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EP2668164A1 - Neue azacoumarinderivate mit einer mdr-pumpen-hemmungswirkung - Google Patents

Neue azacoumarinderivate mit einer mdr-pumpen-hemmungswirkung

Info

Publication number
EP2668164A1
EP2668164A1 EP12706636.3A EP12706636A EP2668164A1 EP 2668164 A1 EP2668164 A1 EP 2668164A1 EP 12706636 A EP12706636 A EP 12706636A EP 2668164 A1 EP2668164 A1 EP 2668164A1
Authority
EP
European Patent Office
Prior art keywords
compound
methyl
dimethoxy
substituted
phenylquinolin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12706636.3A
Other languages
English (en)
French (fr)
Inventor
Anne DOLEANS-JORDHEIM
Jean FRENEY
Charles Dumontet
Ahcène BOUMENDJEL
Jean-Baptiste VERON
Yung-Sing Wong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universite Joseph Fourier Grenoble 1
Hospices Civils de Lyon HCL
Universite Claude Bernard Lyon 1
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite Joseph Fourier Grenoble 1
Hospices Civils de Lyon HCL
Universite Claude Bernard Lyon 1
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Universite Joseph Fourier Grenoble 1, Hospices Civils de Lyon HCL, Universite Claude Bernard Lyon 1 filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP2668164A1 publication Critical patent/EP2668164A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—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
    • A61K31/431—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 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/025—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics

Definitions

  • the subject of the present invention is new azacoumarin derivatives having an inhibitory activity of bacterial efflux pumps (IPE activity), in particular of the NorA pump, responsible for antibiotic resistance of MDR ("Multidrug Resistance”) type, as well as such compounds for their use to enhance the effect of an antimicrobial agent or for their use as an antimicrobial agent.
  • IPE activity bacterial efflux pumps
  • NorA pump responsible for antibiotic resistance of MDR ("Multidrug Resistance") type
  • antibiotic efflux systems Some of these resistances, identified in several Gram-positive and Gram-negative bacteria, especially those implicated in so-called nosocomial infections (acquired at the hospital), are linked to antibiotic efflux systems. These efflux results in decreased intracellular concentrations of antimicrobial agents and thus their effectiveness (Efflux-mediated resistance to fluoroquinolones in gram-positive bacteria and mycobacteria: Keith Poole, Antimicrobial Agents and Chemotherapy 2000, 44 (10), 2595- 2599).
  • the antibiotics concerned by this type of resistance belong, for example, to the classes of fluoroquinolones, tetracyclines or macrolides. It should be noted that this type of resistance is also evident with regard to certain antiparasitic and anti-tumor agents.
  • Bacterial efflux pumps are active transmembrane protein transporters functioning by the energy generated by the electrochemical gradient of the cytoplasmic membrane Microbiologicai Reviews, 1996, 575-608) or by the hydrolysis of ⁇ .
  • the function of these systems is identical despite their structural diversity and their energy source: they oppose the intracellular accumulation of their substrates such as heavy metals, bile salts, and in this case, antibiotics.
  • these systems have a negative impact on antibiotic therapy because they can (i) partially reduce the activity of the antibiotic, (ii) potentiate the effect of other pre-existing resistance mechanisms (enzymatic inactivation of the antibiotic or modification of its target, alteration of bacterial membrane permeability ...) / (iii) promote the emergence of bacteria resistant to conventional antibiotics as a result of genetic mutations (eg fluoroquinolone gyrases), (iv) in general, facilitate adaptation and persistence of bacteria in vivo.
  • inhibitors of bacterial efflux pumps is one of the possible solutions to fight against the bacterial resistance related to the efflux of antibiotics ⁇ Journal of Medicinal Chemistry 2001, 44 (2), 261-268, Antimicrobial agents and Chemotherapy 2001, 45 (1), 105-16, Antimicrobial Agents and Chemotherapy 1999, 43, 2404-2408 and Antimicrobial Agents and Chemotherapy 2003, 47 (2), 719-726)).
  • the microorganisms concerned by these inhibitors are antibiotic-resistant bacteria via an efflux mechanism, in particular staphylococci such as Staphylococcus aureus, streptococci such as Streptococcus pneumoniae, enterococci such as Enterococcus faecalis or E faecium, or other bacterial species including Bacillus subtil / s, Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, etc.
  • Various pumps can be targeted, including the NorA pump, responsible for the expulsion of hydrophilic fluoroquinolones (norfloxacin and or ciprofloxacin).
  • inhibitors of efflux pumps and in particular the NorA pump could thus occupy an important therapeutic place by being used in particular in combination with different antimicrobial agents such as antibiotics or antiseptics. These inhibitors could give a boost of activity to antibiotics that have become ineffective on multi-resistant bacteria by increasing their intracellular concentration. They could also secure the use of certain other antibiotics by significantly reducing the emergence of resistance, including the appearance of mutations in their targets. It should be noted that competitive-type inhibitors should be active on a large number of microorganism species, given the relative specificity of the pumps for the substrate and the homologies between the different carriers.
  • the inventors have identified new inhibitors of efflux pumps, in particular the NorA pump.
  • the inventors have demonstrated that these compounds, of azacoumarin type structure were able to restore the activity of a class of usual antibiotics of the family of fluoroquinolones vis-à-vis resistant bacterial strains.
  • These inhibitors used in particular pharmaceutical compositions, improve the action of an antibiotic whose effectiveness has been reduced, due to its expulsion by NorA pump.
  • These inhibitors can also be used in diagnostic tests for the identification of strains expressing the resistance phenotype.
  • the minimum inhibitory concentrations (MIC) of the antibiotic used in the treatment could be determined in the presence or absence of one of these inhibitors.
  • the results obtained should provide information on the existence and nature of a resistance mechanism to be considered in treatment.
  • R 1 and R 2 which may be identical or different, each independently represent a hydrogen atom or an unsubstituted or substituted (C 1 -C 12) alkyl group,
  • R 3 represents a hydrogen atom or an unsubstituted or substituted (C 1 -C 6) alkyl group, or an unsubstituted or substituted benzyl group,
  • R4 represents a (Ci-Ci 2) unsubstituted or substituted alkyl, aryl or heteroaryl, said aryl and heteroaryl groups may be unsubstituted or substituted
  • R5 is (Ci -C 2) unsubstituted or substituted alkyl
  • R 4 and R 5 are linked by a saturated hydrocarbon chain with 3 or 4 carbon atoms
  • the compounds of formula (I) according to the invention have one or more or all of the following characteristics:
  • R 3 represents a hydrogen atom, or a methyl or benzyl group
  • R 1 and R 2 which are identical or different, each independently represent a hydrogen atom or a methyl group
  • R 5 represents a methyl group
  • R 4 represents a benzyl, phenyl, naphthyl, thiophenyl and indolyl group, said groups possibly being unsubstituted or substituted by one or more substituents chosen from chlorine, bromine, iodine and fluorine atoms, (C 1 -C 6 ) alkyl and (Ci-C 6) alkoxy.
  • the compounds of formula (I) according to the invention have one or more or all of the following characteristics:
  • R3 represents a hydrogen atom
  • R 4 represents an unsubstituted phenyl group, an unsubstituted heteroaryl (and especially thiophenyl or indolyl) group or a phenyl group carrying one, two, three or four substituents chosen from chlorine, bromine, iodine and fluorine atoms, the groups (Ci-C 6) alkyl and (Ci-C6) alkoxy, the substituents chlorine or methoxy being preferred,
  • R 5 represents a methyl group
  • Ri represents a hydrogen atom
  • R 2 represents a (C 1 -C 6) alkyl group, and in particular methyl.
  • the compounds of formula (I) according to the invention have one or more or all of the following characteristics:
  • R3 represents a group of hydrogen, or a (C1-C6) alkyl group and in particular methyl
  • R4 represents an aryl, aryl (C1-C6) alkyl group, and in particular benzyl, or a heteroaryl group
  • R 5 represents a (C 1 -C 6 ) alkyl group, and especially methyl
  • Ri represents a methyl group
  • R 2 represents a (CI-C O) alkyl, and especially methyl.
  • the subject of the present invention is also compounds 1.1 to 1.16 as such, as well as the compounds as such of formula (Ip):
  • R 1 and R 2 which are identical or different, each independently represent a hydrogen atom or an unsubstituted or substituted (C 1 -C 2 ) alkyl group,
  • R 3 represents a hydrogen atom or an unsubstituted or substituted (Ci-C 6 ) alkyl group, or an unsubstituted or substituted benzyl group,
  • R 5 represents an unsubstituted or substituted C1-C11 alkyl group, optionally in hydrated form or in the form of a salt acceptable for administration to animals or plants.
  • the compounds of formula (Ip) according to the invention have one or more or all of the following characteristics:
  • R5 represents a methyl group
  • R3 represents a hydrogen atom or a methyl or benzyl group
  • R 1 and R 2 which are identical or different, each independently represent a hydrogen atom, or a methyl group.
  • alkyl is meant, when not more precise, a saturated hydrocarbon radical, linear or branched.
  • group (C 1 -C 6 ) alkyl is meant an alkyl group which has from 1 to 6 carbon atoms.
  • alkyl group mention may be made of methyl, ethyl and n-methyl groups.
  • aryl group is meant a mono-, bi- or polycyclic carbocycle, preferably comprising from 6 to 12 carbon atoms, comprising at least one aromatic group, for example a phenyl, cinnamyl or naphthyl group. Phenyl is the most preferred aryl group.
  • heteroaryl group is meant a mono-, bi- or polycyclic carbocycle, preferably containing from 6 to 12 carbon atoms, and comprising at least one heteroatom and aromatic group.
  • a heteroaryl group mention may be made of thiophenyl, indolyl, pyridyl, benzopheranyl and benzothiophenyl groups.
  • substituted group such a mono or poly-substituted group, by two or more identical or different substituents chosen from: a fluorine, chlorine, bromine or iodine atom, a hydroxy group, (Ci-Cl 2 ) alkyl, (C 1 -C 2 ) acenyl, (C 1 -C 2 ) alkoxy, (C 5 -C 12 ) cycloalkyl, benzyloxy, aryl, sulfhydryl, carboxy, or an amino group -NRaR b with Ra and R b same or different which represent , each independently of one another, a hydrogen atom or a (C 1 -C 2 ) alkyl group or else R a and R b are linked together to form, together with the nitrogen atom to which they are bonded piperidine, pyrrolidine, piperazine, N- (C 1 -C 2 ) alkylpiperazine or morpholine.
  • Benzyl is
  • alkenyl is an alkyl group as defined above comprising a double bond.
  • Vinyl, allyl, isopropenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl are examples of such alkenyl groups.
  • alkoxy refers to an O-alkyl group.
  • cycloalkyl denotes a cycloalkyl group comprising from 3 to 10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bridged cycloalkyl groups such as adamantyl, bicyclo [3.2.1] optanyl groups.
  • heterocycloalkyl means a cycloalkyl such as defined above, comprising one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • Sulfhydryl is -SH and carboxyl -COOH.
  • treatment means any prophylactic or suppressive therapeutic measure of a disease or disorder leading to a desirable clinical effect or any beneficial effect, including in particular the suppression or decrease of one or more symptoms, regression, slowing or cessation of the progression of the disorder associated with it.
  • terapéuticaally effective amount is meant any amount of a composition that improves one or more of the characteristic parameters of the condition being treated.
  • potentiator of the effect of an antimicrobial agent is meant that the antimicrobial effect of an antimicrobial agent is increased, when the latter is used in combination with the potentiating agent, namely a compound of formula (I ) Yes P). This increase can in particular be highlighted on one of the tests presented in the examples below.
  • the antimicrobial effect then observed is increased by at least a factor of 4 relative to the reference activity obtained with the tested antimicrobial agent in the absence of a potentiating agent, namely the compound of formula (I ) or (Ip), which means that the minimum inhibitory concentration of the antimicrobial agent then obtained is at least divided by 4 relative to that required in the absence of potentiating agent.
  • antibiotic agent in particular substances capable of inhibiting the growth of microorganisms, or even of killing them.
  • antibiotics having bacteriostatic activity (substance inhibiting bacterial growth) and bactericidal (substance killing bacteria). More particularly, the IPE activity of the molecules favors the class of fluoroquinolones including ciprofloxacin.
  • the compounds used in the context of the invention are prepared according to conventional techniques.
  • the compounds of formula (I) can be obtained according to SCHEME 1 below, wherein R 3 , and R 5 are as defined above for (I), R ' 1 and R' 2 respectively represent R 1 and R 2 as defined above for (I) or a precursor group thereof, X represents a halogen atom and in particular chlorine and R 'represents an alkyl group and especially an ethyl group.
  • the compound of formula (II) can, for its part, be obtained from the compound of formula (III) commercial or obtained by simple chemical syntheses, either by action of an acid chloride R4-CH2-C (0 ) -Cl, in the presence of triethylamine, or by the action of an acid R4-CH2-C (O) -OH, in the presence of triethylamine and an acid such as bis (2-oxo-3-oxazolidinyl) acid; ) phosphonic acid (BOP-CI).
  • the compounds of formula ( ⁇ ) thus prepared can correspond to a compound of formula (I), if the groups R'i and R'2 are respectively Ri and R2. It is also possible to obtain the desired group Ri or 2 from a precursor group R'i or R'2 after one or more transformations.
  • the molecules of formula (I) are therefore of simple chemical access, and can be obtained at a low cost of preparation.
  • the salts of the compounds according to the invention are prepared according to techniques well known to those skilled in the art.
  • the salts of the compounds of formula (I) and (Ip) according to the present invention include those with inorganic or organic acids or bases which allow a suitable separation or crystallisation of the compounds of formula (I) or (Ip), as well as as pharmaceutically acceptable salts.
  • Suitable acids are: oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulfonate, paratoluenesulfonate, mesylate, besylate, isotionate.
  • physiologically acceptable salts such as sodium, potassium and calcium salts.
  • compound in hydrated form there may be mentioned, for example, the semihydrates, monohydrates and polyhydrates.
  • the compounds of formula (I) and (Ip) above also include those in which one or more hydrogen, carbon or halogen atoms, in particular chlorine or fluorine atoms, have been replaced by their radioactive isotope, for example the tritium or carbon-14.
  • radioactive isotope for example the tritium or carbon-14.
  • the functional groups optionally present in the molecule of the compounds of formula (I) or (Ip) and in the reaction intermediates can be protected, either in permanent form or in temporary form, by protecting groups which ensure a unambiguous synthesis of the expected compounds.
  • the protection and deprotection reactions are carried out according to techniques well known to those skilled in the art.
  • temporary protective group of amines, alcohols or carboxylic acids is meant protective groups such as those described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G., ed. John Wiley and Sons, 2006 and in Protecting Groups, Kocienski P.J., 1994, Georg Thieme Verlag.
  • the inventors have demonstrated the potentiating effect of the compounds according to the invention by fluoroquinolones, and in particular hydrophilic fluoroquinolones such as norfloxacin or ciprofioxacin, on gram-positive bacteria belonging to the staphylococcus or enterococcus genera. These effects include resistant strains, such as methicillin-resistant Staphylococcus aureus strains (MRSA) or glycopeptides (GISA for Glycopeptides Intermediate S. aureus).
  • MRSA methicillin-resistant Staphylococcus aureus strains
  • GISA glycopeptides
  • the compounds according to the invention have an activity improving by a factor 2 to 128 the activity of the conventional antibiotic.
  • the mechanism of action of this potentiating effect goes through an inhibitory activity of bacterial efflux pumps and, in particular, of NorA.
  • the compounds according to the invention can therefore be used to potentiate the effect, that is to say increase the effect, of antimicrobial agents and in particular antibiotics become inactive on resistant strains via an efflux mechanism.
  • potentiation it is meant that by combining a compound of formula (I) or (Ip) with an antimicrobial agent, an antimicrobial effect superior to that obtained with one or other of the compounds and even synergistic, is obtained. ie greater than the sum of the effects obtained separately.
  • the compounds of formula (I) or (Ip) can thus be used to restore the action of traditional antibiotics, in cases where efflux pumps are responsible for significant resistance to these antibiotics.
  • antibiotic resistance include resistance to quinolones of Staphylococcus aureus and Streptococcus pneumoniae, as well as various resistance of Pseudomonas aeruginosa (ASMNews, (1997), 63, 605-610).
  • ASMNews (1997), 63, 605-610).
  • the compounds of formula (I) or (Ip) can be used in pharmaceutical or phytosanitary compositions intended to restore the efficacy of antibiotic agents which have been affected by a NorA expulsion mechanism.
  • These compositions may contain, in addition to the inhibitor, an antibiotic, in particular of the family of fluoroquinolones, and a usual excipient allowing ingestion and transport of the active principles.
  • the compounds according to the invention may be used for the preparation of a medicament with antimicrobial activity or, preferably, for the preparation of a medicinal product intended to improve the action of antimicrobial agents of which efficiency is affected by efflux pump mechanisms, in particular NorA.
  • the administration of a compound of formula (I) or (Ip) is therefore accompanied by the administration of the antimicrobial agent whose activity is to be improved.
  • the compound of formula (I) or (Ip) may be formulated in combination with said antimicrobial agent or formulated separately. It can also be used for performing diagnostic tests such as an antibiogram to highlight, for the strain concerned, an efflux resistance mechanism.
  • the subject of the present invention is therefore also the compounds of formula (Ip), as well as compounds 1.1 to 1.16, their pharmaceutically compatible salts, or optionally solvents or hydrates, as medicaments.
  • compositions administrable to plants and animals contain an effective dose of a compound according to the invention or an acceptable salt, solvate or hydrate thereof, and suitable excipients.
  • Said excipients are chosen according to the form and the desired mode of administration.
  • the active ingredients of formula (I) or (Ip) above, or their salts, solvates and hydrates may be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of infectious diseases related to resistant bacteria. or not.
  • Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal, dosage forms.
  • the compounds according to the invention can be used in creams, ointments, lotions or eye drops.
  • the dose of active ingredient preferably varies between 1 and 100 mg per kg of body weight per day.
  • the compound (I) or (Ip) and the antimicrobial agent whose effect is to be potentiated are advantageously administered in a ratio of 4 to 1.
  • the main active ingredient is mixed with a pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative, or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a quantity predetermined active ingredient.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
  • compositions containing a compound of the invention may also be in liquid form, for example, solutions, emulsions, suspensions or syrups.
  • suitable liquid carriers may be water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
  • a preparation in the form of syrup, elixir or dropwise administration may contain the active ingredient together with a preferred calorie-free sweetener, methylparaben and propylparaben as an antiseptic as well as a flavoring agent and a flavoring agent. appropriate dye.
  • the water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents, or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or preservatives. taste correctors.
  • compositions containing a number of active ingredients in combination, one of which is a compound (I) or (Ip) and the other an antimicrobial agent as previously defined.
  • the subject of the present invention is also the use of the inhibitors as defined above in diagnostic methods and in particular their use for demonstrating in vitro the presence in a biological sample of antibiotic-resistant bacteria and their degree. of resistance.
  • Derivative 2 (1.52 g, 4.39 mmol) is dissolved in f-BuOH (5 mL / mmol).
  • f-BuOK (5 eq.) is added and the solution is stirred at room temperature for 12 hours.
  • the f-BuOH is then evaporated under vacuum and a saturated solution of NH4Cl is added.
  • the solution is extracted with ethyl acetate (AcOEt), washed with water, then with saturated NaCl solution and finally dried over MgSO-.
  • the organic phase is concentrated and the product is crystallized in MeOH and the crystals are washed with CH 2 Cl 2 to provide the pure product 3.
  • 3-Amino-5-methoxyphenol 7 (prepared according to Chakraborti, AK, Sharma, L, Nayak, MK 3. Org Chem 2002, 67, 6406-6414.) Is placed in a flask, with the derivative of ethyl acetoacetate 8 (2 to 1.1 equiv) dissolved in chlorobenzene. The reaction mixture is placed in a microwave reactor. The reaction proceeds at 160 ° C and 130 W for a time of between 5 and 30 min.
  • the same reaction can be performed by thermal heating.
  • the reaction medium is placed directly at 165 ° C. in a graphite bath.
  • the reaction mixture is refluxed under argon between 2 and 72 hours.
  • the product of the reaction precipitates in chlorobenzene at room temperature, it is filtered and then washed with dichloromethane.
  • All the compounds according to the invention are solubilized in dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • the highest concentration that can be used during the experiments is determined taking into account the toxicity of the solvent (final concentration of DMSO in contact with the bacteria of less than 3%) as well as the capacity of the compound to solubilize in medium.
  • Mueller Hinton II (MH II) Indeed, certain compounds precipitate dilutions of DMSO-based solutions in MH II medium.
  • the antibiotic used is a fluoroquinolone: ciprofloxacin. Its solubilization is carried out in sterile osmosis water or MH II acidified with a solution of HCl. Twenty ⁇ l of 12 N HCl (or 5 ⁇ l of 35% HCl) are required to solubilize 10 mg of ciprofloxacin in 1 ml of sterile osmosis H 2 0. -Bacterial strains
  • the strain allowing the screening of the compounds is a strain of Staphylococcus aureus derived from the "American Type Culture Collection" or ATCC called S. aureus ATCC 29213.
  • This potentiating effect is evaluated by comparing the MIC of ciprofloxacin alone with that of ciprofloxacin associated with a compound according to the invention according to the MIC method. This was performed according to the protocol described by the Antibiogram Committee of the French Society of Microbiology (CASFM) and the Clinical and Laboratory Standards Institute (CLSI). The determination of the MICs is carried out in round-bottomed 96-well micro-plate in MH II liquid medium. A dilution range of ciprofloxacin is carried out in MH II medium.
  • each well of a first column are mixed 100 ⁇ l of a bacterial suspension at 10 6 CFU / ml, 50 ⁇ l of a dilution range of ciprofloxacin and 50 ⁇ l of MH II.
  • each well of a second column are mixed 100 ⁇ l of a bacterial suspension at 10 6 CFU (Colony Forming Unit) / ml, 50 ⁇ l a concentration range of ciprofloxacin and 50 ⁇ l of a solution of a compound according to the invention at the highest possible concentration.
  • the lowest antibiotic concentration for which no bacterial growth is observed is recorded in the 2 columns with and without synthetic molecule.
  • a compound according to the invention has a potentiating effect on the activity of ciprofloxacin compared to the effect of ciprofloxacin only if the MIC of it is lowered by a dilution factor> 4 in the presence of this compound. Evaluation of the antibiotic activity of the compounds according to the invention alone
  • the antibiotic activity of a molecule is evaluated by the MIC technique.
  • the determination of the MIC of a molecule is carried out in a 96-well microplate, in a MH II liquid medium according to the CASFM and CLSI protocol.
  • a dilution range of the molecule is carried out beforehand in MH II medium.
  • 100 ⁇ l of a bacterial suspension of S. aureus ATCC 29213 (10 6 CFU / ml) 50 ⁇ l of the dilution range of the test compound and 50 ⁇ l of MH II.
  • After 18-24 h of incubation at 37 ° C, the molecules having shown inhibition of bacterial development are listed as having antibiotic activity.
  • the lowest concentration of compound for which no bacterial growth is observed is the MIC (lowest concentration inhibiting growth of bacteria).
  • the 16 compounds according to the invention tested potentiate the activity of ciprofloxacin (to different degrees).
  • the antibiotic used is ciprofloxacin with the same dilution as in paragraph B1.
  • Compound 1.12 is also used under the same conditions as in paragraph B1. - Bacterial strains
  • ATCC strains Nine of these strains are ATCC strains and 47 are of clinical origin and come from the East Bron Biology Center. Eighteen staphylococcal strains are tested: 1 strain of S. epidermidis, 2 strains of 5. aureus, 10 MRSA (S. Meticillin-resistant Aureus) and VISA (S. aureus of intermediate susceptibility to Vancomycin). Sixteen strains of enterococci are also tested, ie 9 faecium and 7 faecafis. These last 2 species include 2 vancomycin-sensitive strains (1 per species), and 14 resistant strains (VRE, respectively 8 £ faecium and 6 £ faecalis). The other genres are listed in TABLE 6 above.
  • the antibiotic activity of compound 1.12 is evaluated by the technique of (MIC) according to the protocol described above, taking into account the blood requirements of certain strains.
  • strains tested 28 were found to be more sensitive to ciprofloxacin when compound 1.12 was associated with it. These strains are Gram-positive bacteria of the Staphylococcus and Enterococcus type, including resistant (or even multiresistant) strains:
  • SASM S. aureus sensitive to meticillin
  • SASM S. aureus sensitive to meticillin
  • VISA S. aureus of intermediate sensitivity to vancomycin
  • VSE Vancomycin-sensitive Enterococci
  • ERV Vancomycin-Resistant Enterococcus
  • the C Is of ciprofloxacin are divided by a factor> 16 in the presence of the compound 1.12 except for a strain whose activity is> 4.
  • Two strains of E faecium ERV not listed in the 28 previously mentioned are weakly sensitive to the action of the combination of compound 1.12 with ciprofloxacin (factor> 2).
  • strains sensitive to the action of compound 1.12 alone are the same strains (clean antibiotic effect of compound 1.12).
  • the antibiotics used are erythromycin, ciprofloaxacin, vancomycin, tetracycline and oxacillin.
  • Ciprofloxacin is prepared as previously described.
  • Vancomycin is taken up at a concentration of 10 mg / mL of sterile reverse osmosis water. The solution is then diluted 10-fold and then 15.6-fold in MHII broth to obtain a stock solution of 64 ⁇ g / mL (16 ⁇ g / mL in well).
  • the tetracycline is taken up in sterile osmosis water at a concentration of 10 mg / tetracycline.
  • the solution is then diluted 10-fold and then 31.3-fold in MHII broth to obtain a stock solution of 32 ⁇ g / mL (8 ⁇ g / mL in well).
  • the oxacillin is taken up in sterile osmosis water at a concentration of 10 mg / ml
  • the solution is then diluted 10-fold and then 62.5-fold in MH II broth to obtain a stock solution of 16 mg / ml. (4 mg / mL in cup).
  • the S. aureus strains used are:
  • the sensitivity of S. aureus ATCC 29213 to the combination of ciprofloxacin antibiotic molecules and compound 1.12 and the effect of each of the two molecules on the activity of the other are determined by the chessboard method. This method is carried out in 96-well plate with round bottom (12 columns by 8 lines). Different concentrations of ciprofloxacin and compound 1.12 are obtained by diluting their stock solutions in MH II broth. Fifty microliters of the dilution range of compound 1.12 are deposited in each well of columns 1 to 10, each line corresponding to a dilution of this compound. Fifty microliters of the dilution range of ciprofloxacin are deposited in the wells of columns 2 to 10, each column corresponding to a dilution.
  • the reading of the plate is done visually.
  • the 200 ⁇ of reagents introduced into each well are either turbid (bacterial growth) or translucent (lack of bacterial growth).
  • the fractional inhibitory concentration (FIC) was calculated by summing the FIC FIC compound 1.12 and ciprofloxacin (FIC C i pr o) according to the following formulas (FIC1 February 1st.):
  • FIC1.12 MIC of compound 1.12 in combination with ciprofloxacin / MIC of compound 1.12 alone
  • -FICcipro MIC of compound 1.12 in combination with ciprofloxacin / MIC of ciprofloxacin alone
  • a FIC ⁇ 0.5 corresponds to a synergy between the two molecules
  • a FIC> 4 corresponds to an antagonism of the two molecules
  • a FIC between 0.5 and 4 corresponds to an absence of interaction between the two molecules.
  • a synergistic or antagonistic effect of the two molecules is defined by a decrease> 2 log 10 CFU / ml and an increase> 2 log 10 CFU / ml between the wells containing the combination of the two molecules and those containing the most active molecules.
  • the chessboard method highlights:
  • FIG. ⁇ 0.5 A synergistic combination (FIC ⁇ 0.5) antibacterial of 1.12 and ciprofloxacin sur5. aureus ATCC 29213 or resistant strains of the type SARM (strain ST07 1012) and VISA (strain V4). Lack of interaction (FIC> 0.5 but ⁇ 4) between 1.12 and oxacillin, erythromycin, tetracycline, vancomycin on the same bacterial strain.
  • Some of these compounds also possess significant antibiotic activity. In combination with ciprofloxacin, their action becomes synergistic with that of the antibiotic (and not simply additive). This synergy makes it possible to reduce the antibiotic concentrations used in vitro to destroy the bacteria and presumably those used in vivo (reduction of the toxic effects attributed to the anti-infectious molecules). This activity is found even on strains SARM and VISA. The presence of a synergistic effect is probably related to the inhibitory activity of the efflux pumps of the compounds according to the invention.
  • the molecules whose IPE effect has been evaluated are: 1.1 (24 ⁇ / L), 1.6 (16 ⁇ / L) and 1.14 (31 pmol / L).
  • the antibiotics with which these molecules have been associated are: ciprofloxacin and norfloxacin; tetracycline; oxacillin; erythromycin and vancomycin.
  • Bacterial Strains The bacterial strains tested are S. aureus ATCC 29213; S. aureus 1199b overexpressing NorA as well as S. aureus 1199 the strain from which it is derived; S. aureus K1712 not expressing NorA as well as S. aureus 8325.4 (the strain from which it is derived).
  • Compound 1.6 allows an improvement in MICs of factors 4, 8 or even 16 when in the presence of norfloxacin and ciprofloxacin. This activity is particularly notable when the compound associated with one of the two fluoroquinolones is evaluated with the strain 1199b overexpressing NorA. This activity is however zero when the associations are evaluated on the strain K1712. Finally, this activity is not very effective when the molecule is coupled to non-fluoroquinolone antibiotics.

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