 1 mL of N-methylmorpholine (10.0 mmol) and 1.7 g of PyBOP (3.2 mmol).
• the coupling product is obtained after purification by liquid chromatography on gel of silica (SiO 2 6OA CC 70-200 ⁇ m, eluent: dichloromethane / ethanol 90/10 (v / v) in the form of an orange oil (1.1 g, 52%) in admixture ⁇ 2 / ⁇ 3 45 / 55, used as is in the next step.
• the oxidation reaction is carried out according to the procedure described in Example 5.2 from 1.1 g of the ⁇ 2 / ⁇ 3 mixture of Example 18.3 (1.6 mmol) and 0.7 g of acid 3 chloroperoxybenzoic (4.1 mmol).
• the oxidation product is obtained after recrystallization dichloromethane / ether in the form of an orange powder (0.5 g, 39%).
• the deprotection reaction is carried out according to the procedure described in Example 5.4 from 0.2 g of "(6R, 7R) -3-acetoxymethyl-7 - ⁇ [4- (2-diethylaminoethylamino)] - quinoline-2-carbonyl] amino] -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester "(Example 18.5) (0.3 mmol) ), 0.1 mL of anisole (1.3 mmol) and 0.2 mL of trifluoroacetic acid (3.2 mmol). After returning to ambient temperature, the reaction mixture is filtered.
• the filtrate is precipitated with ether and the new filtered precipitate is washed with dichloromethane.
• the latter is solubilized in water and brought to pH 5 with an aqueous solution of NaHCO 3 at 5% (w / v).
• the aqueous phase is evaporated to dryness and the product is extracted with 40 mL of DMF with stirring.
• the suspension is filtered and the filtrate is evaporated to dryness in vacuo.
• the product is obtained in the form of an orange powder (50 mg, 29%).
• PA 1123 (Example 19) (0.1 g, 0.2 mmol) in 10 ml of chloroform is added dropwise 0.4 ml of a solution of 5 M HCl in the 2-propanol (2.0 mmol). After 1 h with magnetic stirring at 0 C 1 the product is precipitated with diethyl ether and filtered. The solid is then stirred again with 100 mL of chloroform for 3 h, then it is filtered, washed with ethanol and with diethyl ether before being dried under vacuum. PA 1126 is obtained in the form of a yellow powder (0.1 g, 77%).
• the reaction medium is diluted with 200 ml of dichloromethane and washed successively with twice 200 ml of water and then 200 ml of water saturated with NaCl.
• the organic phase is dried over magnesium sulfate, filtered and then concentrated on a rotary evaporator until the product begins to precipitate.
• the precipitation is continued at 60 ° C. for 24 h and the filtered product is washed with cold dichloromethane (60 ° C.) and then with diethyl ether before being dried under vacuum.
• PA 1129 is obtained in the form of a white powder (0.1 g, 7%).
• reaction medium After returning to ambient temperature, the reaction medium is concentrated to dryness on a rotary evaporator and purified by liquid chromatography on silica gel (SiO 2 60? CC 6-35 ⁇ m, eluent: dichloromethane / methanol / ammonia 30% 88/10 / 2 v / v / v).
• PA 1173 is obtained after recrystallization from ethanol / water at 60 ° C. in the form of a white powder (0.2 g, 16%).
• Example 26 exemplifies the manufacture of hybrid molecules of the aminoquinoline-streptogramin family
• the suspension obtained is filtered and the precipitate is washed with acetone. After concentration on a rotary evaporator, the filtrate is purified by liquid chromatography on silica gel (SiO 2 60? CC 6? 35 microns, eluent: dichloromethane / methanol / ammonia 30% 92/6/2 v / v / v). PA 1182 is obtained as a pale yellow powder (0.3 g, 44%).
• Examples 27 to 29 below exemplify the manufacture of hybrid molecules of the aminoquinoline diaminopyrimidine family.
• the filtrate is injected into a suspension under argon of the mixture Z and 2 - ⁇ 4- [2- (7-chloroquinolin-4-ylamino) -ethoxy] -benzyl ⁇ -3-phenylamino-acrylonitrile (example 27.2) (0.5 g, 1.1 mmol) in 3 mL of absolute ethanol and this mixture is refluxed for 7 h. After cooling to room temperature, the suspension is filtered and the precipitate is washed successively with water, ethanol and then with diethyl ether. PA 1154 is obtained in the form of a white powder (0.1 g, 26%).
• This compound is prepared according to the procedure described in Example 27.1 from 1.2 g of "(2-bromo-ethyl) - (7-chloroquinolin-4-yl) -amine” (4.3 mmol 0.9 g of vaniline (6.0 mmol) and 1.8 g of potassium carbonate (12.8 mmol) in 20 ml of dimethylformamide.
• the product is obtained in the form of a white powder without purification by liquid chromatography on silica gel but after washing the solid with ethanol (1.0 g, 69%).
• This compound is prepared according to the procedure described in Example 27.2 from 0.5 g of "4- [2- (7-chloro-quinolin-4-ylamino) -ethoxy] -3-methoxy-benzaldehyde" (example 28.1) (1.3 mmol), 0.2 g of anilinopropionitrile (1.5 mmol) and 0.2 g of potassium tert-butoxide (1.5 mmol) in 5 ml of dry dimethylsulfoxide.
• the product is obtained as a mixture of Z and E 1 in the form of a white powder, after recrystallization at 6 ° C. in ethanol to which a few drops of water have been added (0.3 g, 46%).
• PA 1161 is prepared according to the procedure described in Example 27.3 from 0.3 g of guanidine hydrochloride (3.1 mmol), 0.4 g of potassium tert-butoxide (3.1 mmol), and 0.5 g. "2- ⁇ 4- [2- (7-Chloroquinolin-4-ylamino) -ethoxy] -3-methoxy-benzyl ⁇ -3-phenylamino-acrylonitrile" (Example 28.2) (1.0 mmol) in 3 mL of absolute ethanol. After reflux in ethanol, the product is filtered hot and washed with methanol. PA 1161 is obtained in the form of a white powder (0.1 g, 21%).
• This compound is prepared according to the procedure described in Example 27.2 from 1.5 g of "3- [2- (7-chloro-quinolin-4-ylamino) -ethoxy] -4,5-dimethoxybenzaldehyde" (Example 29.1) (3.9 mmol), 0.6 g of anilinopropionitrile (4.2 mmol) and 0.5 g of potassium tert-butoxide (4.4 mmol) in 5 ml of dry dimethylsulfoxide.
• the product is obtained in mixture Z and E 1 in the form of a white powder, after recrystallization at 60 ° C. in ethanol to which a few drops of water have been added (1.1 g, 53%).
• PA 1187 is prepared according to the procedure described in Example 27.3 from 0.3 g of guanidine hydrochloride (3.1 mmol), 0.3 g of potassium tert-butoxide (3.1 mmol), and 0.5 g. "2- ⁇ 3- [2- (7-Chloroquinolin-4-ylamino) -ethoxy] -4,5-dimethoxy-benzyl ⁇ -3-phenylamino-acrylonitrile" (Example 29.2) (1.0 mmol) in 6 mL of absolute ethanol. The reflux in ethanol is prolonged until 20 h and after return to ambient temperature, the product is extracted with chloroform in biphasic medium chloroform / water.
• Example 30 exemplifies the manufacture of hybrid molecules of the aminoquinoline-macrolide family.
• PA 1169 is obtained after recrystallization from propan-2-ol / water 1/1 v / v at 6 ° C, in the form of a white powder (0.3 g, 22%).
• PA 1158 is prepared according to the procedure described in Example 31 starting from 100 mg of vancomycin hydrochloride (0.1 mmol), 32 mg of "4- (7-chloroquinolin-4-ylamino) butyraldehyde” (example 32.2) (0.1 mmol), 0.04 mL of diisopropylethylamine (0.2 mmol) and 17 mg of sodium cyanoborohydride (0.3 mmol) in 3 mL of dry dimethylformamide. The product is purified by semi-preparative HPLC with an isocratic gradient at 17% eluent B for 45 min and a flow rate of 17 ml / min.
• the trifluoroacetic acid salt of PA 1158 is obtained after lyophilization of the collected fractions, in the form of a white powder (10 mg, 9%).
• This compound is prepared according to the procedure described in Example 32.1 from 2.0 g of 4,7-dichloroquinoline (10.0 mmol), and 3.3 ml of aminoacetaldehyde dimethylacetal (30.0 mmol). The product is obtained after recrystallization from a dichloromethane / hexane mixture, in the form of a beige powder (2.3 g, 87%).
• PA 1159 is prepared according to the procedure described in Example 31 starting from 100 mg of vancomycin hydrochloride (0.1 mmol), 24 mg of "(7-chloroquinolin-4-ylamino) acetaldehyde” (Example 33.2) (0.1 mmol), 0.05 mL of diisopropylethylamine (0.3 mmol) and 13 mg of sodium cyanoborohydride (0.2 mmol) in 3 mL of dry dimethylformamide.
• the product is purified by semi-preparative HPLC with an isocratic gradient of 16% eluent B for 45 min and a flow rate of 17 ml / min.
• the trifluoroacetic acid salt of PA 1159 is obtained after lyophilization of the fractions collected, in the form of a white powder (9 mg, 8%).
• reaction mixture is stirred for 7 h at room temperature before the addition of a mixture of "N 1 - (7-chloro-quinolin-4-yl) -ethane-1,2-diamine" (prepared according to the described method). by B. Meunier et al. ChemBioChem 2000, 1 I 281-283) (0.5 g, 2.0 mmol) and triethylamine (0.3 mL, 2.0 mmol) in 15 mL of dichloromethane. Stirring is continued for 17 hours at room temperature. The reaction medium is then diluted with 20 ml of dichloromethane and washed successively with 10 ml of a 1 M aqueous sodium hydroxide solution and then 2 times with 50 ml of water.
• reaction medium After stirring for 24 h at room temperature, the reaction medium is diluted with 100 mL of chloroform and washed with 3 times 10OmL of a saturated solution of bicarbonate water. The organic phase is dried over sodium sulphate, filtered and then concentrated on a rotary evaporator. The product is then purified by liquid chromatography on silica gel (SiO 2 60 ° C. 6-35 ⁇ m, eluent: dichloromethane / methanol 85/15). PA 1185 is obtained after recrystallization from chloroform / n-hexane as a white powder (0.3 g, 24%).
• This compound is prepared according to the procedure described in Example 34 starting from 0.6 g of "3-fluoro-4-morpholin-4-yl-phenyl) -5-hydroxymethyl-oxazolidin-2-one" (2.1 mmol), 0.3 mL triethylamine (2.1 mmol), 0.2 g of triphosgene (0.8 mmol), 0.5 g of "N 1 ⁇ o-chloro-quinolin-2- yl) -ethane-1,2-diamine (2.1 mmol) (prepared according to the method described by TJ Egan et al., J.
• PA 1196 is obtained in the form of a white powder after purification by liquid chromatography on silica gel (SiC 6 60 6 CC 6 -35 ⁇ m, eluent: chloroform / methanoi 91.5 / 8.5 v / v) followed by recrystallization from chloroform / n-hexane (0.5 g, 48%).
• Example 38 Stability Tests of the Aminoalginine-Cephalosporin Hybrid Molecules at Physiological pH and Acid pH
• exemplary aminoquinoline-cephalosporin hybrid molecules was determined in solution at 37 ° C. at physiological pH (pH 7, 75/25 v / v phosphate / acetonitrile buffer) and at acid pH (pH 1, 0.1 M HCl).
• PA 1088 100 100 100 100 100 - - - 81
• PA1074 100 100 100 100 100 100 100 97 88 87
• EXAMPLE 39 Antibacterial Activity of the Hybrid Molecules The antibacterial activity of the exemplary hybrid molecules was evaluated by determining the minimum inhibitory concentrations (MIC) in ⁇ g / mL per micromethod in a liquid medium and minimum bactericidal concentrations (MBC) in ⁇ g / mL.
• MIC minimum inhibitory concentrations
• MMC minimum bactericidal concentrations
• Staphylococcus aureus MSSA methicillin-sensitive CIP 4.83
• Staphylococcus aureus MRSA clinical isolate resistant to methicillin
• Staphylococcus aureus NorA efflux-resistant quinolone
• Staphylococcus aureus MsrA efflux-resistant macrolide
• Staphylococcus aureus VISA intermediate sensitivity to vancomycin
• CIP 106757 Staphylococcus epidermidis MSCNS (methicillin-sensitive Staphylococcus coagulase) E93
• Staphylococcus epidermidis MRCNS methicillin-resistant Staphylococcus coagulase
• Streptococcus pneumoniae PSSP penicillin-sensitive CQI 201 and CIP 69.
• PA 1046 (ex 5) CM 0.20 0.012 0 0,, 000066 0 0,, 0055 0.003 6.25 0.78 3.12 CMB> 50 0.012 00,, 002255 00,, 11 0.003 50 0.78 25
• PA 1089 (example 6) MIC 0.20 nd 0 0,, 3399 0 0,, 3399 nd 6.25 nd 3.12 CMB 0.39 nd 00,, 3399 00,, 3399 nd 12.5 nd> 50
• PA 1092 (ex 8) MIC 12.5 nd 1 1,, 5566 6 6,, 2255 nd> 50 nd 12.5 CMB> 50 nd 33,, 1122 1122,, 55 nd> 50 nd 50
• PA 1037 (ex 9) MIC 0.39 nd 1 1,, 5566 3 3,, 1122 nd 6.25 nd 6.25 CMB> 50 nd 33,, 1122 66,, 2255 nd 25 nd 25
• PA 1053 (ex 12) C CMMII 0 0,, 7788 nd 1 1,, 5566 3 3,, 1122 nd 25 n ndd 6 6,, 2255 K *
• PA 1074 (ex 14) C CMMII 0 0,, 7788 nd 2 255 2 255 nd 50 n ndd 5 500 C CMMBB 11,, 5566 nd 5500 5500 nd> 50 n ndd>> 5500
• PA 1100 (ex 15) C CMMII 0 0,, 2200 0.006 0 0,, 2200 0 0,, 3399 0.003 12.5 0 0,, 7788 0 0,, 7788 C CMMBB 2 255 0.006 00,, 7788 00, , 3399 0.003 25 11,, 5566 2255
• PA 1101 (ex 16) C CMMII 0 0,, 2200 0.006 0 0,, 2200 0 0,, 2200 0.0015 25 0 0,, 7788 1 1,, 5566 C CMMBB 2 255 0.006 00,, 7788 00, , 3399 0.0015 25 00,, 7788 1122,, 55
• CIP 102514 7-ACA 7-aminocephalosporanic acid
• PA 1117 (7-chloro-quinolin-4-ylamino) acetic acid
• PA 1046 Coupling product between 7-ACA and PA 1117.
• aminoquinoline-nitroimidazole hybrid molecules are active on an anaerobic bacterium strain.
• Aminoquinoline significantly improves the activity of streptogramins as shown in the example of the table above.
• raminoquinlein provides an interesting activity gain on penicillin-sensitive pneumoniae but also on an efflux-resistant macrolide strain.
• MSCNS epidermidis 0.78 0.05 0.05 0.003

Applications Claiming Priority (3)

Publications (1)

Family

ID=36000414

Family Applications (1)

Country Status (8)

Families Citing this family (16)

Family Cites Families (33)

• 2005
  • 2005-07-26 CA CA002572442A patent/CA2572442A1/fr not_active Abandoned
  • 2005-07-26 EP EP05793347A patent/EP1771456A2/de not_active Withdrawn
  • 2005-07-26 BR BRPI0514381-0A patent/BRPI0514381A/pt not_active IP Right Cessation
  • 2005-07-26 AU AU2005279050A patent/AU2005279050A1/en not_active Abandoned
  • 2005-07-26 WO PCT/FR2005/001937 patent/WO2006024741A2/fr active Application Filing
  • 2005-07-26 JP JP2007523114A patent/JP2008508243A/ja active Pending
• 2006
  • 2006-09-07 US US11/516,692 patent/US20070060558A1/en not_active Abandoned
• 2007
  • 2007-02-08 NO NO20070725A patent/NO20070725L/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events