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WO2020169683A1 - Dérivés d'hydrazonopyrrolidine à utiliser dans la prévention et/ou le traitement de troubles associés à acinetobacter baumannii - Google Patents

Dérivés d'hydrazonopyrrolidine à utiliser dans la prévention et/ou le traitement de troubles associés à acinetobacter baumannii Download PDF

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WO2020169683A1
WO2020169683A1 PCT/EP2020/054393 EP2020054393W WO2020169683A1 WO 2020169683 A1 WO2020169683 A1 WO 2020169683A1 EP 2020054393 W EP2020054393 W EP 2020054393W WO 2020169683 A1 WO2020169683 A1 WO 2020169683A1
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char
alkyl
compound
mmol
halo
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Inventor
Anca Elena DASCALU
Muriel ROULEAU BILLAMBOZ
Alina GUINET
Benoît RIGO
Emmanuelle LIPKA BELLOLI
Ruben Christiaan HARTKOORN
Coline PLE
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Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Yncrea Hauts de France
Institut Pasteur
Universite de Lille
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Yncrea Hauts de France
Institut Pasteur
Universite de Lille
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/427—Thiazoles not condensed 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to hydrazonopyrrolidine derivatives compounds for use for preventing and/or treating disorders associated to Acinetobacter baumannii.
  • the present invention also relates to pharmaceutical compositions containing said compounds and the process for preparing said compounds.
  • Acinetobacter baumannii is a Gram-negative coccobacillus, a commensal of the skin, especially its moist regions, and of the digestive tract.
  • Acinetobacter is mainly responsible for nosocomial infections, especially in immune-depressed patients.
  • the associated pathologies are sepsis, pneumopathy, meningitis, endocarditis, abscess, wound superinfection, urinary tract infection.
  • the main species involved is Acinetobacter baumannii.
  • Acinetobacter is strictly aerobic, oxidase negative and catalase positive.
  • the use of glucose via the oxidative pathway is common but may be absent.
  • Acinetobacter baumannii has emerged as one of the most problematic pathogens in healthcare facilities. It is involved in 2% to 4% of nosocomial infections in the EU and the USA. Its capacity for long-term survival in hospitals, combined with the emergence of resistance, potentiates its ability for nosocomial spread. This pathogen generally targets the most vulnerable patients. Nosocomial pneumonia is the most common infection. Recently, however, bacteraemia and infections of the skin, the soft tissue, the urinary tract or the central nervous system have emerged as highly problematic for certain institutions.
  • the main antibiotics used to treat it are carbapenems, ampicillin in combination with sulbactam, tigecycline, aminoglycosides and colistin.
  • carbapenems ampicillin in combination with sulbactam, tigecycline, aminoglycosides and colistin.
  • 61 % of Acinetobacter baumannii strains are resistant to carbapenems and 65% have combined resistance to at least 3 classes among carbapenems, ampicillin/sulbactam, aminoglycosides, cephalosporins, fluoroquinolones and piperacillin.
  • the mortality rate for multidrug-resistant A. baumannii nosocomial infections is 25%, while the overall mortality rate for nosocomial infections is 0.9%.
  • the reference antibiotics are cephalosporinases as first-line treatment, with a high failure rate due to the resistances observed.
  • the antibiogram of A. baumannii infection must be broad and complete in order to choose the best therapeutic approach.
  • Colistin a polypeptide antibiotic of the polymyxin family, often remains the drug used as a last resort against resistant strains.
  • certain multidrug-resistant strains with colistin resistance have recently been described.
  • a second strategy aims to increase the sensitivity of bacterial strains to known antibiotics.
  • a third strategy is to discover new compounds capable of selectively controlling the bacterium Acinetobacter baumannii.
  • the inventors have discovered new compounds with antibacterial properties that are specific to the multidrug-resistant bacterium Adnetobacter baumannii.
  • the compounds of the invention are therefore capable of selectively controlling the bacterium Adnetobacter baumannii.
  • a first object of the invention is a compound of the following general formula (I ):
  • A is a group selected from (Cr -Cio)alkyl, (C 3 -Cio)cycloalkyl, aryl or heteroaryl; said (Ci -Ci 0 )alkyl group being optionally substituted with one or several groups selected from halo, oxo, -CF 3 , -CN, - N0 2 , -NO + , -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 COR 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 RS, CO 2 R 7 , -COR 8 , -CONR 7 R 8 , - CO(NR 7 R 8 ) 2 , -C0NR 7 NR 8 R 9 , -SR ?
  • n 1 , 2 or 3;
  • R and R’ are, independently of one another, hydrogen, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -N0 2 , -
  • Ri is a hydrogen atom or a (Ci -Cio)alkyl group being optionally substituted with one or several groups selected from halo, oxo, -CF 3 , -CN, -N0 2 , -NCT, -OR 7 , -NR R 8 , -NR 7 NR 8 R 9 , -NR 7 COR 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 RS, C0 2 R 7J -CORS, -CONR 7 R 8 , -CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR 7 , -S(0) 2 R 7 , -OCOR 7 , -OCONR 7 R 8 , and -0S(0) 2 R 7 ; and
  • Each R 7 to R 9 are, independently of one another, hydrogen atom, halo, (CrC 6 )alkyl or halofCr C 6 )alkyl;
  • Another object of the invention is a pharmaceutical composition comprising at least one compound of formula (I) of the invention and at least one pharmaceutically acceptable excipient, for use for preventing and/or treating disorders associated to Acinetobacter baumannii.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • At least one other active ingredient such as one other active ingredient that can be used for preventing and/or treating disorders associated to Acinetobacter baumannii
  • the term“pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
  • pharmaceutically acceptable salt or solvate is intended to mean, in the framework of the present invention, a salt or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.
  • pharmaceutically acceptable salts comprise:
  • Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents.
  • solvates due to the presence of water these solvates are also called hydrates) or ethanol.
  • (CrCio)alkyl refers to a straight or branched saturated hydrocarbon chain containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ferf-butyl, n-pentyl, iso-pentyl, sec- pentyl, ieri-pentyl, n-hexyl, iso-hexyl, sec-hexyl, tert-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • (Ci-C 6 )alkyl refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, f-butyl, n-pentyl, iso-pentyl, sec- pentyl, ferf-pentyl, n-hexyl, iso-hexyl, sec-hexyl, terf-hexyl, and the like.
  • (C3-Cio)cycloalkyl refers to a hydrocarbon monocycle, bicycle or tricycle (i.e. comprising fused rings), each cycle having having 3 to 6 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, decahydronaphthyl, indenyl, indanyl, adamantyl and the like.
  • aryl refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more, notably 1 or 2, fused rings, such as, for example, a phenyl or naphthyl group.
  • fused rings such as, for example, a phenyl or naphthyl group.
  • it will be a phenyl group.
  • the term“5- or 6-membered aryl” as used in the present invention refers to an aryl as defined above having 5 or 6 carbon atoms in the ring(s).
  • (Ci-C 6 )alkylaryl refers to an aryl group as defined above, bound to the molecule via a (CrC 6 )alkyl group as defined above.
  • heteroaryl refers an aromatic hydrocarbon monocycle or bicycle (i.e. comprising fused rings), each cycle having advantageously 5 or 6 members, notably 6 members, and 1 to 4, notably 1 or 2, carbon atoms having each been replaced with a heteroatom such as a nitrogen, sulfur or oxygen atom, preferably nitrogen or oxygen atom.
  • a heteroaryl can be notably thiophene, furan, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazoles (1 ,2,3-triazole and 1 ,2,4-triazole), benzofuran, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, isoquinoline, quinoxaline, quinazoline, etc.
  • heteroaryl refers to a heteroaryl as defined above having 5 or 6 atoms in the ring(s).
  • halogen refers to a fluorine, bromine, chlorine or iodine atom.
  • stereoisomers is intended to designate diastereoisomers or enantiomers. These are therefore optical isomers. Stereoisomers which are not mirror images of one another are thus designated as “diastereoisomers,” and stereoisomers which are non- superimposable mirror images are designated as“enantiomers”.
  • a first object of the invention is a compound of formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, wherein A, X, Y, n, R and R’ are as defined above.
  • n is an integer between 1 to 3.
  • n is 1 or 2, more advantageously, n is 1.
  • A is a group selected from (Ci -Ci 0 )alkyl, (C 3 -Ci 0 )cycloalkyl, aryl or heteroaryl; said (Ci-Ci 0 )alkyl group being optionally substituted with one or several groups selected from halo, oxo, -CF3, -CN, -NO 2 , -NO + , -OR7, -NR7R8, -NR7NR8R9, -NR7COR8, -NR7CO 2 R8, - NR 7 S(0) 2 R8, CO2R7, -CORs, -CONR7R8, -CO(NR 7 R 8 )Z, -CONR7NR8R9, -SR7, -S(0) 2 R 7 , -OCOR7, -OCONR7R8, and -0S(0) 2 R 7 ; said (C 3 -Ci 0 )cycloalkyl group being optionally
  • A is a group selected from (CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl or heteroaryl; said (Ci-C 6 )alkyl group being optionally substituted with one or several groups selected from halo, oxo, R7, -CORS, -CON said (C 3 - C 6 )cycloalkyl group being optionally substituted with one or several groups selected from halo, oxo, (C,-C 6 )alkyl, -CF 3 , -CN, -NO2, -NO + , -OR7, -NR 7 R 8 , -NR 7 NR 8 R9, -NR 7 C0R 8 , -NR7CO2R8, -NR 7 S(0) 2 R8, CO2R7, -CORs, -CONR7R8, -CO(NR 7 R 8 )2, -C0NR 7 NR 8 R 9 , -SR?,
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (Ci-C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO + , -OR 7 , - -CO2R7, -CORs, -CONR7R8, - being as defined above.
  • A is a group selected from aryl or 5-6-membered heteroaryl, said group being optionally substituted with one or several groups selected from halo, (C t -Cijalkyl, -CF 3 , -CN, -NO2, - N0 + , -OR?, -NRyRs, -NRyCORs, -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R8, -NR 7 NR 8 R9, -CONR 7 NR 8 R9, -C0 2 R 7 , -COR 8 , - C0NR 7 R S , -CO(NR 7 R 8 ) 2 , -SR 7 , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , and -0S(0) 2 R 7; R 7 to R9 being as defined above.
  • A is a group selected from phenyl, naphthyl, pyridyl, pyrrolyl, furyl, thienyl, benzotriazolyl said group being optionally substituted with one or several groups selected from halo, (C r C 6 )alkyl, 8 , -NR 7 NRsR 9 , - CONR 7 NR 8 R 9 , , and -0S(0) 2 R 7; R 7 to R 9 being as defined above.
  • A is of the following formula (Ai):
  • one or two R 2 to R 3 ⁇ 4 are, independently of one another, halo, -CF 3 , -CN, NO% -N0 2 , -OR 7 , -NR 7 R 8 , -NR 7 COR 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , -NR 7 NR 8 R 9 , -CONRzNRsR,, -C0 2 R 7 , -COR S , -CONR 7 R 8 , -CO(NR 7 R 8 ) 2 , -SR 7 , -S(0) 2 R 7 , -OCOR 7 , -0C0NR 7 R 8 , -0S(0) 2 R 7 , or (Ci -C 6 )alkyl, preferably halo, -CF 3 , -CN, -0R 7 , -NR 7 R 8 , NO ⁇ , -N0 2 , -OR 7 , -NR 7
  • X is -NRr, -S-, -0- or -CH 2 -
  • Ri is a hydrogen atom or a (Ci-Cio)alkyl group being optionally substituted with one or several groups selected from halo, oxo, - CF 3 , -CN, -N0 2 , -NO ⁇ , -OR ? , -NR 7 R S , -NR 7 NR S R 9 , -NR 7 COR S , -NR 7 C0 2 R S , -NR 7 S(0) 2 R S , COIR ?
  • X is -NRr, -S-, -0- or -CH 2 -, and Ri is a hydrogen atom or a (CrC t o)alkyl group.
  • X is -NRr or -CH 2 -, and Ri is a hydrogen atom or a (CrCio)alkyl group.
  • X is -NRr, Ri being a hydrogen atom or a (CrCio)alkyl, preferably a hydrogen atom or a (Ci -C 6 )alkyl, more preferably a hydrogen atom.
  • X is -NH-.
  • Y is a single bond, -CO- or -S0 2 -.
  • Y is a single bond or -S0 2 -. More advantageously, Y is a single bond.
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (C, -C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO", -0R 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , - NR 7 S(0) 2 R 8 , CO 2 R 7 , -COR 8 , -CONR 7 R 8 , -CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR 7 , -S(0) 2 R 7 , -OCOR 7 , -OCONR 7 R 8 , or -0S(0) 2 R 7 .
  • R and R’ are, independently of one another, H, -F, -N0 2 , -CF 3 or -Cl.
  • n 1 , 2 or 3;
  • X is -NRr, -S-, -0- or -CH 2 -, with Ri being a hydrogen atom or a (Ci -Ci 0 )alkyl group;
  • Y is a single bond, -CO- or -S0 2 -;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-Ce)alkyl, -CF 3 , -CN, -N0 2 , -NO", -0R 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) Z R 8 , C0 2 R 7 , -C0R 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR 7 , -S(0) 2 R 7 , -OCOR 7 , -OCONR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • X is -NRr, with Ri being a hydrogen atom or a (CrCio)alkyl group;
  • Y is a single bond, -CO- or -S0 2 -;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO", -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , C0 2 R 7 , -C0R 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • X is -NRr, -S-, -0- or -CH 2 -, with Ri being a hydrogen atom or a (CrCio)alkyl group;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO", -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 COR 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 RS, C0 2 R 7 , -COR 8 , -CONR 7 R 8 , - C0(NR 7 RS) 2 , -C0NR 7 NRSR 9 , -SR?, -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 RS, or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (CrC 6 >alkyl, -CF 3 , -CN, -N0 2 , -NO", -0R 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , -NR 7 NR 8 R 9 , -CONR 7 NR 8 R 9 , -C0 2 R 7 , -C0R 8 , -C0NR 7 R 8 , -CO(NR 7 R 8 ) 2 , -SR 7 , - S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , and -0S(0) 2 R 7 ;
  • X is -NRr, -S-, -0- or -CH 2 -, with Ri being a hydrogen atom or a (CrCio)alkyl group;
  • Y is a single bond, -CO- or -S0 2 -; and • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF3, -CN, -NOz, -NO + , -OR , -NR 7 R 8 , -NR NR R , -NR 7 COR 8 , -NR 7 CO Z R 8 , -NR 7 S(0) Z R 8 , CO 2 R 7 , -COR 8 , -CONR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 or 2;
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (CrC 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO + , -OR 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 C0 2 R 8 , -NR 7 S(0) 2 RS, -NR 7 NR 8 R 9 , -CONR 7 NR 8 R 9 , -C0 2 R 7 , -COR 8 , -C0NR 7 R 8 , -CO(NR 7 RS) 2 , -SR 7 , - S(0) 2 R 7 , -0C0R 7 , -OCONR 7 RS, and -0S(0) 2 R 7 ;
  • X is -NRr, with Ri being a hydrogen atom or a (Ci -Ci 0 )alkyl group;
  • Y is a single bond, -CO- or -S0 2 -;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 8 )alkyl, -CF3, -CN, -NOz, -NO", -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R b , -NR 7 S(0) 2 R 8 , C0 2 R 7 , -C0R 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0)ZR 7 , -0C0R 7 , -OCONRZRS, or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (CrCe)alkyl, -CF3, -CN, -N0 2 , -NO", -0R 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , -NR 7 NR 8 R 9 , -C0NR 7 NR 8 R 9 , -C0 2 R 7 , -COR 8 , -C0NR 7 R 8 , -CO(NR 7 R 8 ) 2 , -SR 7 , - S(0)ZR 7 , -0C0R 7 , -OCONRZRS, and -0S(0) 2 R 7 ;
  • X is -NRr, -S-, -0- or -CH 2 -, with Ri being a hydrogen atom or a (Ci -Cio)alkyl group;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO", -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 COR 8 , -NR 7 CO 2 R 8 , -NR 7 S(0)ZR 8 , CO 2 R 7 , -COR 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NRSR 9 , -SR?, -S(0) 2 R 7 , -0C0R 7 , -OCONR 7 RS, or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • A is of the general formula (Ai ) as defined above;
  • X is -NRr, -S-, -0- or -CH 2 -, with Ri being a hydrogen atom or a (CrCuj)alkyl group;
  • Y is a single bond, -CO- or -S0 2 -;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF 3 , -CN, -NOz, -NO", -0R 7 , -NR 7 RS, -NR 7 NRSR 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , COZR 7 , -CORS, -CONR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 or 2;
  • A is of the general formula (Ai ) as defined above;
  • X is -NRr, with Ri being a hydrogen atom or a (CrCio)alkyl group;
  • Y is a single bond, -CO- or -S0 2 -; and • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF , -CN, -NOz, -NO + , -OR , -NR 7 R 8 , -NR NR R , -NR 7 COR 8 , -NR 7 CO Z R 8 , -NR 7 S(0) Z R 8 , CO 2 R 7 , -COR 8 , -CONR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 , 2 or 3;
  • A is of the general formula (Ai ) as defined above;
  • X is -NRr, -S-, -O- or -CH 2 -, with Ri being a hydrogen atom or a (Ci -Ci 0 )alkyl group;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (CrC 6 )alkyl, -CF , -CN,
  • n 1 or 2;
  • n 1 or 2;
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (Ci -C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO ⁇ , -0R 7 , -NR 7 R 8 , -NR 7 COR 8 , -
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -NOz, -NO + , -0R 7 , -NR 7 RS, -NR 7 NRSR 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , COZR 7 , -CORS, -CONR 7 R 8 , - CO(NR 7 R 8 ) 2 , -C0NR 7 NR 8 R 9 , -SR 7 , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • n 1 or 2;
  • A is of the general formula (Ai ) as defined above;
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -NOz, -NO + , -0R 7 , -NR 7 RS, -NR 7 NRSR 9 , -NR 7 COR 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , C0 2 R 7 , -CORS, -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -C0NR 7 NR 8 R 9 , -SR ?
  • Ri is a hydrogen atom or a (Ci-Ci 0 )alkyl, preferably a hydrogen atom or a (CrC 6 )alkyl, more preferably a hydrogen atom; A, R and R’ being as defined above.
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (CrC 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO + , -0R 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 C0 2 R 8 , -NR 7 S(0) 2 RS, -NR 7 NR 8 R 9 , -CONR 7 NR 8 R 9 , -C0 2 R 7 , -CORg, -CONR 7 R 8 , -C0(NR 7 R 8 ) 2 , -SR 7 , - S(0) 2 R 7 , -0C0R 7 , -OCONR 7 RS, and -0S(0) 2 R 7 ;
  • Ri is a hydrogen atom or a (Ci-C 10 )alkyl
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO + , -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , CO 2 R 7 , -COR 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR ? , -S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , or -0S(0) 2 R 7 .
  • A is a group selected from aryl or heteroaryl, said group being optionally substituted with one or several groups selected from halo, (CrCeJalkyl, -CF 3 , -CN, -N0 2 , -NO + , -0R 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , -NR 7 NR 8 R 9 , -C0NR 7 NR 8 R 9 , -C0 2 R 7 , -COR 8 , -C0NR 7 R 8 , -CO(NR 7 R 8 ) 2 , -SR 7 , - S(0) 2 R 7 , -0C0R 7 , -0C0NR 7 R 8 , and -0S(0) 2 R 7 ;
  • Ri is a hydrogen atom
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN, -N0 2 , -NO", -OR 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 CO 2 R 8 , -NR 7 S(0) 2 R 8 , C0 2 R 7 , -C0R 8 , -C0NR 7 R 8 , - CO(NR 7 RS) 2 , -C0NR 7 NRSR 9 , -SR?, -S(0) 2 R 7 , -0C0R 7 , -OCONR 7 RS, or -0S(0) 2 R 7 .
  • A is of the general formula (Ai ) as defined above;
  • Ri is a hydrogen atom or a (Ci-Ci 0 )alkyl
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C & )alkyl, -CF 3 , -CN, -N0 2 , -NO", -0R 7 , -NR 7 R 8 , -NR 7 NR 8 R 9 , -NR 7 C0R 8 , -NR 7 C0 2 R 8 , -NR 7 S(0) 2 R 8 , CO 2 R 7 , -COR 8 , -C0NR 7 R 8 , - CO(NR 7 R 8 ) 2 , -CONR 7 NR 8 R 9 , -SR 7 , -S(0) 2 R 7 , -OCOR 7 , -OCONR 7 R 8 , or -0S(0) 2 R 7 .
  • A is of the general formula (A t ) as defined above;
  • Ri is a hydrogen atom
  • R and R’ are, independently of one another, hydrogen atom, halo, oxo, (Ci-C 6 )alkyl, -CF 3 , -CN,
  • each R , Re, and R 9 are, independently of one another, hydrogen atom, halo, (CrCeJalkyl or halo(Ci-C 6 )alkyl.
  • the compound of the invention can be advantageously in the form of a pharmaceutically acceptable salt, such as a salt selected from the group of hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like.
  • a pharmaceutically acceptable salt such as a salt selected from the group of hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic
  • the compound according to the present invention can be in particular selected from the compounds 1 to 55, advantageously 1 to 22 and 23 to 53, in particular 1 to 22, preferably from compounds 1 to 12, 19 to 21 , 23 to 29 and 32 to 53, in particular from compounds 1 to 12 and 19 to 21 of the examples below and the pharmaceutically acceptable salts and solvates thereof, in particular the hydrochloride salts thereof.
  • the present invention also relates to the compounds of formula (I) as defined above, for use as antibacterial agent.
  • the present invention also relates to a method for preventing and/or for treating disorders associated to Adnetobacter baumannii, comprising the administration to a person in need thereof of an effective dose of a compound of formula (I) as defined above.
  • the present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a drug for preventing and/or treating disorders associated to Adnetobacter baumannii.
  • the disorders associated to the human Acinetobacter baumannii may be in particular bacteremia, septic shock, ventilator-associated pneumonia, extensive soft tissue necrosis, and rapidly progressive systemic infections that ultimately lead to multi-organ failure and death are prone to occur in severely immunocompromised hosts.
  • Said rapidly progressive systemic infections may be in particular pneumonia; bronchiolitis; tracheobronchitis; suppurative infection (eg abscesses) in any organ system, including the lungs, urinary tract, skin and soft tissues; bacteremia; septic shock; meningitis (primarily after neurosurgical procedures), cellulitis, or phlebitis in patients with an indwelling venous catheter; ocular infections; native or prosthetic valve endocarditis; osteomyelitis; septic arthritis; or pancreatic and liver abscesses.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the invention as disclosed above as active ingredient, in particular as antibacterial agent and/or antioxidant agent, and a pharmaceutically acceptable excipient, for use for preventing and/or treating disorders associated to Adnetobacter baumannii.
  • compositions according to the invention may be formulated notably for topical administration, oral administration or for injection, wherein said compositions are intended for mammals, including humans.
  • the pharmaceutical composition can be administered orally by means of tablets and gelatin capsules.
  • a solid composition When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
  • the tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.
  • a preparation in gelatin capsules may be obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.
  • aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents are used.
  • compositions according to the invention may also be administered topically by all the means and in particular cream, gel, stick or serum
  • the active ingredient may be administered in unit dosage forms of administration, in mixture with standard pharmaceutical carriers, to animals or to humans.
  • compositions according to the invention may further comprise at least one other active ingredient, such as one other antibacterial agent, advantageously one other active ingredient that can be used for preventing and/or treating disorders associated to Adnetobacter baumannii.
  • the other active ingredient is advantageously selected from any antibiotic compound currently used to prevent and/or treat disorders associated to Adnetobacter baumannii such as penicillins, cephalosporins, trimethoprim-sulfamethoxazole, fluoroquinolones, aminoglycosides, carbapenems, colistin, and polymyxins.
  • the present invention relates also to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • At least one other active ingredient such as one other active ingredient that can be used for preventing and/or treating disorders associated to Adnetobacter baumannii, for use for preventing and/or treating disorders associated to Acinetobacter baumannii.
  • the other active ingredient is advantageously selected from any antibiotic compound currently used to prevent and/or treat disorders associated to Acinetobacter baumannii such as penicillins, cephalosporins, trimethoprim-sulfamethoxazole, fluoroquinolones, aminoglycosides, carbapenems, colistin, and polymyxins.
  • any antibiotic compound currently used to prevent and/or treat disorders associated to Acinetobacter baumannii such as penicillins, cephalosporins, trimethoprim-sulfamethoxazole, fluoroquinolones, aminoglycosides, carbapenems, colistin, and polymyxins.
  • the present invention also relates to a method for preventing and/or treating disorders associated to Acinetobacter baumannii, comprising the administration to a person in need thereof of an effective dose of a pharmaceutical composition as defined above.
  • the present invention also relates to the use of a pharmaceutical composition as defined above, for the manufacture of a drug for the prevention and/or the treatment of disorders associated to Acinetobacter baumannii.
  • the disorders associated to the human Acinetobacter baumannii may be in particular bacteremia, septic shock, ventilator-associated pneumonia, extensive soft tissue necrosis, and rapidly progressive systemic infections that ultimately lead to multi-organ failure and death are prone to occur in severely immunocompromised hosts.
  • Said rapidly progressive systemic infections may be in particular pneumonia; bronchiolitis; tracheobronchitis; suppurative infection (eg abscesses) in any organ system, including the lungs, urinary tract, skin and soft tissues; bacteremia; septic shock; meningitis (primarily after neurosurgical procedures), cellulitis, or phlebitis in patients with an indwelling venous catheter; ocular infections; native or prosthetic valve endocarditis; osteomyelitis; septic arthritis; or pancreatic and liver abscesses.
  • the subject in need thereof is a mammal, in particular an animal or the human.
  • the subject in need thereof is the human.
  • the compounds of the invention (I) can be obtained by a one or two steps process as described in Scheme 1.
  • the derivative (IV) can be transformed to its activated form (Via or Vlb) by methyloxonium tetrafluoroborate (Me 3 OBF 4 ) in dichloromethane as described by Mahatthananchai and Bode in Chemical Science 2012, 3(1), 192- 197 or by Romanov- ichailidis et al in Organic Letters 2012, 14(18), 4906-4909.
  • Via An alternative route to (Via) may be the use of dimethylsulfate under heating as reported by Schann et al in the Journal of Medicinal Chemistry 2001, 44, 1588- 1593 so as by Fasseur et al in J. Heterocycl. Chem. 1992, 29, 1285
  • Derivative (Vlb) is obtained by thionation of compound IV with the Lawesson reagent as described by Matsumoto, Yohei et al in Chemistry - A European Journal, 2018, 24(23), 6062-6066 or using trimethyloxonium tetrafluoroborate (Me 3 OBF ) and NaSFI as described by Kaloustian and Khouri in Tetrahedron Letters, 1981, 22(5), 413- 16.
  • Flydrazine derivatives of general formula (V) may then be added to a solution of the activated intermediate (VI) in presence of a catalytic amount of acid.
  • the reaction can be followed by NMR and is stopped as soon as compound (VI) has been totally converted.
  • intermediate (VI) is dissolved in ethanol in presence of 1 %mol equivalent of HCl and hydrazine derivatives of general formula (V) are added dropwise.
  • the mixture can be then heated, for example at 60 ° C until completion of the reaction. If needed, the compound obtained may be then recovered as stable salts in particular stable hydrochloride salts after treatment, purification and salification.
  • the products 1 -53 can be obtained by a one or two steps process as described in Scheme 1 .
  • the lactam derivative A is transformed to its iminoether B.
  • the iminoether B could be obtained by treatment of lactam A by use of trimethyloxonium tetrafluoroborate (Me 3 OBF ) in dichloromethane as described by Mahatthananchai and Bode in Chemical Science 2012, 3(1), 192- 197 or by Romanov-Michailidis et al in Organic Letters 2012, 14(18), 4906-4909.
  • An alternative route to iminoether B may be the use of dimethylsulfate under heating as reported by Schann et al in the Journal of Medicinal Chemistry 2001, 44, 1588- 1593 so as by Fasseur et al in J. Heterocycl. Chem. 1992, 29, 1285.
  • Hydrazine derivatives C may then be added to a solution of iminoether B in presence of a catalytic amount of acid.
  • the reaction can be followed by NMR and is stopped as soon as the iminoether B has been totally converted.
  • intermediate B is dissolved in ethanol in presence of 1%mol equivalent of HCl and phenylhydrazine derivatives C are added dropwise. The mixture is then heated to 60 ° C until completion of the reaction.
  • the products 1 -49 are then recovered as stable hydrochloride salts after treatment, purification and salification.
  • Example 8 2-(2-(m-tolyl) hydrazono) pyrrolidine hydrochloride - 8 Following the general procedure, 2-(2-(m-tolyl)hydrazono)pyrrolidine hydrochloride was obtained through the reaction of 5-methoxy-3,4-dihydro-2H-pyrrole (2 g, 20.1 mmol) and m-tolylhydrazine hydrochloride (3.2 g, 20.1 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50°C for 3 h. The crude product was obtained by the evaporation of residual solvent and after transformed into the corresponding salt, employing acetyl chloride in MeOH. The obtained salt was washed with ethanol, affording 8 as a white solid (1 .8 g, 40 % yield),
  • Example 14 Af-(pyrrolidin-2-ylidene) benzenesulfonohydrazide hydrochloride - 14 Following the general procedure, N'-(pyrrolidin-2-ylidene)benzenesulfonohydrazide was obtained through the reaction of 5-methoxy-3,4-dihydro-2H-pyrrole (2 g, 20.1 mmol) and benzenesulfonohydrazide (3.4 g, 20.1 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50 ° C for 3 h.
  • N'-(pyrrolidin-2-ylidene)benzohydrazide hydrochloride - 18 Following the general procedure, N'-(pyrrolidin-2-ylidene)benzohydrazide hydrochloride was obtained through the reaction of 5-methoxy-3,4-dihydro-2H-pyrrole (1 .24 g, 12.8 mmol) and benzohydrazide (1 .74 g, 12.8 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50°C for 3 h. The crude product was obtained by the evaporation of left solvent and after transformed into the corresponding salt, employing acetyl chloride in MeOH. The obtained salt was washed with ethanol, affording 18 as a white solid (2.15 g, 70 % yield),
  • Example 20 Methyl 5-(2-hydrazono)pyrrolidine-2-carboxylate hydrochloride - 20 Following the general procedure, methyl 5-(2-hydrazono)pyrrolidine-2-carboxylate hydrochloride was obtained through the reaction of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate (2 g, 12.8 mmol) and phenylhydrazine (1.4 g, 12.8 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50 °C for 3 h.
  • methyl 5-(2-(2,5-dichlorophenyl)hydrazono)pyrrolidine-2- carboxylate hydrochloride was obtained through the reaction of methyl 5-methoxy-3,4-dihydro-2H- pyrrole-2-carboxylate (2 g, 12.8 mmol) and 2,5-dichlorohydrazine (2.26 g, 12.8 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50°C for 3 h. The crude product was obtained by the evaporation of residual solvent and after transformed into the corresponding salt, employing acetyl chloride in MeOH. The obtained salt was washed with ethanol, affording 21 as a white solid (2.38 g, 55 % yield),
  • methyl 5-(2-picolinoylhydrazono)pyrrolidine-2-carboxylate hydrochloride was obtained through the reaction of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2- carboxylate (2 g, 12.8 mmol) and picolinohydrazide (1.75 g, 12.8 mmol), in the presence of 37% HCl (0.2 mmol), in 30 mL EtOH. The mixture was stirred at 50° C for 3 h. The crude product was obtained by the evaporation of left solvent and after transformed into the corresponding salt, employing acetyl chloride in MeOH. The obtained salt was washed with ethanol, affording 22 as a yellowish solid (2.1 g, 55 % yield),
  • 2-(2-(naphthalen-1 -yl)hydrazono)pyrrolidine hydrochloride was obtained through the reaction of 5-methoxy-3,4-dihydro-2H-pyrrole (0.5 g, 5 mmol) and naphthalen- 1 -ylhydrazine hydrochloride (1.0 g, 5 mmol) in 20 mL EtOH. The mixture was stirred at 50° for 3 h. The crude product was washed with ethanol, affording a white solid (1.0 g, 76 % yield),
  • methyl 5-(2-(4-nitrophenyl)hydrazono)pyrrolidine-2-carboxylate hydrochloride was obtained through the reaction of methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2- carboxylate (0.5 g, 3.2 mmol) and (4-nitrophenyl)hydrazine (0.49 g, 3.2 mmol), in 30 mL EtOH. The mixture was stirred at 50° for 3 h and the precipitate was filtered off. The obtained solid was washed with ethanol, affording the wanted compound as a red solid (0.5 g, 57 % yield),
  • Ratio conformer 1 /conformer 2 94/06
  • a sampling of the products of the present invention were tested for their activity against Acinetobacter baumannii (A. baumannii) as well as against the following bacteria: Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae), Escherichia coli (E. coli), and Pseudomonas aeruginosia (P. aeruginosa).
  • the title compound 1 was also tested against the following fungi/yeasts: Candida albicans (C. albicans) and Cryptococcus neoformans (C. neoformans).
  • the minimum inhibitory concentration (MIC) for Acinetobacter baumannii was determined using the colorimetric resazurine microtitre assay (REMA). Briefly, ampules of frozen bacterial stocks were thawed, and bacteria diluted into Cation Adjusted Mueller Hinton Broth (CAMHB, Difco), to a final working concentration (OD600, optical density at 600 nm, of 0.0003 for A. baumannii). Working bacterial cultures were then added to the wells of a 96-well plate using a repeater pipette (100 pL in all wells, except first column with 200 pL).
  • test compound was added at a concentration of 10 mg/mL in DMSO, giving a final concentration of 100 pg/mL (lower concentrations were used for more potent compounds). Eleven serial 1 -in-2 dilutions were then made down the plate by transferring 100 pL between wells. The last column of the plate remained without compound as control. Plates were then incubated at 37 ° C for 5 hrs. To evaluate bacterial viability, 10 pL of 0.025% resazurin was added to the wells and let to incubate for up to 2 hours.
  • Bacterial resazurin turnover to fluorescent resorufin was measured by fluorescence (Ex, 530 nm, Em: 590 nm).
  • the MIC was defined as the concentration of compound that prevented the turnover of resazurin (less than 10 % resazurin turnover compared to the non-treated control).
  • HepG2 cells human hepatocellular cell line, ATCC HB-8065
  • ATCC American Type Culture Collection
  • DMEM Dulbecco’s modified Eagle’s Medium
  • FBS heat-inactivated fetal bovine serum
  • HepG2 cells were seeded at a density of 2500 cells/well on a 96-well plate in 100 ml of DMEM without red phenol supplemented with 10% FBS. Cells were allowed to attach overnight.
  • the title compound 20 exhibits a high selectivity towards Acinetobacter baumannii, being inactive against the other bacterial or fungal/yeast strains tested.

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Abstract

La présente invention concerne des composés de formule générale (I) ou un sel et/ou un solvate pharmaceutiquement acceptable de ceux-ci, destinés à être utilisés pour prévenir et/ou traiter des troubles associés à Acinetobacter baumannii. La présente invention concerne également des compositions pharmaceutiques contenant lesdits composés.
PCT/EP2020/054393 2019-02-19 2020-02-19 Dérivés d'hydrazonopyrrolidine à utiliser dans la prévention et/ou le traitement de troubles associés à acinetobacter baumannii Ceased WO2020169683A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2016016291A1 (fr) * 2014-07-30 2016-02-04 Ferrer Internacional, S.A. Arylhydrazides contenant une fraction 2-pyridone en tant qu'agents antibactériens sélectifs
WO2018020004A1 (fr) * 2016-07-29 2018-02-01 Abac Therapeutics, S.L Agents antibactériens à base de 2-pyrrolidine phénylhydrazides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016291A1 (fr) * 2014-07-30 2016-02-04 Ferrer Internacional, S.A. Arylhydrazides contenant une fraction 2-pyridone en tant qu'agents antibactériens sélectifs
WO2018020004A1 (fr) * 2016-07-29 2018-02-01 Abac Therapeutics, S.L Agents antibactériens à base de 2-pyrrolidine phénylhydrazides

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FASSEUR ET AL., J. HETEROCYCL. CHEM., vol. 29, 1992, pages 1285
HILBIG, SABINE ET AL: "Zur Chemie und antibiotischen Aktivität des Carbolegerlings (Agaricus xanthoderma)", ANGEWANDTE CHEMIE, vol. 97, no. 12, December 1985 (1985-12-01), pages 1063 - 1064, XP002793048, ISSN: 0044-8249, DOI: 10.1002/ange.19850971222 *
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PEREIRA DE SÁ NÍVEA ET AL: "Thiazole compounds with activity againstCryptococcus gattiiandCryptococcus neoformans in vitro", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 102, 17 July 2015 (2015-07-17), pages 233 - 242, XP029267389, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2015.07.032 *
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